Several clinical trials have studied the effects of PUFAs in CAD. The initial trial which evaluated the effects of fish oil in CAD was the Diet and Reinfarction Trial (DART).22 This was a randomized, non blinded, controlled trial which evaluated 2,033 male patients 4-6 weeks after an MI. The patients were followed for 2 years and divided into 3 study groups according to either fat intake (<30% of total calories), fiber intake (≥18 grams/day), and fatty fish intake (2 servings of oily fish per week). The primary endpoint was mortality and secondary endpoints were cardiac death and nonfatal MI. The group who received fatty fish displayed a 29% reduction (p<0.05) in mortality compared to the other study groups. The incidence of cardiac death was reduced in the fatty fish group by 33% (p<0.05). The study investigators speculated that the observed benefits of fatty fish intake was acquired from a reduction in SCD.
The Japan Eicosapentaenoic acid (EPA) Lipid Intervention Study (JELIS) trial23 studied 18,645 hypercholesterolemic patients (total cholesterol≥250 mg/dL) in Japan who received statins with (n=9326) or without (n=9319) 1800 mg of EPA daily. The study was a randomized, open labeled, blinded study with 5 year patient follow-up. The primary endpoint was any major adverse coronary event (MACE), including sudden death, fatal and non-fatal MI, and other non-fatal events such as unstable angina, angioplasty, stenting, or coronary artery bypass grafting (CABG). Patients receiving EPA showed a 19% relative reduction in major coronary events (p=0.011). EPA treated patients also had 24% risk reduction in unstable angina and a 19% risk reduction in nonfatal coronary events. Thus, EPA administration showed beneficial effects in Japanese patients with hypercholesterolemia.
The GISSI-Prevenzione trial9 (Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico) enrolled 11,324 patients three months after a MI to assess the effects of vitamin E (300 mg daily), PUFAs (1 gram daily), or no supplements on cardiovascular disease post MI. Patients were followed for 3.5 years and the primary endpoints included death, nonfatal MI, and stroke. Vitamin E showed no effect while PUFAs reduced death, combined death, non-fatal MI, and stroke. PUFAs reduced primary endpoints by 15% (p=0.023) and all cause mortality by 20%. Cardiovascular death was decreased by 30% and sudden deaths were decreased by 45%. The benefits were derived from a reduction in overall cardiovascular, coronary, and sudden death. This was a critical study which supported the tremendous cardioprotective benefits of PUFAs in patients after an MI.
A review by Harper et al.24 evaluated the effects of PUFAs in CAD. Fourteen randomized clinical trials were included with patients administered 0.85 to 4.8 grams of PUFAs daily. The review concluded that PUFAs may reduce total mortality, coronary artery disease death, and sudden death. Since it was a review of 14 randomized clinical trials, the composite reduction of total mortality amongst all the studies was not provided. However, the largest study included in the review, GISSI Prevenzione trial, consisting of 11,324 patients reported a 20% total mortality reduction and a 30% reduction of cardiovascular death. Therefore, the daily consumption of 0.5 to 1.8 grams of EPA and DHA may provide significant cardiovascular benefits.24
However, other studies have showed no significant effects of PUFAs in CAD. The recently published OMEGA Trial25 was a randomized, double-blind, placebo-controlled, prospective, multicenter, German study evaluating the effects of omega-3-acid ethyl esters-90 (1 gram/day for 1 year) on the incidence of SCD post-MI. In addition to treatment with PUFAs, enrolled patients were treated with optimal medical therapy for CAD. Patients (3,851) were randomized 3 to 14 days post-MI and underwent coronary angiography (93.8%) and percutaneous coronary intervention (77.8%) with a follow-up of 365 days. Secondary end-points included total mortality and non-fatal clinical events. The study did not reveal a significant benefit with the use of Omacor in addition to currently recommended treatments post-MI versus control in the primary (sudden cardiac death, 1.5% compared to 1.5%, p=0.84), secondary endpoints (total mortality, 4.6% compared to 3.7%, p=0.18), or major adverse cardiovascular events (10.4% to 8.8%, p=0.1).25 However, the study had certain limitations which may have confounded the results. The inclusion criteria for the patient enrollment period post-MI was extended during the study (3 days to 14 days post-MI) and the study did not reach statistical power. Therefore, further studies may be necessary to validate the results of this trial.
A study by Galan et al.26 (SU.FUL.OM3 trial), investigated the effects of PUFAs, B vitamins, or both in the prevention of major cardiovascular events in patients with a history of stroke or coronary artery disease. The double-blind, randomized, placebo controlled trial studied 2,501 patients with a history of myocardial infarction, unstable angina, or ischemic stroke. Patients received daily supplementation with either 5-methyltetrahydrofolate (560 micrograms), vitamin B-6 (3 mg), and vitamin B-12, or placebo; patients received omega-3 fatty acids (600 mg of eicosapentanoic acid and docosahexaenoic acid versus placebo. Mean duration of supplementation was 4.7 years with primary endpoints of non-fatal myocardial infarction, ischemic stroke, or death from cardiovascular cause (fatal MI, stroke, or sudden death). Secondary endpoints included acute coronary syndrome without MI, resuscitation from sudden death, coronary angioplasty, coronary artery bypass surgery, ventricular arrhythmia, supraventricular arrhythmia, cardiac failure, deep venous thrombosis, transient ischemic attack, pulmonary embolism, any vascular procedure, and death from all causes. The study found no significant difference in the prevention of cardiovascular disease with the use of omega-3 fatty acids in patients with a history of ischemic heart disease or strokes. The lack of positive results may be attributed to the initiation of PUFAs 101 days post-MI. The study may represent a true lack of effect associated with PUFAs or an inadequate dose to achieve possible benefits.
A study by Kromhout et al.27, evaluated the effects of PUFAs on cardiovascular events post-MI. In a multicenter, double-blind, placebo-controlled trial, 4,837 post-MI patients were randomized to receive 40 months of either margarine with combination of EPA and DHA, margarine with alpha-linolenic acid (ALA), margarine with EPA-DHA and ALA, or placebo. The primary endpoint (fatal and nonfatal cardiovascular events and cardiac interventions) were not significantly reduced with EPA-DHA, though treatment in a subgroup of women with ALA, compared to placebo and EPA-DHA alone approached statistical significance. The estimated dose of PUFAs in this study was only 376 mg daily, and of ALA was 1.9 g daily.
PUFAs have cardiovascular benefits with a possible reduction in the incidence of all cause cardiac mortality in CAD. Since PUFAs have with minimal adverse effects, it may be considered in conjunction with optimal medical therapy for CAD. Patients who are refractory or intolerant to statins secondary to rhabdomyolysis or other associated side effects may benefit from PUFA consumption for cholesterol reduction. Since they decrease triglycerides and VLDL while increasing HDL, the overall cardiovascular risk profile for atherosclerosis is improved.
However, some studies have shown no beneficial effects of PUFAs for CAD, perhaps limited by the doses used. Therefore, further studies are necessary to unequivocally define the potential benefits for CAD. The final decision to administer PUFAs for cardiovascular protection in CAD should be based on overall individual patient characteristics and consideration of the potential merits.
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