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The Lancet

Volume 354, Issue 9177, 7 August 1999, Pages 447-455
The Lancet

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Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial

https://doi.org/10.1016/S0140-6736(99)07072-5Get rights and content

Summary

Background

There is conflicting evidence on the benefits of foods rich in vitamin E (α-tocopherol), n-3 polyunsaturated fatty acids (PUFA), and their pharmacological substitutes. We investigated the effects of these substances as supplements in patients who had myocardial infarction.

Methods

From October, 1993, to September, 1995, 11 324 patients surviving recent (≤3 months) myocardial infarction were randomly assigned supplements of n-3 PUFA (1 g daily, n=2836), vitamin E (300 mg daily, n=2830), both (n=2830), or none (control, n=2828) for 3·5 years. The primary combined efficacy endpoint was death, non-fatal myocardial infarction, and stroke. Intention-to-treat analyses were done according to a factorial design (two-way) and by treatment group (four-way).

Findings

Treatment with n-3 PUFA, but not vitamin E, significantly lowered the risk of the primary endpoint (relativerisk decrease 10% [95% CI 1–18] by two-way analysis, 15% [2–26] by four-way analysis). Benefit was attributable to a decrease in the risk of death (14% [3–24] two-way, 20% [6–33] four-way) and cardiovascular death (17% [3–29] two-way, 30% [13–44] four-way). The effect of the combined treatment was similar to that for n-3 PUFA for the primary endpoint (14% [1–26]) and for fatal events (20% [5–33]).

Interpretation

Dietary supplementation with n-3 PUFA led to a clinically important and satistically significant benefit. Vitamin E had no benefit. Its effects on fatal cardiovascular events require further exploration.

Introduction

The protective effects of foods rich in n-3 polyunsaturated fatty acids (PUFA) derived from marine vertebrates, vitamin E (α-tocopherol), and their pharmacological equivalents on cardiovascular risk has been of interest for the past 20 years.1, 2, 3, 4 Since a low rate of coronary heart disease was reported in the Eskimo population exposed to a diet rich in fish oil,5 several studies have explored and supported antiatherogenic, antithrombotic, and antiarrhythmic effects of n-3 PUFA.2, 3, 4 Although no consensus existed on the underlying mechanism of action, focus was placed on the ability of triglycerides to lower high-dose n-3 PUFA (registration approval was given for this indication), and to modify membrane composition.2, 3, 4 A protective role in the secondary prevention of coronary heart disease was seen for fatty fish in the Diet And Reinfarction Trial (DART).6

By contrast, large observational cohort studies7, 8, 9, 10 support the role of vitamin E as an antioxidant against the proatherogenic and prothrombotic effects of LDL oxidation.11, 12, 13 However, controlled trials testing this hypothesis in populations with different background cardiovascular risk produced controversial results. No decrease in cardiovascular events was seen with low-dose (50 mg daily) vitamin E supplementation in smokers;14 a significant decrease in non-fatal myocardial infarction and an increase in fatal cardiovascular events was reported with a daily regimen of 400–800 mg vitamin E in patients with angiographically proven coronary atherosclerosis.15

A possible complementary role for these two dietary components has been purported: vitamin E could improve the role of n-3 PUFA through protection from lipid peroxidation, by acting independently on the same or closely related atherogenic and thrombotic mechanisms, or both.4, 16

We investigated in the Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico (GISSI)-Prevenzione trial the independent and combined effects of n-3 PUFA and vitamin E on morbidity and mortality after myocardial infarction.17

Section snippets

Patients

We enrolled patients with recent (≤3 months) myocardial infarction. Eligible patients had no contraindications to the dietary supplements (ie, known allergy to n-3 PUFA or α-tocopherol, or known congenital defects of coagulation), were able to provide informed written consent, and had no unfavourable short-term outlook (eg, overt congestive heart failure, cancers, &c). We did not define age limits.

Study design

We used a multicentre, open-label design, in which patients were randomly allocated to four

Results

Between October, 1993, and September, 1995, 11 324 patients were recruited (figure 1) by 172 participating centres (130 cardiological departments and 42 rehabilitation centres) across Italy. Information on vital status at the end of the study was 99·9% complete for a total person-time of 38 053 years. Median time from the index myocardial infarction to randomisation was 16 days. Baseline demographic and clinical characteristics were well balanced across the groups (table 1) and define a

Discussion

Treatment with n-3 PUFA significantly decreased, over 3·5 years, the rate of death, non-fatal myocardial infarction, and stroke. No effect was seen for vitamin E. When data were analysed by four-way analysis, the size of the beneficial effect of n-3 PUFA became more evident and more clearly significant; the absence of a significant effect was confirmed for vitamin E.

The degree of the effects on rates of death deserves to be specifically highlighted and is suggestive of hypotheses that could

References (60)

  • JH Christensen et al.

    Fish consumption, ω-3 fatty acids in cell membranes, and heart rate variability in survivors of myocardial infarction with left ventricular dysfunction

    Am J Cardiol

    (1997)
  • JX Kang et al.

    Prevention and termination of the β-adrenergic agonist-induced arrhythmias by free polyunsaturated fatty acids in neonatal rat cardiac myocytes

    Biochem Biophys Res Commun

    (1995)
  • MJ Mitchinson et al.

    Mortality in the CHAOS trial

    Lancet

    (1999)
  • A Ness et al.

    Mortality in the CHAOS trial

    Lancet

    (1999)
  • JM Rapola et al.

    Randomised trial of alphatocopherol and beta-carotene supplements on incidence of major coronary events in men with previous myocardial infraction

    Lancet

    (1997)
  • S MacMahon et al.

    Blood pressure, stroke, and coronary heart disease, part 1, prolonged differences in blood pressure: prospective observational studies corrected for the regression dilution bias

    Lancet

    (1990)
  • R Collins et al.

    Blood pressure, stroke, and coronary heart disease, part 2, short-term reductions in blood pressure: overview of randomised drug trials in their epidemiological context

    Lancet

    (1990)
  • P Weber et al.

    Vitamin E and human health: rationale for determining recommended intake levels

    Nutrition

    (1997)
  • EK Porkkala-Sarataho et al.

    A randomized, single-blind, placebo-controlled trial of the effects of 200 mg α-tocopherol on the oxidation resistance of atherogenic lipoproteins

    Am J Clin Nutr

    (1998)
  • FJ De Waart et al.

    Vitamin E supplementation in elderly lowers the oxidation rate of linoleic acid in LDL

    Atherosclerosis

    (1997)
  • GS Omenn

    What accounts for the association of vegetables and fruit with lower incidence of cancers and coronary heart disease?

    Ann Epidemiol

    (1995)
  • P Jha et al.

    The antioxidant vitamins and cardiovascular disease: a critical review of epidemiological and clinical trial data

    Ann Intern Med

    (1995)
  • AP Simopoulos

    ω-3 fatty acids in the prevention-management of cardiovascular disease

    Can J Physiol Pharmacol

    (1997)
  • R Marchioli et al.

    Per i Ricercatori GISSI-Prevenzione. Il quadro di riferimento biochimico, farmacologico, epidemiologico del GISSI-Prevenzione

    G Ital Cardiol

    (1993)
  • HO Bang et al.

    The composition of food consumed by Greenland Eskimos

    Acta Med Scand

    (1976)
  • EB Rimm et al.

    Vitamin E consumption and the risk of coronary heart disease in men

    N Engl J Med

    (1993)
  • MJ Stampfer et al.

    Vitamin E consumption and the risk of coronary disease in women

    N Engl J Med

    (1993)
  • LH Kushi et al.

    Dietary antioxidant vitamins and death from coronary heart disease in postmenopausal women

    N Engl J Med

    (1996)
  • Marchioli R. Antioxidant vitamins and prevention of cardiovascular disease: laboratory, epidemiological, and clinical...
  • D Steinberg

    Antioxidants in the prevention of human atherosclerosis

    Circulation

    (1992)
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