The Heart Outcomes Prevention Evaluation Study - HOPE - Vitamin E and HOPE TOO


The goal of the trial was to evaluate vitamin E and ramipril for prevention of myocardial infarction (MI), stroke, or cardiovascular death in patients at high risk for cardiovascular events.


Vitamin E, a naturally occurring antioxidant vitamin, and ramipril, an angiotensin-converting enzyme (ACE) inhibitor, will be associated with a reduction in the risk of MI, stroke, or cardiovascular death in an at-risk population.

Study Design

Study Design:

Patients Enrolled: 9,541
Mean Follow Up: Mean follow-up 4.5 years
Mean Patient Age: Mean age 66 years
Female: 27

Patient Populations:

Age ≥55 years; and history of coronary artery disease, stroke, peripheral vascular disease, or diabetes plus at least one other cardiovascular risk factor (hypertension, elevated total cholesterol levels, low high-density lipoprotein cholesterol levels, cigarette smoking, or documented microalbuminuria)


Heart failure, known low ejection fraction (<40%), use of an ACE inhibitor or vitamin E, uncontrolled hypertension or overt nephropathy, or MI or stroke within four weeks prior to enrollment

Primary Endpoints:

Combined endpoint of MI, stroke, or cardiovascular death

Secondary Endpoints:

Death from any cause; unstable angina, defined as worsening angina or angina at rest requiring hospitalization; hospitalization for heart failure with clinical and radiologic signs of congestion; revascularization or limb amputation; the development of overt nephropathy or the need for dialysis or laser therapy among patients with diabetes; and the development of heart failure or new or worsening angina regardless of the need for hospitalization

Drug/Procedures Used:

Patients were randomized to vitamin E (400 IU/day, n=4,761) or placebo (n=4,780). In a factorial design, patients were also randomized to ramipril (10 mg/day, n=4,645) or placebo (n=4652). Following the initial HOPE trial, sites were given the option to continue in the HOPE TOO trial, which extended the duration of treatment and follow-up for an average of 2.6 years. Of the 267 initial sites, 174 participated in the HOPE TOO extension trial.

Principal Findings:

Baseline characteristics were well balanced between the treatment groups, with 53% having a prior MI, 56% stable angina, 26% unstable angina, 43% peripheral vascular disease, and 38% diabetes. At final visit, vitamin E was taken by 89.2% of patients in the vitamin E group and 3.4% in the placebo group.

The primary endpoint of cardiovascular death, MI, or stroke did not differ between the vitamin E group and the placebo group (16.2% vs. 15.5%, relative risk [RR] 1.05, p=0.33). There was also no difference in each of the individual components of the composite endpoint: cardiovascular death (7.2% vs. 6.9%, RR 1.05, p=0.54); MI (11.2% vs. 11.0%, RR 1.02, p=0.74); and stroke (4.4% vs. 3.8%, RR 1.17, p=0.13).

Total mortality was 11.2% in each treatment group (p=0.99). Heart failure occurred more frequently in the vitamin E group (11.0% vs. 9.6%, RR 1.17, p=0.02). The rate of revascularization or limb amputation trended higher in the vitamin E group (17.8% vs. 16.5%, RR 1.09, p=0.07), but there was no difference in the other secondary endpoints of hospitalization for unstable angina (12.3% vs. 11.9%, RR 1.04, p=0.52), hospitalization for heart failure (3.4% vs. 3.0%, RR 1.12, p=0.32), new angina (5.8% vs. 5.1%, RR 1.15, p=0.11), worsening angina (25.5% vs. 24.8%, RR 1.02, p=0.63), or complications of diabetes (7.1% vs. 6.8%, RR 1.06, p=0.47). There was no difference in cancer (11.6% vs 12.3%, RR 0.94, p=0.30).

Results for cancer, major cardiovascular events, and heart failure were similar in the subgroup of patients who continued on in the HOPE-TOO study, an extension of duration from the original HOPE trial.


Among patients at high risk for cardiovascular events, treatment with vitamin E was not associated with a reduction in the primary endpoint of cardiovascular death, MI, or stroke, or in any of the individual endpoints, compared with placebo. On the contrary, the secondary endpoints of heart failure and revascularization or limb amputation were more common in the vitamin E group.

Prior to the present large-scale randomized trial, several observational studies had suggested that consumption of vitamin E may lower the progression of coronary artery lesions and lower the rate of cardiovascular events. However, the nonrandomized nature of these studies prevented definitive conclusions on the benefit of vitamin E. Additionally, prior randomized studies showed conflicting results, with some using a lower dose.

It should be noted that the lack of benefit observed in the present trial with a vitamin E supplement does not reflect the benefit that may be associated with the consumption of foods that are high in vitamin E. The present trial was continued in order to assess the effect of vitamin E on the incidence of cancer.


HOPE and HOPE-TOO Investigators. Effects of Long-term Vitamin E Supplementation on Cardiovascular Events and Cancer. JAMA. 2005;293:1338-1347.

Yusuf S, Dagenais G, Pogue J, Bosch J, Sleight P. Vitamin E supplementation and cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 2000;342:154-60.

Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 2000;342:145-53.

The HOPE (Heart Outcomes Prevention Evaluation) Study: the design of a large, simple randomized trial of an angiotensin-converting enzyme inhibitor (ramipril) and vitamin E in patients at high risk of cardiovascular events. The HOPE study investigators. Can J Cardiol 1996;12:127-37.

Keywords: Myocardial Infarction, Stroke, Follow-Up Studies, Risk Factors, Ramipril, Smoking, Cholesterol, alpha-Tocopherol, Heart Failure, Lipoproteins, HDL, Hypertension, Diabetes Mellitus

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