Vitamin E did not reduce myocardial infarction, death, or stroke in adults at high risk for cardiovascular events

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Vitamin E did not reduce myocardial infarction, death, or stroke in adults at high risk for cardiovascular events

The Heart Outcomes Prevention Evaluation Study Investigators. Vitamin E supplementation and cardiovascular events in high-risk patients. N Engl J Med 2000 Jan 20;342:154-60

QUESTION: In adults who have a high risk for cardiovascular events, do vitamin E supplements improve cardiovascular outcomes?

Design

Randomised {allocation concealed*}†, blinded {patients, clinicians, and outcome assessors}^#,* placebo controlled trialwith a 2 × 2 factorial design and a mean follow up of 4.5 years (Heart Outcomes Prevention Evaluation [HOPE] study).

Setting

161 centres in North America, 76 in 14 western European countries, and 30 in Argentina and Brazil.^#

Patients

9541 patients (mean age 66 y, 73% men) who were >= 55 years of age and had a history of coronary artery disease, stroke, peripheral vascular disease, or diabetes and >= 1 other cardiovascular disease risk factor. Exclusion criteria were heart failure, ejection fraction < 0.4, use of an angiotensin converting enzyme inhibitor or vitamin E, uncontrolled hypertension, nephropathy, or myocar. dial infarction (MI) or stroke in the previous four weeks. Follow up was 99.9%.^#

Intervention

Patients were allocated to one of four groups: ramipril and vitamin E; ramipril and placebo; vitamin E and placebo; or placebo alone. 4761 adults were assigned to vitamin E and 4780 to placebo. Doses were 10 mg/day of ramipril and 400 IU/day of vitamin E .

Main outcome measures

Combined outcome of MI, stroke, or death from cardiovascular causes. Secondary outcomes included all cause mortality.

Main results

Vitamin E and placebo groups did not differ for any out. come (table).

Vitamin E v placebo for adults at high risk for cardiovascular events§

Outcomes at mean 4.5 years Vitamin E Placebo RRI (95% CI) NNH

Myocardial infarction, stroke, or cardiovascular mortality 16% 15% 5% (-4 to 15) Not significant

Cardiovascular mortality 7.1% 6.9% 5% (-10 to 21) Not significant

Myocardial infarction 11.2% 11.0% 2% (-9 to 14) Not significant

Stroke 4.4% 3.8% 17 (-4 to 42)% Not significant

All cause mortality 11% 11% 0% (-11 to 12) Not significant

§Abbreviations defined in glossary; RRI, NNH, and CI calculated from data in article.

Conclusion

In adults at high risk for cardiovascular events, vitamin E, 400 IU/day, did not reduce myocardial infarction, stroke, or death.
†The HOPE Study Investigators. Can J Cardiol 1996;12:127-37.
^#The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 2000;342:145-53.

COMMENTARY
Research linking low density lipoprotein (LDL) oxidation with atherogenesis led to expectations that antioxidant sup. plements would reduce cardiovascular disease. The HOPE study is yet another large, randomised, controlled trial that fails to show any cardiovascular benefit from antioxidants.^1,2 Although a single tertiary prevention trial found that vitamin E reduced the risk for non.fatal MIs, results were challenged because supplements were taken for a relatively short time, treatment groups were not comparable at baseline, and cardiovascular mortality risk was unaffected.³
Why was vitamin E not effective for the high risk patients in the HOPE study? Healthy adults receiving 400 IU of vitamin E can substantially increase plasma antioxidant concentrations and inhibit LDL oxidation. However, patients with existing disease may need higher doses because of increased oxidative stress. Another possibility is that longer term antioxidant treatment is required, although an observational study found that two years of supplemental intake was sufficient to lower the risk for coronary disease. 1 Ongoing trials are also looking at combinations of antioxidants, which may be more effective than a single supplement.¹ Furthermore, several of these trials address potential sex differences in outcomes by enrolling only women; women made up just 27% of the HOPE study participants.
How should antioxidants be used in practice? Vitamin E is clearly safe, but no conclusive evidence exists to show that supplements reduce cardiovascular disease. While awaiting results from ongoing trials, providers should encourage patients to eat fruits and vegetables and to continue with proven strategies to prevent cardiovacular disease.
Richard M Hoffman job title
Albuquerque Veterans Affairs Medical Center Albuquerque, New Mexico, USA

1 Jha P, Flather M, Lonn E, et al. The antioxidant vitamins and cardiovascular disease. A critical review of epidemiologic and clinical trial data. Ann Intern Med 1995;123:860-72.

2 GISSI.Prevenzione Investigators. Dietary supplementation with n.3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI.Prevenzione trial. Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico. Lancet 1999;354:447-55.

Stephens NG, Parsons A, Schofield PM, et al. Randomised controlled trial of vitamin E in patients with coronary disease: Cambridge Heart Antioxidant Study (CHAOS). Lancet 1996;347:781-6.