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<tr class="header">
<th colspan="11"><p><strong>Appendix A</strong></p>
<p><strong>Intervention Trials Published 1992-2000 with Omega-3 Fatty
Acids (EPA and DHA) Including a Measure of Blood Pressure in the
Protocol</strong></p>
<p><strong>[Shaded rows indicate beneficial effect of Omega-3 fatty
acids (EPA and DHA)]</strong></p></th>
</tr>
<tr class="odd">
<th><strong>Reference</strong></th>
<th colspan="2"><strong>Study design</strong></th>
<th colspan="2"><strong>Duration</strong></th>
<th colspan="2"><strong>Intake</strong></th>
<th colspan="2"><strong>Subjects</strong></th>
<th colspan="2"><strong>Results</strong></th>
</tr>
</thead>
<tbody>
<tr class="odd">
<td><p>Andreassen et al. 1997</p>
<h2 id="jacc-19972961324-31">JACC 1997;29(6):1324-31</h2>
<p>[Norway]</p></td>
<td colspan="2">Randomized, double-blind, placebo-controlled trial.</td>
<td colspan="2">24 weeks (6 months)</td>
<td colspan="2"><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 colspan="2"><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 colspan="2"><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>
</tr>
<tr class="even">
<td colspan="2"><p>Bao et al. 1998</p>
<h2 id="hypertension">Hypertension</h2>
<p>1998;32:710-17</p>
<p>[Australia]</p></td>
<td colspan="2">Randomized, control factorial design</td>
<td colspan="2"><p>16 weeks</p>
<p>4 week familiarization period for baseline measurements</p></td>
<td colspan="2"><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 colspan="2"><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>
</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 colspan="2">Randomized, placebo-controlled trial.</td>
<td colspan="2">12 weeks</td>
<td colspan="2"><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 colspan="2">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 colspan="2"><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>
</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 colspan="2">Randomized, patient-blind, placebo controlled study
design.</td>
<td colspan="2">4 weeks (28 days)</td>
<td colspan="2"><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 colspan="2"><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 colspan="2"><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>
</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 colspan="2">Randomized, single-blind, placebo-controlled study
design</td>
<td colspan="2">4 weeks</td>
<td colspan="2"><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 colspan="2"><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 colspan="2"><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><u>Norepinephrine</u>:</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><u>Angiotensin II</u>:</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></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 colspan="2">Randomized, single-blind, placebo controlled study
design.</td>
<td colspan="2"><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 colspan="2"><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 colspan="2"><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 colspan="2"><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>
</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 colspan="2">Randomized, double-blind, placebo controlled trial</td>
<td colspan="2">12 weeks (3 months)</td>
<td colspan="2"><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 colspan="2"><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 colspan="2"><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>
</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 colspan="2">Randomized, double-blind controlled trial</td>
<td colspan="2">8 weeks</td>
<td colspan="2"><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 colspan="2"><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 colspan="2"><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></td>
</tr>
<tr class="odd">
<td colspan="2"><p>Grundt et al. 1995</p>
<p><em>J Internal Med</em> 1995;237:249-259</p>
<p>[Norway]</p></td>
<td colspan="2">Randomized, double-blind, placebo controlled trial.</td>
<td colspan="2"><p>12 weeks on K85</p>
<p>10 weeks run-in period</p></td>
<td colspan="2"><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 colspan="2"><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>The EPA and DHA levels in serum phospholipids increased
significantly (p&lt;0.05) with n-3 PUFAs supplementation.</td>
</tr>
<tr class="even">
<td colspan="2"><p>Hansen et al. 1993</p>
<p><em>Eur J Clin Nutr</em> 1993;47:497-507</p>
<p>[Norway]</p></td>
<td colspan="2"><p>Randomized</p>
<p>Double blind</p>
<p>Placebo-controlled</p></td>
<td colspan="2">7 weeks</td>
<td colspan="2"><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 colspan="2"><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>BP:</u> NS</p>
<p><u>TxB2:</u> ↓ vs. control for Tri (P=0.035) &amp; EE
(P=0.0002).</p></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 colspan="2">Double-blind, randomized, controlled trial.</td>
<td colspan="2"><p>20 weeks</p>
<p>(5 months)</p></td>
<td colspan="2"><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 colspan="2"><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 colspan="2"><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).</td>
</tr>
<tr class="even">
<td><p>Howe et al. 1994</p>
<p>Journal of Human Hypertension</p>
<p>1994;8:43-49</p>
<p>[Australia]</p></td>
<td colspan="2">Randomized, double-blind controlled study</td>
<td colspan="2">6 weeks following a 4 week run-in</td>
<td colspan="2"><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 colspan="2"><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 colspan="2"><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>
</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 colspan="2">Randomized, double-blind, placebo-controlled, parallel
study</td>
<td colspan="2"><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 colspan="2"><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 colspan="2"><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 colspan="2"><p><u>BP:</u> no significant changes were seen in any of
the treatment groups from either study.</p>
<p>EPA ↑ both in plasma and platelet phospholipids significantly in all
5 treatment groups compared to baseline (p&lt;0.05).</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 colspan="2">Randomized double-blind, placebo controlled crossover
study</td>
<td colspan="2">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 colspan="2"><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 colspan="2">8 normotensive men</td>
<td colspan="2"><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>
</tr>
<tr class="odd">
<td><p>Landmark et al. 1993</p>
<p>Journal of Human Hypertension</p>
<p>1993;7:25-32</p>
<p>[Norway]</p></td>
<td colspan="2">Randomized double-blind, crossover, placebo-controlled
study</td>
<td colspan="2"><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 colspan="2"><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 colspan="2"><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 colspan="2"><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>
</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 colspan="2"><p>Randomized, double-blind, placebo controlled,
two-period</p>
<p>crossover study design</p></td>
<td colspan="2">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 colspan="2"><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 colspan="2"><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 colspan="2"><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>
</tr>
<tr class="odd">
<td colspan="2"><p>Luostarinen et al. 1995</p>
<p><em>Nutrition Research</em> 1995;15(7):953-968</p>
<p>[Sweden]</p></td>
<td colspan="2"><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 colspan="2"><p>4 weeks on FO</p>
<p>4 weeks on FO+E</p>
<p>6 weeks washout period</p></td>
<td colspan="2"><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 colspan="2">11 subjects with normal or mildly high TG levels were
recruited.</td>
<td><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>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>
</tr>
<tr class="even">
<td colspan="2"><p>Mackness et al. 1994</p>
<p><em>Eur J Clin Nutr</em> 1994;48:859-865</p>
<p>[U.K.]</p></td>
<td colspan="2"><p>Randomized,</p>
<p>Double-blind,</p>
<p>Placebo- controlled</p>
<p>Multi-center (7)</p></td>
<td colspan="2">14 weeks</td>
<td colspan="2"><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 colspan="2"><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>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>
</tr>
<tr class="odd">
<td colspan="2"><p>Mori et al. 1994</p>
<p><em>Am J Clin Nutr</em> 1994;59:1060-8</p>
<p>[Australia]</p></td>
<td colspan="2">Randomized, controlled trial.</td>
<td colspan="2">12 weeks</td>
<td colspan="2"><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 colspan="2">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>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>
</tr>
<tr class="even">
<td><p>Morris, et. al.</p>
<p>1993</p>
<h2 id="am-j-clin-nutr">Am J Clin Nutr</h2>
<p>1993;57:59-64</p>
<p>[U.S.]</p></td>
<td colspan="2">Randomized, double-blind, placebo-controlled crossover
study design</td>
<td colspan="2"><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 colspan="2"><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 colspan="2"><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 colspan="2"><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></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 colspan="2"><p>Randomized, double-blind, cross-over study
design.</p>
<p>.</p></td>
<td colspan="2"><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 colspan="2"><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 colspan="2"><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 colspan="2"><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).</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 colspan="2"><p>Randomized,</p>
<p>parallel</p>
<p>single-blind</p></td>
<td colspan="2"><p>13 weeks</p>
<p>(90 days)</p>
<p>with a 30- day stabilization period prior to intervention</p></td>
<td colspan="2"><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 colspan="2"><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 colspan="2"><u>Blood pressure</u>: no significant changes</td>
</tr>
<tr class="odd">
<td colspan="2"><p>Nordoy et al. 1998</p>
<p><em>J. Intern Med</em> 1998;243:163-170</p>
<p>[Norway]</p></td>
<td colspan="2"><p>Randomized,</p>
<p>double-blind,</p>
<p>placebo-controlled trial.</p></td>
<td colspan="2"><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 colspan="2"><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 colspan="2"><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>DBP:</u> ↓ (p=0.054)</p>
<p><u>SBP:</u> NS</p></td>
</tr>
<tr class="even">
<td><p>Passfall et al. 1993</p>
<p>The Clinical Investigator</p>
<p>1993;71:628-633</p>
<p>[Germany]</p></td>
<td colspan="2">Randomized, double-blind, crossover study</td>
<td colspan="2"><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 colspan="2"><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 colspan="2"><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 colspan="2"><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>
</tr>
<tr class="odd">
<td><p>Prisco et. al. 1998</p>
<p><em>Thrombosis Res.</em> 1998; 91:105-12</p>
<p>[Italy]</p></td>
<td colspan="2">Randomized double-blind, parallel group trial.</td>
<td colspan="2"><p>16 weeks</p>
<p>(4 months) supplementation with a 2 month follow-up after
discontinuation of PUFAs</p></td>
<td colspan="2"><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 colspan="2"><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 colspan="2"><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>
</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 colspan="2"><p>Randomized single-blind, controlled trial</p>
<p>Multicenter</p></td>
<td colspan="2">24 weeks (6 months)</td>
<td colspan="2"><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 colspan="2"><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 colspan="2"><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>
</tr>
<tr class="odd">
<td colspan="2"><p>Salachas et al. 1994</p>
<p><em>J Vascular Disease</em> 1994;45(12):1023-1031.</p>
<p>[Greece, England]</p></td>
<td colspan="2"><p>Randomized,</p>
<p>double-blind,</p>
<p>placebo-controlled trial.</p></td>
<td colspan="2"><p>12 weeks</p>
<p>(2-weeks run-in period first.)</p></td>
<td colspan="2"><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 colspan="2"><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><u>SBP &amp; DBP:</u> trend ↓</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 colspan="2">A randomized, double-blind, placebo controlled
study.</td>
<td colspan="2">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 colspan="2"><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 colspan="2"><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 colspan="2"><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>
</tr>
<tr class="odd">
<td><p>Toft et al. 1995</p>
<p><em>Ann Intern Med</em> 1995;123:911-918</p>
<p>[Norway]</p></td>
<td colspan="2">Randomized, double-blind, placebo-controlled.</td>
<td colspan="2">16 weeks</td>
<td colspan="2"><p>4 g/d fish oil as ethyl esters (Omacor) (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 colspan="2"><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 colspan="2"><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>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>
</tr>
<tr class="even">
<td><p>Vandongen et al. 1993</p>
<p><em>Hypertension</em> 1993;22:371-9</p>
<p>[Australia]</p></td>
<td colspan="2">Randomized, placebo-controlled trial.</td>
<td colspan="2">12 weeks with an initial 1-week baseline period.</td>
<td colspan="2"><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 colspan="2"><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 colspan="2"><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>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></td>
</tr>
<tr class="odd">
<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 colspan="2">Randomized double-blind controlled trial</td>
<td colspan="2">12 weeks</td>
<td colspan="2"><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 colspan="2"><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 colspan="2"><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>
</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 colspan="2">Randomized, controlled trial.</td>
<td colspan="2">16 weeks (4 months)</td>
<td colspan="2"><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 colspan="2"><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 colspan="2"><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>
</tr>
</tbody>
</table>

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