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<th colspan="11"><p><strong>Appendix B</strong></p>
<p><strong>Intervention Trials Published 1992-2000 with Omega-3 Fatty
Acids (EPA and DHA) Including a Measure of Vasodilation in the
Protocol</strong></p>
<p><strong>[Shaded rows indicate beneficial effect of Omega-3 Fatty
Acids (EPA and DHA)]</strong></p></th>
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<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>
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<td><p>Fleischhauer et al. 1993</p>
<p><em>JACC</em> 1993;21(4):982-9</p>
<p>[U.S.]</p></td>
<td colspan="2">Controlled trial.</td>
<td colspan="2">3 weeks</td>
<td colspan="2"><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 colspan="2"><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 colspan="2"><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>
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<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>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>
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<td><p>Kothny, et. al. 1998</p>
<h2 id="atherosclerosis">Atherosclerosis</h2>
<p>1998; 140:181-86</p>
<p>[Germany]</p></td>
<td colspan="2">Randomized double-blind placebo controlled study
trial.</td>
<td colspan="2">24 hours</td>
<td colspan="2"><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 colspan="2"><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 colspan="2"><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>
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<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"><u>Vasoactive hormones:</u> no significant change in
norepinephrine, epinephrine, or dopamine, or on plasma renin
activity.</td>
</tr>
<tr class="odd">
<td colspan="2"><p>Watts et al. 1995</p>
<p><em>Can J Cardiol</em> 1995;11:110G-114G</p>
<p>[UK]</p></td>
<td colspan="2"><p>Randomized, single-blind.</p>
<p>Dietary intervention trial.</p></td>
<td colspan="2">156 weeks (39 months)</td>
<td colspan="2"><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 colspan="2"><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>
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