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Abstract & Commentary
Synopsis: ACE inhibition with ramipril caused a significant reduction in cardiovascular end points as well as a decrease in the development of diabetes and renal dysfunction.
Source: American Heart Association Annual Scientific Sessions, November 7-10, 1999, Atlanta, GA.
The heart outcomes prevention evaluation (hope) trial randomized 9541 high-risk patients to the angiotensin-converting enzyme (ACE) inhibitor ramipril (10 mg/d) or placebo and vitamin E (400 IU/d) or placebo for a mean follow-up period of 4.5 years. This international study was carried out in 267 hospitals and 19 countries, with the majority of patients coming from the United States. The ramipril arm was stopped in early 1999 because of a favorable outcome for the ACE inhibitor; the vitamin E arm has continued. The study population consisted of individuals with documented coronary artery disease (CAD), cerebrovascular, or peripheral vascular disease. In addition, diabetics without vascular disease with at least one additional CAD risk factor were enrolled. All individuals were older than 55 years of age. Patients had no history of heart failure; hypertensives could be enrolled if blood pressure was controlled (46% had hypertension). Thirty-eight percent had diabetes, 11% had a previous stroke, 43% had peripheral vascular disease, and two-thirds had an elevated cholesterol level. Eighty-one percent of all patients had CAD, half with a prior myocardial infarction (MI). The results were striking, with a robust 20-25% reduction in relative risk favoring ramipril for all vascular end points. (See Table.) There was a 22% reduction in the primary end point of cardiac death, stroke, or nonfatal MI (17.7% vs 14.1%). There was a major decrease in stroke and in new heart failure as well as for revascularization. Of interest, new onset diabetes was decreased by 32% (P = 0.002). New renal dysfunction/dialysis or microalbuminuria was also decreased by ramipril. An echo substudy of approximately half the entire cohort (mean ejection fraction of 60%) demonstrated comparable risk reductions for all end points as the entire cohort. Higher risk patients had a greater reduction in events than those at lower risk. It was concluded that lowering of blood pressure only accounted for a small proportion of the decrease of MI and other end points; individuals in the highest quartile of baseline systolic blood pressure had the greatest risk reduction. The hypertensive and nonhypertensive patients had no difference in benefit from ramipril. Vitamin E had no effect on total mortality, cardiovascular deaths, or other end points.
Comment by Jonathan Abrams, MD
These data have already achieved considerable attention and were formally announced at the European Cardiac Society Meeting at the end of August. The benefits of the ACE inhibitor in individuals who ordinarily would not be treated with such a drug are impressive and concordant with a large amount of vascular biology research, endothelial function studies, and mechanistic hypotheses regarding prevention or slowing progression of vascular disease. These data raise the question as to whether all individuals who meet the HOPE criteria should be treated with an ACE inhibitor. Given that the entire cohort had an event rate of cardiac death, stroke, or MI of greater than 3% per year, it seems reasonable that for patients with documented vascular disease, representing the majority of the HOPE cohort, or individuals at high risk for future events (e.g., diabetics with risk factors or those with multiple CAD risk factors), ACE inhibitor therapy should be considered. There is considerable disappointment regarding the antioxidant hypothesis because of the null effects of vitamin E. Earlier data this year from the GISSI-3 trial were also negative in a large population given vitamin E. Some believe that the combination of vitamin E and vitamin C, or the use of different antioxidants, will be necessary to really test the oxidation hypothesis. Certainly, HOPE and GISSI-3 deflate the present enthusiasm for routine use of antioxidant vitamins. (Dr. Abrams is Professor of Medicine, Division of Cardiology, University of New Mexico, Albuquerque.)
|HOPE||End Points (Ramipril vs Placebo)|
|RAM (%)||PLAC (%)||P Value||RR|
|CV death, MI, or stroke||14.1||17.7||0.001||0.78|
|Note: The New England Journal of Medicine has taken the unusual step of premature electronic publication of this trial on its electronic website:|
a. There was a 20-25% reduction in relative risk favoring ramipril for all vascular end points.
b. There was a 22% reduction in the primary end point of cardiac death, stroke, or nonfatal MI.
c. New onset diabetes was decreased by 32%.
d. All of the above