The HOPE trial: Ramipril significantly reduces cardiovascular events in high-risk patients with normal ejection fractions [Classics Series]

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1. Ramipril significantly reduces cardiovascular events including MI, stroke and death in high risk-patients in the absence of left ventricular dysfunction

Original Date of Publication: January 20, 2000

Study Rundown: The HOPE trial was the first to provide evidence for the potential benefit of angiotensin-converting-enzyme inhibitors (ACE-Is) for vascular protection in preventing adverse cardiac outcomes among a broad range of high-risk patients with normal ejection fractions. After its publication, there was some criticism that the blood pressure lowering effect of ramipril may have accounted for the improved cardiac outcomes, as opposed to the medication itself. However, most patients did not have baseline hypertension in this study and the difference in blood pressure between the two groups was very small.

Even in the absence of reduced ejection fraction or high blood pressure, the addition of ramipril for high-risk patients at least 55 years of age may be considered for protection against adverse cardiovascular outcomes and death.

Click to read study in NEJM

Primer: Prior to the publication of the HOPE trial, the benefit of ACE-Is had been well established in improving long-term outcomes in patients with heart failure associated with reduced left ventricular ejection fraction. There was also evidence for the value of these medications in controlling blood pressure, particularly in diabetic patients in the presence of microalbuminuria. At the time, however, there was limited evidence as to whether ACE-Is provided any cardiovascular protection in the absence of left ventricular dysfunction. That is, there was uncertainty as to whether the blockade of the renin-angiotensin system offers any inherent benefit in improving cardiac outcomes in high-risk populations, independent of its effect on blood pressure or preventing the progression of systolic heart failure.

The HOPE trial was published in The New England Journal of Medicine in 2000. This landmark randomized control study looked at the effect of ramipril on major cardiovascular events in high-risk patients over 55 years old with normal ejection fractions.

Relevant Reading:

1. Fox KM, EURopean trial On reduction of cardiac events with Perindopril in stable coronary Artery disease Investigators. Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: Randomised, double-blind, placebo-controlled, multicentre trial (the EUROPA study). Lancet 2003;362(9386):782-788.
2. Braunwald E, Domanski MJ, Fowler SE, et al. Angiotensin-converting-enzyme inhibition in stable coronary artery disease. N Engl J Med 2004;351:2058-2068.
3. Heart Outcomes Prevention Evaluation (HOPE) Study Investigators. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: Results of the HOPE study and MICRO-HOPE substudy. Heart Outcomes Prevention Evaluation Study Investigators. Lancet 2000;355(9200):253-259.

In-Depth [randomized, control study]: This large, double-blind, randomized control study included 9,541 patients from 281 centers internationally. Patients with known low ejection fraction (EF<40%), history of heart failure or who were already on a ACE-inhibitor were excluded from this study. Patients were randomized to either receive 1) placebo or 2) ramipril titrated up to 10mg daily. Primary outcomes were myocardial infarction, stroke, or death from cardiovascular causes. The trial lasted a total of 5 years. The ramipril group demonstrated significantly reduced cardiovascular outcomes (i.e., MI, stroke, death) compared to the placebo group. This finding held true among a broad range of patients in this study: subgroup analysis showed that the benefit of ramipril was consistent despite sex, age, cardiac risk factors, presence of diabetes, evidence of cardiovascular disease, baseline blood pressure, or evidence of microalbuminuria. The most common adverse effect of ramipril was cough.

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