<table>
<colgroup>
<col style="width: 8%" />
<col style="width: 8%" />
<col style="width: 6%" />
<col style="width: 8%" />
<col style="width: 9%" />
<col style="width: 13%" />
<col style="width: 14%" />
<col style="width: 16%" />
<col style="width: 6%" />
<col style="width: 9%" />
</colgroup>
<thead>
<tr class="header">
<th colspan="10"><p><strong>Appendix E</strong></p>
<p><strong>Alphabetical Listing of Observational Studies Published 1992
through 2000 with Omega-3 Fatty Acids (EPA and DHA)</strong></p>
<p><strong>as Food or Dietary Supplement Source Examining Heart Disease
Endpoints and Mortality</strong></p></th>
</tr>
<tr class="odd">
<th><strong>Reference</strong></th>
<th><strong>Objective</strong></th>
<th><strong>Study design</strong></th>
<th><strong>Length of Follow-up</strong></th>
<th><strong>Intake</strong></th>
<th><strong>Subjects</strong></th>
<th><strong>Results</strong></th>
<th><strong>Conclusions/Comments</strong></th>
<th><strong>Data Quality</strong></th>
<th><strong>Adverse Effects/ Safety</strong></th>
</tr>
</thead>
<tbody>
<tr class="odd">
<td><p>Albert et al. 1998</p>
<p><em>JAMA</em> 1998;279:23-28</p>
<p>[U.S. – Physician’s Health Study]</p></td>
<td><p>To prospectively examine the association between fish consumption
and sudden cardiac death ascertained from medical records and firsthand
reports among male physicians enrolled in the Physicians’ Health
Study</p>
<p>(provides additional years of follow-up, excludes fish oil supplement
users, and examines additional outcome, fatal cardiac death, compared to
Morris et al. 1995)</p></td>
<td>Prospective cohort</td>
<td>11 years (1982-1995)</td>
<td>0.20 g/day mean intake of marine n-3 fatty acids (5.9 g/month);
categories of fish intake were based on response to food frequency
questionnaire administered 12 months after enrollment. Stratified by
quintiles of number of fish servings. Validity of questionnaire assessed
by repeated assessment methods in subset of 127 men and percent measured
in adipose tissue of 118 of 127 men.</td>
<td><p>20,551 U.S. male physicians, ages 40-84, free of MI, stroke,
transient ischemic attack, or cancer who participated in a clinical
trial to receive aspirin, beta carotene, both active drugs or two
placebos in 1982. Dietary intake of certain foods assessed at 2 time
points during the trial.</p>
<p>Excluded from analysis subjects taking fish oil supplements
(n=777)</p>
<p>Observed 133 sudden cardiac deaths in the follow-up period</p></td>
<td><p><u>Sudden cardiac death</u>: Adjusted for numerous other
factors:</p>
<ul>
<li><p>&lt;1 fish servings per week (1-3 per month) (RR: 0.64; 95%CI:
0.26-1.58)</p></li>
</ul>
<ul>
<li><p>1-&lt;2 per week (RR: 0.47; 95% CI: 0.23-0.98)</p></li>
</ul>
<ul>
<li><p>2-&lt;5 per week (RR: 0.51, 95% CI: 0.25-1.04)</p></li>
</ul>
<ul>
<li><p>5 per wk (RR: 0.39; 95% CI: 0.15-0.96)</p></li>
</ul>
<p>(p-value for trend: 0.11).</p>
<p>Results were equivalent by quintile of estimated n-3 fatty acid
intake.</p>
<p><u>MI:</u> No association between fish consumption and MI was
observed.</p>
<p><u>Other CV Outcomes and Total Mortality</u>: No association with
nonsudden cardiac death, CHD death, or cardiovascular mortality.
Significant association with total mortality.</p></td>
<td><p><u>Conclusions</u>: The authors concluded that, ”in this large,
prospective cohort study, low to moderate intake of fish—at least 1 fish
meal per week—was associated with a 52% lower risk of sudden death
compared with less than monthly consumption, even after controlling for
several confounders…Our data add to the existing totality of evidence
that consuming at least 1 meal of fish per week may substantially reduce
the risk of sudden cardiac death.”</p>
<p><u>Comments</u>: Least protective effect observed for dark meat fish,
the fish with the highest n-3 fatty acid content. Linear dose-response
relationship with fish intake not observed, but low number of subjects
in lowest (little or no fish) intake (referent) group; potential
threshold effect identified</p>
<p>Used two dietary assessments but still may not reflect long-term fish
consumption pattern. Validation of dietary intake with phospholipids
included only a small subset of participants.</p>
<p>Supplemented death certificate information with other sources for
cause of death.</p></td>
<td>1</td>
<td>Not reported</td>
</tr>
<tr class="even">
<td><p>Ascherio et al. 1995</p>
<p><em>NEJM</em> 1995;332:977-82</p>
<p>[U.S.- Health Professional’s Follow-up Study]</p></td>
<td>To examine the association between coronary disease and fish
consumption in a large cohort of male health professionals</td>
<td>Prospective cohort</td>
<td>6 years</td>
<td><p>0.58 g/day n-3 fatty acids (median intake in the highest intake
quintile). Represents a median of 5.9 servings of fish per week.</p>
<p>Average fish intake was assessed in 1986 for the previous year.
Validated the responses using alternate food assessment methods and
biologic markers.</p></td>
<td>44,895 males ages 40-74 in 1986, excluded if physician-diagnosed
with MI, angina, stroke, transient ischemic attack, or peripheral artery
disease, followed for 6 years to ascertain coronary disease events. 1543
coronary disease events (non-fatal and fatal MI, coronary artery bypass,
or angioplasty) were observed. Participants were enrolled as part of the
Health Professionals Follow-up Study.</td>
<td><p><u>TC:</u> At baseline, no difference in TC levels between fish
consumption groups (i.e. no effect of fish consumption, but numerous
other factors affecting serum cholesterol were not controlled). No other
serum lipids reported.</p>
<p><u>CHD outcomes</u>: After adjusting for confounders, no significant
difference in risk for any of the CHD outcomes was observed by n-3 fatty
acid intake or dietary fish intake with the exception of a higher risk
of coronary artery bypass surgery among those with higher fish
intake.</p></td>
<td><p><u>Conclusions</u>: The authors reported that no evidence of an
association between the intake of either marine n-3 fatty acids or fish
and risk of CHD was observed in this study.</p>
<p><u>Comments:</u> Excluded any participants with previous evidence of
CVD (hypercholesterolemia, diabetes, or hypertension) who may have
changed diet as a result. However, 1986 dietary assessment may not
reflect differences in fish intake in years prior to the study.</p></td>
<td>2</td>
<td>None reported</td>
</tr>
<tr class="odd">
<td><p>Burchfiel et al. 1996</p>
<p><em>Ann. Epidemiol.</em> 1996;6:137-146</p>
<p>[U.S.-Honolulu Heart Program]</p></td>
<td>To examine at the relationship between risk factors for CHD and
intramural myocardial lesions determined at autopsy.</td>
<td>Prospective cohort</td>
<td>16-19 years</td>
<td><p>Not quantified</p>
<p>Fish intake assessed at baseline (between 1965-1968) using 24-hour
recall interviews and by asking directly how often the participant ate
fish. Intake categorized as less than 2 times/week or 2 times or
more/week.</p></td>
<td>120 Japanese-Americans who were participants of the Honolulu Heart
Program, who died during the follow-up period (between 1965 and 1984),
and who were free of moderate or severe coronary atherosclerosis at
autopsy. Participants were 45-68 years old at baseline.</td>
<td><p><u>Any myocardial lesion:</u> After controlling for confounders,
significant protective association between fish intake 2 times per week
compared to &lt;2 times per week (OR=0.35, 95% CI: 0.15-0.86)</p>
<p><u>Small MI lesion:</u> After adjusting for confounders, significant
protective association between fish intake 2 times per week compared to
&lt;2 times per week (OR=0.35, 95% CI: 0.15-0.83)</p></td>
<td><p><u>Conclusions:</u> The authors concluded that fish consumption
was an independent predictor of myocardial lesions at autopsy,
suggesting the beneficial effects of dietary fish intake may operate
through nonatherosclerotic mechanisms.</p>
<p><u>Comments</u>: No association between serum TG measured at baseline
and presence of MI lesions.</p></td>
<td>3</td>
<td></td>
</tr>
<tr class="even">
<td><p>Daviglus et al. 1997</p>
<p><em>NEJM</em> 1997;336:1046-1053</p>
<p>[U.S. – Chicago Western Electric Study]</p></td>
<td>To examine the association between fish consumption and the 30-year
risk of death from MI (sudden or non-sudden), CHD, CVDs, and all causes
in the Chicago Western Electric Study.</td>
<td>Prospective cohort</td>
<td>30 years</td>
<td><p>35 g/day or more in the highest quartile compared to 18-34 g/day,
1-17 g/day, or none (referent group)</p>
<p>Daily fish consumption estimated based on two food consumption
assessments performed at baseline (1957), 1 year apart. Assessments were
based on the 28 days prior to the interview.</p></td>
<td>1822 male workers at Western Electric in 1957, followed for
mortality for 30 years. There were 293 deaths from MI, 430 from CHD, 573
from CVD, and 1042 from any cause.</td>
<td><p><u>MI:</u> Significantly reduced risk in highest consumption
group (RR=0.56; 95% CI: 0.33-0.93); significant dose-response trend
(p=0.017)</p>
<p><u>CHD death:</u> Significantly reduced risk in highest consumption
group (RR=0.62; 0.40-0.94); significant dose-response trend
(p=0.04).</p>
<p><u>CVD death:</u> NS reduced risk in highest consumption group
(RR=0.74; 0.52-1.06); significant dose-response trend (p=0.01)</p>
<p><u>Nonsudden MI death:</u> Significantly reduced risk in highest
consumption group(RR=;0.33; 0.12-0.91) significant dose-response trend
(p=0.007)</p>
<p><u>Sudden MI death:</u> NS reduced risk in highest consumption group
RR=0.68; 0.37-1.25); no linear dose-response trend (p=0.337)</p></td>
<td><p><u>Conclusions</u>: The authors concluded that a significant,
independent, inverse graded association was observed between base-line
fish consumption and 30-year risk of death from heart disease, due
particularly to nonsudden death from MI.</p>
<p><u>Comments</u>: Adjustment for foods instead of nutrients yielded
equivalent results.</p>
<p>Effect modification by age: protective effect of fish consumption on
MI and nonsudden MI only observed in subjects over age 47 years at
baseline.</p>
<p>Cause of death based on death certificate only; no review of medical
records or other sources.</p></td>
<td>2</td>
<td></td>
</tr>
<tr class="odd">
<td><p>Dolecek 1992</p>
<p><em>P Soc Exper Biol Med</em> 1992;200:177-182</p>
<p>[U.S. – Multiple Risk Factor Intervention Trial, MRFIT]</p></td>
<td>To examine the relationships between dietary PUFA intakes and
mortality outcomes</td>
<td>Prospective cohort using one arm of a randomized controlled clinical
trial</td>
<td>10.5 years of follow-up</td>
<td>175 mg/day (mean) of the three long chain n-3 fatty acids found in
fish oils. Estimated intake based on 24-hour dietary recall assessment
at baseline and at years 1, 2, and 3 of follow-up.</td>
<td>522 deaths among the members of the men assigned to the Usual Care
group (i.e., no special interventions). Of these deaths, 175 were due to
CHD and 232 due to CVD.</td>
<td><p>RRs presented 3 ways:</p>
<ul>
<li><p>by grams of fish n-3 intake as a continuous variable</p></li>
<li><p>by percent of total daily kcal as continuous variables</p></li>
<li><p>by quintile of fish consumption.</p></li>
</ul>
<p><u>CHD:</u></p>
<p>Grams fish n-3: RR: 0.39 (p&lt;0.01)</p>
<p>%kcal fish n-3: RR: 0.62 (p&lt;0.05)</p>
<p>Quintile V-grams: 0.61 (p for trend: &lt;0.05)</p>
<p>Quintile V - % kcal: 0.60 (p for trend: &lt;0.01)</p>
<h1 id="cvd">CVD:</h1>
<p>Grams fish n-3: RR: 0.38 (p&lt;0.01)</p>
<p>%kcal fish n-3: RR: 0.64 (p&lt;0.01)</p>
<p>Quintile V-grams: 0.50 (p for trend: &lt;0.05)</p>
<p>Quintile V - % kcal: 0.55 (p for trend: &lt;0.01)</p></td>
<td><p><u>Conclusions:</u> The author concluded that the results of this
evaluation support the hypothesis that fatty acids found primarily in
fish oils protect against CVD.</p>
<p><u>Comments:</u></p>
<p>Used multiple years of 24-hour intake data to characterize usual
consumption</p>
<p>Dropouts not described, and completeness of ascertainment of deaths
not described.</p></td>
<td>2</td>
<td></td>
</tr>
<tr class="even">
<td><p>Garcia-Closas et al. 1993</p>
<p><em>Eur J Clin. Nutr</em> 1993;47 (Suppl 1):S85-S90</p>
<p>[Spain]</p></td>
<td>To compare data on average fish and fatty fish consumption trends
from 1976 to 1985 in some Mediterranean and northern European countries
and IHD rates</td>
<td>Ecologic</td>
<td>Not applicable</td>
<td>Not quantified; based on food balance sheets in 1985, average fish
consumption ranged from approximately 10 g/day in Yugoslavia to 80 g/day
in Norway. In 1985, fish oil consumption ranged from &lt;1g/day in
Yugoslavia to 5 g/day in Denmark.</td>
<td>Residents of Mediterranean countries (Spain, Yugoslavia, and Italy)
compared to northern European countries (Norway, Denmark).</td>
<td>From 1976-1985, fish consumption increased in Italy and Norway,
remained approximately the same in Spain and Yugoslavia, and decreased
in Denmark. Similar trends were observed for fish oil consumption. IHD
mortality decreased in Italy, Denmark, and Norway, and increased in
Spain and Yugoslavia.</td>
<td><p><u>Conclusion:</u> The authors concluded that these
epidemiological data show that the average population level of fish
supply is not positively correlated with IHD mortality when comparing
northern European and Mediterranean countries.</p>
<p><u>Comments</u>: Population-based data not useful for an outcome such
as IHD with a number of important risk factors that could vary between
and within countries.</p></td>
<td>3</td>
<td>None reported</td>
</tr>
<tr class="odd">
<td><p>Guallar et al. 1995</p>
<p><em>J Am Coll Cardiol</em> 1995;25:387-94</p>
<p>[U.S. - U.S. – Physician’s Health Study]</p></td>
<td>To investigate the association between fish oil levels in plasma
cholesterol esters and phospholipids and the incidence of MI in a cohort
of apparently healthy men.</td>
<td>Nested case-control study based on 21,071 U.S. physicians 40 - 84
years old in 1982, free of MI or other CHD enrolled in a randomized
trial to receive aspirin or beta-carotene.</td>
<td>Not applicable</td>
<td>Not quantified/not applicable. Blood levels of EPA, DHA, and both
fish oils combined were examined as markers of fish consumption.</td>
<td>222 case-control pairs for cholesterol esters and 213 pairs for
phospholipids. Cases were participants who had sent a plasma sample at
the time of study enrollment and who had had a MI in the first 5 years
of follow-up. Controls were selected among non-MI participants who had
given a blood sample and were matched by age and smoking status.</td>
<td>Blood levels of EPA, DHA, and both fish oils were similar for MI
cases and their matched controls; no statistically significant
differences between the cases and controls were observed. Similarly, in
models adjusting for other cardiovascular risk factors, no significant
difference in blood levels of these fish oils between cases and controls
was observed.</td>
<td><p><u>Conclusions</u>: The authors concluded that increased levels
of fish oils in plasma lipids conferred no significant reduction in the
risk of MI. Morris et al. (1992) report on the association between fish
consumption and risk of CHD is this same cohort, and not association was
observed.</p>
<p><u>Comments</u>: Because it is possible that subjects with early
symptoms of CHD or at higher risk of CHD could be aware of the benefits
of fish consumption, the authors controlled for the possible effect of
other risk factors for CHD in their analysis.</p></td>
<td>1</td>
<td>Fish oils did not modify or interfere with the protective effect of
aspirin on the incidence of MI.</td>
</tr>
<tr class="even">
<td><p>Kromhout et al. 1995</p>
<p><em>Int J Epidemiol</em> 1995;24: 340-345.</p>
<p>[The Netherlands – the Rotterdam cohort]</p></td>
<td>To investigate the relation between fish consumption and CHD
mortality in elderly men and women in the Netherlands who were followed
for 17 years.</td>
<td>Prospective cohort study</td>
<td>17 years</td>
<td>24.0 g/day fish among fish eaters (26.0 g/day for males and 21.9
g/day for females) based on usual consumption patterns for the 14 days
prior to the interview conducted at baseline in 1971. Subjects
categorized as fish eaters/not fish eaters. Approximately 60% of the
participants were fish eaters.</td>
<td><p>272 subjects (137 males, 135 females) who were patients in a
medical practice in 1971 and who were born before 1907. In 1971, average
ages were 71 for men and 70 for females.</p>
<p>No exclusions for existing CHD-related conditions.</p></td>
<td><p>Males, at baseline</p>
<p>(unadjusted), fisheaters vs. nonfisheaters:</p>
<p><u>TG:</u>  (NS)</p>
<p><u>TC:</u>  (NS)</p>
<p>Females, at baseline</p>
<p>(unadjusted), fisheaters vs. nonfisheaters:</p>
<p><u>TG:</u>  (NS)</p>
<p><u>TC:</u>  (NS)</p>
<p><u>MI mortality:</u> (RR adjusted for age, gender, preexisting MI or
angina):</p>
<p>0.58 (95% CI: 0.34-0.99)</p>
<p><u>MI mortality:</u> (RR adjusted further for dietary confounders
such as fat intake): 0.50 (95% CI: 0.28-0.89)</p></td>
<td><p><u>Conclusions</u>: The authors concluded that fish intake showed
a significant protective effect against CHD mortality and the prevalence
of MI in elderly males and females.</p>
<p><u>Comments</u>: Potential for misclassification of fish intake based
on a two-week food consumption survey. Possible that those with
prevalent MI, angina, or other CHD risk factors had increased fish
consumption due to diagnosis.</p>
<p>Small sample size and wide CIs when stratifying.</p>
<p>Serum TG was not significantly associated with CHD in this
study.</p></td>
<td>2</td>
<td>Not reported</td>
</tr>
<tr class="odd">
<td><p>Kromhout et al. 1996</p>
<p>Int J Epidemiol 1996;25:753-759</p>
<p>[Finland, Italy, Greece, former Yugoslavia, Japan, U.S., Italy,
Servia, Belgrade, Netherlands: Seven Countries Study]</p></td>
<td>To examine the association between 25-year mortality CHD rates and
alcohol, fish, fiber, and antioxidant vitamins in 16 cohorts established
between 1958 and 1964</td>
<td>Prospective cohort study with ecologic components</td>
<td>25 years</td>
<td><p>Not quantified for individuals. Means for the 16 cohorts were
skewed right, and ranged from no fish consumption in the Veliku Krsna,
Serbia cohort to 207 g/day in a fisherman’s village in Japan.</p>
<p>Dietary information based on small random samples in 14/16 cohorts
gathered between 1959-1964 using the weighed record method. Means of
sample used for fish and fiber for cohort. Means for alcohol,
-carotene, Vitamin C, and Vitamin D based on analyses of blood samples
for the small samples.</p></td>
<td><p>12,763 men ages 40-59 years enrolled between 1958 and 1964 in the
Seven Countries Study, as 16 cohorts.</p>
<p>5,973 men died in the 25-year follow-up period, but the number of CHD
deaths is not reported.</p>
<p>Smoking information was collected for each individual at
baseline.</p>
<p>Blood samples were collected in 1987-1988.</p></td>
<td><u>CHD mortality</u>: Fish consumption was independently
significantly associated with reduced CHD mortality, but the association
became non-significant when adjusted for saturated fatty acids and
flavonoid intake and prevalence of cigarette smoking.</td>
<td><p><u>Conclusions:</u> The authors concluded that the cross-cultural
analyses showed that alcohol, fish, fiber, and antioxidant vitamins do
not explain population differences in CHD after controlling for
saturated fatty acids and flavonoids intake, and cigarette smoking.</p>
<p><u>Comments</u>: Multivariate analyses limited to controlling for
four variables only (the dietary factor of interest, saturated fatty
acids intake, flavonoids intake, and cigarette smoking.</p></td>
<td>3</td>
<td>Not applicable</td>
</tr>
<tr class="even">
<td><p>Morris et al. 1995</p>
<p><em>Am J Epidemiol</em> 1995;142:166-175</p>
<p>[U.S. – Physicians’ Health Study]</p></td>
<td>To prospectively examine the association between fish consumption
and several cardiac events and CHD-related death ascertained from
medical records and firsthand reports among male physicians enrolled in
the Physicians’ Health Study</td>
<td>Prospective cohort</td>
<td>4 years (1983-January 1988)</td>
<td>0.24 g/day mean intake of marine n-3 fatty acids, based on average
of 2.1 fish meals per week. Fish intake based on response to food
frequency questionnaire administered 12 months after enrollment.
Validity of questionnaire assessed by repeated assessment methods in
subset of 127 men.</td>
<td><p>21,185 U.S. male physicians, ages 40-84, free of MI, stroke,
transient ischemic attack, or cancer who participated in a clinical
trial to receive aspirin, beta carotene, both active drugs or two
placebos in 1982. Excluded events in the first year of follow-up.</p>
<p>During follow-up period, there were 281 MIs, 173 strokes, 121 CVD
deaths, and 525 combined vascular deaths.</p></td>
<td><p>No significant relationship was observed for any of the outcomes
examined:</p>
<p>Total MI (fish meals/wk, RR, 95%CI):</p>
<p>&lt;1: 1.0 (referent)</p>
<p>1: 1.5 (1.1-2.1)</p>
<p>2-4: 1.2 (0.9-1.9)</p>
<p>5: 0.9 (0.4-1.8)</p>
<p>(p for trend=0.72)</p>
<p>RRs and trends were similar for nonfatal MI, stroke, CV death, and
total CV events. RRs were generally higher (but nonsignificant) in the
higher consumption groups.</p></td>
<td><p><u>Conclusions:</u> The authors concluded that fish consumption
was not found to be associated with a reduced risk of MI or other
cardiovascular events in this study.</p>
<p><u>Comments:</u> Subjects in high fish consumption group tend to have
higher cholesterol, family history of MI, hypertension, and angina, and
more likely to report vigorous exercise, lower proportion of obesity,
never smokers, and more vitamin use.</p></td>
<td>2</td>
<td>Not reported.</td>
</tr>
<tr class="odd">
<td><p>Seidelin et al. 1992</p>
<p><em>Am. J. Clin. Nutr.</em> 1992; 55:1117-9</p>
<p>[Denmark]</p></td>
<td>To investigate the possible protective effects of fish against CHD
by examining concentrations of n-3 fatty acids in adipose tissue to
determine if persons with the lowest degree of coronary artery disease
have the highest level of n-3 fatty acids</td>
<td>Cross-sectional</td>
<td>Not applicable</td>
<td>Not quantified</td>
<td>40 consecutive autopsies performed at a Copenhagen hospital from
July 1 to August 30, 1990. Median age: 77 years (range: 52-90
years)</td>
<td><p>The degree of coronary artery disease (CAD) was quantified by
calculating the percentage of luminal stenosis that was due to
atherosclerosis. Three categories of degree of stenosis were created:
highest CAD (n=13), intermediate CAD (n=14), and lowest CAD (n=13). The
authors reported that the groups were comparable with respect to body
weight and age (data not presented).</p>
<p>A statistically significant inverse relationship with DHA was
observed. After controlling for body weight and age, those with the
highest CAD had the lowest DHA tissue concentrations (p&lt;0.01).</p>
<p>Significant inverse relationships were not observed for any of the
other fatty acids examined (16:0, 16:1n-9, 18:0, 18:1n-9,
18:2n-6)</p></td>
<td><p><u>Conclusions</u>: The authors concluded that this study
supports the hypothesis that fish consumption is associated with a
reduced risk of CAD.</p>
<p><u>Comments</u>: As stated by the authors, autopsy studies are
subject to selection bias. Causes of death of the autopsied subjects not
presented. Gender also not presented.</p></td>
<td>2</td>
<td>Not applicable</td>
</tr>
<tr class="even">
<td><p>Simon et al. 1995</p>
<p><em>Am J Epidemiol</em> 1995;142:469-476</p>
<p>[U.S. – Multiple Risk Factor Intervention Trial, MRFIT]</p></td>
<td>To examine the relation between serum fatty acid levels and CHD</td>
<td>Nested case-control study using cases of CHD from the non-
intervention group of a clinical trial</td>
<td>Not applicable</td>
<td>Not quantified; serum fatty acid concentrations of n-3 fatty acids
at time of enrollment used as a marker of dietary n-3 intake</td>
<td>188 participants (94 cases and 94 matched controls) from the
Multiple Risk Factor Intervention Trial (MRFIT) selected for high
cholesterol, DBP and smoking status. Cases had suffered a fatal or
non-fatal MI in the 6.9 years of follow-up. Controls were matched on
age, date of randomization, and clinical center.</td>
<td><p>At baseline, cases compared to controls:</p>
<p><u>TG:</u> No difference.</p>
<p><u>TC:</u> No difference.</p>
<p><u>LDL:</u> No difference.</p>
<p><u>HDL:</u> No difference.</p>
<p>DHA and docosapentaenoic lower in cases (p&lt;0.05); EPA also lower,
but p&gt;0.05.</p>
<p>Risk of CHD significantly lower for those with higher DHA and
docosapentaenoic levels</p></td>
<td><p><u>Conclusions</u>: The authors concluded that the study findings
were consistent with other studies in demonstrating that high levels of
polyunsaturated fatty acids are associated with decreased cardiovascular
risk.</p>
<p><u>Comments</u>: Generalizability to those not at high risk of CHD
unknown.</p>
<p>Possibility of oxidative damage from using stored serum
specimens.</p>
<p>Serum fatty acid profile may not represent long-term dietary intake
pattern.</p></td>
<td>2</td>
<td>Not reported</td>
</tr>
<tr class="odd">
<td><p>Yamori et al. 1994</p>
<p><em>Health Reports</em> 1994:6(1):22-27</p>
<p>[WHO CARDIAC study (includes Core and Complete studies); mulitcenter,
multicountry]</p></td>
<td>To investigate the relation between biological markers of diets to
hypertension in the Core study and to CVD mortality in the Complete
study.</td>
<td>Cross-sectional (nutritional biomarkers); ecologic (CVD mortality
rates)</td>
<td>Not applicable</td>
<td>Not quantified.</td>
<td><p>Population size not presented. The CARDIAC study population
includes 100 men and 100 women randomly selected at 55 centers in 24
countries.</p>
<p>This results of these analysis are based on results from over 5,000
subjects from multiple centers in many countries who were not on
medication and from whom 24-hour urine was collected.</p></td>
<td><p>None of the findings presented for the Core study (hypertension)
were relevant.</p>
<p>In the Complete study (CVD mortality), polyunsaturated fatty acid
ratios and n-3 fatty acids in the serum phospholipids were associated
with a reduced risk of CHD mortality (p&lt;0.05). Further, high levels
of urinary taurine (a biological marker of shellfish protein) was
significantly associated with reduced risk of CHD mortality
(p&lt;0.01).</p></td>
<td><p><u>Conclusions:</u> The authors that the results suggest a
beneficial effect of polyunsaturated fatty acids, particularly n-3 fatty
acids rich in seafood on the prevention of CHD.</p>
<p><u>Comments:</u> Study methods not presented. Appears to apply the
cross-sectionally obtained biologic markers from subjects to
age-adjusted country-specific stroke mortalities.</p></td>
<td>2</td>
<td>Not applicable</td>
</tr>
</tbody>
</table>

<table>
<colgroup>
<col style="width: 8%" />
<col style="width: 8%" />
<col style="width: 6%" />
<col style="width: 8%" />
<col style="width: 9%" />
<col style="width: 13%" />
<col style="width: 14%" />
<col style="width: 15%" />
<col style="width: 6%" />
<col style="width: 9%" />
</colgroup>
<thead>
<tr class="header">
<th colspan="10"><p><strong>Appendix F</strong></p>
<p><strong>Alphabetical Listing of Intervention Trials Published 1992
through 2000 with Omega-3 Fatty Acids (EPA and DHA)</strong></p>
<p><strong>as Food or Dietary Supplement Source Examining Heart Disease
Endpoints and Mortality</strong></p></th>
</tr>
<tr class="odd">
<th><strong>Reference</strong></th>
<th><strong>Objective</strong></th>
<th><strong>Study design</strong></th>
<th><strong>Duration</strong></th>
<th><strong>Intake</strong></th>
<th><strong>Subjects</strong></th>
<th><strong>Results</strong></th>
<th><strong>Conclusions/Comments</strong></th>
<th><strong>Data quality</strong></th>
<th><strong>Adverse effects/Safety</strong></th>
</tr>
</thead>
<tbody>
<tr class="odd">
<td><p>de Lorgeril et al. 1999</p>
<p><em>Circulation</em> 1999; 99:779-785</p>
<p>[France: The Lyon Diet Heart Study]</p></td>
<td>To determine if a Mediterranean-type diet, compared to a prudent
Western-style diet, may reduce recurrence after a first MI</td>
<td>Randomized, single-blind controlled trial</td>
<td>46 months (mean length of follow-up after first MI)</td>
<td>Not specified/not applicable. Serum DHA was used as a marker of
dietary intake.</td>
<td><p>2850 person-years of observation:</p>
<p>1467 in the Med. Diet Group;</p>
<p>1383 in the control group</p>
<p>Consecutive patients who survived first MI randomized to Med. or
Western diet. All subjects &lt;70 years old.</p></td>
<td><p><u>Cardiac deaths</u>: ↓ (p=0.01)</p>
<p><u>Nonfatal MI:</u> ↓ (p=0.0001)</p>
<p><u>All cause deaths:</u> ↓ (p=0.03)</p>
<p>Plasma α-linolenic and DHA concentrations were nonsignificantly
inversely associated with risk of recurrence</p></td>
<td><p><u>Conclusions</u>: The authors concluded that the results from
the intermediate analysis of the Lyon study, i.e., a significant
reduction of the rates of cardiovascular complications, were not changed
by continued follow-up of subjects.</p>
<p><u>Comments</u>: No possible to attribute the reductions in CHD and
all-cause death to marine oil intake.</p></td>
<td>1</td>
<td>Not reported</td>
</tr>
<tr class="even">
<td><p>Johansen et al. 1999a</p>
<p><em>J Am Coll Cardiol</em> 1999;33:1619-26</p>
<p>[Norway]</p></td>
<td>To determine if n-3 FAs supplementation from two weeks before
through six months after angioplasty will reduce the frequency of
restenosis.</td>
<td>Randomized, placebo-controlled, double-blind prospective trial.</td>
<td>26 weeks (6 months and 2 weeks)</td>
<td><p>5.04 g/d of EPA+DHA capsules (ethyl esters)
(Omacor<sup>®</sup>)</p>
<p>2.7 g/d EPA</p>
<p>2.34 g/d DHA (treatment)</p>
<p>Corn oil (placebo)</p>
<p>Compliance: serum phospholipid fatty acid analyses, capsule
count.</p></td>
<td><p>388 patients</p>
<p>Treatment: 196</p>
<p>Placebo: 192</p>
<p>Patients who were accepted for elective percutaneous transluminal
coronary angioplasty were recruited from April 1992 through February
1996.</p></td>
<td><p><u>TG:</u> ↓ (p&lt;0.001)</p>
<p><u>TC:</u> NS differences between the groups. In both groups TC
levels at six months were significantly different (p&lt;0.01) from
baseline levels (intra group differences).</p>
<p><u>HDL:</u> NS</p>
<p>NS differences in the incidence (OR=1.05) or in the occurrence
(OR=1.25) of restenosis was observed between the two groups.</p>
<p>EPA and DHA ↑ significantly (p&lt;0.001) in the Omacor<sup>®</sup>
group.</p></td>
<td><p><u>Conclusion:</u></p>
<p>The authors conclude that, “supplementation with 5.1 g n-3 FAs/d for
six months, initiated at least two weeks prior to coronary angioplasty
did not reduce the incidence of restenosis”.</p>
<p><u>Comments:</u></p>
<p>Dietary intake of macronutrients was assessed for 261 subjects
(treatment n=130, placebo n=131) using a standardized dietary
questionnaire.</p>
<p>No differences were observed between the two groups at baseline
except BMI was significantly higher in the treatment group compared to
the placebo group and statins were used more frequently in placebo
group.</p></td>
<td>1</td>
<td>Diarrhea or nausea in three (1.5%) patients receiving the treatment
and two (1%) patients receiving the placebo.</td>
</tr>
<tr class="odd">
<td><p>Salachas et al. 1994b</p>
<p><em>J Vascular Disease</em> 1994;45(12):1023-1031.</p>
<p>[Greece, England]</p></td>
<td>To investigate beneficial effects on various parameters with a low
dose of fish oil concentrate in patients with coronary artery disease
(CAD).</td>
<td><p>Randomized,</p>
<p>double-blind,</p>
<p>placebo-controlled trial.</p></td>
<td><p>12 weeks</p>
<p>(2-weeks run-in period first.)</p></td>
<td><p>3 g/d EPA+DHA*</p>
<p>1.8 g/d EPA</p>
<p>1.2 g/d DHA</p>
<p>(5 1-g capsules from Seven Seas twice daily)</p>
<p>Control: olive oil</p>
<p>Compliance:</p>
<p>Capsule count.</p></td>
<td><p>39 patients w/ CAD &amp; 1-yr history of stable angina
pectoris</p>
<p>20 test</p>
<p>19 control</p>
<p>@ 95% male</p>
<p>50 patients entered trial, 11 drop outs</p></td>
<td><p><u>TG:</u> ↓ 22% @ 8wks (P&lt;0.01) but ↑ @ 12 weeks such that
(&gt;0.10) vs. baseline value.</p>
<p><u>Angina:</u> ↓ 41% vs. baseline (P&lt;0.05); control ↑ (NS)</p>
<p><u>GTN intake:</u> ↓ 38% vs. baseline (P&lt;0.05). Control ↑
(NS).</p>
<p><u>Exercise test duration:</u> ↑ 22.6% (P&lt;0.01) vs. baseline.
Control NS.</p>
<p><u>Exercise Double Product:</u> ↑ 26% (P&lt;0.01) vs. baseline.
Control NS.</p>
<p><u>Platelet aggregation ratio:</u> NS</p>
<p><u>Beta Thromboglobulin:</u> NS</p>
<p><u>SBP &amp; DBP:</u> trend ↓</p></td>
<td><p><u>Conclusions:</u></p>
<p>A low dose of Fish oil may exert beneficial effects on clinical
status of patients w/CAD. The lab methods used in this study did not
demonstrate inhibition of platelet activity under basal conditions.</p>
<p><u>Comments:</u></p>
<p>*Total EPA+DHA intake not clear – 3 or 6 g/d?</p>
<p>Dietary intake not monitored during trial.</p>
<p>Patients using antianginal medication continues therapy but did not
alter the dose regimen.</p></td>
<td>2</td>
<td>"All the subjects in both groups tolerated the supplements without
any adverse effects." None of the patients had an increased
susceptibility to bruising.</td>
</tr>
<tr class="even">
<td><p>Singh et al. 1997</p>
<p><em>Cardiovasc Drugs Ther</em> 1997;11:485-491</p>
<p>[India]</p></td>
<td>To determine if fish oil (EPA) and mustard oil therapy can provide
rapid protection against ischemic damage and complications in patients
with suspected acute myocardial infarction (AMI).</td>
<td>Randomized, double-blind, placebo-controlled</td>
<td>52 weeks (1 year)</td>
<td><p>1.8 g/day of EPA+DHA (Maxepa fish oil capsules)</p>
<p>1.08 g/d EPA</p>
<p>0.72 g/d DHA (group A)</p>
<p>Group B: 100 mg/d of aluminum hydroxide and 20 g/day mustard oil (ALA
2.9 g/d)</p>
<p>Group C: 100 mg/d of aluminum hydroxide (placebo group)</p>
<p>Compliance: capsule counts</p></td>
<td><p>360 subjects with suspected AMI</p>
<p>Group A: 122</p>
<p>Group B: 120</p>
<p>Group C: 118</p>
<p>The subjects were patients admitted over a period of 30 months at the
Medical Hospital and Research Centre with a clinical diagnosis of
suspected acute AMI. Those subjects who had likely suffered AMI with the
onset of symptoms in the preceding 24 hours were recruited.</p></td>
<td><p>TC: No significant effect of fish oil or mustard oil.</p>
<p>TG: Modest changes with fish oil.</p>
<p>HDL: Modest changes with fish oil and mustard oil.</p>
<p>Total cardiac events: ↓ significantly in the fish oil (RR=0.7) and
mustard oil (RR=0.81) groups compared with the placebo group (24.5% and
28% vs. 34.7%, respectively, p&lt;0.05) after 1 year.</p>
<p>Nonfatal infarctions: ↓ significantly in the fish oil (RR=0.51) and
mustard oil (RR=0.59) groups compared with the placebo group (13.0% and
15.0% vs. 25.4%, respectively, p&lt;0.01).</p>
<p>Total cardiac deaths: ↓ significantly in the mustard oil (RR=0.6) and
the fish oil (RR=0.52) groups compared with the placebo group (13.3% and
11.4% vs. 22.0%, respectively, p &lt; 0.01) .</p>
<p>Total cardiac arrhythmias: The fish oil and mustard oil groups also
showed a significant reduction in total cardiac arrhythmias (RR=0.46 for
both, p&lt;0.05 for both) compared with the placebo group.</p>
<p>Left ventricular enlargement: The fish oil and mustard oil groups
showed a significant reduction in left ventricular enlargement (RR=0.51
fish oil, 0.58 mustard oil, p&lt;0.01 both) compared with the placebo
group.</p>
<p>Angina pectoris: The fish oil and mustard oil groups showed a
significant reduction in angina pectoris (RR=0.42 fish oil, 0.51 mustard
oil, p&lt;0.05 for both) compared with the placebo group.</p>
<p>Significant ↓ in diene conjugates in both groups.</p></td>
<td><p><u>Conclusion:</u></p>
<p>The results suggest, “that fish oil and mustard oil, possibly due to
the presence of n-3 FAs, may provide rapid protective effects in
patients with AMI”.</p>
<p><u>Comments:</u></p>
<p>Dietary intake was not monitored or assessed, but subjects were asked
to consume a low-fat diet.</p>
<p>No exclusion criteria were used.</p>
<p>All parameters were similar among the three groups except for higher
incidence of previous angina pectoris and MI and higher number of
smokers in group A.</p>
<p>Data on compliance not reported</p></td>
<td>1</td>
<td>Belching (n=6, 4.9%) and nausea (n=8, 6.6%) in patients receiving
fish oil supplements</td>
</tr>
<tr class="odd">
<td><p>Valagussa et al. 1999</p>
<p><em>Lancet</em> 1999;354:447-55</p>
<p>[Italy]</p></td>
<td>To study the independent and combined effects of n-3 PUFAs and
vitamin E on morbidity and mortality after MI.</td>
<td><p>Randomized, control trial. Open label design.</p>
<p>Multicenter (172)</p></td>
<td>189 weeks (3.5 years).</td>
<td><p>0.850-0.882 g/d (850-882 mg) of EPA + DHA as ethyl esters (n-3
group) (n-3 PUFAs group)</p>
<p>300 mg/d vitamin E (vitamin E group)</p>
<p>n-3 + vitamin E group</p>
<p>Control group</p>
<p>Compliance: capsule counts</p></td>
<td><p>11324 subjects.</p>
<p>Patients surviving recent (≤ 3 months) MI were recruited from October
1993 through September 1995 from 172 centers (cardiology department and
rehabilitation center).</p>
<p>n-3 group: 2836 patients</p>
<p>vitamin E group: 2830 patients</p>
<p>n-3 + vit E group: 2830 patients</p>
<p>control group: 2828 patients</p></td>
<td><p><u>TG:</u> Small but significant decrease in TG with n-3
treatment.</p>
<p><u>TC:</u> NS change with n-3 or any other treatment.</p>
<p><u>LDL:</u> NS change with n-3 or any other treatment.</p>
<p><u>HDL:</u> NS change with n-3 or any other treatment.</p>
<p>Glycaemia: NS change with n-3 or any other treatment.</p>
<p><u>Fibrinogen:</u> NS change with n-3 or any other treatment.</p>
<p>The 10% relative decrease in risk for combined primary endpoint of
death, non-fatal MI and non-fatal stroke was significant (95% CI 1-18,
p=0.048) with two-way factorial analysis. The relative decrease in risk
for the combined end point was 15% (CI 2-26, p=0.023) and for
cardiovascular death, non-fatal MI and no-fatal stroke was 20% (CI 5-32,
p=0.008) with four-way factorial analysis.</p>
<p>Benefit was attributed to a decrease in the risk of death (14% [CI
3-24] two-way, 20% [CI 6-33] four-way) and cardiovascular death (17% [CI
3-29] two-way, 30% [CI 13-44] four-way).</p>
<p>The effect of the combined treatment with n-3 PUFAs + vitamin E was
similar to that for n-3 PUFAs for the primary endpoint (14% [CI 1-26])
and for fatal events (20% [CI 5-33]).</p>
<p>No difference across the treatment was observed for non-fatal
cardiovascular events.</p>
<p>The effects of vitamin E treatment were similar to the
control.</p></td>
<td><p><u>Conclusion:</u></p>
<p>The authors conclude that, “long-term n-3 PUFAs (1g/d)
supplementation was beneficial for death, and for combined death,
non-fatal MI and stroke in patients with MI and have Mediterranean
dietary habits”.</p>
<p><u>Comments:</u></p>
<p>Conducted intent-to-treat analysis.</p>
<p>Age limits were not defined.</p></td>
<td>1</td>
<td>Patients receiving n-3 PUFAs and vitamin E reported gastrointestinal
disturbances (4.9 % n-3, 2.9% vitamin E) and nausea (1.4 % n-3, 0.4%
vitamin E). 3.8% of the n-3 patients and 2.1% of the vitamin E patients
discontinued the treatment because of the side effects.</td>
</tr>
<tr class="even">
<td><p>von Schacky et al. 1999</p>
<p><em>Ann Intern Med</em> 1999;130:554-562</p>
<p>[Germany]</p></td>
<td>To determine the effect of dietary intake of omega-3 FAs on the
course of coronary artery atherosclerosis in humans.</td>
<td>Randomized, Double-blind, Placebo-controlled</td>
<td><p>112 weeks</p>
<p>(2 years)</p></td>
<td><p>3.4 g/d EPA+DHA</p>
<p>2.1 g/d EPA, 1.3 g/d DHA)</p>
<p>Months 1-3</p>
<p>Next 21 months:</p>
<p>1.71 g/d EPA+DHA</p>
<p>Control: FAs mixture reflecting composition of avg. European
diet.</p>
<p>Compliance:</p>
<p>interview, capsule counts, FAs analysis.</p></td>
<td><p>233 patients w/ angiographically proven coronary artery
disease.</p>
<p>111 test</p>
<p>112 control</p>
<p>Ratio Males:Females not given.</p></td>
<td><p><u>TG:</u> NS between groups</p>
<p><u>TC:</u> NS between groups</p>
<p><u>LDL:</u> ↓ (p&lt;0.05)</p>
<p><u>HDL:</u> NS between groups</p>
<p><u>Coronary Atherosclerosis (expert panel):</u> Test group showed
less progression and more regression vs. control group (p&lt;0.041)</p>
<p><u>Coronary Atherosclerosis (luminal diameter):</u> NS between
groups</p>
<p><u>CVD events incl. MI:</u> ↓ (p=0.1)</p></td>
<td><p><u>Conclusions:</u></p>
<p>"Dietary intake of n-3 FAs modestly mitigates the course of coronary
atherosclerosis in humans"</p>
<p><u>Comments:</u></p>
<p>Dietary habits not reviewed over 2-yr period.</p>
<p>Subjective measurement of angiograms by expert panel.</p>
<p>Text and Table 3 data differ.</p></td>
<td>2</td>
<td><p>Dose and preparation well tolerated.</p>
<p>No adverse affects attributed to test material.</p></td>
</tr>
</tbody>
</table>

<table>
<colgroup>
<col style="width: 8%" />
<col style="width: 8%" />
<col style="width: 6%" />
<col style="width: 8%" />
<col style="width: 9%" />
<col style="width: 13%" />
<col style="width: 14%" />
<col style="width: 15%" />
<col style="width: 6%" />
<col style="width: 9%" />
</colgroup>
<thead>
<tr class="header">
<th colspan="10"><p><strong>Appendix G</strong></p>
<p><strong>Alphabetical Listing of Observational Studies Published 1992
through 2000 with Omega-3 Fatty Acids (EPA and DHA)</strong></p>
<p><strong>as Food or Dietary Supplement Source Examining Heart Disease
Related Endpoints or Biomarkers</strong></p></th>
</tr>
<tr class="odd">
<th><strong>Reference</strong></th>
<th><strong>Objective</strong></th>
<th><strong>Study design</strong></th>
<th><strong>Length of Follow-up</strong></th>
<th><strong>Intake</strong></th>
<th><strong>Subjects</strong></th>
<th><strong>Results</strong></th>
<th><strong>Conclusions/Comments</strong></th>
<th><strong>Data Quality</strong></th>
<th><strong>Adverse Effects/ Safety</strong></th>
</tr>
</thead>
<tbody>
<tr class="odd">
<td><p>Anntolainen et al. 1996</p>
<p><em>Eur J Clin. Nutr</em> 1996;50: 741-746</p>
<p>[Finland]</p></td>
<td>To investigate the differences between a high-fish and a low-fish
diet by examining both dietary and plasma antioxidant levels and fatty
acid composition, and test the hypothesis that a high fish and fish oil
intake can cause a less beneficial antioxidant/pro-oxidant ratio <em>in
vivo</em> compared to a low intake.</td>
<td>Cross-sectional</td>
<td>Not applicable</td>
<td><p>1.3 g/day mean fish n-3 PUFA in high fish group compared to 0.15
g/day in the low fish group, based on 103 g/day fish (mean) intake in
the high fish group compared to 4.9 g/day fish in the low-fish
group.</p>
<p>Fish intake assessed using a 3-day food recall questionnaire (n=1861
subjects) used to identify high and low fish eaters. No subjects took
fish oil supplements.</p></td>
<td><p>82 subjects</p>
<p>High fish intake: 41 subjects</p>
<p>Low fish intake: 41 subjects</p>
<p>Same male:female ratio in both groups: 21:20</p>
<p>Mean age in both groups was 54 years.</p>
<p>No significant differences in baseline characteristics between the
two groups.</p></td>
<td><p><u>Serum n-3 PUFA</u>:</p>
<p>9.6% of total FA in high fish group compared to 6.2% in low fish
group (p&lt;0.001)</p>
<p><u>Serum EPA:</u></p>
<p>2.1% of total FA in high fish group compared to 1.0% in low fish
group (p&lt;0.001)</p>
<p><u>Serum DHA:</u></p>
<p>6.6% of total FA in high fish group compared to 4.3% in low fish
group (p&lt;0.001)</p></td>
<td><p><u>Conclusions:</u> The authors concluded that the high fish diet
resulted in higher intakes of n-3 PUFA and fish n-3 PUFA (namely EPA and
DHA) that can be ascribed to fish intake.</p>
<p><u>Comments</u>: Fish eaters had other dietary differences (such as
higher vegetable intake and lower coffee intake) that indicate that fish
eaters diets, in general, may be healthier.</p>
<p>Potential biases in selection of subjects to participate in clinical
portion of the study.</p></td>
<td>2</td>
<td>A five-fold higher serum mercury level was found in the high-fish
group compared to the low fish group. However, the mean level in high
fish-eaters was 51% of the WHO permissible tolerable daily intake.</td>
</tr>
<tr class="even">
<td><p>Archer et al. 1998</p>
<p><em>Arterioscler. Thromb. Vasc. Biol.</em> 1998. 18:1119-1123</p>
<p>[U.S.]</p></td>
<td>To investigate the relationship between fish, linolenic acid, EPA,
and DHA consumption and plasma concentrations of hemostatic factors</td>
<td>Retrospective cohort</td>
<td><p>4 weeks</p>
<p>(30 day recall period)</p></td>
<td><p>0.23-0.34 g/day EPA+DHA</p>
<p>(0.14-0.21 g/day DHA, 0.09-0.13 g/day EPA ) - high fish group</p>
<p>0.09-0.11 g/day EPA+DHA</p>
<p>(0.06-0.08 g/day DHA, 0.03 g/day EPA) - moderate fish group</p>
<p>0.03 EPA + DHA (0.03 g/day DHA, 0.0005 g/day EPA ) - low fish
group</p>
<p>subjects categorized into no fish, low fish, moderate fish, and high
fish consumption groups based on 30-day recall</p>
<p>average of 10 g/day fish consumed by males; 8.4 g/day by
females</p></td>
<td><p>1,672 healthy subjects</p>
<p>783 male/889 female;</p>
<p>mean age approximately 32 years</p>
<p>Low fish group: n=312</p>
<p>Moderate fish group: n=272</p>
<p>High fish group: n=317</p>
<p>No fish: n=771</p></td>
<td><p><u>Factor VIII:</u> NS changes</p>
<p><u>von Willebrand factor</u>: NS changes</p>
<p><u>Factor VII</u>: significant ↑ for males in high fish vs. no fish
consumption group (p&lt;0.05); NS difference between other groups</p>
<p><u>Fibrinogen</u>: NS changes</p></td>
<td><p><u>Conclusions:</u></p>
<p>Authors concluded that, “the data from this study provides no
evidence of an association between intake of fish and fibrinogen, Factor
VIII and von Willebrand factor for any sex or race group, and no
evidence of an association between dietary linolenic acid, EPA and DHA
and the above parameters.” “Habitual fish intake in populations that do
not consume large amount of fish has no beneficial effect on hemostatic
factors. The influence of dietary fish and n-3 fatty acids on hemostatic
factors is still unresolved.”</p>
<p><u>Comments</u>:</p>
<p>Subjects a subset of the Coronary Artery Risk Development in Young
Adults (CARDIA) study.</p></td>
<td>2</td>
<td>Not reported.</td>
</tr>
<tr class="odd">
<td><p>Ascherio et al. 1995</p>
<p><em>NEJM</em> 1995;332:977-82</p>
<p>[U.S.- Health Professional’s Follow-up Study]</p></td>
<td>To examine the association between coronary disease and fish
consumption in a large cohort of male health professionals</td>
<td>Prospective cohort</td>
<td>6 years</td>
<td><p>0.58 g/day n-3 fatty acids (median intake in the highest intake
quintile). Represents a median of 5.9 servings of fish per week.</p>
<p>Average fish intake was assessed in 1986 for the previous year.
Validated the responses using alternate food assessment methods and
biologic markers.</p></td>
<td>44,895 males ages 40-74 in 1986, excluded if physician-diagnosed
with MI, angina, stroke, transient ischemic attack, or peripheral artery
disease, followed for 6 years to ascertain coronary disease events. 1543
coronary disease events (non-fatal and fatal MI, coronary artery bypass,
or angioplasty) were observed. Participants were enrolled as part of the
Health Professionals Follow-up Study.</td>
<td><p><u>TC:</u> At baseline, no difference in TC levels between fish
consumption groups (i.e. no effect of fish consumption, but numerous
other factors affecting serum cholesterol were not controlled). No other
serum lipids reported.</p>
<p><u>CHD outcomes</u>: After adjusting for confounders, no significant
difference in risk for any of the CHD outcomes was observed by n-3 fatty
acid intake or dietary fish intake with the exception of a higher risk
of coronary artery bypass surgery among those with higher fish
intake.</p></td>
<td><p><u>Conclusions</u>: The authors reported that no evidence of an
association between the intake of either marine n-3 fatty acids or fish
and risk of CHD was observed in this study.</p>
<p><u>Comments:</u> Excluded any participants with previous evidence of
CVD (hypercholesterolemia, diabetes, or hypertension) who may have
changed diet as a result. However, 1986 dietary assessment may not
reflect differences in fish intake in years prior to the study.</p></td>
<td>2</td>
<td>None reported</td>
</tr>
<tr class="even">
<td><p>Christensen et al. 1997</p>
<p><em>Am. J. Cardiol.</em> 1997; 79:1670-3</p>
<p>[Denmark]</p></td>
<td>To examine the correlation between heart rate variability (HRV),
fish consumption, and platelet concentration of long-chain n-3
PUFAs</td>
<td>Cross-sectional</td>
<td>Not applicable</td>
<td>Not quantified; subjects classified as non-fisheaters, fish once per
week, or fish two or more times per week based on interview with
patients; platelet DHA</td>
<td><p>52 MI survivors diagnosed between November 1991 and August 1993
in a Copenhagen hospital. (These subjects were subsequently randomized
to receive fish supplements or a placebo; see Christensen et al.
1996).</p>
<p>Mean age: 63 years (range 48-75 years)</p></td>
<td><p><u>Fish consumption</u>: Plasma DHA, EPA, AA, and AA/DHA were all
significantly associated with fish consumption (p&lt;0.05, p&lt;0.05,
p&lt;0.01, and p=0.06, respectively). SDNN (standard deviation of all
normal RR intervals in the 24-hour period) was not associated with fish
consumption (p-value not reported), although “heart rate variability
[HRV] tended to be higher among fish consumers than non-fish
consumers.”</p>
<p><u>Platelet DHA levels</u>: Mean RR (ms, over a 24-hour period) was
non-significantly positively associated with a higher concentration of
DHA in platelets. Two additional measures, the SDNN and the SDDN Index
(mean of all the standard deviations of all normal RR intervals for all
5-minute segments of the 24-hour period) were significantly higher in
the group with the highest platelet DHA concentrations (p&lt;0.01 and
p&lt;0.00001, respectively). Smokers had significantly lower platelet
DHA concentrations and lower SDNN than nonsmokers. A significant
correlation was reported between DHA and SDNN after controlling for
smoking (r=0.30, p&lt;0.05). Platelet DPA and heart rate variability
(HRV) were not significantly correlated.</p></td>
<td><p><u>Conclusions</u>:</p>
<p>The authors concluded that the findings of this study “suggest that
fish consumption potentially could protect against sudden cardiac death
in patients with a previous myocardial infarction.”</p>
<p><u>Comments</u>:</p>
<p>Smoking is a significant confounder for HRV (as measured by
SDNN).</p></td>
<td>2</td>
<td>Not applicable</td>
</tr>
<tr class="odd">
<td><p>Guallar et al. 1999</p>
<p><em>Aterioscler Thromb Vasc Biol</em> 1999;19:1111-1118</p>
<p>[Europe – European Multicenter Case-Control Study on Antioxidants,
Myocardial Infarction, and Breast Cancer, EURAMIC]</p></td>
<td>To examine the association between omega-3 fatty acid in adipose
tissue and risk of MI (MI)</td>
<td>Case-control</td>
<td>Not applicable</td>
<td>Not specified/not applicable. DHA concentration in adipose tissue
was used as a marker of fish intake.</td>
<td><p>1339 subjects</p>
<p>639 MI cases: men 70 years of age or younger, residents of a European
country or Israel, diagnosed with their first MI in a participating
hospital in 1991 or 1992</p>
<p>700 controls: selected using 4 methods: random sampling from local
population registers, hospital patients, residents in the medical
facility’s catchment area, or the case’s friends or relatives</p></td>
<td>With all study centers combined, the mean level of -linolenic (ALA)
in adipose tissue was significantly lower in the MI cases than in
controls (0.03% lower; 95% CI: 0.05 to 0.01). DHA levels were not
significantly different for all centers combined, nor for any of the
countries, even those with higher per capita fish consumption.</td>
<td><p><u>Conclusions</u>: The authors concluded that in this study,
“there was no evidence of a protective effect of adipose DHA, reflecting
long-term fish intake, on the risk of myocardial infarction….</p>
<p>Participants with undetectable or very low levels of omega-3 fatty
acids were also not at increased risk of myocardial infarction.”</p>
<p><u>Comments</u>: According to the authors, adipose DHA is considered
a good indicator of fish intake.</p></td>
<td>3</td>
<td>None reported</td>
</tr>
<tr class="even">
<td><p>Kromhout et al. 1995</p>
<p><em>Int J Epidemiol</em> 1995;24: 340-345.</p>
<p>[The Netherlands – the Rotterdam cohort]</p></td>
<td>To investigate the relation between fish consumption and CHD
mortality in elderly men and women in the Netherlands who were followed
for 17 years.</td>
<td>Prospective cohort study</td>
<td>17 years</td>
<td>24.0 g/day fish among fish eaters (26.0 g/day for males and 21.9
g/day for females) based on usual consumption patterns for the 14 days
prior to the interview conducted at baseline in 1971. Subjects
categorized as fish eaters/not fish eaters. Approximately 60% of the
participants were fish eaters.</td>
<td><p>272 subjects (137 males, 135 females) who were patients in a
medical practice in 1971 and who were born before 1907. In 1971, average
ages were 71 for men and 70 for females.</p>
<p>No exclusions for existing CHD-related conditions.</p></td>
<td><p>Males, at baseline</p>
<p>(unadjusted), fisheaters vs. nonfisheaters:</p>
<p><u>TG:</u>  (NS)</p>
<p><u>TC:</u>  (NS)</p>
<p>Females, at baseline</p>
<p>(unadjusted), fisheaters vs. nonfisheaters:</p>
<p><u>TG:</u>  (NS)</p>
<p><u>TC:</u>  (NS)</p>
<p><u>MI mortality:</u> (RR adjusted for age, gender, preexisting MI or
angina):</p>
<p>0.58 (95% CI: 0.34-0.99)</p>
<p><u>MI mortality:</u> (RR adjusted further for dietary confounders
such as fat intake): 0.50 (95% CI: 0.28-0.89)</p></td>
<td><p><u>Conclusions</u>: The authors concluded that fish intake showed
a significant protective effect against CHD mortality and the prevalence
of MI in elderly males and females.</p>
<p><u>Comments</u>: Potential for misclassification of fish intake based
on a two-week food consumption survey. Possible that those with
prevalent MI, angina, or other CHD risk factors had increased fish
consumption due to diagnosis.</p>
<p>Small sample size and wide CIs when stratifying.</p>
<p>Serum TG was not significantly associated with CHD in this
study.</p></td>
<td>2</td>
<td>Not reported</td>
</tr>
<tr class="odd">
<td><p>Parkinson et al. 1994</p>
<p><em>Am J Clin. Nutr</em> 1994;59:384-388</p>
<p>[U.S. – Alaska]</p></td>
<td>To examine the relationship between diet, plasma fatty acid
composition, and bleeding times of residents of two Yupik Eskimo
villages in the Yukon-Kuskokwim Delta of southwestern Alaska</td>
<td>Cross-sectional</td>
<td>Not applicable</td>
<td><p>Not quantified</p>
<p>Dietary information collected using 2-month dietary recall (July and
August 1985) to capture the frequency of foods consumed, but not portion
size. Included questions about specific types of fish, marine and land
mammals, fowl, and types of cooking oils used.</p></td>
<td><p>79 residents of two Eskimo villages, randomly selected by age and
gender category:</p>
<p>40 residents of a river village</p>
<p>39 residents of a coastal village</p>
<p>Excluded subjects who were receiving anticoagulant therapy or who had
used aspirin-containing substances 2 weeks prior to blood draw.</p>
<p>Plasma fatty acid analyses were compared with selected age-specific
volunteers from the University of Oregon Family Heart Study and Lipid
Clinic.</p></td>
<td><p>Coastal residents reported consuming significantly (p&lt;0.01)
more marine fish, marine mammals, birds, and consuming items with seal
oil.</p>
<p>Total plasma n-3 fatty acids were significantly higher in the coastal
and river-dwelling Alaskan adults and children compared to the
non-Native controls.</p>
<p>Between villages, n-3 fatty acids were significantly higher in the
coastal village, but only for EPA (p&lt;0.001) and DHA (p=0.004), and
not alpha-linolenic acid. In both villages, DHA and EPA both increased
significantly with increasing age. In the coastal and river villages,
increasing EPA was significantly associated with increasing salmon
consumption. Additionally, in the coastal village, consumption of marine
fish and use of seal oil were positively associated with EPA.</p></td>
<td><p><u>Conclusions:</u> The authors concluded that elevated
concentrations of plasma n-3 fatty acids were found among the Alaskan
native Eskimos in two separate villages, coastal and along a river, when
compared to non-Native controls. The higher concentrations were
associated with marine sources for both villages.</p>
<p><u>Comments</u>: Although dietary recall captured only 2 months of
food consumption patterns, and not seasonal differences, food sources
are most likely marine-based at any time during the year.</p>
<p>Participant selection not fully described; may be some
selection/participation bias.</p></td>
<td>2</td>
<td><p>Normal bleeding times:</p>
<p>88% of river-village (mean of 5.5 min); 98% of coastal village (mean
of 5.2 minutes). A total of 3 participants with bleeding times longer
than normal using Simplate method (2.3-9.3 minutes), but no association
with high n-3 fatty acids or EPA.</p>
<p>Platelet counts of both villages at or above normal, with not
association with dietary intakes of n-3 fatty acids.</p></td>
</tr>
<tr class="even">
<td><p>Pauletto et al. 1996</p>
<p><em>Lipids</em> 1996;31:S309-S312</p></td>
<td>To examine the serum fatty acid profiles in two genetically
homogeneous populations: one that lived near a coastal area that
consumes a fish diet (FD) and one 90 miles from the coast consuming
mostly a vegetarian diet (VD)</td>
<td>Cross-sectional</td>
<td>Not applicable</td>
<td>500 g/day fish intake estimated from 25 families in the coastal
village compared to no animal protein in the vegetarian village</td>
<td><p>116 men and women for the fatty acid and lipid profiles</p>
<p>FD: 26 males and 35 females</p>
<p>VD: 24 males and 31 females</p>
<p>1276 participants in the blood pressure and L(a)
measurements</p></td>
<td><p><u>TG</u>: ↓ FD (p&lt;0.001)</p>
<p><u>TC</u>: ↓ FD (p&lt;0.05)</p>
<p><u>Lp(a):</u> ↓ FD (p&lt;0.001)</p>
<p><u>SBP</u>: ↓ FD (p&lt;0.001)</p>
<p><u>DBP</u>: ↓ FD (p&lt;0.001)</p>
<p><u>Serum EPA:</u> ↑ FD (p&lt;0.001)</p>
<p><u>Serum DHA:</u> ↑ FD (p&lt;0.001)</p></td>
<td><p><u>Conclusions</u>: The authors concluded that in this
genetically homogeneous population living on different diets, the
populations differ on the prevalence of several important CHD risk
factors. The high DHA and other FA content of the FD subjects reflect
consumption of local fish containing high levels of these FA.</p>
<p><u>Comments:</u> Analysis of local fish revealed high levels of n-3
FA, especially DHA, in fish.</p>
<p>Comparability of study subjects from the two populations not
presented, especially on age</p></td>
<td>3</td>
<td>Not reported</td>
</tr>
<tr class="odd">
<td><p>Simon et al. 1995</p>
<p><em>Am J Epidemiol</em> 1995;142:469-476</p>
<p>[U.S. – Multiple Risk Factor Intervention Trial, MRFIT]</p></td>
<td>To examine the relation between serum fatty acid levels and CHD</td>
<td>Nested case-control study using cases of CHD from the non-
intervention group of a clinical trial</td>
<td>Not applicable</td>
<td>Not quantified; serum fatty acid concentrations of n-3 fatty acids
at time of enrollment used as a marker of dietary n-3 intake</td>
<td>188 participants (94 cases and 94 matched controls) from the
Multiple Risk Factor Intervention Trial (MRFIT) selected for high
cholesterol, DBP and smoking status. Cases had suffered a fatal or
non-fatal MI in the 6.9 years of follow-up. Controls were matched on
age, date of randomization, and clinical center.</td>
<td><p>At baseline, cases compared to controls:</p>
<p><u>TG:</u> No difference.</p>
<p><u>TC:</u> No difference.</p>
<p><u>LDL:</u> No difference.</p>
<p><u>HDL:</u> No difference.</p>
<p>DHA and docosapentaenoic lower in cases (p&lt;0.05); EPA also lower,
but p&gt;0.05.</p>
<p>Risk of CHD significantly lower for those with higher DHA and
docosapentaenoic levels</p></td>
<td><p><u>Conclusions</u>: The authors concluded that the study findings
were consistent with other studies in demonstrating that high levels of
polyunsaturated fatty acids are associated with decreased cardiovascular
risk.</p>
<p><u>Comments</u>: Generalizability to those not at high risk of CHD
unknown.</p>
<p>Possibility of oxidative damage from using stored serum
specimens.</p>
<p>Serum fatty acid profile may not represent long-term dietary intake
pattern.</p></td>
<td>2</td>
<td>Not reported</td>
</tr>
<tr class="even">
<td><p>Siscovick et al. 1995</p>
<p><em>JAMA</em> 1995;274:1363-1367</p>
<p>[U.S. - Seattle]</p></td>
<td>To determine whether dietary intake of n-3 unsaturated fatty acids
is associated with a reduced vulnerability to life-threatening
arrythmias.</td>
<td>Case-control study</td>
<td>Not applicable</td>
<td>0.18 g/day (5.3 g/month) EPA and DHA in controls; 0.14 g/day (4.3
g/month) in cases; estimated for the month prior to the interview using
a Seafood Intake Scale specific to Pacific Northwest seafood</td>
<td>827 subjects: 334 out-of-hospital sudden cardiac arrest cases
attended by paramedics in Seattle and suburban King County. Patients
with existing CHD, other risk factors for CHD, and those taking fish oil
supplements were excluded. 493 controls, selected by random digit
dialing matched by age and sex, with generally same exclusion
criteria.</td>
<td><p><u>Hypercholesterolemia:</u></p>
<p>Cases: 24%</p>
<p>Controls: 22% (NS)</p>
<p><u>Mean Dietary EPA and DHA intake:</u></p>
<p>Cases: 4.3 g/month</p>
<p>Controls: 5.3 g/month (p=0.02) (but unadjusted for significant
differences in smoking, education, hypertension, diabetes mellitus,
family history of MI or sudden death, caffeine, and dietary fat
intake.</p>
<p>Adjusted OR (95% CI) by quartile of n-3 fatty acid intake compared to
non-fish eaters:</p>
<p>1<sup>st</sup>: 0.9 (0.8–0.9)</p>
<p>2<sup>nd</sup>: 0.7 (0.6-0.9)</p>
<p>3<sup>rd</sup>: 0.5 (0.4-0.8)</p>
<p>4<sup>th</sup>: 0.4 (0.2-0.7)</p>
<p>Adjusted ORs for RBC membrane levels similar, and significant for
2<sup>nd</sup>, 3<sup>rd</sup>, and 4<sup>th</sup> quartiles compared to
1<sup>st</sup> quartile.</p></td>
<td><p><u>Conclusions</u>: The authors concluded that both dietary
intake and red blood cell membrane levels of n-3 polyunsaturated fatty
acids EPA and DHA significantly reduce the risk of primary cardiac
arrest.</p>
<p><u>Comments</u>: Validated the food frequency questionnaire using
spouses and red blood cell membrane fatty acid measurements for a subset
of subjects.</p></td>
<td>2</td>
<td>Not applicable</td>
</tr>
<tr class="odd">
<td><p>Siscovick et al. 1995; 2000</p>
<p><em>JAMA</em> 1995;274:1363-1367</p>
<p><em>Am. J. Clin. Nutr</em>. 2000;71(suppl):208S-12S</p>
<p>[U.S. - Seattle]</p></td>
<td>To determine whether dietary intake of n-3 unsaturated fatty acids
is associated with a reduced vulnerability to life-threatening
arrythmias.</td>
<td>Case-control study</td>
<td>Not applicable</td>
<td>0.18 g/day (5.3 g/month) EPA and DHA in controls; 0.14 g/day (4.3
g/month) in cases; estimated for the month prior to the interview using
a Seafood Intake Scale specific to Pacific Northwest seafood</td>
<td>827 subjects: 334 out-of-hospital sudden cardiac arrest cases
attended by paramedics in Seattle and suburban King County. Patients
with existing CHD, other risk factors for CHD, and those taking fish oil
supplements were excluded. 493 controls, selected by random digit
dialing matched by age and sex, with generally same exclusion
criteria.</td>
<td><p>Results reported in 1995 and 2000 publications were equivalent
except as indicated.</p>
<p><u>Hypercholesterolemia:</u></p>
<p>Cases: 24%</p>
<p>Controls: 22% (NS)</p>
<p><u>Mean Dietary EPA and DHA intake:</u></p>
<p>Cases: 4.3 g/month</p>
<p>Controls: 5.3 g/month (p=0.02) (but unadjusted for significant
differences in smoking, education, hypertension, diabetes mellitus,
family history of MI or sudden death, caffeine, and dietary fat
intake.</p>
<p>Adjusted OR (95% CI) by quartile of n-3 fatty acid intake compared to
non-fish eaters (all statistically significant):</p>
<p>1<sup>st</sup>: 0.9 (0.8–0.9)</p>
<p>2<sup>nd</sup>: 0.7 (0.6-0.9)</p>
<p>3<sup>rd</sup>: 0.5 (0.4-0.8)</p>
<p>4<sup>th</sup>: 0.4 (0.2-0.7)</p>
<p>1995: Unadjusted and adjusted ORs for RBC membrane levels were
statistically significantly lower in the 2<sup>nd</sup>, 3<sup>rd</sup>
and 4<sup>th</sup> quartiles compared to the 1<sup>st</sup> quartile
(lowest fish intake).</p>
<p>2000: Unadjusted and adjusted ORs for RBC membrane levels were
statistically significantly lower in the 2<sup>nd</sup>, 3<sup>rd</sup>
and 4<sup>th</sup> quartiles compared to the 1<sup>st</sup> quartile
(lowest fish intake). However, after adjusting for other risk factors,
adjusted ORs for PUFAs concentrations in RBC membranes were not
statistically significantly different by seafood intake group.</p></td>
<td><p><u>Conclusions</u>: The authors concluded that modest amounts of
long-chain n-3 PUFAs from seafood (96 g or 3 ounces of fatty fish per
week) are associated with a reduction in risk of primary cardiac arrest,
but that higher amounts are not associated with a further risk
reduction.</p>
<p><u>Comments</u>: Validated the food frequency questionnaire using
spouses and red blood cell membrane fatty acid measurements for a subset
of subjects.</p>
<p>Discrepant results for RBC membrane PUFA concentrations reported in
1995 publication compared to 2000 publication not discussed.</p></td>
<td>2</td>
<td>Not applicable</td>
</tr>
</tbody>
</table>

<table>
<colgroup>
<col style="width: 8%" />
<col style="width: 8%" />
<col style="width: 6%" />
<col style="width: 8%" />
<col style="width: 9%" />
<col style="width: 13%" />
<col style="width: 14%" />
<col style="width: 15%" />
<col style="width: 6%" />
<col style="width: 9%" />
</colgroup>
<thead>
<tr class="header">
<th colspan="10"><p><strong>Appendix H</strong></p>
<p><strong>Alphabetical Listing of Intervention Trials Published 1992
through 2000 with Omega-3 Fatty Acids (EPA and DHA)</strong></p>
<p><strong>as Food or Dietary Supplement Source Examining Heart Disease
Related Endpoints or Biomarkers</strong></p></th>
</tr>
<tr class="odd">
<th><strong>Reference</strong></th>
<th><strong>Objective</strong></th>
<th><strong>Study design</strong></th>
<th><strong>Duration</strong></th>
<th><strong>Intake</strong></th>
<th><strong>Subjects</strong></th>
<th><strong>Results</strong></th>
<th><strong>Conclusions/Comments</strong></th>
<th><strong>Data quality</strong></th>
<th><strong>Adverse effects/Safety</strong></th>
</tr>
</thead>
<tbody>
<tr class="odd">
<td><p>Abe, et. al.</p>
<p>1998</p>
<p>Aterioscler Thromb Vasc Biol.</p>
<p>1998;18:723-31</p>
<p>[U.S.]</p></td>
<td>To examine the relationship between hypertriglyceridemia
dyslipidemia (high triglycerides/low HDL) and levels of soluble cell
adhesion molecules (sCAMs) and other risk factors.</td>
<td>Randomized, placebo controlled</td>
<td><p>6 weeks</p>
<p>Initial dietary phase (AHA Step I Diet) lasted 6 weeks for all
subjects prior to tx.</p>
<p>After 6 weeks of the placebo-controlled study, the study was
extended. 31 subjects, including those who had been randomized to
placebo, received 4 g/d of Omacor for 28 weeks (7 months; n = 28) or 52
weeks (12 months; n = 9).</p></td>
<td><p>4 g/d Omacor (a highly purified formulation of the ethyl esters
of n-3 FAs: specific levels of EPA/DHA not specified).</p>
<p>Compliance:</p>
<p>Not reported</p></td>
<td><p>59 subjects total (33 males and 26 females)</p>
<p>39 subjects (22 males and 17 females) with hypertriglyceridemia
(serum triglycerides <u>&gt;</u>500 mg/dl but <u>&lt;</u>2000 mg/dl)</p>
<p>20 subjects (11 males and 9 females) with normolipidemic levels</p>
<p>(LDL levels &lt;160 mg/dl and fasting triglyceride &lt;150 mg/dl</p>
<p>Three groups:</p>
<p>1) Placebo hypertriglyceridemia control group (n = 20)</p>
<p>2) Omacor hypertriglyceridemia tx. group</p>
<p>( n = 19)</p>
<p>3) Normolipidemic control group</p>
<p>(n = 20)</p>
<p>AHA Step I Diet maintained during 6-week treatment period.</p>
<p>Two subjects (of 41) were not included in the analysis for the
following reasons: 1 subject in the Omacor group was not available for
the follow-up period and one subject in the placebo group did not have
specimen available for assessment of sCAMs.</p></td>
<td><p><u>TG:</u> ↓ 26% in the Omacor group after 6 weeks vs. 4% ↑ in
the placebo (p=0.03). After &gt; 6 months on Omacor (n = 27) TG levels ↓
47%.</p>
<p><u>TC:</u> ↓ 11% in the Omacor group after 6 weeks vs. 1% in the
placebo (p = 0.09). After &gt; 6 months on Omacor (n = 27) TC levels ↓
21%.</p>
<p><u>HDL:</u> ↑ 14% in the Omacor group (22 mg/dl) after 6 weeks vs. ↓
6% in the placebo (20 mg/dl) (p = 0.03).</p>
<p><u>Soluble E-selectin (sE-selectin):</u> The levels were
significantly ↑ in the Omacor group after 6 weeks (+11%) vs. placebo
group (-2%) (p = 0.01). Long-term administration of Omacor (&gt; 6
months; n = 27) led to a significant ↓ in levels of sE-selectin (16%;
p&lt;0.0001). In both univariate and multivariate analyses, the larger ↓
in sE-selectin were associated with NIDDM (NIDDM; p = 0.004). The % ↓ in
sE-selectin was 32% in pts with NIDDM and 12% in pts without NIDDM.</p>
<p><u>Soluble intercellular adhesion molecule-1 (sICAM-1):</u> Remained
unchanged and similar in the Omacor and placebo group. Long-term
administration of Omacor (&gt; 6 months; n = 27) led to a significant ↓
in levels of sICAM-1 (9%; p = 0.02).</p>
<p><u>Soluble vascular cell adhesion molecule-1 (sVCAM-1)</u>: Remained
unchanged and similar in the Omacor and placebo group.</p>
<p>Percent changes in sCAMs were not associated with % changes in TG, TC
or HDL.</p>
<p>Additional data on effects of recombinant soluble vascular cell
adhesion (rsVCAM-1) on THP-1 (a human acute monocytic leukemia-derived
cell line) and peripheral blood monocyte adhesion to human umbilical
vein endothelial cells (HUVEC) stimulated with IL-1 for 24 hours under
flow conditions are not reported here.</p></td>
<td><p><u>Conclusions</u>:</p>
<p>The authors concluded that, “the levels of sE-selectin, sICAM-1 and
sVCAM-1 in the serum of patients with hypertriglyceridemia were
increased, and multivariate analysis showed that this increase was
independent of other risk factors (TG, TC, HDL). These results support
previous <em>in vitro</em> data suggesting that disorders of TG and HDL
metabolism may promote atherogenisis through effects on CAMs and that tx
of dyslipidemia with fish oil may alter vascular cell activation."</p>
<p>Comments:</p>
<p>It was not specified that this was a blinded study design.</p></td>
<td>1</td>
<td>Not reported</td>
</tr>
<tr class="even">
<td><p>Adler and Holub 1997</p>
<p><em>Am J Clin Nutr</em> 1997;65:445-50</p>
<p>[Canada]</p></td>
<td>To examine if garlic powder in combination with fish oil will be
effective in reducing elevated TC, LDL and TG concentration in
hypercholesterolemic men.</td>
<td>Randomized, single-blind, placebo-controlled, trial.</td>
<td><p>12 weeks</p>
<p>3 weeks run-in period before 12 week treatment period.</p></td>
<td><p>3.6 g/d of EPA+DHA (Nupulse, fish oil capsules)</p>
<p>2.160 g/d EPA, 1.440 g/d DHA.</p>
<p>Four groups:</p>
<ol type="1">
<li><p>Fish oil + garlic placebo</p></li>
<li><p>garlic + fish oil placebo</p></li>
<li><p>fish oil + garlic</p></li>
<li><p>garlic placebo + fish oil placebo</p></li>
</ol>
<p>Compliance: serum phospholipid fatty acid analyses, capsule
count.</p></td>
<td><p>46 hypercholesterolemic men.</p>
<p>Fish oil: 10 subjects</p>
<p>Garlic: 12 subjects</p>
<p>Fish oil + garlic: 13 subjects</p>
<p>Placebo: 11</p>
<p>The inclusion criteria was total cholesterol &gt; 200 mg/dl.</p></td>
<td><p><u>TG:</u> ↓ significantly (-37.3%) with fish oil treatment and
with garlic + fish oil.</p>
<p><u>TC:</u> ↓ significantly in the fish oil + garlic group (-12.2%)
and garlic group (-11.5%) but not in the fish oil group.</p>
<p><u>LDL:</u> ↑ significantly (+8.5%) in the fish oil group by 3 weeks
and persisted until 12 weeks.</p>
<p><u>HDL:</u> ↑ significantly from baseline levels in both fish oil
groups but no differences between the four groups.</p>
<p><u>TC/HDL and LDL/HDL ratio:</u> ↓ significantly in garlic and garlic
+ fish oil group but not in fish oil group.</p>
<p>No changes in lipid parameters in the placebo group compared to
baseline levels.</p>
<p>A significant ↓ in mean systolic, diastolic and arterial pressure was
observed in all 3 groups relative to the placebo group.</p>
<p>The ratio of EPA to AA ↑ significantly (p&lt;0.001) in the fish oil
group.</p></td>
<td><p><u>Conclusion:</u></p>
<p>Fish oil supplementation significantly decreased TG concentrations
and increased LDL concentrations whereas garlic supplementation
significantly decreased both TC and LDL in hypercholesterolemic men.
Garlic + fish oil reversed the moderate fish oil-induced rise in LDL.
Coadministration of garlic with fish oil had a beneficial effect on
serum lipid and lipoprotein concentrations.</p>
<p>Comments:</p>
<p>3-day diet records were collected before and during supplementation
to assess dietary intakes.</p></td>
<td>1</td>
<td>One subject (10%) reported a slight feeling of nausea with fish oil
supplement. No other effects except for occasional belching were
reported with the fish oil or the oil placebo treatment.</td>
</tr>
<tr class="odd">
<td><p>Agren et al. 1996</p>
<p><em>Eur J Clin Nutr</em> 1996;50(11):765-771</p>
<p>[Finland]</p></td>
<td>To determine if moderate amounts of n-3 FAs in different forms
affect fasting and postprandial lipid and lipoprotein
concentrations.</td>
<td>Randomized, single-blind, controlled trial.</td>
<td>15 weeks</td>
<td><p>2.28 g/d of EPA+DHA (Bio-marine fish oil capsules) (fish oil
group)</p>
<p>1.33 g/d EPA</p>
<p>0.95 g/d DHA</p>
<p>Fish diet group: 4.3 fish containing meals per week (1.05
EPA+DHA/d)</p>
<p>DHA oil group: 1.68 g/d DHA (from algae)</p>
<p>Control group</p>
<p>Compliance: phospholipid fatty acid analyses</p></td>
<td><p>55 healthy male subjects were recruited from the university
student population.</p>
<p>Fish diet: 13 subjects</p>
<p>Fish oil: 14 subjects</p>
<p>DHA oil: 14 subjects</p>
<p>Control: 14 subjects.</p>
<p>The study was carried out in the Departments of Physiology and
Clinical Nutrition of University of Kuopio.</p>
<p>The number of subjects for the fat load test were different for the
fish diet (n=12), control (n=12) and DHA-oil (n=13) groups.</p></td>
<td><p><u>TG:</u> ↓ significantly (p&lt;0.05) in plasma in all groups
compared to the control group, but most of the decrease was in the VLDL
TG.</p>
<p><u>TC:</u> No change</p>
<p><u>HDL:</u> HDL<sub>2</sub>/HDL<sub>3</sub> cholesterol ratio ↑ (50%,
p&lt;0.05) in all 3 treatment groups when compared to the control group.
The total HDL was significantly different in the fish diet (p&lt;0.01)
group compared to the control group.</p>
<p><u>apo B:</u> ↓ significantly (p&lt;0.05) in the fish oil group when
compared to the control in the VLDL.</p>
<p>The postprandial total plasma and chylomicron TG, measured as area
under the response curve ↓ significantly in the fish diet and fish oil
groups.</p>
<p>HDL concentrations ↓ slightly after a test meal and then ↑ slightly
(above baseline) but significantly in all groups after 8 hrs with the
exception of the fish oil group.</p>
<p>Plasma phospholipid EPA and DHA concentration ↑ significantly in all
groups when compared to the control group.</p>
<p>Changes in lipid profile of VLDL and other fractions, and specific
changes in plasma concentrations of EPA and DHA with the treatments are
detailed in the paper.</p></td>
<td><p><u>Conclusion:</u></p>
<p>The results suggest that moderate intake of n-3 FAs from fish diet,
fish oil or DHA oil lowers both fasting and postprandial TG
concentrations.</p>
<p><u>Comments:</u></p>
<p>Diet records were collected prior to the beginning of the study.</p>
<p>Unequal number of subjects in each group.</p>
<p>University students population.</p></td>
<td>1</td>
<td>1 (1.8%) subject did not consume fish oil capsules due to abdominal
complaint not related to supplementation. Subjects did not report any
difficulties with taking the capsules.</td>
</tr>
<tr class="even">
<td><p>Agren et al. 1997</p>
<p><em>Prostaglandins, Leukotrienes and Essen. Fatty Acids</em> 1997. 57
(4/5):419-421</p>
<p>[Finland]</p></td>
<td>To investigate the effects of increased n-3 fatty acid intake in the
form of fish, fish oil or EPA-free DHA-oil on several hemostatic factors
and platelet aggregation</td>
<td><p>Randomized,</p>
<p>parallel</p>
<p>controlled</p></td>
<td>15 weeks</td>
<td><p>2.28 g/day DHA + EPA</p>
<p>(1.3 g/day EPA and 0.95 g/day DHA from 4 g/day fish oil
(Bio-Marin))</p>
<p>1.05 g/day EPA+DHA</p>
<p>(0.38 g/day EPA and 0.67 g/day DHA from fish</p>
<p>diet - 4.3 meals/ wk)</p>
<p>1.68 g/day DHA (from 4 g/day DHA oil (Martek))</p>
<p>Control: not reported if control group received placebo or no
supplementation/food</p>
<p>Compliance: not reported</p></td>
<td>55 healthy male subjects</td>
<td><p><u>Factor X</u>: ↓ in fish diet group vs. baseline (p&lt;0.05);
no significant changes in any other group.</p>
<p><u>Collagen-induced platelet aggregation</u>: ↓ in fish diet and fish
oil groups vs. baseline (p&lt;0.05); tendency for ↑ in DHA oil group
(NS) that was inversely correlated with change in fasting triglyceride
levels.</p>
<p><u>Prothrombin time</u>: NS change</p>
<p><u>Activated partial thromboplastin time</u>: NS change</p>
<p><u>Fibrinogen</u>: NS change</p>
<p><u>Factor VII</u>: NS change</p>
<p><u>Prothrombin fragment 1+2</u>: NS change</p>
<p><u>Tissue factor pathway inhibitor</u>: NS change</p>
<p><u>ADP-induced platelet aggregation</u>: NS change</p></td>
<td><p><u>Conclusions:</u></p>
<p>“Results show that moderate amounts of n-3 fatty acids in the form of
fish diet or fish oil inhibit platelet aggregation but do not affect
hemostatic factors and that EPA-free DHA oil is not effective in
decreasing <em>in vitro</em> platelet aggregability.”</p>
<p><u>Comments</u>:</p>
<p>Dietary intake not evaluated.</p></td>
<td>2</td>
<td>Not reported.</td>
</tr>
<tr class="odd">
<td><p>Almdahl et al. 1993</p>
<p><em>Scand J Thor Cardiovasc</em> 1993;27:81-86</p>
<p>[Norway]</p></td>
<td>To explore the possibility of monocyte and platelet trapping during
reperfusion after cold cardioplegic arrest and to determine if
pretreatment with n-3 FAs would modify these behavior.</td>
<td>Randomized, double-blind, placebo-controlled trial.</td>
<td>6 weeks</td>
<td><p>5.04 g/d EPA + DHA as ethyl esters (3.15 g/d EPA, 1.89 g/ DHA;
K-85 capsules) (n-3 group)</p>
<p>placebo: corn oil</p>
<p>Compliance:</p>
<p>Serum FA analysis.</p></td>
<td><p>18 patients with angina pectoris and accepted for coronary artery
bypass surgery were recruited. Both groups were on antiangina medication
and the patients were asked to discontinue antiplatelet medication prior
to operation. The subjects were administered with n-3 FAs or placebo
prior to operation.</p>
<p>n-3 group: n=9</p>
<p>placebo: n=9</p>
<p>Blood samples were collected from coronary sinus and aorta at 5, 10
and 30 minutes after the release of aortic cross-clamp.</p></td>
<td><p><u>TG:</u> ↓ (20%) with n-3 FAs compared to placebo.</p>
<p>Monocyte count: At 5 and 10 minutes monocyte count was lower in both
groups in the coronary sinus than in the aortic blood, but the
difference was NS.</p>
<p><u>Platelet count:</u> NS change in platelet count at 5, 10 and 30
minutes in both groups.</p>
<p><u>Mean platelet volume:</u> NS change in at 5, 10 and 30 minutes in
both groups.</p>
<p><u>Monocyte thromboplastin activity:</u> The activity <em>in
vivo</em> was slightly lower (NS) in blood samples from coronary sinus
compared to aortic samples, and the difference between the groups was
NS. In the <em>in vitro</em> LPS-stimulated monocytes the activity was
consistently lower in the coronary sinus samples compared to the aorta
at 5, 10 and 0 minutes (p&lt;0.05). NS difference between the groups. No
correlation was observed between the arteriovenous monocyte
thromboplastin gradient and the duration of cardioplegic ischemia.</p>
<p>Serum EPA ↑ (3 fold) with n-3 FAs compared to placebo.</p></td>
<td><p><u>Conclusions:</u></p>
<p>The authors suggest that, “the monocytes most sensitive to activation
may be trapped in the coronary circulation during reperfusion of the
human heart after cold cardioplegic ischemia. No beneficial effects on
monocyte or platelet behavior were found after preoperative treatment
with an ethyl ester compound of n-3 FAs”.</p>
<p><u><br />
Comments:</u></p>
<p>Diets were not assessed.</p></td>
<td>1</td>
<td>Not reported</td>
</tr>
<tr class="even">
<td><p>Andreassen et al. 1997</p>
<h2 id="jacc-19972961324-31">JACC 1997;29(6):1324-31</h2>
<p>[Norway]</p></td>
<td>To determine if prophylactic administration of n-3 FAs will prevent
hypertension in cyclosporine-treated heart transplant recipients.</td>
<td>Randomized, double-blind, placebo-controlled trial.</td>
<td>24 weeks (6 months)</td>
<td><p>3.4 g/d EPA + DHA as ethyl esters (Omacor, 1.86 g/d EPA, 1.5 g/d
DHA, 4 g/d fish oil) (fish oil group)</p>
<p>Placebo: 4 g/d corn oil</p>
<p>Compliance:</p>
<p>Capsule count, serum phospholipid FA analysis.</p></td>
<td><p>28 consecutive orthotopic heart transplant recipients were
recruited. The treatment was started 4 days after the operation and all
patients were on triple immunosuppressive regimen (cyclosporine,
azathioprine and prednisolone).</p>
<p>Fish oil group: n=14</p>
<p>Placebo: n=14</p>
<p>Two subject of the 30 (1 in each group) died due to vascular
rejection.</p></td>
<td><p><u>TG:</u> ↓ significantly with fish oil (124 ± 27 mg/dl)
compared to baseline (181 ± 29 mg/dl, p&lt;0.05) and placebo (197 ± 31
mg/dl). TG ↑ in the placebo group compared to baseline (183 ± 11
mg/dl).<u><br />
TC:</u> Significant ↑ with fish oil (baseline 193 ± 15, 6 months 247 ±
16 mg/dl, p&lt;0.01) and placebo (baseline 208 ± 19, 6 months 290 ± 16
mg/dl, p&lt;0.01).<u><br />
HDL:</u> Significant ↑ with fish oil (baseline 30 ± 3, 6 months 52 ± 5
mg/dl, p&lt;0.01) and placebo (baseline 32 ± 4, 6 months 52 ± 4 mg/dl,
p&lt;0.01).</p>
<p><u>DBP:</u> NS ↑with fish oil (10 ± 3 mm Hg) compared to baseline. A
significant and consistent ↑ in the placebo group (21 ± 2 mm Hg)
compared to baseline. Significant difference between the groups
(p&lt;0.01).</p>
<p><u>SBP:</u> A slight ↓ with fish oil (2 ± 4 mm Hg) compared to
baseline. A significant and consistent ↑ in the placebo group (17 ± 4 mm
Hg) compared to baseline. Significant difference between the groups
(p&lt;0.01).</p>
<p><u>Arterial pressure:</u> Greater and persistent ↑ in the placebo
group after 6 months compared to fish oil treatment (p&lt;0.05).</p>
<p><u>Reactive hypermia:</u> Prior to the operation no difference
between the groups was found in the levels of skin rest perfusion, peak
reactive hyperemia, recovery time from the hyperemic response and the
perfusion debt repayment area. After the operation peak hyperemic levels
improved significantly in both groups.</p>
<p>The recovery time for hyperemic perfusion to return to preocclusive
levels ↑ slightly in the fish oil group but ↓ significantly in the
placebo group. The hyperemic perfusion was significantly higher in the
fish oil group (3310 ± 52 arbitrary units) compared to the placebo group
(1867 ± 350 arbitrary units) (p&lt;0.05).</p>
<p>Serum phospholipid EPA (p&lt;0.01) and DHA (p&lt;0.01) ↑
significantly compared to the baseline, and EPA levels were higher
compared to placebo (p&lt;0.05).</p></td>
<td><p>Conclusions:</p>
<p>The authors concluded that, “postoperative daily administration of 4
g of n-3 FAs in heart transplant recipients is effective as hypertension
prophylaxis, depending on increase in serum EPA and DHA acids.
Preservation of microvascular endothelial function, demonstrated by a
more pronounced response to forearm skin ischemia in the treatment
group, may contribute to the hypotensive role of n-3 FAs”.</p>
<p><u>Comments:</u></p>
<p>Diets were not assessed but the subjects were asked to avoid
cod-liver oil.</p></td>
<td>1</td>
<td><p>The fish oil capsules were well tolerated except for mild
abdominal discomfort.</p>
<p>One (7%) patient in the fish oil group and three (21%) in the placebo
group had minor strokes.</p></td>
</tr>
<tr class="odd">
<td><p>Arteaga et al. 1993</p>
<p><em>Rev. Med Chile</em> 1993;<em>121:618-625</em> (ABSTRACT,
foreign)</p>
<p>[Chile]</p></td>
<td>To examine effects of different doses of n-3 on serum lipids and
lipoproteins in dislipidemic patients with coronary artery disease.</td>
<td>Parallel groups</td>
<td>8 weeks</td>
<td><p>6 g/d n-3, Group 1</p>
<p>4 g/d n-3, Group 2</p>
<p>2 g/d n-3, Group 3</p>
<p>(Ratio EPA:DHA not given)</p>
<p>Control: none</p>
<p>Compliance:</p>
<p>not reported in abstract.</p></td>
<td><p>21 total</p>
<p>7 per group</p></td>
<td><p><u>TC:</u> ↓ w/ 4 &amp; 6 g/d n-3, but NS w/ 2 g/d n-3.</p>
<p><u>LDL:</u> ↑ w/ 6 g/d n-3, but NS w/ 2 g/d n-3.</p>
<p><u>VLDL cholesterol:</u> ↓ w/ 6 g/d n-3, ↑ w/ 4 g/d n-3, but NS w/ 2
g/d n-3.</p>
<p><u>VLDL TG:</u> ↓ w/ 4&amp;6 g/d n-3, but NS w/2 g/d n-3.</p>
<p><u>HDL:</u> ↑ w/ 4 g/d n-3, but NS w/ 2 g/d n-3.</p></td>
<td><p><u>Conclusions:</u></p>
<p>n-3 FAs are ineffective as the only treatment for dislipidemias
refractory to diet.</p>
<p><u>Comments:</u></p>
<p>Summarized from abstract.</p>
<p>Small sample size</p></td>
<td>2</td>
<td>Adverse effects &amp; tolerance not reported in abstract.</td>
</tr>
<tr class="even">
<td><p>Axelrod et al. 1994</p>
<p><em>Diabetes Care</em> 1994;17(1):37-44</p>
<p>[U.S.]</p></td>
<td>To study the effects of a low dose of n-3 FAs on platelet function
and other cardiovascular risk factors in patients with NIDDM.</td>
<td><p>Randomized,</p>
<p>double-blind,</p>
<p>controlled trial.</p></td>
<td><p>6 weeks</p>
<p>6 week washout</p></td>
<td><p>2.5 g/d EPA+DHA</p>
<p>1.5g/d EPA</p>
<p>1 g/d DHA</p>
<p>(SuperEPA capsules)</p>
<p>Control:</p>
<p>Safflower oil</p>
<p>Compliance: interviews mid-study</p></td>
<td><p>18 patients</p>
<p>w/NIDDM</p>
<p>and meeting HbA<sub>1C</sub> and hemoglobin criteria.</p>
<p>9 test</p>
<p>9 control</p>
<p>2 dropouts</p>
<p>Male:female ratio not given.</p></td>
<td><p><u>TG:</u> ↓ (43 mg/dl, p=0.077) after 6 weeks with fish oil
compared to safflower</p>
<p><u>TC:</u> ↑ (p=0.030) with fish oil compared to safflower at 6
weeks.</p>
<p><u>LDL:</u> NS vs. safflower</p>
<p><u>HDL:</u> NS vs. safflower</p>
<p><u>Fasting glucose:</u> NS vs. safflower</p>
<p><u>HbA<sub>1C</sub>:</u> ↑ with fish oil (4 weeks 0.56%, p=0.009; 6
weeks 0.72%,p=0.006) compared to safflower. At the end of washout period
the differences were not significant between the groups.</p>
<p><u>SBP:</u> ↓ in upright (p=0.092) vs. safflower, NS supine.</p>
<p><u>DBP:</u> NS upright &amp; supine</p>
<p><u>Collagen-induced platelet aggregation:</u> ↓ dose/response curve
vs. safflower (p=0.035) and vs. baseline (p=0.022).</p>
<p><u>ADP-induced platelet aggregation:</u> NS</p>
<p><u>TXB<sub>2</sub> platelet generation:</u> NS</p>
<p><u>TXB<sub>2</sub> serum concentration:</u> NS</p>
<p>↑ EPA (p&lt;0.020),↑ DHA (p&lt;0.041) &amp; ↑ DPA (p&lt;0.00075) vs.
baseline. Other FAs NS vs. baseline.</p></td>
<td><p><u>Conclusion:</u></p>
<p>Beneficial effect demonstrated on collagen-induced platelet
aggregation and generation of TXA<sub>2</sub> (measured as stable
derivative of TXB<sub>2</sub>), plasma TG levels, and upright SBP in
NIDDM patients who were in moderate metabolic control.</p>
<p><u>Comments:</u></p>
<p>Small sample size.</p>
<p>Dietary history and intake evaluated. Control group consumed higher
amount of protein compared to fish oil group (p=0.05).</p></td>
<td>2</td>
<td>"No subject experienced gastrointestinal or other side effects in
either group."</td>
</tr>
<tr class="odd">
<td><p>Badalamenti et al. 1997</p>
<p><em>Hepatology</em> 1997. 25:313-316.</p>
<p>[Spain]</p></td>
<td>To investigate the effects of a 1-month dietary supplementation with
fish oil on renal function and vasoactive compounds in cirrhotic
patients</td>
<td>Non-randomized, parallel, controlled</td>
<td>4 weeks</td>
<td><p>6 g/day EPA + DHA</p>
<p>(3.24 g/day EPA (27%), 2.76 g/day DHA (23%)) from 12 g/day fish
oil</p>
<p>All subjects received fish oil supplementation.</p>
<p>Compliance: plasma fatty acid chromatography</p></td>
<td><p>23 subjects</p>
<p>17 cirrhosis patients with ascites (10 male/7 female). Nine cirrhotic
patients with normal renal function. Eight cirrhotic patients with renal
failure</p>
<p>6 healthy subjects (sex- and age-matched) served as
controls.</p></td>
<td><p><u>Bleeding time</u>: slight NS ↑ in cirrhotic patients with
normal renal function (819 seconds to 983 seconds (+20%), NS) and
patient with renal failure (633 seconds to 777 seconds (+22.7%), NS)
after fish oil supplementation. ↑ reached significance when patients
were considered collectively (from 744 seconds to 872 seconds (+17.2%,
p=0.0068)</p>
<p>In all groups, plasma levels of EPA and DHA ↑ after 1 month of
supplementation. There was no significant difference between cirrhosis
patients and controls.</p></td>
<td><p><u>Conclusions</u>:</p>
<p>Authors concluded that, “the undesired effect of prolonged bleeding
time (as well as a reduction in arterial pressure) observed in the study
argue against the use of fish oil in doses of 6 g/d in cirrhotic
patients with ascites and renal failure.”</p>
<p><u>Comments</u>:</p>
<p>Intake of EPA+DHA higher than 3 g/day.</p>
<p>Study not randomized.</p>
<p>Small study population.</p>
<p>Bleeding time for the healthy control subjects not reported.</p>
<p>Diets not assessed.</p></td>
<td>2</td>
<td>A significant reduction in mean arterial pressure was observed in
both groups of renal patients.</td>
</tr>
<tr class="even">
<td><p>Bagdade et al. 1996</p>
<p><em>Diabetologia</em> 1996;39:487-491</p>
<p>[U.S]</p></td>
<td>To determine if fish oil supplementation can normalize cholesteryl
ester transfer (CET) and lipoprotein composition in IDDM patients.</td>
<td>Uncontrolled clinical study</td>
<td>8 weeks (2 months)</td>
<td><p>4.6 g/d of EPA and DHA as methyl esters (3.6 g/d of EPA and 1 g/d
of DHA) (4.6 g/d of fish oil, Super-EPA)</p>
<p>Compliance:</p>
<p>Capsule count</p></td>
<td><p>9 IDDM subjects (6 females and 3 males) were recruited. Both IDDM
and normal subjects were treated with fish oil.</p>
<p>Fish oil: n=9</p>
<p>Normal subjects</p></td>
<td><p><u>TG:</u> NS ↓ (p&lt;0.1) with fish oil treatment (baseline 1.10
± 0.77 mmol/l, fish oil 0.86 ± 0.46 mmol/l).</p>
<p><u>TC:</u> No change with fish oil.</p>
<p><u>Fasting glucose:</u> NS change in plasma glucose levels after fish
oil treatment (baseline 7.66 ± 5.22 mmol/l, fish oil 9.49 ± 5.44
mmol/l).</p>
<p><u>Plasma fructosamine:</u> NS change in plasma glucose levels after
fish oil treatment.</p>
<p><u>apo E:</u> No change with fish oil.</p>
<p>No change in mean daily insulin dose.</p>
<p>Prior to fish oil treatment the CET from HDL to VLDL+LDL was
significantly higher in the IDDM patients compared to the normal
subjects. After 2 months of fish oil supplementation the cholesteryl
ester net mass transfer ↓ significantly in fish oil group (p&lt;0.01),
the transfer also ↓ in the normal subjects and the responses were
indistinguishable between the groups. Cholesterol ester transfer protein
mass ↑ significantly (p&lt;0.05) in the fish oil group (baseline 2.04
μg/ml, fish oil 2.48 μg/ml).</p></td>
<td><p>Conclusions:</p>
<p>The authors suggest that, “the capacity of marine lipids to reverse
the accelerated CET without altering glycemic control suggests that
these agents may have an adjunctive role to play in the nutritional
therapy of IDDM”.</p>
<p><u>Comments:</u></p>
<p>Diets were not assessed but the subjects were asked to follow the
standard American Diabetes Association diet and to continue glucose
monitoring at home.</p>
<p>Small sample size.</p>
<p>The sample size for normal subjects is not provided.</p>
<p>Not controlled trial.</p></td>
<td>2</td>
<td>Fish oil was well tolerated by all subjects.</td>
</tr>
<tr class="odd">
<td><p>Bairati et al. 1992</p>
<p><em>Can J Cardiol</em> 1992;8(1):41-46.</p>
<p>[Quebec, Canada]</p></td>
<td>To evaluate the effects of a fish oil concentrate on BP and serum
lipids in patients with coronary artery disease who had BP controlled by
antihypertensive drugs.</td>
<td><p>Randomized, double-blind</p>
<p>placebo-controlled trial.</p></td>
<td><p>30 weeks</p>
<p>(3 weeks prior to PTCA and 6 mo. after)</p></td>
<td><p>4.5 g/d EPA+DHA</p>
<p>2.7 g EPA</p>
<p>1.8 g DHA</p>
<p>(15 g/d MaxEPA - 5 capsules taken 3X/d)</p>
<p>Control:</p>
<p>Olive oil</p>
<p>Compliance:</p>
<p>Counting capsules</p></td>
<td><p>125 patients</p>
<p>referred to the Quebec heart Institute for a PTCA</p>
<p>66 test</p>
<p>59 control</p>
<p>80% male each group</p>
<p>80 dropouts</p></td>
<td><p><u>TG:</u> ↓ (p&lt;0.0001) vs. control</p>
<p><u>TC:</u> NS</p>
<p><u>LDL:</u> ↑ (p&lt;0.05)</p>
<p><u>HDL:</u> ↑ (p&lt;0.05)</p>
<p><u>SBP and heart rate:</u> Less ↑ in FO group than control
(P&lt;0.002 for BP, p&lt;0.01 for hr.)</p>
<p><u>DBP:</u> NS</p></td>
<td><p><u>Conclusions:</u></p>
<p>This study "documented the beneficial effects of fish oil on BP and
TG levels in patients treated for coronary artery disease. Fish oil
appears to have no effect on TC and only marginal independent influence
on HDL &amp; LDL"</p>
<p><u>Comments:</u></p>
<p>High drop-out rate.</p>
<p>Concurrent use of medications (beta-blockers, channel blockers,
others)</p>
<p>Dietary intake not assessed.</p>
<p>Exclusion criteria not given.</p></td>
<td>1</td>
<td>Mild side effects reported by both groups (NS between groups)</td>
</tr>
<tr class="even">
<td><p>Baker and Najadah 1996</p>
<p><em>Sports Med Training and Rehab</em> 1996;6:287-297</p>
<p>[Kuwait]</p></td>
<td>To determine the effects of fish oil supplements alone, exercise
alone or fish oil and exercise combined on serum cholesterol levels and
cholesterol fractions in pre and postmenopausal women.</td>
<td>Randomized, controlled trial</td>
<td>12 weeks</td>
<td><p>0.285 g/d of EPA+DHA</p>
<p>(Maxepa, 171 mg/d EPA and 114 mg/d DHA)</p>
<p>(Fish oil group)</p>
<p>Exercise group</p>
<p>Exercise + fish oil group</p>
<p>Control group (daily lifestyle)</p>
<p>Compliance: Not measured</p></td>
<td><p>70 women selected from a larger voluntary cohort.</p>
<p>The subjects did not have CHD and were sedentary.</p>
<p>Premenopausal group: 35 women</p>
<p>Postmenopausal group: 35 women</p>
<p>The pre and postmenopausal women were divided into 4 groups</p>
<p>Exercise group: 20 women (pre + postmenopausal)</p>
<p>Exercise + fish oil group: 20 women (pre + postmenopausal)</p>
<p>Fish oil group: 20 women (pre + postmenopausal)</p>
<p>Control group: 10 women (pre + postmenopausal)</p></td>
<td><p><u>TG:</u> No change in any groups throughout the study.</p>
<p><u>TC:</u> ↓ significantly (p≤0.05) in pre -menopausal women in fish
oil only and fish oil + exercise groups, but significant ↓ observed only
in fish oil + exercise group in postmenopausal women. NS ↓ in
postmenopausal fish oil only group.</p>
<p><u>LDL:</u> ↓ in all groups: pre and postmenopausal in both fish oil
only and fish oil + exercise groups.</p>
<p><u>HDL:</u> No change observed by 12 weeks in fish oil only and fish
oil + exercise pre and postmenopausal groups. Interim ↓ observed at 4
and 8 weeks in these 4 groups, but became non-significant by 12
weeks.</p>
<p><u>Body fat:</u> No change in any groups throughout the
study.</p></td>
<td><p>Conclusion: The authors concluded that, “only a modest change in
serum lipids was observed, and that the differences from the control
group were inconclusive. They stated that the evidence is insufficient
to recommend that women ingest fish oil supplements to reduce risk of
CHD”.</p>
<p>Comments:</p>
<p>Diets were not assessed.</p>
<p>Premenopausal women had higher baseline body mass compared to the
postmenopausal women. NS difference between the baseline body mass and
post test body mass for any groups.</p></td>
<td>3</td>
<td>Not reported</td>
</tr>
<tr class="odd">
<td><p>Balestrieri et al. 1996</p>
<p><em>Recenti Progressi in Medicina</em> 1996;87(3):102-105</p>
<p>[Italy]</p></td>
<td>To evaluate the effect of fish oil ethyl ester on lipid and
lipoprotein serum concentrations in individuals with familial
hypercholesterolemia</td>
<td>Randomized, double-blind, controlled, cross over.</td>
<td><p>4 weeks of each treatment</p>
<p>separated by a 4 week washout</p></td>
<td><p>5.1 g/d of EPA+DHA (Esapent fish oil capsules, 6g fish oil)</p>
<p>2.55 g/d EPA</p>
<p>2.55 g/d DHA</p>
<p>6 g/d of olive oil in control group</p>
<p>Compliance:</p>
<p>Not reported</p></td>
<td><p>14 patients with familial hypercholesterolemia (FH). Three had
established CHD. All maintained Step 1 AHA diet and treatment with
simvastatin throughout the trial.</p>
<p>Fish Oil : 7 subjects</p>
<p>Olive Oil: 7 subjects</p>
<p>Two subjects (1 from each group) did not complete the study due to
acute health problems</p></td>
<td><p><u>TG</u>: no significant variation with fish oil (97 ± 25 vs. 90
± 26 mg/dl) compared to baseline.</p>
<p><u>TC</u>: no significant variation (298 ± 41 vs. 300 ± 49 mg/dl)
compared to baseline.</p>
<p><u>HDL</u>: no significant variation (51 ± 16 vs. 53 ± 21 mg/dl)
compared to baseline.</p>
<p><u>LDL</u>: no significant variation (228 ± 46 vs. 228 ± 50 mg/dl)
compared to baseline.</p>
<p><u>apo AI</u>: no significant variation (116 ± 47 vs. 127 ± 47 mg/dl)
compared to baseline.</p>
<p><u>apo B</u>: no significant variation (205 ± 44 vs. 204 ± 42 mg/dl)
compared to baseline.</p>
<p><u>Lp(a)</u>: no significant variations compared to
baseline.</p></td>
<td><p><u>Conclusions</u>:</p>
<p>N3 marine oil at the dosage of 5.1 g/day did not influence lipid and
lipoprotein concentrations in FH patients on chronic simvastatin
treatment.</p></td>
<td>1</td>
<td>One (7%) patient complained of an aftertaste during the study</td>
</tr>
<tr class="even">
<td><p>Bao et al. 1998</p>
<h2 id="hypertension">Hypertension</h2>
<p>1998;32:710-17</p>
<p>[Australia]</p></td>
<td>To examine the effects of dietary fish and weight reduction on
ambulatory blood pressure in overweight hypertensives</td>
<td>Randomized, control factorial design</td>
<td><p>16 weeks</p>
<p>4 week familiarization period for baseline measurements</p></td>
<td><p>3.65 g/d n-3 FAs (approximate level, given as a fish meal).</p>
<p>Four groups:</p>
<p>Control</p>
<p>Fish diet</p>
<p>Weight loss</p>
<p>Fish diet + weight loss</p>
<p>Compliance:</p>
<p>Diet records and plasma phospholipid FA composition</p></td>
<td><p>63 overweight nonsmoking men and postmenopausal women, aged 40-70
years taking antihypertensive medication for at least 3 months</p>
<p>Control: 16 subjects</p>
<p>Fish diet: 17 subjects</p>
<p>Weight loss: 16 subjects</p>
<p>Fish diet + weight loss: 14 subjects</p>
<p>12 weeks after the start of dietary treatment, all subjects were put
on a weight-stabilizing diet for 4 weeks and continued on fish if they
were in those groups.</p>
<p>6 subjects of the 69 recruited withdrew because they were unable to
maintain the schedule of laboratory visits.</p></td>
<td><p><u>BP:</u> Significant additive effects of dietary fish and of
weight reduction on awake BP. Awake SBP ↓ with fish oil (-6.8 ± 2.6 mm
Hg, p=0.006) and weight loss (-6.2 ± 2.6 mm Hg, p=0.012) compared to
baseline. Awake DBP ↓ with fish oil (-5.1 ± 1.7 mm Hg, p=0.001) and
weight loss (-4.2 ± 1.7 mm Hg, p=0.003) compared to baseline. Mean awake
SBP/DBP ↓ in fish group (6.0 ± 2.2/3.0 ± 1.4 mm Hg), ↓ in weight loss
group (5.5 ± 2.9/2.2 <u>+</u> 1.3 mm Hg) and ↓ in the fish +
weight-reduction group (13.0 ± 2.4/9.3 ± 1.4 mm Hg) after adjustment for
age, baseline weight and baseline value. Significant main effect of fish
on 24-hour DBP (-3.2 ± 1.5 mm Hg, p=0.011) but not on SBP. Neither fish
nor weight reduction independently affected asleep BP.</p>
<p><u>Heart rate:</u> Significant ↓ in 24-hour heart rate with dietary
fish (-3.1 ± 1.4 bpm, p=0.036) and awake ambulatory heart rates (-4.2 ±
1.6 bpm, p=0.013) compared to baseline. Weight reduction had a
significant effects in asleep heart rate only (-3.2 ± 1,7 bpm, p=0.037).
No significant interactions between weight loss and fish diets on
ambulatory heart rate.</p>
<p><u>Weight loss:</u> Energy-restricted diets (Groups 3 + 4) had
significant weight loss (5.6<u>+</u> 0.8 kg, p&lt;0.0001). There was no
weight loss in the groups (1 + 2) who continued their usual energy
intake.</p>
<p>Total n-3 FAs was measured in plasma phospholipids, but the data were
not reported.</p>
<p>Blood and urinary ion measurements not reported in this
summary.</p></td>
<td><p><u>Conclusions:</u></p>
<p>The authors concluded that, “ the incorporation of a daily meal of
fish rich in n-3 FAs into a reduced-fat, energy-restricted diet in obese
treated hypertensive subjects resulted in additive effects in reducing
ambulatory BP, as well as beneficial effects on heart rate.”</p>
<p><u>Comments:</u></p>
<p>Subjects kept diet records, with food being weighed or measured.
Dietary intake was monitored by the same dietician throughout the study,
with completion of a 3-day diet records/month (2 weekdays and 1 weekend
day).</p></td>
<td>1</td>
<td>Not reported</td>
</tr>
<tr class="odd">
<td><p>Barbir et al. 1992</p>
<p><em>Am J Cardiol</em> 1992;70:1596-1601</p>
<p>[UK]</p></td>
<td>To determine and compare the efficacy and safety of Maxepa and
bezafibrate in cardiac transplant patients.</td>
<td>Randomized, open trial.</td>
<td>12 weeks (3 months) on fish oil</td>
<td><p>10 g/d fish oil (Maxepa)</p>
<p>400 mg bezafibrate</p>
<p>Compliance:</p>
<p>Not reported</p></td>
<td><p>87 cardiac transplant recipients with hyperlipidemia were
recruited. Most patients were on immunosuppression drugs.</p>
<p>Fish oil group: n=44</p>
<p>Bezafibrate group: n=43</p>
<p>Two subjects in the fish oil group withdrew because of nausea and one
subject in the bezafibrate group withdrew because of adverse effects of
the drug.</p></td>
<td><p><u>TG:</u> ↓ with fish oil (36%) and bezafibrate (31%) at 1
month. The changes were maintained at 2 and 3 months.<u><br />
TC:</u> NS effect of fish oil, ↓ with bezafibrate. The changes were
maintained at 2 and 3 months.<u><br />
LDL:</u> NS effect of fish oil, ↓ with bezafibrate. The changes were
maintained at 2 and 3 months.<u><br />
HDL:</u> NS effect of fish oil, ↑ with bezafibrate. The changes were
maintained at 2 and 3 months.<u><br />
apo A1:</u> NS effect of fish oil, ↑ with bezafibrate. The changes were
maintained at 2 and 3 months.<u><br />
apo B:</u> NS effect of fish oil, ↓ with bezafibrate. The changes were
maintained at 2 and 3 months.</p>
<p><u>Lp (a):</u> ↑ with fish oil (23%) and with bezafibrate (18%). The
changes were maintained at 2 and 3 months.<u><br />
Fibrinogen:</u> ↑ with fish oil, but ↓ with bezafibrate.</p>
<p>Factor II: ↓ with fish oil, but ↑ with bezafibrate.</p>
<p><u>Factor IX:</u> ↑ with fish oil and bezafibrate.</p>
<p><u>Factor X:</u> ↓ with fish oil and bezafibrate.</p>
<p>Bezafibrate treatment significantly increased factor VIIc, VIIIc, and
decreased tissue plasminogen activator activity but had no significant
effect on fibrinolysis.</p>
<p>The adjusted group mean was calculated for all hemostatic variables
after adjusting for the effect of the baseline levels. All these
recipients had prothrombotic changes before the treatment.</p></td>
<td><p>Conclusions:</p>
<p>The authors conclude that, ‘bezafibrate has better lipid-,
apoprotein- and hemostatic modifying properties than does Maxepa, but
its potentially adverse effect on renal function needs further
investigation”.</p>
<p><u>Comments:</u></p>
<p>Diets not assessed</p>
<p>No control group</p></td>
<td>1</td>
<td><p>Fish oil group:</p>
<p>One patient (2.3%) died of congestive heart failure and 13 (29.5%)
patients reported adverse events. Adverse events reported (in decreasing
frequency) were dizziness, gastric intolerance, skin irritation,
tonsillitis and fatigue. Most events (n=9, 20.5%) were considered
moderately severe and possibly related to fish oil (n=6, 13.6%). Two
subjects withdrew because of nausea. Therapeutic cyclosporin blood
levels decreased NS with fish oil.</p>
<p>Bezafibrate group:</p>
<p>15 subjects (34.9%) reported adverse events such as nausea, leg
cramps, headaches, tonsillitis and precipitation of gouty arthritis. One
patient (2.3%) had acute rejection episode. Most events were considered
as moderate (n=8 18.2%) and were possibly related to the drug. One
subject withdrew because of adverse effects of the drug. Mean serum
creatinine levels increased with bezafibrate. Therapeutic cyclosporin
blood levels decreased NS, and alkaline phosphatase levels decreased
significantly with bezafibrate.</p></td>
</tr>
<tr class="even">
<td><p>Barstad et al. 1995</p>
<p><em>Blood Coagulation and Fibrinolysis</em> 1995;6:374-381</p>
<p>[Norway]</p></td>
<td>To examine the effect of 2.4 g/d n-3 on acute collagen-induced
thrombus formation in flowing non-anticoagulated blood in healthy
men.</td>
<td><p>Open study</p>
<p>(Not randomized, not blinded, not controlled)</p></td>
<td>12 weeks</td>
<td><p>2.4 g/d n-3 FAs (Triomar capsules containing 60% n-3, 30% EPA,
20% DHA)</p>
<p>Control: none</p>
<p>Compliance: method not reported.</p></td>
<td>15 healthy males</td>
<td><p><u>TG:</u> ↓ NS (P&lt;0.1)</p>
<p><u>TC:</u> ↓ NS (P&lt;0.08)</p>
<p><u>LDL:</u> NS</p>
<p><u>HDL:</u> NS</p>
<p><u>Plasma fibrinogen:</u> ↓ vs. baseline (P&lt;0.0006).</p>
<p><u>Serum FAs:</u> ↑ EPA (P,0.0001), ↑ DHA (P&lt;0.0001)</p>
<p><u>Plasma FPA &amp; Beta TG:</u> NS</p>
<p>Surface coverage with platelets on collagen (%) not affected.
Subsequent platelet aggregate formation not affected. Deposition of
fibrin (%) at apex of the stenosis ↓ vs. baseline (P&lt;0.03). Fibrin
deposition at 650 &amp; 2600s-1 not affected.</p></td>
<td><p><u>Conclusions:</u></p>
<p>The n-3 supplementation in this study did not sufficiently alter
platelet function and/or hemorheological factors to protect against
acute collagen-induced platelet thrombus formation.</p>
<p><u>Comments</u>:</p>
<p>Not randomized, blinded, or controlled.</p>
<p>Dietary habits not evaluated.</p></td>
<td>3</td>
<td>No adverse effects of the supplement were reported.</td>
</tr>
<tr class="odd">
<td><p>Beilin et al. 1993</p>
<p><em>J Hypertension</em> 1993;11(suppl 5):S318-319</p>
<p>[Australia]</p></td>
<td>To determine the influence of dietary fat intake on BP, heart rate
and serum lipid response to n-3 fats from fish or purified fish
oils.</td>
<td>Randomized, placebo-controlled trial.</td>
<td>12 weeks</td>
<td><p>3.2 – 4.1 g/d of n-3 FAs from fish.</p>
<p>1.3 g/d EPA approximate amount from fish oil or fish</p>
<p>Placebo contained olive, palm and safflower oils.</p>
<p>7 treatments were assigned</p>
<p>Group 1: 40% fat diet + placebo</p>
<p>Group 2: 40% fat diet + fatty fish (1 fish meal) + placebo</p>
<p>Group 3: 40% fat diet + 6 fish oil capsules (1 g each)</p>
<p>Group 4: 40% fat diet + fatty fish (1 fish meal) + 6 fish oil
capsules</p>
<p>Group 5: 40% fat diet + 12 fish oil capsules</p>
<p>Group 6: 30% fat diet alone + placebo</p>
<p>Group 7: 30% fat diet + fatty fish (1 fish meal) + placebo</p>
<p>Compliance: diet records, platelet phospholipid fatty acid
analyses.</p></td>
<td>138 healthy nonsmoking males were recruited. The entry criteria were
BMI of &lt;33 kg/m<sup>3</sup>, SBP 130-159 mm Hg, DBP 80-90 mm Hg,
serum TC of 5.2-6.9 mmol/l.</td>
<td><p><u>TC:</u> Significant group effects (p&lt;0.001). ↑ with
addition of fish (5%) or fish oil (8%) to the high fat diet. Fish plus
fish oil ↑ TC by 2%. The 30% fat diet alone ↓ TC (5%) and this was
maintained by the addition of fish to the diet.</p>
<p><u>TG:</u> Significant group effects (p&lt;0.001). ↓ with addition of
fish (group 2, 20%) or fish oil (group 3, 14%) to the high fat diet.
Fish + fish oil ↓ TG by 43% (group 4). The addition of fish to 30% fat
diet reduced TG (group 7, 23%).</p>
<p><u>HDL:</u> Significant group effects (p&lt;0.001). HDL and
HDL<sub>2</sub> ↑ with fish and fish oil and were comparable between
groups. HDL ↑ in groups 2-5 by 6-9%. The HDL<sub>2</sub> ↑ in these
groups by 30-36%. The 30% fat diet alone ↓ HDL by approximately 6%.
Addition of fish to 30% fat diet increased HDL<sub>2</sub> by 15%.</p>
<p>LDL: Significant group effects (p&lt;0.001). LDL ↑ by 8-12% with fish
or fish oil consumption. The 30% fat diet alone ↓ LDL by 10%. The fall
in LDL with addition of fish to the 30% fat diet was attenuated
(3%).</p>
<p>HR: The supine heart rate fell (p&lt;0.01) in fish and fish oil
groups and increased in control groups (1 and 6). A significant
independent relationship was observed between the increase in n-3 FAs
and fall in HR (r<sup>2</sup>=0.0513, p=0.014).</p>
<p>BP: No significant group effect on changes in the supine BP. The
average decrease was greater in the 40% fat, fish or fish oil groups
compared to the control and the two 30% fat groups. The increase in n-3
and the decrease in n-6 FAs in platelet phospholipid, independently
influenced supine SBP (p=0.015) and DBP (p=0.0061) after adjusting for
weight and urinary variables.</p>
<p>Platelet phospholipid n-3 FAs ↑ significantly (p&lt;0.001) and n-6
FAs ↓ significantly (p&lt;0.001) with fish and fish oil supplementation
in groups 2-5 and 7.</p></td>
<td><p>Conclusion:</p>
<p>The results suggest that, “a low-salt diet, reduced in total fat, and
including at least one substantial fish meal a day, may favorably affect
lipid profiles and BP”.</p>
<p>Comments:</p>
<p>Combined fish meal and purified fish oil treatment.</p>
<p>The subjects were on a low-sodium diet (&lt;90 mmol/d)</p></td>
<td>1</td>
<td></td>
</tr>
<tr class="even">
<td><p>Berrettini et al. 1996</p>
<p><em>Thrombosis &amp; Haemostasis</em> 1996;75(3):395-400</p>
<p>[Italy]</p></td>
<td>To examine the effect of 3g/d n-3 on plasma lipids and hemostatic
factors in patients with chronic atherosclerotic diseases.</td>
<td><p>Randomized</p>
<p>double-blind, controlled trial.</p></td>
<td>16 weeks</td>
<td><p>3 g/d EPA+DHA ethyl esters</p>
<p>EPA:DHA = 1.46</p>
<p>(Seacor capsules)</p>
<p>Control: corn oil</p></td>
<td><p>39 w/ chronic vascular atherosclerotic diseases.</p>
<p>Test: 20</p>
<p>Control: 19</p>
<p>1 dropout placebo group</p>
<p>Compliance: capsule count</p></td>
<td><p><u>TG:</u> ↓ with time effect (P=0.003) beginning with a
significant difference after the 2<sup>nd</sup> week (P=0.0009)</p>
<p><u>TC:</u> NS</p>
<p><u>LDL:</u> ↑ (P=0.0089), time effect (P=0.0014)</p>
<p><u>HDL:</u> ↑ with time effect (P=0.0001), time to treatment
interaction (P=0.0002), linear trend over time (P=0.18x10-6)</p>
<p>Hemostatic assays:</p>
<p><u>Factor VII clotting activity:</u> NS</p>
<p><u>TFPI activity:</u> ↑ with time effect (P=0.029), time to treatment
interaction (P=0.003), linear trend over time (P=0.0001).</p>
<p><u>Plasma F1+2:</u> ↓, treatment effect (P=0.016), linear trend over
time (P=0.07) with ↓ after 16 weeks NS (p=0.06)</p></td>
<td><p><u>Conclusions:</u></p>
<p>Some beneficial effects of n-3 supplementation on both hyperlipidemia
and hypercoagulability of patients with atherosclerotic vascular disease
were observed.</p>
<p><u>Comments:</u></p>
<p>Patients asked to maintain normal diet and physical activity. Dietary
influence otherwise not analyzed/reported.</p>
<p>Actual data not reported (graphs only)</p>
<p>2 subjects had diabetes in test group vs. 3 in control group. 10
subjects had hypertension in test group vs. 9 in control group.</p>
<p>At baseline, TC and F1+2 plasma levels were higher in test group vs.
control group (P&lt;0.05).</p></td>
<td>2</td>
<td>3 of 20 patients in the active treatment groups reported occasional
fish after taste. No other side-effects were observed.</td>
</tr>
<tr class="odd">
<td><p>Blok et al. 1997</p>
<h2 id="eur-j-clin-invest-1997271003-1008">Eur J Clin Invest
1997;27:1003-1008</h2>
<p>[Netherlands]</p></td>
<td>To determine the effects of fish oil on cytokine levels.</td>
<td><p>Randomized, single-blind, placebo controlled trial.</p>
<p>Multicenter</p></td>
<td><p>52 weeks (1 year) on fish oil</p>
<p>2-week baseline period</p>
<p>6 month follow-up period</p></td>
<td><p>2.92 g/d EPA + DHA (2.43 g/d EPA, 0.49 g/d DHA from 9 g of fish
oil as methyl esters) (9 g fish oil group)</p>
<p>1.95 g/d EPA + DHA from 6 g of fish oil (6 g fish oil group)</p>
<p>0.97 g/d EPA + DHA from 3 g of fish oil (3 g fish oil group)</p>
<p>Placebo</p>
<p>Compliance:</p>
<p>Capsule count, fatty acid analysis</p></td>
<td><p>58 healthy monks (10 vegetarians) (ages 21-87 years) were
recruited form one Trappist and three Benedictine monasteries. The
subjects were not on medications that would influence lipid metabolism
or non-steroidal anti-inflammatory drugs.</p>
<p>9 g fish oil group: n=14</p>
<p>6 g fish oil group: n=15</p>
<p>3 g fish oil group: n=15</p>
<p>Placebo: n=14</p></td>
<td><p><u>Circulating cytokines:</u> The levels of cytokines were
determined only in the placebo and 9 g fish oil group. The
concentrations of all cytokines were low.</p>
<p>IL-1β: The concentration was above the detection limit. No
significant difference between the two treatment groups at any time
point, either in absolute concentrations or changes relative to
baseline.</p>
<p><u>IL-6:</u> The concentration was below the detection limit.</p>
<p>TNF-α: The concentration was above the detection limit. No
significant difference between the two treatment groups at any time
point, either in absolute concentrations or changes relative to
baseline.</p>
<p>IL-1Ra: The concentration was above the detection limit. No
significant difference between the two treatment groups at any time
point, either in absolute concentrations or changes relative to
baseline.</p>
<p><u><em>Ex vivo</em> production of cytokines after whole blood
stimulation:</u></p>
<p><u>IL-1β:</u> Endotoxin-stimulated secretion was significantly ↑
during fish oil supplementation compared to the follow-up period. No
significant differences in the <em>ex vivo</em> production of IL-1β
between the four groups at any time point.</p>
<p><u>TNF-α:</u> Endotoxin-stimulated secretion was significantly ↑ with
fish oil supplementation. Although differences over time were not
statistically significant. No significant differences in the <em>ex
vivo</em> production of TNF-α between the four groups at any time
point.</p>
<p><u>IL-1Ra:</u> Endotoxin-stimulated secretion was significantly
higher during fish oil supplementation compared to the follow-up period.
No significant differences in the <em>ex vivo</em> production of IL-1Ra
between the four groups at any time point.</p>
<p>Baseline circulating cytokine levels were not different between
vegetarians and non-vegetarians. Cytokine production capacity was not
different between the vegetarians and non-vegetarians at the end of the
follow-up period.</p>
<p>EPA levels in erythrocyte lipids ↑ with fish oil
supplementation.</p></td>
<td><p>Conclusions:</p>
<p>The results suggest that, “long-term supplementation with fish oil
does not affect <em>ex vivo</em> cytokine production in man”.</p>
<p>Comments:</p>
<p>The subjects completed 3-day diet record during the study and they
were interviewed by dietician to assess dietary intake.</p>
<p>No data provided only graphs.</p></td>
<td>1</td>
<td>Not reported</td>
</tr>
<tr class="even">
<td><p>Boberg et al. 1992</p>
<p><em>Eur J Clin Nutr</em> 1992;22:645-650</p>
<p>[Sweden]</p></td>
<td>To determine the effects of n-3 FAs on serum lipids, glucose
homeostasis in patients with NIDDM.</td>
<td>Randomized, double-blinded, placebo controlled, crossover
trial.</td>
<td><p>8 weeks on each treatment.</p>
<p>The subjects were initially randomized to either the olive oil or
fish oil group for 8 weeks and then the treatments were switched for 8
weeks.</p>
<p>No washout period.</p></td>
<td><p>3 g/d of EPA + DHA (1.8 g/d of EPA and 1.2 g/d DHA) (2 capsules
of MaxEPA/d) (fish oil group)</p>
<p>Olive oil (placebo group)</p>
<p>Compliance:</p>
<p>Capsule counts and FAs analyses in plasma and platelets</p></td>
<td>14 NIDDM subjects (12 men and 2 women) receiving dietary treatment
for at least one year were recruited. Most of the subjects were on
hypoglycemic drugs and some patients were receiving hypertension
treatment.</td>
<td><p>TG: ↓ significantly (27%, p&lt;0.01) with fish oil treatment
compared to the baseline.</p>
<p><u>TC:</u> No change with fish oil.</p>
<p><u>LDL:</u> There was an ↑ in LDL (6%, p=0.05) with fish oil and a ↓
in LDL (7%, NS) with olive oil when compared to the baseline levels. The
changes during the fish oil and oil olive periods were significantly
different (p&lt;0.001).<u><br />
HDL:</u> NS ↑ (8%) with fish oil.</p>
<p><u>VLDL:</u> VLDL TG ↓ significantly (36%, p&lt;0.05) with fish oil
treatment compared to the baseline. The changes with fish oil treatment
were significantly different from the changes observed with the placebo
(p&lt;0.01).<u><br />
LDL/HDL:</u> No change in the ratio with fish oil treatment but ↓ by 10%
during the placebo period.</p>
<p><u>apolipoprotein B:</u> No change with fish oil treatment but ↓ by
7% with olive oil. The changes during the two treatment periods were
significantly different (p=0.01).</p>
<p><u>apolipoprotein A1:</u> ↓ by 6% with fish oil treatment and ↑ by 3%
with olive oil. The changes during the two treatment periods were
significantly different (p&lt;0.05).</p>
<p><u>Fasting glucose:</u> ↑ with fish oil (16%) and placebo (13%)
treatment and the changes during the treatments were NS. Fasting blood
glucose and glucose levels after iv glucose injection ↑ with MaxEPA and
intermediate with placebo.</p>
<p><u>Fasting insulin:</u> No change after the two treatment periods.
Insulin levels after an iv glucose similar to baseline value after
MaxEPA or placebo treatment.</p>
<p><u>Plasma C-peptide:</u> No change after the two treatment
periods.</p>
<p><u>Glycated hemoglobin:</u> ↑ significantly (9%, p=0.01) with MaxEPA
while the levels remained unchanged in the placebo group, when the
comparison was restricted to the first treatment period.</p>
<p>Fibrinogen: No changes with MaxEPA.</p>
<p>Factor VIIc: No changes with MaxEPA.</p>
<p><u>PAI-1:</u> PAI-1 concentrations ↑ significantly by 21% with MaxEPA
treatment, but no change was observed with placebo. The changes during
the two treatment groups were significantly different (p&lt;0.01). The
PAI-1 activity also increased with MaxEPA treatment.</p>
<p><u><br />
</u>Peripheral insulin sensitivity and the fractional removal rate at
the iv glucose tolerance test, measured by using euglycemic clamp
technique was same for MaxEPA and placebo.</p>
<p>No changes in insulin levels were observed despite the changes in
blood glucose with MaxEPA.</p>
<p>A significant ↑ in EPA and DHA concentrations in plasma lipid esters
and platelet phospholipids was observed with MaxEPA treatment.</p>
<p>No changes in free FAs concentrations with MaxEPA.</p></td>
<td><p>Conclusions:</p>
<p>The authors suggest that, “in spite of the reduction of the TG
concentrations and unchanged insulin levels, there was a significant
increase of the activity of PAI-1 after MaxEPA suggesting a possible
impairment of the fibrinolytic capacity”.</p>
<p>Comments:</p>
<p>Diets were not assessed but the subjects were asked to continue their
routine diet and avoid any major changes in physical activity.</p>
<p>No washout period.</p></td>
<td>1</td>
<td>The side-effects were mild and transient not related to n-3 FAs
intake.</td>
</tr>
<tr class="odd">
<td><p>Bonaa et al. 1992</p>
<p><em>Arteriosclerosis and Thrombosis</em> 1992;12:675-681</p>
<p>[Norway]</p></td>
<td>To determine the changes in serum lipids, lipoprotein, and
apolipoprotein levels with EPA + DHA and examine the relation between
the changes in serum lipid or lipoprotein concentrations and plasma
phospholipid fatty acid levels to assess the possible separate effects
of EPA and DHA.</td>
<td>Randomized, double-blind, controlled trial.</td>
<td><p>10 weeks</p>
<p>6 months observation period prior to treatment.</p></td>
<td><p>5.1 g/d EPA+DHA</p>
<p>as ethyl esters</p>
<p>3.3 g/d EPA</p>
<p>1.8 g/d DHA</p>
<p>6 g/d of fish oil (K85) (fish oil group)</p>
<p>6 g/d corn oil (corn oil group)</p>
<p>Compliance:</p>
<p>Capsule counts, plasma phospholipid FAs analyses and unannounced
dietary 24-hour dietary recall.</p></td>
<td><p>156 healthy men and women recruited from a population health
survey.</p>
<p>Fish oil group: 72 subjects</p>
<p>Corn oil group: 74 subjects</p>
<p>The subjects were considered healthy based on medical history and
other clinical and laboratory examinations.</p></td>
<td><p><u>TG:</u> ↓ significantly by 21% in fish oil group when compared
to baseline (p&lt;0.001) and the corn oil group ((p&lt;0.01). A
significant inverse association (p&lt;0.035) between increase in EPA
levels and decrease in TG was observed in the fish oil group. No
association was observed with DHA.</p>
<p>HDL: ↑ significantly in both fish oil (p&lt;0.05) and corn oil group
(p&lt;0.01) compared to the baseline levels. Significant positive
correlation (p&lt;0.001) between EPA levels and HDL in fish oil group.
Inverse correlation (p&lt;0.05) between DHA and HDL.<br />
apo A-1: No change with fish oil. ↑ significantly with corn oil
(p&lt;0.01). Significant positive correlation (p&lt;0.01) between EPA
levels and apo A-1 in fish oil group. Inverse correlation (p&lt;0.001)
between DHA and apo A-1. The differences in apo A-1 levels between the
two groups were removed when the difference in the plasma phospholipid
DHA levels between the groups was controlled.<br />
apo B: Changes in EPA or DHA were not associated with changes in apo
B.</p>
<p><u>LDL:</u> Changes in EPA or DHA were not associated with changes in
LDL.</p>
<p>Plasma phospholipid EPA (p&lt;0.001) and DHA (p&lt;0.001) levels ↑
significantly in fish oil group compared to the corn oil group.</p></td>
<td><p>Conclusion:</p>
<p>The study suggests that “EPA and DHA are divergently associated with
HDL, possibly through different mechanisms”.</p>
<p><u>Comments:</u></p>
<p>During the 6 months observation period the subjects were asked to
continue with their usual diets and living habits. During the study
diets were not assessed.</p>
<p>Dietary carbohydrate was significantly higher in the corn oil group
compared to the fish oil group.</p>
<p>Body weights increased in both groups significantly compared to the
baseline but no differences between the groups.</p></td>
<td>1</td>
<td>13.9 and 9.5% of subjects in the fish oil and corn oil groups
reported mild or moderate abdominal discomfort and did not consume the
prescribed number of capsules.</td>
</tr>
<tr class="even">
<td><p>Bonnema et al. 1995</p>
<p><em>Diab Nutr Metab</em> 1995;8:81-87</p>
<p>[Denmark]</p></td>
<td>To compare the effects of fish oil and olive oil on small vessel
compliance in diabetic patients with incipient vascular
complications.</td>
<td>Randomized, double-blind parallel trial.</td>
<td>24 weeks (6 months)</td>
<td><p>2.331 g/d EPA + DHA (1.407 g/d of EPA and 0.924 g/d of DHA, 6
Pikasol<sup>®</sup> capsules per day) (fish oil group)</p>
<p>Olive oil group</p>
<p>Compliance:</p>
<p>Capsule count</p></td>
<td><p>27 type I and type II diabetic patients (15 men, 13 women)
(insulin treated) without hypertension or hyperlipidemia were
recruited.</p>
<p>Fish oil group: n=14</p>
<p>Olive oil group: n=13</p>
<p>One subject (of 14) in the olive oil group dropped out because of
dyspeptic discomfort.</p></td>
<td><p><u>TG:</u> NS change with fish oil compared to the baseline or
olive oil.<u><br />
TC:</u> NS change with fish oil compared to the baseline or olive
oil.<u><br />
HDL:</u> NS change with fish oil compared to the baseline or olive
oil.<u><br />
Fasting glucose:</u> ↑ significantly (p&lt;0.05) with fish oil (9.2 ±
4.1 mmol/l) compared to olive oil (8.6 ± 4.9 mmol/l).</p>
<p><u>Glycated hemoglobin:</u> NS ↓ in both groups.</p>
<p><u>P-fibrinogen:</u> NS change with fish oil compared to the baseline
or olive oil.</p>
<p><u>BP:</u> Unaffected by either treatment.</p>
<p><u>Heart rate:</u> Unaffected by either treatment.</p>
<p><u>Arterial compliance:</u> ↓ with fish oil compared to the baseline.
A significant ↑ (p&lt;0.05) with olive oil compared to baseline. The
difference between the groups was significant (p&lt;0.01).</p>
<p><u>Venous compliance:</u> NS change in both groups.</p>
<p><u>Vascular resistance:</u> NS ↓ in both groups.</p>
<p>Serum creatinine, microalbuminuria, urine albumin and 24-hr urine
albumin did not change significantly with fish oil compared to olive
oil, or baseline. Urine albumin was higher in fish oil group but there
was no difference between the groups.</p></td>
<td><p>Conclusions:</p>
<p>The authors concluded that, “fish oil, in contrast to olive oil, has
an unfavorable effect on peripheral arterial compliance in patients with
diabetes as well as deteriorating their blood glucose control”.</p>
<p><u>Comments:</u></p>
<p>No control group</p>
<p>The patients received a diabetic diet during the study.</p></td>
<td>1</td>
<td><p>Patients did not complain of adverse effects except 1 patient
(7%) in the olive oil group withdrew because of dyspeptic
discomfort.</p>
<p>Two patients (14%) in the fish oil group had urinary albumin
excretion above the definition of microalbuminuria.</p></td>
</tr>
<tr class="odd">
<td><p>Borthwick 1998</p>
<p><em>Clin Drug Invest</em> 1998;15(5):397-404</p>
<p>[U.K.]</p></td>
<td>To investigate the effects and tolerability of an n-3 ethyl ester
concentrate on serum lipid concentrations in patients with
hyperlipidemia.</td>
<td><p>Randomized</p>
<p>Double-blind,</p>
<p>Placebo-controlled</p>
<p>Multi-center</p></td>
<td><p>12 weeks</p>
<p>(10 week run-in controlled diet, 12 weeks n-3)</p></td>
<td><p>3.4 g/d EPA+DHA</p>
<p>(4 1-g Omacor capsules @85% EPA+DHA)</p>
<p>Control: Corn oil</p>
<p>Compliance:</p>
<p>7 interview occasions</p></td>
<td><p>47 patients attending any of the participating study centers;
and</p>
<p>w/ hyperlipidemia</p>
<p>TG 2-10 mmol/L,</p>
<p>TC ≥5.2 mmol/L</p>
<p>Test 29</p>
<p>Control 26</p>
<p>@ 80% men both groups</p>
<p>55 patients randomized,</p>
<p>8 dropouts</p></td>
<td><p><u>TG:</u> ↓ vs. baseline (p=0.0001) &amp; vs. control
(p&lt;0.0001)</p>
<p><u>TC:</u> NS</p>
<p><u>HDL:</u> ↑ NS both groups</p>
<p><u>Serum Lipids:</u> ↑ EPA+DHA (p&lt;0.0001)</p></td>
<td><p><u>Conclusions:</u></p>
<p>4 g/d Omacor (3.4g EPA+DHA) produced a significant reduction in serum
TG in patients with hyperlipidemia.</p>
<p><u>Comments:</u></p>
<p>Therapeutic diet control 10 weeks preceding trial and during
trial.</p>
<p>LDL not analyzed.</p></td>
<td>2</td>
<td><p>Test substance "well tolerated throughout the treatment
period."</p>
<p>Effects reported by both groups include nausea, indigestion, and
diarrhea. Also influenza, sore throat, rash, chest infection and
headache.</p>
<p>5 severe adverse events (4 treatment vs. 1 control): 2 nausea,
angina, and backache, rash. 3 serious adverse events (angina) in 2
patients (1 each group).</p></td>
</tr>
<tr class="even">
<td><p>Brister and Buchanan 1997</p>
<p><em>Adv Exp Med Biol</em> 1997;433:275-278</p>
<p>[Canada]</p></td>
<td>To determine if linoleic acid supplementation before Coronary artery
bypass grafting (CABG) will increase vessel wall
13-hydroxyoctadecadienoic acid (13-HODE) synthesis, thereby decreasing
vessel wall adhesivity to platelets at the time of surgery.</td>
<td>Randomized, placebo-controlled trial.</td>
<td>4 weeks of treatment before CABG</td>
<td><p>3.2 g/d fish oil DHA (18% EPA, 12% DHA) (Marine fish oil (MFO)
group)</p>
<p>Evening primrose oil (EPO) group</p>
<p>EPO + MFO group</p>
<p>Placebo group</p>
<p>Compliance:</p>
<p>Not reported</p></td>
<td>60 patients undergoing elective CABG were recruited. Dietary
supplementation was discontinued following CABG.</td>
<td><p><u>Platelet aggregation:</u> No effect of treatments and no
differences between the treatment group.</p>
<p><u>Platelet adhesivity:</u> No effect of treatments and no
differences between the treatment group.</p>
<p><u>Platelet TxA<sub>2</sub> synthesis:</u> No differences among
groups.</p>
<p>12-hydroxyeicosatetraenoic acid (12-HETE) synthesis: No differences
among groups.</p>
<p><u>13-HODE:</u> The 13-HODE levels in internal mammary artery (IMA) ↑
in patients receiving EPO (1210 ± 343 ng/gm/cm<sup>2</sup>, p&lt;0.01),
but remained unchanged in patient receiving MFO (487 ± 139
ng/gm/cm<sup>2</sup>) or EPO + MFO (799 ± 149 ng/gm/cm<sup>2</sup>)
compared to the placebo group (640 ± 321 ng/gm/cm<sup>2</sup>). Similar
results were obtained for synthesis of 13-HODE in saphenous vein (SV)
but the levels were &gt; 3 fold less than in IMA (data for SV not
given).</p></td>
<td><p>Conclusions:</p>
<p>Dietary marine fish oil supplementation had no effect on platelet
aggregation and adhesivity, platelet TxA<sub>2</sub> synthesis, 12 HETE
and 13-HODE synthesis. No effect on 13-HODE synthesis may suggest that
MFO does not increase vessel wall thromboresistance.</p>
<p><u>Comments:</u></p>
<p>Diets not assessed</p>
<p>Data for all end points not reported.</p></td>
<td>2</td>
<td>Not reported</td>
</tr>
<tr class="odd">
<td><p>Cerbone et al. 1999</p>
<p><em>Thromb Haemost</em> 1999;82:128-133</p>
<p>[Italy]</p></td>
<td>To compare the effects of short-term supplementation of moderate
doses of n-3 FAs on platelet lipid composition and aggregation with the
effects of olive oil.</td>
<td>Open trial</td>
<td>4 weeks on n-3 FAs followed by 6 months of washout and then 4 weeks
on olive oil.</td>
<td><p>2.28 g/d of n-3 FAs (Esapent, 85% EPA + DHA)</p>
<p>3 g/d olive oil.</p>
<p>Compliance:</p>
<p>Platelet and plasma EPA and DHA analysis.</p></td>
<td>14 (10 men and 4 females) healthy normolipidemic subjects.</td>
<td><p><u>TG:</u> ↓ significantly (p&lt;0.02) with n-3 FAs (0.67 ± 0.25
g/l) compared to baseline (1.04 ± 0.58 g/l). No effect of olive oil.</p>
<p><u>ADP induced platelet aggregation:</u> The amount of ADP needed to
cause 50% aggregation increased after n-3 FA supplementation compared to
baseline and it persisted 1 to 2 months after supplementation.</p>
<p><u>Collagen induced platelet aggregation:</u> The amount of collagen
needed to cause 50% aggregation increased after n-3 FA supplementation
compared to baseline and it persisted 1 to 2 months after
supplementation.</p>
<p><u>pH of Na<sup>+</sup>/H<sup>+</sup> reverse transport:</u> The
impaired sensitivity to ADP (p=0.036) and to a lesser extent to collagen
(p=0.068) were related to the changes in the intracellular pH of the
Na<sup>+</sup>/H<sup>+</sup> reverse transport</p>
<p><u>TxB<sub>2</sub> synthesis:</u> ↓ by 40-60% (p&lt;0.05) at
withdrawal of n-3 FA supplementation. No correlation between
TxB<sub>2</sub> synthesis and platelet aggregation.</p>
<p><u>ATP secretion:</u> No effect of n-3 FA.</p>
<p><u>cAMP formation:</u> No effect of n-3 FA.</p>
<p><u>cytosolic [Ca<sup>+</sup>]:</u> No effect of n-3 FA.</p>
<p><u>thrombin induced fibrinogen:</u> No effect of n-3 FA.</p>
<p><u>vWF binding:</u> No effect of n-3 FA.</p>
<p><u>PgE<sub>1</sub> binding to platelets:</u> No effect of n-3 FA.</p>
<p>The above mentioned parameters remained unchanged with olive oil
treatment.</p>
<p>Platelet EPA (5-6 fold higher, p&lt;0.01) and DHA (2 fold higher,
p&lt;0.01) increased significantly with n-3 FAs and remained higher 30
and 90 days after terminating the supplementation. Plasma EPA increased
7-8 fold with n-3 FA compared to baseline and returned to baseline after
4 weeks of withdrawal. Plasma DHA increased 3-4 fold with n-3 FA
supplementation and remained elevated for 8 weeks following
withdrawal.</p></td>
<td><p><u>Conclusions:</u></p>
<p>The results suggests, “a long-lasting impairment of platelet
sensitivity to ADP and collagen; changes in the pH values of the
Na<sup>+</sup>/H<sup>+</sup> reverse transport and a simultaneous
persistent accumulation of EPA and DHA in platelet phospholipids, after
stopping a short-course dietary supplementation of moderate amounts of
n-3 FA ethyl esters”</p>
<p><u>Comments:</u></p>
<p>The subjects were asked to maintain their usual diet and refrain from
alcohol, salmon and kippers during the duration of the study.</p>
<p>Not a randomized, double-blind trial.</p></td>
<td></td>
<td><p>The supplementation was well tolerated and no adverse effects
were reported.</p>
<p>No effect on blood clotting function (PT, APTT, fibrinogen, and
platelet count) was observed. One subject (7%) experienced easy
bruising. No effect of olive oil on the above mentioned parameters was
observed.</p></td>
</tr>
<tr class="even">
<td><p>Chin and Dart</p>
<p>1994</p>
<p>Clin Exp Pharma Physiol</p>
<p>1994;21:749-55</p>
<p>[Australia]</p></td>
<td>To examine the therapeutic restoration of endothelial function in
hypercholesterolemic subjects by fish oils.</td>
<td>Randomized, patient-blind, placebo controlled study design.</td>
<td>4 weeks (28 days)</td>
<td><p>5.88 g/d EPA + DHA (3.56 g EPA and 2.32 g DHA, given as 20 g/d
maxEPA capsules, which is equivalent to approximately 340 g of mackerel
or 500 g salmon).</p>
<p>Placebo was a mixture of celestial, safflower and olive oils given in
capsules at 20 g/d. This mixture has previously been shown to have no
effect on forearm vascular reactivity.</p></td>
<td><p>23 subjects</p>
<p>7 normal TC controls (males, mean age 52.3 ± 3.3 years).</p>
<p>9 high-TC controls (7 males and 2 females, mean age 49.6 ± 4.2
years); 5 were previously untreated and 4 had tx (simvastin and/or
questran) withdrawn from a minimum of 4 weeks prior to study.</p>
<p>6 hypercholesterolemic subjects (6 males and 1 female; mean age 44.3
± 4.9 years) given fish oil. These subjects were either previously untx,
or their lipid-lowering therapy was withdrawn for a minimum of 4 weeks,
during which time they consumed mixed oil placebo capsules before
switching to fish oil capsules.</p>
<p>6 (4 males, 2 females) untreated subjects were treated with lipid
lowering drugs for 4 weeks.</p></td>
<td><p><u>TG:</u> No differences between the groups at baseline. Dietary
fish oil had no effect in hypercholesterolemic subjects.</p>
<p><u>TC</u>: Mean TC levels were higher (58.9%) at the time of the
study in hypercholesterolemic subjects compared to the control subjects.
Dietary fish oil had no effect on TC levels in hypercholesterolemic
subjects. ↓ significantly with lipid-lowering therapy.</p>
<p><u>LDL:</u> Mean LDL levels were higher (89%) at the time of the
study in hypercholesterolemic subjects compared to the control subjects.
Dietary fish oil (6.97 ± 0.73 mmol/l) had no effect on LDL levels in
hypercholesterolemic subjects compared to baseline (6.29 ± 0.38 mmol/l).
↓ significantly with lipid-lowering therapy.</p>
<p><u>HDL:</u> No differences between the groups at baseline. Dietary
fish oil had no effect in hypercholesterolemic subjects.</p>
<p><u>BP:</u> Mean BP was not different in the hypercholesterolemic and
control subjects at baseline. Fish oils or lipid-lowering therapy had no
effect on BP measurements of the hypercholesterolemic subjects.</p>
<p><u>Forearm blood flows:</u> No differences between the groups at
baseline. No effect of dietary fish oil (p = 0.55) or lipid-lowering
therapy. The dose-response curve to acetylcholine was significantly
blunted in subjects with high cholesterol (p&lt;0.001). The responses to
sodium nitroprusside were not different between the two groups (p =
0.37). Dietary fish oils significantly augmented the response to
acetylcholine (p = 0.011) but had no effects on responses to
nitroprusside (p = 0.94) in subjects with high cholesterol.</p></td>
<td><p>Conclusions:</p>
<p>The authors concluded that, “endothelium-dependent relaxation is
impaired in subjects with high cholesterol levels and that this
impairment can be reversed by ↓ LDL level. In addition, we demonstrate
that restoration of endothelial function can occur without changes in
LDL levels, by dietary supplementation with fish oils. [Thus], our major
new finding is that dietary supplementation with fish oils, in the
absence of any other form of therapy, augments acetylcholine responses
in hypercholesterolemic subjects. Furthermore, this restoration occurs
without any change in either TC or LDL.” It was also noted that dietary
fish oil did not affect levels of TC, LDL, HDL or TG in subjects with
high TC and LDL.</p>
<p><u>Comments:</u></p>
<p>Small sample size for each group.</p>
<p>Diets were not assessed.</p>
<p>No units for TC, LDL, TG and HDL were specified in the publications.
The units reported above (mmol/l) for these parameters were assumed to
be the correct units.</p></td>
<td>2</td>
<td>Not reported</td>
</tr>
<tr class="odd">
<td><p>Chin, et. al., 1993</p>
<p><em>Hypertension</em></p>
<p>1993; 21:22-28</p>
<p>[Australia]</p></td>
<td>To examine if marine oil induces changes in vascular reactivity that
may contribute to their cardioprotective effect</td>
<td>Randomized, single-blind, placebo-controlled study design</td>
<td>4 weeks</td>
<td><p>5.88 g/d EPA + DHA (20 g/d maxEPA capsules; 3.56 g/d EPA, 2.32
g/d DHA). Group 1</p>
<p>2.94 g/d EPA + DHA (10/d maxEPA capsules; 1.78 g/d EPA, 1.16 g/d
DHA). Group 2</p>
<p>1.47 g/d EPA + DHA (5 g/d maxEPA capsules: 0.90 g/d EPA + 0.58 g/d
DHA) Group 3</p>
<p>20 g/d mixed oil placebo capsules (formulated to contain
approximately equivalent concentrations of saturated FAs and monoenes to
the maxEPA capsules). The polyunsaturated/saturated ratio was similar
for both capsules, as was the caloric load. Group 4</p>
<p>Compliance:</p>
<p>Platelet membrane n-3 FA analysis.</p></td>
<td><p>29 healthy adult males (18-32 years old); BP &lt;140/&lt;90 mm
Hg, TC &lt;5.5mmol/l and TG &lt;2.0 mmol/l.</p>
<p>Group 1: n= 6</p>
<p>Group 2: n = 6</p>
<p>Group 3: n = 8</p>
<p>Group 4: n = 9</p></td>
<td><p><u>BP</u>: There were no effects on resting SBP or DBP,
irrespective of tx regimen. Also, neither norepinephrine (up to 100
ng/min, p&gt;0.05) nor angiotensin II (up to 32 ng/min) had any systemic
vasoconstrictor or reflex action (based on mean arterial pressure and
heart rate monitoring).</p>
<p><u>Basal forearm blood flow:</u> With the exception of 10 g/d maxEPA,
basal forearm blood flow measurements remained unchanged after fish oil
supplementation. Significant ↓ (p&lt;0.05) with 10 g/d maxEPA for 28
days.</p>
<p><u>Forearm vascular resistance:</u> ↑ significantly after 10 g/d
maxEPA (vs. after oil).</p>
<p><u>Forearm vascular reactivity:</u></p>
<p>Norepinephrine:</p>
<p>At 20 g/d maxEPA, responses to norepinephrine were significantly
attenuated, measured as area under the dose response curve (p&lt;0.05)
or analysis of the slopes of the dose response curves (p&lt;0.05). These
responses returned to pre-tx levels after 2 months’ discontinuation of
20 g/d maxEPA and were unaltered by mixed oil placebo. Responses to
norepinephrine were also attenuated after 10 and 5 g/d maxEPA (p values
not specified), although the effect at 10 g/d was difficult to interpret
due to the aforementioned ↓ basal forearm blood flow measurements noted
at 10 g/d maxEPA.</p>
<p>Angiotensin II:</p>
<p>Forearm vascular resistance in response to infusion with angiotensin
II were significantly suppressed in the 20 g/d maxEPA group
(p=&lt;0.05). These responses were also significantly suppressed by
maxEPA at the lower doses of 10 and 5 g/d (both ps&lt;0.05). Mixed oil
placebo had no effect.</p>
<p>Responses returned to normal levels with both norepinephrine and
angiotensin II after a 2-month washout period.</p>
<p>Platelet membrane EPA and DHA levels ↑ dose-dependently with maxEPA
supplementation compared to placebo supplementation. Combined EPA + DHA
levels↑ by approximately 103%, 230% and 372% in subjects on the 5, 10
and 20 g/d maxEPA regimen, respectively.</p></td>
<td><p>Conclusions:</p>
<p>The authors concluded that, “forearm vasoconstrictor responses to the
sympathetic nervous system neurotransmitter norepinephrine and the
renin-angiotensin system effector angiotensin II were markedly
attenuated after dietary supplementation with marine oils.”</p>
<p>Comments:</p>
<p>Diets were not assessed.</p>
<p>Small sample size for each group.</p></td>
<td>2</td>
<td>Not reported</td>
</tr>
<tr class="even">
<td><p>Christensen et al. 1995</p>
<p><em>Nutr Res</em> 1995;15(1):1-8</p>
<p>[Denmark]</p></td>
<td>To examine the effect of n-3 supplementation on ventricular
arrhythmias and plasma lipids and lipoproteins.</td>
<td><p>Randomized,</p>
<p>double-blind,</p>
<p>placebo-controlled trial.</p></td>
<td>16 weeks</td>
<td><p>4.3 g/d EPA+DHA</p>
<p>(Pikasol triglyceride capsules)</p>
<p>Control: corn oil</p>
<p>Compliance: Plasma FAs analysis</p></td>
<td><p>19 patients discharged from Aalborg Hospital Dept Cardiology with
diagnosis of ventricular tachyarrhythmia.</p>
<p>Test: 9</p>
<p>Control: 10</p></td>
<td><p><u>TG:</u> ↓ (P&lt;0.05)</p>
<p><u>TC:</u> NS test; ↓ control (P&lt;0.05)</p>
<p><u>LDL:</u> NS test; ↓ control (P&lt;0.05)</p>
<p><u>HDL:</u> NS</p>
<p><u>Ventricular Extrasystoles per 48h:</u> ↓ mean VE (NS)</p>
<p><u>Serum FAs:</u> ↑ EPA (P,0.05); ↓ AA (P&lt;0.05)</p></td>
<td><p><u>Conclusions:</u></p>
<p>A trend towards a reduction in VE was observed, but no significant
effects could be demonstrated, possibly due to small sample size.</p>
<p><u>Comments:</u></p>
<p>Small sample size. 65% mean VE reduction necessary to reach
statistical significance with sample size of present study.</p>
<p>EPA vs. DHA content not reported.</p></td>
<td>2</td>
<td>Adverse effects not reported.</td>
</tr>
<tr class="odd">
<td><p>Christensen et al. 1996</p>
<h2 id="bmj">BMJ</h2>
<p>1996;312:677-8</p>
<p>[Denmark]</p></td>
<td>To determine if n-3 fatty acids might reduce malignant ventricular
arrhythmias and sudden cardiac death.</td>
<td>Randomized, double-blind placebo controlled trial</td>
<td>12 weeks</td>
<td><p>4.3 g/d EPA+DHA (Pikasol fish oil capsules, 8 g total capsule
weight)</p>
<p>Placebo: olive oil</p>
<p>Compliance:</p>
<p>Platelet fatty acid profile</p></td>
<td><p>49 patients who had suffered MI and had a ventricular ejection
fraction below 0.4</p>
<p>fish oil group: 26 patients</p>
<p>Control group: 23 patients</p>
<p>6 subjects withdrew from the study for reasons unrelated to
treatment.</p></td>
<td><p><u>Heart rate variability:</u> significant increase compared to
baseline and control (p=0.04 and 0.01, respectively)</p>
<p>↑ in platelet EPA and DHA levels with fish oil supplementation
compared to placebo.</p></td>
<td><p>Conclusions:</p>
<p>The authors conclude that, “n-3 polyunsaturated fatty acids may
increase heart rate variability in survivors of MI” and thus may “have
an antiarrhythmic effect in humans, which could in part explain the
reduced mortality reported in post-MI patients”.</p>
<p>Comments:</p>
<p>Medication and diet were kept constant during the trial.</p></td>
<td>1</td>
<td>Not reported</td>
</tr>
<tr class="even">
<td><p>Christensen et al. 1998</p>
<p><em>Clinical Nephrology</em> 1998;49(2):102-106</p></td>
<td>The objective of the study was to determine 24-hour heart rate
variability (HRV) in patients with chronic renal failure (CRF), to
compare their HRV with HRV in patients with a previous myocardial
infarction, and to examine associations between HRV in patients with CRF
and the content of n-3 PUFA in granulocytes.</td>
<td>Randomized, double-blind, placebo controlled trial.</td>
<td>12 weeks</td>
<td><p>5.2 g/d n-3 PUFA (Pikasol<sup>®</sup>) (n-3 PUFA group)</p>
<p>Olive oil: placebo group</p>
<p>Compliance:</p>
<p>Granulocyte fatty acid analysis</p></td>
<td><p>17 subjects with CRF were enrolled.</p>
<p>n-3 PUFA group: n=11</p>
<p>Placebo group: n=6</p>
<p>52 post-MI patients with left ventricular dysfunction were used to
compare the HRV</p>
<p>Off the 29 subjects that were recruited 10 subjects withdrew due to
nausea and data for 2 subjects was not evaluated due to technical
difficulties</p></td>
<td><p><u>HRV:</u> The mean RR (=mean of all normal RR intervals during
the 24-hour recording) ↑ significantly (p&lt;0.05) with n-3 PUFA
treatment. Due to a small sample size in the placebo group, the two
groups were not compared. The two groups were pooled and divided based
on their SDNN (=standard deviation of all normal RR intervals) levels;
SDNN &lt; 86 ms and ≥ 86 ms. The n-3 PUFA levels in granulocytes were
significantly higher in the patients with highest SDNN values compared
to the lowest SDNN. A significant positive correlations were observed
between the EPA (r=0.70, p&lt;0.01), DHA (r=0.58, p&lt;0.05), and total
n-3 PUFA in granulocytes (r=0.71, p&lt;0.01) and SDNN in the 17
patients.</p>
<p>At baseline the mean SDNN and RR values were significantly lower in
the CRF patients compared to the patients with previous MI and left
ventricular dysfunction.</p>
<p>N-3 PUFA in granulocytes increased significantly with n-3 PUFA
supplementation.</p></td>
<td><p><u>Conclusions:</u></p>
<p>The authors concluded that, “HRV was decreased in CRF patients
indicating a cardiovascular autonomic dysfunction. The positive
correlation between the n-3 PUFA content in cell membranes and HRV
suggests that the effects of an increased intake of n-3 PUFA in CRF
patients should be further studied”.</p>
<p><u>Comments:</u></p>
<p>Cross-sectional study because the patients were divided based on
their SDNN levels and not by their treatment.</p>
<p>Diets were not assessed</p></td>
<td>2</td>
<td>4 (26.7%) and 6 (42.9) patients in the n-3 PUFA and placebo group,
respectively withdrew due to nausea. Two patients in the placebo group
had problems with Holter readings, hence the number of patients
evaluated were 6.</td>
</tr>
<tr class="odd">
<td><p>Christensen et al. 1999</p>
<p><em>AM J Clin Nutr</em> 1999;70:331-337</p>
<p>[Denmark]</p></td>
<td>To examine the correlation between FAs in blood cell membranes and
heart rate variability (HRV) in healthy subjects.</td>
<td>Randomized, double-blind, placebo-controlled trial.</td>
<td>12 weeks</td>
<td><p>5.9 g/d EPA+DHA as TG</p>
<p>3 g/d EPA</p>
<p>2.9 g/d DHA</p>
<p>6.6 g/d n-3 PUFAs (Pikasol) (high dose fish oil group)</p>
<p>1.7 g/d EPA+DHA as TG + placebo</p>
<p>0.9 g/d EPA</p>
<p>0.8 g/d DHA</p>
<p>2 g/d n-3 PUFAs (low dose fish oil group)</p>
<p>Olive oil (placebo)</p>
<p>Compliance: Not measured</p></td>
<td><p>60 healthy subjects were recruited from among the medical staff,
bank employees and students at institutions.</p>
<p>High dose fish oil group: 20 subjects</p>
<p>Low dose fish oil group: 20 subjects</p>
<p>Placebo: 20 subjects</p></td>
<td><p>TG: ↓ significantly (p&lt;0.05) after supplementation with 2 g/d
of n-3 PUFAs. ↓ significantly with 6.6 g/d of n-3 PUFAs when compared to
baseline levels (p&lt;0.01) and control group levels (p&lt;0.05).</p>
<p>No changes in other plasma lipids and lipoproteins with n-3
supplementation.</p>
<p>A dose dependent effect of n-3 PUFAs on HRV in men was observed but
not in women. At baseline a positive correlation between DHA content in
cell membranes and HRV was observed in men but not in women.</p>
<p>Effects of n-3 PUFAs on individual HRV indexes are discussed in
detail in the paper.</p>
<p>Significant increase in cellular concentrations of EPA and DHA with
largest increase in the high dose fish oil group.</p></td>
<td><p><u>Conclusion:</u></p>
<p>The authors conclude that, “the study showed a beneficial effect of
n-3 PUFAs on HRV in healthy men, suggesting an antiarrhythmic effect of
n-3 PUFAs. No such effect was observed in women”.</p></td>
<td>1</td>
<td>Dietary supplements were well tolerated and no subjects dropped out
of the study.</td>
</tr>
<tr class="even">
<td><p>Cirillo et al. 1994</p>
<p><em>World Rev. Nutr. Diet`.</em> 1994. 76:60-63.</p>
<p>[Italy]</p></td>
<td>To investigate possible antiplatelet mechanisms of n-3 fatty acids
independent of the synthesis of prostaglandins and thromboxane and
evaluate whether n-3 fatty acids could have a long-lasting platelet
inhibitory effect after a short-course of n-3 fatty acid
supplementation</td>
<td>Not controlled</td>
<td>4 weeks</td>
<td><p>5.1 g/day n-3 FA ethyl esters</p>
<p>(2.55 g twice daily) EPA/DHA ratio: 1:4</p>
<p>Compliance:</p>
<p>Not reported</p></td>
<td><p>10 healthy subjects (8 male/2 female)</p>
<p>age range: 24-30 years</p></td>
<td><p><u>Skin bleeding time</u>: slightly prolonged (NS) at end of 4-wk
supplementation; no change after 3 months following cessation of
supplementation.</p>
<p><u>Platelet adhesion to glass</u>: no change</p>
<p><u>Platelet aggregation in response to collagen</u>: ↓ significantly
after a prolonged lag phase (p&lt;0.01, 1-2 months after
supplementation)</p>
<p><u>Platelet aggregation in response to ADP</u>: ↓ significantly
(similarly to response to collagen)</p>
<p><u>Platelet aggregation in response to AA</u>: no change</p>
<p><u>Platelet secretion of ATP</u>: normal</p>
<p><u>Platelet levels of cAMP</u>: normal</p>
<p><u>Platelet binding to fibrinogen</u>: no change</p>
<p><u>Membrane glycoproteins</u>: no change</p></td>
<td><p><u>Conclusions</u>:</p>
<p>Short-term supplementation with n-3 fatty acids produces a
long-lasting inhibition of platelet aggregation that is independent of
the binding of fibrinogen to its specific receptor.</p>
<p><u>Comments</u>:</p>
<p>Study was not controlled.</p>
<p>Results presented qualitatively only; actual data not presented.</p>
<p>Diet not assessed.</p></td>
<td>3</td>
<td>Not reported.</td>
</tr>
<tr class="odd">
<td><p>Clandinin et al. 1997</p>
<p><em>Biochimica et Biophysica Acta</em> 1997;1346:247-252</p>
<p>[Canada]</p></td>
<td>To determine if n-3 intake results in a relationship between the
amount of 16:0 or 18:0 esterified to cholesterol in the LDL that is
predictive of the LDL cholesterol content.</td>
<td><p>Randomized, double-blind, placebo-controlled, crossover
trial.</p>
<p>All subjects were first asked to consume placebo (olive oil) for 3
months and then randomized to either n-3 from fish oil or n-3 from
flaxseed oil for 3 months. The treatments were then switched for the
next 3 months.</p></td>
<td><p>12 weeks (3 months) on fish oil</p>
<p>3 months on flaxseed oil</p>
<p>3 months on olive oil (placebo)</p></td>
<td><p>35 mg/kg bw/d of EPA+DHA (fish oil group)</p>
<p>35 mg/kg bw/d of 18:3n-3 from flaxseed (flaxseed oil group)</p>
<p>Olive oil (placebo group)</p>
<p>Compliance:</p>
<p>phone call</p></td>
<td>26 healthy, normal, free-living, non-smoking subjects.</td>
<td><p><u>TG:</u> Moderate but significant ↓ in TG with fish oil
(p&lt;0.05) compared to placebo and flaxseed oil groups.</p>
<p><u>TC:</u> No effect of fish oil or flaxseed oil.</p>
<p><u>LDL:</u> Significant positive correlation between increases in
intake of EPA and DHA from fish oil and increased levels of these FAs in
LDL. Stearic and palmitic acid content of the LDL cholesterol ester was
highly predictive of LDL cholesterol amount during the fish oil
treatment compared to pretreatment period.</p>
<p><u>HDL and VLDL:</u> Fish oil intake was negatively associated with
the total amount of FAs in VLDL and HDL fractions.</p>
<p>The average intake of fish containing meal was once per week. The EPA
and DHA intake was 0.03 and 0.06 g/d, respectively indicating that the
fish consumed was low in fat and low in EPA and DHA.</p>
<p>The EPA and DHA intake increased by 3 and 8%, respectively with fish
oil supplementation.</p></td>
<td><p>Conclusion:</p>
<p>The observations of the study suggest that “consumption of n-3 FAs,
particularly EPA and DHA, at the physiological level of intake reported
herein, seem to affect the partitioning or metabolic preferences of the
LDL particle for specific FAs”.</p>
<p>Comments:</p>
<p>7-day diet records were collected during the placebo, fish oil and
flaxseed oil treatment. Diets were analyzed using a nutritional
database. The subjects were counseled to continue with their dietary
patterns and not to change their fat intake.</p>
<p>No washout period.</p></td>
<td>2</td>
<td></td>
</tr>
<tr class="even">
<td><p>Connor et al. 1993</p>
<p><em>Annals of New York Academy of Sciences</em> 1993;683:337-340</p>
<p>[U.S.]</p></td>
<td>To determine the long-term effects of fish oil on plasma lipids,
lipoprotein and gylcemic control in hypertriglyceridemic patients with
NIDDM.</td>
<td>Randomized, double-blind, placebo controlled crossover trial.</td>
<td><p>24 weeks</p>
<p>6 months on each treatment without a washout period.</p>
<p>Initial 3-month baseline period on eucaloric low fat, high complex
carbohydrate diet prior to assignment of treatments.</p></td>
<td><p>6 g/d of EPA + DHA (4.1 g/d EPA, 1.9 g/d DHA; 15 g/d of fish oil
(Promega<sup>®</sup>) fish oil)</p>
<p>15 g/d olive oil: placebo</p>
<p>Compliance:</p>
<p>Not reported</p></td>
<td>16 hypertriglyceridemic subjects (3 women, 13 men) with NIDDM were
recruited. The subjects received hypoglycemic agents or hypoglycemic
agents with insulin.</td>
<td><p><u>TG:</u> ↓ significantly (p&lt;0.0004) with fish oil (42%, 260
± 98 mg/dl) compared to the olive oil (449 ± 254 mg/dl).<u><br />
TC:</u> Slight ↑ compared to baseline with fish oil, non-significant
difference between the groups.</p>
<p><u>LDL:</u> ↑ significantly with fish oil (145 ± 33 mg/dl) compared
to the olive oil (117 ± 31 mg/dl, p&lt;0.0003) and baseline (114 ± 31
mg/dl).</p>
<p><u>HDL:</u> No change with either fish or olive oil.<u><br />
VLDL:</u> ↓ significantly (p&lt;0.0001) with fish oil (41 ± 14 mg/dl)
compared to the olive oil (72 ± 38 mg/dl).</p>
<p><u>Fasting plasma glucose:</u> Non-significant ↑ with fish oil (178 ±
52 mg/dl) compared to the olive oil (172 ± 43 mg/dl) and baseline (161 ±
56 mg/dl).</p>
<p><u>Glycated hemoglobin:</u> Non-significant ↑ with fish oil (10.1 ±
3.3 %) compared to the olive oil (9.4 ± 2.5 %) and baseline (8.8 ± 2.6
%).</p>
<p><u>C-peptide:</u> Non-significant ↑ with fish oil (2.36 ± 1.20 mg/dl)
compared to the olive oil (2.71 ± 1.25 mg/dl) and baseline (1.13 ± 0.87
mg/dl).</p>
<p><u>24-hr urinary glucose:</u> Non-significant ↑ with fish oil (18.01
± 31.5 mg/dl) compared to the olive oil (19.27 ± 43.1 mg/dl) and
baseline (8.03 ± 17.8 mg/dl).</p>
<p><u>24-hr urinary C-peptide:</u> Non-significant ↑ with fish oil (169
± 108 mg/dl) compared to the olive oil (151 ± 83 mg/dl) and baseline
(160 ± 81 mg/dl).</p>
<p>Plasma EPA and DHA levels increased after the fish oil
supplementation.</p></td>
<td><p>Conclusions:</p>
<p>The results suggests that, “diabetic control did not deteriorate
after 6 months of fish oil…and VLDL-TG and VLDL-TC decreased
significantly after fish oil; plasma TC and HDL did not change. The LDL
was significantly increased with fish oil….suggesting that these
patients may also need further dietary and or pharmaceutical therapy to
maintain an LDL level compatible with a low risk of coronary disease.
The study emphasizes the safe use of fish oil over a 6-month period in
diabetic patients”.</p>
<p><u>Comments:</u></p>
<p>No washout period</p>
<p>Diets were assessed during the monthly visits.</p></td>
<td>2</td>
<td>Not reported</td>
</tr>
<tr class="odd">
<td><p>Conquer and Holub 1996</p>
<p><em>J Nutr</em> 1996;126:3032-3039</p>
<p>[Canada]</p></td>
<td>To determine the influence of dietary supplementation with DHA (from
algae), on serum/platelet DHA status, the estimated retroconversion of
DHA to EPA, and risk factors for heart disease in vegetarian
subjects.</td>
<td>Randomized, double-blind, controlled study.</td>
<td><p>6 weeks (treatment)</p>
<p>3 week washout period.</p></td>
<td><p>1.62 g/d DHA (from algae, encapsulated triglyceride oil,
DHASCO<sup>TM</sup>)</p>
<p>Control group: vegetable oil</p>
<p>Compliance: capsule count, serum and platelet phospholipid FA
levels.</p></td>
<td><p>24 young healthy vegetarians (12 males, 12 females) from the
Guelph community who reported no intake of meat for the past 6 months
were recruited.</p>
<p>DHA group: 12 subjects (6 males and 6 females)</p>
<p>Control group: 12 subjects (6 males and 6 females)</p></td>
<td><p><u>TC:</u> NS change in the DHA group, ↑ at 6 weeks in the
control group. TC: HDL ratio ↓ by 16% (p&lt;0.05) in the DHA group.</p>
<p><u>TG:</u> ↓ significantly by 3 (22%, p&lt;0.05) and 6 weeks (16%,
p&lt;0.05) in the DHA group.<u><br />
LDL:</u> NS change in the DHA group. LDL:HDL ratio ↓ by 22% (p&lt;0.05)
in the DHA group.<u><br />
HDL:</u> ↑ significantly in the DHA group (p&lt;0.05).</p>
<p><u>Collagen-induced platelet aggregation:</u> NS change in the DHA
group.</p>
<p><u>Collagen-induced thromboxane A<sub>2</sub> formation:</u> NS
change in the DHA group.</p>
<p><u>Serum viscosity:</u> NS change in the DHA group.</p>
<p><u>Fibrinogen:</u> NS change in the DHA group.</p>
<p><u>factor VIIc:</u> NS change in the DHA group.</p>
<p>Serum phospholipid DHA levels ↑ by 246% and EPA levels ↑ by 117% in
the DHA group. Platelet phospholipid DHA levels ↑ by 225% and EPA levels
↑ by 176% in the DHA group.</p></td>
<td><p><u>Conclusion:</u></p>
<p>The authors conclude that, “DHA supplementation markedly enhanced the
DHA status (of serum and platelets), provided for the formation of
substantial EPA, and lowered the TC:HDL and LDL:HDL ratios”.</p>
<p>Comments:</p>
<p>Diet records were collected to assess dietary intake of nutrients. 20
subjects completed dietary questionnaire.</p></td>
<td>1</td>
<td>Not reported</td>
</tr>
<tr class="even">
<td><p>Conquer and Holub 1998</p>
<p><em>J Lip Res</em> 1998;39:286-292</p>
<p>[Canada]</p></td>
<td>To determine the potential of a vegetarian source of supplementary
DHA to increase DHA-NEFA concentrations in the circulation of Asian
Indian subjects to levels that have been found to exhibit anti-platelet
aggregatory and anti-arrhythmic effects <em>in vitro</em>.</td>
<td>Placebo controlled, clinical trial</td>
<td>6 weeks (42 days)</td>
<td><p>1.5 g/d DHA (DHASCO<sup>TM</sup>) (high DHA group)</p>
<p>0.75 g/d DHA (low DHA group)</p>
<p>Placebo</p>
<p>Compliance:</p>
<p>Capsule count, serum phospholipid fatty acid analysis.</p></td>
<td><p>19 healthy subjects were recruited from the Guelph community.</p>
<p>3 of the 22 subjects that were initially recruited dropped out due to
personal reasons, or were excluded because they did not comply with the
dose requirement.</p>
<p>High DHA group: n=7</p>
<p>Low DHA group: n= 6</p>
<p>Placebo group: n= 6</p></td>
<td><p><u>TG:</u> NS effect (high DHA: baseline 1.04 ± 0.30, 3 weeks
0.91 ± 0.19, 6 weeks 0.98 ± 0.33 mmol/l; low DHA: baseline 1.41 ± 0.35,
3 weeks 1.20 ± 0.34, 6 weeks 1.29 ± 0.44 mmol/l; control group: baseline
1.02 ± 0.18, 3 weeks 1.20 ± 0.38, 6 weeks 1.25 ± 0.35 mmol/l)</p>
<p><u>TC:</u> NS effect of DHA</p>
<p><u>HDL:</u> NS effect of DHA<u><br />
LDL:</u> NS effect (high DHA: baseline 2.61 ± 0.35, 3 weeks 2.60 ± 0.37,
6 weeks 2.70 ± 0.46 mmol/l; low DHA: baseline 2.66 ± 0.40, 3 weeks 2.60
± 0.41, 6 weeks 2.42 ± 0.83 mmol/l; control group: baseline 2.71 ± 0.21,
3 weeks 2.57 ± 0.26, 6 weeks 2.47 ± 0.16 mmol/l)</p>
<p><u>TC/HDL ratio:</u> NS effect of DHA</p>
<p><u>LDL/HDL ratio:</u> NS effect of DHA</p>
<p><u>Serum Lp(a):</u> NS effect of DHA</p>
<p><u>SBP:</u> NS effect of DHA</p>
<p><u>DBP:</u> NS effect of DHA</p>
<p><u>Resting HR:</u> NS effect of DHA</p>
<p>Serum phospholipid DHA (as mol % of total fatty acids) increased by
167% and 193% in the low DHA (p&lt;0.05) and high DHA (p&lt;0 05)
groups, respectively compared to the baseline. The absolute serum DHA as
NEFA increased by 212% with the low dose of DHA and further by 70% with
high dose of DHA. NS increase in EPA in both DHA groups. The DHA/AA
ratio increased in both DHA groups.</p></td>
<td><p>Conclusions:</p>
<p>The authors suggest that, “DHA supplementation at levels
approximately &lt;2% of the daily fat intake can provide a strategy for
increasing circulating DHA-NEFA to levels (7.5 –12.7 μM as found herein
and potentially higher) which may offer anti-platelet aggregatory
benefits as well as anti-arrhythmic effects under physiological
conditions. Any potential clinical benefits of DHA supplementation to
both Asian Indians and other remains to be evaluated in future more
lengthy trials”.</p>
<p><u>Comments:</u></p>
<p>Diets were not assessed.</p>
<p>Not mentioned if randomized and double-blinded.</p>
<p>Small sample size per group.</p></td>
<td>2</td>
<td>Not reported</td>
</tr>
<tr class="odd">
<td><p>Contacos et al. 1993</p>
<p><em>Arterioscler Thromb</em> 1993;13:1755-1762</p>
<p>[Australia]</p></td>
<td>To determine the safety and efficacy of pravastatin and fish oil
alone and in combination for patients with mixed hyperlipidemia and to
evaluate their effects on composition of subfraction of VLDL and
LDL.</td>
<td>Randomized, single-blind, placebo-controlled trial.</td>
<td><p>6 weeks treatment</p>
<p>6 weeks run-in phase prior to treatment.</p></td>
<td><p>3 g/d n-3 FAs, EPA/DHA 2:1 (himega 6 g/d)</p>
<p>(fish oil group)</p>
<p>pravastatin group</p>
<p>pravastatin placebo</p>
<p>All subjects were put on combined a fish oil and pravastatin therapy
for 12 weeks after the initial 6 weeks on single therapy because they
had not achieved desirable lipid levels.</p>
<p>Compliance:</p>
<p>capsule count</p></td>
<td>31 outpatients (men and women) recruited from a lipid clinic at the
Royal Prince Alfred Hospital. The subjects had type IIB
hyperlipidemia.</td>
<td><p><u>TG:</u> Plasma TG ↓ by 30% (p&lt;0.05) with fish oil.
Nonsignificant ↓ with pravastatin. When fish oil was added significant
(p&lt;0.05) ↓ in TG compared to week 0.</p>
<p><u>TC:</u> No change with fish oil. ↓ significantly with pravastatin
treatment. Significant ↓ when pravastatin was added to fish oil.</p>
<p><u>LDL:</u> Nonsignificant ↑ (13%) with fish oil. ↓ significantly
with pravastatin treatment. Significant ↓ when pravastatin was added to
fish oil.</p>
<p><u>HDL:</u> No significant changes with any treatments.</p>
<p><u>apo A-I:</u> No significant changes with any treatments.</p>
<p><u>apo B:</u> ↓ significantly with pravastatin treatment. Significant
↓ when pravastatin was added to fish oil.</p>
<p><u>LDL Stokes diameter:</u> ↑ significantly (25 to 25.9 nm)
(p&lt;0.05) with fish oil. No change with pravastatin.</p>
<p><u>LDL composition:</u> No change with any treatments.</p>
<p><u>VLDL fractions:</u> Significant ↓ (p&lt;0.05) in VLDL lipids with
fish oil, but the composition of VLDL remained unchanged. Nonsignificant
↓ in VLDL lipid concentration with pravastatin. Further ↓ with fish oil
addition.</p>
<p><u>IDL fractions:</u> No changes in IDL composition or concentration
with fish oil. Nonsignificant ↓ in IDL lipid concentration with
pravastatin. Further ↓ in IDL lipids with fish oil addition.</p>
<p>The placebo group that received combined treatment showed significant
reductions in plasma TG, TC, LDL, VLDL, IDL and apo B levels.</p></td>
<td><p><u>Conclusion:</u></p>
<p>The results show that “in patients with mixed hyperlipidemia
pravastatin lowered TC more than TG, whereas fish oil lowered TG but not
TC. The combination of pravastatin plus fish oil reduced both TC and TG
and appeared safe to use in the short term. Fish oil decreased the
concentration of VLDL. However, the combination of pravastatin and fish
oil effectively reduced the concentration of VLDL and IDL”.</p>
<p><u>Comments:</u></p>
<p>Intent-to-treat analyses</p>
<p>1 subject had lipid values more than 3SD of the group mean and had
cystinuria, hence was excluded from the analyses.</p>
<p>6-week dietary run-in period, diets during the study was not
assessed.</p>
<p>Placebo group had more females and were older compared to other
groups, but no significant difference in plasma lipids and
apolipoprotein levels was observed between the groups at
baseline.</p></td>
<td>1</td>
<td>1 woman (3.2%) developed nausea on fish oil treatment. No other
drug-related adverse events were reported.</td>
</tr>
<tr class="even">
<td><p>Davidson et al. 1997a</p>
<p><em>Am J Cardio</em> 1997;80:797-798</p>
<p>[U.S.]</p></td>
<td>To examine the efficacy of therapy with simvastatin (S) plus marine
oil (MO) compared with either S or MO alone in patients w/ combined
hyperlipidemia.</td>
<td><p>Randomized</p>
<p>double-blind,</p>
<p>placebo-controlled trial.</p></td>
<td>12 weeks</td>
<td><p>3.6 g/d EPA+DHA</p>
<p>in SuperEPA marine oil (MO)</p>
<p>EPA:DHA = 1.5</p>
<ol type="1">
<li><p>7.2 g MO</p></li>
<li><p>10 mg/d S</p></li>
<li><p>10g/d MO + 10 mg/d S</p></li>
</ol>
<p>Compliance:</p>
<p>Capsule counts, 85+% compliance for each group.</p></td>
<td><p>29 patients w/ combined hyperlipidemia</p>
<p>LDL 160-240 mg/dl</p>
<p>HDL ≤ 50 or 60mg/dl (male or female)</p>
<p>TC 200-600 mg/dl</p>
<p>Test groups:</p>
<ol type="1">
<li><p>n=10</p></li>
<li><p>n=10</p></li>
<li><p>n=9</p></li>
</ol>
<p>1 drop out</p></td>
<td><p><u>TG:</u> ↓ MO (p&lt;0.05), ↓ S (p&lt;0.01),</p>
<p>↓ S+MO (p&lt;0.001).</p>
<p>Less ↓ in S group than other 2 groups.</p>
<p><u>Non HDL:</u> ↓S (p&lt;0.001) vs. baseline &amp; (&lt;0.05) vs. MO.
↓ MO+S (p&lt;0.001) vs. baseline.</p>
<p><u>HDL:</u> ↑ S (p&lt;0.05),</p>
<p>↑ S+MO vs. baseline &amp; MO group (p&lt;0.05). MO group NS.</p>
<p><u>TC/HDL:</u> MO ↓ NS.</p>
<p>↑ S vs. baseline (p&lt;0.001) &amp; vs. MO (p&lt;0.05). ↑ S+MO vs.
baseline (p&lt;0.001) &amp; vs. MO (p&lt;0.05).</p></td>
<td><p><u>Conclusions:</u></p>
<p>Concurrent administration of S+MO is effective for improving TG,
non-HDL &amp; HDL cholesterol in patients with combined hyperlipidemia.
Results suggest no attenuation of individual effects of MO and S on
serum profile.</p>
<p><u>Comments:</u></p>
<p>Dietary intake assessed, low-fat diet followed throughout study.</p>
<p>Discrepancy w/ study dosing (10 vs. 7.2 g MO in S+MO group?)</p>
<p>Small sample size/group</p></td>
<td>2</td>
<td>No adverse effects were reported.</td>
</tr>
<tr class="odd">
<td><p>Davidson et al. 1997b</p>
<p><em>Journal of American College of Nutrition</em>
1997;16(3):236-243</p>
<p>[U.S.]</p></td>
<td>To determine the effects of high doses of DHA on serum lipids in
individuals with combined hyperlipidemia (CHL) and to evaluate the
bioavailability of DHA administered in a triglyceride form.</td>
<td>Randomized, double-blind, placebo-controlled study with 3 parallel
groups.</td>
<td><p>6 weeks</p>
<p>6 week dietary run-in period</p>
<p>4 weeks placebo run-in period followed by 6 weeks on treatment with
placebo or DHA.</p></td>
<td><p>2.5 g/d of DHA as triglyceride (6 g/d of DHASCO<sup>®</sup>,
produced from microalgae)</p>
<p>1.25 g/d of DHA + placebo (3 g/d of DHASCO)</p>
<p>6 g/d of placebo (mixture of corn and soybean oil)</p>
<p>Compliance: Measured (method not specified)</p></td>
<td><p>26 subjects with CHL (LDL 130-220 mg/dl; TG 150-400 mg/dl) were
recruited from Chicago.</p>
<p>2.5 g/d DHA group: 9 subjects</p>
<p>1.25 g/d group: 9 subjects</p>
<p>Placebo group: 8 subjects (1 subjects dropped out due to personal
reasons)</p></td>
<td><p><u>TG:</u> ↓ significantly with 1.25 (20.9%) and 2.5 g/d of DHA
(17.6%) (p&lt;0.01 for both groups). The maximal effect was observed
with the lower dose. No change in the placebo group. Changes in serum TG
was associated with changes in non-HDL (r=0.46, p&lt;0.06) and HDL
(r=-0.47, p&lt;0.06), but not with LDL changes.<u><br />
LDL:</u> ↑ significantly (13.6%, p&lt;0.001) in the 2.5 g/d DHA group. A
dose-dependent ↑ in LDL was observed with increasing doses of DHA
(r=0.35, p&lt;0.09). NS changes from baseline in the placebo and 1.25
g/d/ DHA groups.<u><br />
HDL:</u> ↑ by 6% in both groups supplemented with 1.25 or 2.5 g/d of DHA
(p&lt;0.03). Slight but NS ↑ in the placebo group (5.2%).</p>
<p>Non-HDL: ↑ significantly (5.7%, p&lt;0.04) in the 2.5 g/d DHA group.
NS changes from baseline in the placebo and 1.25 g/d/ DHA groups.</p>
<p>Prior to the treatment, significant negative correlations between
phospholipid DHA with LDL and non-HDL concentrations were observed, and
the variability in non-HDL and LDL concentrations was explained by
phospholipid DHA levels. After 6 weeks of treatment with DHA these
correlations did not exist. No association between plasma DHA and TG or
HDL levels was observed before or after treatment.</p>
<p>A dose-dependent ↑ in plasma phospholipid DHA levels was observed
(r=0.94, p&lt;0.0001). The DHA levels ↑ by 3 fold in the group taking
2.5 g/d of DHA. Palmitoleic acid, AA and oleic acid ↓ in both DHA
groups.</p></td>
<td><p>Conclusion:</p>
<p>The authors conclude that, “dietary DHA, in absence of EPA, can
affect lipoprotein cholesterol and TG levels in patients with CHL. The
desirable TG and HDL changes were present at a dose which did not
significantly increase non-HDL or LDL. These preliminary findings
suggest that dietary supplementation with 1.25 g/d of DHA provided in a
triglyceride form, may be an effective tool to aid in the management of
hypertriglyceridemia”.</p>
<p>Comments:</p>
<p>3-day diet records were collected prior to and during the study. The
subjects were asked to follow NCEP step 1 diet during the dietary
stabilization period and during the placebo and treatment periods.</p>
<p>Subjects who did not consume &lt;30% of energy from fat during the
treatment were excluded from statistical analysis (<em>a
priori</em>).</p>
<p>Subjects were asked to discontinue lipid-lowering medications at
least 4 weeks prior to the first qualifying blood draw.</p>
<p>No significant differences in the baseline characteristics between
the 3 groups. The addition of 6 g/d of fat did not cause changes in body
weight.</p></td>
<td>1</td>
<td>The placebo and the DHA supplements were well tolerated. Side
effects such as burping, indigestion, sinus congestion, etc. were
reported. The frequency of reported side effects between the placebo and
DHA groups was not significantly different.</td>
</tr>
<tr class="even">
<td><p>De Maat et al. 1994</p>
<p><em>Fibrinolysis</em> 1994. 8 (Suppl.2):50-52</p>
<p>[The Netherlands]</p></td>
<td>To evaluate the effect of fish oil and vitamin E on fibrinogen and
C-reactive protein in healthy volunteers</td>
<td>Not controlled</td>
<td>1 week</td>
<td><p>9.0 g/day EPA + DHA from 30 g/day fish oil (Maxepa) containing
5.4 g EPA, 3.6 g DHA, 60 mg vitamin E</p>
<p>Compliance:</p>
<p>Not reported</p></td>
<td><p>11 healthy volunteers</p>
<p>age range: 18-22 years</p></td>
<td><p><u>Fibrinogen</u>: NS change</p>
<p><u>C-reactive protein</u>: NS change</p></td>
<td><p><u>Conclusions</u>:</p>
<p>Short-term administration of fish oil does not influence the levels
of fibrinogen or C-reactive protein in healthy persons with normal
levels.</p>
<p><u>Comments</u>:</p>
<p>Short study duration.</p>
<p>Study was not controlled.</p>
<p>Diet not assessed.</p>
<p>Some pre- and post-treatment fibrinogen values were below the normal
range of 2-4 g/l.</p></td>
<td>3</td>
<td>Not reported.</td>
</tr>
<tr class="odd">
<td><p>De Marchi et al. 1995</p>
<p><em>Nephr. Dialysis Transplant.</em> 1995. 10:1007</p>
<p>(ABSTRACT)</p>
<p>[Italy]</p></td>
<td>To evaluate the effects of n-3 fatty acids on uremic dyslipidemia
and other cardiovascular risk factors</td>
<td>Double-blind, cross-sectional, placebo-controlled</td>
<td><p>8 weeks</p>
<p>per treatment period</p></td>
<td><p>3 g/day EPA + DHA</p>
<p>or placebo (no other information provided)</p>
<p>Compliance:</p>
<p>Not reported</p></td>
<td><p>80 subjects</p>
<p>30 nondiabetic, hemodialysis patients served as treatment group.</p>
<p>50 healthy subjects served as the control group.</p></td>
<td><p><u>TC</u>: no change</p>
<p><u>HDL</u>: no change</p>
<p><u>TG</u>: no change</p>
<p><u>Lipoprotein (a)</u>: no change</p>
<p><u>apoA-I</u>: slight significant ↑ (p&lt;0.05)</p>
<p><u>apoA-I/apoB ratio</u>: NS change</p>
<p><u>apoA-I/apoC-III ratio</u>: NS change</p>
<p><u>Fibrinogen</u>: no change</p>
<p><u>Factor VII</u>: no change</p>
<p><u>Prothrombin fragment 1 &amp; 2</u>: no change</p>
<p><u>D-dimer</u>: no change</p></td>
<td><p><u>Conclusions</u>:</p>
<p>Supplementation with n-3 fatty acids has negligible effects on uremic
dyslipidemia and other parameters of coagulation and fibrinolysis.</p>
<p><u>Comments</u>:</p>
<p>Summarized from abstract.</p>
<p>Results presented qualitatively only.</p>
<p>Type of placebo not reported.</p></td>
<td></td>
<td>Not reported.</td>
</tr>
<tr class="even">
<td><p>Deslypere 1992</p>
<p><em>Verhandelingen Koninklijke Academie Voor Geneeskunde Van
Belgie</em> 1992;54(3):189-216</p></td>
<td>To determine the effects of n-3 FAs on parameters associated with
enhanced risk for CHD and to monitor hematological changes during the
study as well as some aspects of liver and kidney functions.</td>
<td>Randomized, double-blind, placebo-controlled, trial.</td>
<td>52 weeks (12 months) on n-3 FAs</td>
<td><p>3.37 g/d of n-3 FAs (high fish oil group)</p>
<p>2.24 g/d of n-3 FAs (medium fish oil group)</p>
<p>1.12 g/d n-3 FAs (low fish oil group)</p>
<p>Olive oil + palm oil (placebo group)</p>
<p>Compliance: capsule counts, interview, FAs analyses</p></td>
<td><p>58 healthy subjects were recruited from 4 different Trappist or
Benedictine monasteries.</p>
<p>High fish oil group: 14 subjects</p>
<p>Medium fish oil group: 15 subjects</p>
<p>Low fish oil group: 15 subjects</p>
<p>Placebo group: 14 subjects</p></td>
<td><p><u>TC:</u> No change with n-3 FAs</p>
<p><u>TG:</u> A significant (p&lt;0.01) dose-dependent ↓ in TG on days
7, 14, 28, 56 and 363 was observed with n-3 FAs. The decrease
(p&lt;0.01) was more pronounced when the 3 fish oil groups were combined
and compared to the placebo group on all visits. A significant
(p&lt;0.005) dose-dependent short, middle and long term effect was
observed with n-3 FAs on TG concentrations. <u><br />
LDL:</u> No change with n-3 FAs<u><br />
HDL:</u> A borderline significant (p&lt;0.05) dose-dependent ↑ was
observed with n-3 FAs at days 3, 7 and 28.<u><br />
apo A1:</u> No effect with n-3 FAs on apo A1 and apo A1/B ratio.</p>
<p><u>apo B:</u> A ↓ in the highest fish oil group was apparent compared
to an increase in other groups (p&lt;0.05)</p>
<p><u>Lp(a):</u> No effect with n-3 FAs. When Lp(a) phenotypes are
separated, fish oil treatment does not lower Lp(a) levels and in some
cases increases the levels.</p>
<p><u>Plasma fibrinogen:</u> No inter or intra group differences were
observed with n-3 FAs on plasma fibrinogen levels.</p>
<p><u><em>factor VIII</em>:</u> Both placebo and fish oil groups showed
a decrease in <em>factor VIII</em>.</p>
<p><u><em>Antithrombine III</em>:</u> No effect of n-3 FAs</p>
<p><u>Plasma <em>t-PA</em>:</u> No effect of n-3 FAs</p>
<p><u><em>PAI</em>:</u> No effect of n-3 FAs</p>
<p><u><em>IVY</em> bleeding time:</u> No differences among the
groups.</p>
<p><u>Glucose:</u> HbA1C and serum glucose levels were not different
between the 4 groups before and during supplementation (placebo or fish
oil)</p></td>
<td><p>Conclusion:</p>
<p>The author concluded that, “n-3 FAs had no influence on different
cardiovascular risk parameters in men (BP, HDL, LDL, apoproteins, Lp(a),
HbA1c, coagulation and fibrinolysis factors). Only TG concentrations
decreased when more than 2 g/d n-3 FAs were taken. It is therefore
improbable that the proposed anti-atherosclerotic action of n-3 FAs is
mediated through an effect on these parameters, the role of TG in the
pathogenesis of CHD is still debatable”.</p>
<p><u>Comments:</u></p>
<p>3-day diet records were collected on days 0, 182 and 363. Dietician
completed dietary history interview. Data was analyzed using the Dutch
Food Composition table.</p></td>
<td>1</td>
<td>Biochemical parameters were normal at the start of the study and
throughout the study except for an increase in total and direct
bilirubin in the high fish oil group and decrease of WBC count and Hb in
all subjects.</td>
</tr>
<tr class="odd">
<td><p>Ding et al. 1997</p>
<p>Biochemical Society Transactions 1997;25:S687</p>
<p>[U.K.]</p></td>
<td>To determine the effects of n-3 on TG and VLDL apo B turnover,
changes in fatty acid profile and determine parameters such as the
n-6/n-3 ratio and unsaturation index.</td>
<td><p>Clinical trial</p>
<p>Blood samples were collected before and after fish oil
treatment.</p></td>
<td>4 weeks</td>
<td><p>3 g/d EPA+DHA</p>
<p>1.8 g/d EPA</p>
<p>1.2 g/d DHA</p>
<p>fish oil concentrate (Maxepa)</p>
<p>Compliance: Not measured</p></td>
<td>9 healthy normolipidaemic male subjects.</td>
<td><p><u>TG:</u> Both plasma (p&lt;0.01) and VLDL (p&lt;0.01) TG ↓
significantly.</p>
<p><u>VLDL:</u> VLDL total cholesterol ↓ significantly (p&lt;0.01).</p>
<p>A shift in n-3 FAs in all compartments of lipid classes (p&lt;0.05)
was observed with the short term supplementation with n-3 FAs.</p>
<p>The unsaturation index remained unchanged, suggesting that n-3 was
efficiently absorbed and it replaced n-6 FAs.</p></td>
<td><p>Conclusion:</p>
<p>Both plasma and VLDL TG levels ↓ significantly.</p>
<p>VLDL total cholesterol ↓ significantly. A shift in n-3 FAs in all
compartments of lipid classes was observed</p>
<p>and the unsaturation index remained unchanged, suggesting that n-3
was efficiently absorbed and it replaced n-6 FAs.</p></td>
<td>3</td>
<td></td>
</tr>
<tr class="even">
<td><p>Du Plooy, et. al.</p>
<p>1992</p>
<p>Prostaglandins Leukotrienes and Essential Fatty Acids</p>
<p>1992;46:315-21</p>
<p>[South Africa]</p></td>
<td>To examine the cumulative dose response effects of EPA and DHA on
BP, plasma lipid profile and diet pattern in mild to moderate essential
hypertensive patients.</td>
<td>Randomized, single-blind, placebo controlled study design.</td>
<td><p>24 weeks</p>
<p>A run-in period of 4 weeks was used to screen subjects based on blood
pressure, followed by 6 weeks tx. each with 4 increasing cumulative
doses of fish oil.</p></td>
<td><p>13.333 g/d EPA + DHA (10 g/d EPA and 3.333 d/d DHA) for 6 weeks
preceded by</p>
<p>1.333 g/d EPA + DHA (1.0 g/d EPA and 0.333 g/d DHA) for 6 weeks
preceded by</p>
<p>0.133 g/d EPA + DHA (0.10 g/d EPA and 0.033 g/d DHA) for 6 weeks
preceded by</p>
<p>0.013 g/d EPA + DHA (0.010 g/d EPA and 0.003 g/d DHA) for 6
weeks.</p>
<p>Doses were given in ascending order of dose, administered as gelatin
capsules containing 0.5 ml fish oil. The highest dose of fish oil was
given as a liquid instead of capsules due to the high volume of fish oil
required to achieve 13.333 g/d of EPA + DHA.</p>
<p>Placebo was olive oil, also given as gelatin capsules (with 0.5 ml
olive oil).</p>
<p>Compliance:</p>
<p>Plasma FAs analysis.</p></td>
<td><p>26 subjects</p>
<p>Mildly hypertensive (diastolic BP≥ 96 but ≤ 120 mm Hg), black, ages
21-65 years old.</p>
<p>Olive oil control,</p>
<p>n = 12</p>
<p>Fish oil group,</p>
<p>n = 14</p></td>
<td><p><u>TG</u>: No effects seen within or between groups.</p>
<p><u>TC</u>: No effects seen within or between groups, except for a
transitory ↓ in the placebo group at 18 weeks (p&lt;0.025).</p>
<p><u>HDL</u>: No effects seen within or between groups.</p>
<p><u>HDL:TC:</u> No effects seen within or between groups.</p>
<p><u>DBP:</u> NS differences between the placebo group and the fish oil
group in any phase of the study. Both groups showed significant ↓ in DBP
(placebo 107 mm Hg at study initiation to 99 mm Hg after 18 weeks (p
&lt;0.025) and to 96 mm Hg after 24 weeks (p&lt;0.005); fish oil group
105 mm Hg at study initiation to 100 mm Hg but only at 24 weeks
(p&lt;0.05).</p>
<p><u>SBP:</u> NS differences between the placebo group and the fish oil
group in any phase of the study. Both groups also showed significant ↓
in SBP (placebo group from 164 mm Hg at study initiation to 153 mm Hg
after 12 weeks (p&lt;0.05), to 145 mm Hg after 18 weeks (p&lt;0.025) and
after 24 weeks (p&lt;0.05); fish oil group from 165 mm Hg at study
initiation to 158 mm Hg after 18 weeks (p&lt;0.05), to 156 mm Hg after
24 weeks (p&lt;0.05).</p>
<p><u>Arterial BP:</u> NS differences between the placebo group and the
fish oil group in any phase of the study. Both groups also showed
significant ↓ in SBP (placebo group from 126 mm Hg at study initiation
to 119 mm Hg after 12 weeks (p&lt;0.025), to 114 mm Hg after 18 weeks
(p&lt;0.005), and to 113 mm Hg (p&lt;0.005) after 24 weeks; fish oil
group from 125 mm Hg at study initiation to 119 mm Hg after 24 weeks
(p&lt;0.05).</p>
<p><u>Gamma-glutamyl-transpepsidase:</u> No effects seen within or
between groups.</p>
<p>The plasma EPA levels ↑ from its base value after 12 weeks (0.10 g/d
EPA) (but p &gt;0.05) and continued to increase for the rest of the
trial (p &lt;0.005 at both 18 and 24 weeks). After 18 weeks (1.333 g/d
EPA + DHA) the difference between the placebo and EPA group became
significant (p&lt;0.005). The EPA level ↑ approx. 20-fold while the dose
level ↑ was 1000-fold. There were no significant changes in plasma DHA
between or within any group. Other FAs were also measured, but the data
are not reported here.</p></td>
<td><p><u>Conclusions</u>:</p>
<p>The authors concluded that, “EPA could not lower BP in essential
hypertensive black patients, that the effect of placebo should not be
underestimated and that EPA had no beneficial effect on lipids over and
above a therapeutic diet except perhaps the lowering of plasma free AA
with a concomitant decrease in the yield of detrimental
metabolites.”</p>
<p><u>Comments:</u></p>
<p>Dietary histories were collected by dieticians using the 24-hour
recall and food frequency questionnaire.</p></td>
<td>1</td>
<td>Subjects consuming fish oil reported↑ stool frequency most often (8
subjects (57%) over the entire 24-week period).</td>
</tr>
<tr class="odd">
<td><p>Dunstan et al. 1997</p>
<p><em>Diabetes Care</em> 1997;20(6):913-921</p>
<p>[Australia]</p></td>
<td>To determine the independent and combined effects of n-3 fatty acids
and moderate aerobic exercise on serum lipids and gylcemic control in
dyslipidemic NIDDM patients on a low fat diet</td>
<td>Randomized, controlled parallel trial.</td>
<td><p>8 weeks of treatment</p>
<p>4 weeks of initial baseline period.</p></td>
<td><p>3.6 g/d n-3 FAs provided by 1 fish meal.</p>
<p>Control group: no fish meal</p>
<p>Compliance: weekly interview, weighted diet records, and platelet
phospholipid FA levels.</p></td>
<td><p>49 dyslipidemic subjects with NIDDM were recruited through local
media publicity. These subjects were not taking insulin or lipid
lowering drugs. All subjects were on low fat diet. The subjects were
either assigned to fish diet or no fish diet. Within each group the
subjects were assigned light or moderate exercise.</p>
<p>Fish + moderate exercise: F/ME group, n=14</p>
<p>Fish + light exercise: F group, n=12</p>
<p>No fish + moderate exercise: ME group, n=11</p>
<p>No fish + light exercise: Control group, n=12</p>
<p>Of the 55 subjects, six subjects withdrew either due to changes in
medication or other commitments.</p></td>
<td><p>TG: Significant ↓ (p=0.03) with addition of fish to the low fat
diet. TG ↓ significantly with F/ME and F diet (both p=0.0001).</p>
<p>TC: No significant group effects.</p>
<p>HDL: Significant ↓ in HDL<sub>3</sub> (p=0.02) and ↑ in
HDL<sub>2</sub> (p=0.01) with addition of fish to the low fat diet. ↑ in
HDL<sub>2</sub> with F/ME and F diet (p=0.02).<br />
LDL: Non-significant ↑ in LDL with addition of fish in the low fat diet.
In regression analysis the ↑ in LDL was significant (p=0.03) with fish.
No significant group effects.</p>
<p>After adjusting for age, sex and change in body weight the main
effects of fish on TG, and HDL were unaffected.</p>
<p>Fasting glucose: Measured at home showed a significant ↑ (p=0.0002)
in the F group throughout the study compared to the control group after
adjusting for age, sex and change in body weight. Significant ↓ was
observed for the F/ME (p=0.001) and ME (p=0.001) groups. n-3 fatty acid
composition was independently associated with the rise in fasting
glucose (p=0.03, adjusted r<sup>2</sup>=0.76) after adjusting for age,
sex, and change in body weight.</p>
<p>AUC glucose: n-3 fatty acid composition was independently associated
with the glucose AUC (p=0.04, adjusted r<sup>2</sup>=0.79) after
adjusting for age, sex, and change in body weight.</p>
<p>Fasting insulin: No significant main effects of fish or moderate
exercise. ↓ significantly (p=0.05) in the F group compared to the
control group.</p>
<p>AUC insulin: No significant main effects of fish or moderate
exercise.</p>
<p>Glycated hemoglobin: Significant ↑ (p&lt;0.05) in the F group which
was attenuated in the F/ME group (p=0.44). n-3 fatty acid composition
was independently associated with the rise in glycated hemoglobin
(p=0.01, adjusted r<sup>2</sup>=0.83) after adjusting for age, sex, and
change in body weight.</p>
<p>Significant reduction in fasting glucose, AUC for glucose and
glycated hemoglobin with moderate exercise compared to light exercise.
Regression analysis after adjusting for sex, age and change in body
weight did not show the differences between the exercise groups.</p>
<p><u><br />
</u>Except for SBP no significant differences between the groups at
baseline.</p>
<p>The platelet phospholipid n-3 FAs concentration in ↑ significantly
(p=0.001) in the fish eating groups.</p></td>
<td><p>Conclusions:</p>
<p>The authors concluded that, “a reduced fat diet incorporating one
fish meal reduces serum TG and increases HDL<sub>2</sub> in dyslipidemic
patients. Associated deterioration in gylcemic control can be prevented
by a concomitant program of moderate exercise”.</p>
<p>Comments:</p>
<p>Diets were assessed by weekly interview with a dietitian and from
weighted food records.</p></td>
<td>1</td>
<td>Not reported</td>
</tr>
<tr class="even">
<td><p>Dunstan et al. 1999</p>
<p><em>Thromb. Haemost.</em> 1999 81:367-372</p>
<p>[Australia]</p></td>
<td>To examine the independent and combined effects of n-3 fatty acids
derived from one daily fish meal and aerobic exercise training, on
components of coagulation and fibrinolysis in dyslipidemic NIDDM
consuming a low-fat (30% total energy intake) diet</td>
<td>Randomized, controlled</td>
<td><p>8 weeks</p>
<p>4 week period prior to intervention to determine baseline
values</p></td>
<td><p>3.6 g/day n-3 FA</p>
<p>from low fat diet (≤ 30% of daily energy intake) ± 1 fish meal per
day</p>
<p>Subjects assigned to light (10 min) or moderate (30 min) exercise
groups.</p>
<p>Control group: no fish and light exercise</p>
<p>Compliance: weekly food checklists, weight diet food records,
erythrocyte phospholipids</p></td>
<td><p>49 subjects with treated NIDDM</p>
<p>mean age: approx. 53 years</p>
<p>Fish and moderate exercise: n=14</p>
<p>Fish and light exercise: n=12</p>
<p>No fish and moderate exercise: n=11</p>
<p>Control (light exercise): n=12</p>
<p>6 withdrawals due to changes in medication or other
commitments</p></td>
<td><p><u>Plasma plasminogen activator (tPA) antigen</u>: ↓ by about 2
ng/ml in fish and moderate exercise, fish and low exercise, and no fish
and moderate exercise groups (p&lt;0.05). Changes were negatively
associated with erythrocyte ω-3 fatty acid composition (p=0.03) and
HDL-C (p=0.02).</p>
<p><u>PAI-1 antigen</u>: NS changes.</p>
<p><u>Plasma fibrinogen</u>: NS changes.</p>
<p><u>Coagulation factor VIIc</u>: ↑ by 4.9% relative to control for
fish and light exercise group (p=0.02). No change in fish and no fish
moderate exercise groups. Positively associated with fasting blood
glucose (p=0.004).</p>
<p>In fish groups, the % composition of n-3 fatty acids increased and
n-6 fatty acids decreased compared to controls (p&lt;0.05) after 8
weeks</p></td>
<td><p><u>Conclusions</u>:</p>
<p>The reduction in tPA antigen seen with dietary fish and regular
moderate exercise may be indicative of reduced thrombotic potential and
decreased cardiovascular risk, and that moderate exercise can prevent
the increase in coagulation factor VIIc associated with dietary
fish.</p>
<p><u>Comments</u>:</p>
<p>Intake of EPA &amp; DHA not reported.</p>
<p>Dietary assessment by weekly food checklists &amp; interviews.</p>
<p>Subjects continued taking anti-diabetic and antihypertensive
medications during study.</p>
<p>Results for fibrinolytic factors after 8 weeks reported only in bar
graphs.</p></td>
<td>2</td>
<td>Not reported.</td>
</tr>
<tr class="odd">
<td><p>Engstrom et al. 1996</p>
<p>Prostaglandins, Leukotrienes and Essential Fatty Acids</p>
<p>1996;54(6);419-425</p>
<p>[Sweden]</p></td>
<td>“To investigate the effects of supplementation of a stabilized fish
oil with extra vitamin E on the whole blood production of some
eicosanoids in man”</td>
<td>Randomized, double-blind, controlled crossover study</td>
<td><p>4 week treatment</p>
<p>with either fish oil or fish oil supplemented with vitamin E, at
which point patients crossed over following a six week washout
period</p></td>
<td><p>8.85 g/day EPA+DHA (Eskimo-3, 30 ml/day total oil)</p>
<p>5.34 g/day EPA<br />
3.51 g/day DHA</p>
<p>Fish oil group: 30 ml/day fish oil w/ 1.5 IU/g vit.E</p>
<p>Supplemented group: 30 ml/day fish oil w/ 4.5 IU/g vit. E</p>
<p>Compliance:</p>
<p>Subject reports and fish oil count, as well as plasma fatty acid
analysis</p></td>
<td>12 men with normal to slightly raised triglyceride levels. 3
subjects are receiving medication for uncomplicated hypertension, 1 had
suffered MI, 1 had type 2 diabetes, 2 were being treated for high
cholesterol</td>
<td><p><u>TG:</u> significantly ↓ with fish oil (2.1 ± 0.6 vs. 1.2 ± 0.2
mmol/l, p&lt;0.001) compared to baseline. Significant ↓ with fish oil +
vit E from baseline.</p>
<p><u>TXB<sub>2</sub></u>: significantly ↓ (40%, p&lt;0.05) compared to
baseline. Significant ↓ with fish oil + vit E from baseline.</p>
<p><u>6-keto-PGF<sub>1</sub>/TXB<sub>2</sub> ratio:</u> ↓ (27%) compared
to baseline. Significant ↓ with fish oil + vit E from baseline.</p>
<p><u>LTB<sub>4</sub>:</u> production ↓ 17% (p&lt;0.05) compared to
baseline.</p>
<p><u>6-keto PGF<sub>1α</sub>:</u> NS ↓ with fish oil (5%) and fish oil
+ vit E.</p>
<p>Plasma EPA and DHA ↑ significantly (p&lt;0.001) compared to
baseline.</p></td>
<td><p>Conclusions:</p>
<p>The authors concluded that, “stabilized fish oil had a marked effects
on eicosanoid production which may be important for its cardiovascular
effect. A further increase of the vit E content had no additional
effects”</p>
<p>Comments:</p>
<p>Subjects gained a significant amount of weight during the course of
the trial (2%, p&lt;0.01) suggesting that the increased oil intake was
not compensated for by reduced food intake</p>
<p>Instructed to not change their diets or lifestyle during the
trial.</p></td>
<td>1</td>
<td>No report of dropouts or adverse effects</td>
</tr>
<tr class="even">
<td><p>Eritsland et al. 1992</p>
<p><em>Thrombosis Research</em> 1992;65(1):S75 (ABSTRACT)</p>
<p>[Oslo]</p></td>
<td>To determine the effects of long-term supplementation of n-3 PUFA on
lipoproteins, coagulation and fibrinolysis in patients with stenosing
coronary artery disease.</td>
<td>Randomized, controlled trial. 2X2 factorial design</td>
<td>36 weeks (9 months)</td>
<td><p>3.4 g/d n-3 PUFA</p>
<p>All patients randomly received either aspirin or warfarin. They were
further randomized to n-3 PUFA group or no n-3 PUFA group
(control).</p></td>
<td><p>370 patients with coronary artery bypass grafting</p>
<p>n-3 PUFA group: n=179</p>
<p>Control group: n=191</p></td>
<td><p><u>TG:</u> Significant ↓ (1.7 ± 0.06 to 1.3 ± 0.06 mmol/l) with
n-3 PUFA compared to control (p&lt;0.05).<u><br />
TC:</u> NS ↑ with n-3 PUFA.<u><br />
HDL:</u> Significant ↑ (1.0 ± 0.02 to 1.11 ± 0.02 mmol/l) with n-3 PUFA
compared to control (p&lt;0.05).<u><br />
Fibrinogen:</u> NS ↑ with n-3 PUFA.</p>
<p><u>FPA:</u> NS ↓ with n-3 PUFA.</p>
<p><u>D-dimer:</u> Significant ↓ (400 ± 15.8 to 345 ± 21.6 mmol/l) with
n-3 PUFA compared to control (p&lt;0.05).<u><br />
PAI activity:</u> NS ↓ with n-3 PUFA.</p></td>
<td><p>Conclusions:</p>
<p>The authors concluded that, “the increase in HDL cholesterol and
decline in TG levels during long-term n-3 PUFA supplementation point to
a less atherogenic profile. The decreased FPA and D-dimer concentrations
in this group may indicate a reduced activation of the coagulation
system”.</p>
<p>Comments:</p>
<p>Summarized from abstract.</p></td>
<td></td>
<td>Not reported</td>
</tr>
<tr class="odd">
<td><p>Eritsland et al. 1994a</p>
<p><em>Fibrinolysis</em> 1994;8:120-125</p>
<p>[Norway]</p></td>
<td>To assess long-term effects of n-3 FAs supplementation on components
in the fibrinolytic system and on serum lipids and to relate the
potential changes to the FAs profile in serum phospholipids.</td>
<td><p>Randomized</p>
<p>controlled trial, but no placebo</p></td>
<td><p>26 weeks</p>
<p>(6 months)</p></td>
<td><ol start="4" type="1">
<li><p>g EPA+DHA</p></li>
</ol>
<p>ethyl esters</p>
<p>(4 g K85 highly concentrated fish oil)</p>
<p>Control: Medication alone (ASA or Warfarin)</p>
<p>2X2 factorial design:</p>
<ol type="1">
<li><p>ASA (16)</p></li>
<li><p>ASA + n-3 (15)</p></li>
<li><p>Warfarin (13)</p></li>
<li><p>Warfarin+n-3 (14)</p></li>
</ol>
<p>Compliance:</p>
<p>Not reported</p></td>
<td><p>58 w/ coronary artery disease that underwent bypass grafting. TG
≥ 1.5 mmol/l.</p>
<p>Test: 29</p>
<p>Control: 29</p>
<p>90+% males each group.</p></td>
<td><p><u>TG:</u> ↓ 34% test group (P=0.001) vs. 11.1% in control
group.</p>
<p><u>TC:</u> ↓ but NS between groups</p>
<p><u>LDL:</u> ↓ but NS between groups</p>
<p><u>HDL:</u> ↑ but NS between groups</p>
<p><u>Serum FAs:</u> ↑ EPA, ↓ linoleic in test group. ↑ linoleic in
control group, NS in n-3 concentration in control group.</p>
<p><u>Fibrinogen:</u> NS between groups</p>
<p><u>PAI-1 activity:</u> NS between groups</p>
<p><u>PAI-1 antigen:</u> ↑ test,↓ control (p=0.039 between groups)</p>
<p><u>serum D-dimer after VO:</u> NS between groups.</p>
<p>Minor changes in t-PA activity and antigen both before and after
venous occlusion.</p>
<p>In both groups, inverse correlation between change in serum FAs and
change in TG (r=0.35, p=0.008). Correlation between changes in serum FAs
and PAI-1 antigen (r=0.28, p=0.036).</p></td>
<td><p><u>Conclusions:</u></p>
<p>Authors concluded that, “moderate n-3 supplementation reduced TG w/o
altering TC of patients in study. Except for slight increase in PAI-1
antigen, no influence on fibrinolytic parameters or fibrinogen
concentration was detected”.</p>
<p><u>Comments:</u></p>
<p>Not placebo controlled.</p>
<p>Not blinded.</p>
<p>Dietary intake not assessed but "general dietary advice" provided at
least once during trial.</p>
<p>Many P values not provided.</p></td>
<td>3</td>
<td><p>"The antithrombotic treatment and the n-3 FAs concentrate were
well tolerated."</p>
<p>No adverse effects reported.</p></td>
</tr>
<tr class="even">
<td><p>Eritsland et al. 1994b</p>
<p>Scand J Clin Lab Invest</p>
<p>1994;54;273-280</p>
<p>[Norway]</p></td>
<td>Examine the long-term effects of n-3 fatty acids on serum lipids and
glycemic control in moderately hypertriglyeridemic patients undergoing
coronary bypass grafting</td>
<td>Randomized controlled trial</td>
<td>24 weeks (6 months)</td>
<td><p>3.4 g/day EPA+DHA (K 85 fish oil concentrate, 4 g of fish
oil)</p>
<p>2.07 g/day EPA</p>
<p>1.28 g/day DHA</p>
<p>Control group</p>
<p>Compliance:</p>
<p>FA analysis</p></td>
<td><p>57 patients suffering from stenosing coronary artery disease who
had undergone coronary artery bypass grafting (CABG) with elevated serum
TG levels, but not defined to have diabetes</p>
<p>All patients received either aspirin or warfarin</p>
<p>Fish oil group: 28 patients</p>
<p>Control group 29 patients</p></td>
<td><p><u>TG:</u> significant ↓ in fish oil (33.2%) but not in the
control group (11.1%) compared to baseline. Significant differences
between the groups (p=0.002).</p>
<p><u>TC</u>: no significant differences compared to control.</p>
<p><u>HDL</u>: no significant differences compared to control.</p>
<p><u>LDL</u>: no significant differences compared to control.</p>
<p><u>Glucose</u>: fasting glucose slightly ↑ from baseline compared to
control (fish oil -0.2 vs. control –0.5 mmol/l). Borderline significant
difference between the groups (p=0.054). Glucose levels 1 hour after
OGTT were not different between the groups.</p>
<p><u>Insulin</u>: fasting insulin significantly ↓ with fish oil from
baseline compared to control (-2 vs. 0 mlUml<sup>-1</sup>, p=0.039).
Insulin levels 1 hour after OGTT were not different between the groups.
Changes in fasting insulin levels were inversely correlated to the
changes in serum phospholipid n-3 FAs levels (r=-0.32, p=0.016).</p>
<p><u>C-peptide</u>: no significant difference compared to control (-0.1
vs. + 0.03 mmol/l change from baseline, p=0.175) in fasting C-peptide.
C-peptide levels 1 hour after OGTT were not different between the
groups.</p>
<p><u>AUC for glucose:</u> ↓ in both groups after 6 months compared to
baseline. The ↓ was more in the control group and difference between the
groups reached borderline significance. (p=0.064).</p>
<p><u>AUC for insulin:</u> No differences between the groups.</p>
<p><u>AUC for C-peptide:</u> No differences between the groups.</p>
<p>Serum DHA ↑ significantly from baseline compared to control (+19.7
vs. –6.5, p&lt;0.002). Serum EPA ↑ significantly from baseline compared
to control (+ 60.3 vs. –2, p&lt;0.001). Serum linoleic acid ↓
significantly from baseline compared to control (+35.5 vs. –34.2,
p&lt;0.001). Serum AA ↓ borderline significant from baseline compared to
control (+6.9 vs. –4.2, p=0.046).</p></td>
<td><p>Conclusions:</p>
<p>The authors conclude that, “long term effects on glucose
homeostasis….are probably of little clinical significance in this
patient group”</p>
<p><u>Comments</u>:</p>
<p>Dietary records were obtained from a random sample of 19 subjects in
the treatment group and 21 patients in the control group, both at
baseline and at study termination</p>
<p>Study does not control for the increased fat intake due to the fish
oil with a corresponding oil placebo, although intake of fat and fatty
acids were not significantly different between the treatment and control
groups</p></td>
<td>1</td>
<td>Fish oil was well tolerated</td>
</tr>
<tr class="odd">
<td><p>Eritsland et al. 1995a</p>
<p><em>Am J Clin Nutr</em> 1995;61:831-6</p>
<p>[ Norway]</p></td>
<td>To investigate the long-term metabolic effects of n-3 FAs in
patients with coronary artery disease.</td>
<td><p>Randomized</p>
<p>controlled trial, no placebo</p>
<p>(Not blinded)</p></td>
<td><p>36 weeks</p>
<p>(9 months)</p></td>
<td><p>3.4g/d EPA+DHA</p>
<p>2.1 g/d EPA</p>
<p>1.3 g/d DHA</p>
<p>(4 g/d Omacor fish oil)</p>
<p>Control: Unsupplemented</p>
<p>Compliance:</p>
<p>Serum FAs</p></td>
<td><p>511 patients</p>
<p>w/ stenosing coronary artery disease who were undergoing bypass
surgery.</p>
<p>260 test</p>
<p>251 control</p>
<p>(99 drop outs)</p>
<p>@85% males</p></td>
<td><p><u>TG:</u> ↓ (P&lt;0.0001)</p>
<p><u>TC:</u> NS between groups</p>
<p><u>LDL:</u> NS between groups</p>
<p><u>HDL:</u> NS between groups</p>
<p><u>apo A:</u> NS between groups</p>
<p><u>apo B:</u> NS between groups</p>
<p><u>Serum FAs profile:</u> ↑ n-3 &amp; n-6 (p&lt;0.0001).</p>
<p><u>Plasma glucose:</u> NS between groups</p>
<p><u>Insulin:</u> NS between groups</p>
<p><u>C-peptide:</u> NS between groups</p></td>
<td><p><u>Conclusion:</u></p>
<p>The dose in this study "resulted in significant alterations in FAs in
serum phospholipids and a decline in serum TG."</p>
<p><u>Comments:</u></p>
<p>Aspirin or warfarin were given to patients throughout study.</p>
<p>Control group had more subjects with diabetes (P=0.017).</p>
<p>Not placebo-controlled study.</p>
<p>Dietary intake assessed.</p>
<p>No exclusion criteria given.</p></td>
<td>1</td>
<td>"No adverse effects ascribed to FO concentrate could be demonstrated
in the measured serum concentrations of lipids, apolipoproteins, liver
enzymes, or TBARS, and no influence on glucose homeostasis was
seen."</td>
</tr>
<tr class="even">
<td><p>Eritsland et al. 1995b</p>
<p><em>Scan J Clin Lab Invest</em> 1995;55:295-300</p>
<p>[Norway]</p></td>
<td>The objective was to determine serum Lp(a) levels in patients with
stenosing coronary artery disease, examine the relation between Lp(a)
levels and other serum lipids and with fibrinolytic variables and to
study the long-term effect of n-3 PUFAs on Lp(a) after bypass
surgery.</td>
<td><p>Randomized, controlled trial.</p>
<p>The subjects were randomly assigned to either fish oil or control
group after the bypass surgery.</p></td>
<td>24 weeks (6 months)</td>
<td><p>1 g/d of n-3 PUFAs as ethyl esters (Omacor<sup>®</sup>) (51% EPA,
32% DHA) (n-3 PUFAs group)</p>
<p>Control group</p>
<p>Compliance: Not measured</p></td>
<td><p>549 subjects with stenosing coronary artery disease undergoing
bypass surgery.</p>
<p>Fish oil group: 280 subjects</p>
<p>Control group: 269 subjects.</p>
<p>Serum Lp(a) levels were determined in 601 subjects and compared to 99
healthy subjects.</p></td>
<td><p><u>Lp(a):</u> No effect of n-3 PUFAs on Lp(a) levels was observed
after 6 months. After stratifying baseline Lp(a) levels as high and low,
a small but significant decrease (p=0.023) in Lp(a) levels with n-3
PUFAs was observed in the high level group, but not in the low level
group. No effect of PUFAs on Lp(a) in groups with high or low baseline
TG levels.</p>
<p>Women in both the patient (p=0.012) and the reference groups
(p=0.001) had higher Lp(a) levels compared to men and their was a
negative correlation between Lp(a) and age in the patient (women) but
not in the reference group. The median Lp(a) levels were significantly
higher in the patient group.</p>
<p>No significant correlations between Lp(a) and TC, HDL.</p>
<p>No significant correlations between Lp(a) and fibrinogen, PAI-1
activity or antigen, plasma D-dimer, plasminogen, BMI and BP.</p>
<p>Significant ↑ in EPA and DHA levels was observed in n-3 PUFAs
compared to baseline and control group (p&lt;0.001 for both EPA and DHA
and for baseline and control)</p></td>
<td><p><u>Conclusion:</u> I</p>
<p>The Lp(a) was higher in patients with CAD than in the reference
group. No association between the levels of Lp(a) and other lipoproteins
or on fibrinolytic variables was observed. No effect of n-3 PUFAs on
Lp(a) levels was observed.</p>
<p><u>Comments:</u></p>
<p>The subjects received general dietary advice and were asked to
refrain from fish oil products.</p></td>
<td>2</td>
<td></td>
</tr>
<tr class="odd">
<td><p>Eritsland et al. 1995c</p>
<p><em>Blood Coagulation and Fibrin</em>. 1995. 6:17-22</p>
<p>[Norway]</p></td>
<td>To assess the long-term effects of a moderate dose of n-2
polyunsaturated fatty acids on hemostatic variables in patients with
coronary artery disease</td>
<td>Randomized, controlled</td>
<td><p>9 months</p>
<p>(starting on the second postoperative day)</p></td>
<td><p>3.32 g/day EPA + DHA from</p>
<p>4 g/day fish oil</p>
<p>(1 g fish oil capsules contained 51% EPA, 32% DHA, and 3.7 mg vitamin
E) ±</p>
<p>antithrombotic treatment with aspirin or warfarin</p>
<p>Compliance: serum phospholipid fatty acids</p></td>
<td><p>511 patients undergoing coronary artery bypass surgery</p>
<p>mean age: 59.9 years (fish oil group); 59.4 years (control group)</p>
<p>% male: 85.8% (fish oil group); 87.6% (control group)</p>
<p>Aspirin + n-3 FA: 143</p>
<p>Aspirin alone: 148</p>
<p>Warfarin + n-3 FA: 174</p>
<p>Warfarin alone: 145</p>
<p>99 patients withdrawn due to: deviation from assigned treatment (66),
death (12), started anti-diabetic or lipid- lowering drug therapy during
study (11), angiography before 9 months (9), and absence at 9 months
visit (1).</p></td>
<td><p><u>TG</u>: ↓ significantly (-19.1%) in fish oil group,
p&lt;0.0001 when compared to control group</p>
<p><u>Bleeding episodes</u>: NS differences in frequency of bleeding
episodes between the fish oil and control group, and for patients who
received aspirin compared to those who received warfarin (total number
of bleeding episodes were 8, 10, 14, and 17 for patients who received
aspirin, aspirin + fish oil, warfarin, and warfarin + fish oil,
respectively).</p>
<p><u>Bleeding time</u>: ↑ NS for both fish oil and control patients; NS
difference between groups</p>
<p><u>Platelet count</u>: ↑ in both fish oil and control group, but fish
oil group had less of an increase (group difference was of borderline
significance, p=0.054).</p>
<p><u>Beta-thromboglobulin</u>: NS difference between groups.</p>
<p><u>Fibrinogen</u>: NS change</p>
<p><u>Factor VII</u>: NS change</p>
<p><u>Fibrinopeptide A</u>: NS change</p>
<p><u>D-Dimer</u>: NS change</p>
<p><u>PAI-1 activity</u>: NS change</p>
<p><u>PAI-1 antigen</u>: small ↑ in fish oil group; small ↓ in control
group (group difference of borderline significance, p = 0.077)</p>
<p><u>Thrombin-antithrombin III complexes</u>: NS ↓ compared to control
(p=0.37)</p>
<p>Serum phospholipid n-3 fatty acids ↑ by 45% in fish oil group and
were nearly unchanged in control group. Serum EPA ↑ by 140%; serum DHA ↑
by 14%. Serum phospholipid n-6 fatty acid levels ↓ by 7% in the fish oil
group and ↑ by 10% in the control group.</p></td>
<td><p><u>Conclusions</u>:</p>
<p>Long-term supplementation with a moderate dose of n-3 PUFAs had not
effect on the hemostatic variables; no excess bleeding episodes could be
ascribed to fish oil supplementation even when combined with aspirin or
warfarin.</p>
<p><u>Comments</u>:</p>
<p>Dietary intake not evaluated.</p>
<p>All pre- and post-study bleeding time values were within the normal
range.</p>
<p>4.2% and 9.6% of patients in the fish oil group and control groups,
respectively, were diabetic.</p></td>
<td>2</td>
<td>Gastrointestinal complaints reported by 34 patients (treatment
groups of patients not reported)</td>
</tr>
<tr class="even">
<td><p>Eritsland et al. 1995d</p>
<p><em>Thrombosis Res.</em> 1995;77(4):337-46</p>
<p>[Norway]</p></td>
<td>To examine the influence of a moderate dietary supplementation with
EPA and DHA on LPS stimulated monocyte procoagulant activity (PCA)</td>
<td>Randomized controlled, trial.</td>
<td><p>24 weeks</p>
<p>(6 months)</p>
<p>All subjects studied before and 6 months after coronary artery bypass
grafting (CABG)</p></td>
<td><p>3.4 g/d EPA + DHA ethyl esters. The ratio of EPA:DHA being about
2:1.</p>
<p>The EPA/DHA was given in</p>
<p>4 g n-3 PUFA concentrate (Omacor™,),</p>
<p>Series One:</p>
<p>(All received ASA)</p>
<p>12 receiving n-3 PUFA</p>
<p>12 controls</p>
<p>Series Two:</p>
<p>(5 pts from each group received ASA and the other 22 received
warfarin).</p>
<p>16 receiving n-3 PUFAs</p>
<p>16 controls</p>
<p>Compliance:</p>
<p>Fatty acids in serum phospholipids were measured</p></td>
<td><p>24 pts. Series One:</p>
<p>12 receiving n-3 PUFAs and</p>
<p>12 controls</p>
<p>32 pts. Series Two:</p>
<p>16 receiving n-3 PUFAs and</p>
<p>16 controls</p>
<p>All subjects had stenosing coronary artery disease and underwent
CABG.</p></td>
<td><p><u>Series 1, standard culture monocytes tested in patient heparin
plasma:</u></p>
<p>No differences between groups in the formation of FPA (p=0.69).</p>
<p>The amount of EPA ↑ 3X in the n-3 PUFA group and slightly↓ in the
control group. A similar pattern was noted for DHA. The group
differences were statistically significant (DHA, p=0.015 and EPA p
&lt;0.001). No group differences in AA.</p>
<p>Series Two: patient monocytes tested in standard heparin plasma:</p>
<p>The change from baseline to 6 months for FPA formation was not
significantly different in the PUFA and control group nor were there any
differences between the groups.</p>
<p>There were no group differences in the LPS stimulated release of IL-6
after 6 months (p=0.79). There was a significant correlation between the
logged values of FPA and IL-6 at baseline (r=0.70, p=0.00001) and
between the logged changes (6 months – baseline) in FPA and IL-6 values
(r=0.64, p=0.0001).</p>
<p>Significantly ↑ amounts of EPA (p &lt;0.001) and total n-3 fatty
acids in the n-3 PUFA compared to the control group after 6 months (p
&lt;0.001).</p></td>
<td><p><u>Conclusions:</u></p>
<p>The authors concluded that, “a moderate dose of n-3 PUFAs given for 6
months to patients operated for coronary artery disease resulted in
significantly ↑ amounts of n-3 PUFAs in serum phospholipids. However,
neither PCA of LPS stimulated standard monocytes incubated with patient
plasma, nor PCA and IL-6 release of LPS stimulated patient monocytes
upon incubation in standard plasma were affected by the n-3 PUFA
supplementation.”</p>
<p>Comments:</p>
<p>The diets were not assessed.</p></td>
<td>2</td>
<td>Not reported</td>
</tr>
<tr class="odd">
<td><p>Eritsland et al. 1996</p>
<p><em>Am J Cardiol</em> 1996;77:31-36</p>
<p>[Norway]</p></td>
<td>To examine the effects of fish oil (rich in n-3 FAs) supplementation
on 1-year graft occlusion rate in patients under going coronary artery
bypass surgery.</td>
<td>Randomized, controlled trial.</td>
<td>52 weeks (1 year)</td>
<td><p>3.32 g/d of EPA+DHA (Omacor<sup>®</sup> fish oil capsules as
ethyl esters)</p>
<p>EPA=2.04 g/d DHA=1.28 g/d</p>
<p>Treatment: fish oil capsules + either warfarin or aspirin</p>
<p>Control: warfarin or aspirin</p>
<p>Compliance: serum phospholipid fatty acid analyses, capsule
count.</p></td>
<td><p>556 patients admitted for coronary artery bypass grafting.</p>
<p>Treatment: 289 subjects</p>
<p>Control: 267 subjects</p></td>
<td><p><u>TG:</u> ↓ (p&lt;0.001)</p>
<p><u>TC:</u> NS between groups</p>
<p><u>LDL:</u> NS between groups</p>
<p><u>HDL:</u> NS between groups</p>
<p><u>Bleeding time:</u> NS between groups</p>
<p>Significant differences in TC, LDL and HDL levels and in bleeding
time were observed in both fish oil and control groups after 1 year of
the study (within groups). All parameters ↑ significantly (p&lt;0.001)
at the end of the study in both groups.</p>
<p>Vein graft occlusion rates per distal anastomoses were reduced in the
fish oil group (27%) compared to the control group (33%) (OR=0.77). The
number of patients having ≥ 1 occluded vein grafts was lower in the fish
oil group (OR=0.72).</p>
<p>A significant trend to fewer patients with vein graft occlusions with
increasing relative change in serum phospholipid n-3 FAs levels during
the study in the fish oil group was observed (p&lt;0.0037).</p>
<p>Serum phospholipid n-3 FAs concentrations ↑ in fish oil
group.</p></td>
<td><p><u>Conclusion:</u></p>
<p>The results suggest that increased dietary intake of n-3 FAs after
coronary artery bypass grafting was associated with a slightly reduced
frequency of vein graft occlusions.</p>
<p><u>Comments:</u></p>
<p>Diet records were obtained from a subset (n=225) of the sample.</p>
<p>Twenty-five subjects in the aspirin+fish oil group and 16 subjects in
the warfarin+fish oil group were withdrawn from the study because of
death or other complications.</p></td>
<td>1</td>
<td>16 (5.5%) and 12 (4.5%) subjects had dyspepsia, belching, diarrhea
and nausea and withdrew from the study in the treatment and control
group, respectively. Six (2.1%) subjects had difficulty swallowing the
fish oil capsules. Few subjects (n=24, 8.3) in the treatment and control
group (n=8, 3%) had milder abdominal complaints, but continued with the
study.</td>
</tr>
<tr class="even">
<td><p>Fasching et al. 1996</p>
<p><em>Horm Metab Res</em> 1996;28:230-236</p>
<p>[Austria]</p></td>
<td>To determine the effects of n-3 FAs on plasma lipid profile and
glucose metabolism and to compare its effects on a molar basis with that
of Gemfibrozil in hyperlipidemic NIDDM patients.</td>
<td>Randomized, open, crossover trial.</td>
<td><p>2 weeks</p>
<p>The subjects underwent a 2-month run-in phase. Then they were
randomly assigned to either fish oil or Gemfibrozil for 2 weeks. After 2
weeks the treatments were reversed with a 8-week washout period between
the treatments.</p></td>
<td><p>4.674 g/d EPA + DHA as triacylglycerols (2.890 g/d EPA and 1.784
g/d DHA, EPAX5000TG) (fish oil)</p>
<p>Gemfibrozil 900 mg and equaled 25% of the ingested molar amount of
n-3 FAs.</p>
<p>Compliance:</p>
<p>Plasma EPA and DHA levels.</p></td>
<td><p>10 hyperlipidemic subjects with NIDDM were recruited in the
diabetes outpatient clinic.</p>
<p>Initially 13 subjects were recruited but 3 subjects were excluded for
the following reasons: one subject developed acute pancreatitis, one
subject had problems with venous blood sampling and one patient left the
country.</p></td>
<td><p><u>TG:</u> ↓ by 18% (p&lt;0.01) with fish oil and 39%
(p&lt;0.001) with Gemfibrozil treatment. Significant ↓ on 2400 kcal diet
during the run-in period.<u><br />
TC:</u> ↓ by 6% (p&lt;0.05) with fish oil and 13% (p&lt;0.01) with
Gemfibrozil treatment. Significant ↓ on 2400 kcal diet during the run-in
period.<u><br />
LDL:</u> No significant ↓ with fish oil (baseline 4.86 ± 1.22 mmol/l,
fish oil 4.78 ± 1.24 mmol/l), but a 15% ↓ (p&lt;0.01) with Gemfibrozil
treatment.<u><br />
HDL:</u> No effect of either treatment on HDL<sub>2</sub> and
HDL<sub>3</sub>.<u><br />
VLDL:</u> ↓ by 34% (p&lt;0.001) with fish oil and 50% (p&lt;0.001) with
Gemfibrozil treatment.</p>
<p><u>VLDL-TG:</u> ↓ by 27% (p&lt;0.01) with fish oil and 44%
(p&lt;0.01) with Gemfibrozil treatment.<u><br />
apo A:</u> No effect of either treatment.</p>
<p><u>apo B:</u> ↓ by 10% (p&lt;0.05) with fish oil and 17% (p&lt;0.01)
with Gemfibrozil treatment.</p>
<p><u>Insulin:</u> NS ↑ with fish oil and Gemfibrozil treatment compared
to baseline.</p>
<p><u>Fasting glucose:</u> NS ↑ during fish oil treatment (9.83 ± 3.50
mmol/l) compared to baseline (9.05 ± 3.44 mmol/l), but no change with
Gemfibrozil.</p>
<p><u>C-peptide:</u> NS ↑ with fish oil and Gemfibrozil treatment
compared to baseline.</p>
<p>AUC-glucose: No change with fish oil and Gemfibrozil treatment after
ivGTT.</p>
<p>AUC-insulin: NS ↓ with fish oil and Gemfibrozil treatment after
ivGTT.</p>
<p>AUC-C-peptide: NS ↓ with fish oil and Gemfibrozil treatment after
ivGTT.</p>
<p><u>Glycated hemoglobin:</u> No change with fish oil or Gemfibrozil
treatment on basal concentrations (baseline 7.4 ± 1.9, fish oil 7.5 ±
2.0 %).</p>
<p>Plasma DHA and EPA concentration ↑ by 120% and 520%, respectively
following fish oil treatment.</p></td>
<td><p>Conclusions:</p>
<p>The authors conclude that, “(a) neither treatment affected the
carbohydrate metabolism in patients with NIDDM, and (b) a greater
hypolipidemic efficacy had to be assigned to Gemfibrozil than to fish
oil. It would therefore appear that Gemfibrozil acts as a useful
lipostatic pharmacologic compound, whilst fish oil could serve as a
potential ingredient of a prudent cardio-protective diet which favors
the low plasma TG concentrations found in NIDDM patients”.</p>
<p>Comments:</p>
<p>The subjects were provided dietary counseling and were asked to
maintain 2400 kcal diet.</p></td>
<td>1</td>
<td>2 subjects (20%) in the fish oil group and 1 (10%) subject in the
Gemfibrozil group reported mild epigastric discomfort. No effect of
either treatment was observed on blood analysis, renal and hepatic
parameters.</td>
</tr>
<tr class="odd">
<td><p>Fisher et al. 1998</p>
<p><em>J Lipid Res</em> 1998;39:388-401</p>
<p>[U.S.]</p></td>
<td>The aim of the study was to examine the effect of dietary fish oil
on apo B metabolism in hypertriglyceridemic, NIDDM subjects on
isocaloric, isofat diets.</td>
<td>Controlled, crossover trial.</td>
<td><p>3 weeks (21 days)</p>
<p>The subjects were fed safflower oil for 21 days and then fish oil for
21 days with a 1-month washout period between the two diets.</p></td>
<td><p>0.249 g/d (249 mg/g of EPA +DHA (1 g menhaden oil capsules))
(fish oil group)</p>
<p>&lt;1 mg/g of n-3 oils from safflower (safflower group)</p>
<p>Compliance:</p>
<p>Not reported</p></td>
<td>5 NIDDM subjects (1 female and 4 males) were recruited and admitted
to the Clinical Research Center. The subjects received a weight
maintenance diet for the duration of the study.</td>
<td><p>TG: ↓ significantly (p&lt;0.01) with fish oil supplementation
(safflower 591 mg/dl, fish oil 201 mg/dl).<br />
TC: No significant change with fish oil.<br />
LDL: No significant ↑ with fish oil (average: safflower 77 mg/dl, fish
oil 107 mg/dl, p&lt;0.08)<br />
HDL: No significant ↑ with fish oil.<br />
VLDL: ↓ significantly (p&lt;0.01) with fish oil supplementation
(safflower 410 mg/dl, fish oil 62 mg/dl).</p>
<p><u>IDL:</u> ↓ significantly (p&lt;0.01) with fish oil supplementation
(safflower 194 mg/dl, fish oil 111 mg/dl).<u><br />
apo B:</u> No significant change with fish oil. VLDL-apo B (p&lt;0.04)
and LDL-apo B (p&lt;0.03) levels ↓ significantly, but IDL-apo B levels
did not change.<br />
<u>VLDL-TG/VLDL-apo B:</u> NS ↓ with fish oil.</p>
<p><u>IDL-TG/IDL-apo B:</u> NS ↓ (p&lt;0.07) with fish oil.</p>
<p><u>LDL/LDL-apo B:</u> NS change with fish oil.</p>
<p>Data on kinetic/compartmental modeling and apo B metabolism is not
discussed in this summary.</p></td>
<td><p>Conclusions:</p>
<p>The authors concluded that, “while these subjects demonstrated an
anticipated fall in VLDL-TG concentration and VLDL-apo B production, the
interesting finding is the manner in which apo B responds to this
dietary perturbation, in keeping with the hypothesis that apo B
metabolism adjusts in response to changing states of lipid
metabolism”.</p>
<p>Comments:</p>
<p>Each subject received both treatment but not in a crossover
manner.</p>
<p>Small sample size.</p></td>
<td>1</td>
<td>No reported</td>
</tr>
<tr class="even">
<td><p>Fleischhauer et al. 1993</p>
<p><em>JACC</em> 1993;21(4):982-9</p>
<p>[U.S.]</p></td>
<td>To determine if dietary fish oil supplementation enhances
endothelial-mediated vasodilator responses in human heart transplant
recipients.</td>
<td>Controlled trial.</td>
<td>3 weeks</td>
<td><p>5 g/d EPA + DHA as cod liver oil or fish oil supplement
(Multi-EPA) (3.4 g/d EPA, 2.3 g/d DHA) (fish oil group)</p>
<p>Control group: normal diet and medication.</p>
<p>Compliance:</p>
<p>Bottle and capsules counts.</p></td>
<td><p>14 heart transplant recipients selected for annual coronary
arteriography were recruited. The patients had to discontinue all
vasoactive medication at least 8 hr before the study.</p>
<p>Fish oil group: n=7</p>
<p>Control group: n=7</p>
<p>2/9 subjects not included in the analysis because they had
angiographically evident transplant CAD.</p>
<p>ACh was infused in the left anterior descending (LAD) coronary artery
in both the control and fish oil groups at concentrations of
10<sup>-6</sup>, 10<sup>-5</sup>, 10<sup>-4</sup> and 10-3 mol/l. Left
circumflex coronary artery was not infused with ACh in both groups
(control vessel).</p></td>
<td><p><u>Fish oil group:</u> All patients experienced vasodilation with
fish oil with the peak effect at 10<sup>-5</sup> or 10<sup>-4</sup>
mol/l of ACh. At higher doses of ACh the vasodilation response was
reduced and vasoconstriction was observed. The control vessel remained
unchanged. The vasodilation response in the ACh-infused (10<sup>-5</sup>
or 10<sup>-4</sup> mol/l) vessel was significantly different from the
control vessel (p&lt;0.01) and the baseline values of the infused vessel
(p&lt;0.05). The response to ACh was significantly different between the
groups at 10<sup>-5</sup> (p&lt;0.05), 10<sup>-4</sup> (p&lt;0.005) and
10<sup>-3</sup> (p&lt;0.01) mol/l of ACh.</p>
<p><u>Control group:</u> At lower dose of ACh, two patients had minimal
vasodilation response and five patients did not response. At higher
doses of ACh six patients had vasoconstriction. One patient had no
vasomotor response at any dose. The infused vessel showed
vasoconstriction but the control vessel remained unchanged.</p>
<p>ACh infusion did not affect blood pressure or heart rate in the
control or fish oil groups.</p></td>
<td><p>Conclusions:</p>
<p>The authors conclude that, “dietary supplementation with fish oil
significantly alters endothelium-dependent coronary vasodilation in
heart transplant recipients without alteration of the responses to
endothelium-independent vasodilation. Whether this enhancement of
endothelial function can beneficially alter the natural history of heart
transplant atherosclerosis warrants further study”.</p>
<p>Comments:</p>
<p>Diets were not assessed.</p>
<p>Not randomized placebo controlled trial.</p></td>
<td>2</td>
<td>The fish oil was well tolerated. One patient (14.3%) complained of
gastrointestinal distress and frequent belching. Two patients (28.6%)
complained of fishy smell and/or fishy breath associated with fish oil
treatment. Six patients said that they would continue with the fish oil
treatment if it proves beneficial. The patients did not have difficulty
with hemostasis after catheterization.</td>
</tr>
<tr class="odd">
<td><p>Franzen et al. 1993</p>
<p><em>Medizinische Klinik</em> 1993;88:134-138. (ABSTRACT, German)</p>
<p>[Germany]</p></td>
<td>To investigate the long-term effects of low dose dietary fish oil
supplementation on serum lipids and lipoproteins.</td>
<td>Double-blind, controlled</td>
<td>52 weeks (1 yr.)</td>
<td><p>3.15 g/d n-3</p>
<p>(Amount EPA+DHA not reported, 9 g/d fish oil)</p>
<p>Control: olive oil</p>
<p>Compliance: serum FAs analysis.</p></td>
<td>Number not reported. All patients with normal or moderately elevated
serum lipids.</td>
<td><p><u>TG:</u> ↓ 26% w/ FO, NS for olive oil.</p>
<p><u>HDL</u>: ↑ 26% w/ FO, ↑ 18% w/ olive oil</p></td>
<td><p><u>Conclusions:</u></p>
<p>None reported in abstract.</p>
<p><u>Comments:</u></p>
<p>Summarized from abstract</p></td>
<td>3</td>
<td>Adverse effects and tolerance not reported in abstract.</td>
</tr>
<tr class="even">
<td><p>Freese and Mutanen 1997a</p>
<p><em>Am. J. Clin. Nutr.</em> 1997. 66:591-598</p>
<p>[Finland]</p></td>
<td>To compare the effects of ALA in linseed oil and EPA + DHA in fish
oil on platelet function and hemostatic factors in healthy subjects</td>
<td>Randomized, double-blind, parallel</td>
<td><p>4 week treatment period</p>
<p>12 week follow-up period</p></td>
<td><p>mean EPA + DHA intake: 5.2 g/day (2.9 g/day EPA, 2.3 g/day DHA),
range: 4-7.6 g/day, from</p>
<p>11.5 g/day fish oil</p>
<p>linseed oil (5.9 g/day ALA)</p></td>
<td><p>46 healthy subjects</p>
<p>age range: 20-44 years</p>
<p>17 male/19 female</p></td>
<td><p><u>TC:</u> ↓ but returned to baseline during follow-up in the
fish oil group.</p>
<p><u>TG:</u> ↓ but returned to baseline during follow-up in the fish
oil group.</p>
<p><u>HDL:</u> No effect on HDL observed.</p>
<p>Linseed oil had no effect on these parameters.</p>
<p><u>Bleeding time</u>: ↑ (+18.5%) in fish oil group but returned to
baseline during follow-up; also ↑ in linseed oil group but did not
return to baseline during follow-up.</p>
<p><u>Factor VIIc</u>: ↑ in both groups</p>
<p><u>PAI-1 activity</u>: ↑ in both groups, but returned to baseline
during follow-up period</p>
<p>No significant differences in collagen-induced aggregation,
thromboxane B<sub>2</sub> (TXB<sub>2</sub>) production, platelet
aggregation to I-BOP, urinary excretions of 1,1-dehydro-thromboxane
B<sub>2</sub>, β-thrombo-globulin, bleeding time, coagulation factors
(plasma fibrinogen concentration, antithrombin III activity, factor VII
coagulant activity) and PAI-1 activity observed between treatment
groups.</p>
<p>Fish oil supplementation increased DHA in platelet lipids by 39% and,
EPA by 115%. Linseed oil supplementation increased EPA by 17% but had no
significant effect on DHA levels.</p></td>
<td><p><u>Conclusions</u>:</p>
<p>Authors concluded that, “supplementation with high amounts of ALA
from vegetable oil or EPA+DHA from a marine source produces similar
changes on hemostatic factors”.</p>
<p><u>Comments</u>:</p>
<p>No statistical analysis conducted on changes in parameters within a
group (baseline vs. treatment period); data for the various platelet
aggregation factors only presented graphically; EPA + DHA intake higher
than 3 g/day; subjects asked to maintain normal dietary habits;
stability of diets checked by 48-hr recall during each period.</p></td>
<td>2</td>
<td>Well tolerated. No major gastric side effects were reported; no
dropouts occurred due to the supplements.</td>
</tr>
<tr class="odd">
<td><p>Freese and Mutanen 1997b</p>
<p><em>Thrombosis Res.</em> 1997. 85(2):147-152</p>
<p>[Finland]</p></td>
<td>To investigate the postprandial responses of Factor VIIc, PAI-1
activity and platelet function in healthy normolipidemic subjects before
and after supplementation of ALA in linseed oil or EPA+DHA in fish
oil</td>
<td>Randomized, controlled trial.</td>
<td><p>4 weeks</p>
<p>with a 12-week follow-up period</p></td>
<td><p>5.49 g/day EPA + DHA</p>
<p>(3.04 g/day EPA, 2.45 g/day DHA); 12.2 g/day fish oil (Pikasol) +
sunflower oil</p>
<p>Control: 11.9 g/day linseed oil (6.21 g/day ALA)</p>
<p>Compliance: Platelet lipid FA analysis</p></td>
<td><p>30 healthy normolipidemic subjects; 15 male, 15 female</p>
<p>Fish oil: n=16</p>
<p>Control: n=14</p></td>
<td><p><em>Fasting values:</em></p>
<p><u>TG</u>: significant ↓ compared to baseline and control group (NS
change in control group)</p>
<p><u>TC</u>: significant ↓ (NS change in control group)</p>
<p><u>Factor VII coagulant activity (FVIIc)</u>: ↑ in fish oil group,
p&lt;0.05</p>
<p><u>PAI-1 activity</u>: ↑ in fish group, p&lt;0.05</p>
<p><u>ADP-induced platelet aggregation</u>: significant ↑ at 2 μmol/l
ADP, p&lt;0.05 (no significant change for other doses - 1 and 3
μmol/l)</p>
<p><u>Collagen induced platelet aggregation</u>: significantly ↑ at 0.5
μg/ml collagen, p&lt;0.05 (NS changes for other dose levels - 1 and 3
μg/ml)</p>
<p><u>Thromboxane B<sub>2</sub></u>: NS change</p>
<p><em>Postprandial values:</em></p>
<p><u>Factor VII coagulant activity (FVIIc):</u> significantly ↑ before
and after supplementation (p&lt;0.05)</p>
<p><u>PAI-1 activity</u>: ↓ after supplementation (p&lt;0.05)</p>
<p><u>ADP-induced platelet aggregation</u>: significantly ↓
(p&lt;0.05)</p>
<p><u>Collagen induced platelet aggregation</u>:</p>
<p>significantly ↓ (p&lt;0.05)</p>
<p><u>Thromboxane B<sub>2</sub></u>: NS change</p>
<p>All levels returned to normal during the 12-week follow-up period
except for collagen-induced aggregation and Factor VII coagulant
activity.</p>
<p>No significant change in any parameter in the control group.</p>
<p>Plasma EPA, DPA, and DHA ↑ with the fish oil supplementation; ALA ↑
with linoleic acid supplementation.</p></td>
<td><p><u>Conclusions</u>:</p>
<p>“When the n-3 fatty acid status of healthy subjects is modified
either with ALA or EPA+DHA, postprandial responses of Factor VIIc and
ADP-induced platelet aggregation are affected.”</p>
<p><u>Comments</u>:</p>
<p>Habitual diets assessed by repeated 48-hour recalls; diets did not
change during study period.</p></td>
<td>2</td>
<td>Supplements were well tolerated. No major gastric side effects were
reported. Glucose levels increased by 5.5% with fish oil
(p&lt;0.05).</td>
</tr>
<tr class="even">
<td><p>Friedberg et al. 1994</p>
<p><em>Diabetologia</em> 1994;37(1):A67 (ABSRACT)</p></td>
<td>To determine the long-term effects of fish oil supplementation added
to a linoleic acid enriched diet on cholesterol ester transfer protein
(CETP) and lecithin-cholesterol acyltransferase (LCAT) in NIDDM
subjects.</td>
<td>Randomized, control trial.</td>
<td>16 weeks (4 months)</td>
<td><p>3 g/d of EPA + DHA (1.8 g/d of EPA and 1.2 g/d of DHA) (fish oil
group)</p>
<p>Corn oil (control group)</p>
<p>Compliance:</p>
<p>Not reported in the abstract.</p></td>
<td><p>16 NIDDM subjects.</p>
<p>All subjects first consumed a saturated fat diet before they were
assigned to the treatments. Both the control and the treatment group
received linoleic acid enriched diet throughout the treatment.</p>
<p>Fish oil group: n=9</p>
<p>Control group: n=7</p></td>
<td><p>The LCAT activity ↓ significantly (p=0.04) in the corn oil group
(-18.6 ± 11.4) compared to the fish oil group (-7.9 ± 19.8).</p>
<p>CEPT activity ↓ significantly with fish oil treatment.</p>
<p>At the beginning of the treatment the TG, HDL, LDL, CEPT, LCAT and
glycated hemoglobin levels were similar.</p></td>
<td><p>Conclusions:</p>
<p>The authors conclude that, “the addition of fish oil to a linoleic
acid enriched diet mitigates the decrease of LCAT activity induced in
type 2 patients by a linoleic acid enriched diet”.</p>
<p><u>Comments:</u></p>
<p>Summarized from abstract.</p>
<p>Small sample size in each group.</p></td>
<td></td>
<td>Not re[ported</td>
</tr>
<tr class="odd">
<td><p>Fuchs et al. 1992</p>
<p><em>J Clin Pharmacol</em> 1992;32:639-642.</p>
<p>[Israel]</p></td>
<td>To examine the relationship between big platelets and hyperlipidemia
of various types, and the effect of various lipid-lowering modalities on
big platelets.</td>
<td><p>Randomized,</p>
<p>double-blind,</p>
<p>placebo-controlled</p>
<p>cross-over trial.</p></td>
<td><p>8 weeks test</p>
<p>4 weeks washout</p>
<p>8 weeks control</p>
<p>or reverse.</p></td>
<td><p>15 g/d fish oil</p>
<p>(Amount EPA+DHA not reported.)</p>
<p>Control: corn and olive oils</p>
<p>Compliance: not reported</p></td>
<td><p>27 w/ hypertriglyceridemia</p>
<p>Test: 15</p>
<p>Control: 12</p></td>
<td><p><u>TG:</u> ↓ (P&lt;0.05)</p>
<p><u>TC:</u> NS</p>
<p><u>HDL:</u> ↑ (P&lt;0.05)</p>
<p><u>Big platelets %:</u> NS (measured microscopically, big defined as
having diameter exceeding half the diameter of adjacent
erythrocytes.)</p>
<p><u>Platelet count:</u> NS</p></td>
<td><p><u>Conclusions:</u></p>
<p>Changes in cholesterol did not induce changes in big platelets.</p>
<p><u>Comments:</u></p>
<p>Study had 2 parts. 2<sup>nd</sup> group studied had familiar
hypercholesterolemia. Results from Group 2 of study not reported in this
summary.</p>
<p>Dietary influence not assessed.</p>
<p>Amount of EPA &amp; DHA not reported. Fish oil test material
composition not reported.</p></td>
<td>3</td>
<td>Adverse effects &amp; tolerance not reported.</td>
</tr>
<tr class="even">
<td><p>Goh et al. 1997</p>
<p><em>Diabetologia</em> 1997;40:42-52</p>
<p>[Canada]</p></td>
<td>To examine the effects of n-3 fatty acids on plasma lipid, and
lipoprotein fatty acid content of NIDDM individuals.</td>
<td>Randomized, double-blind, crossover trial.</td>
<td><p>12 weeks (3 months) on each treatment (fish oil or linseed oil)
with an initial 3-month olive oil placebo period.</p>
<p>The subjects were assigned to a high polyunsaturated/saturated group
(high P/S, n=10) or a low polyunsaturated/saturated group (low P/S,
n=18) based on 7 day diet analysis. They were then given olive oil for 3
months. After the placebo period the treatments were started in each
group.</p></td>
<td><p>35 mg/kg/d of EPA+DHA (fish oil group)</p>
<p>35 mg/kg/d of linolenic acid: Linseed oil group</p>
<p>Olive oil: placebo</p>
<p>Compliance:</p>
<p>EPA and DHA levels in lipoproteins, pill counts, telephone or
personal interview</p></td>
<td>28 NIDDM patients were recruited from the outpatient Metabolic
Clinic at the University of Alberta Hospital.</td>
<td><p>TG: ↓ significantly (p&lt;0.05) in both the high P/S group and
low P/S group with fish oil compared to linseed oil or placebo. Low P/S
group: fish oil 1.52 ± 0.19, linseed oil 2.18 ± 0.31, olive oil 2.13 ±
0.31 mmol/l. High P/S group: fish oil 1.36 ± 0.46, linseed oil 2.33 ±
0.77, olive oil 1.94 ± 0.54 mmol/l.</p>
<p><u>TC:</u> Not influenced by the type of n-3 fatty acids
consumed.</p>
<p>LDL: Fish oil and linseed oil did not affect the plasma LDL levels.
Low P/S group: fish oil 4.08 ± 0.23, linseed oil 3.98 ± 0.31, olive oil
3.79 ± 0.19 mmol/l. High P/S group: fish oil 3.35 ± 0.23, linseed oil
3.20 ± 0.20, olive oil 3.33 ± 0.21 mmol/l.</p>
<p><u>Fasting glucose:</u> Not influenced by the type of n-3 fatty acids
consumed.</p>
<p><u>Insulin:</u> Not influenced by the type of n-3 fatty acids
consumed.</p>
<p><u>Glucagon:</u> Not influenced by the type of n-3 fatty acids
consumed.</p>
<p>EPA and DHA content ↑ in all lipoprotein lipid classes.</p></td>
<td><p>Conclusions:</p>
<p>The authors concluded that, “in NIDDM patients intake of EPA and DHA,
at a level that can be achieved by the consumption of normal foods, for
example fish that are high in EPA, will result in a significant
reduction in the plasma TG levels without deleterious changes occurring
in other plasma lipid parameters or measures of diabetic control”.</p>
<p>Comments:</p>
<p>7-day diet records were collected at the end of each treatment period
for dietary analysis.</p>
<p>No washout period</p></td>
<td>1</td>
<td>Not reported</td>
</tr>
<tr class="odd">
<td><p>Goode et al. 1997</p>
<h2 id="circulation">Circulation</h2>
<p>1997;96:2802-2807</p>
<p>[UK]</p></td>
<td>“To examine the effects of fish oils given to hypercholesterolemic
patients on small artery function <em>in vitro</em>”.</td>
<td>Randomized, double-blind, placebo controlled trial</td>
<td>12 weeks (3 months)</td>
<td><p>3 g/day EPA+DHA (Maxepa fish oil capsules, assumed 1 g capsules
for a total of 10 g/day oil) 1.8 g/day EPA,</p>
<p>1.2 g/day DHA</p>
<p>Control group: olive oil (assume 1 g capsules for 10 g/day oil)</p>
<p>Compliance:</p>
<p>Pill count</p></td>
<td><p>28 subjects recruited either through the hospital (treatment) or
by advertisement (control)</p>
<p>Study group: 8 hypercholesterolemic (HC) patients and 6 healthy
age-sex matched control individuals</p>
<p>control group: 8 hypercholesterolemic (HC) patients and 6 healthy
age-sex matched control individuals</p></td>
<td><p><u>TG:</u> NS change with fish oil compared to baseline in either
HC or control patients.</p>
<p><u>TC</u>: NS change with fish oil compared to baseline in either HC
or control patients.</p>
<p><u>LDL</u>: NS ↓ with fish oil in HC patients (5.98 ± 0.16 5.77 ±
0.15 mmol/l) and control patients (3.13 ± 0.34 – 3.06 ± 0.29 mmol/l)
compared to baseline.</p>
<p><u>HDL</u>: NS change with fish oil compared to baseline in either HC
or control patients.</p>
<p><u>SBP</u>: NS change with fish oil compared to baseline in either HC
or control patients.</p>
<p><u>DBP</u>: NS change with fish oil compared to baseline in either HC
or control patients.</p>
<p>Response of preconstricted small arteries to acetylcholine
demonstrated improvement in relaxation compared to baseline (p=0.0054)
for HC patients</p>
<p>No significant response of preconstricted arteries to sodium
nitroprusside in either control or HC patients.</p>
<p>EPA and DHA ↑ significantly compared to baseline in red blood cell
membrane.</p></td>
<td><p>Conclusions:</p>
<p>The authors concluded that, “marine fish oil significantly improved
endothelial function in peripheral small arteries in HC patients. This
may provide a mechanism for the beneficial effects of these fatty acids
in coronary heart disease”.</p>
<p>Comments:</p>
<p>All HC subjects had been on an AHA step 1 diet for at least three
months prior to the trial.</p>
<p>Diets were not assessed during the trial</p></td>
<td>1</td>
<td>Not reported</td>
</tr>
<tr class="even">
<td><p>Gray et al. 1996</p>
<h2 id="pharmacotherapy">Pharmacotherapy</h2>
<p>1996;16(2):295-300</p>
<p>[U.S.]</p></td>
<td>“To evaluate the effects on n-3 fatty acids on blood pressure
control and lipid levels”</td>
<td>Randomized, double-blind controlled trial</td>
<td>8 weeks</td>
<td><p>3.4 g/day EPA + DHA (menhaden oil produced by NMFS and provided
by NIH, 18 g of total oil)</p>
<p>2.16 g/day EPA</p>
<p>1.28 g/day DHA</p>
<p>Control group: 18 g/day corn oil</p>
<p>Compliance:</p>
<p>Pill count</p></td>
<td><p>19 subjects (all male) with essential hypertension which was not
optimally controlled with one or more antihypertensive drugs</p>
<p>fish oil group: 9 subjects</p>
<p>control group: 10 subjects</p>
<p>All subjects continued to take antihypertensive drugs and maintain
their normal dietary habits.</p></td>
<td><p><u>TG</u>: significant ↓ at 4 weeks (40.9%, p&lt;0.05) compared
to baseline, but ↑again at 8 weeks so that TG levels were not
significantly different from baseline.</p>
<p><u>TC</u>: no significant change compared to baseline.</p>
<p><u>HDL</u>: no significant change compared to baseline.</p>
<p><u>LDL</u>: significant ↑ at 4 weeks (13.5%) and at 8 weeks (19.1%)
compared to baseline (both ps&lt;0.05)</p>
<p><u>SBP:</u> ↓ significantly in the fish oil group compared to
baseline after 4 weeks (148 to132, p&lt;0.05) but the ↓ was less
pronounced at 8 weeks (148 to134, p&lt;0.05). No difference in the
change in sitting SBP at week 8 between the placebo (-6.4%) and the fish
oil group (-8.8%).</p>
<p><u>DBP:</u> ↓ significantly in the fish oil group after 4 weeks (97
to 90, p&lt;0.05) but the ↓ was less pronounced at 8 weeks (97 to 91,
p&lt;0.05). Sitting DBP ↓ significantly in the placebo group at week 8
(94 to 88, p&lt;0.05). There was no difference in the change in sitting
DBP at week 8 between the placebo (-6.3%) and the fish oil group
(-6.6%).</p>
<p><u>Platelets:</u> significant ↓ at 4 weeks (p&lt;0.05) compared to
baseline.</p>
<p><u>Prothrombin time:</u> no significant difference compared to
baseline.</p>
<p><u>Partial thromboplastin time:</u> no significant difference
compared to baseline.</p></td>
<td><p>Conclusions:</p>
<p>The authors concluded that, "adjunctive fish oil supplementation did
not substantially augment blood pressure lowering in treated
hypertensive men with suboptimally controlled blood pressure. Effects on
plasma lipid values were mixed, with an increase in LDL cholesterol and
a decrease in plasma TG levels”.</p>
<p><u>Comments</u>:</p>
<p>No measure of diets in the study. All subjects maintained their
normal dietary habits</p></td>
<td>1</td>
<td><p>No drop outs due to adverse effects. 4 subjects in the test group
complained of intermittent headaches (36%) while 3 in the placebo group
had gastrointestinal complaints (30%) including nausea, indigestion and
diarrhea. 2 drop outs prior to follow up in the fish oil group for
reasons unrelated to the study.</p>
<p>Uric acid: increased in the treatment group (p=0.078) compared to
baseline. Other standard blood chemistries and liver function tests
remained unchanged</p></td>
</tr>
<tr class="odd">
<td><p>Grundt et al. 1995</p>
<p><em>J Internal Med</em> 1995;237:249-259</p>
<p>[Norway]</p></td>
<td>To determine the effect of n-3 FAs as ethyl ester (K85) on several
interacting atherogenic risk factors, including insulin metabolism,
blood lipid and lipoprotein levels and BP in hyperlipidemic patients who
are not responding to therapeutic diet.</td>
<td>Randomized, double-blind, placebo controlled trial.</td>
<td><p>12 weeks on K85</p>
<p>10 weeks run-in period</p></td>
<td><p>3.4 g/d of EPA+DHA (K85) (n-3 PUFAs group)</p>
<p>4 g/d corn oil (corn oil group)</p>
<p>Compliance: fish intake, capsule counts, serum phospholipid fatty
acid analyses</p></td>
<td><p>57 subjects were recruited from 1 center with serum TG of ≥ 2.0
mmol L<sup>-1</sup> and of ≤ 15.0 mmol L<sup>-1</sup>and serum TC of ≥
6.0 mmol L<sup>-1</sup>.</p>
<p>n-3 PUFAs group: 28 subjects</p>
<p>Placebo group: 29 subjects</p></td>
<td><p><u>TG:</u> ↓ significantly (28%, p&lt;0.05, as early as 4 weeks)
after 12 weeks of n-3 supplementation compared to baseline levels. A
significant transient ↓ was observed with corn oil at 4 weeks but NS ↓
was noted by 8 and 12 weeks.</p>
<p><u>TC:</u> ↓ significantly (p&lt;0.05) in both groups.</p>
<p><u>HDL:</u> ↑ significantly at 4 and 8 weeks (p&lt;0.05) with n-3
PUFAs. The increase was NS at 12 weeks.</p>
<p><u>Lp(a):</u> No significant changes with n-3 PUFAs.</p>
<p>apo A: No significant changes with n-3 PUFAs in apo A-1.</p>
<p><u>apo B:</u> ↓ significantly in corn oil group but not in n-3 PUFAs
group.<u><br />
BP:</u> Significant ↓ in systolic and DBP (p&lt;0.05) with n-3
PUFAs.</p>
<p><u>Heart rate:</u> Significant ↓ in heart rate (p&lt;0.05) with n-3
PUFAs.</p>
<p><u>Serum glucose:</u> No change with n-3 PUFAs.</p>
<p><u>Plasma insulin:</u> No change with n-3 PUFAs in insulin and
proinsulin levels. No change in the insulin:glucose and
proinsulin:glucose ratio with n-3 PUFAs.</p>
<p>The EPA and DHA levels in serum phospholipids increased significantly
(p&lt;0.05) with n-3 PUFAs supplementation.</p></td>
<td><p>Conclusion:</p>
<p>The authors conclude that, “the atherogenic risk profile was improved
with n-3PUFA (K85) in subjects with combined hyperlipidemia, but n-3 FAs
supplementation did not affect glucose/insulin homeostasis”.</p>
<p><u>Comments:</u></p>
<p>Intent-to-treat analyses.</p>
<p>During the run-in period the subjects did not consume any dietary
supplements containing n-3 PUFAs.</p>
<p>Subjects were asked to maintain a stable diet. The weekly intake of
fishmeal was registered prior to the n-3 supplementation and at the end
of the study. Therapeutic (low fat diet (30% or less energy from fat))
diet was consumed throughout the study period. The subjects were given
written and oral instructions about dietary changes.</p></td>
<td>1</td>
<td><p>Both the groups reported mild side effects mainly
gastrointestinal complaints.</p>
<p>No change in insulin and glucose levels with n-3 PUFAs.</p></td>
</tr>
<tr class="even">
<td><p>Grundt et al. 1999</p>
<h2 id="thromb-haemost">Thromb Haemost</h2>
<p>1999;81:561-5</p>
<p>[Norway]</p></td>
<td>“To assess the influence of n-3 fatty acids on homocysteine and
several coagulation factors.”</td>
<td>Randomized, double-blind placebo controlled trial</td>
<td>12 weeks following a 10 week run-in dietary adjustment period</td>
<td><p>3.4 g/day EPA+DHA (4 g/day fish oil capsules)</p>
<p>Control group: 4 g/day corn oil</p>
<p>Compliance:</p>
<p>Pill count, fish intake, and fatty acid profile</p></td>
<td><p>56 patients (51 males and 6 females) with combined hyperlipidemia
who received no antihyperlipemic medication</p>
<p>Treatment group: 28 patients</p>
<p>Control group: 28 patients</p>
<p>One subject of the 57 recruited was withdrawn for administrative
reasons.</p></td>
<td><p><u>TG</u>: 28% ↓ after 12 weeks of fish oil supplementation
compared to baseline (p&lt;0.05).</p>
<p><u>HDL</u> ↑ significantly (p&lt;0.05) after 4 and 8 weeks of fish
oil treatment.</p>
<p><u>TC</u>: ↓ significantly in both groups (p&lt;0.05).</p>
<p><u>Hcy</u>: no significant change from baseline.</p>
<p><u>Fibrinogen</u>: no significant change from baseline in both
groups.</p>
<p><u>Coagulation factor VII</u>: no significant change from baseline in
both groups.</p>
<p><u>TFPI</u>: no significant change from baseline with fish oil
supplementation.</p>
<p><u>PAI</u>: ↑ significantly in the treatment group (p&lt;0.05) and
tended to ↓ in the corn oil group (NS).</p>
<p><u>Bleeding time</u>: ↑ NS by 30 seconds in the treatment group.</p>
<p><u>Total platelet count</u>: ↓ by 3.3% in the treatment group
(p&lt;0.05).</p>
<p>NS difference between the groups in the relative changes in
hemostatic variables.</p>
<p>Serum phospholipids EPA and DHA levels ↑ significantly in the
treatment group (p&lt;0.05).</p></td>
<td><p>Conclusions:</p>
<p>The authors conclude that, “the antiatherogenic effect, and
especially the triglyceride lowering potential of n-3 fatty acids
supplementation, was not related to a change in total plasma Hcy in
subjects with combined hyperlipidemia. The antithrombotic effects in the
present setting were modest”.</p>
<p>Comments:</p>
<p>The weekly intake of fish meals was recorded prior to the dietary
intervention, prior to the drug treatment and at the end of the study.
The subjects consumed therapeutic diets during the run-in and treatment
periods. Subjects were given written and oral instructions regarding the
dietary changes. Subjects did not use dietary supplements or medication
w/n-3 FAs during the run-in period. Patients were instructed to maintain
a stable diet.</p>
<p>Stable BMI indicated no dietary changes and intake of fish was
stable.</p></td>
<td>1</td>
<td>Not reported.</td>
</tr>
<tr class="odd">
<td><p>Gustafsson et al. 1996</p>
<p><em>J Hum Nutr Dietet</em> 1997;9:135-145</p>
<p>[Sweden]</p></td>
<td>To evaluate the metabolic effects of fish-oil enriched seafood
products and whether the effects were equivalent to those observed with
pure fish oil preparations.</td>
<td>Double-blind, randomized cross-over trial</td>
<td>3 weeks on each treatment with a minimum 4-week washout period
between treatments</td>
<td><p>3 g/day n-3 FAs during the fish oil period supplied by fish oil
concentrate (EPAX 300TG) in various fish products;</p>
<p>0.3 g/day during sunflower oil (control) period</p></td>
<td>24 subjects (5 females, 19 males) recruited from an ongoing health
survey at a local company. All had borderline-high blood lipid levels.
Mean age was 48.1 years. No concurrent medications.</td>
<td><p><u>TG:</u>  (p=0.0067)</p>
<p><u>TC</u>: NS</p>
<p><u>LDL</u>:  (p=0.0612)</p>
<p><u>HDL</u>: NS</p>
<p><u>SBP</u>:  (p=0.0004)</p>
<p><u>Free FAs</u>:  (0.0025)</p>
<p>No significant change in fasting blood glucose or serum insulin
during the fish oil or control periods.</p>
<p>Serum phospholipids analyzed during the experimental and control
periods, and diaries kept throughout study. Significant increases in EPA
and DHA observed during fish oil period, and in DHA during control
period.</p></td>
<td><p><u>Conclusion</u>: The authors concluded that diets containing
n-3 enriched seafood products caused significant reductions of the serum
TG and of SBP in healthy subjects, compared with sunflower oil-enriched
diets.</p>
<p><u>Comments</u>:</p>
<p>Small sample size</p>
<p>Good dietary assessment and compliance</p></td>
<td>2</td>
<td>Not reported</td>
</tr>
<tr class="even">
<td><p>Haban et al. 1998</p>
<p><em>Bratisl</em> <em>Lek Listy</em> 1998;99(1):37-42 (ABSTRACT,
foreign)</p>
<p>[Slovakia]</p></td>
<td>To determine the effects of relatively low dose of n-3 PUFA in NIDDM
patients.</td>
<td>Clinical trial.</td>
<td>4 weeks (28 days)</td>
<td><p>2.85 g/d of EPA+DHA (10 capsules of MAXEPA<sup>®</sup>)</p>
<p>(1.7 g/d of EPA and 1.15 g/d of DHA)</p>
<p>Compliance:</p>
<p>Serum EPA and DHA levels</p></td>
<td>21 NIDDM patients with dyslipoproteinemia type IV were treated with
n-3 PUFA.</td>
<td><p><u>TG:</u> Significant ↓ (p&lt;0.005) with n-3 PUFA
supplementation (baseline 3.592 ± 0.214 mmol/l, after treatment 2.670 ±
0.173 mmol/l). In individual patients the final to baseline TG ratio
negatively correlated with the relative percentage of EPA in
phospholipids after the treatment (p&lt;0.03, r= -0.474)</p>
<p><u>TC:</u> No significant change with n-3 PUFA</p>
<p><u>LDL:</u> Small but significant ↑ (p&lt;0.05) with n-3 PUFA. The
LDL values increased from 3.825 ± 0.137 mmol/l at baseline to 4.365 ±
0.199 mmol/l after n-3 PUFA treatment.</p>
<p><u>HDL:</u> Significant ↑ (p&lt;0.02) with n-3 PUFA (baseline 0.977 ±
0.044 mmol/l, after treatment 1.152 ± 0.052 mmol/l).</p>
<p>VLDL: Significant ↓ (p&lt;0.002) with n-3 PUFA supplementation
(baseline 1.567 ± 0.074 mmol/l, after treatment 1.196 ± 0.084
mmol/l).</p>
<p>Fasting glucose: No significant change</p>
<p>(baseline 8.906 ± 0.893 mmol/l, after treatment 9.324 ± 0.750
mmol/l)</p>
<p>Glycated hemoglobin: No significant change (baseline 7.092 ± 0.675
mmol/l, after treatment 8.264 ± 0.528 mmol/l).</p>
<p>The percentage of EPA, DPA and DHA ↑ significantly (all p&lt;0.001)
with n-3 PUFA supplementation.</p>
<p>The PGI<sub>2</sub>-to-thrmboxane TxA<sub>2</sub> ratio ↑
significantly with n-3 PUFA supplementation.</p></td>
<td><p>Conclusions:</p>
<p>The authors did not have a conclusion.</p>
<p><u>Comments:</u></p>
<p>Summarized from abstract.</p></td>
<td></td>
<td>Not reported</td>
</tr>
<tr class="odd">
<td><p>Haglund et al. 1992</p>
<p>Nutrition Research 1992;12:455-468</p>
<p>[Sweden]</p></td>
<td>To study the effect of the degree of purification of fish oils on
various serum lipid parameters, atherogenic index, and fibrinogen.</td>
<td><p>Randomized</p>
<p>Double blind</p>
<p>Placebo-controlled</p>
<p>Cross-over</p></td>
<td>4 weeks</td>
<td><p>5.4 g EPA ONLY in</p>
<ol type="1">
<li><p>30 ml Eskimo-3 semi-purified fish oil (SPFO)</p></li>
</ol>
<p>or</p>
<ol start="2" type="1">
<li><p>30 ml KABI highly purified fish oil (HPFO)</p></li>
</ol>
<p>Control: 30 ml Soybean oil</p>
<p>Compliance:</p>
<p>Interview, measure remaining oil, serum FAs analysis</p></td>
<td><p>13 in each group -</p>
<p>SPFO:</p>
<p>8 male, 5 female</p>
<p>Avg TG: 1.9 mmol/l</p>
<p>Avg TC: 5.4 mmol/l</p>
<p>HPFO:</p>
<p>9 male, 4 female</p>
<p>Avg TG: 2.7 mmol/l</p>
<p>Avg TC: 5.6 mmol/l</p></td>
<td><p><u>TG:</u> ↓ 45% SPFO vs. baseline (p&lt;0.05). ↓ 43% HPFO vs.
baseline (p&lt;0.01).</p>
<p><u>TC:</u> ↓ SPFO vs. baseline (P&lt;0.05).</p>
<p>↓ HPFO (NS).</p>
<p><u>LDL calculated:</u> NS ↓ SPFO vs. baseline, NS ↑ HPFO vs.
baseline</p>
<p><u>HDL:</u> ↑ 17% SPFO vs. baseline (p&lt;0.01).</p>
<p>↑ HPFO (NS) vs. baseline</p>
<p><u>apo A:</u> ↓ SPFO 19% vs. baseline (p&lt;0.05).</p>
<p>↓ HPFO (NS) vs. baseline</p>
<p><u>Atherogenic index:</u> ↓ SPFO vs. baseline (P&lt;0.05). ↓ HPFO vs.
baseline (NS).</p>
<p><u>Fibrinogen:</u> ↓ SPFO vs. baseline (P&lt;0.01). ↓ HPFO vs.
baseline (P&lt;0.05).</p>
<p><u>Malondialdehyde:</u> ↑ 54% SPFO vs. baseline (P&lt;0.01). ↑ 89%
HPFO vs. baseline (P&lt;0.001).</p>
<p><u>Plasma glucose:</u> ↑ SPFO (NS).</p>
<p>↑ HPFO vs. baseline (P&lt;0.001).</p>
<p><u>Serum EPA:</u> ↑ SPFO 404% (P&lt;0.001). ↑ HPFO 445%
(P&lt;0.001)</p>
<p><u>Serum DHA:</u> ↑ SPFO 37% (P&lt;0.001). ↑ HPFO 59%
(P&lt;0.001).</p></td>
<td><p><u>Conclusion:</u></p>
<p>Highly purified fish oils may not have better effects than
semipurified fish oil concentrates.</p>
<p><u>Comments:</u></p>
<p>Dietary intake assessed.</p>
<p>Drop outs not reported.</p>
<p>Authors questioned adequacy of 2-week washout period.</p></td>
<td>1</td>
<td><p>"Both FO preparations were tolerated by all subjects without any
major adverse effects."</p>
<p>No further detail on adverse effects reported.</p></td>
</tr>
<tr class="even">
<td><p>Haglund et al. 1993</p>
<p><em>Nutrition Research</em> 1993;13:1351-1365</p>
<p>[Sweden]</p></td>
<td>To study the effects of fish oil supplemented with pyridoxine and
folic acid on risk factors for cardiovascular disease.</td>
<td><p>Double blind</p>
<p>crossover</p></td>
<td><p>4 weeks test</p>
<p>5 weeks washout</p>
<p>4 weeks crossover</p></td>
<td><p>30 ml/d fish oil (FO) alone or with 80 mg pyridoxine and 10 mg
folic acid.</p>
<p>(Eskimo-3 fish oil, 19% EPA, 13% DHA)</p>
<p>Compliance: interview, measure remaining oil after trial.</p></td>
<td>12 males, healthy or with slightly increased blood lipids</td>
<td><p><u>TG:</u> ↓ (P&lt;0.01) FO alone vs. baseline</p>
<p><u>TC:</u> NS</p>
<p><u>LDL (calculated):</u> ↑(NS)</p>
<p><u>HDL:</u> ↑ (P&lt;0.05) FO alone vs. baseline</p>
<p><u>Atherogenic index:</u> ↓ (P&lt;0.05) FO alone vs. baseline</p>
<p><u>Plasma Glucose:</u> ↑ (P&lt;0.05) FO alone vs. baseline</p>
<p><u>tPA-ACT:</u> ↓ (P&lt;0.01) FO alone vs. baseline</p>
<p><u>PAI-1-AG:</u> ↑ (P&lt;0.01) FO alone vs. baseline</p>
<p>NS change in fibrinogen, homocysteine, pyridoxal 5'phosphate, and
folate.</p>
<p>NS change for tPA-AG and PAI-1-ACT.</p>
<p>Results from FO plus pyridoxine and folic acid not reported
here.</p></td>
<td><p><u>Conclusions:</u></p>
<p>The synergistic effects of fish oil and these B vitamins on lipid
metabolism, fibrinogen synthesis, and possibly tPA and PAI-1 metabolism
may be of importance when fish oils are prescribed to persons with risk
factors for CVD.</p>
<p><u>Comments:</u></p>
<p>Participants instructed not to change their diet habits, but diet
otherwise not assessed.</p>
<p>Some data points not given in study though reported in results
section.</p>
<p>Randomization, selection methods, not reported.</p></td>
<td>2</td>
<td>The fish oil and the supplementations were tolerated by all subjects
without adverse effects.</td>
</tr>
<tr class="odd">
<td><p>Haglund et al. 1994</p>
<p><em>Am. J. Cardiol.</em> 1994. 74:189-192</p>
<p>[Sweden]</p></td>
<td>To evaluate the long-term effects of fish oil on some parameters of
fibrinolysis and lipoprotein(a) in healthy subjects</td>
<td><p>Not controlled</p>
<p>(Study A)</p>
<p>Double-blind, crossover (Study B)</p></td>
<td><p>48 weeks</p>
<p>(12 months)</p>
<p>Study A</p>
<p>3 weeks</p>
<p>per treatment, with a 2- week washout in- between</p>
<p>Study B</p></td>
<td><p>9 g/day n-3 fatty acids (Study B)</p>
<p>4.5 g/day n-3 fatty acids, mainly EPA + DHA [from 15 ml fish oil,
(ESKIMO-3)] -Study A</p>
<p>Study B subjects received fish oil plus a high dose of vitamin E (1.5
IU/g)</p>
<p>or</p>
<p>fish oil plus a low dose of vitamin E (0.3 IU/g) - Study B</p>
<p>The fish oil used contained 40% n-3 fatty acids (19% EPA and 13%
DHA)</p></td>
<td><p>15 healthy subjects with normal or slightly increased serum
lipids; mean age: 41 years; 11 male/4 female (Study A)</p>
<p>12 healthy subjects; mean age: 51 years; 10 male/2 female (Study
B)</p></td>
<td><p>Study A:</p>
<p><u>TG</u>: ↓ significantly</p>
<p><u>TC</u>: no change</p>
<p><u>HDL</u>: no change</p>
<p><u>LDL</u>: no change</p>
<p><u>Plasma lipoprotein(a)</u>: ↓ significantly (-15%) compared to
baseline values (p&lt;0.05)</p>
<p><u>PAI-1 antigen</u>: ↑ significantly (+90%) compared to baseline
values (p&lt;0.01)</p>
<p><u>PAI-1 activity</u>: ↑ significantly (+75%) compared to baseline
values (p&lt;0.01)</p>
<p><u>t-PA antigen</u>: ↓ significantly (-33%) compared to baseline
values (p&lt;0.05)</p>
<p><u>Plasma fibrinogen</u>: ↓ significantly (-17%) compared to baseline
values (p&lt;0.05)</p>
<p>Study B:</p>
<p><u>TG</u>: ↓ significantly (-48%) with vitamin E rich fish oil
(p&lt;0.01); NS ↓<br />
(-21%) with fish oil + 0.3 IU/g</p>
<p><u>Lp(a)</u>: no change</p>
<p><u>PAI-1 antigen</u>: ↑ significantly (+63%) with fish oil + 0.3 IU/g
vitamin E (p&lt;0.01); slight, NS ↑ with vitamin E-rich fish oil.</p>
<p><u>PAI-1 activity</u>: ↑ significantly (+25%) with fish oil + 0.3
IU/g vitamin E (p&lt;0.01); slight, NS ↑ with vitamin E-rich fish
oil.</p>
<p><u>t-PA antigen</u>: no change</p>
<p><u>Fibrinogen</u>: ↓ significantly (-11%) with vitamin E-rich fish
oil; no change with fish oil + 3 IU/g</p></td>
<td><p><u>Conclusions</u>:</p>
<p>Authors concluded that “(n-3) fatty acids consistently decrease
triglyceride levels and increase PAI-1 activity and antigen levels
without affecting t-PA levels… The consistent increase in PAI-1 activity
and antigen may be a nonspecific response to maintain vascular
hemostasis. The addition of vitamin E may be important in overcoming the
potentially deleterious oxidant effect of fish oil.”</p>
<p><u>Comments</u>:</p>
<p>Small sample size.</p>
<p>Study A not controlled.</p>
<p>Diets not assessed, but subjects asked to maintain normal dietary
habits during the study period.</p></td>
<td>3</td>
<td>Not reported.</td>
</tr>
<tr class="even">
<td><p>Haglund et al. 1998</p>
<p><em>Nutr Biochem</em> 1998;9:629-635</p>
<p>[Sweden]</p></td>
<td>To compare the effects of fish oil and fish oil + evening primrose
oil (FO+PEO) on plasma phospholipids, blood lipids, glucose,
homocysteine, fibrinogen and fibrinolysis.</td>
<td>Double-blind, crossover trial.</td>
<td><p>8 weeks</p>
<p>4 weeks on fish oil</p>
<p>5 weeks wash out period</p>
<p>4 weeks on FO+PEO.</p></td>
<td><p>32% EPA+DHA mixture (30 ml fish oil (ESKIMO-3<sup>®</sup>)</p>
<p>19% EPA</p>
<p>13% DHA (fish oil group)</p>
<p>FO+EPO (30 ml)</p>
<p>Compliance: interview, capsule counts, plasma phospholipids FAs
analyses.</p></td>
<td>12 healthy subjects or with moderately increased blood lipids (10
men, 2 post menopausal women)</td>
<td><p><u>TG:</u> ↓ significantly by 36% and 29% respectively after fish
oil (P&lt;0.01) and FO+EPO treatment (before and after comparison), but
no significant difference between the groups.</p>
<p><u>TC:</u> Small changes in TC with both treatments.</p>
<p><u>LDL:</u> Small changes in TC with both treatments.</p>
<p><u>HDL:</u> ↑ by 6 and 5% respectively in the fish oil and FO+EPO
groups.</p>
<p><u>Atherogenic index:</u> FO+EPO and fish oil treatments reduced the
atherogenic index by 12 and 6%, respectively. Significant difference
(P&lt;0.05) between the groups.</p>
<p><u>Plasma glucose:</u> No change with FO+EPO, but NS increase with
fish oil.</p>
<p><u>C peptide and insulin:</u> Nonsignificant changes.</p>
<p><u>Plasma homocysteine:</u> ↓ significantly (10%, p&lt;0.05) with
FO+EPO but NS (4%) with fish oil treatment. No difference between the
groups.</p>
<p><u>Plasma fibrinogen:</u> ↓ by 10 (p&lt;0.05) and 8% (p&lt;0.05) with
fish oil and FO+EPO treatments, respectively.</p>
<p><u>tPA antigen:</u> No change</p>
<p><u>PAI-1 activity:</u> ↑ by 50 (p&lt;0.05) and 23%, respectively with
fish oil and FO+EPO treatments.</p>
<p><u>PAI-1 antigen:</u> ↑ by 49% (p&lt;0.05) with fish oil, but no
change with FO+EPO treatment. Significant difference between the two
groups (p&lt;0.05)</p>
<p>An increase in n-3 FAs particularly EPA (p&lt;0.001) and DHA after
fish oil supplementation was observed. With FO+EPO treatment increase in
EPA and DHA was small.</p></td>
<td><p><u>Conclusion:</u></p>
<p>The authors conclude that, “combination of fish oil and evening
primrose oil had a more favorable effect on the atherogenic index and
caused no increase in PAI-1 antigen. The effects on TG and PAI-1 of the
fish oil and mixture appears to be a result of their (n-3) fatty acid
content.</p>
<p><u>Comments:</u></p>
<p>Diets were not assessed, but the subjects were asked to follow their
routine diet and lifestyle and record any significant changes in diet or
lifestyle.</p>
<p>Data not provided; only figures.</p></td>
<td>2</td>
<td></td>
</tr>
<tr class="odd">
<td><p>Hamazaki et al. 1996</p>
<p><em>J Nutr</em> 1996;126:2784-2789</p>
<p>[Japan]</p></td>
<td>To study the effects of DHA-rich fish oil or DHA ethyl ester on
serum lipids.</td>
<td>Randomized, double-blind, placebo-controlled trial.</td>
<td>13 weeks</td>
<td><p>3.6 g/d of DHA-rich fish oil</p>
<p>10-12 capsules of DHA rich fish oil each containing 300 mg oil (49.3%
DHA/100 g DHA-rich fish oil). The number of capsules taken depended on
the body weight (10 capsules for ≤ 50 kg; 11 capsules for &gt; 50 kg but
≤ 55 kg; 12 capsules for &gt;55 kg)</p>
<p>Control oil: 97% soybean oil and 3% fish oil (fish oil was added so
that the control oil had same smell as DHA oil capsules).</p>
<p>Compliance: capsule count</p></td>
<td><p>24 (age 21-30 years) healthy non-smoking students (males and
females) were recruited from Toyama Medical and Pharmaceutical
University.</p>
<p>DHA group: 13 subjects</p>
<p>Control group: 11 subjects</p></td>
<td><p><u>TG:</u> NS change with DHA supplementation<u><br />
TC:</u> NS change with DHA supplementation<u><br />
LDL:</u> NS change with DHA supplementation<u><br />
HDL:</u> ↑ in the control group<u><br />
apo A1:</u> ↑ in the control group compared to the baseline levels
(p&lt;0.01) and DHA group (p&lt;0.05).</p>
<p><u>apo B:</u> NS change with DHA supplementation</p>
<p><u>Lp(a):</u> NS change with DHA supplementation</p>
<p>NS differences in energy and fatty acids intake from food between the
groups. NS changes in body weight in the two groups.</p>
<p>Serum DHA increased by 2 fold (p&lt;0.001) and EPA increased
(p&lt;0.001) in the DHA group. Oleic and linoleic acids decreased in the
DHA group. NS changes in control group.</p></td>
<td><p>Conclusion:</p>
<p>In conclusion, “DHA at a dose of less than 2 g/d did not change serum
lipid concentrations of normolipidemic subjects. The effects of DHA in
hyperlipidemic patients remain to be investigated in a double-blind
study”.</p>
<p><u>Comments:</u></p>
<p>The subjects were asked to consume their routine diets, maintain body
weight and physical activity level.</p>
<p>The subjects completed food frequency questionnaire before, during
and at the end of the study.</p>
<p>Before the double-blind code was broken some subjects were excluded
for the following reasons: mild dyslipidemia, capsule damage due to
improper storage, significant changes in body weight and low DHA levels
in DHA group (after the code was broken.</p>
<p>The baseline serum apo A1 and HDL levels were higher in females in
both the control and DHA groups.</p>
<p>The original purpose of the study was not to determine the effects of
DHA on serum lipids.</p></td>
<td>1</td>
<td><p>1 subject (9.1%) in the control group and 1 (7.7%) subject in the
DHA group lost 4 and 4.5 kg, respectively. One subject (9.1%) in the
control group gained 7 kg.</p>
<p>4 subjects (36.4%) in the control group reported minor effects such
as digestive tract disorder, nervousness, itching and headache.</p>
<p>Three subjects (23.1%) in the DHA group reported digestive tract
disorder and headache.</p>
<p>One subject each in the control (9.1%) and DHA group (7.7%) reported
that they had difficulty in maintaining body weight and that they gained
more weight with the capsules. The subject in the control group gained
less than 2.5 kg and in the DHA group did not gain more than 2.5 kg.</p>
<p>These adverse effects did not lead to discontinuation of the
capsules. The frequency of adverse effects between the two groups was
not significant.</p></td>
</tr>
<tr class="even">
<td><p>Hansen et al. 1993</p>
<p><em>Eur J Clin Nutr</em> 1993;47:497-507</p>
<p>[Norway]</p></td>
<td>To compare the effects of a prolonged daily intake of an ethyl ester
(EE) or triglyceride (Tri) formula of highly purified n-3 PUFAs on
lipids, platelet function, and haemostasis in normolipidemic men.</td>
<td><p>Randomized</p>
<p>Double blind</p>
<p>Placebo-controlled</p></td>
<td>7 weeks</td>
<td><p>3.6 g/d EPA+DHA triglycerides</p>
<p>2.2 EPA, 1.4 DHA</p>
<p>(ACTIVEPA)</p>
<p>or</p>
<p>3.4g/d EPA+DHA ethyl esters</p>
<p>2.2 g/d EPA, 1.2 g/d DHA (K85)</p>
<p>or</p>
<p>Control: Corn oil</p>
<p>Compliance:</p>
<p>Pill count, Serum FAs analysis</p></td>
<td><p>31</p>
<p>normolipidemic, non-obese, normo-tensive males.</p>
<p>Tri: n=11</p>
<p>EE: n=10</p>
<p>Control: n=10</p>
<p>No dropouts.</p></td>
<td><p><u>TG:</u> NS between groups and vs. baseline</p>
<p><u>TC:</u> NS between groups and vs. baseline</p>
<p><u>Serum FAs:</u> ↓ linoleic in Tri &amp; EE groups vs. control
(P&lt;0.001).</p>
<p>↑ EPA&amp;DHA in Tri &amp; EE vs. control (p value not given).</p>
<p><u>BP:</u> NS</p>
<p><u>ADP induced aggregation:</u> ↓ NS for Tri &amp; EE.</p>
<p><u>Collagen induced aggregation:</u></p>
<p>↓ vs. control for Tri (P=0.026) &amp; EE (P=0.0083).</p>
<p><u>TxB2:</u> ↓ vs. control for Tri (P=0.035) &amp; EE (P=0.0002).</p>
<p><u>Plasma fibrinogen:</u> ↓ for EE (P=0.034); ↓ control (P=0.11), but
NS between groups.</p>
<p><u>Plasma tPA:</u> NS</p></td>
<td><p><u>Conclusions:</u></p>
<p>Tri &amp; EE fish oils are well incorporated into plasma lipids and
have similarly beneficial influence on platelet function in men.</p>
<p><u>Comments:</u></p>
<p>Subjects told to maintain their regular physical and dietary habits
during study.</p>
<p>EE &amp; Tri very different EPA and DHA contents.</p>
<p>Small sample group sizes</p></td>
<td>2</td>
<td>"No adverse drug effects were reported during the
intervention."</td>
</tr>
<tr class="odd">
<td><p>Hansen et al. 1998</p>
<p><em>Lipids</em> 33(2):131-137.</p>
<p>[Norway]</p></td>
<td>To examine the effect of n-3 supplementation on fatty acid
absorption, serum phospholipids and postprandial triglyceridemia.</td>
<td><p>Randomized</p>
<p>Double blind</p>
<p>Parallel trial</p></td>
<td><p>5 weeks</p>
<p>(after a 2-wk run-in period)</p></td>
<td><p>4.0 g/d EPA or DHA</p>
<p>ethyl ester</p>
<p>(Pronova capsules)</p>
<p>Compliance: Plasma FA analysis, capsule counts</p></td>
<td><p>14 healthy, normo-lipemic male employees at the Univ. of
Tromso.</p>
<p>EPA: 7</p>
<p>DHA: 7</p>
<p>No dropouts.</p></td>
<td><p><u>TG:</u> ↓ EPA group (P=0.09) vs. base; ↓ DHA group (P=0.11)
vs. base. NS between the two groups.</p>
<p><u>TC:</u> N S</p>
<p><u>HDL:</u> NS</p>
<p><u>Apo A:</u> NS</p>
<p><u>Apo B:</u> NS</p>
<p><u>Serum FA:</u> ↑ EPA both groups; P&lt;0.001 in EPA group and
P&lt;0.05 in DHA group.</p>
<p>↑ DPA in EPA group (P&lt;0.001).</p>
<p>↑ DHA in DHA group (P&lt;0.01).</p>
<p><u>Postprandial TG:</u> ↓ (p=0.2) for EPA group, ↓ (p=0.05) for DHA
group vs. base after 5 weeks.</p>
<p>Results of absorption of EPA and DHA before prolonged dietary
intervention not summarized here.</p></td>
<td><p><u>Conclusions:</u></p>
<p>DHA may be more efficient than EPA in reducing postprandial CM
remnants.</p>
<p><u>Comments:</u></p>
<p>Small sample size.</p>
<p>Subjects asked to maintain physical activity and dietary habits
during trial.</p>
<p>Controlled liquid diet during study.</p>
<p>Not placebo-controlled.</p></td>
<td>2</td>
<td>None of the participants experienced discomfort, nausea, or diarrhea
after ingestion of the liquid test meal with addition of EPA or
DHA.</td>
</tr>
<tr class="even">
<td><p>Harris and Muzio 1993</p>
<p><em>Am J Clin Nutr</em> 1993;58:68-74</p>
<p>[US]</p></td>
<td>To determine whether increased clearance of chylomicrons was the
mechanism for reduction of postprandial lipemia by fish oil.</td>
<td><p>Double blind</p>
<p>Cross-over</p>
<p>Randomized</p></td>
<td><p>4 weeks treatment</p>
<p>4 weeks placebo</p>
<p>4+ weeks washout</p></td>
<td><p>4.5 g/d EPA+DHA</p>
<p>(estimated dose)</p>
<p>Actual dose: 0.640 g/d EPA+DHA ethylesters/10 kg bw. Mean bw not
given. A 70 kg person would take 4.5 g/d EPA+DHA.</p>
<p>Control: Olive oil ethyl esters</p>
<p>Compliance:</p>
<p>Pill counts</p></td>
<td><p>8 normolipidemic</p>
<p>4 male, 4 female</p></td>
<td><p><u>TG:</u> ↓ vs. baseline (p&lt;0.001) and placebo
(p&lt;0.02)</p>
<p><u>TC:</u> NS</p>
<p><u>LDL:</u> NS</p>
<p><u>HDL:</u> NS</p>
<p><u>VLDL:</u> ↓ vs. placebo (p&lt;0.01)</p>
<p><u>apo A:</u> NS</p>
<p><u>apo B:</u> NS</p></td>
<td><p><u>Conclusion:</u></p>
<p>Marine FAs reduce chylomicron remnant concentrations.</p>
<p><u>Comments:</u></p>
<p>Distribution of EPA &amp; DHA in FO not given.</p>
<p>Two patients had only 6d washout between treatments. One was in test
group but EPA plasma levels had returned to baseline by day 6.</p>
<p>Patients were U of KS medical staff/students</p>
<p>Dietary intake evaluated.</p>
<p>Small sample size.</p></td>
<td>2</td>
<td>Only one pt had side effects of heartburn, headache "possibly
associated with n-3 FAs"</td>
</tr>
<tr class="odd">
<td><p>Harris et al. 1993</p>
<p><em>J Nutr Biochem</em> 1993;4:706-712</p>
<p>[U.S.]</p></td>
<td>To determine how rapidly serum lipoprotein levels and fatty acid
composition change after n-3 supplementation and return to normal levels
in hypertriglyceridemic patients and to evaluate how n-3 FAs alter the
susceptibility of lipoproteins to Cu-induced oxidation.</td>
<td>Randomized, double-blind, placebo- controlled trial.</td>
<td><p>4 weeks (fish oil)</p>
<p>4 weeks placebo</p>
<p>1 week washout period</p></td>
<td><p>n-3 FAs as ethyl esters 1 capsule per 10 kg bw/d (1 g n-3 FAs per
capsule)</p>
<p>olive oil (placebo)</p>
<p>Compliance: capsule counts</p></td>
<td>10 mildly (9 men and 1 woman) hypertriglyceridemic patients were
recruited from the Lipid and Arteriosclerosis Prevention Clinic at the
University of Kansas Medical Center.</td>
<td><p><u>TG:</u> ↓ significantly (37%, p&lt;0.001) with n-3 FAs.</p>
<p><u>LDL:</u> ↑ significantly (23%, p&lt;0.02) with n-3 FAs</p>
<p><u>apo B:</u> LDL apo B ↑ by 22% and plasma apo B ↑ by 10%
(p&lt;0.02) with n-3 FAs</p>
<p><u>HDL:</u> HDL<sub>2</sub> ↑ by 56% (p&lt;0.02) with n-3 FAs.</p>
<p><u>Lp(a):</u> ↑ but not significantly with n-3 FAs.</p>
<p>No effect on Simplate bleeding time with n-3 FAs</p>
<p>Cu-induced ex vivo oxidation of apo-B containing lipoprotein ↑
significantly (p&lt;0.05) with n-3 FAs compared to the placebo.</p>
<p>Plasma phospholipid EPA and DHA levels ↑ significantly (p&lt;0.001
for both) with n-3 FAs.</p>
<p>No effect of placebo was observed on any parameters.</p>
<p>The diets remained stable during both periods.</p></td>
<td><p><u>Conclusion:</u></p>
<p>The authors conclude that, “n-3 FAs ethyl esters are affective
hypotriglyceridemic agents, and that they impact metabolism very
quickly. How they may alter the atherogenic process is not clear from
this study because some risk factors worsened and others improved”.</p>
<p><u>Comments:</u></p>
<p>The washout period was intentionally short because previous studies
showed a rapid return to baseline conditions.</p>
<p>Diet records were collected at each period and analyzed by
professional nutrition system.</p></td>
<td>2</td>
<td>The supplements were well tolerated with no reported side
effects.</td>
</tr>
<tr class="even">
<td><p>Harris et al. 1997</p>
<p><em>Journal of Cardiovascular Risk</em></p>
<p>1997;4:385-391</p>
<p>[U.S.]</p></td>
<td>To examine the effects of Omacor on severe hypertriglyceridemia</td>
<td>Randomized, double-blind, prospective parallel-group placebo
controlled study</td>
<td>16 weeks following a 4 week dietary run-in period</td>
<td><p>3.4 g/day EPA+DHA (Omacor concentrated EPA &amp; DHA as ethyl
esters, 4 g total supplement)</p>
<p>1.92 g/day EPA</p>
<p>1.52 g/day DHA</p>
<p>placebo group: corn oil</p>
<p>Compliance:</p>
<p>Study reports compliance rate, but does not state the nature of the
measure.</p></td>
<td><p>42 patients with elevated serum triglycerides</p>
<p>study group: 22 patients</p>
<p>control group 20 patients</p></td>
<td><p><u>TG:</u> significant ↓ with Omacor (-45 ± 23%) and ↑ with
placebo (16 ± 35%) compared to baseline. Significant difference in the
changes from baseline between the groups (p&lt;0.0001).</p>
<p><u>TC</u>: significant ↓ with Omacor (15%) from baseline compared to
placebo (p=0.001).</p>
<p><u>TC:HDL:</u> significant ↓ with Omacor (20%, p=0.0013) compared to
placebo.</p>
<p><u>LDL</u>: significant ↑ with Omacor from baseline (32%) compared to
the placebo (2.05 ± 0.93 vs. 2.69 ± 0.98 mmol/l). Significant difference
in the changes from baseline between the groups (p=0.0014).</p>
<p><u>VLDL</u>: significant ↓ with Omacor (32%, p=0.0001) compared to
placebo.</p>
<p><u>HDL</u>: significant ↑ with Omacor from baseline (13%, p=0.004)
compared to placebo.</p>
<p><u>Apo A1</u>: no significant change from baseline in both
groups.</p>
<p><u>Glucose:</u> NS ↑ with Omacor from baseline (104 ± 17 vs. 105 ± 20
mg/dl)</p>
<p><u>HbAIc (%):</u> NS ↓ with Omacor from baseline (5.3 ± 0.6 vs. 4.9 ±
0.4).</p>
<p>Omacor significantly ↑ levels of EPA (p&lt;0.001), DHA (p&lt;0.001),
linoleic (p&lt;0.02) and AA (p&lt;0.02) in serum phospholipids.</p></td>
<td><p>Conclusions:</p>
<p>The authors concluded that, “treatment with Omacor markedly decreased
TG concentrations in patients with severe hypertriglyceridemia…[and]
should diminish the risk for acute pancreatitis, and may also reduce the
long-term risk for cardiovascular disease”.</p>
<p>Comments:</p>
<p>All patients were instructed to follow the NCEP step 1 diet, and
dietary assessment was performed at 0, 8 and 16 weeks.</p>
<p>Patients were instructed to maintain stable lifestyle, including
diet, exercise, smoking and alcohol consumption throughout the trial.
Also patients discontinued taking gemfibrozil and products such as cod
liver oil or lipid decreasing fibers at least 4 weeks before the
trial.</p></td>
<td>1</td>
<td><p>Four patients (18%) in the treatment group reported
gastrointestinal problems during the trial</p>
<p>Three patients (15%) in the control group reported gastrointestinal
problems during the trial</p>
<p>Omacor had no effect on any safety parameters measured, including
glucose, hemoglobin A1c, liver enzymes, kidney function and platelet
counts.</p>
<p>One patient withdrew from the trial on the advice of his personal
physician that he begin taking a statin rather than the study
drug.</p></td>
</tr>
<tr class="odd">
<td><p>Hartog et al. 1993</p>
<p><em>Journal of American College of Cardiology</em> 1993;21:316
(Presentation paper)</p></td>
<td></td>
<td><p>Double-blind crossover trial.</p>
<p>The subjects were assigned either fish oil or maize oil treatment for
6 weeks and then the treatments were switched.</p></td>
<td><p>6 weeks on fish oil</p>
<p>6 weeks on maize oil</p>
<p>Wash out period not reported</p></td>
<td><p>10 g/d EPA+DHA</p>
<p>6 g/d EPA</p>
<p>4 g/d DHA</p>
<p>20 g/d fish oil</p>
<p>Fish oil treatment</p>
<p>20 g/d maize oil treatment</p>
<p>Compliance: Not reported</p></td>
<td>16 male subjects</td>
<td><p>TG: ↓ significantly (p&lt;0.05) with fish oil compared to maize
oil.<br />
TC: ↓ significantly (p&lt;0.05) with fish oil compared to maize
oil.<br />
LDL: ↓ with fish oil compared to maize oil.<br />
HDL: No change with fish oil.<br />
VLDL: ↓ significantly (p&lt;0.05) with fish oil compared to maize
oil.</p>
<p>Phospholipids: ↓ significantly (p&lt;0.05) with fish oil compared to
maize oil.</p></td>
<td><p>Conclusion:</p>
<p>It is postulated that, “the changes in the chemical composition of
the lipoproteins may influence the atherogenity or anti-atherogenity of
these4 lipoproteins. These effects will partially explain the
anti-atherosclerotic effect of fish consumption”.</p>
<p>Comments:</p>
<p>Summarized from presentation paper.</p></td>
<td>3</td>
<td></td>
</tr>
<tr class="even">
<td><p>Hayashi et al. 1995</p>
<p><em>Curr. Ther. Res.</em> 1995. 56:24-31</p>
<p>[Japan]</p></td>
<td>To investigate the effects of the ethyl ester of icosapentate (ethyl
icosapentate) purified from fish oils on plasma lipids, coagulation
factors VII and X, and PAI-1 in patients with familial combined
hyperlipidemia</td>
<td>Not controlled</td>
<td>8 weeks</td>
<td><p>1.8 g/day ethyl icosapentate</p>
<p>Compliance:</p>
<p>Not reported</p></td>
<td>28 subjects with familial combined hyperlipidemia showing phenotype
IIa, IIb, or IV; age range: 20-69 years</td>
<td><p><u>TC</u>: ↓ significantly (-10%), p&lt;0.05</p>
<p><u>TG</u>: ↓ significantly (-41%), p&lt;0.05</p>
<p><u>LDL</u>: NS change</p>
<p><u>HDL</u>: NS change</p>
<p><u>Apo A-1</u>: NS change</p>
<p><u>Apo B</u>: NS change</p>
<p><u>PAI-1</u>: ↓ significantly (-40%), p&lt;0.01</p>
<p><u>Coagulation factor VII</u>: ↓ significantly (-9%), p&lt;0.01</p>
<p><u>Coagulation factor X</u>: ↓ significantly (-10%),
p&lt;0.01</p></td>
<td><p><u>Conclusions</u>:</p>
<p>Purified ethyl icosapentate appears to have an antiatherogenic effect
and may be useful in the control of coronary heart disease and other
atherosclerotic disorders by lowering plasma lipid content and
increasing antithrombotic action.</p>
<p><u>Comments</u>:</p>
<p>Dietary intake not evaluated.</p>
<p>Study was not controlled.</p>
<p>Small sample size.</p></td>
<td>3</td>
<td>No significant changes occurred in hematology and blood chemistry
parameters (i.e., hemoglobin, hematocrit, RBC, WBC, platelet count,
creatinine, urea, uric acid, Ca, total bilirubin, AST, ALT, total
protein, albumin, etc.); all were within the normal limits.</td>
</tr>
<tr class="odd">
<td><p>Hellsten, et. al.</p>
<p>1993</p>
<p>Current Med Res Opinions</p>
<p>1993;13(3):133-39</p>
<p>[Sweden]</p></td>
<td>To examine the effects on fibrinolytic activity of corn oil and a
fish oil preparation enriched with n-3 PUFAs in a long term study.</td>
<td>Double-blind, randomized, controlled trial.</td>
<td><p>20 weeks</p>
<p>(5 months)</p></td>
<td><p>2.0 g/d on n-3 PUFAs. Exact intake of EPA + DHA was not
specified. The fish oil was given as a total of six 1 g capsules of cod
liver oil in 3 capsules twice daily.</p>
<p>Control subjects</p>
<p>received 6 g/d corn oil preparation, given in three 1 g capsules
twice daily. This corresponded to 0.04 g/d of n-3 PUFAs.</p>
<p>Compliance:</p>
<p>Not reported</p></td>
<td><p>40 males and females with TC &gt; 6.5 mmol/l. The ratio of men to
women was not specified.</p>
<p>n-3 PUFA group: n=20</p>
<p>Control: n=20</p>
<p>1/41 subjects recruited dropped out.</p></td>
<td><p><u>TG:</u> No effects on TG after 5 months in either fish oil
(1.45 ± 0.58 vs. 1.45 ± 0.59 mmol/l; p = 0.59) or corn oil groups (1.36
± 0.48 vs. 1.63 ± 0.84 mmol/l; p = 0.17).</p>
<p><u>TC</u>: No effects on TC after 5 months in either the fish oil
(6.6 ± 1.5 vs. 7.1 ± 1.1 mmol/l; p = 0.28) or corn oil groups (7.1 ± 1.2
vs. 7.1 ± 0.9 mmol/l; p = 0.97).</p>
<p><u>HDL:</u> No effects on HDL after 5 months in either fish oil (1.24
± 0.38 vs. 1.20 ± 0.30 mmol/l; p = 0.66) and corn oil groups (1.15 ±
0.28 vs. 1.09 ± 0.24 mmol/l; p = 0.22).</p>
<p><u>BP:</u> No effects on BP in either the fish oil (systolic BP = 119
± 9 mm Hg; p = 0.49) or corn oil group (systolic BP = 136 ± 27 mm Hg; p
= 0.47). The corn oil group had a higher baseline systolic BP (131 ± 24
mm Hg) compared to the fish oil group (systolic BP = 115 ± 16 mm
Hg).</p>
<p><u>PAI-1 activity:</u> The fish oil and corn oil groups were not
significantly different at baseline. After 5 months treatment, there was
a significant ↓ in PAI-1 activity in the corn oil group (p = 0.008), but
this was not accompanied by ↑ tissue plasminogen activator (t-PA)
activity (p = 0.64). In the cod liver oil group, the PAI-1 levels did
not change significantly (p = 0.83).</p>
<p><u>t-PA mass concentration</u>: ↑ in the cod liver oil group (p =
0.056), but the t-PA activities and t-PA mass concentration before or
after venous occlusion (n = 11 for cod liver oil group and n= 8 for the
corn oil control) did not differ significantly after 5 months treatment
compared to before treatment in either groups.</p></td>
<td><h1 id="conclusions">Conclusions: </h1>
<h1
id="the-authors-concluded-that-our-long-term-trial-shows-that-the-corn-oil-preparation-tended-to-diminish-the-pai-1-while-the-fish-oil-preparation-enriched-in-n-3-pufas-had-no-effect-on-the-pai-1-activity-levels.-the-lack-of-impairment-of-fibrinolysis-of-both-tested-preparations-is-seen-from-the-fact-that-neither-of-them-had-any-significant-effects-on-t-pa-mass-concentrations-and-t-pa-activity-levels-after-venous-occlusion..it-is-concluded-that-in-the-doses-given-here-both-these-preparations-have-small-or-no-effects-on-the-fibrinolytic-system.">The
authors concluded that, “our long term trial shows that the corn oil
preparation tended to diminish the PAI-1, while the fish oil preparation
enriched in n-3 PUFAs had no effect on the PAI-1 activity levels. The
lack of impairment of fibrinolysis of both tested preparations is seen
from the fact that neither of them had any significant effects on t-PA
mass concentrations and t-PA activity levels after venous occlusion…..It
is concluded that, in the doses given here, both these preparations have
small or no effects on the fibrinolytic system.”</h1>
<p><u>Comments:</u></p>
<p>Diets were not assessed. Participants were encouraged not to change
their lifestyle during the trial period.</p></td>
<td>2</td>
<td>Not reported</td>
</tr>
<tr class="even">
<td><p>Henderson et al. 1994</p>
<p><em>J. Pediatr.</em> 1994. 124:400-408</p>
<p>[U.S.]</p></td>
<td>To assess the safety of daily oral supplementation with ethyl esters
of fish oil in cystic fibrosis patients with pancreatic insufficiency
compared to healthy subjects</td>
<td>Randomized double-blind, placebo-controlled</td>
<td>6 weeks</td>
<td><p>5.4 g/day EPA + DHA from 8 g/day encapsulated fish oil</p>
<p>Control: olive oil esters (flavored with 0.4% processed menhaden oil
to give slight fish taste and contained 0.002 g/day EPA+DHA)</p>
<p>Compliance: capsule count, diary, phone calls, plasma and erythrocyte
FA analysis</p></td>
<td><p>24 subjects</p>
<p>12 patients with cystic fibrosis; (mean age: 12 years; 7 male/5
female) received fish oil treatment.</p>
<p>Control: 12 healthy subjects (without cystic fibrosis; mean age: 13
years; 7 male/6 female) received olive oil.</p></td>
<td><p><u>Bleeding incidence</u>: no change</p>
<p><u>Prothrombin time</u>: no change</p>
<p><u>Platelet aggregation to ADP</u>: no change</p>
<p><u>Platelet aggregation to collagen</u>: no change</p>
<p>Plasma and erythrocyte EPA and DHA levels ↑ in both healthy subjects
and subjects with cystic fibrosis; no changes were observed in either
group after administration of olive oil.</p></td>
<td><p><u>Conclusions</u>:</p>
<p>Patients with pancreatic insufficiency who have cystic fibrosis can
absorb large amounts of omega-3 FA ethyl esters into plasma and membrane
phospholipids, without serious adverse effects. Further studies are
needed to determine whether supplementation with omega-3 FA leads to
beneficial therapeutic effects in patients with cystic fibrosis.</p>
<p>Comments:</p>
<p>During study period subjects were asked to refrain from eating fish
or foods cooked in olive oil.</p>
<p>Cystic fibrosis patients continued to receive their usual medication,
including pancreatic enzyme and vitamin (A, D, E, and K)
supplementation.</p></td>
<td>2</td>
<td><p>No significant changes observed for vitamin A, vitamin E,
alkaline phosphatase, alanine aminotransferase, bilirubin, glucose,
albumin, total leukocyte count, hemoglobin, or hematocrit in healthy
subjects or patients with cystic fibrosis.</p>
<p>Cystic fibrosis patients had no changes in blood pressure, heart
rate, height, weight, triceps skin-fold thickness, arm fat area, or
mid-arm circumference.</p>
<p>4 cystic fibrosis patients administered fish oil (2 pts) or olive oil
capsules (2 pts) reported diarrhea and/or eructation. One healthy
subject given fish oil reported eructation.</p></td>
</tr>
<tr class="odd">
<td><p>Herrmann et al. 1995</p>
<p><em>Am J Cardiol</em> 1995;76:459-462</p>
<p>[Germany]</p></td>
<td>To examine the effects of high dose of n-3 FAs on plasma lipoprotein
levels in combination with low energy and low fat diet and
exercise.</td>
<td>Randomized, double-blind, controlled trial.</td>
<td>4 weeks</td>
<td><p>8.5 g/d of n-3 FAs (EPA+DHA and other FAs)</p>
<p>12 g/d of fish oil (fish oil group)</p>
<p>Rapeseed oil capsules rapeseed oil group).</p>
<p>Compliance: serum n-3 FAs analyses</p></td>
<td><p>53 male subjects</p>
<p>Treatment: 35</p>
<p>Control: 18</p>
<p>The subjects were ischemic heart disease patients, hospitalized in a
rehabilitation sanatorium.</p></td>
<td><p><u>TG:</u> ↓ significantly (-20.3%) after 4 weeks of fish oil
treatment</p>
<p><u>TC:</u> ↓ significantly in both groups after 4 weeks of fish oil
(-12.2%) or rapeseed diet (-14.4%)</p>
<p><u>LDL:</u> ↓ significantly in both groups after 4 weeks of fish oil
(-16%) or rapeseed diet (-20.3%)</p>
<p><u>HDL:</u> ↑ significantly (+8.3%) after 4 weeks of fish oil
treatment</p>
<p><u>apo B:</u> ↓ significantly in both groups after 4 weeks of fish
oil (-14.2%) or rapeseed diet (-15.2%).</p>
<p><u>Lipoprotein (a):</u> ↓ by 14% in the fish oil group, but remained
unchanged in the rapeseed oil group.</p>
<p><u>Body weight:</u> ↓ significantly in both groups after 4 weeks of
fish oil or rapeseed diet</p>
<p>The fish oil group was divided into responders and nonresponders
based on the lipoprotein (a) changes. The lipoprotein (a) was reduced by
24% in the responders and increased by 8% in nonresponders. A more
pronounced reduction in apo B and LDL was observed in responders
compared to nonresponders.</p>
<p>Tissue plasminogen activator was reduced by approximately 16% in both
groups.</p></td>
<td><p><u>Conclusion:</u></p>
<p>A significant reduction in serum TC, LDL, TG and body weight and an
increase in HDL was observed in the treatment group (fish oil + low
energy, low fat diet + moderate exercise)</p>
<p><u>Comments:</u></p>
<p>Unequal number of subjects in the treatment and control groups.</p>
<p>Changes in serum n-3 FAs not reported.</p></td>
<td>2</td>
<td>No adverse effects were observed except for mild fish aftertaste in
some patients and fish oil was well tolerated.</td>
</tr>
<tr class="even">
<td><p>Horrocks and Yeo 1999</p>
<p><em>Lipids</em> 1999;34:S313</p>
<p>[Korea]</p></td>
<td>To determine if animal products enriched with n-3 PUFA primarily DHA
has the same effects as fatty fish.</td>
<td>Controlled trial.</td>
<td>4 weeks</td>
<td><p>0.2 % each of EPA and DHA in 585 ml/d of Einstein milk (DHA
group) Generic milk: control group</p>
<p>(study 1)</p>
<p>Study 2:</p>
<p>3 Edison eggs containing DHA (DHA group)</p>
<p>3 generic eggs: control group</p>
<p>Study 3:</p>
<p>Chicken group: 200 g/d of chicken</p>
<p>pork group: 200 g/d of pork</p>
<p>Both chicken and pork were enriched with DHA (DHA group)</p>
<p>Compliance: Not measured</p></td>
<td><p>500 boys (14 years) were recruited (study 1)</p>
<p>DHA group: 250 boys</p>
<p>Control group:250 boys</p>
<p>Study 2:</p>
<p>DHA group: 100 women (20 years)</p>
<p>Control group: 100 women</p>
<p>Study 3:</p>
<p>Chicken group: 20 women</p>
<p>Pork group: 20 women</p></td>
<td><p>TC: No change in study 1. TC ↓ from 174.4 mg/dl to 141.1 mg/dl
(p&lt;0.05) after consuming Edison eggs compared to generic eggs in
study 2. ↓ significantly in women consuming chicken or pork enriched
with DHA.</p>
<p><u>TG:</u> NS ↓ (30%) in study 3.</p>
<p><u>LDL:</u> ↓ from 85.2 to 68.1 mg/dl in women consuming chicken
enriched with DHA after 4 weeks. ↓ from 110.0 to 91.8 mg/dl in women
consuming pork enriched with DHA after 4 weeks.</p>
<p><u>HDL:</u> No change in women consuming chicken or pork enriched
with DHA.</p>
<p>Platelet aggregation: ↓ significantly in study 1 with Einstein milk
(p&lt;0.05) compared to generic milk. ↓ significantly in study 2 with
Edison eggs (p&lt;0.05) compared to generic eggs. ↓ significantly in
women consuming chicken or pork enriched with DHA.</p></td>
<td><p>Conclusion:</p>
<p>“Persons on a Western diet might also improve cardiovascular risk
factors by consuming DHA-enriched foods”.</p>
<p><u>Comments:</u></p>
<p>Three studies summarized in one paper. The paper is not detailed.</p>
<p>The amount of DHA in various food products not quantified.</p></td>
<td>3</td>
<td>Not reported</td>
</tr>
<tr class="odd">
<td><p>Howe et al. 1994</p>
<p>Journal of Human Hypertension</p>
<p>1994;8:43-49</p>
<p>[Australia]</p></td>
<td>To assess the effects of dietary sodium restrictions combined with
fish oil supplementation in hypertensives treated with angiotensin
converting enzyme (ACE) inhibitors.</td>
<td>Randomized, double-blind controlled study</td>
<td>6 weeks following a 4 week run-in</td>
<td><p>5 g n-3 fatty acids (Lipitac Forte fish oil capsules, 8 g total
weight)</p>
<p>Placebo group: olive oil</p>
<p>Low sodium groups: all subjects were place on a low sodium diet.</p>
<p>Normal sodium groups: eight 600 mg tablets of slow release NaCl</p>
<p>Compliance:</p>
<p>Pill count and urinary sodium excretion in the low sodium
groups.</p></td>
<td><p>56 subjects (31 males, 25 female) with uncomplicated essential
hypertension on either captopril (45 subjects) or enalapril (11
subjects). Screening excluded subjects with unstable heart, renal or
liver disease, as well as heavy smokers and drinkers.</p>
<p>fish oil: 14 subjects</p>
<p>fish oil +low sodium: 14 subjects</p>
<p>olive oil: 14 subjects</p>
<p>olive oil + low sodium: 14 subjects</p>
<p>5 subjects withdrew from the study: three for changes in
antihypertensive medication and two for unforeseen medical problems
unrelated to BP</p></td>
<td><p><u>TG</u>: significantly ↓ (27%) compared to baseline, and these
changes were significantly greater than those seen in the placebo group
(p&lt;0.05).</p>
<p><u>TC</u>: no significant changes noted</p>
<p><u>SBP:</u> significant ↓ in the fish oil group from baseline (4.3 ±
1.3 mm Hg, p&lt;0.05) but no significant difference compared to olive
oil. Low sodium diet did significantly ↓ SBP compared to subjects who
maintained their normal diet regardless of whether they were treated
with fish or olive oil.</p>
<p><u>DBP:</u> significant ↓ in the fish oil group from baseline (3.1 ±
1.1 mm Hg, p&lt;0.05) but no significant difference compared to olive
oil.</p>
<p><u>Mean arterial BP:</u> significant ↓ in the fish oil group from
baseline (3.1 ± 1.1 mm Hg, p&lt;0.05) but no significant difference
compared to olive oil. Low sodium diet did significantly ↓ mean arterial
BP compared to subjects who maintained their normal diet regardless of
whether they were treated with fish or olive oil.</p>
<p><u>TxA<sub>2</sub></u>: significantly ↓ (51%) compared to baseline,
and these changes were significantly greater than those seen in the
placebo group (p&lt;0.05).</p>
<p><u>Plasma aldosterone</u>: no significant differences in the
treatment group compared to baseline.</p></td>
<td><p>Conclusions:</p>
<p>The authors conclude that, “the hypertensive effect of ACE inhibitors
can be augmented by sodium restriction alone but supplementing the diet
with fish oil may yield additional cardiovascular benefits”.</p>
<p>Comments:</p>
<p>Dieticians assisted all subjects to attain low sodium diets. The
normal sodium group subjects were given NaCl tablets to return their
sodium intakes to normal levels. Subjects were asked to exclude sources
of fish oil from their diet during the study.</p></td>
<td>1</td>
<td>side effects were not reported</td>
</tr>
<tr class="even">
<td><p>Hsu et al. 2000</p>
<h2 id="am-j-clin-nutr">Am J Clin Nutr</h2>
<p>2000;71:28-35</p>
<p>[Taiwan]</p></td>
<td>To study the relationship between VLDL composition and LDL
concentrations in hyperlipidemic patients treated with fish oil</td>
<td>Clinical trial.</td>
<td>4 weeks</td>
<td><p>3 g/day EPA+DHA (TAMA fish oil capsules, 10 g fish oil) 1.45 g/d
EPA, 1.55 g/d DHA</p>
<p>Control group</p>
<p>Compliance:</p>
<p>Fatty acid analysis</p></td>
<td><p>14 patients (11 men, 3 women) with hypertriglyceridemia,
recruited from outpatients at the hospital.</p>
<p>Each patient followed the AHA step 1 diet, but with traditional
Chinese composition. Patients were instructed to discontinue any lipid
lowering agents at least 8 weeks before the trial.</p>
<p>Control group: 11 healthy (8 men, 3 women) normolipidemic subjects
with height and weight similar to study group.</p></td>
<td><p><u>TG</u>: ↓ significantly with fish oil (5.22 ± 1.68 vs. 2.52 ±
0.59 mmol/l, p&lt;0.05) compared to baseline.</p>
<p><u>TC</u>: ↓ significantly with fish oil (6.33 ± 0.67 vs. 5.79 ± 0.54
mmol/l, p&lt;0.05) compared to baseline.</p>
<p><u>HDL</u>: ↑ significantly with fish oil (1.03 ± 0.20 vs. 1.16 ±
0.15 mmol/l, p&lt;0.05) compared to baseline.</p>
<p><u>LDL</u>: ↑ significantly with fish oil (3.33 ± 0.49 vs. 3.51 ±
0.25 mmol/l, p&lt;0.05) compared to baseline.</p>
<p><u>VLDL</u>: ↓ significantly with fish oil (1.52 ± 0.23 vs. 0.69 ±
0.18 mmol/l, p&lt;0.05) compared to baseline.</p>
<p><u>apo AI</u>: no significant variation (37.14 ± 12.5 vs. 38.92 ± 7.5
μmol/l) compared to baseline.</p>
<p><u>apo B</u>: : ↑ significantly with fish oil (2.05 ± 0.43 vs. 2.27 ±
0.5 μmol/l, p&lt;0.05) compared to baseline.</p>
<p><u>apo CII</u>: no significant variation (6.74 ± 2.02 vs. 6.51 ± 2.24
μmol/l) compared to baseline.</p>
<p><u>apo E</u>: : ↓ significantly with fish oil (2.02 ± 0.47 vs. 1.82 ±
0.47 μmol/l, p&lt;0.05) compared to baseline.</p>
<p><u>LDL particle composition:</u> showed significant ↓ in TG content
(p&lt;0.05) but no significant change in cholesteryl ester, free
cholesterol or phospholipid.</p>
<p><u>Fibroblast binding</u>: significant ↓ (p&lt;0.05) in binding of
[<sup>125</sup>I]LDL to fibroblasts compared to baseline.</p></td>
<td><p>Conclusions:</p>
<p>The authors conclude that, “treatment of hypertriglyceridemic
patients with fish oil caused differential effects on VLDL subfractions
and decreased LDL binding to fibroblast receptors, which may have
contributed to the paradoxical increase in LDL cholesterol
concentration”.</p>
<p><u>Comments</u>:</p>
<p>Not a true control group – control group only measured at baseline,
and not at study termination and did not have the same health status as
the study group.</p>
<p>Diets were not measured in the study</p></td>
<td>2</td>
<td>No reports of adverse effects</td>
</tr>
<tr class="odd">
<td><p>Hwang et al. 1997</p>
<h2 id="am-j.-clin-nutr">Am J. Clin Nutr</h2>
<p>1997;66:89-96</p>
<p>[U.S.]</p></td>
<td>To determine if competition between n-6 and n-3 fatty acids
attenuated the effects of fish oil on lipid and other endpoints relative
to CVD.</td>
<td>Randomized, double-blind, placebo-controlled, parallel study</td>
<td><p>8 weeks for study 1</p>
<p>4 weeks for study 2</p>
<p>Study 1 had a 4 week run-in, while study 2 had a 2 week run
in</p></td>
<td><p>9 g/day n-3 PUFAs (NIH/NOAA Biomedical Test material, 9 g/day
menhaden fish oil capsules)</p>
<p>(study 1)</p>
<p>15 g/day n-3 PUFAs (NIH/NOAA Biomedical Test material, 15 g/day
menhaden fish oil capsules)</p>
<p>(study 2)</p>
<p>Control group (study 1): 9 g/day olive oil as placebo + 16 g/day
olive oil incorporated into the diet</p>
<p>Treatment 1 (study 1): 9 g/day fish oil + 16 g/day safflower oil
incorporated into the diet</p>
<p>Treatment 2 (study 1): 9 g/day fish oil + 8 g/day safflower oil and 8
g/day olive oil incorporated into the diet</p>
<p>Treatment 3 (study 1) 9 g/day fish oil + 16 g/day olive oil
incorporated into the diet</p>
<p>Control group (study 2): 15 g/day olive oil</p>
<p>Treatment 1 (study 2): 6 g/day fish oil+9 g/day olive oil</p>
<p>Treatment 2 (study 2): 15 g/day fish oil</p>
<p>Study 1: baseline diet included 8 g/day of n-6 fatty acids.</p>
<p>Study 2: baseline diet included 16 g/day of n-6 fatty acids</p>
<p>Compliance:</p>
<p>Questionnaire, body weight, fatty acid analysis</p></td>
<td><p>28 subjects for study 1 (16 male, 16 female)</p>
<p>34 subjects for study 2 (18 male, 18 female)</p>
<p>Subjects for both studies were healthy individuals with BMI between
19 and 27 , with normal BP, recruited by newspaper advertising.</p>
<p>Control group (study 1): 8 subjects</p>
<p>Treatment 1 (study 1): 6-8 subjects</p>
<p>Treatment 2 (study 1): 6-8 subjects</p>
<p>Treatment 3 (study 1): 6-8 subjects</p>
<p>Control group (study 2): 11-12 subjects</p>
<p>Treatment 1 (study 2): 11-12 subjects</p>
<p>Treatment 2 (study 2): 11-12 subjects</p></td>
<td><p><u>TG:</u> ↓ significantly in all three treatment groups of study
1 compared to baseline (p&lt;0.05) after 4 and 8 weeks. ↓ significantly
in both treatment group of study 2 compared to baseline (p&lt;0.05). No
significant differences were seen between the three treatment groups in
study 1, nor between the two treatment groups in study 2.</p>
<p><u>TC:</u> no significant changes were seen in any of the treatment
groups from either study.</p>
<p><u>HDL:</u> no significant changes were seen in any of the treatment
groups from either study.</p>
<p><u>LDL:</u> no significant changes were seen in any of the treatment
groups from either study.</p>
<p><u>BP:</u> no significant changes were seen in any of the treatment
groups from either study.</p>
<p><u>Platelet count:</u> no significant changes were seen in any of the
treatment groups from either study.</p>
<p><u>Aggregation in whole blood:</u> no significant changes were seen
in any of the treatment groups from either study.</p>
<p><u>Factor VII activity:</u> no significant changes were seen in any
of the treatment groups from either study.</p>
<p><u>Plasminogen activator inhibitor 1 antigen:</u> no significant
changes were seen in any of the treatment groups from either study.</p>
<p><u>TXB<sub>2</sub>:</u> no significant change in any of the treatment
groups in study 1. Significant ↓ in whole blood concentration for both
treatment groups in study 2 (p&lt;0.05) although there was no
significant difference between the two treatment groups.</p>
<p><u>Plasma fibrinogen:</u> no significant change in any of the
treatment groups in study 1. Significant ↓ in for treatment group 2 in
study 2 (p&lt;0.05) while there was no significant change for group 1 in
study 2.</p>
<p>EPA ↑ both in plasma and platelet phospholipids significantly in all
5 treatment groups compared to baseline (p&lt;0.05).</p></td>
<td><p>Conclusions:</p>
<p>The authors conclude that there is a ”lack of effect of the ratio of
n-3 to n-6 PUFAs on the endpoints measured”</p>
<p>Comments:</p>
<p>Food during the study was provided to subjects which contained
controlled amounts of fats and oils. Daily food diaries were
maintained.</p></td>
<td>1</td>
<td>No treatment related adverse effects were noted in the study.</td>
</tr>
<tr class="even">
<td><p>Imano et al. 1999</p>
<p><em>Jpn J Hyg</em> 1999;53:601-610 (ABSRACT, foreign)</p>
<p>[Japan]</p></td>
<td>To investigate changes in platelet function, count and metabolism
following fish intake among Japanese.</td>
<td><p>Not randomized</p>
<p>Not blinded</p>
<p>Not controlled</p></td>
<td><p>2.5 weeks</p>
<p>(17 days)</p></td>
<td><p>8.5 g/d EPA+DHA</p>
<p>in 200-400 g/d fish added to diets.</p>
<p>Control: none</p>
<p>Compliance: not reported.</p></td>
<td><p>7 healthy</p>
<p>4 male</p>
<p>3 female</p></td>
<td><p><u>TG:</u> ↓</p>
<p><u>Serum FAs:</u> ↑ n-3 2x after 5 days, 3x after 15 days.</p>
<p><u>Fibrinogen:</u> ↓</p>
<p><u>Platelet count:</u> ↓</p>
<p><u>Platelet volume:</u> ↑</p>
<p><u>Large platelet count:</u> ↑</p>
<p><u>Large platelet proportion:</u> ↑</p>
<p><u>Platelet aggregation ADP:</u> NS</p>
<p><u>Platelet aggregation Collagen:</u> ↓</p>
<p><u>Platelet Factor IV:</u> ↓</p></td>
<td><p><u>Conclusions:</u></p>
<p>Habitual fish intake may attenuate the development of atherosclerosis
and prevent ischemic heart disease through suppression of platelet
activity and by reducing platelet counts and serum TG levels.</p>
<p><u>Comments:</u></p>
<p>Summarized from abstract.</p>
<p>Small sample size.</p></td>
<td>3</td>
<td>Adverse effects and tolerance not reported in abstract.</td>
</tr>
<tr class="odd">
<td><p>Johansen et al. 1999a</p>
<p><em>J Am Coll Cardiol</em> 1999;33:1619-26</p>
<p>[Norway]</p></td>
<td>To determine if n-3 FAs supplementation from two weeks before
through six months after angioplasty will reduce the frequency of
restenosis.</td>
<td>Randomized, placebo-controlled, double-blind prospective trial.</td>
<td>26 weeks (6 months and 2 weeks)</td>
<td><p>5.04 g/d of EPA+DHA capsules (ethyl esters)
(Omacor<sup>®</sup>)</p>
<p>2.7 g/d EPA</p>
<p>2.34 g/d DHA (treatment)</p>
<p>Corn oil (placebo)</p>
<p>Compliance: serum phospholipid fatty acid analyses, capsule
count.</p></td>
<td><p>388 patients</p>
<p>Treatment: 196</p>
<p>Placebo: 192</p>
<p>Patients who were accepted for elective percutaneous transluminal
coronary angioplasty were recruited from April 1992 through February
1996.</p></td>
<td><p><u>TG:</u> ↓ (p&lt;0.001)</p>
<p><u>TC:</u> NS differences between the groups. In both groups TC
levels at six months were significantly different (p&lt;0.01) from
baseline levels (intra group differences).</p>
<p><u>HDL:</u> NS</p>
<p>NS differences in the incidence (OR=1.05) or in the occurrence
(OR=1.25) of restenosis was observed between the two groups.</p>
<p>EPA and DHA ↑ significantly (p&lt;0.001) in the Omacor<sup>®</sup>
group.</p></td>
<td><p><u>Conclusion:</u></p>
<p>The authors conclude that, “supplementation with 5.1 g n-3 FAs/d for
six months, initiated at least two weeks prior to coronary angioplasty
did not reduce the incidence of restenosis”.</p>
<p><u>Comments:</u></p>
<p>Dietary intake of macronutrients was assessed for 261 subjects
(treatment n=130, placebo n=131) using a standardized dietary
questionnaire.</p>
<p>No differences were observed between the two groups at baseline
except BMI was significantly higher in the treatment group compared to
the placebo group and statins were used more frequently in placebo
group.</p></td>
<td>1</td>
<td>Diarrhea or nausea in three (1.5%) patients receiving the treatment
and two (1%) patients receiving the placebo.</td>
</tr>
<tr class="even">
<td><p>Johansen et al. 1999b</p>
<p><em>Arterioscler. Thromb. Vasc. Biol.</em> 1999 19:1681-1686</p>
<p>[Norway]</p></td>
<td>To investigate the effect of highly concentrated omega-3 fatty acids
on circulating levels of some endothelial surface molecules indicative
of vascular endothelial function and atherosclerotic activity</td>
<td><p>Randomized,</p>
<p>parallel</p>
<p>controlled</p></td>
<td><p>4 weeks</p>
<p>group I had received 5.1 g/day omega-3 fatty acid for 6 months prior
to study</p>
<p>group II were given placebo (corn oil) for 6 months prior to
study</p>
<p>both groups received supplementation for 4 weeks</p></td>
<td><p>5 g/day EPA+DHA</p>
<p>(2.7 g/day EPA,</p>
<p>2.3 g/day DHA)</p>
<p>both groups received supplementation for 4 weeks</p>
<p>Compliance: serum phospholipid fatty acids</p></td>
<td>54 male patients with coronary heart disease (age range: 40-74
years)</td>
<td><p><u>TC</u>: slight ↓ (group I); no change (group II)</p>
<p><u>HDL</u>: slight ↑ (group I &amp; II)</p>
<p><u>TG</u>: slight ↑ (group I); NS ↓ (group II); change significantly
different in group II vs. group I (p&lt;0.01)</p>
<p><u>Tissue plasminogen activator antigen (tPA)</u>:</p>
<p>slight ↑ (group I); NS ↓ (group II); change significantly different
in group II vs. group I (p&lt;0.01)</p>
<p><u>von Willebrand factor</u>: NS ↓ (group I &amp; II)</p>
<p><u>serum thrombomodulin</u>: slight ↓ (group I); NS ↓ (group II);
significantly higher at baseline (before 4 week treatment period) in
group II (p&lt;0.01), but NS after 4 weeks</p>
<p><u>serum P-selectin</u>: slight ↓ (group I &amp; II)</p>
<p><u>serum E-selectin</u>: NS ↑ (group I &amp; II); change
significantly higher in group I vs. group II (p&lt;0.01)</p>
<p><u>serum vascular cell adhesion molecule-1 (VCAM-1)</u>: NS ↑ (group
I &amp; II); change significantly higher in group I vs. group II
(p&lt;0.01)</p>
<p>Group I had higher serum EPA and DHA concentrations at baseline vs.
group II (p&lt;0.01); after 4 week treatment period EPA concentrations
increased in both groups, but increase was more pronounced in group II
vs. group I (p&lt;0.01); DHA decreased in group I but increased in group
II after 4 weeks.</p></td>
<td><p><u>Conclusion</u>:</p>
<p>Authors concluded that omega-3 fatty acid supplementation decreased
hemostatic markers of artherosclerosis, but may have pro-inflammatory
response that could be adverse (due to increase in inflammatory markers
- e.g., serum E-selectin and soluble VCAM-1), possibly caused by an
increase in lipid peroxidation.</p>
<p><u>Comments</u>:</p>
<p>diets not assessed; study population part of the Coronary Angioplasty
Restenosis Trial (CART)</p></td>
<td>2</td>
<td>Not reported.</td>
</tr>
<tr class="odd">
<td><p>Kaminski et al. 1993</p>
<h2 id="blood">Blood</h2>
<p>1993,81(7):1871-1879</p>
<p>[Germany]</p></td>
<td>To investigate the effect of n-3 fatty acid supplementation on mRNA
expression of both platelet-derived growth factor (PDGF-A) and PDGF-B in
quiescent peripheral blood mononuclear cells</td>
<td>Randomized, observer blind controlled study</td>
<td>6 weeks</td>
<td><p>5.84 g/day EPA+DHA (K85, 7 g/day fish oil concentrate)</p>
<p>3.83 g/day EPA</p>
<p>2.01 g/day DHA</p>
<p>Control group: received no placebo</p>
<p>Compliance:</p>
<p>Incorporation of n-3 fatty acids in mononuclear cell
phospholipids.</p></td>
<td><p>13 healthy males who had taken no medication in the 2 weeks prior
to the study.</p>
<p>Fish oil: 6 subjects</p>
<p>Control: 7 subjects</p></td>
<td><p><u>PDGF-A mRNA in mononuclear cells:</u> ↓ 34% compared to
baseline (p&lt;0.05).</p>
<p><u>PDGF-B mRNA in mononuclear cells:</u> ↓ 30% compared to baseline
(p&lt;0.05).</p>
<p><u>Mononuclear cell fatty acid composition</u>: significant ↑ of EPA
and DHA (p&lt;0.05).</p></td>
<td><p>Conclusions:</p>
<p>The down regulation of gene expression of both PDF-A and PDGF-B may
represent a novel mechanism for the antifibrotic and antiatherosclerotic
action of n-3 fatty acids</p>
<p>Comments:</p>
<p>Subjects were advised to maintain their normal diet and refrain from
taking medication.</p>
<p>Small sample size/group</p></td>
<td>2</td>
<td>Side effects include “fishy hiccups” and occasional mild
gastrointestinal discomfort. Other side effects were not reported.</td>
</tr>
<tr class="even">
<td><p>Katz et al. 1996</p>
<p><em>Nutr.</em> 1996. 12:334-339</p>
<p>[U.S.]</p></td>
<td>To evaluate the safety of omega-3 fatty acids administered
intravenously in cystic fibrosis patients</td>
<td>Randomized, double-blind, controlled</td>
<td>4 weeks</td>
<td><p>Not quantified</p>
<p>150 mg/kg of 10% n-3 FA-containing lipid emulsion (Omegavenous, which
contained 18.3% EPA and 27.6% DHA)</p>
<p>Control: 10% Liposyn III lipid emulsion (contained no EPA or DHA) via
intravenous infusion</p>
<p>Compliance: plasma phospholipid FA analysis</p></td>
<td><p>18 subjects with cystic fibrosis</p>
<p>age range: 10-37 years; 9 male/9 female</p>
<p>n-3 FA: n=9</p>
<p>Control: n=9</p>
<p>The treatments were administered iv.</p></td>
<td><p>Fish oil administration had no effect on coagulation parameters
(actual parameters not reported in paper).</p>
<p>Plasma levels of EPA and DHA increased significantly during the
1-month infusion period.</p></td>
<td><p><u>Conclusions</u>:</p>
<p>Authors concluded that, “intravenous administration of fish oils
enriched with long chain omega-3 FA to patients with cystic fibrosis is
safe and bioavailable.”</p>
<p><u>Comments</u>:</p>
<p>Intravenous route of administration.</p>
<p>Study lacks details on laboratory tests conducted.</p>
<p>The actual coagulation parameters evaluated and measurement data not
reported.</p>
<p>Small sample size.</p>
<p>Patients given a standard parenteral nutrition regimen (glucose,
11.4% amino acid solution, and 20% lipid emulsion supplemented with
minerals, vitamins, electrolytes, and trace elements), and allowed to
continue their normal dietary intake.</p></td>
<td>3</td>
<td>All infusions were well tolerated; no changes in respiratory rate,
blood pressure, pulse rate, or general well-being were observed and no
allergic reactions or subjective side-effects were reported throughout
the study. No changes in bilirubin, alkaline phosphatase, SGOT, SGPT,
hematology, and differential and clinical chemistry parameters were
observed; all were within normal limits.</td>
</tr>
<tr class="odd">
<td><p>Kelley, et. al.</p>
<p>1999</p>
<h2 id="lipids">Lipids</h2>
<p>1999;34(4):317-24</p>
<p>[U.S.]</p></td>
<td>To investigate the effects of feeding DHA on FA composition,
eicosanoid production and select activities of human peripheral blood
mononuclear cells (PBMSC), including natural killer cell activity and
production of inflammatory mediators in healthy young men.</td>
<td>Randomized controlled trial</td>
<td><p>13 weeks (90 days)</p>
<p>30 days of basal diet followed by 90 days of diet with DHA added.
Control group received basal diet for the entire 120 day
period.</p></td>
<td><p>6 g/day DHA (given as 15 g/day of DHASCO™ oil from Martek
Corporation, Columbia, MD) The DHASCO™ oil was added and replaced an
isocaloric amount of safflower oil. Thus, 6 g/day of linoleic acid was
replaced by an equivalent amount of DHA; N=7.</p>
<p>Control group received basal diet throughout the 120 day study
period; n=4.</p></td>
<td><p>11 healthy men, ages 20 – 40 years.</p>
<p>All non-smoking and nondrug users. All subjects were immunized on day
85 with a trivalent 1995-96 influenza vaccine. The subjects lived at the
Metabolic Research Unit of the Western Human Nutrition Research Center
for the duration of the study, except for daily walks or other scheduled
outings. They consumed only those foods prepared by the staff and were
under constant supervision.</p></td>
<td><p><u>NK cell activity:</u> DHA feeding for 83 days (study day 113)
caused a 20% ↓ in NK cell activity compared to the activity before DHA
treatment (p = 0.004). This effect was not seen within the first 55 days
(study day 85; p = 0.82). NK activity for the control group did not
change throughout the study.</p>
<p><u>Secretion of proinflammatory cytokines:</u> DHA feeding caused a
NS ↓ in the secretion of both IL-1 and TNF within 55 days (study day
85)(p = 0.093 and 0.31, respectively). With continued feeding of DHA,
the secretion of these cytokines continued to ↓, and by the end of the
study their concentrations were ↓ by 40-45% as compared to the
concentrations before DHA was fed (p = 0.0004 and 0.0002), respectively.
In the control group, the secretions of these 2 cytokines did not change
during the study.</p>
<p><u>Serum influenza Ab titers:</u> The preimmunization (day 30) and
post immunization (day 113) Ab titers against A/Texas, A/Johannesburg
and B/Harbin strains of influenza virus were not significantly different
between the 2 groups. The differential ↑ between the 2 dietary groups
after A/Texas immunization was almost statistically significant (p =
0.059).</p>
<p><u>Eicosanoid secretion:</u> when compared to day 30, DHA feeding
caused a 60-75% ↓ in concentrations of PGE2 and LTB4 secreted into the
tissue culture media by PBMNC stimulated with LPS (p&lt;0.01).
Eicosanoids secreted by the control group did no change during the
study.</p>
<p>PBMNC FA composition on day 30 was not different between the 2
dietary groups. Dietary DHA ↑ the concentration of DHA in PBMNC from 2.3
wt% on day 30 to 7.4 wt% on day 113. The AA content of PBMNC ↓ from 19.8
to 10.7 wt% with DHA feeding. The EPA concentration did not change, nor
did the concentration of major FAs in the PBMNC from control group (data
not given).</p>
<p>Serum concentration of antioxidant vitamins: Concentrations of
retinol, β-carotene, and ascorbate did not change during the study in
either group. The concentration of α-tocopherol on day 113 was
significantly ↓ in both dietary groups when compared to corresponding
values on day 30 (p&lt;0.04).</p></td>
<td><h1
id="conclusions-the-authors-concluded-that-feeding-dha-to-humans-inhibited-select-immune-cell-functions-but-it-seems-to-be-a-less-potent-and-selective-inhibitor-than-predicted-by-previous-results-obtained-with-fish-oils.our-results-show-that-inhibitory-effects-of-dha-on-immune-cell-functions-varied-with-cell-type-and-that-the-inhibitory-effects-are-not-mediated-through-increased-production-of-pge2-and-ltb4.although-the-subjects-in-the-dha-groupdid-not-show-increased-incidence-of-infections-they-may-be-potentially-at-a-higher-risk.-the-risk-for-infections-may-further-increase-with-the-increased-duration-of-dha-feeding-increased-total-fat-intake-or-increased-oxidative-stress.-the-antiflammatory-effects-of-dha-may-be-useful-in-the-management-of-autoimmune-disorders-however-such-benefits-need-to-be-balance-with-increased-risk-of-infections.">Conclusions:
The authors concluded that, “feeding DHA to humans inhibited select
immune cell functions, but it seems to be a less potent and selective
inhibitor than predicted by previous results obtained with fish
oils….Our results show that inhibitory effects of DHA on immune cell
functions varied with cell type, and that the inhibitory effects are not
mediated through increased production of PGE2 and LTB4….Although the
subjects in the DHA group…did not show increased incidence of
infections, they may be potentially at a higher risk. The risk for
infections may further increase with the increased duration of DHA
feeding, increased total fat intake or increased oxidative stress. The
antiflammatory effects of DHA may be useful in the management of
autoimmune disorders; however, such benefits need to be balance with
increased risk of infections.”</h1>
<p>Comments:</p>
<p>Diets consisted of natural foods (except DHA and vitamin E) and were
fed in a 5 day rotating menu with 3 meals and a post-dinner snack.
Dietary composites from each 5 day menus for both diets were analyzed
for macronutrients.</p></td>
<td>1</td>
<td><p>Adverse effects:</p>
<p>See “results: and “conclusions” for information on the inhibitory
effects of dietary DHA on certain immune functions.</p></td>
</tr>
<tr class="even">
<td><p>Kenny et al. 1992</p>
<h2 id="am-j-cardiol">Am J Cardiol</h2>
<p>1992;70:1347-1352</p>
<p>[U.S.]</p></td>
<td>To determine the effect of fish oil dietary supplementation on blood
pressure, systemic hemodynamics and regional vascular reactivity</td>
<td>Randomized double-blind, placebo controlled crossover study</td>
<td>1 week treatment with either fish oil or safflower oil, after which
patients crossed over following a two week wash out period. Initial
treatment was preceded by a week run-in period</td>
<td><p>3.6 g/day EPA+DHA (Promega fish oil capsules)</p>
<p>2.52 g/day EPA</p>
<p>1.08 g/day DHA</p>
<p>Control group: 9 g/day Safflower oil</p>
<p>Compliance:</p>
<p>Pill count</p></td>
<td>8 normotensive men</td>
<td><p><u>TG</u>: significantly ↓ compared to placebo (p=0.02).</p>
<p><u>TC:</u> no significant difference from placebo.</p>
<p><u>LDL:</u> no significant difference from placebo (94 ± 6 mg/dl in
placebo, 88 ± 9 mg/dl in treatment group).</p>
<p><u>HDL</u>: no significant difference from placebo.</p>
<p><u>Serum glucose</u>: no significant difference from placebo (98 ± 5
mg/dl in placebo, 91 ± 2 mg/dl in treatment).</p>
<p><u>Norepinephrine</u>: no significant difference from placebo.</p>
<p><u>Hematocrit</u>: no significant difference from placebo.</p>
<p><u>TXB<sub>2</sub></u>: no significant difference from placebo.</p>
<p><u>BP:</u> no significant change from placebo.</p>
<p><u>Cardiac output:</u> no significant change from placebo.</p>
<p><u>Systemic vascular resistance:</u> no significant change from
placebo.</p>
<p><u>Forearm vascular resistance and blood flow to angiotensin II:</u>
significantly attenuated by fish oil compared to placebo.</p>
<p><u>Reactive hyperemic blood flow</u>: no significant difference from
placebo.</p>
<p><u>Forearm vascular resistance during reactive hyperemia:</u> no
significant difference from placebo.</p></td>
<td><p>Conclusions:</p>
<p>The authors conclude that, “substitution of a moderate dose of fish
oil for fat in a “Western Diet” selectively attenuates the vascular
response to angiotensin independently of changes in α-adrenergic
vasoconstriction or systemic hemodynamics”.</p>
<p>Comments:</p>
<p>Subjects ate only food provided by the medical research center.</p>
<p>Diets were controlled for fat and caloric intake. During the study
period fat intake was decreased to keep the total fat intake
constant.</p>
<p>Short study period (1 week).</p>
<p>Small sample size.</p></td>
<td>2</td>
<td><p>Side effects are not reported, per se, but the article does note
that “the unpleasant side effects of a larger dose were avoided”.</p>
<p>Serum sodium, potassium, urea nitrogen and creatinine were not
significantly different between the two groups. No differences between
groups were seen in other hematologic, biochemical and neurohumoral
variables, nor in urinary electrolytes.</p></td>
</tr>
<tr class="odd">
<td><p>Kothny, et. al. 1998</p>
<h2 id="atherosclerosis">Atherosclerosis</h2>
<p>1998; 140:181-86</p>
<p>[Germany]</p></td>
<td>To examine the short term effects of n-3 FAs on the radial artery
function in patients with CAD</td>
<td>Randomized double-blind placebo controlled study trial.</td>
<td>24 hours</td>
<td><p>10.3 g/d EPA + DHA (given in 18 capsules over a 24 hour period
and containing a total 18 g of FAs.).</p>
<p>Control group received 18 g of FAs, the composition resembling the
average western diet (mostly C16:0, C18:1n-9 and C18:2n-6)</p>
<p>Compliance:</p>
<p>Capsule count and plasma phospholipid FA composition.</p></td>
<td><p>18 male patients with angiographically proven CAD, aged 47-64
years.</p>
<p>Control group: n =9</p>
<p>Treatment group:</p>
<p>n = 9</p></td>
<td><p>There were no significant differences between control and fish
oil groups on any of the parameters measured on the radial artery,
including vessel diameter, flow mediated vasodilatation, cold pressure
test for vasoconstriction and sublingual gylceryl trinitrate mediated
vasodilatation.</p>
<p>These tests were conducted using high resolution tracking echo
tracking methodology.</p>
<p>In the n-3 fatty acid group, the EPA plasma phospholipid fatty acid
level ↑ from 0.97 to 3.46% (p&lt;0.001) and DHA level ↑ from 2.09 to
2.34% (p = NS), whereas the levels remained constant in the placebo
group.</p></td>
<td><p>Conclusions:</p>
<p>The authors concluded that, “one day of ingestion of a high dose of
dietary n-3 FAs had no effect on radial artery endothelium dependent and
independent function <em>in vivo</em> in pts. with CAD.”</p></td>
<td>1</td>
<td>Not reported</td>
</tr>
<tr class="even">
<td><p>Landmark et al. 1993</p>
<p>Journal of Human Hypertension</p>
<p>1993;7:25-32</p>
<p>[Norway]</p></td>
<td>“The present study was carried out to examine the effects of fish
oil in males with primary hypertension and elevated lipid levels and
particularly to examine the potential role of combining fish oil and
nifedipine, a calcium antagonist, on BP and lipid levels.”</td>
<td>Randomized double-blind, crossover, placebo-controlled study</td>
<td><p>4 week treatment with either fish oil or olive oil, after which
patient crossed over following a 4 week washout</p>
<p>A third 4 week treatment period followed directly after the second
treatment period, in which patients received placebo or fish oil +
nifedipine.</p>
<p>There was a 4 week run-in period prior to the study</p></td>
<td><p>4.55 g/day EPA+DHA (fish oil capsules)</p>
<p>1.75 g/day EPA</p>
<p>2.8 g/day DHA</p>
<p>Control group: Olive oil</p>
<p>Compliance:</p>
<p>Not reported</p></td>
<td><p>18 males with hypertension (WHO stage 1-II)</p>
<p>Patients had not been previously treated for hypertension. None had
other diseases which required medical treatment. Those with bleeding
disorders and signs of liver disease or alcohol abuse were
excluded.</p></td>
<td><p><u>TG:</u> Significant ↓ (24%, p&lt;0.01 vs. baseline and
p&lt;0.001 vs. placebo).</p>
<p>TC: No significant change from baseline or placebo.</p>
<p><u>VLDL</u> Significant ↓ (24%, p&lt;0.01 vs. baseline and p&lt;0.001
vs. placebo).</p>
<p><u>LDL:</u> No significant change from baseline or placebo (4.54 –
4.50 mmol/l for baseline and fish oil respectively, placebo was 4.34
mmol/l).</p>
<p>HDL: No significant change from baseline or placebo.</p>
<p><u>Supine SBP:</u> Significant ↓ from baseline (163 vs. 155.5 mm Hg,
p&lt;0.05), but not significantly different from placebo.</p>
<p>Supine DBP: No significant change from baseline or placebo.</p>
<p><u>Supine HR:</u> Significant ↓ from baseline (74 vs. 67 bpm,
p&lt;0.05), but not significantly different from placebo.</p>
<p><u>Standing SBP:</u> No significant change from baseline or
placebo.</p>
<p><u>Standing DBP:</u> Significant ↓ from baseline (121 vs. 114 mm Hg,
p&lt;0.05), but not significantly different from placebo.</p>
<p><u>Standing HR:</u> No significant change from baseline or
placebo.</p>
<p><u>Plasma renin activity</u>: No significant change from baseline or
placebo.</p>
<p><u>Aldosterone</u>: No significant change from baseline or
placebo.</p>
<p>A significant correlation was noted between changes in mean BP and
changes in TC (p&lt;0.001), LDL (p&lt;0.05), and VLDL
(p&lt;0.0005).</p></td>
<td><p>Conclusions:</p>
<p>The authors concluded that, “the combined administration of fish oil
and nifedipine possesses favorable antihypertensive and metabolic
properties in hypertensive males with elevated lipid levels”.</p>
<p>Comments:</p>
<p>Patients were encouraged to continue their normal lifestyles. No
dietary intervention was done, although patients did discontinue any use
of cod liver oil, or related fish oil products 2 months prior to the
trial.</p></td>
<td>1</td>
<td>No patients withdrew from the study due to side effects, although 2
(11%) patients on fish oil and 1 (5.6%) on placebo complained of light
gastric distress. No patients reported diarrhea.</td>
</tr>
<tr class="odd">
<td><p>Lau et al. 1995</p>
<p><em>Clin. Exp. Rheumatol.</em> 1995. 13:87-90</p>
<p>[Hong Kong]</p></td>
<td>To investigate the effects of fish oil on fibrinolytic parameters in
patients with rheumatoid arthritis</td>
<td>Randomized, double-blind, controlled</td>
<td>6 months</td>
<td><p>2.8 g/day (EPA + DHA) from fish oil (Maxepa) capsules</p>
<p>or placebo (air-filled capsules)</p>
<p>Compliance: pill count and measurement of RBC membrane FA
analysis</p></td>
<td><p>45 patients with rheumatoid arthritis as defined by the Am.
Rheum. Assoc.</p>
<p>age range: 27-69 years; 32 male/13 female</p>
<p>n-3 FA: n=25</p>
<p>Control: n=20</p></td>
<td><p><u>Fibrinogen</u>: ↓ significantly (-17.7%) compared to baseline
and month 3 level (p&lt;0.02) and control (p&lt;0.01)</p>
<p><u>t-PA activity</u>: ↓ significantly (-27.8%) compared to baseline
(p&lt;0.001) and control (p&lt;0.01)</p>
<p><u>PAI-1 activity</u>: NS change</p>
<p>NS change in any of the above parameters for the group receiving
placebo.</p>
<p>Fish oil intake significantly ↑ red blood cell EPA levels
(p&lt;0.001) and significantly ↓ AA levels (p&lt;0.01) compared to
baseline; no changes occurred in DHA levels.</p></td>
<td><p><u>Conclusions</u>:</p>
<p>Authors concluded that, “fish oil supplementation does not appear to
produce an improvement in plasma fibrinolysis” and that “fish oil
appears to impair plasma fibrinolysis” in their patients.</p>
<p><u>Comments</u>:</p>
<p>Diet not assessed.</p></td>
<td>2</td>
<td>No significant changes were observed in any clinical or laboratory
variables of rheumatoid arthritis.</td>
</tr>
<tr class="even">
<td><p>Layne et al. 1996</p>
<p><em>J. Nutr.</em> 1996;126:2130-2140</p>
<p>[Canada]</p></td>
<td>To assess the effect of low doses of FAs from fish or flaxseed oil
on plasma lipid concentrations in normal humans consuming diets with
either high or low dietary polyunsaturated/ saturated (P/S) FAs
ratios.</td>
<td><p>Randomized,</p>
<p>double-blind,</p>
<p>controlled</p>
<p>cross-over</p></td>
<td><p>12 weeks</p>
<p>(3 mo. olive oil, 3 mo. test or control, crossover 3 mo.)</p></td>
<td><p>7 g/d fish oil (example for 70 kg person)</p>
<p>= 35 mg/kg bw/d of olive oil, flaxseed oil, or EPA+DHA.</p>
<p>Compliance:</p>
<p>Pill counts, interviews, serum FAs analysis</p></td>
<td><p>26 normolipidemics</p>
<p>recruited at a university campus.</p>
<p>Low P/S: n=15 with P/S ≤0.74</p>
<p>High P/S: n=11 with</p>
<p>min. P/S 0.43</p>
<p>6 drop outs due to protocol exclusion criteria (altering of fat
intake &amp; P/S group)</p></td>
<td><p><u>TG:</u> ↓ (P&lt;0.05) in Low P/S only.</p>
<p><u>TC:</u> NS</p>
<p><u>LDL:</u> NS</p>
<p><u>HDL:</u> NS</p>
<p><u>Plasma Lipoprotein FAs:</u></p>
<p>Multiple data point changes that indicate increased plasma
concentrations of EPA+DHA. Refer to study for further detail.</p></td>
<td><p><u>Conclusions:</u></p>
<p>Low intake of purified FO induces changes in plasma triacylglycerol,
EPA levels in VLDL, LDL, and HDL, and DHA levels in LDL &amp; HDL that
are apparent after 3 mo.</p>
<p><u>Comments:</u></p>
<p>All data results given.</p>
<p>Small sample population.</p>
<p>Greater FO intake than flaxseed or olive oil.</p></td>
<td>2</td>
<td>No adverse effects reported.</td>
</tr>
<tr class="odd">
<td><p>Lenzi et al. 1996</p>
<p><em>Nephron</em> 1996. 72:383-390</p>
<p>[Italy]</p></td>
<td>To evaluate the influence of n-3 fatty acid (FA) supplementation in
patients with chronic glomerular disease on plasma concentrations of
lipoprotein(a) (Lp(a))</td>
<td>Not randomized, open, prospective</td>
<td>6 weeks</td>
<td><p>7.7 g/day EPA + DHA (9 capsules per day of ethyl esters of n-3 FA
(K-85), each capsule containing 1,000 mg fish oil yielding 85% EPA +
DHA) - Study B</p>
<p>3 g/day EPA + DHA (12 capsules per day of n-3 FA, each capsule
containing 750 mg fish oil (MaxEPA) yielding 33% EPA+DHA) - Study A</p>
<p>Compliance: measured by pill count, n-3 FA in plasma lipids, bleeding
time, and serum thromboxane</p></td>
<td><p>8 patients with chronic glomerular diseases</p>
<p>(age range: 19-70 years</p>
<p>6 male/2 female). One pt had NIDDM;</p>
<p>two pts were hypertensive; five pts were hyper-cholesterolemic</p>
<p>3 subjects were studied twice (studies A and B) and 1 subject was
studied 3 times (once on study A and twice on study B)</p>
<p>Study A: n=9 subjects (1 subject studied twice)</p>
<p>Study B: n=4 subjects (all participated in Study A also)</p></td>
<td><p><u>TC</u>: NS change</p>
<p><u>LDL</u>: NS change</p>
<p><u>HDL</u>: NS change</p>
<p><u>TG</u>: ↓ significantly with both doses; average decrease of -12%
with 3 g/day and -24% with 7.7 g/day</p>
<p><u>Lp(a)</u>: NS change</p>
<p><u>Bleeding time</u>: ↑ significantly with both doses: +21.4% with 3
g/day, +33% with 7.7 g/day (p&lt;0.05)</p>
<p><u>Serum thromboxane</u>: ↓ significantly with both doses: -22.5%
with 3 g/day, -33.8% with 7.7 g/day (p&lt;0.05)</p>
<p>Both doses increased the ratio of n-3 to n-6 fatty acids. % plasma
concentrations of EPA increased 6 times and DHA doubled with the low
dose (3 g/day) and returned to baseline levels 4 weeks after treatment
cessation. % plasma concentrations with the high dose (7.7 g/day) were
not significantly different than those for the low dose.</p></td>
<td><p><u>Conclusions</u>:</p>
<p>Omega-3 FA do not decrease Lp(a) concentrations in renal patients
with chronic glomerular diseases and are not likely to be related to the
degree of proteinuria. In addition, the results demonstrated the
efficacy of n-3 FA in altering serum thromboxane (an index of platelet
function), reflecting alterations of eicosanoid synthesis and
platelet-vessel wall interactions (i.e., bleeding time).</p>
<p><u>Comments</u>:</p>
<p>Study not randomized, placebo-controlled, or blinded.</p>
<p>Small sample size.</p>
<p>Bleeding time and serum thromboxane measured as indices of
compliance. All bleeding time values (pre- and post-study) were within
the normal clinical range.</p>
<p>Diet not assessed, but subjects advised not to change their normal
dietary habits while on study.</p></td>
<td>2</td>
<td>No changes were observed in serum creatinine, serum albumin, or
creatinine clearance throughout the study. Proteinuria was reduced at
both doses; the reduction reached statistical significance only at the
high dose level.</td>
</tr>
<tr class="even">
<td><p>Lervang et al. 1993</p>
<p><em>Scand J Clin Lab Invest</em> 1993;53:417-423</p>
<p>[Denmark]</p></td>
<td>To determine the effects of short-term supplementation with low dose
of n-3 on plasma lipids, hemostasis and neutrophil aggregation in
healthy subjects.</td>
<td>Double-blind, controlled trial.</td>
<td>8 weeks</td>
<td><p>0.65 g/d of n-3 FAs (Epax TG 5500 capsule) (treatment group)</p>
<p>Capsule containing a mixture of FAs found in an average Danish diet
(control)</p>
<p>Compliance: Not measured</p></td>
<td>24 healthy subjects (12 males 12 females)</td>
<td><p><u>TC:</u> No change in both groups.</p>
<p><u>TG:</u> No change in both groups.</p>
<p><u>LDL:</u> No change in both groups.<br />
<u>HDL:</u> No change in both groups.</p>
<p><u>Plasma fibrinogen:</u> No change in both groups.</p>
<p><u>PAI:</u> No change in both groups.</p>
<p><u>Factor VII:</u> No change in the n-3 group, but the levels
increased significantly in the control group.</p>
<p>Platelet aggregation in whole blood or aggregation of isolated
neutrophils was not affected.</p></td>
<td><p><u>Conclusion:</u></p>
<p>In conclusion, “the study does not demonstrate any effect of n-3
supplementation (for 8 weeks) on biochemical risk markers for CHD at an
intake of 0.65 g/d”.</p>
<p><u>Comments:</u></p>
<p>Diets were not assessed. The subjects were not allowed to consume
fish (mackerel, herring and salmon) and were told not to change their
dietary habits or life-style.</p>
<p>No gender effect was observed, hence the data were pooled for both
sexes.</p></td>
<td>2</td>
<td></td>
</tr>
<tr class="odd">
<td><p>Li et al. 1994</p>
<p><em>Kardiologiya</em> 1994. 34:44-48</p>
<p>(ABSTRACT, foreign)</p>
<p>[Russia]</p></td>
<td>To evaluate the effects of eiconol on blood lipids, platelet
function and some characteristics of coagulation in patient with stable
angina and atherogenic dislipidemia</td>
<td>Not controlled</td>
<td>6 months</td>
<td><p>Not quantified</p>
<p>8 g/day eiconal (a food supplement enriched with n-3 PUFAs)</p>
<p>Compliance: not reported.</p></td>
<td>95 patients with functional class II-III stable angina and
atherogenic dislipidemia</td>
<td><p><u>TC</u>: ↓</p>
<p><u>TG</u>: ↓</p>
<p><u>LDL</u>: ↓</p>
<p><u>HDL</u>: ↑</p>
<p><u>Functional activity of platelets</u>: ↓</p>
<p><u>% platelet desaggregation</u>: ↑</p>
<p><u>Reaction time to thromboelastogram</u>: ↑</p>
<p><u>Amplitude of thromboelastogram</u>: ↓</p></td>
<td><p><u>Conclusions</u>:</p>
<p>Fish oil supplementation resulted in changes in blood lipids and
hemostatis that could possibly produce favorable results on the course
of ischemic heart disease.</p>
<p><u>Comments</u>:</p>
<p>Summarized from abstract</p>
<p>Study not controlled.</p></td>
<td></td>
<td>Not reported.</td>
</tr>
<tr class="even">
<td><p>Lofgren, et. al. 1993</p>
<h2 id="am-j-pub-health">Am J Pub Health</h2>
<p>1993;83(2):267-69</p>
<p>[U.S.]</p></td>
<td>To examine the effect of fish oil supplements on blood pressure in
hypertensive and normotensive men with hypercholesterolemia</td>
<td><p>Randomized, double-blind, placebo controlled, two-period</p>
<p>crossover study design</p></td>
<td>12 weeks for each treatment series with a 4 week washout period
between two 12 week tx. regimens. Also an additional 4-week lead-in
during which eligible subjects were randomized to sequence.</td>
<td><p>6.0 g/d EPA + DHA (3.6 g/d EPA + 2.4 g/d DHA (Max EPA™).</p>
<p>Placebo consisted of safflower oil (20 1 g capsules/d; 76% linoleic
acid or 15.2 g of linoleic acid/d),</p>
<p>Compliance:</p>
<p>Capsule count and determination of plasma phospholipids</p></td>
<td><p>38 middle aged men (&lt;60 years old) with
hypercholesterolemia.</p>
<p>Subjects classified as hypertensive if mean DBP was &gt;90 mm Hg and
normotensive if initial DBP was 90 mm Hg or less (and they were not
receiving antihypertensive medications).</p></td>
<td><p><u>BP</u>: NS differences in blood pressure changes between the
fish oil and safflower oil phases of the study. Separate analysis of
hypertensive and normotensive subjects also failed to show any
significant differences in blood pressure changes between the two study
phases (all p&gt;0.10). For normotensive subjects there was a suggestion
of a period effect (change in DBP, p=0.03).</p>
<p>Capsule count and plasma lipid analysis confirmed compliance (data
not reported).</p></td>
<td><p>Conclusions:</p>
<p>The authors concluded that, “ in the current study, they failed to
detect any significant changes from pretreatment values in systolic or
diastolic blood pressure with the use of fish oil supplements. Also, a
subgroup analysis of patients with hypertension failed to demonstrate
any significant change from pretreatment values when comparing the fish
and safflower phases of the study. The study had sufficient power to
conclude with 95% confidence that fish oil supplementation does not
lower diastolic BP by more that 4 mm Hg when compared to safflower
oil.”</p>
<p>Comments:</p>
<p>Diets were not assessed.</p></td>
<td>1</td>
<td>42% of subjects taking fish oil and 40% of subjects taking safflower
oil reported side effects of belching, loose stools and other GI
symptoms. These were minor and did not require specific intervention or
therapy.</td>
</tr>
<tr class="odd">
<td><p>Lungershausen et al. 1994</p>
<p><em>J. Hyperten</em> 1994;12(9):1041-1045</p>
<p>[Australia]</p></td>
<td>To assess effects of n-3 FAs supplementation on BP and plasma lipids
in hypertensives treated with diuretics of beta-blockers.</td>
<td><p>Randomized,</p>
<p>double-blind,</p>
<p>placebo-controlled,</p>
<p>crossover trial.</p></td>
<td><p>6 weeks n-3</p>
<p>(6 weeks control</p>
<p>2 weeks run-in)</p></td>
<td><ol start="4" type="1">
<li><p>g/d EPA+DHA</p></li>
</ol>
<p>1.9 g/d EPA</p>
<p>1.5 g/d DHA</p>
<p>(Omacor capsules)</p>
<p>Control: corn oil</p>
<p>Compliance:</p>
<p>interview, capsule counts</p></td>
<td><p>42 patients recruited by collaborating general practitioners in
Adelaide Australia. Patients</p>
<p>w/ uncomplicated essential hypertension controlled with beta-blockers
or diuretic or combo.</p>
<p>@30% male</p>
<p>1 drop out</p></td>
<td><p><u>TG:</u> ↓ 21% vs. control (p&lt;0.01)</p>
<p><u>TC:</u> NS</p>
<p><u>LDL:</u> NS</p>
<p><u>HDL-2:</u> ↑ 15% vs. control (P&lt;0.01)</p>
<p><u>HDL-3:</u> NS</p>
<p>Similar results in patients taking only beta-blockers.</p>
<p><u>SBP:</u> ↓ (p=0.012) all patients, ↓ (p&lt;0.02) patients on
beta-blockers only.</p>
<p><u>DBP:</u> ↓ (p=0.006) all patients, ↓ (p&lt;0.02) patients on
beta-blockers only.</p></td>
<td><p><u>Conclusions:</u></p>
<p>Moderate N-3 FAs supplementation may further reduce BP in
hypertensives taking concomitant beta blockers or diuretics without
negatively affecting plasma cholesterol.</p>
<p><u>Comments:</u></p>
<p>Participants asked to maintain a "constant" diet and to avoid
consuming fish. Dietary history not otherwise assessed.</p>
<p>Data results to not match Figure 1 in paper.</p></td>
<td>1</td>
<td><p>1 pt withdrawn because of poorly controlled BP.</p>
<p>No adverse effects were reported.</p></td>
</tr>
<tr class="even">
<td><p>Luo et al. 1998</p>
<p><em>Diabetes Care</em> 1998;21(5):717-724</p>
<p>[France]</p></td>
<td>To determine the effects of moderate dose of fish oil on gylcemic
control, insulin sensitivity and hepatic glucose production in
hypertriacylglycerolemic NIDDM patients.</td>
<td>Randomized, double-blind, crossover trial.</td>
<td><p>8 weeks (2 months)</p>
<p>The subjects first underwent a 2-month dietary run- in period. Then
they were randomly assigned to either fish oil of sunflower oil
treatment for 2 months. After 2 month period the treatments were
switched for another 2 months with a 2-month washout period between the
treatments.</p></td>
<td><p>1.8 g/d n-3 PUFA</p>
<p>from 6 g/d of fish oil (fish oil group)</p>
<p>6 g/d of sunflower oil (sunflower oil group)</p>
<p>Compliance:</p>
<p>FAs composition in plasma and erythrocyte membrane
phospholipids.</p></td>
<td><p>10 men with NIDDM were recruited from the outpatient clinic of
the Department of Diabetes.</p>
<p>12 patients were initially recruited but two were excluded for the
following reasons: one patient was excluded because he misunderstood the
experimental design and the second patient stopped the antidiabetic drug
therapy which affected his results.</p></td>
<td><p><u>TG:</u> Significant ↓ (p&lt;0.05) with fish oil (1.73 ± 0.27
mmol/l) compared to the sunflower oil 2.21 ± 0.35 mmol/l).<u><br />
TC:</u> No significant effect of either treatment.<u><br />
LDL:</u> An ↑ with fish oil (2.59 ± 0.21 mmol/l) compared to baseline
(2.22 ± 0.20 mmol/l) and sunflower oil treatment (2.49 ± 0.23
mmol/l).<u><br />
HDL:</u> No significant effect of either treatment on HDL<sub>2</sub> or
HDL<sub>3</sub>.<u><br />
Lipoprotein (a):</u> Significant ↓ (p&lt;0.02) with fish oil (0.14 ±
0.03 g/l) compared to the sunflower oil (0.16 ± 0.03 g/l).<u><br />
Lipoprotein AI:</u> No significant effect of either treatment.</p>
<p><u>Lipoprotein AI:AII:</u> No significant effect of either
treatment.</p>
<p><u>apo A1:</u> No significant effect of either treatment.<u><br />
apo B:</u> No significant effect of either treatment.</p>
<p><u>Fasting glucose:</u> NS ↑ with fish oil (baseline 10.86 ± 1.0
mmol/l, fish oil 11.08 ± 1.0 mmol/l) and a ↓ with sunflower oil
treatment (baseline 11.50 ± 0.90 mmol/l, sunflower oil 11.23 ± 1.20
mmol/l).<u><br />
Fasting insulin;</u> A ↓ with fish oil (baseline 84 pmol/l, fish oil 83
pmol/l) and with sunflower oil treatment (baseline 91 pmol/l, sunflower
oil 76 pmol/l).</p>
<p><u>Glycated hemoglobin:</u> A ↓ with fish oil (baseline 8.8 ± 0.6%,
fish oil 8.7 ± 0.5%) and an ↑ with sunflower oil treatment (baseline 8.6
± 0.5%, sunflower oil 8.9 ± 0.6%).</p>
<p>Basal plasma glucose and insulin were similar after 2 months of
treatment with fish oil and sunflower oil. Basal hepatic glucose
production was similar after both treatments.</p>
<p>Plasma insulin and glucose did not differ significantly during the
clamp after fish oil and sunflower oil treatments. No significant
difference between the treatment on insulin induced suppression of
hepatic glucose production. Exogenous glucose infusion rate was not
different after sunflower or fish oil treatments. The disposal of
glucose increased during the insulin infusion.</p></td>
<td><p>Conclusions:</p>
<p>The authors conclude that, “a moderate dose of fish oil did not lead
to deleterious effects on gylcemic control or whole body insulin
sensitivity in type 2 diabetic men, with preserved
triacylglycerol-lowering capacities”.</p>
<p>Comments:</p>
<p>Dietary counseling was provided prior to the run-in period. Before
the beginning of each treatment dietary questionnaires were completed.
The subjects completed 7 day food diary during the last week of each
treatment period.</p>
<p>The subjects were asked to maintain their routine physical
activity.</p></td>
<td>1</td>
<td>No side-effects or complains were reported for both treatments and
the treatments were well tolerated.</td>
</tr>
<tr class="odd">
<td><p>Luostarinen et al. 1995</p>
<p><em>Nutrition Research</em> 1995;15(7):953-968</p>
<p>[Sweden]</p></td>
<td>To determine the effects of supplementation of fish oil with extra
vitamin E on some variables of lipid and glucose metabolism and on
fibrinolysis on mildly hypertriglyceridemic subjects.</td>
<td><p>Randomized, double-blind, crossover trial.</p>
<p>Half subjects were assigned fish oil (FO) treatment and the other
half was assigned fish oil + vitamin E (FO+E) for 4 weeks. After 6 week
wash out period the treatment was switched for another 4 weeks.</p></td>
<td><p>4 weeks on FO</p>
<p>4 weeks on FO+E</p>
<p>6 weeks washout period</p></td>
<td><p>8.6 g/d of EPA+DHA</p>
<p>5.4 g/d EPA</p>
<p>3.2 g/d DHA</p>
<p>30 ml/d of fish oil (ESKIMO-3) (FO group)</p>
<p>30 ml/d fish oil + vitamin E (FO + E group)</p>
<p>Compliance: reports from subjects, remaining fish oil after the
treatment period and plasma phospholipid FAs analyses</p></td>
<td>11 subjects with normal or mildly high TG levels were
recruited.</td>
<td><p>TG: ↓ significantly with both fish oil treatments
(p&lt;0.001).<br />
TC: No change with both fish oil treatments.<br />
HDL: Minor increases with both treatments.<br />
Lp(a): Plasma Lp(a) ↓ 261 to 211 mg/l in FO group and from 250 to 217
mg/l in FO+E group. The subjects who had higher pretreatment Lp(a)
levels showed a 22% ↓ with FO (p&lt;0.05) and 16% (NS) with FO+E, but
there was no difference between the groups.</p>
<p><u>Plasma fibrinogen:</u> Nonsignificant ↓ with both treatments.</p>
<p><u>PAI-1 activity and antigen:</u> ↑ significantly with both
treatments (p&lt;0.05)</p>
<p><u>Glucose:</u> Fasting plasma glucose concentration ↑ significantly
(p&lt;0.05) with FO but no increase was seen with FO+E. The difference
between the 2 treatments was significant (p&lt;0.05).</p>
<p><u>Insulin:</u> Serum insulin did not change significantly with FO
but increased with FO+E. The insulin/glucose ratio ↑ significantly
(p&lt;0.05) with FO+E but did not change with FO and the difference
between the 2 treatments was significant (p&lt;0.05). The net changes in
plasma glucose and serum insulin were positively correlated with FO+E
treatment (p&lt;0.05)</p>
<p><u>BP:</u> The DBP was not altered by any treatments, but the SBP
decreased with FO (p=0.07)</p>
<p>Atherogenic index was decreased but not significantly with both
treatments.</p>
<p>Pretreatment serum insulin correlated positively with PAI-1 activity,
PAI-1 antigen, and BMI and theses remained unchanged after both
treatments.</p>
<p>The EPA and DHA concentrations increased significantly after both FO
and FO+E treatments (p&lt;0.001 for both treatments). Vitamin E
concentrations increased (p&lt;0.001) with FO+E
supplementation.</p></td>
<td><p>Conclusion:</p>
<p>The authors conclude that, “the extra vitamin E counteracts the blood
glucose increase that is often seen after fish oil intake”.</p>
<p><u>Comments:</u></p>
<p>The subjects were asked not to change their diet or lifestyle
throughout the study.</p>
<p>At the end of the study period the subjects gained weight
significantly (p&lt;0.01) suggesting that the increased intake of fish
oil was not balanced by reducing intake of other food items.</p>
<p>5 subjects with high Lp(a) concentrations (&gt;270 mg/l) had
significantly low pretreatment serum TG levels and PAI-1 activity than
the other 7 subjects. Their serum insulin, BMI and waist-to-hip ratio
were lower.</p>
<p>All data not provided.</p></td>
<td>1</td>
<td></td>
</tr>
<tr class="even">
<td><p>Mackness et al. 1994</p>
<p><em>Eur J Clin Nutr</em> 1994;48:859-865</p>
<p>[U.K.]</p></td>
<td><p>To investigate the effect of a highly concentrated fish oil on
serum lipid and lipoprotein concentrations in patients with primary
hypertriglyceridemia.</p>
<p>Effect of fish oil on type IIB vs. type IV also analyzed.</p></td>
<td><p>Randomized,</p>
<p>Double-blind,</p>
<p>Placebo- controlled</p>
<p>Multi-center (7)</p></td>
<td>14 weeks</td>
<td><p>3.4 g/d EPA <u>or</u> DHA</p>
<p>in 4 g K-85 containing 92% n-3.</p>
<p>Control: corn oil</p>
<p>Compliance:</p>
<p>Not reported.</p></td>
<td><p>79 patients with primary Type IIB or IV hyperlipidemia.</p>
<p>Test: 41 K-85</p>
<p>Control: 38 corn oil</p>
<p>95 patients began trial, 16 drop outs</p>
<p>Males: 63% test, 74% control</p></td>
<td><p><u>TG:</u> ↓ K-85 (p&lt;0.01) vs. control;</p>
<p>↓ Type II (P&lt;0.001) vs. baseline</p>
<p><u>TC:</u> NS</p>
<p><u>LDL:</u> NS</p>
<p><u>HDL:</u> ↑ (NS) K-85; ↑ Type IV (P&lt;0.01) vs. baseline</p>
<p><u>VLDL:</u> ↓ (P&lt;0.01) vs. control; Type II ↓ (P&lt;0.001) vs.
baseline; Type IV ↓ (&lt;0.01) vs. baseline.</p>
<p><u>apo A:</u> NS</p>
<p><u>BP:</u> ↓ test (P&lt;0.02) and control group (P&lt;0.05).</p>
<p><u>Fasting blood glucose:</u> NS</p>
<p>(TG &amp; VLDL changes occurred within 6 weeks and were maintained
thereafter.)</p></td>
<td><p><u>Conclusions:</u></p>
<p>K-85 is effective in lowering TG and VLDL in patients w/ primary
hypertriglyceridemia.</p>
<p><u>Comments:</u></p>
<p>Dietary intake not assessed.</p>
<p>Compliance not adequately reported.</p>
<p>Concurrent medication by patients not reported</p>
<p>Description of fish oil substance not adequate – EPA or DHA or
both?</p></td>
<td>2</td>
<td><p><u>6 K-85 dropouts:</u></p>
<p>3 adverse events (endometrial carcinoma, head injury, cataract)</p>
<p>3 personal reasons</p>
<p><u>10 control drop outs:</u></p>
<p>5 adverse events (coronary artery surgery, MI, 3 angina)</p>
<p>2 non-compliance</p>
<p>3 personal reasons</p></td>
</tr>
<tr class="odd">
<td><p>Malyszko et al. 1996</p>
<p><em>Przegl.Lek.</em> 1996. 53:600-603 (ABSTRACT, foreign)</p>
<p>[Poland]</p></td>
<td>To assess platelet function, hemostatic parameters, and serum lipids
in patients with chronic glomerulo-nephritis treated with Trienyl</td>
<td>Not controlled</td>
<td>6 months</td>
<td><p>Not quantified</p>
<p>Trienyl (fish oil/ omega-3 FA treatment)</p>
<p>Compliance: not reported.</p></td>
<td>7 pts with glomerulo-nephritis</td>
<td><p><u>TC</u>: NS ↑</p>
<p><u>HDL</u>: NS ↑</p>
<p><u>LDL</u>: NS ↑</p>
<p><u>TG</u>: ↓ significantly at 3 months (-69%) and 6 months (-55%)</p>
<p><u>Lp(a)</u>: ↓ at 6 months (-14.8%)</p>
<p><u>Fibrinogen</u>: ↓ significantly at 6 months (-18%)</p>
<p><u>tPA activity</u>: ↓ at 6 months (-7.3%)</p>
<p><u>tPA antigen</u>: NS change</p>
<p><u>PAI antigen</u>: NS change</p>
<p><u>PAI activity</u>: ↓ at 6 months (-15%)</p>
<p><u>Euglobulin</u>: ↑ at 6 mos (+14.2%)</p>
<p><u>Thrombin-antithrombin complexes</u>: NS change</p>
<p><u>Plasmin-antiplasmin complexes</u>: ↑ at 6 mos (+8.9%)</p>
<p><u>Fragment 1&amp;2</u>: NS change</p>
<p><u>Platelet aggregation in whole blood in response to collagen</u>: ↓
significantly at 6 mos (-34.6%)</p>
<p><u>Platelet aggregation in whole blood in response to ADP</u>: ↓
significantly at 6 mos (-24.3%)</p>
<p><u>Platelet aggregation in platelet-rich plasma in response to
collagen</u>: NS change</p>
<p><u>Platelet aggregation in platelet-rich plasma in response to
ADP</u>: NS change</p></td>
<td><p><u>Conclusions</u>:</p>
<p>Authors concluded that, “unsaturated omega 3 fatty acids in Trienyl
alter lipid metabolism, platelet/vessel wall interactions and
proteinuria and therefore might be beneficial in therapy of
glomerulonephritis, particularly in combination treatment.”</p>
<p><u>Comments</u>:</p>
<p>Summarized from abstract.</p>
<p>Small sample size.</p>
<p>Amount of omega-3 FAs in Trienyl not provided.</p>
<p>Study not controlled.</p></td>
<td></td>
<td>Not reported.</td>
</tr>
<tr class="even">
<td><p>Marckmann et al. 1997</p>
<p><em>Arterioscler Thromb Vasc Biol.</em> 1997; 17:3384-3391</p>
<p>[Denmark]</p></td>
<td>To examine the effect of incorporating fish oil (4 g daily) into a
sunflower oil-based margarine on a series of important cardiovascular
markers (blood lipids, coagulation, fibrinolytic markers). Also examined
the effect of a single high fat test meal on a subset of subjects from
each group near the end of the run-in and intervention periods.</td>
<td>Randomized, parallel, double-blind trial</td>
<td>4 weeks intervention (following a 3-week run-in period with only
sunflower oil margarine)</td>
<td>2 g fish oil (Aarhus Olie) (2 g/100 g fat DHA; 1.4 g/100 g fat
EPA)</td>
<td><p>47 nonobese, healthy males with low usual fish consumption.</p>
<p>Fish oil: 23</p>
<p>Sunflower only: 24</p>
<p>None were taking fish oil supplements. Average age: 41 years (range:
29 to 60 years)</p></td>
<td><p><u>TG</u>:  (p&lt;0.01) (with a NS decrease observed in control
group)</p>
<p><u>TC</u>: NS</p>
<p><u>LDL</u>: not reported</p>
<p><u>HDL</u>:  (p&lt;0.01) (but also significantly increased in the
control group)</p>
<p><u>Lp(a):</u> NS</p>
<p><u>apo A</u>: NS (significantly increased in control group)</p>
<p><u>apo B</u>: NS</p></td>
<td><p><u>Conclusions</u>:</p>
<p>The authors concluded that the only effect observed was on lowering
postprandial triglycerides.</p>
<p><u>Comments</u>:</p>
<p>Three dietary recall assessments were conducted during trial to
assess dietary fish and fat consumption. Good compliance to
intervention. Effective blinding.</p>
<p>Small sample size. Groups comparable at baseline with the exception
of FVIIa.</p></td>
<td>2</td>
<td>No statistically significant effect on clotting factors, glucose, or
insulin levels over the 4-week study period. Nonsignificant (p=0.06) 
in postprandial insulin in the fish group.</td>
</tr>
<tr class="odd">
<td><p>Margolin et al. 1991</p>
<p><em>Am J Clin Nutr</em> 1991;53:562-72</p>
<p>[U.S.]</p></td>
<td>To examine the effect of fish oil rich in n-3 FAs (EPA and DHA) on
reduction of elevated BP in elderly subjects and to assess the effects
on lipid and lipoprotein cholesterol concentrations.</td>
<td>Randomized, double-blind, placebo controlled, crossover trial.</td>
<td><p>8 weeks on each treatment with a three week washout period
between the treatments.</p>
<p>Initial 4-week baseline period.</p></td>
<td><p>4.7 g/d EPA + DHA (9 g/d fish oil capsules (1 g capsules, RES-Q
1000) containing 52% EPA + DHA) (n-3 PUFA group)</p>
<p>Corn oil 9 g/d (placebo group)</p>
<p>Compliance:</p>
<p>Capsule count</p></td>
<td>46 patients (29 males and 17 females) with seated resting SBP ≥ 160
mm Hg and seated resting DBP ≥ 90 mm Hg.</td>
<td><p>Since the placebo group had effects on BP it was referred to as
corn oil group and not placebo group.</p>
<p>Due to the sequence and period effects on variables measured, the
data from the two crossover phase were not pooled and analyzed as two
separate experiments.</p>
<p><u>TG:</u> ↓ significantly (p&lt;0.01) in fish oil group (-0.47
mmol/l) vs. corn oil group (-0.1 mmol/l).</p>
<p><u>TC:</u> NS effect of fish oil</p>
<p><u>HDL:</u> NS effect of fish oil</p>
<p><u>LDL:</u> ↑ significantly (p&lt;0.03) in the fish oil group (+0.26
mmol/l) in phase II.</p>
<p>No significant changes in lipids or lipoprotein cholesterol in the
control group.</p>
<p><u>BP:</u> No differences between the groups in the change in BP for
both 8-week treatment periods. Significant reduction (p=0.024) in
standing DBP with fish oil (-5.1 mm Hg) vs. corn oil (-0.72 mm Hg) in
phase II of the study. Seated resting SBP and DBP, and standing SBP and
DBP were lowered in both groups in phase I of the study (p&lt;0.05 for
all) with no further reduction during the second phase compared with the
washout period.</p></td>
<td><p>Conclusions:</p>
<p>The authors concluded that, “in elderly subjects diet plus both n-3
and n-6 supplements (9 g/d) safely and effectively lower SBP and
DBP”.</p>
<p><u>Comments:</u></p>
<p>The subjects were asked to follow AHA phase I diet. 7-day food
diaries for each phase were used to assess dietary intake.</p>
<p>Due to the sequence and period effects on variables measured, the
data from the two crossover phase were not pooled and analyzed as two
separate experiments.</p></td>
<td>1</td>
<td><p>No treatment effects on all laboratory safety endpoints (complete
blood count, renal and electrolyte panels, liver chemical profiles and
measurements of thyroxine (T<sub>4</sub>) and blood sugar) except on
alkaline phosphatase and platelet count. During both treatment periods
alkaline phosphatase levels fell in the fish oil group and corn oil
group (more in fish oil). In the 1<sup>st</sup> and the 2<sup>nd</sup>
treatment period mean platelet count fell in the fish oil group and rose
in the corn oil group.</p>
<p>No group differences in the development of dizziness, diarrhea,
belching, unpleasant mouth taste, bruising, or unusual bleeding.</p>
<p>The frequency of reporting any of these side effects was low. Of the
46 subjects, 1.8% of the subjects reported dizziness, 5.1 had diarrhea,
9.6% had gastrointestinal upset, 4.5% reported belching, 2.3% reported a
bad mouth taste, 0.54% reported unusual bruising and 0.18% reported
unusual bleeding. The intervention appeared to be safe and well
tolerated.</p></td>
</tr>
<tr class="even">
<td><p>McGrath et al. 1996</p>
<p><em>Atherosclerosis</em> 1996;121:275-283</p>
<p>[UK]</p></td>
<td>To determine the effects of fish oil rich in polyunsaturates on
serum lipid peroxides in NIDDM patients.</td>
<td>Randomized, double-blind, placebo controlled crossover trial.</td>
<td>6 weeks on each treatment with a 6 week washout period between the
treatment.</td>
<td><p>3 g/d of EPA + DHA (10 capsules of Maxepa; 1.8 g/d EPA, 1.2 g/d
(DHA) (fish oil group)</p>
<p>Olive oil: placebo group</p>
<p>Compliance:</p>
<p>Pill count, platelet membrane FA analysis.</p></td>
<td>23 NIDDM subjects (20 males and 3 females) were recruited. Diabetes
was controlled by either diet alone or diet + hypoglycemic drugs.</td>
<td><p><u>TG:</u> NS ↓ (p=0.07) with fish oil (1.4 mmol/l) compared to
baseline (1.8 mmol/l) or olive oil (1.6 mmol/l)<u><br />
TC:</u> No significant change with fish oil compared to baseline or
olive oil. <u><br />
LDL:</u> No changes in the amount or composition of LDL with fish oil
compared to baseline or olive oil.<u><br />
HDL:</u> No changes in the amount or composition of LDL with fish oil
compared to baseline or olive oil.<u><br />
VLDL:</u> NS ↓ in VLDL-TC (p=0.06) and VLDL-TG (p=0.06) with fish oil
compared to baseline. No difference between the groups.</p>
<p><u>apo A1:</u> No effect of fish oil or olive oil.</p>
<p><u>apo B:</u> No effect of fish oil or olive oil.</p>
<p><u>Fasting glucose:</u> NS ↑ (p=0.06) with fish oil (11.4 (CI
9.7-13.3) mmol/l), when compared to baseline (10.2 (CI 8.9-11.4)
mmol/l). No changes with olive oil. No differences between the
groups.</p>
<p><u>Glycated hemoglobin:</u> No effect of fish oil or olive oil.
(baseline 9.6% (CI 8.8-10.4%); fish oil 9.9% (CI 8.5-11.3%).</p>
<p><u>Glycosylated LDL:</u> No effect of fish oil or olive oil.</p>
<p>Malondialdehyde: Significantly ↑ with (both p&lt;0.001) fish oil
(1.77 μmol/l) compared to baseline (1.15 μmol/l) or olive oil (1.21
μmol/l).</p>
<p>Significant ↑ in platelet membrane EPA and DHA concentration compared
to the baseline and placebo (both ps&lt;0.001).</p></td>
<td><p>Conclusions:</p>
<p>The results show, “no effect of fish oil on gylcemic control as
assessed by glycosylated hemoglobin and LDL although a rise in fasting
blood glucose just failed to reach significance. Lipid peroxidation in
NIDDM can be exacerbated by dietary fish oil. This potentially adverse
reaction may limit the therapeutic use of fish oils in such
patients”.</p>
<p><u>Comments:</u></p>
<p>Diets were not assessed but the subjects were asked to maintain their
routine diet and exercise.</p></td>
<td>1</td>
<td>Not reported</td>
</tr>
<tr class="odd">
<td><p>McManus et al. 1996</p>
<p><em>Diabetes Care</em> 1996;19(5):463-466</p>
<p>[Canada]</p></td>
<td>To compare the effects of linseed oil (LO) and fish oil (FO) on
lipid, glucose and insulin parameters in NIDDM patients.</td>
<td>Randomized, double-blind, placebo-controlled crossover trial.</td>
<td><p>12 weeks (3 months) on each treatment</p>
<p>Total 9-month:</p>
<p>the subjects underwent a 3-month run-in period with olive oil. Then
they were randomly assigned to either FO or LO for 3 months. After 3
months the treatments were reversed.</p></td>
<td><p>2.8 g/d EPA + DHA mean intake (35 mg/kg of EPA + DHA combined FO
group)</p>
<p>35 mg/kg of olive oil (placebo run-in period)</p>
<p>35 mg/kg of LO</p>
<p>Compliance:</p>
<p>Capsule count</p></td>
<td>11 NIDDM patients (3 women and 8 men) were from a tertiary care
diabetic center. None of the subjects were taking hypoglycemic
drugs.</td>
<td><p><u>TG:</u> ↓ significantly with placebo compared to baseline.
Significantly lower (p&lt;0.05) with FO (0.96 ± 0.20 mmol/l) compared to
LO (1.58 ± 0.41 mmol/l).</p>
<p><u>TC:</u> ↓ significantly with placebo compared to baseline. No
significant difference between the three treatments.</p>
<p><u>LDL:</u> No significant difference between the three treatments
(baseline 3.79 ± 0.37; placebo 3.42 ± 0.28; LO 3.41 ± 0.28; FO 3.39 ±
0.25 mmol/l).</p>
<p><u>HDL:</u> ↓ significantly with placebo compared to baseline. No
significant difference between the three treatments.</p>
<p><u>Fasting glucose:</u> No significant difference between the three
treatments (baseline 8.0 ± 0.7; placebo 7.6 ± 0.6; LO 7.9 ± 0.8; FO 8.2
± 0.9 mmol/l).</p>
<p><u>Glycated hemoglobin:</u> ↑ significantly with placebo compared to
baseline, although the mean was within the normal range. No significant
difference between the three treatments (baseline 0.058 ± 0.004; placebo
0.061 ± 0.004; LO 0.066 ± 0.006; FO 0.065 ± 0.006). Units not
reported.</p>
<p>Fasting insulin: No significant difference between the three
treatments, but a trend towards lowering the fasting insulin was
observed in the LO and FO group.</p>
<p><u>Insulin sensitivity:</u> A non-significant ↓ (p=0.06) with FO. No
change with LO.</p>
<p><u>Glucose effectiveness:</u> No significant change with LO or
FO.</p>
<p><u>Acute insulin response to glucose:</u> No effect of LO or FO.</p>
<p><u>Glucose tolerance:</u> No significant change with LO or
FO.</p></td>
<td><p>Conclusions:</p>
<p>The authors concluded that, “in a population with well-controlled
type II diabetes, 3 months of FO but not LO resulted in lowered TG
levels. Neither LO nor FO significantly affected gylcemic control,
cholesterol values, glucose tolerance, insulin secretion while a NS
trend toward decreased insulin sensitivity was found with FO”.</p>
<p><u>Comments:</u></p>
<p>Diets were assessed using 7-day food diaries at the end of each
3-month period. The subjects were asked to continue their routine
medications and diabetic meal plans throughout the study.</p>
<p>Initial run in period but no washout period between the two
treatments.</p></td>
<td>1</td>
<td>Not reported</td>
</tr>
<tr class="even">
<td><p>McVeigh et al. 1994</p>
<p><em>Arterioscler Thromb</em> 1994;14:1425-1429</p>
<p>[Ireland]</p></td>
<td>To determine the effects of dietary fish oil supplementation on
arterial compliance in patients with NIDDM.</td>
<td>Randomized, double-blind, placebo-controlled, crossover trial.</td>
<td>6 weeks on fish oil or placebo followed by 6 weeks of washout
period. After the washout period the treatments were switched for 6
weeks.</td>
<td><p>3 g/d EPA + DHA (1.8 g/d EPA, 1.2 g/d DHA; MAXEPA) (fish oil)</p>
<p>Placebo: olive oil.</p>
<p>Compliance:</p>
<p>Capsule count, platelet membrane FA analysis.</p></td>
<td>20 (16 men, 4 females) subjects with NIDDM were recruited from
diabetic clinic in Belfast. Diabetes was controlled with diet alone or
diet + hypoglycemic drugs. Subjects were not taking any cardiovascular
drugs.</td>
<td><p><u>TG:</u> NS ↓ with fish oil (1.4 (CI 1.1- 1.8) mmol/l, p=0.08)
compared to baseline (1.8 (CI 1.4-2.2) mmol/l).</p>
<p><u>TC:</u> No effect of the treatments.<u><br />
Fasting glucose:</u> NS ↑ with fish oil (11.4 (CI 9.7- 13.3) mmol/l,
p=0.07) compared to baseline (10.2 (CI 8.9-11.4) mmol/l).</p>
<p><u>Heart rate:</u> No effect of the treatments.</p>
<p><u>Arterial BP:</u> No effect of the treatments.</p>
<p><u>Cardiac output:</u> No effect of the treatments.</p>
<p><u>Stroke volume:</u> No effect of the treatments.</p>
<p><u>Large artery compliance:</u> ↑ with fish oil (1.68 (CI 1.52-1.84)
ml/mm Hg, p&lt;0.01) compared to baseline (1.50 (CI 1.31-1.69) ml/mm Hg)
and olive oil (1.52 (CI 1.35-1.69) ml/mm Hg, p&lt;0.01).</p>
<p><u>Oscillatory compliance:</u> ↑ with fish oil (0.022 (CI
0.016-0.028) ml/mm Hg, p&lt;0.05) compared to baseline (0.015 (CI
0.011-0.019) ml/mm Hg). No differences between the groups.</p>
<p><u>Systemic vascular resistance:</u> No changes.</p>
<p>EPA (p&lt;0.01) and DHA (p&lt;0.01) levels ↑ significantly and AA
levels decreased (p&lt;0.01) in platelet membrane.</p></td>
<td><p><u>Conclusions:</u></p>
<p>The authors concluded that, “short-term dietary supplementation with
fish oils improved the compliance characteristics of the arterial
circulation in patients with NIDDM. Improving arterial wall
characteristics may represent an additional mechanism whereby fish oils
exert their cardioprotective action in humans”.</p>
<p><u>Comments:</u></p>
<p>Diets were not assessed but the subjects adhered to their routine
diet and medications during the duration of the study.</p></td>
<td>1</td>
<td>Not reported</td>
</tr>
<tr class="odd">
<td><p>Meydani et al. 1993</p>
<p>The Journal of Clinical Investigation</p>
<p>1993;2:105-113</p>
<p>[U.S.]</p></td>
<td>To investigate the effect of reductions in dietary fat, saturated
fat and cholesterol, as well as increased fish intake on human cytokine
production and immune response.</td>
<td>Controlled trial</td>
<td>24 week treatment period following a 6 week run-in period. Subjects
could take up to a 4 week break between run in and treatment</td>
<td><p>1.23 g/day EPA+DHA (high fish intake diet)</p>
<p>control group: low fish intake diet which provided 0.27 g/day
EPA+DHA</p>
<p>Compliance:</p>
<p>Fatty acid profile</p></td>
<td><p>21 normolipidemic and normotensive volunteers (11 female, 11
male). Subjects had no evidence of any chronic illness including
endocrine, hepatic, renal, thyroid, or cardiac dysfunction. Subjects
were not on medications which might effect lipid levels, and none
smoked.</p>
<p>Treatment group: 10 individuals (including 3 who had participated in
the control group previously)</p>
<p>Control group: 11 individuals.</p></td>
<td><p><u>TG</u>: ↓ 7% compared to baseline.</p>
<p><u>TC:</u> ↓ 14% compared to baseline.</p>
<p><u>LDL</u>: ↓ 15% compared to baseline.</p>
<p><u>HDL</u>: ↓ 12% compared to baseline.</p>
<p><u>TC:HDL ratio:</u> no significant change.</p>
<p><u>PGE<sub>2</sub></u>: ↓ in production, both spontaneous and PHA (10
and 100ug/ml) stimulated cultures showed reductions (79, 63 and 68%
respectively) however, only the l00 μg/ml stimulated culture change was
statistically significant (p=0.02) compared to baseline.</p>
<p><u>IL-1β:</u> ↓ production (40%, p=0.07 using LPS stimulation and
25%, p=0.3 using <em>Staphylococcus epidermis</em> (S. epi) stimulation)
compared to baseline.</p>
<p><u>TNF:</u> ↓ production using S. epi stimulation (35%, p=0.08)
compared to baseline.</p>
<p><u>IL-6:</u> ↓ production (34%, p=0.03) compared to baseline.</p>
<p><u>Il-2:</u> no significant change from baseline.</p>
<p><u>White blood cells</u>: An analysis of 5 subjects indicated a
significant ↓ in CD4+ cells and an ↑ in CD8+ cells (p&lt;0.005 and
p&lt;0.006, respectively) compared to baseline.</p>
<p><u>Delayed skin hypersensitivity</u>: induration period significantly
↓ (45%, p=0.009) compared to baseline and compared to control (50%,
p=0.01).</p>
<p><u>T cell mitogens Con A</u>: response was ↓ (24%, p=0.03) compared
to baseline and compared to control (56%, p=0.057).</p>
<p><u>T cell mitogens PHA</u>: response was ↓ (30%, p=0.1) compared to
baseline and compared to control (53%, p=0.002).</p>
<p>Significant ↑ in EPA and DHA (313% and 73%, respectively, p=0.0001)
in plasma.</p>
<p>No significant change in plasma tocopherol compared to baseline, but
a significant ↓ when expressed as a function of changes in plasma PUFA
(10%, p=0.04).</p></td>
<td><p>Conclusions:</p>
<p>The authors conclude that, “the NCEP step 2 diet that is high in fish
significantly decreases various parameters of the immune response in
contrast to the diet when it is low in fish. Such alterations may be
beneficial for the prevention and treatment of atherosclerotic and
inflammatory diseases but may be detrimental with regard to host defense
against invading pathogens”.</p>
<p>Comments:</p>
<p>3 individuals participated in both the control and treatment phase of
the study, with at least a 6 month interval between the two phases.</p>
<p>Subjects entered the trial at different time points to avoid seasonal
effects.</p>
<p>The run-in diet was a typical American diet while the treatment diet
was a low-fat, low-cholesterol, high PUFA diet based on the NCEP step 2
recommendations.</p>
<p>All food was provided during the study.</p></td>
<td>2</td>
<td>1 subject was excluded from analysis due to a lack of anticipated
changes in his fatty acid profile, indicating a lack of compliance.</td>
</tr>
<tr class="even">
<td><p>Misso and Thompson 1995</p>
<p><em>Platelets</em> 1995. 6:275-282</p>
<p>[Australia]</p></td>
<td>To assess the effects of fish oil supplementation on platelet
aggregation and ATP release induced by platelet activating factor (PAF)
and other agonists</td>
<td>Double-blind, crossover</td>
<td><p>4 weeks</p>
<p>per treatment period with a 4-week washout period between treatments
and at the end of study</p></td>
<td><p>3.6 g/day EPA + DHA from fish oil capsules (MaxEPA)</p>
<p>Control: 12 g/day olive oil</p></td>
<td><p>12 normal, healthy subjects</p>
<p>age range: 23-40 years</p>
<p>6 male/6 female</p></td>
<td><p><u>TC</u>: NS change</p>
<p><u>TG</u>: NS ↓ with fish oil; NS ↑ with olive oil</p>
<p><u>Platelet aggregation to PAF</u>: NS ↓ in fish oil group; no change
in olive oil group</p>
<p><u>Platelet aggregation to collagen</u>: NS ↓ in fish oil group; no
change in olive oil group</p>
<p><u>Platelet aggregation to ADP</u>: NS change</p>
<p><u>Platelet aggregation to adrenaline</u>: NS change</p>
<p><u>Platelet aggregation to AA</u>: NS change</p>
<p><u>Platelet ATP release induced by PAF</u>: ↓ significantly in fish
oil group (p&lt;0.0005); no change in olive oil group</p>
<p><u>Platelet ATP release induced by collagen</u>: ↓ significantly in
fish oil group (p&lt;0.0005); ↓ in olive oil group at higher collagen
doses</p>
<p><u>Platelet ATP release induced by ADP</u>: ↓ significantly in fish
oil group (p&lt;0.02-0.05); no change in olive oil group</p>
<p><u>Platelet ATP release induced by AA</u>: NS change</p>
<p><u>Platelet ATP release induced by adrenaline</u>: NS change</p>
<p><u>Fibrinogen</u>: NS ↓ with fish oil; ↓ significantly with olive
oil</p>
<p><u>Prothrombin time</u>: ↓ significantly (-8.4%) with fish oil
(p&lt;0.001) and olive oil (-7.8, p&lt;0.0025)</p>
<p><u>Partial thromboplastin time with kaolin</u>: NS change</p>
<p><u>Thrombin clotting time</u>: NS change</p></td>
<td><p><u>Conclusions</u>:</p>
<p>PAF may be an important pro-inflammatory mediator in a number of
disease states, and that the inhibitory effects of fish oil on
PAF-induced platelet activation may contribute to the observed benefits
of fish oil supplementation.</p>
<p><u>Comments</u>:</p>
<p>Small sample size.</p>
<p>Diet not assessed, but subjects asked to maintain normal dietary
habits prior to and during the study.</p></td>
<td>2</td>
<td>Not reported.</td>
</tr>
<tr class="odd">
<td><p>Morgan et al. 1995</p>
<p><em>Diabetes Care</em> 1995;18(1):83-86</p>
<p>[U.S.]</p></td>
<td>To compared the effects of fish oil supplementation to corn oil on
blood lipid profiles and gylcemic control in hyperlipidemic subjects
with NIDDM.</td>
<td>Randomized, double-blind, trial.</td>
<td><p>12 weeks of treatment</p>
<p>Initial baseline period</p>
<p>4 week post-treatment phase</p></td>
<td><p>10.098 g/d EPA + DHA (5.184 EPA, 4.914 DHA, from 18 g of fish
oil)</p>
<p>5.049 g/d EPA + DHA (2.592 g/d EPA, 2.457 g/d DHA, from 9 g of fish
oil)</p>
<p>9 g/d corn oil</p>
<p>18 g/d corn oil</p>
<p>Compliance:</p>
<p>Capsule count</p></td>
<td><p>40 (18 men, 22 women) hyperlipidemic patients with NIDDM were
recruited.</p>
<p>18 g/d fish oil group: n=10</p>
<p>9 g/d fish oil group: n=10</p>
<p>18 g/d corn oil group: n=10</p>
<p>9 g/d corn oil group: n=10</p></td>
<td><p>For fish oil or corn oil treatment the level of supplementation
did not significantly affect blood lipids and gylcemic control. But when
the results of high and low supplementation groups was combined for each
treatment there was significant effect on blood lipids.</p>
<p><u>TG:</u> Significant ↓ (both 6 and 12 weeks p&lt;0.0001) in TG at 6
weeks (4.86 ± 2.76 mmol/l) and 12 weeks (4.67 ± 2.61 mmol/l) with fish
oil compared to an ↑ with corn oil at six (9.26 ± 11.42 mmol/l) and 12
weeks (8.59 ± 7.53 mmol/l). VLDL-TG was significantly lower with fish
oil compared to corn oil at 6 (p=0.02) and 12 (p=0.0001) weeks.<u><br />
TC:</u> NS differences between groups.<u><br />
LDL:</u> Significantly ↑ with fish oil (baseline 3.71 ± 0.78 mmol/l,
fish oil 4.04 ± 0.92 mmol/l) compared to corn oil (baseline 3.87 ± 1.30
mmol/l, corn oil 3.62 ± 1.30 mmol/l) at 6 weeks, but this difference was
not observed at 12 weeks (fish oil 4.08 ± 0.78; corn oil 3.87 ±
1.43).</p>
<p><u>HDL:</u> NS differences between groups.<u><br />
VLDL:</u> Significant ↓ ((p&lt;0.0001) with fish oil (0.71 ± 0.59
mmol/l) compared to corn oil (0.94 ± 0.66 mmol/l) at 6 weeks. At 12
weeks there was a significant ↑ with corn oil compared to 6 weeks
(p=0.04).</p>
<p><u>Fasting glucose:</u> No significant differences between the groups
or over time within the group (fish oil: 0 week 10.4 ± 3.4, 6 weeks 12.2
± 3.5, 12 weeks 11.6 ± 3.4 mmol/l; corn oil: 0 week 11.6 ± 3.5, 6 weeks
12.1 ± 3.3, 12 weeks 12.4 ± 3.5 mmol/l).</p>
<p><u>Glycated hemoglobin:</u> No significant differences between the
groups or over time within the group No significant differences between
the groups or over time within the group (fish oil: 0 week 7.3 ± 1.5, 6
weeks 7.6 ±1.5, 12 weeks 7.7 ± 1.7 mmol/l; corn oil: 0 week 7.6 ± 1.7, 6
weeks 7.7 ± 1.9, 12 weeks 7.8 ± 2.0 mmol/l).</p></td>
<td><p>Conclusions:</p>
<p>The authors concluded that, “fish oil supplementation improved plasma
VLDL, VLDL-TG and TG while having a transient deterioration in LDL in
subjects with NIDDM. Furthermore, fish oil supplementation had no
significant deleterious effect on gylcemic control”.</p>
<p><u>Comments:</u></p>
<p>Diets were not assessed.</p>
<p>No placebo control group</p></td>
<td>1</td>
<td>Not reported</td>
</tr>
<tr class="even">
<td><p>Mori et al. 1992</p>
<p><em>Metabolism</em> 1992;41(10):1059-1067</p>
<p>[U.S.]</p></td>
<td>To examine and compare the effects of supplementing the existing
diet with fish oil or olive oil on lipids and cell function in patients
with peripheral vascular disease.</td>
<td><p>Randomized,</p>
<p>double-blind,</p>
<p>placebo-controlled trial.</p></td>
<td>4 weeks</td>
<td><p>4.6 g/d EPA+DHA</p>
<p>2.8 g/d EPA</p>
<p>1.8 g/d DHA</p>
<p>(MaxEPA capsules)</p>
<p>Control: olive oil</p>
<p>Compliance:</p>
<p>capsule count, serum FAs analysis</p></td>
<td><p>29 males w/ angiographically demonstrated peripheral vascular
disease, recruited by referral from major teaching hospitals and general
practitioners.</p>
<p>Test: 15</p>
<p>Control: 14</p>
<p>No dropouts after study initiation.</p></td>
<td><p><u>TG:</u> ↓ treatment-time effect (P&lt;0.05) and vs. control @
2&amp;4 weeks. (P&lt;0.05).</p>
<p><u>TC:</u> ↑ treatment time effect (P&lt;0.01)</p>
<p><u>LDL:</u> ↑ treatment-time effect (P&lt;0.01). ↑ vs. control (0.05)
@ 4wks.</p>
<p><u>HDL:</u> ↑ vs. baseline (P value not reported)</p>
<p><u>Serum FAs:</u> ↑ EPA (&lt;0.001) &amp; ↓ in AA (P&lt;0.001) vs.
control.</p>
<p><u>Platelet aggregation:</u> ↓ (P&lt;0.05) vs. base</p>
<p><u>Platelet activating factor:</u> ↓ (P&lt;0.05)</p>
<p><u>TXB2:</u> NS fish oil</p>
<p><u>LTB4:</u> ↓</p>
<p><u>LTB5:</u> ↑</p>
<p><u>Neutrophil PAF:</u> NS</p>
<p><u>Plasma lyso-PAF:</u> NS</p></td>
<td><p><u>Conclusions:</u></p>
<p>Authors conclude that, fish oil supplementation in patients with
vascular disease reduced platelet aggregation, neutrophil leukotriene
generation, and an increase in HDL2 fractions. The benefits must be
examined in light of the possible adverse increase in LDL.</p>
<p><u>Comments:</u></p>
<p>One IDDM in test group &amp; one NIDDM in control group.</p>
<p>Subjects asked to maintain normal dietary habits – no assessment of
those habits was reported.</p>
<p>Data for cholesterol effects not reported, graphs only.</p></td>
<td>2</td>
<td>Adverse effects and tolerance were not reported.</td>
</tr>
<tr class="odd">
<td><p>Mori et al. 1994</p>
<p><em>Am J Clin Nutr</em> 1994;59:1060-8</p>
<p>[Australia]</p></td>
<td>To determine the influence of dietary fat intake on the response of
serum lipids to n-3 fats and to investigate possible the effect of fish
and purified n-3 fish oils on plasma lipids.</td>
<td>Randomized, placebo-controlled trial.</td>
<td>12 weeks</td>
<td><p>2.12 g/d EPA+DHA from fish oil (Lipitac, ≈1.3 g/d EPA and ≈0.8
g/d DHA)</p>
<p>2.6 g/d of n-3 from fish oil</p>
<p>3.2 – 4.1 g/d of n-3 FAs from fish.</p>
<p>1.3 g/d EPA approximate amount from fish oil or fish</p>
<p>Placebo contained palm, olive and sunflower oil.</p>
<p>7 treatments were assigned</p>
<p>Group 1: 40% fat diet + placebo</p>
<p>Group 2: 40% fat diet + fatty fish (1 fish meal) + placebo</p>
<p>Group 3: 40% fat diet + 6 fish oil capsules (1 g each)</p>
<p>Group 4: 40% fat diet + fatty fish (1 fish meal) + 6 fish oil
capsules</p>
<p>Group 5: 40% fat diet + 12 fish oil capsules</p>
<p>Group 6: 30% fat diet alone + placebo</p>
<p>Group 7: 30% fat diet + fatty fish (1 fish meal) + placebo</p>
<p>Compliance: diet records, platelet phospholipid fatty acid
analyses.</p></td>
<td>120 healthy nonsmoking males were recruited by media publicity. The
entry criteria was BMI of &lt;30 kg/m<sup>3</sup>, SBP 130-159 mmHg, DBP
80-90 mmHg, serum TC of 5.2-6.9 mmol/l.</td>
<td><p><u>TC:</u> Significant group effects (p&lt;0.001). ↑ with
addition of fish (5%) or fish oil (8%) to the high fat diet. Fish or
fish oil (groups 4 and 5) ↑ TC by 7%. The 30% fat diet alone ↓ TC (5%)
and this was maintained by the addition of fish to the diet.</p>
<p><u>TG:</u> Significant group effects (p&lt;0.001). ↓ with addition of
fish (group 2, 20%) or fish oil (group 3, 14%) to the high fat diet.
Fish + fish oil ↓ TG by 43% (group 4). TG ↓ by 32 % in group consuming
high-dose fish oil (group 5). The addition of fish to 30% fat diet
reduced TG (group 7, 23%).</p>
<p><u>HDL:</u> Significant group effects (p&lt;0.001). HDL and
HDL<sub>2</sub> ↑ with fish and fish oil and were comparable between
groups. HDL ↑ in groups 2-5 by 6-9%. The HDL<sub>2</sub> ↑ in these
groups by 30-36%. All groups 2-5 showed and ↑ in HDL and HDL<sub>2</sub>
compared to control group. The 30% fat diet alone ↓ HDL and
HDL<sub>2</sub> by approximately 6%. Addition of fish to 30% fat diet
increased HDL and HDL<sub>2</sub> by 2 and 15%, respectively.</p>
<p>LDL: Significant group effects (p&lt;0.001). LDL ↑ in groups 2-5 by
8-12% and group 5 showed an ↑ by 16%. The 30% fat diet alone ↓ LDL by
10%. The fall in LDL with addition of fish to the 30% fat diet was
attenuated (3%).</p>
<p>apo B: Significant group effects (p&lt;0.01). apo B ↑ in groups 2-5.
The 30% fat diet alone ↓ apo B by 5% and this was maintained by addition
of fish to the 30% fat diet.</p>
<p>All lipid parameters showed a significant group effect (p&lt;0.01).
Control group 1 showed no changes in any parameters measured.</p>
<p>The supine heart rate fell (p&lt;0.01) in fish and fish oil groups
and increased in control groups (1 and 6).</p>
<p>No significant group effect on changes in the supine BP. Although,
the average decrease was greater in the two 30% fat groups and 40% fat
groups with fish or fish oil compared to the control groups.</p>
<p>Platelet phospholipid n-3 FAs ↑ significantly (p&lt;0.001) and n-6
FAs ↓ significantly (p&lt;0.001) with fish and fish oil supplementation
in groups 2-5 and 7.</p></td>
<td><p>Conclusion:</p>
<p>The study shows that, “plasma lipids are affected similarly by fish
or fish oil in men consuming a 40%-fat diet. Adverse effects of n- 3
fats on TC and LDL are reversed by a 30%-fat diet, whereas one daily
fish meal substantially lowers TG and reverses the fall in HDL that is
usual with a low-fat diet”.</p>
<p>Comments:</p>
<p>The subjects completed diet records before and at the end of the
study. The subjects were provided dietary counseling by dietician
provided recipes and were asked to keep weighted diet records.</p>
<p>Diets were designed so that the total fat intake of groups consuming
fish and fish oil or either was similar to the control groups.</p>
<p>There were differences in cholesterol intake between the groups but
these differences did not correlate with changes in serum cholesterol
and other lipids.</p>
<p>No differences in weight reduction between the groups, and the
greatest weight reduction was in the 30% fat groups.</p>
<p>Combined fish meal and purified fish oil treatment.</p></td>
<td>1</td>
<td></td>
</tr>
<tr class="even">
<td><p>Mori et al. 1997</p>
<p><em>Arterioscler. Thromb. Vasc. Biol</em> 1997. 17(2):279-286</p>
<p>[Australia]</p></td>
<td>To examine and compare the effects of dietary fish and fish oil in a
high-fat (40% fat) or low-fat (30% fat) diet on blood pressure, blood
lipids and platelet function in otherwise healthy men at risk for
cardiovascular disease</td>
<td>Randomized, parallel, controlled</td>
<td><p>12 weeks</p>
<p>(following a 3-week screening period and a 1-week baseline
measurement period)</p></td>
<td><p>2.8-3.7 g/day EPA + DHA (1.5-2.4 g/day DHA and 1.3 g/day EPA
provided by fish</p>
<p>2.1 g/day EPA + DHA (0.8 g/day DHA and 1.3 g/day EPA) provided by
fish oil capsules</p>
<p>high-fat diets:</p>
<p>1. placebo capsules</p>
<p>2. 90-160 g/day fish</p>
<p>3. 6 g/day fish oil capsules</p>
<p>4. 90-160 g/day fish + 6 g/day fish oil capsules,</p>
<p>5. 12 g/day fish oil capsules</p>
<p>low-fat diets:</p>
<p>1. placebo capsules</p>
<p>2. 90-160 g/day fish</p>
<p>Compliance: platelet phospholipid FA analysis</p></td>
<td><p>120 nonsmoking, healthy males, 30-60 years of age</p>
<p>18 withdrawals due to reasons unrelated to treatment</p></td>
<td><p><u>Platelet aggregation to collagen</u>: ↓ in all fish or fish
oil groups (p=0.0487 - low-fat diet and p&lt;0.0001 - high fat diet), no
difference seen between fish and fish oil diets</p>
<p><u>Platelet aggregation to PAF</u>: ↓ in all groups (p&lt;0.05), ↓
more pronounced in fish oil high-fat diet compared to fish high-fat
diet, greatest effect seen with fish oil + fish; fish had a greater
effect as part of a low-fat diet</p>
<p><u>Platelet-derived TXB<sub>2</sub> responses to collagen-induced
aggregation</u>: ↓ in all groups (p&lt;0.05)</p>
<p>Fish or fish oil groups showed a significant ↑ in total omega 3-fatty
acids, EPA, and DHA (p&lt;0.00001) after 12-week dietary intervention
compared to baseline.</p></td>
<td><p><u>Conclusions</u>:</p>
<p>According to authors, dietary n-3 fatty acids have more consistent
favorable effects on cardiovascular risk factors when incorporated into
a low-fat rather a high-fat diet.</p>
<p><u>Comment</u>:</p>
<p>Results of lipid changes reported in Mori et al. 1994.</p></td>
<td>2</td>
<td>Not reported.</td>
</tr>
<tr class="odd">
<td><p>Mori et al. 1999</p>
<p><em>Hypertension</em> 1999;34:253-260</p>
<p>[Australia]</p></td>
<td>To determine if the effects of EPA and DHA differ on BP and HR in
mildly hypertensive men at increased risk of cardiovascular
disease.</td>
<td>Randomized, double-blind, placebo controlled trial.</td>
<td>6 weeks of treatment with an initial 3-week baseline period.</td>
<td><p>3.8 g/d EPA as ethyl esters (EPA group)</p>
<p>3.7 g/d DHA as ethyl esters (DHA group)</p>
<p>4 g/d Olive oil (placebo)</p>
<p>Compliance:</p>
<p>Plasma phospholipid fatty acid analysis</p></td>
<td><p>56 healthy, non-smoking men with mild hyperlipidemia were
recruited from the general community through media advertising.</p>
<p>EPA group: n= 19</p>
<p>DHA group: n= 17</p>
<p>Placebo group: n=20</p>
<p>Off the 59 subjects recruited, 3 subjects withdrew because they were
unable to maintain laboratory schedules or comply with the
capsules.</p></td>
<td><p><u>SBP:</u> 24-hour SBP (-5.8 ± 2.1 mm Hg; p=0.022) and daytime
SBP (-3.5 ± 2.9 mm Hg; p=0.041) ↓ significantly with DHA compared to the
placebo. These effects were observed after adjusting for age, baseline
body weight and baseline BP. Mean nighttime SBP was not affected by DHA.
EPA had no effect on 24-hour, daytime or nighttime SBP.</p>
<p><u>DBP:</u> 24-hour DBP (-3.3 ± 1.3 mm Hg; p=0.029) and daytime DBP
(-2.0 ± 1.1 mm Hg; p=0.046) ↓ significantly with DHA compared to the
placebo. These effects were observed after adjusting for age, baseline
body weight and baseline BP. Mean nighttime DBP was not affected by DHA.
EPA had no effect on 24-hour, daytime or nighttime DBP.</p>
<p><u>HR:</u> 24-hour HR (-3.5 ± 0.8 bpm, p=0.001), daytime HR (-3.7 ±
1.2 bpm, p=0.001) and nighttime HR (-2.8 ± 1.2 bpm, p=0.025) ↓
significantly with DHA after adjusting for age, baseline weight and
baseline ambulatory HR. EPA had no effect on 24-hour, daytime or
nighttime HR.</p>
<p>Plasma phospholipid EPA and DHA levels increased significantly in the
EPA (p&lt;0.0001) and DHA (p&lt;0.0001) groups.</p></td>
<td><p><u>Conclusions:</u></p>
<p>The results suggest that, “DHA is the principal n-3 FA in fish and
fish oils that is responsible for their BP-and HR- lowering effects in
humans”.</p>
<p>Comments:</p>
<p>The subjects were asked to maintain their usual diet and physical
activity and to continue their routine lifestyle.</p>
<p>3-day diet records were collected at baseline and at the end of the
study to assess diets.</p></td>
<td>1</td>
<td>Off the 59 subjects recruited, one subject (1.7%) withdrew because
of gastrointestinal symptoms.</td>
</tr>
<tr class="even">
<td><p>Morris, et. al.</p>
<p>1993</p>
<h2 id="am-j-clin-nutr-1">Am J Clin Nutr</h2>
<p>1993;57:59-64</p>
<p>[U.S.]</p></td>
<td>To examine the effect of fish oil on BP in mild hypertensive
subjects.</td>
<td>Randomized, double-blind, placebo-controlled crossover study
design</td>
<td><p>12 weeks on each treatment.</p>
<p>The subjects were assigned to either placebo, 6 g/d fish oil or 12
g/d fish oil for 12 weeks. After 12 weeks the treatments were switched
for the next 12 weeks followed by the last 12-week treatment period (3
period crossover). Each subject received all 3 treatments. No washout
period between the treatment periods.</p></td>
<td><p>5.53 g/d EPA + DHA (EPA = 4.16 g/d and DHA = 1.37 g/d; total
PUFAs = 6.0 g/d). Given as 12 capsules of 1 g each fish oil preparation
(Promega)</p>
<p>2.77 g/d EPA = DHA (EPA = 2.08 g/d and DHA = 0.69 g/d). Given as 6
capsules of 1 g each fish oil preparation (see above).</p>
<p>Placebo was 6 g/d or 12 g/d, given as either 6 or 12 capsules of 1 g
olive oil each.</p>
<p>Compliance:</p>
<p>Capsule counts and plasma phospholipid FA concentration.</p></td>
<td><p>18 subjects (13 men and 5 women, mean age 46.9 years, and mildly
hypertensive, with baseline BP 139.8/92.4 mm Hg).</p>
<p>Of the 20 subjects that were recruited 2 subjects dropped
out.</p></td>
<td><p><u>BP:</u> BP during all three-treatment periods was lower
compared to the baseline. There were no significant effects of either
dose of fish oil on BP at either 6 or 12 weeks. BP measured at the
clinic showed slight ↑ with low dose of fish oil at 6 and 12 weeks, but
no change with high dose of fish oil at both time points compared to
placebo. Home BP measurements showed no differences between the fish oil
and control group. Combined BP (6 and 12 weeks) measurements at the
clinic in the fish oil group did not differ significantly from the
placebo. BP measurements from both doses of fish oil combined showed NS
effect of fish oil compared to placebo. No carry over effects of
treatments.</p>
<p>NS association between changes in BP with compliance, BP or baseline
dietary fish consumption.</p>
<p>Plasma phospholipid EPA and DHA levels increased in both dose groups
(all p&lt;0.001), although there was no difference between the dose
groups (EPA, p = 0.06; DHA p = 0.33).</p></td>
<td><p><u>Conclusions:</u></p>
<p>The authors concluded that, “ fish oil is not a practical treatment
for mild hypertension”.</p>
<p><u>Comments:</u></p>
<p>Subjects consumed on an average, 2.3 fish meals/week, with 44%
consuming 3 or more fish meals/week and 17% less than 1/week. Tuna was
the primary fish eaten. Mean daily intakes of EPA + DHA = 0.22 g (EPA =
0.07 g and DHA = 0.15 g).</p>
<p>Diets were assessed using semiquantitative food frequency
questionnaire.</p></td>
<td>2</td>
<td>Few adverse effects were reported (exact effects not specified as to
type or incidence) and there was no apparent difference among
periods.</td>
</tr>
<tr class="odd">
<td><p>Mundal et. al.</p>
<p>1993</p>
<p><em>Thrombosis Res.</em> 1993; 72:257-62</p>
<p>[Norway]</p></td>
<td>To examine the effect on n-3 FAs and nifedipine on platelet function
in hypertensive males.</td>
<td><p>Randomized, double-blind, cross-over study design.</p>
<p>.</p></td>
<td><p>4 weeks on EPA + DHA or placebo followed by a 4 week washout. Tx
were then reversed for 8 weeks, with the last 4 weeks EPA + DHA +
nifedipine or placebo + nifedipine.</p>
<p>A 4-week placebo run-in period preceded trial</p></td>
<td><p>4.6 g/d EPA + DHA (EPA = 1.8 g/d and DHA = 2.8 g/d).</p>
<p>Group 1:</p>
<p>fish oil (4 weeks), wash-out (4 weeks), placebo (4 weeks), placebo +
nifedipine (4 weeks).</p>
<p>Group 2: placebo (4 weeks), washout (4 weeks), fish oil (4 weeks),
fish oil + nifedipine (4 weeks).</p>
<p>Compliance:</p>
<p>Pill count.</p></td>
<td><p>18 healthy, hypertensive males with elevated blood lipids taking
no medications.</p>
<p>BP was &gt;145/95. All had TC &gt;6.0 mmol/l and TG &gt; 1.4 mmol/l
or TG &gt;1.8 mmol/l if TC was &lt;6.0 mmol/l.</p>
<p>Group 1: n = 8</p>
<p>Group 2: n = 10</p></td>
<td><p><u>Bleeding time</u>: No effects seen compared to controls when
comparing EPA-DHA vs. placebo tx. with and without (p&gt;0.60)
nifedipine.</p>
<p><u>BP</u>: No effects seen after tx with EPA + DHA on BP compared to
placebo controls (p value not specified). Supine mean blood pressure was
significantly ↓ after nifedipine tx in all subjects tested (p = 0.02, n
= 18).</p>
<p>Heart rate: No effects seen after tx with EPA + DHA compared to
placebo controls (p value not specified). No change in heart rate was
observed after nifedipine tx in all subjects tested (p value not
specified).</p>
<p><u>Plasma -thrombo-globulin:</u> There were no effects seen in the
median plasma -thrombo-globulin (p&gt;0.12) after EPA + DHA tx vs.
placebo controls (and without nifedipine tx). Plasma -thrombo-globulin
↑ significantly (p=0.003, n = 18) after nifedipine tx in all subjects
studied, although there was no difference between the EPA-DHA-nifedipine
vs. placebo-nifedipine groups (p = 0.33).</p>
<p><u>Platelet count:</u> No effects after EPA+ DHA tx vs. placebo
(p=0.65) nor after EPA + DHA + nifedipine tx vs. placebo controls (p
values not specified).</p>
<p><u>Platelet volume:</u> no effects after EPA+ DHA tx vs. placebo
(p=0.96) nor after EPA + DHA + nifedipine tx vs. placebo + nifedipine
controls (p values not specified).</p></td>
<td><p><u>Conclusions:</u></p>
<p>The authors concluded that, “the daily n-3 FA supplementation was
modest…and we could not demonstrate significant changes in baseline
blood platelet parameters.” There was no effect of n-3 FA
supplementation alone on other parameters, such as bleeding time, BP or
heart rate.</p>
<p><u>Comments:</u></p>
<p>2 months prior to inclusion subjects discontinued intake of cod liver
oil or related fish oil products.</p></td>
<td>2</td>
<td><h1
id="all-treatments-were-well-tolerated-with-no-withdrawals-due-to-side-effects.">All
treatments were well tolerated with no withdrawals due to side
effects.</h1></td>
</tr>
<tr class="even">
<td><p>Mundal et al. 1994</p>
<p><em>Thrombosis Res.</em> 1994. 75:285-291</p>
<p>[Norway]</p></td>
<td>To assess whether fish consumption, triglyceride levels and selenium
intake are associated with changes in the cutaneous bleeding time and
some hemostatic variables</td>
<td><p>Randomized, parallel,</p>
<p>controlled</p></td>
<td>6 weeks</td>
<td><p>Not quantified.</p>
<p>Fish-rich meal (about 250 g mackerek, wolf fish, rosefish, or
haddock) every day except Sunday</p>
<p>Control: normal diet ± 70 μg/day selenium</p>
<p>Compliance: serum phospholipid FA analysis</p></td>
<td><p>32 healthy subjects</p>
<p>age range: 21-56 years; 2 male/30 female</p>
<p>Fish diet: n=11</p>
<p>Control: n=21</p></td>
<td><p><u>TC</u>: NS change</p>
<p><u>HDL</u>: NS ↑ (+9.6%)</p>
<p><u>LDL</u>: NS ↑ (+4.4%)</p>
<p><u>TG</u>: ↓ -16.3% after 6 months in fish-eating group compared to
baseline values (p=0.04); NS change in controls</p>
<p><u>Bleeding time</u>: ↑ +13.6% in fish-eating group compared to
baseline values (p=0.05); ↓ in controls</p>
<p><u>Fibrinogen</u>: NS change</p>
<p><u>Antithrombin III</u>: NS change</p>
<p><u>Platelet concentration</u>: ↓ -2.6% (p=0.02)</p>
<p><u>Mean platelet volume</u>: NS change</p>
<p>Greater increase in serum EPA levels in fish-eating group (from 1.2%
of total FA concentration in serum phospholipids to 3.3%) compared to
controls (from 1.1% to 1.2%)</p></td>
<td><p><u>Conclusions</u>:</p>
<p>Some mechanism involving the n-3 FA content of triglyceride-rich
lipoproteins may be involved in prolonged bleeding time.</p>
<p><u>Comments</u>:</p>
<p>All bleeding time values and platelet counts were within the normal
ranges.</p>
<p>EPA + DHA not quantified.</p></td>
<td>3</td>
<td>Not reported.</td>
</tr>
<tr class="odd">
<td><p>Naber et al. 1992</p>
<p><em>Ned Tijdschr Geneeskd</em> 1992;136(31):1511-4 (ABSTRACT,
foreign)</p></td>
<td>To determine the effect of n-3 FAs on lipid profile in
hypertriglyceridaemic patients.</td>
<td>Prospective, double-blind.</td>
<td>12 weeks</td>
<td><p>3 g/d of EPA+DHA</p>
<p>1.8 g/d EPA</p>
<p>1.2 g/d DHA (fish oil)</p>
<p>3 g/d corn oil</p></td>
<td><p>17 subjects recruited from general practice.</p>
<p>Fish oil: 8 subjects</p>
<p>Corn oil: 9 subjects</p></td>
<td><p><u>TG:</u> ↓ with fish oil supplementation.</p>
<p>TC: ↑ with corn oil supplementation.</p>
<p>LDL: ↑ with corn oil supplementation.</p></td>
<td><p><u>Conclusion:</u> Fish oil supplementation decreases TG levels
in hypertriglyceridaemic patients.</p>
<p><u>Comments:</u></p>
<p>Summarized from abstract.</p></td>
<td>NA</td>
<td></td>
</tr>
<tr class="even">
<td><p>Nakamura et al. 1998</p>
<p><em>In vivo</em> 1998;12:311-314</p>
<p>[Japan]</p></td>
<td>To determine the effects of EPA on serum remnant-like particle
cholesterol (RLP-C), serum lipids and fatty acids composition NIDDM
patients.</td>
<td>Clinical trial.</td>
<td>12 weeks (3 months)</td>
<td><p>1.8 g/d EPA (1800 mg/d of EPA ethyl esters)</p>
<p>0.9 g/d EPA (900 mg/d of EPA ethyl esters)</p>
<p>Compliance: Plasma EPA concentration</p></td>
<td><p>10 subjects with NIDDM.</p>
<p>Some subjects were treated for hyperlipidemia.</p>
<p>EPA 1800 mg/d: n=4</p>
<p>EPA 900 mg/d: n=6</p></td>
<td><p><u>TG:</u> NS ↓ (baseline 1.83 mmol/l to 1.36 mmol/l after
treatment)</p>
<p><u>TC:</u> NS ↓</p>
<p><u>HDL:</u> NS ↑<u><br />
RLP-C:</u> ↓ significantly with EPA supplementation from 14.5 ± 5.3
mg/dl to 3.3 ± 0.8 mg/dl, p&lt;0.01).</p>
<p><u>Glycated hemoglobin:</u> No significant ↓ was observed with EPA
supplementation.</p>
<p>Serum RLP-C levels were inversely correlated (r= -0.516, p&lt;0.05)
with the ratio of EPA to AA in the plasma.</p>
<p>Plasma EPA ↑ (p&lt;0.01) and the ratios of EPA to AA in the plasma ↑
significantly (p&lt;0.01) with EPA supplementation.</p></td>
<td><p><u>Conclusions:</u></p>
<p>The authors conclude that, “the administration of EPA decreased serum
RLP-C levels in diabetic patients, and suggested that EPA had the
beneficial effects against atherosclerosis in diabetic patients by
decreasing RLP-C concentrations”.</p>
<p>Comments:</p>
<p>Small sample size in each group</p>
<p>Only EPA supplementation</p>
<p>No true control group</p>
<p>Study design not provided.</p></td>
<td>3</td>
<td>Not reported.</td>
</tr>
<tr class="odd">
<td><p>Nelson et al. 1997a</p>
<p><em>Lipids</em> 1997; 32:1137-1146</p>
<p>[U.S]</p></td>
<td>To determine if dietary DHA (commercial availability of a natural
triglyceride (TG)) has independent effects on blood lipids and lipid
metabolism.</td>
<td>Single-blind controlled trial</td>
<td>12 weeks (90 days)</td>
<td><p>6 g/d DHA as a TG (from 15 g of DHASCO<sup>®</sup>oil) fed in a
cold yogurt cocktail.</p>
<p>Low DHA: &lt;50 mg/d of DHA</p>
<p>All subjects were given low DHA diet for 30 days and then eight
subjects (group A) were given high DHA diet for 90 days and four
subjects were continued on low DHA diet (Group B, control).</p></td>
<td><p>10 normal volunteers were recruited and the research was
conducted in the metabolic research unit of the Western Human Nutrition
Research Center.</p>
<p>Control: 4 subjects</p>
<p>DHA diet: 6 subjects</p></td>
<td><p><u>TG:</u> Plasma TG levels ↓ significantly (p&lt;0.004) on DHA
diet when compared to low DHA diet.</p>
<p><u>TC:</u> No change after the DHA diet.</p>
<p><u>LDL:</u> No change after the DHA diet.</p>
<p><u>HDL:</u> ↑ significantly (p&lt;0.02) on high DHA diet compared to
low DHA diet.</p>
<p><u>apo A:</u> NS change</p>
<p><u>apo B:</u> NS change</p>
<p><u>Lp(a):</u> NS change</p>
<p><u>apo E:</u> ↑ significantly (p&lt;0.002) on high DHA diet compared
to low DHA diet.</p>
<p>A four-fold increase in plasma DHA and EPA levels was observed on
high DHA diet. No changes in DHA and EPA levels were observed on low DHA
diet.</p>
<p>A three-fold increase in DHA levels in adipose tissue was observed on
high DHA diet, but no changes were observed in EPA levels in the adipose
tissue.</p></td>
<td><p><u>Conclusion:</u></p>
<p>The authors conclude “ that dietary DHA (6 g/d) lowers plasma TG but
does not affect cholesterol levels significantly. DHA is reconverted to
EPA in significant amounts. It appears that DHA can be a safe and
perhaps beneficial supplement to human diets”.</p>
<p><u>Comments:</u></p>
<p>Statistical comparisons between the control and DHA diet group
because of the small sample size.</p>
<p>The nutrient composition of the diets was analyzed using the nutrient
database.</p></td>
<td>2</td>
<td>Not reported</td>
</tr>
<tr class="even">
<td><p>Nelson et al. 1997b</p>
<p><em>Lipids</em> 1997. 32(11):1129-1136</p>
<p>[U.S.]</p></td>
<td>To determine if a diet containing only DHA has any effect on
platelet function <em>in vitro</em>, bleeding times, coagulation
factors, and platelet fatty acid composition in healthy, normal
volunteers.</td>
<td><p>Randomized,</p>
<p>parallel</p>
<p>single-blind</p></td>
<td><p>13 weeks</p>
<p>(90 days)</p>
<p>with a 30- day stabilization period prior to intervention</p></td>
<td><p>6 g/day DHA from 15 g of DHASCO oil (high-DHA diet) (Group A)</p>
<p>Group B: &lt;0.05 g/day DHA (low-DHA diet)</p>
<p>both groups received the low-DHA diet during the 30-day stabilization
period</p>
<p>Compliance: Platelet lipid FA analysis</p></td>
<td><p>10 healthy male subjects; mean age: 33 years</p>
<p>Group A: n=6</p>
<p>Group B: n=4</p>
<p>no significant difference in body weight, blood pressure, or bleeding
time between subjects at study entry</p>
<p>2 subjects were unable to complete the protocol.</p></td>
<td><p><u>Bleeding time</u>: NS in bleeding (from a mean of 9.4
minutes observed after the 30-day low-DHA diet to 8 minutes after the
high-DHA diet, p=0.06). NS  in control group (5.9 minutes to 6.4).</p>
<p><u>Erythrocyte count</u>: no significant changes</p>
<p><u>Hemoglobin levels</u>: no significant changes</p>
<p><u>Average hematocrit</u>: no significant changes</p>
<p><u>Blood pressure</u>: no significant changes</p>
<p><u>Platelet counts (whole blood)</u>: NS  in both groups.</p>
<p><u>ADP-induced platelet aggregation</u>: NS  with high-DHA diet; NS
 with control diet</p>
<p><u>Collagen-induced platelet aggregation</u>: NS in both
groups.</p>
<p><u>Prothrombin time</u>: no significant changes</p>
<p><u>Activated partial thromboplastin time</u>: no significant
changes</p>
<p><u>Antithrombin-III</u>: NS  with high-DHA diet (p=0.11); NS  with
control diet (p=0.13)</p>
<p>Significantly higher concentration of EPA in whole platelets after
intake of high-DHA diet compared to baseline values (2.67 weight %
versus 0.34 weight %, p&lt;0.05). DHA concentration increased about
three-fold after intake of high-DHA diet.</p></td>
<td><p><u>Conclusions</u>:</p>
<p>Authors concluded that, “adding 6 g/day of dietary DHA for 90 days to
a typical Western diet containing less than 0.05 g/day of DHA produces
no observable physiological changes in blood coagulation, platelet
function, or thrombotic tendencies in healthy, adult males.”</p>
<p><u>Comments</u>:</p>
<p>Small study population.</p>
<p>Patients resided in the research metabolic unit during the study
period on controlled diets.</p>
<p>Experimental group had unaccounted mean bleeding time during run-in
phase that reverted to baseline during treatment phase.</p>
<p>Large standard deviations in the group mean were observed.</p></td>
<td>2</td>
<td>Dietary DHA at 6 g/day “appears to have no short-term adverse
consequences”</td>
</tr>
<tr class="odd">
<td><p>Nenseter et al. 1992</p>
<p>Arteriosclerosis and Thrombosis</p>
<p>1992;12:369-379</p>
<p>[Norway]</p></td>
<td>To examine the effects of n-3 PUFAs on LDL and how these changes
affected metabolism.</td>
<td>Randomized controlled trial</td>
<td>16 weeks (4 months)</td>
<td><p>4.61 g/day EPA+DHA (K85 fish oil capsules, 6 g/day total oil)</p>
<p>2.83 g/day EPA</p>
<p>1.78 g/day DHA</p>
<p>Control group: 6 g/day corn oil</p>
<p>Compliance:</p>
<p>Plasma phospholipid FAs profile</p></td>
<td><p>23 subjects (8 males, 15 females) who were normolipidemic</p>
<p>Fish oil group: 12 subjects</p>
<p>Control group: 11 subjects</p></td>
<td><p><u>LDL:</u> LDL cholesteryl esters ↓ significantly with fish oil
compared to the control group (0.97 vs. 1.19 mg/mg protein, p&lt;0.05),
while the total lipids per mg LDL protein was significantly ↓ in LDL
compared to the control (p&lt;0.05).</p>
<p><u>ApoB:</u> ↑ significantly with fish oil compared to the control
(p&lt;0.05).</p>
<p><u>Index of unsaturation:</u> ↑ significantly in LDL cholesteryl
esters, phospholipids and TG in the treatment group (p&lt;0.01,
p&lt;0.05, p&lt;0.01, respectively).</p>
<p><u>LDL particle size:</u> no significant change compared to
control.</p>
<p><u>Metabolism of LDL by HepG2 Cells:</u> not significantly different
from control</p>
<p><u>Metabolism of LDL by human skin fibroblasts:</u> not significantly
different from control.</p>
<p><u>Susceptibility of LDL to lipid peroxidation:</u> no significant
differences with fish oil compared to control.</p>
<p><u>Uptake rate of LDL by peripheral blood mononuclear cells:</u> no
significant differences with fish oil compared to control.</p>
<p>Plasma phospholipid n-3 fatty acids ↑ significantly in the treatment
group compared to baseline (p&lt;0.01) and control (p&lt;0.001). ↑ in
EPA and DHA in LDL.</p></td>
<td><p>Conclusions:</p>
<p>The authors conclude that, “n-3 PUFAs induced some changes in the
lipid moiety of LDL; however, these changes had no measurable effect on
the cellular metabolism of LDL.”</p>
<p>Comments:</p>
<p>Dietary questionnaires were completed prior to the trial</p></td>
<td>1</td>
<td>No adverse effects were noted in the study</td>
</tr>
<tr class="even">
<td><p>Nilsen et al. 1993</p>
<p>Thrombosis and Haemostasis</p>
<p>1993;70(6):900-902</p>
<p>[Norway]</p></td>
<td>This study “was designed to evaluate whether preoperative loading
with n-3 fatty acids might modify the postoperative acute phase changes
in monocyte-reactivity, tissue factor pathway inhibitor and tissue
plasminogen activator inhibitor.”</td>
<td>Randomized, double-blind, controlled trial.</td>
<td>10 weeks (67 ± 30 days) for treatment group and 12 weeks (85 ± 23
days) for control group prior to surgery</td>
<td><p>5.1 g/day EPA+DHA (Pronova fish oil capsules, 6 g/day total
oil)</p>
<p>control group: 6 g/day corn oil</p>
<p>Compliance:</p>
<p>Serum phospholipid FA analysis.</p></td>
<td><p>20 patients with CHD and elevated serum lipids prior to coronary
bypass surgery. Patients on oral anticoagulants were excluded from the
trial</p>
<p>Fish oil group: 10 patients</p>
<p>Control group: 10 patients</p>
<p>The treatment was discontinued prior to surgery.</p></td>
<td><p><u>Thromboplastin synthesis</u>: LPS stimulated thromboplastin
synthesis ↑ significantly in the fish oil group (99%, p=0.01) and the
control group 44% ↑ (p=0.02) compared to baseline. The synthesis ↑
further by 83% in the fish oil group and 169% in the control group one
week after the surgery. In the control group thromboplastin activity in
the unstimulated cells ↑ one week after the surgery.</p>
<p><u>TxB<sub>2</sub></u>: release from platelets after LPS stimulation
was not significantly changed in either group during the preoperative
period compared to baseline.</p>
<p><u>Fibrinogen</u>: no significant change with fish oil compared to
baseline or control group during preoperative period. Significant ↑ in
both groups postoperatively, but no differences between the groups.</p>
<p><u>TFP1</u>: no significant change with fish oil compared to baseline
or control group during preoperative period. NS ↓ in both groups during
the postoperative period.</p>
<p><u>TAT</u>: no significant change with fish oil compared to baseline
or control group during preoperative period. Significant ↑ in both
groups postoperatively, but no differences between the groups.</p>
<p><u>PAI</u>: no significant change with fish oil compared to baseline
or control group during preoperative period. Significant ↑ in both
groups postoperatively, but no differences between the groups.</p>
<p>Serum phospholipid EPA tripled with fish oil
supplementation.</p></td>
<td><p>Conclusions:</p>
<p>The authors conclude that, “no improvement was noted in LPS
stimulated monocyte thromboplastin synthesis after a prolonged
supplementation period with a concentrated ethyl ester compound of n-3
fatty acids in patients with CHD… Preoperative loading with n-3 fatty
acids did not modify reactive postoperative changes in [the measured]
parameters.”</p>
<p>Comments:</p>
<p>This is a sub-study of the one which looks at other lipid and
coagulation variables.</p>
<p>The study does not assess the diets of the patients.</p></td>
<td>1</td>
<td>Not reported.</td>
</tr>
<tr class="odd">
<td><p>Nordoy et al. 1993</p>
<p><em>Am J Clin Nutr</em> 1993;57:634-9</p></td>
<td>To investigate the interaction of diets with a high and a low intake
of saturated FAs with a fish oil concentrate rich in n-3 FAs.</td>
<td><p>Placebo-controlled</p>
<p>Not random</p>
<p>(Blinding not reported)</p></td>
<td><p>3 weeks test periods:</p>
<p>3 weeks. high saturated (HS) FAs diet, 3 weeks</p>
<p>HS + n-3.</p>
<p>6 weeks washout.</p>
<p>3 weeks low saturated (LS) FAs diet, 3 weeks LS + n-3.</p>
<p>All subjects followed same sequence.</p></td>
<td><p>4.77 EPA+DHA</p>
<p>3.06 g/d EPA</p>
<p>1.71 g/d DHA</p>
<p>(12 g/d EPAX 5000 TG)</p>
<p>Control: olive oil</p>
<p>Controlled diets during test periods.</p>
<p>Uncontrolled diets during washout period.</p>
<p>Compliance: Daily reports, serum FAs analysis.</p></td>
<td>6 healthy men were recruited from university staff and surrounding
community.</td>
<td><p><u>TG:</u> ↓ (P&lt;0.02) in both groups on n-3 vs. non n-3
groups.</p>
<p><u>TC:</u> ↓ (P&lt;0.01) in both groups on n-3 vs. non-n-3
groups.</p>
<p><u>LDL:</u> NS</p>
<p><u>HDL:</u> ↓ (P&lt;0.01) in both groups on n-3 vs. non n-3
groups.</p>
<p><u>VLDL:</u> ↓ (P&lt;0.01) in both groups on n-3 vs. non n-3
groups</p>
<p><u>apo A,B,CIII,E:</u> NS</p>
<p><u>Serum FAs:</u> ↑ EPA &amp; DHA (P&lt;0.01) vs. diets without
n-3.</p></td>
<td><p><u>Conclusions:</u></p>
<p>Results indicate that dietary SFAs and n-3 FAs have independent
mechanisms of actions on the plasma lipids and lipoproteins.</p>
<p><u>Comments:</u></p>
<p>Very small sample size.</p></td>
<td>2</td>
<td>“The subjects tolerated the diets including the fish oil without any
adverse effects.”</td>
</tr>
<tr class="even">
<td><p>Nordoy et al. 1994</p>
<p><em>J. Lab. Clin. Med.</em> 1994. 123:914-920</p>
<p>[U.S.]</p></td>
<td>To evaluate whether a diet high in saturated fat would counteract
the beneficial effects of n-3 fatty acids on <em>in vivo</em> platelet
and vascular eicosanoid formation and other hemostatic parameters
associated with arterial thrombosis</td>
<td>Randomized, double-blind, crossover</td>
<td><p>3 weeks</p>
<p>per treatment period, with a 6-week washout between periods</p></td>
<td><p>1.7 g/day EPA + DHA</p>
<p>(6.1 g/day n-3 FA from encapsulated fish oil concentrate (EPAX)
containing 68% n-3 content (35% EPA, 19% DHA)</p>
<p>Subjects fed:</p>
<ol start="4" type="1">
<li><p>a high-fat diet (39% of energy),</p></li>
<li><p>a high-fat diet + n-3 FA,</p></li>
<li><p>a low fat diet (25% of energy), or</p></li>
<li><p>a low fat diet + n-3 FA</p></li>
</ol>
<p>Compliance: plasma fatty acid composition, participant interviews,
and leftover meals</p></td>
<td><p>6 normolipidemic males</p>
<p>age range: 27-58 years (mean: 39.7 years)</p></td>
<td><p><u>Skin bleeding time</u>: ↑ significantly for n-3 FA + low
saturated-fat diet compared to n-3 FA + high saturated-fat diet
(p&lt;0.02).</p>
<p><u>Platelet count</u>: NS change</p>
<p><u>Mean platelet volume</u>: NS change</p>
<p><u>Fibrinogen</u>: NS change</p>
<p><u>Factor VII activity</u>: NS change</p>
<p><u>Phospholipase C-sensitive component of factor VI</u>I: NS
change</p>
<p><u>Antithrombin III</u>: NS change</p>
<p><u>Protein S antigen</u>: NS change</p>
<p><u>Protein C activity</u>: NS change</p>
<p><u>Thromboxane A<sub>2</sub></u>: ↓ significantly with n-3 FA + low
saturated-fat diet (as assessed by urinary metabolites <em>in
vivo</em>)</p>
<p><u>Thromboxane A<sub>3</sub></u>: slightly ↑ synthesis with both
diets</p>
<p><u>Prostacylcin production</u>: ↓ for low-fat diet compared to
high-fat diet</p>
<p><u>Prostacyclin I<sub>3</sub></u>: slightly ↑ synthesis with both
diets</p>
<p>Serum fatty acid levels (predominately EPA and DHA) increased
similarly with both the low saturated-fat and high saturated-fat
diets.</p></td>
<td><p><u>Conclusions</u>:</p>
<p>The effects of EPA and DHA on platelet and vascular function and
eicosanoid production are modulated by the content of saturated fatty
acids in the diet, and that a diet low in dietary fats supplemented with
n-3 FA favorably affects platelet function and platelet vascular
interactions.</p>
<p><u>Comments</u>:</p>
<p>Small sample size.</p>
<p>All bleeding time measurements were within the normal clinical
range.</p>
<p>Actual data for the various coagulation factors not presented (except
for bleeding time, platelet count, and platelet volume).</p>
<p>Dietary intake evaluated; subjects administered prescribed
diets.</p></td>
<td>2</td>
<td>All diets were well tolerated, without any adverse effects. No
significant changes were observed in red cell count, white cell count,
or hemoglobin concentrations.</td>
</tr>
<tr class="odd">
<td><p>Nordoy et al. 1998</p>
<p><em>J. Intern Med</em> 1998;243:163-170</p>
<p>[Norway]</p></td>
<td>To evaluate the efficiency and safety of treatment with Simvastatin
(S) and n-3 FAs in patients w/ combined hyperlipidemia.</td>
<td><p>Randomized,</p>
<p>double-blind,</p>
<p>placebo-controlled trial.</p></td>
<td><p>5 weeks EPA+DHA intervention</p>
<p>1. 16 weeks dietary run-in</p>
<p>2. 5 weeks S</p>
<p>3. 5 weeks S+n-3</p></td>
<td><p>3.4 g/d EPA+DHA</p>
<p>1.8 g/d EPA &amp;</p>
<p>1.6 g/d DHA</p>
<p>(4 1-g capsules Omacor fish oil)</p>
<p>Control: corn oil</p>
<p>Compliance:</p>
<p>Capsule counting, Serum FAs analysis.</p></td>
<td><p>41 patients with combined hyperlipidemia,</p>
<p>TG 2-15 mmol/l &amp; TC &gt;5.3 mmol/l after run-in.</p>
<p>Recruited from the Lipid Clinic Dept of Medicine.</p>
<p>Test: 21</p>
<p>Control: 20</p>
<p>@70% men.</p></td>
<td><p>Results following 5-weeks EPA+DHA intervention.</p>
<p><u>TG:</u> ↓ (P=0.007)</p>
<p><u>TC:</u> ↓ (P=0.052)</p>
<p><u>LDL:</u> ↑ NS (p=0.4)</p>
<p><u>HDL:</u> NS</p>
<p><u>apo A:</u> NS</p>
<p><u>apo B:</u> NS</p>
<p><u>Serum FAs:</u> ↑ EPA (P=0.0002), ↑ DHA (P=0.0003), ↓ 18:2n6
(P=0.011).</p>
<p><u>apo e:</u> ↓ (p=0.035)</p>
<p><u>DBP:</u> ↓ (p=0.054)</p>
<p><u>SBP:</u> NS</p>
<p><u>Plasma glucose:</u> NS</p>
<p><u>Plasma insulin:</u> NS</p>
<p><u>HbAIC:</u> NS</p>
<p>Further results on lipid peroxides and antioxidants reported in
article but not summarized here.</p></td>
<td><p><u>Conclusions:</u></p>
<p>Combined treatment of S + n-3 FAs seems to be an efficient and safe
alternative for patients w/ combined hyperlipidemia.</p>
<p><u>Comments:</u></p>
<p>1 test &amp; 2 control patients had diabetes.</p>
<p>Exclusion criteria not given.</p>
<p>Extensive dietary assessment.</p>
<p>Test group diet higher intake of PUFAs, EPA, DHA.</p>
<p>Some p-values in text didn't match tables.</p></td>
<td>1</td>
<td>"No side-effects of Simvastatin or n-3 FAs capsules were
registered."</td>
</tr>
<tr class="even">
<td><p>Olszewski &amp; McCully 1993</p>
<p><em>Coronary Artery Disease</em> 1992;4(1): 53-60</p>
<p>[Poland]</p></td>
<td>To determine the effect of fish oil on serum homocysteine levels in
hyperlipemic men.</td>
<td><p>Placebo-controlled,</p>
<p>crossover trial</p>
<p>(randomization and blinding not reported)</p></td>
<td><p>3 weeks test, 3 weeks control</p>
<p>followed by</p>
<p>8 weeks uncontrolled interval</p>
<p>followed by</p>
<p>3 weeks control, 3 week test</p>
<p>(reverse for second group).</p></td>
<td><p>3.6 g/d EPA+DHA</p>
<p>2.16 g/d EPA</p>
<p>1.44 g/d DHA</p>
<p>(12 g/d Activepe capsules)</p>
<p>Control: olive oil</p>
<p>Controlled, prepared diets during test periods, not during washout
period.</p>
<p>Compliance:</p>
<p>Not reported.</p></td>
<td>15 hyperlipemic males</td>
<td><p><u>TG:</u> ↓ (P&lt;0.05) in group who took olive oil first
followed by fish oil.</p>
<p><u>VLDL:</u> ↓ trend (P&lt;0.06) in group who took olive oil first
followed by fish oil.</p>
<p><u>TC:</u> NS</p>
<p><u>LDL:</u> NS</p>
<p><u>HDL:</u> NS</p>
<p><u>apo B:</u> NS</p>
<p><u>Homocysteine:</u> ↑ control group (p&lt;0.05) &amp; ↓ in test
group (P&lt;0.01) vs. baseline.</p></td>
<td><p><u>Conclusions:</u></p>
<p>“The results of this study suggest that lowering of plasma
homocysteine by these micronutrients may be potentiated by dietary fish
oil, but further study is needed.”</p>
<p><u>Comments:</u></p>
<p>Study reports, “two subjects were studied in both groups 1 and
2.”</p>
<p>Serum homocysteine data values not reported</p>
<p>Small sample size.</p>
<p>Very short test duration.</p>
<p>Dropouts not reported.</p></td>
<td>2</td>
<td>Adverse effects and tolerance not reported.</td>
</tr>
<tr class="odd">
<td><p>Oosthuizen et al. 1994</p>
<p><em>Thrombosis &amp; Haemostasis</em> 1994;72(4):557-562</p>
<p>[South Africa]</p></td>
<td>To examine the effects of a moderate dose of fish oil (6g/d) on
several cardiovascular risk markers including plasma fibrinogen, in a
group of 20 healthy individuals.</td>
<td><p>Randomized</p>
<p>Double blind</p>
<p>Placebo controlled</p>
<p>Cross-over</p></td>
<td><p>6 weeks</p>
<p>3 weeks washout</p>
<p>6 weeks crossover</p></td>
<td><p>1.58 g/d EPA+DHA</p>
<p>1.14 g/d EPA</p>
<p>0.44 g/d DHA</p>
<p>6 g/d n-3</p>
<p>(12 capsules/d Efamed)</p>
<p>Control: olive oil</p>
<p>Compliance: FAs analysis, other methods not reported, but compliance
was evaluated.</p></td>
<td><p>20 healthy normolipidaemic subjects</p>
<p>10 male, 10 female</p></td>
<td><p><u>TG:</u> ↓ vs. baseline (P&lt;0.05)</p>
<p><u>TC:</u> NS during test period, ↓ during olive oil supplementation
(P&lt;0.01).</p>
<p><u>LDL:</u> NS</p>
<p><u>HDL:</u> NS</p>
<p><u>Free FAs:</u> NS</p>
<p><u>Serum FAs:</u> ↑ EPA and DHA vs. baseline (P&lt;0.001) and vs.
control (P&lt;0.05).</p>
<p><u>Serum insulin:</u> ↑ in women during olive oil supplementation
(P&lt;0.05) .</p>
<p><u>Plasma fibrinogen:</u> ↓ (P&lt;0.05) with test and olive oil vs.
baseline in women, who had higher baseline values than the men.</p>
<p><u>Plasma factors Vc, VIIc, Xc:</u> ↓ in women during fish oil intake
vs. baseline. Xc also lower for women during olive oil intake.</p>
<p><u>Factor VIIIc:</u> NS</p>
<p><u>PAI-1 activity:</u> ↑ during test period for males and females
(P&lt;0.05) vs. baseline. ↑ for females only during olive oil
intake.</p>
<p>Plasminogen activity and tissue plasminogen activator antigen not
affected.</p></td>
<td><p><u>Conclusions:</u></p>
<p>This study demonstrated that both fish oil and olive oil intake
decreased plasma fibrinogen levels in women who had high initial levels
and not in men who had lower baseline levels.</p>
<p><u>Comments:</u></p>
<p>Side-effects of belching and aftertaste affected the double-blind
design of the study.</p>
<p>Dietary habits reported to be constant during study though actual
influence of diet not assessed.</p></td>
<td>2</td>
<td>Complaints about belching and a “fishy” after-taste reported by most
subjects.</td>
</tr>
<tr class="even">
<td><p>Orengo et al. 1992</p>
<p><em>Arch Dermatol Res</em> 1992;284:219-221</p>
<p>[U.S.]</p></td>
<td>To determine if fish oil would alter the minimal erythema dose in
humans.</td>
<td>Randomized, placebo-controlled trial.</td>
<td>4 weeks</td>
<td><p>4g/d of EPA+DHA from fish oil lipid (fish oil group) (Promega
capsules)</p>
<p>2.8 g/d EPA</p>
<p>1.2 g/d DHA</p>
<p>Gelatin capsules (placebo group)</p>
<p>Compliance: Not measured</p></td>
<td><p>19 subjects</p>
<p>Fish oil group: 10 subjects.</p>
<p>Placebo group: 9 subjects.</p>
<p>The subjects in both groups had skin type 3 (sometimes burn, always
tan).</p></td>
<td><p><u>TG:</u> ↓ by 40 mg/dl (p&lt;0.02) in the fish oil group.</p>
<p><u>TC:</u> No change in the fish oil group.</p>
<p><u>PGE<sub>2</sub>:</u> No change in the fish oil group.</p>
<p>Minimal erythema dose ↑ significantly (p&lt;0.02) in the fish oil
group.</p>
<p>No significant changes in any parameters were observed in the placebo
group.</p></td>
<td><p><u>Conclusion:</u></p>
<p>A significant increase in minimal erythema dose and a significant
decrease in TG levels was observed with fish oil supplementation.</p>
<p><u>Comments:</u></p>
<p>Diets were not assessed.</p></td>
<td>2</td>
<td>Most subjects reported excessive eructation with malodorous breath
during the study period in the fish oil group. Some subjects reported
diarrhea if all ten fish oil capsules were taken as a single dose verses
divided dose.</td>
</tr>
<tr class="odd">
<td><p>Osterud et al. 1995</p>
<p><em>Lipids</em> 1995. 30:1111-1118</p>
<p>[Norway]</p></td>
<td>To assess the effects of supplemental intake of various marine oils
known to be part of the Eskimo diet in changing biological parameters
that might be important in explaining their low incidence of coronary
heart disease</td>
<td>Randomized, parallel, controlled</td>
<td>10 weeks</td>
<td><p>Not quantified.</p>
<p>15 ml/day Harp seal blubber oil, cod liver oil, oil from blubber of
Minke whales, seal blubber oil/ cod liver oil</p>
<p>(Minke whale oil: 12.2 % w/w EPA + DHA</p>
<p>Harp seal oil:</p>
<p>17.9 % w/w EPA + DHA</p>
<p>Cod liver oil:</p>
<p>22.6 % w/w EPA + DHA)</p>
<p>Control: no oil</p>
<p>Compliance: Serum phospholipid FA analysis</p></td>
<td><p>134 healthy subjects</p>
<p>age range: 18-60 years (mean age: 29 years)</p>
<p>72 male/62 female</p>
<p>Seal oil: n=27</p>
<p>Cod liver oil: n=26</p>
<p>Seal/Cod liver oil: n=27</p>
<p>Whale oil: n=26</p>
<p>Control: n=28</p></td>
<td><p><u>TC</u>: NS change in any group</p>
<p><u>HDL</u>: ↑ significantly (+7%) in seal/cod liver oil group
(p&lt;0.05); ↑ significantly (+11%) in whale oil group (p&lt;0.005)</p>
<p><u>TG</u>: ↓ significantly (-23%) in cod liver oil group only
(p&lt;0.05)</p>
<p><u>Fibrinogen</u>: no change</p>
<p><u>FVIIc</u>: no change</p>
<p><u>Prothrombin fragment 1+2 (F1+2)</u>: ↓ significantly (-25%) in
whale oil group; NS change in other groups</p>
<p><u>LPS-induced TNF-α activity in monocytes of whole blood</u>: ↓
significantly in whale oil group; NS ↓ in seal/cod liver oil group</p>
<p><u>LPS-induced TF activity in monocytes of whole blood</u>: ↓
significantly in seal/cod liver oil and whale oil groups; NS ↓ in all
other groups</p>
<p><u>Thromboxane B<sub>2</sub></u>: ↓ significantly (-43.7%) in whale
oil group (p&lt;0.01); NS ↓ in all other fish oil groups</p>
<p>Serum levels of EPA and DHA were significantly increased in all fish
oil groups.</p></td>
<td><p><u>Conclusions</u>:</p>
<p>Authors concluded that, “daily dietary supplementation with whale oil
alone or seal/cod live oil in combination appeared to have the most
pronounced effects on some selected biological parameters thought to
play a role in cardiovascular disease.”</p>
<p><u>Comments</u>:</p>
<p>Diet not assessed but subjects asked to maintain usual dietary habits
during the study.</p>
<p>EPA + DHA not quantified.</p></td>
<td>2</td>
<td>Not reported.</td>
</tr>
<tr class="even">
<td><p>Otto et al. 1996</p>
<p><em>Metabolism</em> 1996. 45:1305-1311</p>
<p>[Germany]</p></td>
<td>To investigate the effects of supplementation with n-3 FA in a
lipid-lowering diet in well-defined dyslipoproteinemia and familial
dysbeta-lipoproteinemia on plasma lipoproteins and hemorrheology</td>
<td>Not controlled</td>
<td><p>8 weeks</p>
<p>of fish oil (2-week acclimation period with low dose n-3 FA followed
by 6-week test period with high dose n-3 FA)</p>
<p>1 week baseline period prior to study</p>
<p>1 week washout period between n-3 FA and fenofibrate treatment (week
12)</p>
<p>8 weeks of therapy with fenofibrate (starting with week 12)</p></td>
<td><p>3 g/day EPA + DHA from 6 g/day fish oil capsules containing 3.6 g
ethyl esters</p>
<p>(test period)</p>
<p>1.5 g/day EPA + DHA from 3 g/day fish oil capsules containing 1.8 g
n-3 FA ethyl esters (50% EPA, 33% DHA) (acclimation period)</p>
<p>Subjects administered 250 mg slow-release fenofibrate starting after
12 weeks</p>
<p>Compliance: plasma EPA and DHA concentrations</p></td>
<td><p>23 subjects with primary hypertriglyceridemia (plasma
triglycerides &gt; 2.85 mmol/l;</p>
<p>mean age: 45.7 years;</p>
<p>22 male/1female). Fifteen subjects had familial hypertriglyceridemia
(FHTG); 8 subjects had familial dysbetalipoproteinemi-a (FDL)</p>
<p>2 withdrawals: 1 due to pregnancy, the other due to gastrointestinal
effects</p></td>
<td><p><u>TC</u>: ↓ by 12% in FHTG subjects with fenofibrate
(p&lt;0.05); ↓ by 25% and 22% in FDL subjects with n-3 FA and
fenofibrate, respectively (p&lt;0.05)</p>
<p><u>HDL</u>: NS change</p>
<p><u>HDL<sub>2</sub></u>: ↓ in FHTG subjects with n-3 FA (p&lt;0.05);
NS change in FDL subjects</p>
<p><u>HDL<sub>3</sub></u>: ↑ in FHTG subj. with fenofibrate (p&lt;0.05);
NS change in FDL subjects</p>
<p><u>LDL</u>: ↑ by 44% and 27% in FHTG subjects during n-3 FA and
fenofibrate intake, respectively (p&lt;0.01); NS change in FDL
subjects.</p>
<p><u>Total TG</u>: ↓ by 44% and 36% in FHTG subjects during n-3 FA and
fenofibrate intake, respectively (p&lt;0.05); ↓ by 48% and 35% in FDL
subj. with n-3 FA and fenofibrate, respectively (p&lt;0.05)</p>
<p><u>VLDL-C</u>: ↓ in FHTG and FDL subjects during n-3 FA or
fenofibrate intake (p&lt;0.05);</p>
<p><u>VLDL-TG</u>: ↓ in FHTG and FDL subjects during n-3 FA or
fenofibrate intake (p&lt;0.05);</p>
<p><u>Ratio VLVL-C:VLDL-TG</u>: NS change</p>
<p><u>apo A-1</u>: NS change for FHTG or FDL subjects during fish oil or
fenofibrate intake.</p>
<p><u>apoB</u>: NS change in FHTG subjects with n-3 FA; ↓ in FHTG
subjects with fenofibrate only and in FDL subjects with both treatments
(p&lt;0.05)</p>
<p><u>Fibrinogen</u>: NS change in FHTG subjects; ↓ by 20% at wk 20 with
fenofibrate in FDL subjects vs. washout (p&lt;0.05).</p>
<p><u>Plasma viscosity</u>: NS change in FHTG subjects; ↓ by 6% at wk 20
with fenofibrate in FDL subjects vs. washout (p&lt;0.05).</p>
<p><u>Standard blood viscosity</u>: NS change in FHTG subjects; ↓ at all
shear rates at wk 20 with fenofibrate in FDL subjects vs. washout period
(p&lt;0.05).</p>
<p><u>RBC filterability (as measured by clogging and transit time)</u>:
NS change</p>
<p><u>RBC aggregation</u>: ↓ significantly for stasis in FHTG subjects
at weeks 4 and 8 of n-3 FA oil intake and week 12 (washout) vs.
baseline; ↓ for shear rate 3/s in FHTG subjects at weeks 4-8 of n-3 FA
intake vs. baseline (p&lt;0.05).</p>
<p>Plasma concentrations of EPA and DHA ↑ significantly with both doses
of n-3 FA.</p></td>
<td><p><u>Conclusions</u>:</p>
<p>Omega-3 FA and fenofibrate have comparable effects on lipid
parameters in FDL and FHTG patients; however, fenofibrate may be
preferred for use in patients with FDL because of its beneficial effects
on hemorrheological parameters.</p>
<p><u>Comments</u>:</p>
<p>Only a 1-week washout period between n-3 FA intake and
fenofibrate.</p>
<p>Diet not assessed. All subjects started a lipid-lowering diet for 4
weeks prior to start of study.</p>
<p>Subjects were not allowed to take lipid-lowering drugs for at least 6
weeks.</p></td>
<td>2</td>
<td>1 subject withdrew from study due to abdominal discomfort with 3.6
g/day n-3 FA. No significant changes occurred in body weight,
prothrombin index, blood glucose, or γ-glutamyl trans-peptidase during
treatment with fish oil or fenofibrate. A slight increase in creatinine
was observed in subjects with familial hyper-triglyceridemia during
fenofibrate therapy.</td>
</tr>
<tr class="odd">
<td><p>Passfall et al. 1993</p>
<p>The Clinical Investigator</p>
<p>1993;71:628-633</p>
<p>[Germany]</p></td>
<td>“To examine the effects of dietary fish oil…supplementation on blood
pressure, intracellular free platelet calcium, plasma lipoproteins and
circulating vasoactive substances such as norepinephrine, epinephrine,
and renin in patients with essential hypertension.”</td>
<td>Randomized, double-blind, crossover study</td>
<td><p>6 week treatment with either fish oil or olive oil, after which
patient crossed over following a 4 week washout</p>
<p>The study was preceded by a 4 week run-in period in which subjects
discontinued medication.</p></td>
<td><p>2.16 g/day EPA+DHA</p>
<p>(Eicosapen fish oil capsules, 9g/day total fish oil)</p>
<p>1.26 g/day EPA</p>
<p>0.9 g/day DHA</p>
<p>Control group: 9 g/day olive oil</p>
<p>Compliance:</p>
<p>Not reported</p></td>
<td><p>10 subjects (4 male, 6 female) with essential hypertension (DBP
of 95-104 mm Hg)</p>
<p>Two of the 12 subjects initially recruited dropped out of the study,
but the reasons were not reported.</p></td>
<td><p><u>TG:</u> significant ↓ (p&lt;0.01) compared to baseline.</p>
<p><u>TC:</u> no significant change from baseline or placebo.</p>
<p><u>LDL:</u> no significant change with fish oil from baseline or
placebo (fish oil 138 ± 11.4; baseline 139 ± 9.8; placebo 129 ± 10
mmol/l).</p>
<p><u>HDL:</u> no significant change from baseline or placebo.</p>
<p><u>SBP:</u> no significant change from baseline or placebo.</p>
<p><u>DBP:</u> significant ↓ (p&lt;0.05) compared to baseline.</p>
<p><u>Intracellular free platelet calcium:</u> significant ↓ (p&lt;0.05)
compared to baseline.</p>
<p><u>Vasoactive hormones:</u> no significant change in norepinephrine,
epinephrine, or dopamine, or on plasma renin activity.</p></td>
<td><p>Conclusions:</p>
<p>The authors conclude that, “a moderate increase in dietary fish oil
reduces diastolic blood pressure, intracellular free platelet calcium,
and plasma TG in patients with essential hypertension.”</p>
<p>Comments:</p>
<p>Diets were not assessed in the study</p>
<p>Final evaluations of two subjects were conducted 1-2 weeks
early.</p></td>
<td>1</td>
<td>Not reported.</td>
</tr>
<tr class="even">
<td><p>Pelikánová et al. 1993</p>
<p><em>Annals New York Academy Sciences</em> 1993;683:272-278</p>
<p>Also in <em>Cas Lek Ces</em> 1992;131(22):668-672 (ABSTRACT,
foreign)</p>
<p>[Czech Republic]</p></td>
<td>To determine the effect of fish oil on glucose homeostasis in mildly
obese men with NIDDM.</td>
<td>Randomized, placebo controlled trial.</td>
<td><p>3 weeks</p>
<p>An initial 4-week run-in period before randomization.</p></td>
<td><p>3.1 g/d of n-3 FAs (15 ml/d of fish oil, Martens
Oil-Activapa)</p>
<p>15 ml/d of saline was given to the placebo group</p>
<p>The men were on hypoglycemic drugs.</p>
<p>Compliance:</p>
<p>Serum phospholipid FA analysis</p></td>
<td><p>20 mildly obese men with NIDDM treated with oral hypoglycemic
agents.</p>
<p>Fish oil group: n=10</p>
<p>Placebo group: n=10</p></td>
<td><p><u>TG:</u> Did not change significantly (fish oil 1.53 ± 0.65,
baseline 1.49 ± 0.97; placebo 2.01 ± 0.60, baseline 1.90 ± 0.7
mmol/l).</p>
<p><u>TC:</u> Did not change significantly (fish oil 6.44 ± 1.2,
baseline 6.62 ± 0.88; placebo 6.22 ± 0.72, baseline 6.13 ± 1.0
mmol/l).</p>
<p><u>HDL:</u> Did not change significantly.</p>
<p><u>Fasting glucose:</u> No significant changes with fish oil (no
data).</p>
<p><u>Postprandial glucose:</u> No significant changes with fish oil (no
data).</p>
<p><u>Fasting insulin:</u> No significant changes with fish oil (no
data).</p>
<p><u>Postprandial insulin:</u> No significant changes with fish oil (no
data).</p>
<p><u>Fasting C-peptide:</u> No significant changes with fish oil (no
data).</p>
<p><u>Postprandial C-peptide:</u> No significant changes with fish oil
(no data).</p>
<p>No changes were observed in insulin action during the
hyperinsulinemic isoglycemic clamp and no changes were observed in
insulin binding to receptors on erythrocytes.</p>
<p>Significant increase (p&lt;0.01) in serum phospholipid n-3
FAs.</p></td>
<td><p><u>Conclusions:</u></p>
<p>The authors conclude that, “during short-term administration, no
adverse effects of low dose fish oil on glucose homeostasis were found
in mildly obese NIDDM patients treated with oral hypoglycemic
agents”.</p>
<p><u>Comments:</u></p>
<p>Diets were not assessed but the patients consumed their usual
diet.</p>
<p>Data for all endpoints not reported, figures presented.</p></td>
<td>2</td>
<td>Not reported.</td>
</tr>
<tr class="odd">
<td><p>Perani et al, 1995</p>
<p><em>Riv. It. Biol. Med.</em> 1995;15:87-93 (ABSTRACT, foreign)</p>
<p>[Italy]</p></td>
<td>To assess the impact of n-3 supplementation on cardiovascular risk,
BP, plasma lipoproteins, and LDL oxidizability in patients with primary
endogenous hypertri-glyceridemia.</td>
<td>Randomized</td>
<td>Not reported</td>
<td><p>Not given</p>
<p>Standard hypolipidemic diet alone or supplemented with n-3.</p></td>
<td><p>Number not given.</p>
<p>Patients with primary endogenous hypertriglyceridemia.</p></td>
<td><p><u>TG:</u> ↓ significant (p-value not given)</p>
<p><u>LDL:</u> “enhanced susceptibility of LDL to in vitro oxidation.
Moreover, the anti-oxidized LDL IgG autoantibody titer rose during n-3
treatment.”</p>
<p><u>DBP:</u> ↓ significant (p-value not given)</p></td>
<td><p><u>Conclusions:</u></p>
<p>Although the effects on TG and BP were favorable, the LDL
oxidizability findings are of concern and suggest a cautious use of
PUFAs in patients with primary hypertriglyceridemia.</p>
<p><u>Comments:</u></p>
<p>Summarized from abstract.</p></td>
<td>NA</td>
<td>Not addressed in abstract.</td>
</tr>
<tr class="even">
<td><p>Perisichetti et al. 1996</p>
<p><em>Minerva Urol. Nefrol.</em> 48:137-138</p>
<p>[Italy]</p></td>
<td>To investigate whether n-3 PUFA can reduce two important risk
factors of atherosclerosis and atherothrombosis</td>
<td>Not controlled</td>
<td><p>24 weeks</p>
<p>(6 months)</p></td>
<td><p>3 g/day n-3 FA in capsules, each capsule contained 1,000 mg n-3
FA (with EPA and DHA in a reciprocal ratio of 0.9-1.5)</p>
<p>Compliance: not reported.</p></td>
<td>18 hypertriglyceridemic and hyperfibrinogenemic maintenance dialysis
patients; none were diabetic</td>
<td><p><u>TC</u>: ↓</p>
<p><u>LDL</u>: ↓ (-19%)</p>
<p><u>HDL</u>: NS change</p>
<p><u>TG</u>: ↓ (-55%)</p>
<p><u>Fibrinogen</u>: ↓ (-35%)</p></td>
<td><p><u>Conclusions</u>:</p>
<p>Oral administration of n-3 FA may be beneficial in reducing at least
2 major thrombosis risk factors (i.e., fibrinogen and triglyceride
levels).</p>
<p><u>Comments</u>:</p>
<p>Limited statistical analysis; limited study details.</p>
<p>Study was not controlled.</p></td>
<td>3</td>
<td>Not reported.</td>
</tr>
<tr class="odd">
<td><p>Prisco et al. 1994; 1995</p>
<p><em>Thrombosis Res.</em> 1994. 76:237-244</p>
<p><em>Metabolism</em> 1995. 44:562-569</p>
<p>[Italy]</p></td>
<td>To investigate the influence of a moderate dose of n-3 PUFA ethyl
ester supplementation on lipid profile, blood clotting, and fibrinolysis
in healthy subjects</td>
<td>Randomized, double-blind, parallel, controlled</td>
<td><p>16 weeks</p>
<p>(4 months)</p></td>
<td><p>3.44 g/day EPA + DHA from 4 g capsules of EPA and DHA ethyl
esters (ESAPENT)</p>
<p>Control: 4 g/day olive oil</p>
<p>Compliance: capsule count, platelet phospholipid FA analysis</p></td>
<td><p>20 healthy male subjects with normal physical exam, hematology
analyses, blood pressure, and cholesterol levels mean age: 32 years (age
range: 27-41 years)</p>
<p>n-3 FA: n=10</p>
<p>Control: n=10</p></td>
<td><p><u>TC</u>: NS change</p>
<p><u>HDL</u>: NS change</p>
<p><u>TG</u>: NS ↓ after 2 and 4 months of supplementation (-25%); no
change with placebo</p>
<p><u>Lp(a)</u>: NS ↓; no change with placebo</p>
<p><u>Plasminogen</u>: NS change</p>
<p><u>Alpha 2-antiplasmin</u>: NS change</p>
<p><u>PAI-1 activity</u>: NS change</p>
<p><u>PAI-1 antigen</u>: NS change</p>
<p><u>Fibrinogen</u>: NS ↓</p>
<p><u>Prothrombin fragment 1+2</u>: NS change</p>
<p><u>Serum thromboxane B<sub>2</sub></u>: ↓ significantly; no change
with placebo</p>
<p><u>Collagen aggregation threshold</u>: ↑ significantly; no change
with placebo</p>
<p>Platelet phospholipid (phosphatidylcholine, phosphatidylethanolamine,
and phosphatidylinositol) concentrations of total n-3 PUFA, EPA and DHA
increased after 2 and 4 months of supplementation. Most returned to
baseline levels 2-3 months after cessation of supplementation.</p></td>
<td><p><u>Conclusions</u>:</p>
<p>Supplementation with a moderate dose of n-3 PUFA ethyl esters does
not affect PAI-1 plasma levels. Both platelet lipids and function are
influenced by n-3 PUFA ethyl ester supplementation and significant
alterations are detectable even after 2 months of wash-out</p>
<p><u>Comments</u>:</p>
<p>Diet not assessed, but subjects asked to maintain usual dietary
habits.</p></td>
<td>2</td>
<td>Abdominal discomfort and diarrhea reported in 2 subjects who
consumed olive oil; no adverse effects reported in subjects consuming
EPA + DHA capsules.</td>
</tr>
<tr class="even">
<td><p>Prisco et. al. 1998</p>
<p><em>Thrombosis Res.</em> 1998; 91:105-12</p>
<p>[Italy]</p></td>
<td>To examine the effect of medium-term supplementation with a moderate
dose of n-3 PUFAs on blood pressure in mild hypertensive patients.</td>
<td>Randomized double-blind, parallel group trial.</td>
<td><p>16 weeks</p>
<p>(4 months) supplementation with a 2 month follow-up after
discontinuation of PUFAs</p></td>
<td><p>3.44 g/d EPA + DHA as ethyl esters (EPA 2.04 g, DHA 1.40 g) given
as four 1 g capsules (Esapent)</p>
<p>Placebo: Olive oil, 4 g/d</p>
<p>Compliance:</p>
<p>Capsule count and RBC phosphotidyl-choline fatty acid
analysis.</p></td>
<td><p>32 men (16 mild hypertensive, non-diabetic, normolipidemic males
and 16 normotensive males)</p>
<p>Group 1: EPA/DHA hypertensives, n=8</p>
<p>Group 2: Olive oil hypertensive, n=8</p>
<p>Group 3: EPA/DHA normotensive, n=8</p>
<p>Group 4: Olive oil normotensive, n=8</p>
<p>All participants were following Mediterranean diet rich in olive oil,
but this was not quantitated.</p></td>
<td><p><u>TG</u>: A slight ↓ in TG was observed in Group 1 (1.7 ± 0.2
mmol/l baseline to 1.4 <u>+</u> 0.2 mmol/l at 4 months; p&lt;0.05) and
Group 3 (1.6 ± 0.2 baseline to 1.6 ± 0.3 mmol/l at 4 months; p&lt;0.05).
No changes in the control group.</p>
<p><u>TC</u>: No changes were observed in any group (data not
shown).</p>
<p><u>HDL</u>: No changes were observed in any group (data not
shown).</p>
<p><u>BP:</u> Both systolic and diastolic↓ during the n-3 PUFA
supplementation in the hypertensive pts. (Group 1) (p&lt;0.05 vs.
baseline). The effect was maximum in Group 1 after 2 months with no
further effect at 4 months and a return to baseline values during the
recovery period. No changes in BP were noted in hypertensives treated
with olive oil (Group 2). The normotensives (Groups 3 and 4) had no
significant change in BP during the supplementation period compared to
baseline.</p>
<p>Significant ↑ in EPA and DHA levels in RBC-PC after 2 months of tx in
Groups 1 and 3, whereas no change was observed in Groups 2 and 4. At 4
months the levels were higher compared to baseline but not at 2 months.
During recovery, levels of different FAs returned to pre-tx
levels.</p></td>
<td><p><u>Conclusions:</u></p>
<p>The authors concluded that, “the present study indicates a clear-cut,
although not marked, effect of n-3 PUFA ethyl ester supplementation on
the BP of hypertensives, while BP was unmodified in normotensives,
despite similar changes in FA composition.”</p>
<p><u>Comments:</u></p>
<p>The authors concluded that “the main limitation of this study is the
low number of subjects included…..{and} this fact does not allow us to
draw general conclusions.”</p>
<p>Diets were not assessed but the subjects stated that their diets were
not modified.</p></td>
<td>1</td>
<td>No significant side effects were observed except for occasional fish
aftertaste in two (25%) subjects in group 1 and two (25%) subjects in
group 3.</td>
</tr>
<tr class="odd">
<td><p>Quazi et al. (1994)</p>
<p><em>Bangladesh Med. Res Counc Bull</em> 199;20(1):1-7</p>
<p>[Bangladesh]</p></td>
<td>To observe the effects of hilsa fish on serum lipid profiles in
hypercholesterolemic subjects</td>
<td>Clinical trial</td>
<td>40 weeks (10 months); with follow-up at 5 and 10 months</td>
<td>Not quantified; suggested to hypercholester-olemic subjects that
they consume 100 g (two pieces) hilsa fish. Hilsa body oil low in long
chain n-3 PUFAs (only 2% of total FAs compared to 15-20% in marine fish
oils). Normal cholesterolemics were advised to continue usual diet.</td>
<td><p>40 subjects at baseline</p>
<p>17 hyper-cholesterolemic (&gt;250 mg/dL) at 5 and 10 month
follow-up;</p>
<p>17 normal cholesterolemics (&lt;200 mg/dL) ) at 5 and 10 month
follow-up</p></td>
<td><p><u>TG:</u>  (NS)</p>
<p><u>TC</u>:  (NS)</p>
<p><u>LDL</u>:  (NS)</p>
<p><u>HDL</u>:  (NS)</p>
<p>TG, TC, and LDL all decreased in the fish group, and HDL increased,
but the changes were not statistically significant. No changes were
observed in the most of the lipid parameters of the control group; TG
decreased slightly, but the change was not statistically
significant.</p></td>
<td><h1 id="conclusions-1">Conclusions</h1>
<p>The authors concluded that despite the fact that hilsa fish is not
high in n-3 FAs, a hypocholesterolemic effect was observed among
hyper-cholesterolemic subjects who consumed the fish.</p>
<p><u>Comments</u>:</p>
<p>Reasons for nonparticipation/loss to followup not stated. Possible
changes in diet over the study period not assessed.</p>
<p>Subjects in the two groups were different at baseline: those in
experimental group not only had higher TC, but were older, had higher
initial bodyweight, and higher BP</p>
<p>Baseline measurements of participants (n=20 per group) not followed
at 5 and 10 months (n=17 at each time point) included.</p></td>
<td>3</td>
<td>Not reported</td>
</tr>
<tr class="even">
<td><p>Rambjør et al. 1996</p>
<p><em>Lipids</em> 1996;31:S-45-S-49</p>
<p>[U.S.]</p></td>
<td>To compared the effects of relatively pure EPA and DHA to a fish oil
concentrate (FOC) (EPA+DHA) on fasting lipids, lipoproteins and
phospholipid fatty acid composition.</td>
<td>Randomized, single-blinded, placebo-controlled trial.</td>
<td><p>3 weeks</p>
<p>Placebo for 2 weeks</p>
<p>Treatment for 3 weeks</p></td>
<td><p>5 g/d of n-3 FAs as ethyl esters (FOC group)</p>
<p>3g/d DHA ethyl esters (DHA group)</p>
<p>3 g/d EPA ethyl esters (EPA group)</p>
<p>Olive oil group (placebo)</p>
<p>Compliance: capsule counts</p></td>
<td><p>49 normolipidemics were recruited from the University of Kansas
medical center staff and student population. The TG levels were in the
higher end of (50-90<sup>th</sup> percentile for age and sex) normal
range.</p>
<p>EPA group: 25 subjects</p>
<p>DHA group: 9 subjects</p>
<p>FOC: 35 subjects</p>
<p>Placebo: Olive oil</p></td>
<td><p><u>TG:</u> ↓ by 20% (p&lt;0.001) with FOC. EPA ↓ TG by 16% while
DHA had no effect.</p>
<p><u>TC:</u> No change.</p>
<p><u>LDL:</u> ↑ by 10% (p&lt;0.05) with FOC. EPA ↑ LDL by 6%
(p&lt;0.01) while DHA had no effect.</p>
<p><u>HDL:</u> No change in total HDL, but HDL<sub>2</sub> ↑ by 27%
(p&lt;0.01) and HDL<sub>3</sub> ↓ by 6% (p&lt;0.01). Total HDL ↑ by 6%
(p&lt;0.05) with EPA. HDL<sub>2</sub> ↑ by 38% and HDL<sub>3</sub> ↓ by
8% (both p&lt;0.05) with DHA.</p>
<p><u>VLDL:</u> ↓ by 20% (p&lt;0.001) with FOC. EPA ↓ VLDL by 16%.</p>
<p>Plasma phospholipid EPA and DHA levels ↑ by 4 and 2 fold respectively
with FOC supplements compared to placebo. EPA supplementation ↑ EPA (4
fold) but not DHA levels. DHA supplementation doubled DHA levels and ↑
EPA levels. Plasma AA and linoleic acid levels ↓ significantly with FOC
and EPA supplements.</p></td>
<td><p><u>Conclusion:</u></p>
<p>The authors conclude that, “ EPA appears to be primarily responsible
for TG-lowering (and LDL raising) effects of fish oil.</p>
<p><u>Comments:</u></p>
<p>Diets were not assessed but the subjects were asked to maintain their
background diets.</p>
<p>The subjects recruited were from the university</p>
<p>population.</p></td>
<td>2</td>
<td></td>
</tr>
<tr class="odd">
<td><p>Ramirez-Tortosa et al. 1999</p>
<p><em>British Journal of Nutrition</em> 1999;82:31-39</p>
<p>[Spain]</p></td>
<td>To evaluate the effects of diets enriched MUFA (olive oil) or olive
oil + n-3 PUFAs on plasma lipid profile and susceptibly of LDL to
oxidation in free-living Spanish male patients with Peripheral Vascular
Disease (PVD).</td>
<td><p>Longitudinal crossover trial</p>
<p>24 subjects were assigned olive oil for 3 months followed by 3 month
washout period and then assigned to olive oil + fish oil for 3
months.</p></td>
<td><p>12 weeks (3 months) on olive oil + fish oil</p>
<p>12 weeks olive oil</p>
<p>12 weeks washout period</p></td>
<td><p>16 g/d fish oil (as maltodextrin-starch microcapsules). The
powder was consumed mixed with either water or fruit juice.</p>
<p>Olive oil used in cooking (O)</p>
<p>Olive oil + fish oil (OF)</p>
<p>Control (C)</p>
<p>Compliance:</p>
<p>interview</p></td>
<td><p>37 subjects diagnosed with PVD were recruited from a group of
cardiovascular outpatients followed-up by the Department of Vascular
Surgery.</p>
<p>Olive oil, olive oil + fish oil: 24 subjects</p>
<p>Control group; 13 subjects</p>
<p>Reference group: 20 healthy individuals</p></td>
<td><p><u>TC:</u> No change with OF</p>
<p><u>TG:</u> ↓ significantly with OF compared to O, C and reference
groups (p&lt;0.05).</p>
<p><u>HDL:</u> No change with OF</p>
<p><u>LDL:</u> No change OF</p>
<p>The lag phase of Cu-mediated LDL oxidation was longer with OF
compared to other groups (p&lt;0.05)</p>
<p>The uptake of LDL macrophages was reduced significantly in OF group
compared to C group (p&lt;0.05).</p>
<p>The LDL oxidation was lowest with O but the lag phase did not
increase.</p>
<p>Plasma EPA and DHA levels increased with OF compared to baseline, O,
C and reference groups.</p>
<p>The reference group was separated from the patients groups (O, OF, C)
using clinical functional measures.</p>
<p>Yao and claudicometry indices were significantly different between
the patient groups (O, OF, C) and the reference group
(p&lt;0.005).</p></td>
<td><p><u>Conclusion:</u></p>
<p>The authors conclude that, “consumption of olive oil together with a
dietary supplement of fish oil may be useful in the nutritional
management of patients suffering from peripheral vascular disease in
terms of increasing plasma n-3 long chain PUFAs and decreasing
susceptibility of LDL to oxidation”.</p>
<p><u>Comments:</u></p>
<p>The subjects attended dietary counseling before starting with the
study. Food habits were assessed using dietary survey during each
periods. Diets were assessed using food records, weighted food intake
and evaluation of recipes.</p>
<p>Body weights and BMI did not change between olive oil and olive oil +
fish oil periods.</p></td>
<td>1</td>
<td></td>
</tr>
<tr class="even">
<td><p>Rivellese et al. 1996</p>
<p><em>Diabetes Care</em> 1996;19(11):1207-1213</p>
<p>[Italy]</p></td>
<td>To determine the effect of long-term supplementation of moderate
dose of fish oil on insulin sensitivity, lipid metabolism, blood glucose
and serum insulin concentrations.</td>
<td>Randomized, double-blind, placebo controlled with a parallel group
sequence.</td>
<td><p>24 weeks (6 months)</p>
<p>The subjects underwent a 4-week washout period during which they were
stabilized on isoenergetic diet and hypoglycemic treatment and all
hypolipidemic drugs were withdrawn. After the washout period all
subjects consumed placebo capsules for 3 weeks during the run-in period.
After the run-in period treatments were assigned to the
subjects</p></td>
<td><p>2.5 g/d EPA + DHA (0.96 g/d EPA and 1.59 g/d DHA) for the first 2
months. The dose was reduced to 1.7 g/d EPA + DHA (0.64 g/d EPA and 1.06
g/d DHA) for the remaining 4 months) (fish oil group)</p>
<p>Placebo: olive oil (the olive oil dose was also reduced after 2
months0.</p>
<p>Compliance:</p>
<p>RBC phospholipid FA analysis.</p></td>
<td><p>16 hypertriglyceridemic patients with NIDDM were recruited from
diabetic clinic. Some patients had moderate arterial hypertension.</p>
<p>Multicenter trial.</p>
<p>Fish oil: n=8</p>
<p>Placebo: n=8</p></td>
<td><p><u>TG:</u> Significant ↓ (p&lt;0.01) with fish oil (2.92 ± 0.23
mmol/l) compared to baseline (3.85 ± 0.32 mmol/l). The decrease was
mainly due to a significant reduction (45%) of VLDL-TG without any
changes in TG content of LDL and HDL. No effect of placebo.<u><br />
TC:</u> NS change with fish oil. No effect of placebo.<u><br />
LDL:</u> Significant ↑ (p&lt;0.01) with fish oil (3.29 ± 0.49 mmol/l)
compared to baseline (2.88 ± 0.20 mmol/l). No effect of
placebo.<u><br />
HDL:</u> NS change with fish oil. No effect of placebo.<u><br />
VLDL:</u> Significant ↓ (p&lt;0.05) with fish oil (1.47 ± 0.13 mmol/l)
compared to baseline (2.77 ± 0.76 mmol/l). No effect of placebo.</p>
<p><u>LDL/HDL:</u> NS ↑ with fish oil. No effect of placebo.<u><br />
Fasting glucose:</u> No significant change with fish oil (baseline 10.2
± 1.2 mmol/l, 6 months 10.9 ± 0.5 mmol/l)</p>
<p><u>Postprandial glucose:</u> No significant change with fish oil
(baseline 12.9 ± 1.8 mmol/l, 6 months 12.1 ± 1.7 mmol/l)</p>
<p><u>Fasting insulin:</u> Significant ↑ (p&lt;0.01) with fish oil
(105.6 ± 15.6 pmol/l) compared to baseline (75 ± 9 pmol/l). The net
change after fish oil supplementation was not significantly different
from the net change after placebo.</p>
<p>Postprandial insulin: No significant change with fish oil or placebo
and no significant differences between the groups.</p>
<p><u>Glycated hemoglobin:</u> Slight but non-significant ↑ ion both
groups (fish oil 1%, placebo 0.7%). No group differences in the net
change.</p>
<p><u>Insulin sensitivity:</u> Peripheral insulin-stimulated glucose
disposal was not affected by fish oil or placebo. Glucose utilization
during the euglycemic clamp was same at baseline and after 6 months on
fish oil or on placebo. Blood glucose during the clamp did not change
significantly from baseline in fish oil or placebo group. The time to
reach euglycemia and the steady-state insulin levels achieved during the
clamp were similar to the baseline for the fish oil and placebo group.
No significant correlation was observed between the changes in insulin
sensitivity and cell membrane n-3 FAs composition.</p>
<p>Fish oil significantly ↓ fasting non-essential fatty acid levels but
not postprandial, and the decrease was significantly different from the
placebo.</p>
<p>EPA and DHA levels ↑ significantly (both p&lt;0.001) in erythrocyte
phospholipid membrane with fish oil treatment compared to
baseline.</p></td>
<td><p><u>Conclusions:</u></p>
<p>The authors conclude that, “in NIDDM patients with
hypertriglyceridemia, moderate amounts of fish oil induce a long-term
significant reduction in plasma TG, VLDL-TG, and non-essential fatty
acids, without deteriorating blood glucose control. However, this amount
of n-3 FAs was unable to improve insulin sensitivity in this group of
patients”.</p>
<p>Comments:</p>
<p>Diets were assessed using semiquantitative dietary questionnaire at
the beginning and at the end of the study.</p></td>
<td>1</td>
<td>Not reported.</td>
</tr>
<tr class="odd">
<td><p>Roche and Gibney 1995</p>
<p><em>Proc. Nutr. Soc.</em> 1994. 54:89A (ABSTRACT)</p>
<p>[Ireland]</p></td>
<td>To evaluate the interactive effects of a chronic low-fat diet and
low-dose fish oil supplementation on postprandial plasma
triacylglycerolemia (TAG) and coagulation factor VII activity (FVIIc) in
healthy subjects.</td>
<td>Not a randomized, controlled trial.</td>
<td>16 weeks</td>
<td><p>0.9 g/day n-3 PUFA from fish oil</p>
<p>Subjects consumed either a:</p>
<p>low-fat diet + fish oil,</p>
<p>low-fat w/o fish oil,</p>
<p>full-fat diet (normal diet) + fish oil, or</p>
<p>full-fat diet w/o fish oil</p>
<p>Compliance: not reported.</p></td>
<td><p>32 healthy subjects</p>
<p>3 male/5 female</p>
<p>Low fat + fish oil: n=8</p>
<p>Low fat, no fish oil: n=8</p>
<p>Full fat + fish oil: n=8</p>
<p>Full fat, no fish oil: n=8</p></td>
<td><p><u>TG</u>: fasting levels ↑ significantly for low-fat diet w/o
fish oil; fasting levels ↓ significantly for low-fat diet + fish oil
(p=0.015); postprandial levels ↓ significantly for full-fat diet + fish
oil (p=0.049)</p>
<p><u>FVIIc</u>: both fasting and postprandial levels ↓ significantly in
low-fat diet + fish oil and low-fat diet w/o fish oil</p></td>
<td><p><u>Conclusions</u>:</p>
<p>Authors concluded that, “low fat diets significantly reduced fasting
and postprandial FVIIc activity and low-dose fish oil supplements
significantly reduce the hypertriacylglycerolemic effects of a low-fat
diet.”</p>
<p><u>Comments</u>:</p>
<p>Summarized from abstract.</p>
<p>Small sample size.</p>
<p>Study was not randomized.</p>
<p>Data presented in table for TAG are inconsistent with results
reported in text.</p></td>
<td></td>
<td>Not reported.</td>
</tr>
<tr class="even">
<td><p>Roche and Gibney 1996</p>
<p><em>European Journal of Clinical Nutrition</em> 1996;50:617-624</p>
<p>[Ireland]</p></td>
<td>To examine the individual and combined effect of low-fat diet and
low dose of n-3 FAs on fasting and postprandial TG metabolism and plasma
cholesterol concentration and HDL metabolism.</td>
<td>Randomized, controlled trial.</td>
<td>16 weeks</td>
<td><p>0.8 g/d fish oil</p>
<p>0.44 g/d EPA</p>
<p>0.36 g/d DHA</p>
<p>Group 1: low fat diet + fish oil</p>
<p>Group 2: low fat diet</p>
<p>Group 3: usual fat diet + fish oil</p>
<p>Group 4: usual fat diet</p>
<p>Platelet phospholipid fatty acid analyses, diet analyses, capsule
counts</p></td>
<td><p>32 healthy subjects (12 men, 20 females)</p>
<p>8 subjects per group</p></td>
<td><p><u>TG:</u> Fasting plasma TG ↓ significantly (p≤0.05) in group 3
on usual fat diet and fish oil. TG ↑ significantly (p≤0.05) in group 2
on low-fat diet without fish oil supplementation. The area under the
curve of postprandial TG and the maximal postprandial TG concentration
was reduced (p≤0.05) in group 3 on usual fat diet and fish oil. In group
receiving low-fat diet and fish oil the area under the curve of
postprandial TG and the maximal postprandial TG concentration was ↑
(p≤0.05). The time taken to reach the peak postprandial TG concentration
was ↓ in group 3 on usual fat diet and fish oil.</p>
<p><u>TC:</u> ↓ significantly (p≤0.05) in both groups receiving fish
oil.</p>
<p><u>HDL:</u> A significant ↓ (p≤0.05) in HDL<sub>3</sub> was observed
in group 3 on usual fat diet and fish oil. HDL<sub>2</sub>
concentrations increased significantly in group on low-fat diet and fish
oil supplementation.</p>
<p>Platelet phospholipid EPA (p≤0.0006) and DHA (p≤0.00001)
concentrations were ↑ in groups receiving fish oil supplementation.</p>
<p>A significant ↓ in BMI, energy intake and energy derived from fat and
a significant ↑ in energy from carbohydrate, protein and alcohol was
observed in both low fat groups. No significant changes in BMI or
nutrient intake were observed in the usual dietary fat group.</p></td>
<td><p>Conclusion:</p>
<p>The study demonstrated that, “some of the deleterious effects of a
low-fat diet, reduced concentrations of the cardioprotective
HDL<sub>2</sub> cholesterol fraction and increased fasting plasma TG
concentrations were prevented when a low dose of fish oil was provided
with a low-fat diet. However postprandial TG is adversely affected when
the low-fat diet was supplemented with fish oil.</p>
<p><u>Comments:</u></p>
<p>The subjects volunteered to participate either in the low-fat or
usual dietary fat intake group.</p>
<p>7-day diet records were collected prior to the treatment. Diets were
analyzed using nutrient database. The subjects were advised about
low-fat diet such that the fat intake was reduced by minimum of10% of
energy.</p></td>
<td>2</td>
<td></td>
</tr>
<tr class="odd">
<td><p>Rossing et al. 1996</p>
<p><em>Diabetes Care</em> 1996;19(11):1214-1219.</p>
<p>[Denmark]</p></td>
<td>To determine the beneficial effects of fish oil on albuminuria,
glomerular filtration rate, systemic blood pressure and dyslipidemia in
normotensive IDDM patients with diabetic nephropathy.</td>
<td>Randomized, double-blind parallel placebo controlled trial.</td>
<td>52 weeks (1 year)</td>
<td><p>4.6 g/d of EPA + DHA (2 g/d EPA and 2.6 g/d DHA from 21 ml of
cod-liver oil given as Eskisol Fish oil Emulsion) (cod-liver oil
group)</p>
<p>21 ml of olive oil (olive oil group)</p>
<p>Compliance:</p>
<p>Fatty acids in platelets.</p></td>
<td><p>29 IDDM patients with persistent albuminuria were recruited from
outpatient clinic at Steno Diabetes Center during 1992.</p>
<p>Cod-live oil: n=14</p>
<p>Olive oil: n=15</p>
<p>36 patients were randomized, but 7 patients dropped out for the
following reasons: 4 patients (3 receiving cod-liver oil and 1 receiving
olive oil) stopped because of nausea; 1 patient receiving placebo became
pregnant; 1 patient receiving placebo developed glomerulonephritis and 1
patient receiving cod-liver oil developed breast cancer.</p></td>
<td><p><u>TG:</u> ↓ significantly at 6 (p≤0.01) and 12 (p≤0.01) months
from 0.97 mmol/l to 0.67 and 0.80 mmol/, respectively with cod-liver oil
compared to baseline. The decrease in TG with cod-liver oil was
significant at 6 ((p=0.001) and 12 (p&lt;0.05) months compared to the
olive oil.</p>
<p><u>TC:</u> ↑ significantly from 5.05 ± 0.2 mmol at baseline to 5.39 ±
0.2 mmol/l and 5.51 ± 0.3 mmol/l at 6 (p≤0.01) and 12 (p&lt;0.05)
months, respectively with cod-liver oil when compared to the baseline.
The increase with cod-liver oil at 6 months was significantly
(p&lt;0.05) different from olive oil.<u><br />
LDL:</u> ↑ significantly from 2.93 ± 0.2 mmol at baseline to 3.41 ± 0.22
mmol/l and 3.52 ± 0.24 mmol/l at 6 (p≤0.01) and 12 (p&lt;0.05) months,
respectively with cod-liver oil when compared to the baseline. The
increase with cod-liver oil at 6 months was significantly (p&lt;0.05)
different from olive oil.<u><br />
HDL:</u> NS change in both groups.</p>
<p><u>VLDL:</u> ↓ significantly at 6 (p≤0.01) and 12 (p≤0.01) months
from 0.45 mmol/l to 0.31 and 0.37 mmol/, respectively with cod-liver oil
compared to the baseline. The decrease in VLDL with cod-liver oil was
significant at 6 ((p=0.001) and 12 (p&lt;0.05) months compared to the
olive oil.</p>
<p><u>apo A1:</u> NS change in both groups.</p>
<p><u>apo (a):</u> NS change in both groups.</p>
<p><u>apo B:</u> NS change in both groups.</p>
<p><u>Glycated hemoglobin:</u> NS change in both groups.</p>
<p><u>BP:</u> No significant change in ambulatory blood pressure between
and among the groups during the study.</p>
<p>A significant ↑ in platelet EPA and DHA concentrations in the
cod-liver oil group compared to the placebo group at 6 and 12
months.</p>
<p>Data on endpoints assessing kidney function is not reported in this
summary.</p></td>
<td><p>Conclusions:</p>
<p>The authors conclude that, “the study does not suggest that fish oil
has beneficial effects on albuminuria, kidney function, blood pressure
and dyslipidemia in normotensive IDDM patients suffering from diabetic
nephropathy”.</p>
<p>Comments:</p>
<p>Diets were not assessed.</p></td>
<td>1</td>
<td>17% of subjects dropped out because of nausea in the cod-liver oil
group.</td>
</tr>
<tr class="even">
<td><p>Roulet et al. 1997</p>
<p><em>J. Parenteral and Enteral Nutr.</em> 1997 21(6):296-301</p>
<p>[Switzerland]</p></td>
<td>To investigate whether phospholipid platelet composition and
function can be modified within a few days by intravenous infusion of
n-3 long-chain fatty acids.</td>
<td>Randomized, controlled</td>
<td><p>1 week</p>
<p>(7 days)</p></td>
<td><p>4 g/day EPA+ DHA (by iv administration),</p>
<p>soybean fat emulsion + 10% marine fish oil emulsion (Omegavenos,
Fresenius AG)</p>
<p>28.45 mg/kg/day DHA (2 g/day), 28.16 mg/kg/day EPA (2 g/day) (fish
oil group)</p>
<p>Control group: soybean fat emulsion</p>
<p>Compliance: Platelet lipid FA analysis</p></td>
<td><p>19 patients with esophageal epidermoid carcinoma undergoing
elective total esophagectomy</p>
<p>Fish oil: n=10</p>
<p>Control: n=9</p></td>
<td><p><u>Bleeding time</u>: NS change in either group, but tended to ↓
in fish oil group (from 4.3 to 3.3 minutes, -23%); bleeding time was
higher at baseline for fish oil group compared to the control group (4.3
vs. 2.9 minutes)</p>
<p><u>Maximum reaction speed with collagen-induced aggregation
factor</u>: decreased (p&lt;0.02) (no change in control group)</p>
<p><u>Latency with collagen-induced aggregation factor</u>: increased
(p&lt;0.002)</p>
<p>No change in maximum reaction speed, latency, or maximal aggregation
with ADP-induced aggregation factor or maximal aggregation with
collagen-induced aggregation factor.</p>
<p>Fish oil supplementation resulted in increased EPA in platelet
phosphatidylcholine and phosphatidylethanolamine (p&lt;0.01); NS changes
in DHA.</p></td>
<td><p><u>Conclusions:</u></p>
<p>Authors concluded that, “iv infusion of a moderate amount of fish oil
modifies the EPA content of phospholipids in platelets and partially
modifies some parameters of platelet function.”</p>
<p><u>Comments:</u></p>
<p>iv administration.</p>
<p>Diet not assessed</p>
<p>Short study duration.</p>
<p>Small study population.</p></td>
<td>3</td>
<td>“No toxic effect, in particular no increase of postoperative
bleeding and no perturbation of hepatic and renal function was observed
during fish oil infusion.”</td>
</tr>
<tr class="odd">
<td><p>Russo et al. 1995</p>
<p><em>J Hypertension</em> 1995;13:1823-1826</p>
<p>[Italy]</p></td>
<td>To examine the effects of low dose of n-3 PUFAs on ambulatory blood
pressure monitoring parameters in individuals with mild essential
hypertension</td>
<td>Clinical trial</td>
<td><p>16 weeks (4 months)</p>
<p>Initial 3 month run-in period</p>
<p>4-month treatment period followed by 4-month washout period.</p></td>
<td><p>2.6 g/d EPA + DHA (three, 1 g n-3 PUFA capsules containing 85%
EPA and DHA)</p>
<p>Compliance: erythrocyte membrane fatty acid analysis.</p></td>
<td>24 subjects with mild essential hypertension were recruited from
Hypertension Outpatients Clinic in 1993-1994. The subjects had no
cardiovascular complications or any concomitant disease.</td>
<td><p><u>TG:</u> NS effect of n-3 PUFA.</p>
<p><u>TC:</u> NS effect of n-3 PUFA.</p>
<p><u>HDL:</u> NS effect of n-3 PUFA.</p>
<p><u>SBP:</u> NS effect of n-3 PUFA on 24 h, daytime, nighttime,
day-night and office SBP.</p>
<p><u>DBP:</u> NS effect of n-3 PUFA on 24 h, daytime, nighttime,
day-night and office DBP.</p>
<p><u>HR:</u> NS effect of n-3 PUFA on 24 h, daytime and nighttime
HR.</p>
<p><u>Glucose:</u> NS effect of n-3 PUFA (Run-in 5.7 ± 0.6, n-3 PUFA 5.6
± 0.6, and washout 5.8 ± 0.9 mmol/l).</p>
<p><u>Fibrinogen:</u> NS effect of n-3 PUFA.</p>
<p><u>Factor VII:</u> NS effect of n-3 PUFA.</p>
<p>Erythrocyte n-3 PUFA concentrations increased significantly at the
end of the treatment period (p&lt;0.001). The levels returned to
baseline at the end of the washout period.</p></td>
<td><p>Conclusions:</p>
<p>The authors concluded that, “the present data show that low doses of
n-3 PUFAs as a single treatment are not effective in lowering BP or HR
in mild essential hypertensive patients, despite a significant change in
the fatty acid cell membrane composition. Nor does this treatment seem
likely to affect BP variability or the diurnal rhythm”.</p>
<p><u>Comments:</u></p>
<p>Not a placebo controlled, randomized trial.</p>
<p>Diets were not assessed but the subjects were asked to maintain their
usual dietary habits.</p></td>
<td>2</td>
<td>Mild gastrointestinal symptoms such as fishy taste and eructations
were reported by more than half of the patients, but none complained of
an easy tendency to bleed.</td>
</tr>
<tr class="even">
<td><p>Sacks et al. 1994</p>
<p><em>Journal of Hypertension</em> 1994;12(7):S23-S31</p>
<p>[U.S.]</p></td>
<td>The aim was “to study the effects of moderate doses of fish oil on
blood pressure and high-density lipoprotein (HDL)-cholesterol”</td>
<td><p>Randomized single-blind, controlled trial</p>
<p>Multicenter</p></td>
<td>24 weeks (6 months)</td>
<td><p>2.4 g/d of EPA +DHA (ProMega sardine oil capsules, 6g of fish
oil)</p>
<p>1.44 g/d EPA</p>
<p>0.96 g/d DHA</p>
<p>Olive oil placebo group:</p>
<p>6 g/d of olive oil</p>
<p>Potassium group:</p>
<p>3 tablets of potassium placebo that mainly consisted of
cellulose.</p>
<p>Compliance:</p>
<p>Pill count and n-3 fatty acids in the plasma</p></td>
<td><p>350 healthy individuals with mean diastolic blood pressure of
80-95 mm Hg at baseline, enrolled from 7 academic medical centers.</p>
<p>Only those who took greater than 66% of placebo tablets provided in a
pre-trial eligibility study were included in the study.</p>
<p>Fish oil: 175 subjects</p>
<p>Placebo group: 175 (86 w/ Olive oil and 89 w/ potassium)</p></td>
<td><p><u>TC</u>: NS ↑ with fish oil compared to olive oil.</p>
<p><u>HDL</u>: No effect on total HDL, but significant ↑ (43%) in
HDL<sub>2</sub> with fish oil. HDL<sub>3</sub> ↓ significantly after 3
months on fish oil but not after 6 months.</p>
<p><u>SBP</u>: NS ↓ with fish oil compared to placebo however, those
subjects who showed the largest increases in plasma DHA levels exhibited
significantly greater decreases in SBP.</p>
<p><u>DBP</u>: NS ↓ with fish oil compared to placebo and no significant
correlation between DBP and changes in n-3 fatty acid levels.</p>
<p>Significant increases in n-3 fatty acids in the plasma
(p&lt;0.001).</p></td>
<td><p><u>Conclusions</u>:</p>
<p>The authors conclude that, “dietary supplementation with fish
oil…does not lower blood pressure in normotensive subjects”</p>
<p><u>Comments</u>:</p>
<p>24 h diet-recalls and food-frequency questionnaires were collected at
baseline and at 6 months.</p>
<p>Baseline and 24 week results are reported with different n
values.</p>
<p>Authors assumed some BP values. Patients who missed a follow-up visit
at either 3 or 6 months were assumed to have a BP equal to the previous
visit, unless the visit was missed for a reason related to BP.</p></td>
<td>1</td>
<td><p>Adverse effects reported in questionnaires at 13 and 26 weeks
included unpleasant taste (26.4 and 35.6% at each time period,
respectively). This effect was significant when compared to the control
group (p&lt;0.001). No other significant effects were reported (measured
appetite, stomach upset or nausea, easy bruising, nosebleeds and
excessive bleeding from cuts).</p>
<p>No discussion was provided on the reasons for dropouts throughout the
study.</p></td>
</tr>
<tr class="odd">
<td><p>Sacks et al. 1995</p>
<p><em>J Am Coll Cardiol</em> 1995;25(7):1492-8</p>
<p>[U.S.]</p></td>
<td>To test the effect of a moderate dose of fish oil on atherosclerosis
in native coronary arteries.</td>
<td><p>Randomized, Partially-blinded,</p>
<p>Placebo-controlled</p></td>
<td>121 weeks (28 mo.)</td>
<td><p>4.8 g/d EPA+DHA</p>
<p>2.9g/d EPA</p>
<p>1.9 g DHA</p>
<p>6 g/d n-3</p>
<p>(Promega capsules)</p>
<p>Control: Olive oil</p>
<p>Compliance: pill counts.</p></td>
<td><p>59 patients</p>
<p>w/ narrowing lumen diameter and TC&lt;250mg/ld TG&lt;350 mg/dl.</p>
<p>31 test</p>
<p>28 control</p>
<p>55 males, 4 females</p></td>
<td><p><u>TG:</u> ↓ 30% (p= 0.007)</p>
<p><u>TC:</u> NS</p>
<p><u>LDL:</u> NS</p>
<p><u>HDL:</u> NS</p>
<p><u>apo A:</u> NS</p>
<p><u>apo B:</u> NS</p>
<p><u>Adipose tissue:</u></p>
<p>Tissues in test group were enriched w/n-3 (p&lt;0.0001) from FO.</p>
<p><u>Lumen diameter:</u> NS (p&lt;0.05) between groups.</p></td>
<td><p><u>Conclusions:</u></p>
<p>No evidence that atherosclerosis progression is affected by FO
supplementation, as measured over a 2.4 yr period by change in lumen
diameter.</p>
<p><u>Comments:</u></p>
<p>Both groups gained 2 kg bw during trial (p&lt;0.005).</p>
<p>Hypocholesterolemic drug therapy for elevated cholesterol required in
4 patients in test group.</p>
<p>Diet records completed and analyzed.</p>
<p>Patients and personnel responsible for lab measurements, cardiac
catheterization, and analysis of angiography films were
blinded.</p></td>
<td>1</td>
<td>No adverse effects attributed to fish oil intake.</td>
</tr>
<tr class="even">
<td><p>Salachas et al. 1994a</p>
<p><em>Review of Clinical Pharmacology and Pharmocokinetics,
International Edition</em> 1994;7:127-130</p>
<p>[Greece]</p></td>
<td>To determine the effects of n-3 FAs in patients with stable
angina.</td>
<td>Double-blind, placebo-controlled trial.</td>
<td>12 weeks</td>
<td><p>10 g/d fish oil capsules (Maxepa, EPA 18.6 and DHA 12.1%) (n-3
group)</p>
<p>Olive oil (placebo group)</p>
<p>Compliance: Not measured</p></td>
<td><p>39 subjects with coronary heart disease were recruited (37 men, 2
women)</p>
<p>n-3 group: 20 subjects</p>
<p>placebo: 19 subjects</p></td>
<td><p><u>TG:</u> ↓ significantly in group taking n-3 FAs (22%,
p&lt;0.01) by 8 weeks and returned to their initial levels by 12 weeks.
Nonsignificant ↑ with placebo.</p>
<p>TC: No change with n-3 FAs or placebo.</p>
<p>HDL: No change with n-3 FAs or placebo.</p></td>
<td><p>Conclusion:</p>
<p>The authors concluded that, ”Maxepa fish oil is a safe lipid lowering
agent that has a favorable effect especially on the reduction of TG
levels.</p>
<p><u>Comments:</u> Diets were not assessed.</p>
<p>The study design and methods not discussed in detail.</p></td>
<td>3</td>
<td>No side effects were reported.</td>
</tr>
<tr class="odd">
<td><p>Salachas et al. 1994b</p>
<p><em>J Vascular Disease</em> 1994;45(12):1023-1031.</p>
<p>[Greece, England]</p></td>
<td>To investigate beneficial effects on various parameters with a low
dose of fish oil concentrate in patients with coronary artery disease
(CAD).</td>
<td><p>Randomized,</p>
<p>double-blind,</p>
<p>placebo-controlled trial.</p></td>
<td><p>12 weeks</p>
<p>(2-weeks run-in period first.)</p></td>
<td><p>3 g/d EPA+DHA*</p>
<p>1.8 g/d EPA</p>
<p>1.2 g/d DHA</p>
<p>(5 1-g capsules from Seven Seas twice daily)</p>
<p>Control: olive oil</p>
<p>Compliance:</p>
<p>Capsule count.</p></td>
<td><p>39 patients w/ CAD &amp; 1-yr history of stable angina
pectoris</p>
<p>20 test</p>
<p>19 control</p>
<p>@ 95% male</p>
<p>50 patients entered trial, 11 drop outs</p></td>
<td><p><u>TG:</u> ↓ 22% @ 8wks (P&lt;0.01) but ↑ @ 12 weeks such that
(&gt;0.10) vs. baseline value.</p>
<p><u>Angina:</u> ↓ 41% vs. baseline (P&lt;0.05); control ↑ (NS)</p>
<p><u>GTN intake:</u> ↓ 38% vs. baseline (P&lt;0.05). Control ↑
(NS).</p>
<p><u>Exercise test duration:</u> ↑ 22.6% (P&lt;0.01) vs. baseline.
Control NS.</p>
<p><u>Exercise Double Product:</u> ↑ 26% (P&lt;0.01) vs. baseline.
Control NS.</p>
<p><u>Platelet aggregation ratio:</u> NS</p>
<p><u>Beta Thromboglobulin:</u> NS</p>
<p><u>SBP &amp; DBP:</u> trend ↓</p></td>
<td><p><u>Conclusions:</u></p>
<p>A low dose of Fish oil may exert beneficial effects on clinical
status of patients w/CAD. The lab methods used in this study did not
demonstrate inhibition of platelet activity under basal conditions.</p>
<p><u>Comments:</u></p>
<p>*Total EPA+DHA intake not clear – 3 or 6 g/d?</p>
<p>Dietary intake not monitored during trial.</p>
<p>Patients using antianginal medication continues therapy but did not
alter the dose regimen.</p></td>
<td>2</td>
<td>"All the subjects in both groups tolerated the supplements without
any adverse effects." None of the patients had an increased
susceptibility to bruising.</td>
</tr>
<tr class="even">
<td><p>Saldeen et al. 1998</p>
<p><em>Nutr Research</em> 1998;18(9):1483-1492</p>
<p>[Sweden]</p></td>
<td>To determine the effect of a small dose of fish oil substituted for
margarine in bread on serum TG and plasma phopholipid FAs, α-tocopherol,
TBARS and glucose.</td>
<td>Randomized single-blind, control trial.</td>
<td>4 weeks</td>
<td><p>1 g/d fish oil (ESKIMO-3<sup>®</sup>) in bread (EPA 18% and DHA
13% of the total FAs) (fish oil bread)</p>
<p>1 g margarine in bread (margarine bread)</p>
<p>Compliance: Not measured</p></td>
<td><p>17 healthy subjects</p>
<p>Fish oil bread: 9 subjects</p>
<p>Margarine bread: 8 subjects</p></td>
<td><p><u>TG:</u> ↓ significantly (p&lt;0.05) with fish oil
supplementation, no change with margarine bread.</p>
<p><u>TC:</u> No change with fish oil bread.</p>
<p><u>HDL:</u> No change with fish oil bread.</p>
<p><u>Plasma α tocopherol:</u> No change with either bread.</p>
<p><u>TBARS and glucose:</u> No change with either bread.</p>
<p>Plasma phospholipid EPA and DHA levels increased after 2 weeks
supplementation with fish oil in bread (p&lt;0.05).</p></td>
<td><p><u>Conclusion:</u></p>
<p>The study indicates that small amount of fish oil substituted for
margarine in bread has significant effects on blood lipids without any
signs of lipid peroxidation.</p>
<p><u>Comments:</u></p>
<p>Diets were not assessed but the subjects were asked not to change
their diets and record any significant changes in their diets or
lifestyle during the treatment period.</p>
<p>No data provided only figures.</p></td>
<td>2</td>
<td>Not reported</td>
</tr>
<tr class="odd">
<td><p>Salvi et al. 1993</p>
<p>Current Therapeutic Research</p>
<p>1993;53(6):717-721</p>
<p>[Italy]</p></td>
<td>The aim of the study was to evaluate “the effect of fish oil
supplements on serum Lp(a) concentrations in patients with heterozygous
familial hypercholesterolemia (FH) and high levels of Lp(a) who were
receiving chronic treatment with simvastatin.”</td>
<td>Study was not blinded or placebo controlled.</td>
<td>4 weeks</td>
<td><p>5.1 g/day EPA+DHA (Esapent fish oil capsules, 6 g/day total
oil)</p>
<p>2.55 g/day EPA</p>
<p>2.55 g/day DHA</p>
<p>Compliance:</p>
<p>Not reported</p></td>
<td>10 patients with heterozygous familial hypercholesterolemia (FH) who
were receiving chronic treatment with simvastatin</td>
<td><p><u>TG</u>: ↓ by 23% and 33% (p&lt;0.001) at 2 and 4 weeks,
respectively with fish oil compared to baseline.</p>
<p><u>TC</u>: ↓ by 8% and 14% at 2 and 4 weeks, respectively with fish
oil compared to baseline (both p&lt;0.05)</p>
<p><u>LDL</u>: ↓ by 9% and 14% at 2 and 4 weeks, respectively with fish
oil compared to baseline (both p&lt;0.05).</p>
<p><u>HDL</u>: no significant change compared to baseline.</p>
<p><u>Serum Lp(a</u>): no significant change with fish oil compared to
baseline.</p></td>
<td><p>Conclusions:</p>
<p>The authors conclude that, “fish oil slightly but significantly
decreased total cholesterol and LDL cholesterol”</p>
<p>Comments:</p>
<p>Patients were asked to continue the same lipid-lowering diet that
they had been following.</p></td>
<td>2</td>
<td>Not reported</td>
</tr>
<tr class="even">
<td><p>Salvig, et. al.</p>
<p>1996</p>
<h2 id="brit-j-obs-gyn">Brit J Obs Gyn</h2>
<p>1996; 103:529-33</p>
<p>[Denmark]</p></td>
<td>To examine the effect of fish oil supplementation on BP during the
third trimester of pregnancy.</td>
<td>A randomized, double-blind, placebo controlled study.</td>
<td>12 weeks (started at week 30 of gestation and continued up to 42
weeks of gestation; duration for individual participant depended upon
exact delivery date).</td>
<td><p>2.2 g/d EPA + DHA (1.28 g EPA/d and 0.92 g DHA/d and a total of
2.7 g/d n-3 PUFAs [Pikasol])</p>
<p>One control group received four 1-g capsules of olive oil (containing
72% oleic acid and 12 % linoleic acid).</p>
<p>A second control group received no supplement.</p>
<p>Compliance: Capsule counts based on weight.</p></td>
<td><p>533 pregnant women started on study at week 30 gestation.</p>
<p>Fish oil group started with n= 266.</p>
<p>Olive controls started with n = 136</p>
<p>No oil control group started with n = 131.</p>
<p>Exact N on study varied each week with delivery dates for individual
study participants. Last dates for study was week 42 of
gestation.</p></td>
<td><p><u>BP:</u> Mean BP ↑ during the course of the third trimester in
all groups, but this ↑ was not significantly different between the
groups (p value not given). Stratification for fish intake at entry and
compliance did not alter these results.</p>
<p>Systolic hypertension (BP &gt; 140 mm Hg) at any time was observed in
105 women in the fish oil, 53 in the olive oil and 42 in the no oil
group. Diastolic hypertension (BP &gt; 90 mm Hg) at any time was
observed in 14 women in the fish oil, 14 in olive oil and 5 women in the
no oil group. No differences were seen between the groups in proportion
of women with hypertension. Although, there were less women in the fish
oil group with DBP above 90 mm Hg.</p></td>
<td><p><u>Conclusions</u>:</p>
<p>The authors concluded that, “2.7 g/d of marine n-3 fatty acids
provided in the third trimester of normal pregnancy showed no effect on
blood pressure.”</p>
<p><u>Comments:</u></p>
<p>At baseline, the latest 2 – 3 months of fish consumption was
estimated by a simple food frequency questionnaire.</p></td>
<td>1</td>
<td>Not reported.</td>
</tr>
<tr class="odd">
<td><p>Sanders et al. 1997</p>
<p><em>Arterioscler. Thromb. Vasc. Biol.</em> 1997. 17:3449-3460</p>
<p>[London]</p></td>
<td>To compare the effects on plasma lipid concentrations and hemostatic
factors of n-6 and n-3 fatty acids in diets providing 30% of the energy
from fat (with &lt;10% of energy provided by saturated fatty acids &amp;
14% provided by oleic acid)</td>
<td>Randomized, cross-over-design</td>
<td><p>two 3-week (21 days) periods with a 8-week washout period in
between</p>
<p>all subjects fed a saturated fat diet for 3 weeks prior to
study</p></td>
<td><p>food</p>
<p>the saturated diet: 4% of total energy provided by PUFAs, trace
amounts of DHA and EPA</p>
<p>n-3 diet: 5 g/day (1.5% of energy) EPA + DHA (olive oil and fish oil
- Max EPA, Seven Seas)</p>
<p>n-6 diet: 5 g/day linoleic acid</p></td>
<td>26 healthy, normolipidemic, non-obese males; age range: 18-34 years
(mean: 23 years)</td>
<td><p><u>TG:</u> The n-3 diet produced lower fasting TG (p&lt;0.0001)
concentrations. There was no change in fasting TG with the saturated or
n-6 diet. Postprandial TG increased after all diets (p&lt;0.001).
Highest increase occurred with the n-6 diet (but the increase was not
significantly different than the other diets).</p>
<p><u>TC:</u> The saturated diet produced higher fasting TC
(p&lt;0.0001). There was no change in fasting TC with the n-3 or n-6
diets. TC decreased in all diets for up to 2 hours postprandially, and
tended to recover thereafter. Lowest decrease seen with the n-3 diet
(-5.6%).</p>
<p><u>LDL:</u> The saturated diet produced higher fasting LDL
(p&lt;0.0001). There was no change in fasting LDL with the n-3 or n-6
diets. No postprandial analysis of LDL concentrations conducted.</p>
<p><u>HDL:</u> The n-3 diet produced lower fasting HDL<sub>3</sub>
(p&lt;0.003) and higher fasting HDL<sub>2</sub> concentrations
(p=0.001). There was no change in these parameters with the saturated or
n-6 diet. No significant difference in fasting HDL concentrations
between diets. Postprandial HDL<sub>3</sub> and HDL decreased with all
diets. The n-3 diet had the highest decrease in postprandial
HDL<sub>3</sub> (-20%) and the lowest decrease in HDL (-7.4%).</p>
<p><u>Apo A:</u> The n-3 diet produced lower fasting apo AI
(p&lt;0.005), apo AII (p&lt;0.0001). There was no change in these
parameters with the saturated or n-6 diet. NS decrease in postprandial
AI with the n-3 and n-6 diets. Significant decrease in postprandial AI
for the saturated diet (p&lt;0.05). Postprandial AII was significantly
decreased with the n-3 and saturated diet (p&lt;0.05); a nonsignificant
decrease occurred with the n-6 diet.</p>
<p><u>apo B:</u> The saturated diet produced higher fasting apo B
(p&lt;0.001) concentrations. There was no change in fasting apo B with
the n-3 or n-6 diets. Postprandial apo B was reduced for all diets.</p>
<p><u>Factor VII antigen</u>: NS change</p>
<p><u>Factor VIIc activity</u>: ↑ by 7% for n-3 diet compared to
saturated fat diet (p≤0.01) and by 5% compared to n-6 diet (p=0.19).</p>
<p><u>Fibrinogen</u>: ↑ by 10% for the n-6 diet compared to the n-3 diet
(p=0.004) and saturated fat diet (p=0.02).</p>
<p><u>Prothrombin fragment 1 + 2</u>: NS change</p>
<p><u>PAI-1 activity</u>: NS change</p>
<p><u>tPA activity</u>: NS change</p>
<p><u>von Willebrand factor</u>: similar for n-3 and n-6 diets; lower
for saturated diet compared to other diets (p≤0.01).</p>
<p><u>β-thromboglobulin</u>: similar for n-3 and n-6 diets; lower for
saturated diet compared to other diets (p≤0.01).</p>
<p><u>Platelet count</u>: similar for n-3 and n-6 diets; higher for
saturated diet compared to other (p≤0.05).</p></td>
<td><p><u>Comments</u>:</p>
<p>erythrocyte lipid analysis showed some crossover effect for subjects
who received the n-3 first; however, no crossover effect was noted in
analysis of plasma EPA and DHA concentrations; baseline measurements for
most hemostatic factors not reported.</p></td>
<td>2</td>
<td>Not reported.</td>
</tr>
<tr class="even">
<td><p>Santos et al. 1995</p>
<p><em>Ann Nutr Metab</em> 1995;39:52-62</p>
<p>[Spain]</p></td>
<td>To examine the correlation between increased intake of n-3 PUFAs
from fish with changes in serum lipid profile in CHD patients.</td>
<td>Clinical trial</td>
<td><p>4 weeks</p>
<p>Modified diet for 8 weeks</p>
<p>and fish diet for 4 weeks.</p>
<p>Prior to fish diet, CHD patients given dietary advice to prevent
ischemic cardiopathy. The recommendations followed for 8 weeks, followed
by a diet modified to increase intake of n-3 FAs by consuming fish
(salmon, swordfish, hake, small sardines) instead of meat for 4
weeks.</p>
<p>Dietary intake of reference subjects was assessed at the baseline for
comparison.</p></td>
<td>Not quantified</td>
<td><p>40 men</p>
<p>Reference group: 20 healthy subjects</p>
<p>Treatment group: 20 men previously diagnosed with myocardial
infarction or angina pectoris.</p></td>
<td><p><u>Plasma n-3 fatty acid levels</u>:</p>
<p>Baseline: NS</p>
<p>After 8 weeks: NS</p>
<p><u>Plasma EPA</u>:  (significance not stated)</p>
<p><u>Plasma DHA</u>:  (significance not stated)</p>
<p>Stearic acid :  (significance not stated)</p>
<p>α linolenic acid :  (significance not stated)</p></td>
<td><p><u>Conclusion:</u></p>
<p>The authors conclude “the changes in plasma fatty acid (decrease in
linolenic acid and significant increase in its long-chain derivatives
EPA and DHA) levels may have beneficial effects on CHD”.</p>
<p><u>Comments:</u></p>
<p>Dietary questionnaire were completed buy the subjects before the
start of the study, after 8 weeks on modified diet and after 4 weeks on
fish diet to assess dietary changes and compliance.</p>
<p>Not a controlled, blinded trial.</p></td>
<td>2</td>
<td>Not reported</td>
</tr>
<tr class="odd">
<td><p>Saynor and Gillott 1992</p>
<p><em>Lipids</em> 1992;27:533-538</p>
<p>[England]</p></td>
<td>To determine the long term effects of regular fish oil supplements
on serum TG, TC, LDL and HDL as well as plasma fibrinogen and platelet
count and to examine the undesirable long-term side effects as judged by
clinical chemistry and hematology.</td>
<td>Open study with a control group.</td>
<td>364 weeks (7 years).</td>
<td><p>6.02 g/d EPA+DHA (3.6 g/d EPA, 2.42 g/d DHA)</p>
<p>EPA 18.6 % and DHA 12.1% (MaxEPA)</p>
<p>3.07 g/d EPA+DHA for 6 years.</p>
<p>For 1 year 10 ml of MaxEPA was given twice a day and then the dose
was reduced to 10ml/d for the remaining 6 years.</p>
<p>Compliance: Not measured</p></td>
<td><p>40 subjects</p>
<p>365 (for 1 month) subjects with hyperlipidemia and other conditions
such as MI, angina etc. were recruited. The number of subjects decreased
with time and 40 patients remained at the end of 7 years.</p></td>
<td><p>TG: ↓ significantly (p&lt;0.05) in both groups with raised and
normal baseline TG levels and the ↓ continued for 7 years.<br />
TC: The group with raised baseline TC showed a ↓ (p&lt;0.001) at all
time points except at 48 months. The group with normal baseline TC
showed a significant ↓ (p&lt;0.05) at 84 months.<br />
HDL: ↑ significantly in both groups with raised and normal baseline
levels at all time points (p&lt;0.001) except for 12, 72 and 84 months
where the increase was significant at 1% level (p&lt;0.01).<br />
LDL: ↓ significantly at 60 months (p&lt;0.05) and at 72 and 84 months
(p&lt;0.01).<br />
Plasma fibrinogen: ↓ significantly at 12 months (p&lt;0.01) and at all
other time points (p&lt;0.001)</p>
<p><u>Platelet count:</u> No change during the study.</p></td>
<td><p>Conclusion:</p>
<p>In authors state that, “the type of lipid changes (decrease TG, TC
and increase HDL) observed were those usually considered
antiatherogenic. Reducing fibrinogen may result in beneficial changes in
the pathological processes leading to thrombotic occlusion. The
consumption of MaxEPA by the patients over a seven-year period did not
indicate any adverse effects”.</p>
<p><u>Comments:</u></p>
<p>At the beginning of the study MaxEPA was not available in a capsule
form and the investigators could not find placebo oil with similar
taste, hence the study was conducted as open trial with control
group.</p>
<p>Diets not assessed.</p>
<p>Patients not taking aspirin or lipid lowering drugs were included in
the study.</p>
<p>Data not provided only figures.</p>
<p>Patients joined the study throughout the 7-year period and patients
who dropped out were not included in the analysis.</p></td>
<td>2</td>
<td><p>Some subjects withdrew because of the fishy taste of the
supplements.</p>
<p>No apparent side effects were observed however, 17.5% of subjects had
minor disturbances of routine chemical and hematological parameters (no
more than 2 changes outside the normal range).</p></td>
</tr>
<tr class="even">
<td><p>Schaefer et al. 1996</p>
<p><em>Am J Clin Nutr</em> 1996;63:234-41</p>
<p>[U.S.]</p></td>
<td>To compare the efficacy of high fish and low fish diets in lowering
plasma lipid concentrations in middle-aged and elderly men and
women.</td>
<td>Crossover clinical trial</td>
<td><p>30 weeks</p>
<p>6 week baseline diet</p>
<p>24 weeks high fish or low fish diet</p>
<p>Maximum four weeks washout period between the baseline and high or
low fish diet.</p></td>
<td><p>Not quantified</p>
<p>High fish or low fish NCEP Step 2 diets.</p></td>
<td><p>22 subjects</p>
<p>High fish diet: four men and seven women (n=11)</p>
<p>Low fish diet: seven men and four women (n=11)</p>
<p>Three women participated in both high and low fish diets.</p>
<p>The investigators provided the diets.</p></td>
<td><p><u>TG:</u> Fasting TG remained unchanged with both diets.
Postprandial TG ↓ significantly in the high fish diet group (-23%,
p&lt;0.05)</p>
<p><u>TC:</u> ↓ significantly in high fish (-14%) and low fish diet
(-19%) groups compared to the baseline levels (p&lt;0.0001)</p>
<p><u>LDL:</u> ↓ significantly in high fish (-15%) and low fish diet
(-20%) groups compared to the baseline levels (p&lt;0.0001)</p>
<p><u>HDL:</u> ↓ significantly in high fish (-11%) and low fish diet
(-17%) groups compared to the baseline levels (p&lt;0.0001)</p>
<p><u>apo A-I:</u> ↓ significantly in high fish (-17%) and low fish diet
(-16%) groups compared to the baseline levels (p&lt;0.0001)</p>
<p><u>apo B:</u> ↓ significantly in high fish (-19%) and low fish diet
(-20%) groups compared to the baseline levels (p&lt;0.0001)</p>
<p><u>TC/HDL ratio:</u> No effect of both high or low fish diets</p>
<p><u>LDL particle size</u>:  (p&lt;0.05) in the low fish group but not
in the high fish group.</p>
<p><u>DBP:</u>  in both the high fish diet (p&lt;0.001) and in the low
fish diet (p&lt;0.002) groups.</p>
<p><u>EPA and DHA concentrations</u>:  (significant) and  in AA
concentrations in plasma were observed with Step 2 high fish diet.</p>
<p>On low fish diet plasma EPA was modestly increased and AA was
modestly decreased.</p></td>
<td><p>The authors concluded that both Step 2 diets (high and low fish)
significantly reduce the TC and LDL levels without effecting the TC:HDL
ratio.</p>
<p>The fiber intake in high fish diet and low fish diet groups was
higher by 57% and 37%, respectively compared to their baseline diets.
The confounding effect of high fiber intake on the cholesterol
parameters was not examined.</p></td>
<td>1</td>
<td>Not reported</td>
</tr>
<tr class="odd">
<td><p>Schindler and Rost</p>
<p>1996</p>
<p><em>Z Ernahrungswiss</em> 1996;35:191-198 (ABSTRACT,
foreign)</p></td>
<td>To determine the effect of low doses of n-3 fatty acid
supplementation on the plasma lipids and lipoprotein composition the
threshold of effectiveness.</td>
<td>Clinical study</td>
<td>8 weeks</td>
<td>0.18-1.1 g/d of n-3 FAs in form of fish oil capsules.</td>
<td>20 subjects with primary hyperlipoproteinaemia of phenotypes IIa,
IIb and IV and with proven coronary sclerosis.</td>
<td><p><u>TG:</u> ↓ in all subjects with greatest decrease in patients
who had the highest levels at baseline.</p>
<p><u>TC:</u> No change</p>
<p><u>LDL:</u> No change except for significant increase in type VI
hyperlipoproteinaemia patients.</p>
<p><u>HDL:</u> ↑ significantly in patients with type IIb
hyperlipoproteinaemia.</p>
<p>The minimal dose of n-3 is between 0.18 g – 0.35 g.</p></td>
<td><p><u>Conclusion:</u></p>
<p>The results show beneficial effects of n-3 FAs on plasma lipids and
lipoprotein with respect to reduction in TG and an increase in HDL as
seen in other studies, despite a lower dose of less than 1 g/d.</p>
<p>Comments:</p>
<p>Summarized from abstract.</p></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td><p>Schmidt et al. 1991</p>
<p><em>Arteriosclerosis and Thrombosis</em> 1991;11:429-435</p>
<p>[Denmark]</p></td>
<td>“To investigate whether a reduction in monocyte and neutrophil
chemotaxis could be obtained with a low daily dose (1.3 g) of n-3 PUFAs
and whether a dose-response effect of n-3 PUFAs-given in low (1.3 g),
moderate (4 g), and high (9 g) daily amounts –to healthy volunteers
could be observed”.</td>
<td>Controlled trial</td>
<td><p>18 weeks</p>
<p>6 weeks on each treatment with 6 weeks washout period between the
treatments.</p></td>
<td><p>9 g/d n-3 PUFAs (EPA and DHA 34% and 19% wt/wt total fat,
respectively)</p>
<p>4 g/d n-3 PUFAs</p>
<p>1.3 g/d n-3 PUFAs</p>
<p>Compliance:</p>
<p>Platelet fatty acid analysis</p></td>
<td><p>34 subjects</p>
<p>9 subjects with type IIa hyperlipidemia and 9 normolipidemic, healthy
subjects as control for type IIa subjects.</p>
<p>8 subjects with type IV hyperlipidemia and 8 normolipidemic, healthy
subjects as control for type IV subjects.</p>
<p>All subjects received n-3 PUFA supplementation.</p></td>
<td><p>TC: did not change in the type IIa hyperlipidemic subjects with
n-3 PUFA supplementation.</p>
<p><u>Monocyte chemotaxis:</u> monocyte migration towards autologous
serum decreased significantly in type IIa hyperlipidemic subjects with
n-3 PUFA treatment. The monocyte migration towards autologous serum was
higher in this group before treatment compared to the control group.
Monocyte chemotaxis in the type IV hyperlipidemics did not differ from
the controls. In healthy subjects monocyte chemotaxis was reduced in a
dose-related fashion and was significant even at 1.3 g/d dose.</p>
<p><u>Neutrophil chemotaxis:</u> In both type IIa and IV hyperlipidemic
subjects, neutrophil migration was significantly inhibited with n-3
PUFA. Cell density was significantly reduced in subjects with type IV
hyperlipidemia and in all hyperlipidemic subjects. In healthy subjects
neutrophil chemotaxis was reduced in a dose-related fashion and was
significant even at a lower dose. No effect on spontaneous neutrophil
migration was observed in hyperlipidemic or in healthy subjects with n-3
PUFA.</p>
<p>Platelet EPA (p&lt;0.001) and DHA (p&lt;0.001) levels increased
significantly with n-3 PUFA supplementation.</p></td>
<td><p>Conclusions:</p>
<p>The authors suggest that, “these results lend support to the notion
of an antiatherosclerotic effect of n-3 PUFAs and may provide an
explanation for the hitherto-unexplained effect of low doses of n-3
PUFAs in CHD”.</p>
<p>Comments:</p>
<p>No hyperlipidemic control group</p>
<p>No placebo group</p>
<p>Not double blinded</p>
<p>Diets were not assessed</p></td>
<td>2</td>
<td>The n-3 PUFA supplementation was well tolerated and adverse effects
were not observed.</td>
</tr>
<tr class="odd">
<td><p>Schmidt et al. 1992a</p>
<p><em>Ann Nutr Metab</em> 1992;36:283-287</p>
<p>[Denmark]</p></td>
<td>To determine the effect of n-3 supplementation in men with
hypertriglyceridaemia.</td>
<td>Randomized, crossover with no wash out period between different
doses.</td>
<td><p>24 weeks</p>
<p>8 weeks on 2 g/d n-3 PUFAs</p>
<p>8 weeks on 4 g/d n-3 PUFAs</p>
<p>8 weeks on 9 g/d n-3 PUFAs</p></td>
<td><p>9 g/d n-3 PUFAs</p>
<p>(fish oil concentrate, EPAX 5500TG)</p>
<p>4 g/d n-3 PUFAs</p>
<p>2 g/d n-3 PUFAs</p>
<p>Compliance: direct questioning and capsule counts</p></td>
<td><p>11 subjects with serum triglycerides above 5.2 mmol/l were
recruited from the hospital lipid clinic.</p>
<p>6 subjects took n-3 PUFAs in the order 2, 4 and 9 g/d</p>
<p>5 subjects took n-3 PUFAs in the order 9, 4 and 2 g/d</p></td>
<td><p><u>TG:</u> ↓ significantly (p&lt;0.001) with all three doses of
n-3 PUFAs, and the reductions increased with increased dose.</p>
<p><u>TC:</u> ↓ significantly (p&lt;0.001) with all three doses of n-3
PUFAs, and the reductions increased with increased dose.</p>
<p><u>HDL:</u> ↑ significantly (p&lt;0.05) with all three doses in a
dose-related fashion.</p>
<p><u>apo B:</u> No change</p>
<p><u>apo A<sub>1</sub>:</u> ↑ significantly with 2 g/d dose
(p&lt;0.05), but with other doses a NS increase was observed.</p>
<p>Liver function test, glucose levels and body weights did not change
during the treatment.</p></td>
<td><p><u>Conclusion:</u></p>
<p>The authors indicate that, “the majority of the effect was obtained
after the lowest dose given. This dose is likely to be acceptable to
most subjects for long-term use”.</p>
<p><u>Comments:</u> Diets were not assessed but the subjects were asked
not to change their diets and physical activity.</p>
<p>No washout period between doses.</p></td>
<td>1</td>
<td><p>The fish oil supplements were well tolerated except for belching
and fishy taste.</p>
<p>Liver function test, glucose levels and body weights did not change
during the treatment.</p></td>
</tr>
<tr class="even">
<td><p>Schmidt et al. 1992b</p>
<p>Scand J. Clin. Lab. Invest.</p>
<p>1992;52:221-228</p>
<p>[Denmark]</p></td>
<td>To examine the effects of long-term dietary supplementation with n-3
PUFA on BP, lipid pattern and hemostasis.</td>
<td>Clinical trial</td>
<td>36 weeks (9 months)</td>
<td><p>3.2 g/d EPA+DHA (4 g/d n-3 FAs, Pikasol fish oil capsules)</p>
<p>(2.04 g/day EPA</p>
<p>1.14 g/day DHA)</p>
<p>Compliance:</p>
<p>EPA and DHA platelet fatty acid composition, interview.</p></td>
<td><p>24 healthy volunteers (14 female, 10 males)</p>
<p>All subjects were free of medication, including aspirin, and
non-steroidal anti-inflammatory drugs for at least two weeks prior to
the study.</p>
<p>Participants maintained normal dietary and life-style
patterns.</p></td>
<td><p><u>TG:</u> ↓ significantly with fish oil after 9 months of
treatment and the ↓ was larger than after 6 weeks (median values, before
0.97, 6 weeks 0.84, 9 months 0.77 mmol/l; p&lt;0.001 for before and 9
months and for 6 weeks and 9 months). 3 months after the supplementation
was stopped TG levels returned to baseline (9 months 0.77, 3 months post
treatment 1.0 mmol/l; p&lt;0.001).</p>
<p>TC: NS changes with fish oil</p>
<p><u>HDL:</u> NS changes with fish oil although the time dependent
trend showed an increase in HDL.</p>
<p><u>LDL:</u> NS changes with fish oil<u><br />
TC/HDL ratio:</u> NS changes with fish oil</p>
<p><u>apo A1:</u> NS changes with fish oil</p>
<p>apo B: NS changes with fish oil</p>
<p><u>SBP:</u> ↓ significantly with fish oil after 9 months of treatment
(median values, before 120, 9 months 115 mm Hg, p&lt;0.001). Significant
difference between 6 weeks (120 mm Hg) and 9 months (115 mm Hg,
p&lt;0.01). No difference between 9 months (115 mm Hg) and 3 months
after supplementation (112 mm Hg).</p>
<p><u>DBP:</u> ↓ significantly with fish oil after 9 months of treatment
(median values, before 85, 9 months 75 mm Hg, p&lt;0.001). Significant
difference between 6 weeks (82 mm Hg) and 9 months (75 mm Hg,
p&lt;0.01). No difference between 9 months (75 mm Hg) and 3 months after
supplementation (71 mm Hg).</p>
<p><u>Bleeding time:</u> Significant ↑ with fish oil after 6 weeks and 9
months and remained higher 3 months post treatment (median values,
before 5.3, 6 weeks 6.0, 9 months 6.0, 3 months post 6.0 min; p&lt;0.001
for before and 9 months, p&lt;0.05 9 months and 3 months post,
p&lt;0.001 for time dependent trend).</p>
<p><u>Platelet umber:</u> NS changes with fish oil</p>
<p><u>Platelet volume:</u> NS changes with fish oil</p>
<p><u>Platelet aggregability:</u> NS changes with fish oil</p>
<p><u>Β-thromboglobulin:</u> NS changes with fish oil</p>
<p><u>Fibrinogen:</u> Significant ↑ with fish oil in the period between
6 weeks and 9 months (p&lt;0.001)</p>
<p><u>t-PAag:</u> Significant ↑ after 9 months with fish oil before
venous occlusion (p&lt;0.05).</p>
<p><u>t-PA activity:</u> Significant ↓ after 9 months with fish oil
after venous occlusion (p&lt;0.001).</p>
<p><u>PAI:</u> Significant ↑ after 9 months with fish oil
(p&lt;0.05).</p>
<p><u>Fibronectin antigen:</u> No change</p>
<p><u>VWF:</u> Significant ↓ after 9 months with fish oil
(p&lt;0.05).</p>
<p>Both EPA and DHA levels ↑ significantly with n-3 supplementation for
9 months (both p&lt;0.001)</p></td>
<td><p>Conclusions:</p>
<p>The authors concluded that, no clear benefit on lipid pattern and
hemostasis was achieved with respect to development of CHD”.</p>
<p>Comments:</p>
<p>Diets were not assessed, but the subjects were asked to follow their
routine lifestyle.</p>
<p>Not a controlled study.</p></td>
<td>2</td>
<td>The fish oil was accepted by the subjects and there were no
dropouts. Mild gastrointestinal symptoms such as belching and loose
stools were reported, but these subsided during the supplementation
period.</td>
</tr>
<tr class="odd">
<td><p>Schmidt et al., 1992c</p>
<p>Scand J. Clin. Lab. Invest.</p>
<p>1992;52:229-236</p>
<p>[Denmark]</p></td>
<td>To examine the effect of supplementation with n-3 PUFA for 9 months
on neutrophil and monocyte chemotaxis.</td>
<td>Clinical trial</td>
<td>36 weeks (9 months)</td>
<td><p>3.2 g/d EPA+DHA (4 g/d n-3 FAs, Pikasol fish oil capsules)</p>
<p>(2.04 g/day EPA</p>
<p>1.14 g/day DHA)</p>
<p>Compliance:</p>
<p>EPA and DHA platelet fatty acid composition, interview.</p></td>
<td><p>24 healthy volunteers (14 female, 10 males)</p>
<p>All subjects were free of medication, including aspirin, and
non-steroidal anti-inflammatory drugs for at least two weeks prior to
the study.</p>
<p>Participants maintained normal dietary and life-style
patterns.</p></td>
<td><p><u>Neutrophil chemotaxis</u>: spontaneous migration significantly
↓ after 39 weeks (p &lt;0.01). Directed migration was significantly
inhibited towards two types of chemoattractants (autologous serum and
n-formyl-methionyl-leucylphenylalanine (FMLP) (p&lt;0.01)). Neutrophil
chemotactic responsiveness was decreased towards autologous serum
(p&lt;0.01) after 6 weeks and 9 months, but unchanged with respect to
FMLP.</p>
<p><u>Cell density</u>:</p>
<p>NS change.</p>
<p><u>Monocyte chemotaxis</u>: Significantly ↓ (p&lt;0.01) using both
autologous serum and FMLP.</p>
<p>EPA and DHA platelet fatty acid composition increased.</p></td>
<td><p><u>Conclusions</u>:</p>
<p>The authors conclude that, “supplementation with n-3 PUFA could thus
be beneficial in conditions with increased neutrophil reactivity…[and] a
reduction in monocyte reactivity may thus contribute to the apparent
beneficial effect of n-3 PUFA in coronary heart disease.”</p>
<p><u>Comments</u>:</p>
<p>Several pre-trial blood samples were infected. Thus, baseline values
for 12 participants were based on samples taken 3 months after
supplementation stopped.</p>
<p>Diets were not controlled or measured, but participants were asked to
maintain their normal diet.</p>
<p>No control group.</p></td>
<td>2</td>
<td>No dropouts were recorded, and the fish oil was well tolerated by
all participants</td>
</tr>
<tr class="even">
<td><p>Schmidt et al. 1996</p>
<p>Scand J Clin Lab Invest</p>
<p>1996;56:87-92</p>
<p>[Denmark]</p></td>
<td>To examine the effect of a very low dose of n-3 FAs on monocyte
function in healthy humans.</td>
<td>Double-blind, randomized and placebo-controlled</td>
<td>12 weeks</td>
<td><p>0.5 g/d EPA + DHA (given as one capsule of re-esterified
triglyceride fish oil concentrate containing 0.65 g on n-3 PUFA; EPAX
5500).</p>
<p>Placebo was a mixture of fat approximating the FA content of the
average Danish diet. Capsules (1/d) were given with the evening
meal.</p>
<p>Compliance:</p>
<p>FA composition measured in monocytes.</p></td>
<td><p>32 healthy men (n = 15, age 27-49) and women (n = 17, age 24-52).
Subjects were free of medication, aspirin and other non-steroidal
anti-inflammatory drugs were not allowed for 2 weeks before inclusion
and during the whole study period.</p>
<p>Two groups:</p>
<ol type="1">
<li><p>placebo control</p></li>
<li><p>n-3 PUFA</p></li>
</ol>
<p>Participants were paired (one from control group and one from n-3
group) and each pair was examined on the same day to avoid day-to-day
variability.</p></td>
<td><p>No effects of n-3 PUFAs was observed on monocyte chemotaxis and
chemiluminesence, or on the production of leukotriene B<sub>4</sub>,
IL-6, TNF- or IL-6 from stimulated monocytes.</p>
<p>EPA levels ↑ significantly (p&lt;0.001) in monocytes in subjects
randomized to n-3 PUFA group. DHA and DPA levels ↑ in monocyte membranes
after n-3 PUFA, but the changes in these two long-chain n-3 PUFAs were
not significantly different from baseline or from controls.</p></td>
<td><p><u>Conclusions:</u></p>
<p>The authors concluded that, “in the present study determination of FA
composition of monocytes revealed that the intake of n-3 PUFAs ↑ and was
significantly ↑ in subjects randomized to n-3 PUFAs than in controls. We
were unable to demonstrate any effect of n-3 PUFAs on monocyte
function.</p>
<p>Small changes may have been masked by relatively low sample size and
relatively high inter-assay variability.”</p>
<p><u>Comments:</u></p>
<p>Diets were not assessed, but only subjects with a typical Western
diet eating no more than two fish servings weekly were included. The
subjects were asked to maintain their usual diets and lifestyle during
the duration of the study.</p></td>
<td>1</td>
<td>Not reported</td>
</tr>
<tr class="odd">
<td><p>Seljeflot et al. 1998</p>
<p><em>Eur Clin Invest</em> 1998;28:629-635</p>
<p>[Norway]</p></td>
<td>To determine the effects of n-3 FAs and/or antioxidants on some
biochemical markers of vascular endothelial function such as sTM, vWF,
tPAag, soluble forms of E-selectin, P-selectin and vascular cell
adhesion molecule 1 (VCAM-1) in hyperlipidemic men.</td>
<td>Randomized, double-blind, placebo-controlled, two-by-two factorial
design.</td>
<td>6 weeks</td>
<td><p>4.8 g/d EPA + DHA (n-3 FA)</p>
<p>n-3 placebo (n-placebo)</p>
<p>antioxidant (vitamin E, C and β carotene)</p>
<p>antioxidant placebo (a-placebo)</p>
<p>The subjects received either</p>
<p>n-3 + a-placebo, n-3 + antioxidant, n-placebo + antioxidant or</p>
<p>n-placebo + a-placebo</p>
<p>Compliance:</p>
<p>FA analysis in serum phospholipids</p></td>
<td><p>41 men were recruited from the population attending the screening
program for risk of CHD. The subjects were divided into n-3 or placebo
group and then within each group they were subdivided into antioxidant
or a-placebo group (4 groups).</p>
<p>n-3 group: n=22</p>
<p>antioxidant group: n=19</p>
<p>41 subjects of the 42 completed the study. One subject dropped out
because of the onset of non-fatal MI.</p></td>
<td><p><u>TG:</u> Significant ↓ with n-3 FA compared to baseline
(p=0.044) and n-placebo (p=0.026). No difference with antioxidant
supplementation vs. a-placebo.</p>
<p><u>TC:</u> NS effect of n-3 FA compared to baseline or
n-placebo.<u><br />
HDL:</u> NS effect of n-3 FA compared to baseline or n-placebo.<u><br />
sTM:</u> Significant ↓ with n-3 FA compared to n-placebo (p&lt;0.001). ↓
more with a-placebo vs. antioxidant supplementation (p=0.04).</p>
<p><u>vWF,:</u> Significant ↓ with n-3 FA compared to n-3 placebo
(p=0.034). No difference with antioxidant supplementation vs.
a-placebo.</p>
<p><u>tPAag:</u> No difference in the changes between n-3 and n-placebo
groups. No difference with antioxidant supplementation vs.
a-placebo.</p>
<p><u>VCAM-1:</u> Significant ↑ with n-3 FA (p=0.010). No difference
with antioxidant supplementation vs. a-placebo.</p>
<p>E-selectin: Significant ↑ with n-3 FA (p=0.001).</p>
<p>P-selectin: No difference in the changes between n-3 and n-placebo
groups.</p>
<p>Significant ↑ in EPA (p&lt;0.001) with n-3 FA compared to n-placebo.
Significant ↑ in serum vitamin E concentrations in antioxidant
supplemented group vs. a-placebo group.</p></td>
<td><p><u>Conclusions:</u></p>
<p>The author conclude that, “the reduction in the levels of sTM and vWF
with n-3 FA supplementation could indicate an improvement with regard to
the haemostatic markers of endothelial dysfunction, whereas the
simultaneous increase in the soluble forms of E-selectin and VCAM-1 may
suggest an adverse effect on the inflammatory system. The antioxidant
seem to be neutral in their effects on these endothelial cell
markers”.</p>
<p><u>Comments:</u></p>
<p>Diets were not assessed</p></td>
<td>1</td>
<td>Increase in the soluble forms of E-selectin and VCAM-1 may suggest
an adverse effect on the inflammatory system.</td>
</tr>
<tr class="even">
<td><p>Seljeflot et al. 1999</p>
<p><em>Thrombosis and Hemostasis</em> 1999. 81:566-570</p>
<p>[Norway]</p></td>
<td><p>To investigate the effect of n-3 fatty acid supplementation on
LPS induced production and release of markers of thrombin generation
(procoagulant activity) and markers of inflammation (cytokines and TNF)
in whole blood cultures from patient with atherosclerosis.</p>
<p>To look for differences between groups at baseline and possible
alleviation of such differences after 4 weeks of
supplementation.</p></td>
<td>Randomized, double-blind, controlled</td>
<td><p>4 weeks</p>
<p>6 month pre- study period</p>
<p>baseline measurements taken after 6 month pre- study period</p></td>
<td><p>5.1 g/day of highly concentrated ethyl esters of fatty acids
(ratio of EPA to DHA was 2:1)</p>
<p>Prior to this study, subjects in the fish oil group received fish oil
(same dose as above) and subjects in placebo group received placebo for
6 months.</p>
<p>In this study, subjects from both groups (11 from fish oil, 12 from
placebo group) received fish oil for 4 weeks.</p>
<p>Compliance: serum phospholipids</p></td>
<td><p>23 subjects with atherosclerosis but without clinical
symptoms</p>
<p>7 male/16 female</p>
<p>age range: 43-75 years</p>
<p>All subjects received fish oil.</p></td>
<td><p>↓ TG and serum vitamin E in group II at 4 weeks (p=0.019)</p>
<p>LPS-induced production of procoagulant activity (measured as):</p>
<p><u>Prothrombin fragment 1+2</u>: ↓ in group 1 compared to group II at
baseline (p=0.010); NS difference between groups at 4 weeks; change from
baseline between groups significant (p&lt;0.001).</p>
<p><u>Fibrinopeptide A</u>: ↓ in group I at baseline (p=0.049); NS
difference between groups at 4 weeks.</p>
<p>Lipopolysaccharide-induced production of inflammatory markers
(measured as):</p>
<p><u>Interleukin-1β</u>: NS difference at baseline or 4 weeks</p>
<p><u>Interleukin-6</u>: ↑ in group I at baseline compared to group II
(p=0.053); NS difference between groups at 4 weeks; changes from
baseline between groups significant (p=0.001)</p>
<p><u>Tumor necrosis factor α</u>: ↑ in group I at baseline compared to
group II (p=0.047); NS difference between groups at 4 weeks; changes
from baseline between groups significant</p></td>
<td><p><u>Conclusions:</u></p>
<p>The results may indicate a beneficial effect of n-3 fatty acids on
procoagulant activity and that some inflammatory responses observed seem
to be adverse, possibly due to increased oxidation (demonstrated by
consumption of vitamin E).</p>
<p><u>Comments:</u></p>
<p>Diet not assessed.</p>
<p>No other medication (including anticoagulant treatment) was used
during the study period</p></td>
<td>2</td>
<td>Not reported.</td>
</tr>
<tr class="odd">
<td><p>Sellmayer et al. 1995</p>
<p><em>The American Journal of Cardiology</em> 1995;76:974-977</p>
<p>[Germany]</p></td>
<td>The objective of the study was to determine the antiarrhythmic
effects of dietary supplementation with fish oil rich in EPA and DHA in
patients with spontaneous ventricular premature complexes (VPCs)</td>
<td>Randomized, double-blind, placebo-controlled prospective trial.</td>
<td>16 weeks</td>
<td><p>2.4 g of EPA+DHA from cod liver oil</p>
<p>0.9 g/d EPA</p>
<p>1.5 g DHA (treatment group)</p>
<p>5 g of linoleic acid from sunflower seed oil (placebo group)</p>
<p>Compliance: phone call and serum phospholipid fatty acid
analyses</p></td>
<td>68 outpatients with spontaneous ventricular premature complexes
(VPCs)</td>
<td><p>Lipid parameters not measured.</p>
<p>VPCs ↓ 48%</p>
<p>EPA (2 fold) and DHA (1.7 fold) concentrations ↑ significantly
(p&lt;0.001) in the fish oil group.</p></td>
<td><p><u>Conclusion:</u></p>
<p>The results suggest that dietary supplementation with a moderate dose
of fish oil has antiarrhythmic effects leading to a reduction in VPCs in
patients with frequent ventricular arrhythmias.</p>
<p><u>Comments:</u></p>
<p>Dietary intake was not monitored or assessed.</p></td>
<td>1</td>
<td>Five patients in each group withdrew because of inability to ingest
oil.</td>
</tr>
<tr class="even">
<td><p>Sheehan et al. 1997</p>
<p><em>Am J Clin Nutr</em> 1997;66:1183-1187</p>
<p>[U.S.]</p></td>
<td>To evaluate the effects of ADA-recommended fiber intakes in patients
with NIDDM on fish oil therapy.</td>
<td>Controlled sequential study</td>
<td><p>4 weeks on fish oil treatment followed by 4 weeks on fish oil +
pectin followed by 4 weeks of follow-up control period.</p>
<p>The fish oil treatment period was considered a run-in period for
fiber treatment period.</p></td>
<td><p>6 g/d n-3 FAs from 20 g/d of fish oil (MaxEPA)</p>
<p>15 g/d pectin</p>
<p>Compliance:</p>
<p>FA analysis</p></td>
<td><p>15 (12 men, 3 women) nonobese subjects with NIDDM were recruited.
Diet or diet + oral agents or diet + insulin was used to control
diabetes.</p>
<p>All subjects were treated with fish oil for 4 weeks followed by fish
oil + pectin followed by control period. During the control period the
subjects did not receive fish oil or pectin treatment and followed their
diabetic diet.</p></td>
<td><p><u>TG:</u> ↓ significantly (41%, p&lt;0.05) with fish oil
compared to baseline. No further reduction with addition of
fiber.<u><br />
TC:</u> NS change with fish oil compared to baseline. Significant ↓
(p&lt;0.05) after addition of fiber compared to baseline (p&lt;0.001)
and fish oil (p&lt;0.05).<u><br />
LDL:</u> NS ↑ with fish oil (4.40 ± 0.93 mmol/l) compared to baseline
(4.32 ± 1.58 mmol/l). Significant ↓ after addition of fiber compared to
baseline (p&lt;0.05) and fish oil (p&lt;0.05).<u><br />
HDL:</u> No change with fish oil or with addition of fiber compared to
baseline.<u><br />
VLDL:</u> ↓ significantly (36%, p&lt;0.05) with fish oil compared to
baseline. No further reduction with addition of fiber.</p>
<p><u>Fasting glucose:</u> NS change with fish oil (7.88 ± 2.6 mmol/l),
fish oil + fiber (7.72 ± 2.6 mmol/l) compared to baseline (7.72 ± 2.7
mmol/l).</p>
<p><u>Postprandial glucose:</u> NS change with fish oil (10.77 ± 4.9
mmol/l), fish oil + fiber (10.44 ± 5.1 mmol/l) compared to baseline
(10.38 ± 5.3 mmol/l).</p>
<p><u>Fasting insulin:</u> NS change with fish oil (159 ± 102 pmol/l),
fish oil + fiber (131 ± 71 pmol/l) compared to baseline (140 ± 81
pmol/l).</p>
<p><u>Glycated hemoglobin:</u> NS change with fish oil (6.5 ± 2.0%),
fish oil + fiber (6.7 ± 2.6%) compared to baseline (7.0 ± 2.7%).</p>
<p><u>Glycated albumin:</u> NS change with fish oil (2.2 ± 1.0%), fish
oil + fiber (2.7 ± 1.8%) compared to baseline (2.5 ± 1.7%).</p>
<p><u>Body weight:</u> NS change with fish oil or fish oil +
fiber.<u><br />
</u></p>
<p>Analysis of plasma lipid fractions showed a ↓ in TG (46%, p&lt;0.05)
phospholipids (27%, p&lt;0.05) and a slight ↓ in free FA fraction but no
change in cholesterol ester fraction compared to baseline. Addition of
fiber reduced cholesterol esters (34%, p&lt;0.05), TG (44%, p&lt;0.05)
and phospholipids (42%, p&lt;0.05) compared to fish oil.</p>
<p>The lipid indexes at the end of the control period were similar or
slightly lower compared to the baseline. Glycated hemoglobin and
glycated albumin, and body weight was maintained during the control
period. Fasting plasma glucose and insulin, and postprandial glucose
levels at the end of the control period were similar to baseline
values.</p>
<p>EPA and DHA concentrations ↑ in plasma lipid fractions, plasma TG
fractions and in plasma cholesterol ester fractions.</p>
<p>Plasma Zn, Mg, and Cu levels were not affected by fiber treatment.
Urinary Zn (p&lt;0.05), Mg and Cu excretion decreased with fiber
treatment.</p></td>
<td><p>Conclusions:</p>
<p>The authors conclude that, “a high fiber intake may be beneficial in
fish oil treated diabetic patients”.</p>
<p><u>Comments:</u></p>
<p>Diets were not assessed</p>
<p>Not randomized, blinded placebo-controlled trial.</p></td>
<td>1</td>
<td>Not reported</td>
</tr>
<tr class="odd">
<td><p>Silva et al. 1996</p>
<p><em>International Journal of Cardiology</em> 1996;57:75-80</p>
<p>[Portugese]</p></td>
<td>To determine if fish consumption affected the triglyceride lowering
capacity of fish oils.</td>
<td>Randomized, double-blind trial</td>
<td><p>8 weeks (2 months) of treatment</p>
<p>4 weeks of washout or diet period</p></td>
<td><p>3.6 g/d EPA+DHA</p>
<p>(12 g/d of fish oil)</p>
<p>2.16 g/d EPA</p>
<p>1.44 g/d DHA</p>
<p>(fish oil group)</p>
<p>Soy oil</p>
<p>Compliance: capsule counts</p></td>
<td>35 subjects (25 females and 10 males) with hypertriglyceridaemia
were recruited from the Atherosclerosis Out-patient Clinic of the
University Hospital of Coimbra.</td>
<td><p><u>TG:</u> No effect on TG in patients consuming more than 6 fish
meals per week. Inverse relation (r=-0.352) between the number of meals
with fish per week and TG lowering effect of fish oils</p>
<p><u>TC:</u> No significant effect of fish oil</p>
<p><u>LDL:</u> No significant effect of fish oil</p>
<p><u>HDL:</u> No significant effect of fish oil</p>
<p>Significant increase in glucose levels in both diabetics (p=0.0351)
and non-diabetics (p=0.0218) with fish oil when compared to soya oil
treatment.</p></td>
<td><p><u>Conclusion:</u></p>
<p>The results suggest that, “the triglyceride lowering effect of fish
oil is affected by fish consumption, and confirm that fish oils increase
blood glucose levels in diabetics and non-diabetics”.</p></td>
<td>2</td>
<td><p>30% and 6.7% of the patients in the fish oil and soya oil group
reported minor and transitory side effects.</p>
<p>Significant increase in glucose levels in both diabetics and
non-diabetics.</p></td>
</tr>
<tr class="even">
<td><p>Singh et al. 1997</p>
<p><em>Cardiovasc Drugs Ther</em> 1997;11:485-491</p>
<p>[India]</p></td>
<td>To determine if fish oil (EPA) and mustard oil therapy can provide
rapid protection against ischemic damage and complications in patients
with suspected acute myocardial infarction (AMI).</td>
<td>Randomized, double-blind, placebo-controlled</td>
<td>52 weeks (1 year)</td>
<td><p>1.8 g/day of EPA+DHA (Maxepa fish oil capsules)</p>
<p>1.08 g/d EPA</p>
<p>0.72 g/d DHA (group A)</p>
<p>Group B: 100 mg/d of aluminum hydroxide and 20 g/day mustard oil (ALA
2.9 g/d)</p>
<p>Group C: 100 mg/d of aluminum hydroxide (placebo group)</p>
<p>Compliance: capsule counts</p></td>
<td><p>360 subjects with suspected AMI</p>
<p>Group A: 122</p>
<p>Group B: 120</p>
<p>Group C: 118</p>
<p>The subjects were patients admitted over a period of 30 months at the
Medical Hospital and Research Centre with a clinical diagnosis of
suspected acute AMI. Those subjects who had likely suffered AMI with the
onset of symptoms in the preceding 24 hours were recruited.</p></td>
<td><p>TC: No significant effect of fish oil or mustard oil.</p>
<p>TG: Modest changes with fish oil.</p>
<p>HDL: Modest changes with fish oil and mustard oil.</p>
<p>Total cardiac events: ↓ significantly in the fish oil (RR=0.7) and
mustard oil (RR=0.81) groups compared with the placebo group (24.5% and
28% vs. 34.7%, respectively, p&lt;0.05) after 1 year.</p>
<p>Nonfatal infarctions: ↓ significantly in the fish oil (RR=0.51) and
mustard oil (RR=0.59) groups compared with the placebo group (13.0% and
15.0% vs. 25.4%, respectively, p&lt;0.01).</p>
<p>Total cardiac deaths: ↓ significantly in the mustard oil (RR=0.6) and
the fish oil (RR=0.52) groups compared with the placebo group (13.3% and
11.4% vs. 22.0%, respectively, p &lt; 0.01) .</p>
<p>Total cardiac arrhythmias: The fish oil and mustard oil groups also
showed a significant reduction in total cardiac arrhythmias (RR=0.46 for
both, p&lt;0.05 for both) compared with the placebo group.</p>
<p>Left ventricular enlargement: The fish oil and mustard oil groups
showed a significant reduction in left ventricular enlargement (RR=0.51
fish oil, 0.58 mustard oil, p&lt;0.01 both) compared with the placebo
group.</p>
<p>Angina pectoris: The fish oil and mustard oil groups showed a
significant reduction in angina pectoris (RR=0.42 fish oil, 0.51 mustard
oil, p&lt;0.05 for both) compared with the placebo group.</p>
<p>Significant ↓ in diene conjugates in both groups.</p></td>
<td><p><u>Conclusion:</u></p>
<p>The results suggest, “that fish oil and mustard oil, possibly due to
the presence of n-3 FAs, may provide rapid protective effects in
patients with AMI”.</p>
<p><u>Comments:</u></p>
<p>Dietary intake was not monitored or assessed, but subjects were asked
to consume a low-fat diet.</p>
<p>No exclusion criteria were used.</p>
<p>All parameters were similar among the three groups except for higher
incidence of previous angina pectoris and MI and higher number of
smokers in group A.</p>
<p>Data on compliance not reported</p></td>
<td>1</td>
<td>Belching (n=6, 4.9%) and nausea (n=8, 6.6%) in patients receiving
fish oil supplements</td>
</tr>
<tr class="odd">
<td><p>Sirtori et al. 1997</p>
<p><em>Am J Clin Nutr</em> 1997;65:1874-81</p>
<p>[Italy]</p></td>
<td>To evaluate the effects of low-dose of n-3 FAs on lipid and
lipoprotein concentrations and to evaluate the effects on clinical
abnormalities of hypertriglyceridemia, particularly altered glucose
metabolism and arterial hypertension.</td>
<td><p>Randomized, double-blind, placebo-controlled trial.</p>
<p>Multicenter.</p></td>
<td><p>24 weeks (6 months)</p>
<p>Run-in period was ≥ 4 weeks.</p>
<p>2 months on high dose of EPA+DHA</p>
<p>4 months on low-dose of EPA+DHA</p></td>
<td><p>2.580 g/d (2580 mg/d) of EPA+DHA as ethyl esters for 2 months
(high dose).</p>
<p>(Esapent capsules)</p>
<p>1530 mg/d EPA 1050 mg/d DHA</p>
<p>1.720 g/d (1720 mg/d) of EPA+DHA as ethyl esters for 4 months (low
dose)</p>
<p>1020 mg/d EPA 700 mg/d DHA</p>
<p>Placebo: Olive oil</p>
<p>The dose of olive oil was reduced during the last 4 months.</p>
<p>Compliance: capsule counts</p></td>
<td><p>935 subjects</p>
<p>Treatment: 470 subjects</p>
<p>Placebo: 465 subjects</p>
<p>Subjects with either type IIB or IV hyperlipoproteinemias with at
least one additional risk factor such as NIDDM, arterial hypertension or
impaired glucose tolerance were recruited from 63 clinical
groups.</p></td>
<td><p><u>TG:</u> Significant ↓ in the TG concentration in the n-3 group
(21.53%, p&lt;0.0001) compared to the placebo group after 6 months of
treatment.</p>
<p><u>TC:</u> NS change in TC between the n-3 and placebo group at all
time points with both intent-to-treat and per protocol analysis.</p>
<p><u>LDL:</u> Significant ↑ (6%, p=0.048) in LDL at the end of six
months in the n-3 group compared to the placebo group (3%).</p>
<p><u>HDL:</u> NS change in HDL between the n-3 and placebo group at all
time points with intent-to-treat analysis. The HDL concentrations
increased in male patients with impaired glucose tolerance or NIDDM
compared to the normoglycemic (p&lt;0.05).</p>
<p><u>Fasting glucose:</u> No significant change with n-3 (baseline 8.26
± 2.17; 6 months 8.16 ± 2.05 mmol/l) or with placebo (baseline 8.14 ±
2.06; 6 months 7.93 ± 2.05 mmol/l).</p>
<p><u>Glycated hemoglobin:</u> No significant change with n-3 (baseline
7.25 ± 1.56; 6 months 7.05 ± 1.64 mmol/l) or with placebo (baseline 7.14
± 1.63; 6 months 6.89 ± 1.42 mmol/l).</p>
<p><u>Insulinemia:</u> No significant change with n-3 (baseline 115.9 ±
64.0; 6 months 112.0 ± 50.7 mmol/l) or with placebo (baseline 111.6 ±
57.2; 6 months 119.7 ± 84.5 mmol/l).</p>
<p><u>Oral glucose tolerance:</u> No effect of n-3 FAs.</p>
<p><u>SBP:</u> No effect of n-3 FAs.</p>
<p>DBP: No effect of n-3 FAs.</p>
<p>Increase in plasma and RBC membrane EPA and DHA
concentrations.</p></td>
<td><p><u>Conclusions:</u></p>
<p>The authors state that, “treatment with a moderate daily dose of n-3
ethyl esters over a prolonged period of time significantly reduced
triacylglycerol concentrations without any worsening of glucose
tolerance in patients with hypertriglyceridemia with and without
impaired glycemic regulation”.</p></td>
<td>1</td>
<td><p>3.8 % and 4.5 % of the subjects in the treatment and placebo
group, respectively reported mild gastrointestinal disturbances.</p>
<p>No significant changes in biochemical and hematological indices were
observed.</p></td>
</tr>
<tr class="even">
<td><p>Sirtori et al. 1998</p>
<p><em>Atherosclerosis</em> 1998;137:419-427</p>
<p>[Italy]</p></td>
<td>To evaluate the long term efficacy of n-3 FAs on gylcemic parameters
and on plasma lipoproteins.</td>
<td><p>Open phase.</p>
<p>Multicenter.</p></td>
<td>24 weeks (6 months)</td>
<td><p>1.720 g/d (1720 mg/d) of EPA+DHA as ethyl esters for 6 months;
1020 mg/d EPA 700 mg/d DHA; ESAPENT<sup>R</sup>)</p>
<p>Compliance: EPA and DHA levels in plasma and RBCs</p></td>
<td><p>863 subjects were given fish oil treatment.</p>
<p>Subjects with either type IIB or IV hyperlipoproteinemia with at
least one additional risk factor such as NIDDM, arterial hypertension or
impaired glucose tolerance were recruited from 63 clinical groups.</p>
<p>5 subjects (total 868) withdrew because of worsening of
NIDDM.</p></td>
<td><p><u>TG:</u> At the end of open treatment phase the plasma TG in
the initial n-3 and placebo group was essentially identical. The group
that received n-3 during the first phase of the study showed a further ↓
from 21.5 to 25.2 %, whereas the reduction in the former placebo group
was 19.5% at the end of open treatment phase.</p>
<p><u>TC:</u> A 3% ↓ in the final 6-month for the total subjects.
Significant ↓ (4.15 %, p&lt;0.001) in patients with type IIB
hyperlipoproteinemia and no difference in reduction in patients with
(-4.7%, p&lt;0.001) and without (-3.8%, p&lt;0.001) NIDDM in this
subgroup.</p>
<p><u>LDL:</u> Minimal ↑ was observed in patients treated with fish oil
for 12 months vs. the 6 month average value. In patients with type IV
and IIB hyperlipoproteinemia with NIDDM, no change was observed,
although type IIB experienced a non-significant ↓ (2.8%). Conversely,
type IV patients had a non-significant ↑ (6.9%) in LDL in the open
treatment phase. In type IV patients without NIDDM a significant ↑
(15.9%, p&lt;0.002) in LDL was observed.</p>
<p><u>HDL:</u> In the final open treatment phase a overall ↑ (7.4%) in
HDL was observed for the whole group. However, when the patients were
divided as NIDDM and non-NIDDM (both type IV or IIB), the ↑ in HDL
reached statistical significance (all p&lt;0.001)</p>
<p><u>Fasting glucose:</u> No difference in fasting glucose at the end
of 12 months of the study in patients from either the n-3 or placebo
group in phase I. NIDDM patients showed no changes after 1 year of n-3
treatment or 6 months for those who got placebo for the first 6
months.</p>
<p><u>Glycated hemoglobin:</u> NIDDM patients showed no changes after 1
year of n-3 treatment or 6 months for those who got placebo for the
first 6 months.</p>
<p><u>Insulinemia:</u> NIDDM patients showed no changes after 1 year of
n-3 treatment or 6 months for those who got placebo for the first 6
months.</p>
<p>BP: No significant changes with fish oil.</p>
<p>Increase in EPA and DHA concentrations in plasma and RBC.</p></td>
<td><p>Conclusions:</p>
<p>The authors concluded that, “administration of n-3 FAs to
hypertriglyceridemic patients with impaired gylcemic control is not
followed by any significant negative consequences. However the authors
feel that the design of the study and the selection criteria used i.e.
excluding grossly obese patients, excluding subjects with unstable
diseases and including diabetic patients undergoing hypoglycemic
treatment does not allow generalization of the findings”.</p>
<p><u>Comments:</u></p>
<p>This paper reports the result of the second phase of the study. In
the first phase a double-blind trial was carried out for the first 6
months and then the open phase trial was conducted. In this open phase
trial all subjects received n-3 FAs. The results reported here are for
the open phase trial.</p>
<p>No control group</p>
<p>Intent to treat analysis</p>
<p>The sample size in the table does not sum up to 863.</p>
<p>Unclear about the exact number of dropouts.</p></td>
<td>1</td>
<td><p>15 patients (1.7 %) in the fish oil group reported side effects.
The most frequent side effects were related to the GI tract, i.e.
halitosis, vomiting, nausea, diarrhea and epigastric pain. The side
effects with fish oil were comparable to the placebo in phase I and
resulted in dropouts.</p>
<p>No major changes were observed in standard laboratory findings,
biochemical, hematological and urinary.</p></td>
</tr>
<tr class="odd">
<td><p>Sorensen et al. 1994</p>
<p><em>Fibrinolysis</em> 1994. 8:54-60</p>
<p>[Denmark]</p></td>
<td>To evaluate the influence of dietary fish oil supplementation in the
third trimester of pregnancy on coagulation and fibrinolysis
variables</td>
<td>Randomized, double-blind, parallel, controlled</td>
<td>7 weeks (from 30<sup>th</sup> to 37<sup>th</sup> week of
gestation)</td>
<td><p>2.7 g/day n-3 FA from four 1 g capsules of fish oil (Pikasol)
containing 32% EPA and 23% DHA) (fish oil group)</p>
<p>olive oil group: 4 g/day olive oil</p>
<p>Control group: no supplementation</p>
<p>Compliance:</p>
<p>capsule count and interview; in subset of subjects, the level of
EPA-derived prostaglandins, thromboxane A<sub>3</sub>, and
prostanglandin I<sub>3</sub> also measured</p></td>
<td><p>84 women in third trimester (30<sup>th</sup> week) of pregnancy,
otherwise healthy</p>
<p>mean age: 29.5 years (range: 23-41 years)</p>
<p>n-3 FA: n=44</p>
<p>Control: n=40 (olive oil and no supplementation group
combined)</p></td>
<td><p><u>TC</u>: NS change</p>
<p><u>HDL</u>: NS ↓ compared to controls (p=0.07)</p>
<p><u>TG</u>: NS change</p>
<p><u>TC/HDL ratio</u>: NS change</p>
<p><u>FVII activity</u>: NS change</p>
<p><u>FVII antigen</u>: NS change</p>
<p><u>Thrombin-antithrombin III complexes</u>: NS change</p>
<p><u>F1+2</u>: NS change</p>
<p><u>Fibrinogen activity</u>: NS change</p>
<p><u>Fibrinogen concentration</u>: NS change</p>
<p><u>Fibrin degradation products (FbDP)</u>: ↑ significantly compared
to controls (p &lt;0.05)</p>
<p><u>tPA antigen</u>: NS change</p>
<p><u>PAI-1 antigen</u>: NS change</p>
<p><u>tPA/PAI-1 antigen ratio</u>: NS change</p>
<p><u>PAI-1 activity</u>: NS change</p>
<p><u>Euglobulin</u>: NS change</p>
<p><u>t-PA activity</u>: NS change</p>
<p><u>Total HRG</u>: NS change</p>
<p><u>Total plasminogen</u>: NS change</p>
<p><u>Free plasminogen</u>: NS change</p>
<p><u>Plasma of α<sub>2</sub>-antiplasmin</u>: NS change</p>
<p><u>Serum of α<sub>2</sub>-antiplasmin</u>: NS change</p>
<p><u>Plasmin-antiplasmin complexes</u>: NS change</p>
<p><u>Dextran sulfate euglobulin fraction</u>: NS change</p>
<p><u>FXII-dependent fibrinolytic activity</u>: NS change</p>
<p><u>Urokinase-type fibrinolytic activity</u>: NS change</p></td>
<td><p><u>Conclusions</u>:</p>
<p>Dietary supplementation with fish oil in late pregnancy had no effect
on blood lipids, serum urate or coagulant activity.</p>
<p><u>Comments</u>:</p>
<p>Subjects reported no major changes in dietary habits during the
study.</p>
<p>Olive oil and no supplementation group combined and served as one
control group.</p></td>
<td>2</td>
<td>No complications of pregnancy reported. Blood pressure was within
the normal range during the study. There were no cases of pre-eclampsia
or preterm birth, and no babies were small for gestational age.</td>
</tr>
<tr class="even">
<td><p>Sorensen et al. 1998</p>
<p><em>Am J Clin Nutr</em> 1998;68:235-41</p>
<p>[Netherlands]</p></td>
<td>To examine the effect of n-3 PUFAs from fish oil on plasma lipids
(in vivo), composition, particle size and oxidation susceptibly of the
LDL particles ex vivo.</td>
<td>Randomized crossover trial.</td>
<td><p>4 weeks treatment with fish oil.</p>
<p>3 weeks run-in period where all subjects consumed sunflower oil.</p>
<p>Subjects were then assigned to fish or sunflower oil for 4
weeks.</p></td>
<td><p>0.91 g/d of EPA+DHA+ DPA (4 g/d fish oil) (fish oil group
(FO))</p>
<p>4 g/d sunflower oil (SO).</p>
<p>Margarine was enriched with either fish oil or sunflower oil.</p>
<p>Compliance: diet records of margarine consumption, LDL fatty acid
composition</p></td>
<td><p>47 subjects</p>
<p>Fish oil: 23 subjects</p>
<p>Sunflower oil: 24 subjects</p></td>
<td><p><u>TG:</u> ↓ significantly when compared to levels before FO
treatment. The decrease was not significantly different from SO
treatment group.</p>
<p><u>HDL:</u> ↑ in HDL in both groups.</p>
<p><u>LDL:</u> No significant difference between the two groups.</p>
<p><u>apo A:</u> ↑ in both groups but significantly in SO group.</p>
<p><u>apo B:</u> No significant difference between the two groups.</p>
<p><u>EPA, DPA and DHA levels:</u> ↑ significantly after treatment with
FO. EPA and DHA in LDL particles was increased causing a small but
significant increase in LDL total cholesterol (p=0.008), although not
significantly different form the SO group.</p>
<p>After fish oil treatment the lag time and maximum rate of LDL
oxidation was reduced when compared to before fish oil treatment and
with the sunflower oil group.</p>
<p>No significant difference was observed in the LDL size between the
two groups.</p></td>
<td><p><u>Conclusion:</u></p>
<p>The authors concluded that consumption of fish oil had no effect on
plasma lipids, LDL size and lipid composition and led to minor changes
in LDL content and oxidation resistance.</p>
<p><u>Comments:</u></p>
<p>Smoking did not affect any parameters examined.</p></td>
<td>1</td>
<td>Not reported</td>
</tr>
<tr class="odd">
<td><p>Suzukawa et al. 1995</p>
<p>Journal of Lipid Research</p>
<p>1995;36:473-484</p>
<p>[Australia]</p></td>
<td>To examine the effect of fish oil supplementation on plasma lipids
and lipoproteins and LDL oxidation in hypertensive patients</td>
<td>Randomized, double-blind, placebo controlled crossover study</td>
<td><p>6 week treatment</p>
<p>with either corn oil or fish oil, at which point patients crossed
over</p>
<p>4 week run in period</p>
<p>No washout period</p></td>
<td><p>2.9 g/d of EPA+ DHA (Omacor fish oil capsules)</p>
<p>1.64 g/d EPA</p>
<p>1.21 g/d DHA</p>
<p>4 g/d corn oil in control group</p>
<p>Compliance:</p>
<p>By interview</p></td>
<td>20 hypertensive patients (14 men and 6 women) managed with either
atenolol or antenolol + diuretic.</td>
<td><p><u>TG</u>: ↓ significantly (p &lt;0.01, -24% and –20%) compared
to baseline and corn oil respectively.</p>
<p><u>TC</u>: no significant change compared to baseline or placebo.</p>
<p><u>LDL</u>: 7.6% ↑ (p &lt;0.01) compared to corn oil.</p>
<p><u>HDL</u>: no significant change for total, HDL<sub>2</sub> or
HDL<sub>3</sub> compared to baseline or placebo.</p>
<p><u>apo B</u>: no significant effect.</p>
<p><u>lipid peroxide</u>: no significant effect compared to baseline or
placebo.</p>
<p><u>LDL oxidation</u>: significantly reduced both in copper oxidation
and macrophage-mediated oxidation compared to baseline.</p>
<p><u>LDL particle size</u>: ↑ significantly (p &lt; 0.01) compared to
baseline.</p></td>
<td><p><u>Conclusions</u>:</p>
<p>The authors conclude that, “dietary supplementation with n-3 fatty
acids increases the oxidizability of LDL which may counteract some of
the beneficial effects of fish oil which relate to the risk of
developing atherosclerosis.”</p>
<p><u>Comments</u>:</p>
<p>This is part of a larger study of 42 individuals that may already be
published elsewhere (reference not provided).</p>
<p>No washout period between treatment with fish oil and corn
oil.</p></td>
<td>1</td>
<td>No adverse effects reported, no drop outs reported.</td>
</tr>
<tr class="even">
<td><p>Swahn et al. 1998</p>
<p><em>Clin Drug Invest</em> 1998;15(6):473-482.</p>
<p>[Sweden]</p></td>
<td>To investigate whether an ethyl ester preparation of FO could
normalize raised plasma concentrations of TG, apo CIII on apo
B-containing particles found in patients w/ recent acute MI.</td>
<td><p>Randomized,</p>
<p>double-blind,</p>
<p>placebo-controlled trial.</p></td>
<td><p>12 weeks</p>
<p>following an 8-w dietary run-in period.</p></td>
<td><ol start="4" type="1">
<li><p>g/d EPA+DHA</p></li>
</ol>
<p>ethyl esters</p>
<p>(4 1-g capsules n-3/day provided by Norsk Hydro AS.)</p>
<p>Control: corn oil</p>
<p>Compliance:</p>
<p>Capsule counts, Serum FAs analysis</p></td>
<td><p>53 with a history of MI more than 3 mo. prior to enrollment and
TG ≥ 2 mmol/l &amp; TC ≤ 10 mmol/l.</p>
<p>@ 80% male</p>
<p>Test: 26</p>
<p>Control: 27</p></td>
<td><p><u>TG:</u> ↓ 23% vs. baseline (P&lt;0.001).</p>
<p><u>TC:</u> NS</p>
<p><u>VLDL-TG:</u> ↓ (P&lt;0.05) between group &amp; vs. baseline.</p>
<p><u>VLDL cholesterol:</u> ↓ (P&lt;0.05) between group &amp; vs.
baseline.</p>
<p><u>IDL-TG:</u> NS</p>
<p><u>IDL cholesterol:</u> NS</p>
<p><u>LDL-TG:</u> NS</p>
<p><u>LDL cholesterol:</u> ↓ (P&lt;0.001) between group &amp;
(P&lt;0.05) vs. baseline.</p>
<p><u>HDL cholesterol:</u> NS</p>
<p><u>HDL2 cholesterol:</u> NS</p>
<p><u>HDL3 cholesterol:</u> NS between group but ↑ vs. baseline
(P&lt;0.001)</p>
<p><u>HDL-TG:</u> NS between group but ↑ vs. baseline (P&lt;0.001)</p>
<p><u>Antithrombin III:</u> ↑ vs. baseline (P&lt;0.05) but NS between
groups</p>
<p><u>PAI-1 activity:</u> NS</p>
<p><u>PAI-1 antigen:</u> NS</p>
<p><u>t-PA antigen:</u> NS</p>
<p>Plasma apolipoprotein concentrations and lipoprotein particle
distributions are reported in the article but not in this
summary.</p></td>
<td><p><u>Conclusions:</u></p>
<p>N-3 FAs had moderate TG lowering effect and increased LDL slightly
while antithrombin III increased in patients with hypertriglyceridaemia
who had recently experienced a MI.</p>
<p><u>Comments:</u></p>
<p>Dietary intake assessed.</p>
<p>Almost all patients taking beta-blockers and aspirin at baseline and
remained so during study.</p></td>
<td>1</td>
<td>Adverse effects not reported in article.</td>
</tr>
<tr class="odd">
<td><p>Swails et al 1993</p>
<p><em>Nutrition</em> 1993;9:211-217</p>
<p>[U.S.]</p></td>
<td>To determine the effect of fish oil supplementation on platelet
aggregation in hospitalized patients.</td>
<td>Randomized</td>
<td>1 week</td>
<td><p>14.2 g/d fish oil. The fish oil is a part of Impact formula used
in enteral feeding (Impact group).</p>
<p>The usual care group received either Osmolite HN, Osmolite with
Propac, Vital HN or Isocal HN.</p>
<p>Compliance:</p>
<p>92 ± 8% compliance for Impact and 92 ± 10% for usual care group for
tube feeding.</p></td>
<td><p>16 patients (nine men, seven women) anticipated to receive
enteral nutrition were recruited form new England Deaconess and New
England Baptist Hospital.</p>
<p>Impact group: n=7 (4 men, 3 women)</p>
<p>Usual care group: n=9 (5 men, 4 women)</p>
<p>Of the 32 patients that were randomized 16 were excluded for the
following reasons: aspirin treatment, less than 7 day of dietary
treatment, missing platelet aggregation data.</p>
<p>The primary diagnosis for patients was head and/or neck cancer and
CAD.</p></td>
<td><u>Platelet aggregation:</u> NS difference between the groups. No
trend of reduced aggregability in the Impact group.</td>
<td><p>Conclusions:</p>
<p>The authors conclude that, “over the short-term, this dose of fish
oil does not alter platelet function in hospitalized surgical
patients”.</p>
<p>Comments:</p>
<p>Small sample size for each group.</p>
<p>Short duration.</p></td>
<td>2</td>
<td></td>
</tr>
<tr class="even">
<td><p>Szostak-Wegierek and Nowicka 1994</p>
<p><em>Pol Arch Med Wewn</em> 1994;92:176-183 (ABSTRACT,
foreign)</p></td>
<td>To determine the effects of fish oil on level and composition of
lipoprotein fractions in hypertriglyceridemic men.</td>
<td>Crossover study. Subjects were divided in group I and II and
received the treatments in reversed order.</td>
<td><p>3 weeks fish oil</p>
<p>3 weeks olive oil.</p>
<p>In 9 patients fish oil was given for 6 weeks</p></td>
<td><p>3.6 g/d EPA+DHA (12/d fish oil)</p>
<p>Olive oil</p></td>
<td></td>
<td><p>Results after olive oil were a control for fish oil.</p>
<p><u>TG:</u> ↓ in serum and VLDL TG was observed with fish oil.</p>
<p><u>TC:</u> Cholesterol in VLDL ↓ with fish oil.</p>
<p><u>LDL:</u> ↑ with fish oil.</p>
<p><u>HDL:</u> ↑ with fish oil.</p>
<p>No changes in serum lipid levels after 6 weeks with fish oil were
observed when compared to the results from 3 weeks.</p></td>
<td><p><u>Conclusion:</u></p>
<p>Decrease in TG with fish oil supplementation.</p>
<p>Comments:</p>
<p>Summarized from abstract.</p></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td><p>Tato, et. al.</p>
<p>1993</p>
<h2 id="clin-invest">Clin Invest</h2>
<p>1993;71:314-18</p>
<p>[Germany]</p></td>
<td>To examine the effects of fish oil concentrate on lipoproteins and
apolipoprotein in familial combined hyperlipidemic subjects.</td>
<td>Randomized, crossover, double-blind, placebo controlled study
design.</td>
<td><p>8 weeks</p>
<p>4-week washout period followed by 4 weeks tx with fish oil or
placebo, than crossover, followed by all subjects on higher dose of fish
oil for 4 weeks followed by all subjects on placebo for the last 4
weeks.</p></td>
<td><p>4.5 g/d EPA + DHA as ethyl esters preceded by 3.0 g/d EPA + DHA.
Doses given as capsules with fish oil concentrate, each capsule
containing 0.3 g EPA and 0.2 g DHA</p>
<p>Placebo control was olive oil (3.0 g/d or 4.5 g/d).</p>
<p>Compliance:</p>
<p>FAs analysis in serum phospholipids.</p></td>
<td><p>9 total, each diagnosed with familial combined hyperlipidemia
(FCH) by family investigation of at least 2 generations.</p>
<p>Lipid lowering drugs were discontinued 4 weeks before the
commencement of the treatments.</p></td>
<td><p><u>TG</u>: ↓ by 32.7% (p&gt;0.05) after 4 weeks tx with 3.0 g/d
n-3 FAs and by 43.9% (p&lt;0.05) after 4 weeks tx with 4.5 g/d. This ↓
was due to a marked ↓ in VLDL-TGs.</p>
<p><u>LDL</u>: No significant change in LDL in the overall group. LDL
and LDL apo B-100 ↑ dose-dependent in 4 pts. Mean LDL levels in this
group ↑ from 4.8 mmol/l after the first control period to 5.7 mmol/l
with 4.5 g/d fish oil tx). Mean LDL apo ↑ from 96 mg/dl after the first
control period to 110 mg/dl with 4.5 g/d fish oil tx). In the other 5
pts there was no effect of fish oil on LDL or LDL apo B-100.</p>
<p><u>HDL:</u> HDL, HDL apo A-I and apo A-II concentrations were not
affected significantly by fish oil tx. HDL/apo A-I + A-II ratio ↑
significantly by 19% with 3 g/d of fish oil treatment.</p>
<p><u>VLDL:</u> ↓ by 47.4% with 4.5 g/d of fish oil.</p>
<p>The mean EPA and DHA content in serum phospholipids ↑ after 3.0 g/d
and EPA ↑ further with 4.5 g/d dose. EPA ↑ dose-dependently in all pts
with fish oil administration.</p></td>
<td><p><u>Conclusions</u>:</p>
<p>The authors concluded that, “moderate doses of EPA and DHA are very
effective in lowering the frequently pathological VLDL concentrations of
FCH. A lowering of LDL from fish oil cannot be expected in FCH, but a
subgroup of patients may respond with an increase in LDL and LDL apo
B-100.”</p>
<p><u>Comments:</u></p>
<p>Diets were not assessed but the patients were asked to follow their
routine weight-maintaining diet and to avoid excessive alcohol
consumption.</p></td>
<td>1</td>
<td>No side effects such as belching or complains about taste or smell
were not reported.</td>
</tr>
<tr class="even">
<td><p>Terano et al. 1994</p>
<p><em>Jpn. J. Geriatrics</em> 1994. 31:596-603 (ABSTRACT; foreign)</p>
<p>[Japan]</p></td>
<td>To evaluate the effect of administration of low doses of fish oil
concentrate on platelet and RBC function in elderly subjects compared to
younger subjects</td>
<td>Parallel</td>
<td><p>4 weeks</p>
<p>(1 month)</p></td>
<td><p>0.25-0.5 g/day EPA from 3-6 capsules of fish oil concentrate</p>
<p>Compliance: plasma phospholipid FA analysis</p></td>
<td><p>36 elderly subjects with no signs or symptoms of cerebrovascular
disease; mean age of 78 years)</p>
<p>Controls were younger subjects (number and mean age not
reported)</p></td>
<td><p><u>Platelet aggregation to collagen</u>: ↓ significantly at all
fish oil doses and at the low and threshold dose of collagen (p&lt;0.05
or p&lt;0.01)</p>
<p><u>Platelet aggregation to ADP</u>: ↓ significantly at all fish oil
doses and ADP concentrations (p&lt;0.05 or p&lt;0.01)</p>
<p>There was a dose dependent ↑ in the plasma concentration of EPA in
both elderly and younger subjects; however, the degree of increase was
less in younger subjects receiving the same doses of EPA compared to
elderly subjects.</p></td>
<td><p><u>Conclusions</u>:</p>
<p>Authors concluded that, “low dose EPA administration can improve the
function of platelet and RBC to an anti-thrombotic state and would be
useful to prevent the occurrence of cerebrovascular diseases in elderly
subjects without any side effects.”</p>
<p><u>Comments</u>:</p>
<p>Summarized from abstract.</p>
<p>Data for younger subjects not quantitatively reported.</p></td>
<td></td>
<td>Not reported.</td>
</tr>
<tr class="odd">
<td><p>Tinker et al 1993</p>
<p><em>FASEB</em> 1993;7(3-4):A170</p></td>
<td>To determine the TG lowering effect of fish oil incorporated within
a medical food.</td>
<td><p>Randomized crossover design.</p>
<p>The subjects were randomized to either fish oil medical food or
vegetable oil for 6 weeks and then the treatments were switched for 6
weeks.</p></td>
<td><p>6 weeks on fish oil in medical food</p>
<p>6 weeks on vegetable oil (control)</p></td>
<td><p>5.1 g/d EPA+DHA</p>
<p>3.6 g/d EPA</p>
<p>1.5 g/d DHA</p>
<p>Vegetable oil</p>
<p>Compliance: Not reported</p></td>
<td>12 non-obese, non-diabetic subjects (8 males, 4 females) with high
TG and low HDL levels.</td>
<td><p><u>TG:</u> ↓ significantly (p&lt;0.0001) with fish oil compared
to control.</p>
<p><u>VLDL:</u> VLDL-TG and VLDL-cholesterol ↓ significantly
(p&lt;0.0001) with fish oil compared to control.<u><br />
</u></p></td>
<td><p><u>Conclusion:</u></p>
<p>The study demonstrates that, “consumption of fish oil in a medical
food decreases fasting plasma TG, VLDL-TG and VLDL-cholesterol in men
and women with hypertriglyceridemia and low HDL”.</p>
<p><u>Comments:</u></p>
<p>Summarized from abstract for presentation.</p>
<p>7-day diet records were collected.</p></td>
<td>2</td>
<td>Not reported</td>
</tr>
<tr class="even">
<td><p>Toft et al. 1995</p>
<p><em>Ann Intern Med</em> 1995;123:911-918</p>
<p>[Norway]</p></td>
<td>To study the effects of n-3 PUFA supplementation on glucose and
insulin kinetics, BP, serum lipids and the incorporation of FAs into
plasma phospholipids in subjects with untreated stable
hypertension.</td>
<td>Randomized, double-blind, placebo-controlled.</td>
<td>16 weeks</td>
<td><p>4 g/d EPA + DHA (Omacor, 4 g/d fish oil as ethyl esters) (fish
oil group)</p>
<p>Placebo group: 4 g/d corn oil.</p>
<p>Compliance:</p>
<p>Capsule count, plasma phospholipid FA analysis, and
interview.</p></td>
<td><p>78 subjects with untreated stable hypertension. 58 subjects who
had participated in a health survey and 26 subjects from primary health
care services were recruited.</p>
<p>Fish oil group: n=38</p>
<p>Placebo: n=40</p>
<p>Of the 84 subjects that were recruited 6 dropped out due to the
following reasons:</p>
<p>Fish oil group (n=4): personal reasons, development of angina
pectoris, increase in DBP.</p>
<p>Placebo group (n=2): personal reasons</p></td>
<td><p>The corn group had higher BMI, waist-to-hip ratio, fasting plasma
glucose and insulin compared to the fish oil group.</p>
<p>TG: NS ↓ with fish oil (9.2 ± 5.3%) and significant ↑ with corn oil
(12 ± 5.9%, p=0.04) and the difference between the groups was
significant (p=0.01).<br />
TC: NS changes with fish oil or corn oil.<br />
LDL: NS ↓ with fish oil (-0.01 ± 0.10 mmol/l, p=0.94) and corn oil
(-0.13 ± 0.11 mmol/l, p=0.22)</p>
<p>HDL: NS change with fish oil, but ↓ significantly with corn oil (7.4
± 3%, p=0.03) and the difference between the groups was significant
(p=0.04).</p>
<p>VLDL: NS ↓ with fish oil (8.9 ± 5.1%) and significant ↑ with corn oil
(12.1 ± 4.5%, p=0.04) and the difference between the groups was
significant (p=0.01).</p>
<p>apo A1: NS change with fish or corn oil compared to baseline.<br />
apo B: NS change with fish or corn oil compared to baseline.</p>
<p><u>Fasting glucose:</u> NS change with fish (+0.1 ± 0.1 mmol/l) and
corn oil (+0.0 ± 0.1 mmol/l) compared to baseline.</p>
<p><u>Fasting insulin:</u> NS change with fish (+7 ± 7 mmol/l) and corn
oil (+9 ± 6 mmol/l) compared to baseline.</p>
<p><u>Glycated hemoglobin:</u> ↑ slightly with fish oil (0.3 ± 0.1
mmol/l, p=0.001) and with corn oil (0.2 ± 0.1 mmol/l, p=0.06) compared
to baseline. No significant difference between the groups.</p>
<p><u>Plasma C-peptide:</u> NS change with fish and corn oil.</p>
<p><u>Insulin sensitivity:</u> NS ↓ in the fish oil group, but
significant ↓ in the men (p=0.02) compared to women receiving fish oil.
The ↓ in men was significantly different from the men receiving corn oil
(p=0.03) and the differences persisted after adjusting for changes in
body weight. Changes in insulin sensitivity between glucose-intolerant
and normoglycemic individuals receiving fish oil were similar.</p>
<p><u>BP:</u> Significantly ↓ in the fish oil group compared to the corn
oil group (p=0.04). No changes in the corn oil group. The effect of fish
oil persisted after adjusting for age, sex, BMI, waist-to-hip ratio and
change in body weight. Individuals with lower baseline plasma
phospholipid n-3 PUFA showed greater changes with fish oil in BP.</p>
<p><u>SBP:</u> Significant ↓ with fish oil (-4.1 ± 1.4 mm Hg, p=0.004)
compared to baseline.</p>
<p><u>DBP:</u> Significant ↓ with fish oil (-3.3 ± 0.8 mm Hg, p=0.0008)
compared to baseline.</p>
<p>Mean arterial pressure: Significant ↓ with fish oil (-3.6 ± 0.9 mm
Hg, p=0.0003) compared to baseline.</p>
<p>First phase insulin release did not change after the treatment.
Second phase insulin release increased significantly in the fish oil
(p=0.01) and corn oil (p=0.04) group but the difference between the
groups was not significant. This increase persisted even after adjusting
for changes in body weight, waist-to-hip ration TG, serum FA, insulin
sensitivity and BP.</p>
<p>The second-phase molar ratio of C-peptide and insulin changed
significantly with fish oil (p=0.002) and corn oil (p=0.02) and the
changes were similar in both the groups.</p>
<p>NS change with fish or corn oil compared to baseline in plasma
non-esterified free FAs.</p>
<p>Plasma phospholipid EPA and DHA ↑ significantly with fish oil (both
p=0.0001) and the n-3:n-6 ratio also ↑ significantly with fish oil
(p=0.0001).</p></td>
<td><p>Conclusions:</p>
<p>The authors concluded that, “dietary supplementation with n-3 PUFAs,
4 g/d, reduces BP and TG in hypertensive persons without adversely
altering glucose metabolism”.</p>
<p>Comments:</p>
<p>Diets were not assessed but the subjects were asked not to change
their diets or lifestyle during the duration of the study.</p></td>
<td>1</td>
<td>6 (15.8%) subjects in the fish oil group and 3 (7.5%) subjects in
the placebo group reported of mild abdominal discomfort. No serious side
effects were observed.</td>
</tr>
<tr class="odd">
<td><p>Toft et al. 1997</p>
<p><em>Arterioscler. Thromb. Vasc. Biol.</em> 1997. 17:814-819</p>
<p>[Norway]</p></td>
<td>To examine the influence of dietary fish oil supplementation on
fibrnolytic function in persons with untreated essential
hypertension</td>
<td>Randomized, double-blind, controlled</td>
<td>16 weeks</td>
<td><p>4 g/day EPA + DHA as ethyl esters (Omacor)</p>
<p>Control: 4 g/day corn oil with 56% linoleic and 26% oleic acid</p>
<p>Compliance: capsule count</p></td>
<td><p>78 hypertensive persons; mean age 53 years; 50 male, 28
female</p>
<p>Subjects taking cod liver oil supplements discontinued use 12 months
before the study</p>
<p>n-3 FA: n=38</p>
<p>Control: n=40</p>
<p>4 withdrawals in fish group due to angina pectoris (1), initiation of
hypertensive treatment (1), and personal reasons (2). 2 withdrawals in
control group due to personal reasons.</p></td>
<td><p><u>TG</u>: NS ↓ (p=0.11) (NS ↑ in control group (p=0.04);
difference between groups significant (p=0.01))</p>
<p><u>PAI-1</u>: NS ↑ (p=0.15) (significant ↑ in control group,
p=0.009)</p>
<p><u>tPA activity</u>: NS ↓ (p=0.24) (significant ↓ in control group,
p=0.0005)</p>
<p><u>Fibrinogen level</u>: ↑ (p=0.0001) (↑ also in control group,
p=0.002)</p>
<p><u>Coagulation factor VII</u>: NS change (both groups)</p>
<p><u>Platelet count</u>: NS change (both groups)</p>
<p>Plasma phospholipid content of n-3 PUFAs ↑ (p=0.0001); there was no
change in n-6 PUFAs (control group: no change in n-3 PUFAs; increase in
n-6 PUFAs).</p></td>
<td><p><u>Conclusions</u>:</p>
<p>“Intervention with fish oil does not adversely affect the
fibrinolytic function in hypertensive subjects. As no change was
observed in glucose homeostasis and a reduction in triglycerides was
demonstrated, dietary supplementation with fish oil may safely be
recommended in essential hypertension.”</p>
<p><u>Comments</u>:</p>
<p>Diet not assessed, but subjects encouraged not to change their diet
or lifestyle while on the study.</p></td>
<td>2</td>
<td>No change in glucose homeostasis was observed. There was a small
increase in proinsulin that was non- significant after adjusting for
body mass index and weight gain.</td>
</tr>
<tr class="even">
<td><p>Tomer et al. 1995</p>
<p><em>Blood</em> 1995. 86:299a (ABSTRACT)</p>
<p>[U.S.]</p></td>
<td>To investigate the effect of n-3 FA on prothrombic activity
associated with steady-state disease</td>
<td>Randomized, double-blind, parallel</td>
<td>6 months</td>
<td><p>0.25 g/kg/day n-3 FA</p>
<p>Compliance: not reported.</p></td>
<td><p>13 subjects with sickle cell disease and frequent painful
episodes</p>
<p>Controls: 10 normal African American subjects</p></td>
<td><p><u>Platelet procoagulant activity</u>: ↑ compared to controls (as
measured by increased binding of certain platelet receptors)</p>
<p><u>RBC procoagulant activity</u>: ↑ compared to controls (as measured
by increased binding of certain receptors)</p>
<p><u>Circulating platelet release products (Factor 4 and
β-thromboglobulin)</u>: ↑ significantly compared to controls</p>
<p><u>Thrombin-antithrombin complexes</u>: ↑ significantly compared to
controls</p>
<p><u>D-dimers</u>: ↑ significantly compared to controls</p>
<p><u>Prothrombin fragment</u>: ↑ significantly compared to controls</p>
<p><u>Plasmin-antiplasmin complexes</u>: ↑ significantly compared to
controls</p></td>
<td><p><u>Conclusions</u>:</p>
<p>Authors concluded that, “these results show that steady-state sickle
cell disease patients exhibit evidence of thrombotic predisposition that
is attentuated by dietary supplementation with n-3 fatty acids.”</p>
<p><u>Comments</u>:</p>
<p>Summarized from abstract.</p>
<p>Small sample size.</p></td>
<td></td>
<td>Not reported.</td>
</tr>
<tr class="odd">
<td><p>Tremoli et al. 1994</p>
<p><em>British Journal of Clinical Pharmacology</em> 1994;37(1):112P</p>
<p>[Italy]</p></td>
<td>To determine 1) if low dose of n-3 FAs administered for relatively
long period of time may have beneficial effects on plasma lipids,
platelet function and thromboxane A<sub>2</sub> (TXA<sub>2</sub>)
biosynthesis. 2) To determine if short term (6 weeks) treatment with 6
g/d of n-3 FAs followed by 12 week treatment with 3 g/d results in more
pronounced effects on the above mentioned variables.</td>
<td><p>Clinical trial</p>
<p>The subjects were given either 3 or 6 g/d of n-3 for 6 weeks and then
all subjects were given 3 g/d of n-3 for 12 weeks.</p></td>
<td><p>18 weeks</p>
<p>6 weeks on either 3 or 6 g/d of n-3 FAs</p>
<p>12 weeks on 3 g/d of n-3 FAs.</p></td>
<td><p>4.56 g/d of EPA+DHA (1 g capsules contain 480 mg EPA and 280 mg
DHA)</p>
<p>6 g/d of n-3 FAs (Treatment B)</p>
<p>2.28 g/d EPA+DHA + 3 g/d olive oil ((Treatment A)</p>
<p>Compliance: Not measured</p></td>
<td><p>16 healthy subjects</p>
<p>3 g/d of n-3 FAs: 8 subjects</p>
<p>6 g/d of n-3 FAs: 8 subjects</p>
<p>All subjects on 3 g/d of n-3 FAs for additional 12 weeks.</p></td>
<td><p><u>TG:</u> A dose-dependent ↓ in plasma TG after 6 weeks on 3 g/d
(p&lt;0.05) and 6 g/d (p&lt;0.01) of n-3 was observed, which was related
to a concomitant increase in plasma EPA. levels. The TG ↓ (p&lt;0.02)
after 18 weeks in the group receiving 6 g/d of n-3 for first 6
weeks.</p>
<p>Platelet function: No changes</p>
<p><u>TXA<sub>2</sub> biosynthesis:</u> No changes</p>
<p><u>AC<sub>50</sub> for collagen:</u> ↑ in both 3 g/d and 6/d of n-3
FAs groups after 18 weeks of treatment (p&lt;0.01).</p>
<p><u>11-dehydro-TXB<sub>2</sub> in urine:</u> ↓ in both 3 g/d and 6/d
of n-3 FAs groups after 18 weeks of treatment (p&lt;0.02).</p>
<p>Platelet phospholipids increased in a dose-dependent manner.</p>
<p>The subjects were followed for 24 weeks after the treatments.
TXA<sub>2</sub> biosynthesis and plasma lipids returned to baseline
levels within 4 weeks after treatment. Platelet aggregation remained
inhibited for 14 weeks and returned to baseline after 24 weeks post
treatment. Plasma EPA and platelet phospholipid EPA levels returned to
baseline levels during the 24 weeks post treatment follow up period,
whereas the DHA levels remained high during the overall follow up
period.</p></td>
<td><p>Conclusion:</p>
<p>The data indicate that, “prolonged treatment with relatively low
doses of n-3 FAs may exert beneficial effects on plasma and platelets,
that may be somewhat enhanced by a short term ‘loading treatment’.</p>
<p>Comments:</p>
<p>Diets not assessed.</p>
<p>Study is not detailed.</p></td>
<td>3</td>
<td></td>
</tr>
<tr class="even">
<td><p>Tremoli et al. 1995</p>
<p><em>Am. J. Clin. Nutr.</em> 1995. 61:607-613</p>
<p>[Italy]</p></td>
<td>To evaluate whether low dose supplementation of n-3 FA for a
prolonged time would produce beneficial effects on plasma lipids,
platelet function, and thromboxane biosynthesis, or whether short-term
loading followed by 12 weeks of treatment would result in more
pronounced effects</td>
<td>Randomized, double-blind, parallel</td>
<td><p>18 weeks</p>
<p>(Group A)</p>
<p>18 weeks,</p>
<p>6 weeks at high dose followed by 12 weeks at the low dose (Group
B)</p>
<p>Subjects followed for an additional 24 weeks</p></td>
<td><p>4.5 g EPA + DHA (from 6 g n-3 FA capsules (Esapent) for 6 weeks
followed by 2.25 g EPA + DHA (from 3 g n-3 FA capsules) for 12 weeks
(Group B)</p>
<p>2.25 g EPA + DHA (from 3 g n-3 FA capsules (Esapent); each 1-g
capsule contained 430 mg EPA and 320 mg DHA ) plus 3 g/day olive oil
(Group A)</p></td>
<td><p>16 healthy volunteers</p>
<p>8 male/8 female</p>
<p>Group A: n=8</p>
<p>Group B: n=8</p></td>
<td><p><u>TC</u>: no change in group A at 6 weeks; moderately ↓ (-8%) at
6 weeks in group B; NS ↓ in both groups at 18 weeks</p>
<p><u>Total TG</u>: ↓ in group A (p&lt;0.05) and group B (p&lt;0.01) at
6 weeks; ↓ in both groups at 18 weeks, (p&lt;0.01 for group B only);
returned to baseline values within 4 weeks after end of treatment.</p>
<p><u>VLDL-TG</u>: ↓ in both groups at 6 weeks (p&lt;0.01); ↓ in both
groups at 18 weeks, (p&lt;0.05 for group B only); returned to base-line
value within 4 weeks after study end.</p>
<p><u>LDL-TG</u>: ↓ in group B at 6 and 18 weeks (p&lt;0.05); returned
to base-line value 4 weeks after end of treatment.</p>
<p><u>HDL-TG</u>: ↓ in group B at 6 and 18 weeks; levels remained ↓ 4
weeks after end of treatment (p&lt;0.01).</p>
<p>Dose dependent ↑ in plasma and platelet EPA and DHA concentrations
occurred after 6 weeks of supplementation.</p>
<p><u>Platelet aggregation to collagen</u>: NS at 6 weeks for both
groups; ↑ at 12 and 18 weeks compared to baseline values (p&lt;0.001).
Levels remained ↑ for 14 weeks after treatment ended.</p>
<p><u>Platelet thromboxane B<sub>2</sub></u>: NS at 6 weeks for both
groups; ↓ at 12 and 18 weeks; significant only for group B at 12 weeks
(p&lt;0.05); levels returned to baseline within 4 weeks after treatment
ended.</p>
<p><u>Urinary excretion of thromboxane metabolites</u>: NS at 6 weeks; ↓
after 12 weeks<br />
(-15% for group A and -19% for group B, p&lt;0.001) compared to baseline
values; ↓ maintained after 18 weeks and returned to baseline 4 weeks
after treatment ended.</p></td>
<td><p><u>Conclusions</u>:</p>
<p>Authors concluded that, 1) “a temporal dissociation between the
effects of n-3 FA on plasma triglycerides and on platelet function
exists; 2) the combination of a “loading” treatment with a relatively
long-term one results in more pronounced effects on both plasma and
platelet variables;” and 3) “n-3 fatty acids may influence platelet
aggregation for relatively long periods (&gt;14 weeks).”</p>
<p><u>Comments</u>:</p>
<p>Small sample size.</p>
<p>Dietary habits not evaluated; however, subjects asked to maintain
normal dietary habits and to refrain from alcoholic beverages and foods
rich in n-3 FA such as salmon, herring, and tuna.</p></td>
<td>2</td>
<td>No changes in body weight or major hematological variables other
than lipids were observed during the study.</td>
</tr>
<tr class="odd">
<td><p>Tsai and Lu 1997</p>
<p><em>J Forums Med Assoc</em> 1997;96(9):718-726</p>
<p>[Taiwan]</p></td>
<td>To compare the effects of dietary n-3 and n-6 FAs on plasma
lipoprotein fractions and to determine if diets rich in n-3 FAs render
human LDL more susceptible to oxidative modification.</td>
<td><p>Randomized trial.</p>
<p>Subjects were randomly assigned to two groups of 8 subjects. One
group received low dose of cholesterol (low cholesterol group) and the
other received high dose of cholesterol (high cholesterol group). Both
groups were given soybean enriched diet for 3 weeks followed by fish oil
rich diet for 3 weeks.</p></td>
<td><p>3 weeks on n-3 FAs</p>
<p>3 weeks on soybean oil</p></td>
<td><p>8.8 g/d EPA+DHA</p>
<p>7.2 g/d EPA</p>
<p>1.6 g/d DHA (20 g/d fish oil capsules) (n-3 group)</p>
<p>20 g/d soybean oil (n-6 group)</p>
<p>Compliance: Not measured</p></td>
<td><p>16 healthy normolipidemic male subjects were recruited form the
medical students population of National Taiwan University.</p>
<p>8 subjects in each cholesterol groups.</p></td>
<td><p><u>TG:</u> ↓ significantly (p&lt;0.05) in both groups with n-3
supplementation. No effect of n-6 FAs in either groups.</p>
<p>TC: ↓ significantly (p&lt;0.05) in both groups with n-3
supplementation.</p>
<p><u>LDL:</u> No effect of n-3 supplementation.</p>
<p><u>HDL:</u> No effect of n-3 supplementation.</p>
<p><u>VLDL:</u> Both VLDL and VLDL-TG ↓ significantly (p&lt;0.05) in
both groups with n-3 supplementation. No effect of n-6 FAs on VLDL-TG in
either groups.</p>
<p>With n-3 supplementation the lag time of conjugated diene formation
for LDL was significantly shorter than for soybean oil. Significant ↑ in
LDL-TBARS concentrations (in vitro oxidation) with n-3 supplementation
in both groups. The mobility of oxidized LDL was higher with n-3 than
with n-6 supplementation. Small LDL particles on n-3 diet.</p>
<p>EPA concentration increased in both groups with n-3 supplementation.
The LDL fatty acid composition did not differ between the 2 groups on
either n-3 or n-6 diet.</p>
<p>No differences in plasma lipid and lipoprotein concentrations between
the low and high cholesterol groups throughout the study. TC ↓ in low
cholesterol group and LDL ↑ in high cholesterol group after 1 week of
diet modification.</p></td>
<td><p>Conclusion:</p>
<p>The authors conclude that, “the n-3 PUFAs of dietary fish oil lowered
plasma concentrations of total and VLDL cholesterol and TG. However,
these FAs seem to result in LDL particles, which are more susceptible to
oxidative modification. Because oxidatively modified LDL may promote
atherogenesis, the beneficial effect of fish oil on prevention of
coronary heart disease is questionable and further investigations are
necessary before consumption of fish oil can be recommended”.</p>
<p><u>Comments:</u></p>
<p>The subjects were asked to continue their regular lifestyle and
physical activity.</p>
<p>The investigators provided the meals and the subjects consumed
fish-free meals for 6 weeks. The nutrient composition was measured using
database for Taiwan food composition.</p>
<p>The subjects were recruited from 1 population group (university
students)</p></td>
<td>2</td>
<td></td>
</tr>
<tr class="even">
<td><p>Turini et al. 1994</p>
<p><em>Am. J. Clin. Nutr.</em> 1994. 60:717-724</p>
<p>[Canada]</p></td>
<td>To compare the effect of dietary supplementation with a liquid
formula containing fish oil or vegetable oil on platelet aggregation,
ethanolamine-containing lysophospholipid generation in stimulated
platelets, and leukotriene production in stimulated neutrophils</td>
<td>Randomized, parallel, controlled</td>
<td>6 weeks</td>
<td><p>4.5 g/day EPA + DHA from 8 oz bottled liquid formula of fish oil
(sardine oil)</p>
<p>Control: 13.8 g/day vegetable oil (mixture of high oleic acid (6.3 g)
safflower and soy oil)</p>
<p>Compliance: phospholipid FA analysis</p></td>
<td><p>20 healthy male subjects</p>
<p>average age: 26 years for controls; 27 years for fish oil
subjects</p>
<p>Fish oil: n=10</p>
<p>Control: n=10</p></td>
<td><p><u>TC</u>: NS change</p>
<p><u>HDL</u>: NS change</p>
<p><u>TG</u>: NS change</p>
<p><u>Platelet aggregation to collagen</u>: ↓ significantly in fish oil
and control groups compared to baseline values (p&lt;0.05)</p>
<p><u>Ethanolamine-containing lysophospholipid induced by stimulated
platelets</u>: NS change between pre- and post-treatment values</p>
<p><u>Ethanolamine-containing lysophospholipid induced by platelets
stimulated by collagen or U46619 ± BW755C</u>: ↑ significantly in both
the fish oil and control groups compared to unstimulated values
(p&lt;0.001)</p>
<p><u>Leukotriene B<sub>4</sub> production by stimulated
neutrophils</u>: ↓ significantly in fish oil group (-41%)</p>
<p><u>5-Hydroxyeicosatetraenoic acid (HETE) production by stimulated
neutrophils</u>: ↓ significantly in fish oil group (-30%)</p>
<p>Fish oil supplementation also resulted in increased concentrations of
leukotriene B<sub>5</sub> and 5-hydroxyeicosapentaenoic acid (HEPE);
concentrations of these products were not detected before treatment and
vegetable oil had no effect on their production.</p>
<p>Total phospholipid FA concentrations increased significantly with
fish oil supplementation compared to vegetable oil. EPA increased 1550%
above controls; DHA increased 110% above controls. FA compositions of
phosphatidylcholine, phosphatidylethanolamine, and
plasmenylenthanolamine increased after fish oil consumption. All had
higher levels of DHA and EPA; plasmenylenthanolamine had a more
pronounced EPA enrichment than the others.</p></td>
<td><p><u>Conclusions</u>:</p>
<p>Authors concluded that, “in view of evidence for the involvement of
neutrohil-derived LTB<sub>4</sub> in atherosclerosis/ thrombosis and
cell injury in early myocardial ischemia, formulated nutritional
products enriched in ω-3 fatty acids may be of value in the prevention
and treatment of cardiovascular risk factors and disease (independent of
the lowering of blood cholesterol).”</p>
<p><u>Comments</u>:</p>
<p>Small sample size.</p>
<p>Diet was not assessed; however, subjects asked to maintain their
usual dietary habits.</p>
<p>Subjects were asked to abstain from taking any medications from 2
weeks before study until the end the 6-week study period.</p></td>
<td>2</td>
<td>Not reported.</td>
</tr>
<tr class="odd">
<td><p>Uauy et al. 1994</p>
<p><em>J. Pediatr.</em> 124:612-620</p>
<p>[U.S.]</p></td>
<td>To evaluate the safety of n-3 FA supplementation with soy and marine
oils in pre-term infant formulas</td>
<td>Randomized, controlled</td>
<td><p>57 weeks</p>
<p>(follow-up from 40 to 57 weeks)</p></td>
<td><p>Not quantified.</p>
<p>Infants were fed human milk (not randomized) or randomized to receive
infant formula with varying amounts of n-3 FA:</p>
<p>Formula A: corn oil (24.2% linoleic acid and 0.5% α-linolenic
acid).</p>
<p>Formula B: soy oil (20.8% linoleic acid and 2.7% α-linolenic
acid).</p>
<p>Formula C: soy oil + marine oil (0.3% DHA -similar to amount in human
milk)</p></td>
<td><p>52 infants with low birth weights (between 1,000-1,500 g) and no
major neonatal morbidity by the tenth day of life.</p>
<p>Human milk: n=9</p>
<p>Formula A: n=13</p>
<p>Formula B: n=16</p>
<p>Formula: C: n=14</p>
<p>Reference group for infants fed human milk were birth-weight matched
infants fed mother’s milk since birth.</p>
<p>18 infants discharged early were not included in study.</p></td>
<td><p><u>Bleeding time</u>: ↑ in infants fed formula C at 37 weeks, but
values did not exceed the normal upper limit (7 minutes); increased
+28.7% and +28% compared to corn oil and soil oil, respectively
(p&lt;0.05).</p>
<p><u>Platelet counts</u>: NS change; all were within normal limits.</p>
<p><u>Rotational membrane fluidity of intact RBCs</u>: NS changes in any
group.</p></td>
<td><p><u>Conclusions</u>:</p>
<p>Dietary supplementation with n-3 FA does not induce adverse effects
on growth, clotting function, erythrocyte membrane fluidity, or vitamin
A and E levels in healthy infants with very low birth weights.</p>
<p><u>Comments</u>:</p>
<p>Infants fed human milk were not randomized.</p></td>
<td>2</td>
<td>No evidence of adverse effects on growth were observed; all group
grew well</td>
</tr>
<tr class="even">
<td><p>Valagussa et al. 1999</p>
<p><em>Lancet</em> 1999;354:447-55</p>
<p>[Italy]</p></td>
<td>To study the independent and combined effects of n-3 PUFAs and
vitamin E on morbidity and mortality after MI.</td>
<td><p>Randomized, control trial. Open label design.</p>
<p>Multicenter (172)</p></td>
<td>189 weeks (3.5 years).</td>
<td><p>0.850-0.882 g/d (850-882 mg) of EPA + DHA as ethyl esters (n-3
group) (n-3 PUFAs group)</p>
<p>300 mg/d vitamin E (vitamin E group)</p>
<p>n-3 + vitamin E group</p>
<p>Control group</p>
<p>Compliance: capsule counts</p></td>
<td><p>11324 subjects.</p>
<p>Patients surviving recent (≤ 3 months) MI were recruited from October
1993 through September 1995 from 172 centers (cardiology department and
rehabilitation center).</p>
<p>n-3 group: 2836 patients</p>
<p>vitamin E group: 2830 patients</p>
<p>n-3 + vit E group: 2830 patients</p>
<p>control group: 2828 patients</p></td>
<td><p><u>TG:</u> Small but significant decrease in TG with n-3
treatment.</p>
<p><u>TC:</u> NS change with n-3 or any other treatment.</p>
<p><u>LDL:</u> NS change with n-3 or any other treatment.</p>
<p><u>HDL:</u> NS change with n-3 or any other treatment.</p>
<p>Glycaemia: NS change with n-3 or any other treatment.</p>
<p><u>Fibrinogen:</u> NS change with n-3 or any other treatment.</p>
<p>The 10% relative decrease in risk for combined primary endpoint of
death, non-fatal MI and non-fatal stroke was significant (95% CI 1-18,
p=0.048) with two-way factorial analysis. The relative decrease in risk
for the combined end point was 15% (CI 2-26, p=0.023) and for
cardiovascular death, non-fatal MI and no-fatal stroke was 20% (CI 5-32,
p=0.008) with four-way factorial analysis.</p>
<p>Benefit was attributed to a decrease in the risk of death (14% [CI
3-24] two-way, 20% [CI 6-33] four-way) and cardiovascular death (17% [CI
3-29] two-way, 30% [CI 13-44] four-way).</p>
<p>The effect of the combined treatment with n-3 PUFAs + vitamin E was
similar to that for n-3 PUFAs for the primary endpoint (14% [CI 1-26])
and for fatal events (20% [CI 5-33]).</p>
<p>No difference across the treatment was observed for non-fatal
cardiovascular events.</p>
<p>The effects of vitamin E treatment were similar to the
control.</p></td>
<td><p><u>Conclusion:</u></p>
<p>The authors conclude that, “long-term n-3 PUFAs (1g/d)
supplementation was beneficial for death, and for combined death,
non-fatal MI and stroke in patients with MI and have Mediterranean
dietary habits”.</p>
<p><u>Comments:</u></p>
<p>Conducted intent-to-treat analysis.</p>
<p>Age limits were not defined.</p></td>
<td>1</td>
<td>Patients receiving n-3 PUFAs and vitamin E reported gastrointestinal
disturbances (4.9 % n-3, 2.9% vitamin E) and nausea (1.4 % n-3, 0.4%
vitamin E). 3.8% of the n-3 patients and 2.1% of the vitamin E patients
discontinued the treatment because of the side effects.</td>
</tr>
<tr class="odd">
<td><p>Vandongen et al. 1993</p>
<p><em>Hypertension</em> 1993;22:371-9</p>
<p>[Australia]</p></td>
<td>To determine if the effects on BP and heart rate (HR) were dependent
on the form of n-3 fats, i.e., as fish oil or fish, and on the presence
of a low or high saturated fat diet.</td>
<td>Randomized, placebo-controlled trial.</td>
<td>12 weeks with an initial 1-week baseline period.</td>
<td><p>4.3 g/d EPA + DHA from fish oil (Lipitac 12 capsules, ≈2.6 g/d
EPA and ≈1.7 g/d DHA)</p>
<p>2.16 g/d EPA+DHA from fish oil (Lipitac 6 capsules, ≈1.3 g/d EPA and
≈0.86 g/d DHA)</p>
<p>3.2 – 4.1 g/d of n-3 FAs from fish.</p>
<p>1.3 g/d EPA approximate amount from fish oil (6 capsules) or fish</p>
<p>Placebo contained palm, olive and sunflower oil.</p>
<p>7 treatments were assigned</p>
<p>Group 1: 40% fat diet + placebo</p>
<p>Group 2: 40% fat diet + fatty fish (1 fish meal) + placebo</p>
<p>Group 3: 40% fat diet + 6 fish oil capsules (1 g each)</p>
<p>Group 4: 40% fat diet + fatty fish (1 fish meal) + 6 fish oil
capsules</p>
<p>Group 5: 40% fat diet + 12 fish oil capsules</p>
<p>Group 6: 30% fat diet alone + placebo</p>
<p>Group 7: 30% fat diet + fatty fish (1 fish meal) + placebo</p>
<p>Compliance: diet records, platelet phospholipid fatty acid
analyses.</p></td>
<td><p>120 healthy nonsmoking males were recruited by media publicity.
The entry criteria was BMI of &lt;30 kg/m<sup>3</sup>, SBP 130-159 mm
Hg, DBP 80-90 mm Hg, serum TC of 5.2-6.9 mmol/l.</p>
<p>Group 1: n=18</p>
<p>Group 2: n=17</p>
<p>Group 3: n=17</p>
<p>Group 4: n=17</p>
<p>Group 5: n=16</p>
<p>Group 6: n=17</p>
<p>Group 7: n=18</p>
<p>Of the 138 subjects that were recruited, 18 subjects did not complete
the study either because they could not comply with the dietary
requirements or were unable to maintain the laboratory visits.</p></td>
<td><p>BP: NS group effect on supine or erect BP. Mean supine and erect
BP fall was ↑ in the 40% fat, fish or fish oil group vs. control and the
30% fat groups. In group 7, a greater percentage of subjects experienced
a ↓ in BP during the trial. Significant positive correlation between ↓
in platelet n-6 FAs and the changes in supine and erect SBP and supine
and erect DBP, Weak negative correlation between the ↑ in n-3 FAs and
supine SBP and DBP and reached significance for erect SBP (r=-0.16,
p=0.44) and DBP (r=-0.16, p=0.38). Significant and independent effect of
n-3/n-6 ratio factor on the change in supine and erect SBP and DBP.
Plasma glucose had an independent effect on change in erect
(r<sup>2</sup>=0.2179, p=0.110) and supine (r<sup>2</sup>=0.2243,
p=0.967) SBP.</p>
<p>HR: Supine HR ↓ in fish and fish oil groups but ↑ significantly
(p&lt;0.01) in the two control groups. Similar effects of fish, fish oil
and control were seen on erect HR but the difference between the
controls and treatments reached borderline significance (p=0.06). The
change in HR correlated with the change in supine SBP (r=0.83,
p&lt;0.0001), erect SBP (r=0.53, p&lt;0.0001), supine DBP (r=0.99,
p&lt;0.0001) and erect DBP (r=0.55, p&lt;0.0001). Positive correlation
between the decrease in n-6 FAs and fall in supine and erect HR.
Negative correlation between the increase in n-3 FAs and fall in supine
(r<sup>2</sup>=0.513, p=0.014) and erect (r<sup>2</sup>=0.0702, p=0.021)
HR.<br />
Glucose: No treatment effect on blood glucose or on glucose:insulin
ratio.</p>
<p>Insulin: No treatment effect.</p>
<p>Platelet phospholipid n-3 FAs: Significant group effect
(p&lt;0.00001), reflecting the incorporation of n-3 FAs and removal of
n-6 FAs in groups consuming fish or fish oil.</p>
<p>Urinary Na excretion ↓, but urinary K excretion was variable with ↑
excretion in the 30% fat control group.</p></td>
<td><p>Conclusion:</p>
<p>The authors summary, “although this study did not show a significant
dietary group effect of n-3 FAs, either as fish or fish oil or in the
presence of a low or high saturated fat diet, on BP and HR in men with
high normal BP, it has demonstrated a significant relation between the
fall in BP and the changes in platelet phospholipid n-3 and n-6 FA
incorporation when the data from n-3 groups and control groups were
combined…. It is suggested that similar changes in phospholipid FA
composition at the vascular and myocardial levels may provide a
mechanism underlying these observations”.</p>
<p>Comments:</p>
<p>The subjects completed seven 24 hr diet records during the study. The
subjects were provided dietary counseling and recipes by dietician.</p>
<p>The subjects were asked to reduce Na intake.</p>
<p>Diets were designed so that the total fat intake of groups consuming
fish and fish oil or either was similar to the control groups.</p>
<p>Combined fish meal and purified fish oil treatment. Fish was provided
to the subjects.</p></td>
<td>1</td>
<td>No adverse effects were reported. Some subjects had difficulty in
consuming the recommended intake of canned salmon hence the amount was
reduced for these individuals.</td>
</tr>
<tr class="even">
<td><p>Ventura et al. 1993</p>
<h2 id="circulation-1">Circulation </h2>
<p>1993;88(2):281-285</p>
<p>[U.S.]</p></td>
<td>To “evaluate the antihypertensive effects of oral supplementation
with n-3 fatty acids in cyclosporine-treated cardiac transplant
recipients”</td>
<td>Randomized double-blind controlled trial</td>
<td>12 weeks</td>
<td><p>3 g/d of EPA+DHA (6 1g capsules)</p>
<p>corn oil group: 6 g/d of corn oil</p>
<p>Compliance:</p>
<p>Not reported</p></td>
<td><p>16 hypertensive orthotopic cardiac transplant recipients (14
male, 2 female)</p>
<p>All patients were on a calcium-channel blocking agent, an
angiotensin-converting enzyme inhibitor or both. All patients also were
receiving immunosuppressive therapy w/ cyclosporine, prednisone and
azathioprine.</p>
<p>Treatment group: 10 patients</p>
<p>Corn oil group: 6 patients</p>
<p>4 patients in the placebo group did not finish the study, two because
of acute allograft rejection and two because of an intolerance to n-6
fatty acids.</p></td>
<td><p><u>TG:</u> NS differences compared to placebo.</p>
<p><u>TC:</u> NS differences compared to placebo.</p>
<p><u>LDL:</u> NS differences compared to placebo.</p>
<p><u>HDL:</u> NS differences compared to placebo.</p>
<p><u>Mean arterial Pressure:</u> 15% decrease (120 ± 7 vs. 102 ± 7 mm
Hg, p&lt;0.0001) compared to both baseline and placebo.</p>
<p><u>Systemic vascular resistance</u>: 32% reduction (2107 ± 45 vs.
1426 ± 60 units, p&lt;0.0001) compared to both baseline and placebo.</p>
<p><u>Left ventricular mass</u>: decreased by 15% from baseline (210 ±
10 vs. 182 ± 12 g, p=ns).</p>
<p><u>E wave velocity/A wave velocity ratio</u>: no significant change
from baseline.</p>
<p><u>Deceleration time</u>: lower by 15% (211 ± 10 vs. 182 ± 12
milliseconds; p=0.05).</p></td>
<td><p>Conclusions:</p>
<p>The authors conclude that, “n-3 fatty acids reduce blood pressure by
decreasing systemic vascular resistance and, therefore, can be used as
an adjuvant for the treatment of hypertension in cyclosporine-treated
cardiac transplant recipients.</p>
<p><u>Comments</u>:</p>
<p>Diets were not assessed</p></td>
<td>1</td>
<td><p>Not reported</p>
<p>Serum creatinine: no significant differences compared to
placebo</p></td>
</tr>
<tr class="odd">
<td><p>Vertkin et al. 1994</p>
<p><em>Kardiologiya</em> 1994;34:22-28 (ABSTRACT, foreign)</p>
<p>[Russia]</p></td>
<td>To investigate the effects of a food supplement enriched with n-3
and of canned fish on plasma lipids, atherogenicity of plasma, and
hemostasis in patients with atherogenic dislipidemia.</td>
<td>Not reported</td>
<td>4 weeks</td>
<td><p>8 g/d Elconol food supplement enriched with n-3</p>
<p>(Amount of EPA+DHA not reported)</p>
<p>OR</p>
<p>80 g/d canned fish</p>
<p>Compliance: not reported</p></td>
<td>65 patients with atherogenic dislipidemia</td>
<td><p><u>TG:</u> ↓ 26% w/ Elconol<u>,</u> ↓ 57% w/ can fish</p>
<p><u>TC:</u> ↓ 28% w/ can fish</p>
<p><u>LDL:</u> ↓ 11% w/ Elconol</p>
<p><u>apo A:</u> ↑ 21% w/ can fish</p>
<p><u>apo B:</u> ↓ 16% w/ can fish</p>
<p><u>Atherogenicity index:</u> ↓ 14% w/ Elconol</p>
<p>No positive action on platelet aggregation was observed.</p></td>
<td><p><u>Conclusions:</u></p>
<p>Elconol and dietetic canned fish produced hypolipidemic action
without side effects and could be recommended for treatment and
prevention of lipid metabolism disturbances.</p>
<p><u>Comments:</u></p>
<p>Summarized from abstract.</p>
<p>Elconol food product not described.</p></td>
<td>3</td>
<td>Inadequate information provided in abstract only.</td>
</tr>
<tr class="even">
<td><p>Vessby et al. 1992</p>
<h2 id="diabetic-med-19929126-133">Diabetic Med 1992;9:126-133</h2>
<p>[Sweden]</p></td>
<td>To evaluate the effects of an isolated change of fat quality on
carbohydrate and lipid metabolism in NIDDM patients on diabetic
diet.</td>
<td><p>Cross over design.</p>
<p>Seven subjects were given diet rich in saturated fat for 3 weeks and
7 were given diet rich in PUFA. After 3 weeks the treatments were
reversed.</p></td>
<td><p>3 weeks</p>
<p>3 weeks on saturated fat diet</p>
<p>3 weeks on PUFA diet</p></td>
<td><p>4-5 g of n-3 FAs (2.4 % EPA and 3.4 % DHA). The PUFA diet
consisted of linoleic acid (31.2 %), linolenic acid (1.9 %) in addition
to EPA and DHA. PUFA was provided by 6 meals (of 14) by including fat
fish such as mackerel, herring or salmon (PUFA diet).</p>
<p>The saturated fat diet consisted of 13.7 % linoleic acid, 2.8 %
linolenic acid, 0.1 % of EPA and no DHA (saturated fat diet).</p>
<p>Compliance:</p>
<p>Fatty acids levels</p></td>
<td><p>14 NIDDM patients (5 men and 10 women) were administered two
isoenergetic diets for two consecutive 3-week periods in a metabolic
ward.</p>
<p>15 subjects were recruited, one subject did not complete the
saturated diet treatment due to illness and was not included in the
final analyses.</p></td>
<td><p>TG: ↓ significantly (p&lt;0.001) on both diets compared to the
baseline.</p>
<p>TC: ↓ significantly (p&lt;0.001) on both diets compared to the
baseline.</p>
<p>LDL: ↓ significantly (p&lt;0.01) from 4.27 ± 1.36 mmol/l at baseline
to 3.8 ± 1.01 mmol/l on PUFA diet and 3.75 ± 0.88 mmol/l on saturated
fat diet.</p>
<p><u>VLDL:</u> ↓ by 60% on PUFA and 43% on saturated fat diets.</p>
<p>apo A-1: ↓ significantly with PUFA (p&lt;0.001) and saturated fat
diet (p&lt;0.01) with no significant difference between the
treatments.</p>
<p>apo B: ↓ significantly with PUFA (p&lt;0.001) and saturated fat diet
(p&lt;0.01) with no significant difference between the treatments.</p>
<p>apo AII: ↓ significantly with PUFA (p&lt;0.001) and saturated fat
diet (p&lt;0.001) with significant difference between the treatments
(p=0.002).</p>
<p><u>Blood glucose:</u> The fasting blood glucose levels were
significantly ↓ (p&lt;0.001) with both the treatments vs. baseline. The
↓ was more pronounced with saturated fat diet vs. PUFA diet. The fasting
glucose ↓ from 11.9 ± 2.9 mmol/l at baseline to 9.3 ± 2.8 mmol/l on PUFA
diet and 7.7 ± 2.3 mmol/l on saturated fat diet (p&lt;0.003). During the
third week of treatment on PUFA diet the fasting, and before and after
lunch blood glucose concentration ↑ significantly vs. the saturated fat
diet. The blood glucose during the breakfast ↓ with both diets, but
significantly ↑ on PUFA than on saturated fat diet.</p>
<p><u>Urinary glucose:</u> On saturated fat diet the excretion was 21
mmol/d compared to 39 mmol/d on PUFA diet.</p>
<p><u>Glycated hemoglobin:</u> ↓ on both diets vs. baseline and the
difference between the diets was NS (baseline 8.9 ± 2.0%, PUFA diet 7.9
± 1.8%, saturated fat diet 7.8 ± 1.5%).</p>
<p><u>Insulin concentrations:</u> NS difference in fasting insulin
concentration or after iv glucagon stimulation. The fasting serum
insulin was not different between the diets but the sum of the insulin
concentrations at the 6 time-points was significantly lower with the
PUFA diet compared to the saturated fat diet.</p>
<p><u>C-peptide concentrations:</u> NS difference in fasting C-peptide
concentration or after iv glucagon stimulation. NS difference in fasting
and after breakfast C-peptide concentrations between the diets.</p>
<p>During the insulin tolerance test the rate constant for blood glucose
disappearance ↑ significantly (p&lt;0.01) with both diets with no
differences between the diets.</p>
<p>Significant ↑ in EPA and DHA concentrations and reduction in
linolenic acid in plasma cholesterol esters on PUFA diet compared to the
saturated fat diet. The linoleic acid levels remained unchanged despite
high levels in the diet.</p></td>
<td><p>Conclusion:</p>
<p>The results of the study suggests that, “an increased content of
PUFA, especially long-chain n-3 fatty acids, in a low fat diet may have
beneficial as well as adverse effects in the management of type 2
diabetes”.</p>
<p>Comments:</p>
<p>No washout period.</p>
<p>The PUFA diet contained more linoleic acid than EPA and DHA compared
to saturated fat diet, hence the effects on biochemical end points
cannot be attributed solely to EPA and DHA.</p></td>
<td>1</td>
<td><p>Both saturated fat and PUFA diets were well accepted by the
subjects.</p>
<p>Mean body weight loss was 0.8 kg and it was similar during both
treatments.</p></td>
</tr>
<tr class="odd">
<td><p>Vognild et al. 1998</p>
<p><em>Lipids</em> 1998;33:427-436</p>
<p>[Norway]</p></td>
<td>To determine the effects of various marine oils and olive oil on
fatty acid composition of serum and platelets, platelets and serum
lipids.</td>
<td>Randomized, double-blind, controlled trial.</td>
<td>12 weeks</td>
<td><p>Not quantified</p>
<p>Cod liver oil (CLO)</p>
<p>Olive oil</p>
<p>Whale oil, refined</p>
<p>Whale oil, unrefined</p>
<p>Seal oil + CLO</p>
<p>Olive + CLO</p>
<p>No oil</p>
<p>The subjects consumed 15 ml of oil.</p></td>
<td><p>266 healthy volunteers (males and females)</p>
<p>Cod liver oil (CLO) group: 25 subjects</p>
<p>Olive oil group: 29 subjects</p>
<p>Whale oil, refined group: 38 subjects</p>
<p>Whale oil, unrefined group: 31 subjects</p>
<p>Seal oil + CLO group: 36 subjects</p>
<p>Olive + CLO group:33 subjects</p>
<p>Control group: 35 subjects</p></td>
<td><p><u>TG:</u> A non-significant (10-12%) decrease in serum TG was
observed in the CLO, CLO/seal and whale oil groups. A strong trend in
the reduction of TG in women in the CLO and CLO/seal oil groups was
observed.</p>
<p><u>TC:</u> No significant change with any treatment.</p>
<p><u>HDL:</u> No significant change with any treatment.</p>
<p>EPA (p&lt;0.01) and DHA concentrations in serum increased in the CLO
and CLO/seal groups. EPA concentrations increased (p&lt;0.01) in the
group receiving whale oil.</p>
<p>A strong positive correlation for 20:5n-3 was observed between FAs in
serum and platelets (r=0.84, p&lt;0.0001).</p>
<p>The concentration of EPA in platelet membrane was higher in CLO,
CLO/seal and olive oil groups.</p>
<p>Platelet membrane fluidity was unchanged in all groups.</p>
<p>Mean platelet volume increased in whale oil groups and in the
CLO/olive oil group. Platelet count was significantly reduced in the
refined whale oil group.</p>
<p>Reduction in TxB<sub>2</sub> was observed in groups receiving CLO,
CLO/seal and CLO/olive oil.</p>
<p>Significant increase in PGE<sub>2</sub> in groups receiving CLO,
CLO/seal and CLO/olive oil. The control group also showed an increase in
PGE<sub>2</sub> levels.</p></td>
<td><p><u>Conclusion:</u></p>
<p>The authors conclude that, “intake of various marine oils causes
changes in platelet membranes that are favorably antithrombotic. The
combination of CLO and olive oil may produce better effects than these
oils given separately. The changes in platelet function are directly
associated with alterations of FAs composition in platelet
membranes”.</p>
<p><u>Comments:</u></p>
<p>Diets were not assessed but the subjects were asked to consume their
regular diets.</p>
<p>The subjects in the control group did not receive any oil and
therefore were not blinded.</p>
<p>The TG in the Whale group was higher compared to other groups
(p&lt;0.05).</p>
<p>Men had higher values for age, TG and cholesterol.</p>
<p>Women had higher values for HDL and TxB<sub>2</sub>.</p>
<p>Methods to determine compliance were not discussed.</p></td>
<td>1</td>
<td></td>
</tr>
<tr class="even">
<td><p>von Schacky et al. 1999</p>
<p><em>Ann Intern Med</em> 1999;130:554-562</p>
<p>[Germany]</p></td>
<td>To determine the effect of dietary intake of omega-3 FAs on the
course of coronary artery atherosclerosis in humans.</td>
<td>Randomized, Double-blind, Placebo-controlled</td>
<td><p>112 weeks</p>
<p>(2 years)</p></td>
<td><p>3.4 g/d EPA+DHA</p>
<p>2.1 g/d EPA, 1.3 g/d DHA)</p>
<p>Months 1-3</p>
<p>Next 21 months:</p>
<p>1.71 g/d EPA+DHA</p>
<p>Control: FAs mixture reflecting composition of avg. European
diet.</p>
<p>Compliance:</p>
<p>interview, capsule counts, FAs analysis.</p></td>
<td><p>233 patients w/ angiographically proven coronary artery
disease.</p>
<p>111 test</p>
<p>112 control</p>
<p>Ratio Males:Females not given.</p></td>
<td><p><u>TG:</u> NS between groups</p>
<p><u>TC:</u> NS between groups</p>
<p><u>LDL:</u> ↓ (p&lt;0.05)</p>
<p><u>HDL:</u> NS between groups</p>
<p><u>Coronary Atherosclerosis (expert panel):</u> Test group showed
less progression and more regression vs. control group (P&lt;0.041)</p>
<p><u>Coronary Atherosclerosis (luminal diameter):</u> NS between
groups</p>
<p><u>CVD events incl. MI:</u> ↓ (p&gt;0.1)</p></td>
<td><p><u>Conclusions:</u></p>
<p>"Dietary intake of n-3 FAs modestly mitigates the course of coronary
atherosclerosis in humans"</p>
<p><u>Comments:</u></p>
<p>Dietary habits not reviewed over 2-yr period.</p>
<p>Subjective measurement of angiograms by expert panel.</p>
<p>Text and Table 3 data differ.</p></td>
<td>2</td>
<td><p>Dose and preparation well tolerated.</p>
<p>No adverse affects attributed to test material.</p></td>
</tr>
<tr class="odd">
<td><p>Walker et al. 1999</p>
<p><em>J. Obstr. Gynecol.</em> 19(1):56-58</p>
<p>[UK]</p></td>
<td>To investigate the effect of low-dose aspirin in conjunction with
fish oil or evening primrose oil in non-pregnant women in order to
determine any effect on platelet AII binding</td>
<td>Randomized, parallel, single-blind</td>
<td>4 weeks (1 month)</td>
<td><p>1.2 g/d EPA + DHA (4 g/d fish oil, 18% EPA, 12.8% DHA) (fish oil
group)</p>
<p>4 g/day evening primrose oil (66-85% linoleic acid)</p>
<p>aspirin</p>
<p>aspirin + fish oil</p>
<p>aspirin + evening primrose oil</p>
<p>Control: no supplementation</p></td>
<td><p>60 healthy, non-pregnant females</p>
<p>Aspirin: n=10</p>
<p>Evening primrose oil: n=10</p>
<p>Fish oil: n=10</p>
<p>Evening primrose + aspirin: n=10</p>
<p>Fish oil + aspirin: n=10</p>
<p>Control: n=10</p></td>
<td><u>Platelet AII binding</u>: ↓ in fish oil only (NS), evening
primrose only (NS), evening primrose + aspirin (NS), and fish oil +
aspirin (p=0.04) groups; NS increase in aspirin only group</td>
<td><p><u>Conclusions</u>:</p>
<p>Authors concluded that aspirin plus fish oil may have a role in
reducing platelet AII binding in women with pregnancy-induced
hypertension or pre-eclampsia</p>
<p><u>Comments:</u></p>
<p>Diet not assessed.</p></td>
<td>2</td>
<td>Not reported.</td>
</tr>
<tr class="even">
<td><p>Wallace et al. 1995</p>
<p><em>Thromb Vasc Biol</em> 1995;15:185-189</p>
<p>[Northern Ireland]</p></td>
<td>To determine the effect of low dose of fish oil supplementation on
cytokines and white cell function in women.</td>
<td>Double-blind trial.</td>
<td><p>4 weeks of treatment</p>
<p>9 weeks post-treatment washout period</p></td>
<td><p>0.72 g/d EPA + DHA (2.4 g/d fish oil containing 18% DHA and 12%
EPA, 0.432 g/d DHA and 0.288 g/d EPA)</p>
<p>Fish oil group</p>
<p>Fish oil + vitamin E group</p>
<p>Compliance:</p>
<p>interview</p></td>
<td><p>33 healthy non-smoking females were recruited. They were not on
any prescribed medication or nutritional supplements.</p>
<p>Fish oil group: n=16</p>
<p>Fish oil + vitamin E group: n=17</p></td>
<td><u>PDGF:</u> ↓ significantly with fish oil (2461 ± 254 ng/l, p≤0.01)
and fish oil + vitamin E (2481 ± 343 ng/l, p≤0.05) supplements after 4
weeks compared to initial values (fish oil 3878 ± 366, fish oil +
vitamin E 3458 ± 333 ng/l). At the end of washout period the levels ↓
further, but the levels were not significantly different from 4 weeks.
NS difference between the groups.<u><br />
Mean peroxidase index:</u> ↑ significantly with fish oil (10.0 ± 2.0,
p≤0.01) and fish oil + vitamin E (-1.2 ± 1.7, p≤0.001) supplements after
4 weeks compared to initial values (fish oil: –3.9 ± 2.3, fish oil +
vitamin E: –5.4 ± 1.8 ng/l). At the end of washout period the levels had
not returned to baseline but were not significantly different from
initial values. NS difference between the groups.<u><br />
Myeloperoxidase:</u> ↓ significantly with fish oil (34.8 ± 3.4 μg/l,
p≤0.01) and fish oil + vitamin E (34.6 ± 7.4 μg/l, p≤0.05) supplements
after 4 weeks compared to initial values (fish oil 70.1 ± 9.8, fish oil
+ vitamin E 60.4 ± 11.7 μg/l). At the end of washout period the levels
↑, but did not return to baseline. NS difference between the
groups.</td>
<td><p>Conclusions:</p>
<p>The authors concluded that, “it is possible that the beneficial
effects on mortality of small amounts of fish oil in the diet might be
at least partly mediated by an effect of n-3 PUFAs on neutrophil
function and cytokine concentration”.</p>
<p>Comments:</p>
<p>No control group.</p>
<p>The number of subjects for each endpoint were different.</p></td>
<td>1</td>
<td>Hiccups and a fishy after taste were reported. The fish oil
supplements were well tolerated by all subjects.</td>
</tr>
<tr class="odd">
<td><p>Watts et al. 1995</p>
<p><em>Can J Cardiol</em> 1995;11:110G-114G</p>
<p>[UK]</p></td>
<td>To determine the association between nutrient intakes and
angiographically determined progression or regression of coronary
atherosclerosis in man.</td>
<td><p>Randomized, single-blind.</p>
<p>Dietary intervention trial.</p></td>
<td>156 weeks (39 months)</td>
<td><p>Not quantified.</p>
<p>Usual care group: received usual cardiological care including
management of non-lipid risk factors.</p>
<p>Diet group: received usual cardiological care plus counseling on
lipid-lowering diet. The lipid-lowering diet provided 8% of energy form
n-6 and n-3 FAs.</p>
<p>Not a dietary supplementation study. Subjects counseled to follow a
lipid –lowering diet for 39 months. Intake of nutrients (both groups)
assessed using diet record, interview and food frequency list;
associations between nutrient intake and CAD evaluated.</p></td>
<td><p>50 male subjects who underwent coronary angiography for the
investigation of angina pectoris or other manifestations of CAD.</p>
<p>Dietary assessments were made using interview, supplemented by
three-day diet records and food frequency list.</p></td>
<td><u>Coronary artery minimum width:</u> Intake of EPA + DHA explained
only 1.4% (p=0.968) of variance in minimum width of coronary
artery.</td>
<td><p><u>Conclusions:</u></p>
<p>No effect of EPA + DHA on changes in coronary artery minimum
width.</p>
<p>Comments:</p>
<p>Not a supplementation study. Association between nutrient intake and
progression and regression of CAD was evaluated.</p>
<p>Data on association between other nutrient intake and progression and
regression of CAD is not reported in this summary.</p></td>
<td>2</td>
<td>Not reported</td>
</tr>
<tr class="even">
<td><p>Wensing et al. 1999</p>
<p><em>Bri. J. Nutr.</em> 1999. 82:183-191</p>
<p>[The Netherlands]</p></td>
<td>To compare the effects of α-linolenic acid with those of DHA/EPA on
platelet aggregation and determine if the potential effects are
age-dependent</td>
<td>Randomized, parallel, controlled</td>
<td><p>6 weeks</p>
<p>3 week run-in period prior to study</p></td>
<td><p>1.6 g/day EPA + DHA (1.05 g/day EPA,</p>
<p>0.55 g/day DHA) from shortening made from a mixture of palm oil,
fully hydrogenated palm oil, menhaden oil, Trisun-80, and high-linoleic
safflower oil (elderly subjects), or</p>
<p>high-oleic shortening (control), or</p>
<p>high-α-linoleic acid shortening (6.8 g/day α-linoleic acid)</p>
<p>younger subjects:</p>
<p>high α-linoleic acid shortening.</p>
<p>Compliance: erythrocyte phospholipids</p></td>
<td><p>50 healthy subjects (17 male/33 female).</p>
<p>38 elderly subjects (age range: 60-78 years, mean: 65 years) and 12
young adults (age range: 16-33 years, mean: 24 years).</p>
<p>EPA/DHA: n=14</p>
<p>Oleic acid: n=11</p>
<p>α-Linolenic acid: n=25 (12 young, 13 elderly)</p>
<p>10 dropouts due to job, study or family commitments (n=5), use of
nonsteroidal anti-inflammatory drugs (n=3), illness (n=1), or blood
donation (n=1)</p></td>
<td><p><u>Platelet aggregation in platelet-rich plasma to ADP</u>: NS
changes</p>
<p><u>Platelet aggregation in platelet-rich plasma to collagen</u>: NS
changes</p>
<p><u>Platelet aggregation in whole blood to ADP</u>: NS changes</p>
<p><u>Platelet aggregation in whole blood to collagen</u>: NS
changes</p>
<p><u>Aggregation time (<em>ex vivo</em>)</u>: ↑ in the EPA/DHA group
compared to the α-linolenic acid group (p=0.006) and oleic acid group
(p=0.004).</p>
<p>No age-dependent effects of α-linolenic observed.</p>
<p>NS difference between group in number of platelets, erythrocytes or
leukocytes. In all groups, the number of platelets increased by 1.3% and
leukocytes by 3.1%; erythrocytes decreased by 3.4%.</p>
<p>1.3% ↑ in plasma EPA (p&lt;0.001) and 0.8% increase in plasma DHA
(p&lt;0.001) in EPA/DHA group compared to other groups.</p></td>
<td><p><u>Conclusions</u>:</p>
<p>The results suggest that α-linolenic acid and EPA/DHA have no effect
on <em>in vitro</em> platelet aggregation. When compared to oleic acid,
EPA/DHA but not α-linolenic acid favorably affects <em>ex vivo</em>
platelet aggregation.</p>
<p><u>Comments</u>:</p>
<p>Not all patients randomly assigned to study groups (spouses allowed
in same groups).</p>
<p>Although shortenings were provided as spreads or incorporated into
pies, cakes or chocolate paste, diets were not assessed. EPA/DHA group
allowed to consume fatty fish but not oleic acid and α-linoleic acid
groups.</p></td>
<td>2</td>
<td>Not reported.</td>
</tr>
<tr class="odd">
<td><p>Westerveld et al. 1993</p>
<p><em>Diabetes Care</em> 1993;16(5):683-688</p>
<p>[Netherlands]</p></td>
<td>To determine a low dose of EPA-E that would effect platelet function
and rheological properties of blood favorably without deleterious
effects on diabetes regulation and lipid metabolism in NIDDM
subjects.</td>
<td>Randomized, double-blind, placebo controlled trial.</td>
<td>8 weeks on treatment followed by 4 weeks of wash-out period.</td>
<td><p>1.8 g/d EPA-E</p>
<p>(high dose group)</p>
<p>0.9 g/d EPA-E</p>
<p>(low dose group)</p>
<p>Olive oil (placebo)</p>
<p>Compliance: capsule counts, plasma EPA-E analyses</p></td>
<td>24 subjects with NIDDM were recruited from the outpatient clinic of
the University Hospital Utrecht.</td>
<td><p><u>TG:</u> No significant change.</p>
<p><u>TC:</u> No significant change.</p>
<p><u>LDL:</u> A slight but significant increase in LDL was observed in
the high dose group (p=0.014 for week 0 verses week 8)</p>
<p><u>apo B:</u> No significant change.</p>
<p><u>Lp(a):</u> No significant change.</p>
<p>No significant differences in the glucose and HbA<sub>1</sub> levels
were observed between groups.</p>
<p>PAF-induced platelet aggregation decreased significantly in high dose
(p=0.039) and low dose (p=0.016) groups.</p>
<p>A significant decrease in ADP-induced platelet aggregation was
observed only in the high dose group (p=0.031).</p>
<p>No significant change in the collagen induced aggregation, Simplate
bleeding time, platelet number and size, platelet adhesion, plasma
viscosity, whole blood viscosity, erythrocyte deformability, total
plasma protein, and fibrinogen was observed between groups.</p>
<p>The EPA concentrations in plasma increased in groups receiving high
and low dose of EPA. The levels declined after the washout
period.</p></td>
<td><p><u>Conclusions:</u></p>
<p>The authors conclude that “purified EPA-E in doses of 900 and 1800
mg/d reduces PAF-induced platelet aggregation without negatively
affecting glycemic control. The unaltered lipid variables in the 900
mg/d group and the slight elevation of LDL in the 1800 mg/d group
suggests a 900 mg/d dose of EPA-E can be administered safely to NIDDM
patients”.</p>
<p><u>Comments:</u></p>
<p>Mean body weight in the high dose group was significantly higher then
the low dose and placebo groups.</p>
<p>Dietary history was obtained prior to treatment. During treatment
diets were not assessed, but subjects were asked to follow their regular
diets.</p></td>
<td>1</td>
<td>No adverse effects were reported.</td>
</tr>
<tr class="even">
<td><p>Yamamoto et al. 1995</p>
<p><em>Jpn Circ J</em> 1995;59:608-616</p>
<p>[Japan]</p></td>
<td>To determine the effects of EPA on acetylcholine (ACh)-induced
coronary vasospasm in patients with variant angina and to determine how
EPA affects coronary vasomotion in response to ACh.</td>
<td>Randomized, controlled trial.</td>
<td>16 weeks (4 months)</td>
<td><p>1.8 g/d EPA (Epadel capsules)</p>
<p>Fish oil group: fish oil + Ca channel blocker</p>
<p>Control group: Ca channel blocker.</p>
<p>EPA treatment was started after the first coronary angiography
examination.</p>
<p>Compliance:</p>
<p>Fatty acid analysis.</p></td>
<td><p>22 (17 males and 5 females) patients with variant angina were
recruited from the Kyushu Kosei Nenkin Hospital.</p>
<p>Fish oil group: n=12 (9 males and 3 females)</p>
<p>Control group: n=10 (8 males and 2 females)</p>
<p>The patients had normal appearing coronary arteries after isosorbide
dinitrate (ISDN) administration. The patients discontinued all drugs
except for nitroglycerine. ACh was infused in all subjects before and
after 4 months of EPA treatment.</p></td>
<td><p>TG: NS difference between the groups.<br />
TC: NS difference between the groups.<br />
LDL: NS difference between the groups.<br />
HDL: NS difference between the groups.</p>
<p>Heart rate: NS difference between the groups.</p>
<p>Arterial pressure: NS difference between the groups.</p>
<p>Coronary artery response to ACh: In the control group ACh provoked
coronary vasospasm in the same spastic sites as seen before treatment
and ACh constricted the non-spastic sites significantly before and after
4 months. In the control group the response to ACh did not change over
time. In the fish oil group ACh induced coronary vasospasm in the
spastic sites, but changed the cholinergic response in the non-spastic
site from vasoconstriction to vasodilation.</p>
<p>Plasma EPA levels ↑ significantly (p&lt;0.01) after 4 months of EPA
supplementation.</p></td>
<td><p>Conclusions:</p>
<p>The authors concluded that, “EPA treatment improved the coronary
vasomotor responsiveness to ACh, but did not inhibit ACh –induced
coronary vasospasm”.</p>
<p><u>Comments:</u></p>
<p>Diets were not assessed.</p></td>
<td>1</td>
<td>Not reported</td>
</tr>
<tr class="odd">
<td><p>Yosefy et al. 1996</p>
<p><em>J. Human Hypertension</em> 1996. 10:S135-S139</p>
<p>[Israel]</p></td>
<td>To determine the minimal time required to observe an effect on blood
pressure, primary hemostasis and lipid profile following oral
administration of EPA on subjects with cardiovascular risk factors</td>
<td>Crossover trial.</td>
<td><p>1.9 weeks</p>
<p>(13 days per treatment period), with a 3-week washout interval in
between each treatment period</p>
<p>Day 1, 5, 9, and 13 were fasting day (20 hrs/day) followed by
refeeding</p></td>
<td><p>4.5 g/day EPA + DHA from 15 1-g capsules of Alsepa deep sea fish
oil containing 180 mg EPA and 120 mg DHA); administered after fasting
and followed by refeeding (Period I)</p>
<p>Subjects fasted and then refeeded w/o fish oil ingestion (Period
II)</p>
<p>Subjects given fish oil as in period I but without fasting and
refeeding (Period III)</p>
<p>Compliance: plasma phospholipid FA analysis</p></td>
<td><p>20 hypertensive, mildly obese, dyslipidemic subjects</p>
<p>mean age: 61.7 years (range: 40-71 years)</p>
<p>8 male/12 female</p></td>
<td><p><u>TC</u>: NS change</p>
<p><u>TG</u>: ↓ significantly with subjects with markedly elevated or
intermediate baseline levels (-36%, p=0.01); NS change in subjects with
low levels at baseline; ↓ significantly in subjects during period I
(-32%); NS change in periods II and III.</p>
<p><u>HDL</u>: NS change</p>
<p><u>LDL</u>: NS change</p>
<p><u>Systolic BP</u>: ↓ by 7.7% in period I (p=0.04); NS change in
periods II and III.</p>
<p><u>Diastolic BP</u>: ↓ by 9.8% in period I (p=0.04); NS change in
periods II and III.</p>
<p><u>Platelet adhesion and aggregation on extracellular matrix (as a %
of surface coverage)</u>: ↓ significantly during period I (p=0.0001); NS
change in periods II and III.</p>
<p><u>Platelet function</u>: NS change</p>
<p><u>Alpha-2-anti-plasmin</u>: ↓ significantly during period I (-8.8%,
p=0.01)</p>
<p><u>Fibrinogen</u>: NS change</p>
<p>Plasma phospholipids increased significantly from 2% to 5.9% after
period I (p=0.01). No significant change was observed in period II, and
concentrations increased significantly from 1.3% to 5.5% in period III
(p=0.01).</p></td>
<td><p><u>Conclusions</u>:</p>
<p>Authors concluded that “repeated fasting and refeeding with fish oil
facilitated plasma exchange of AA for EPA as well as reducing BP,
clinical metabolic parameters, and platelet reactivity.”</p>
<p><u>Comments</u>:</p>
<p>Limited details on study design (i.e., blinded?, randomized?).</p>
<p>Subjects were allowed water and sugar-free tea on fasting day and a
diet on nonfasting days that provided 50% carbohydrates, 30% fats, and
20% proteins.</p></td>
<td>3</td>
<td>Not reported.</td>
</tr>
<tr class="even">
<td><p>Žák et al. 1993</p>
<p>Annals of the New York Academy of Sciences</p>
<p>1993;683:378-379</p>
<p>[Czech Republic]</p></td>
<td>To “evaluate the relations between the composition of fatty acids of
plasma phosphatidylcholine, parameters of glucose tolerance and the
hypolipidemic effects of n-3 fatty acids.”</td>
<td>Uncontrolled trial</td>
<td>3 weeks (21 days)</td>
<td><p>3.3 g/day n-3 fatty acids (Activepa fish oil)</p>
<p>Compliance:</p>
<p>Plasma phosphatidylcholi-ne analysis.</p></td>
<td>25 patients with primary hypertriglyceridemia (HTG)</td>
<td><p><u>TG</u>: ↓ 44% in the treatment group compared to baseline
(p=0.001).</p>
<p><u>TC</u>: no significant change compared to baseline.</p>
<p><u>HDL</u>: ↑ 13% in the treatment group compared to baseline
(p=0.001).</p>
<p><u>Blood Glucose:</u> Significant ↓ (p=0.01) with fish oil (5.42 ±
0.31 mmol/l) compared to baseline (6.29 ± 0.41 mmol/l) after 2 hours of
OGTT. NS change before and 30 and 60 min after OGTT with fish oil.</p>
<p><u>Immunoreactive insulin:</u> Significant ↓ (p=0.05) with fish oil
(84.3 ± 10.1 μU/ml) compared to baseline (108.3 ± 12.1 μU/ml)after 2
hours of OGTT. NS change before and 30 and 60 min after OGTT with fish
oil.</p>
<p>Plasma phosphatidylcholine EPA and DHA levels ↑ significantly with
fish oil compared to baseline (p=0.001).</p></td>
<td><p>Conclusions:</p>
<p>The authors conclude that, “despite the observed positive
correlations between plasma TG and 20:3n-6 concentrations, the relevance
of the changes observed in our model remains unclear.”</p>
<p>Comments:</p>
<p>Diets were not assessed in the study.</p>
<p>No control group</p>
<p>No breakdown of the amount of EPA or DHA in the supplement</p>
<p>Units for glucose assumed to be mmol/l</p></td>
<td>3</td>
<td>Not reported.</td>
</tr>
<tr class="odd">
<td><p>Zak et al. 1997</p>
<p><em>Sborník Lékařskỳ</em> 1997;98:213-224 (ABSRACT, foreign)</p>
<p>[Czech Republic]</p></td>
<td>To study the effects of fish oil supplementation on plasma lipid
risk factors for CHD in subjects with primary hyperlipoproteinemia
(HLP)</td>
<td>Clinical trial.</td>
<td>3 weeks</td>
<td><p>3.5 g/d n-3 FAs</p>
<p>Compliance:</p>
<p>Not reported</p></td>
<td><p>82 subjects (61 men and 21 women) with primary
hyperlipoproteinemia.</p>
<p>HLP IIA: n=9</p>
<p>HLP IIB: n=29</p>
<p>HLP IV: n=35<br />
HLP V: n=7</p>
<p>HLP III: n=2</p></td>
<td><p><u>TG:</u> Significant ↓in all HLP phenotype groups with largest
↓ in HLP IIB, IV and V with fish oil.<u><br />
TC:</u> Significant ↓ for the whole group and in HLP V with fish
oil.<u><br />
HDL:</u> Significant ↓ in HDL<sub>2</sub> and HDL<sub>3</sub> in the
whole group and all phenotypes with fish oil.<u><br />
LDL:</u> NS changes with fish oil.<u><br />
apo A:</u> ↑ significantly in whole group and HLP IIB group with fish
oil.</p>
<p><u>apo B:</u> ↑ significantly in HLP V group with fish oil.</p>
<p><u>Lp (a):</u> ↓ in some subjects with fish oil.</p>
<p><u>DBP:</u> mild ↓ with fish oil.</p>
<p><u>Uricemia:</u> mild ↓ with fish oil.</p></td>
<td><p>Conclusions:</p>
<p>Fish oil supplementation significantly decreased TG, TC and HDL and
increased apo A and apo B (HLP V) in subjects with primary
hyperlipoproteinemia.</p>
<p><u>Comments:</u></p>
<p>Summarized from abstract.</p></td>
<td></td>
<td>Not reported</td>
</tr>
<tr class="even">
<td><p>Zakaria and Bertsch 1992</p>
<p><em>Fortschr Med</em> 1992;110(10):178-82 and 70-76 (ABSRACT,
German)</p>
<p>[Germany]</p></td>
<td>To determine if smaller dose than those recommended for lipid
lowering of n-3 is effective for a large number of unselected
outpatients.</td>
<td><p>Open trial</p>
<p>Multicenter</p></td>
<td>12 weeks</td>
<td>1.1 to 1. 4 g/d of n-3 FAs (fish oil, Eicosapen)</td>
<td>197 outpatients with dyslipoproteinemia.</td>
<td><p>TG: ↓ by 23%</p>
<p><u>TC:</u> ↓ by 10%</p>
<p><u>LDL:</u> ↓ by 5%<u><br />
HDL:</u> ↑ by 16%</p></td>
<td><p><u>Conclusion:</u></p>
<p>The effect of n-3 on systolic and DBP, HDL and TG was greater in
hypertensives patients than in patients with normal BP.</p>
<p><u>Comments:</u></p>
<p>Summarized from abstract.</p></td>
<td></td>
<td>The fish oil was well tolerated. 4 (2%) subjects discontinued the
study because of fishy taste and mild gastrointestinal problems.</td>
</tr>
<tr class="odd">
<td><p>Zambon et al. 1992</p>
<p><em>Am J Clin Nutr</em> 1992;56:447-54</p>
<p>[U.S.]</p></td>
<td>To determine the effects of sulfonylurea glyburide on glucose and
lipid metabolism in patients with NIDDM supplemented with n-3 fatty
acid.</td>
<td><p>Randomized crossover trial.</p>
<p>In phase I glyburide was given to reduce the plasma glucose
levels.</p>
<p>In phase II the patients were randomly assigned to FAs + glyburide or
to fatty acid treatment for 4 weeks. Each subject went through a fatty
acid + glyburide treatment for 4 weeks and fatty acid treatment for 4
weeks</p></td>
<td>8 weeks</td>
<td><p>7.5 g/d of EPA+DHA as ethyl esters</p>
<p>4500 mg/d EPA</p>
<p>3000 mg/d DHA</p>
<p>8 g/d n-3 FAs (Super-EPA capsules)</p>
<p>Compliance: plasma fatty acid analyses</p></td>
<td>10 subjects with NIDDM were recruited from the Diabetes Registry of
the Diabetes and Endocrine Research Center.</td>
<td><p><u>TG:</u> NS↓ with fish oil treatment.</p>
<p><u>TC:</u> No change with fish oil treatment.</p>
<p><u>LDL:</u> ↑ significantly (19.5%, p=0.05) with fish oil.</p>
<p><u>HDL:</u> No change with fish oil treatment.</p>
<p><u>VLDL:</u> ↓ significantly (p&lt;0.05) with fish oil treatment.</p>
<p><u>apo B:</u> ↑ significantly (7.9%, p&lt;0.05) with fish oil.</p>
<p><u>Plasma glucose:</u> ↑ significantly after fish oil supplementation
compared to the baseline concentrations (p=0.008) and compared to
glyburide treatment (p&lt;0.0001). Glyburide + n-3 FAs treatment
decrease the glucose levels, but it was still 16% higher than glyburide
alone.</p>
<p>Postprandial insulin response was decreased significantly after fish
oil supplementation (p&lt;0.05).</p>
<p>A significant increase in plasma EPA (p&lt;0.0001) and DHA
(p&lt;0.0001) concentration was observed with n-3 FAs
supplementation.</p></td>
<td><p><u>Conclusion:</u></p>
<p>The authors conclude that, “ marine lipid concentrates should not be
advocated in the treatment of patients with NIDDM with marginal
hyperlipidemia”.</p>
<p><u>Comments:</u></p>
<p>Diet history was collected prior to treatment, diet records were
collected prior to during and at the end of the treatment.</p></td>
<td>1</td>
<td></td>
</tr>
<tr class="even">
<td><p>Zampelas et al. 1994</p>
<p><em>Eur J Clin Nutr</em> 1994;48:842-848</p>
<p>[U.K.]</p></td>
<td>To examine postprandial lipid and apolipoprotein responses to meals
supplemented with either n-3 or n-6 FAs or a mixed oil formulated to
approximate the fatty acid composition of the UK adult diet.</td>
<td>Randomized (the meals were consumed in random order on separate
occasions). Each subject consumed all 3 meals. On each study day the
subjects consumed standard (to standardized nutrient intake) breakfast,
lunch and snack and continued with their activities. The test meals
differed in their fatty acid content only.</td>
<td>3 days (3 test meals supplemented with these FAs were given on 3
occasions)</td>
<td><p>Not quantified</p>
<p>n-3 FAs meal (form fish oil concentrate, MaxEPA)</p>
<p>Mixed oil meal (palm, olive, coconut and corn oil)</p>
<p>Designed to represent the fatty acid content of the U.K. diet.</p>
<p>Corn oil meal (rich in n-6 FAs)</p></td>
<td>11 healthy male subjects were recruited from the student population
of the University of Surrey.</td>
<td><p><u>TG:</u> The postprandial incremental area under the curve
(IAUC) was significantly (p&lt;0.05) reduced after fish oil meal than
after mixed oil meal. A sharp peak response in TG at 60 min was observed
and the rise was sustained between 180 and 420 min postprandially with
mixed oil meal. With corn oil meal the plasma TG response was
intermediate and no differences were observed with fish or mixed oil
meals. The triacylglycerol-rich-lipoprotein TG (TRL-TG) levels showed
biphasic response after consumption of each meal. The biphasic peaks
were more prominent after mixed oil meal than with fish oil meal. TRL-TG
response to corn oil meal was intermediate. TRL also showed highest
response to mixed oil meal and lowest to fish oil meal.</p>
<p><u>Plasma and TRL-cholesterol:</u> No significant differences in IAUC
for plasma and TRL cholesterol were observed between the three
meals.</p>
<p><u>apo A-1:</u> No significant change with the 3 test oil meals.</p>
<p><u>apo B:</u> No significant change with the 3 test oil
meals.</p></td>
<td><p><u>Conclusion:</u></p>
<p>The findings support the view that, “fish oil decrease postprandial
lipimeia and this may be an important aspect of their beneficial effects
in reducing the risk of CHD”.</p>
<p><u>Comments:</u></p>
<p>The subjects completed 4-day diet records before the treatment and
were asked to continue routine diets. During the test days the meals
were provided by the investigator and consumed at the Clinical
Investigation Unit.</p></td>
<td>2</td>
<td>Not reported</td>
</tr>
</tbody>
</table>

/media/pszemraj/PeterTrove/project-files/DATA/ms-word-files/big-DOC/507383.doc