The Heart Outcomes Prevention Evaluation (HOPE) Study: Limitations and Strengths

Domenic A. Sica, MD; Division of Clinical Pharmacology and Hypertension, Medical College of Virginia, Virginia Commonwealth University, Richmond, VA.

In This Article


The HOPE study showed that ramipril was well tolerated, with the large majority of patients continuing on the full 10-mg dose. There was only a 7.3% excess dropout rate because of ramipril- related cough. In the ramipril group, 82.9% of patients were still taking medication at 1 year, 74.7% at 2 years, 70.9% at 3 years, and 62.5% at 4 years. The numbers of patients taking any ACE inhibitor (including ramipril) were actually higher, with 87.4% of patients in the ramipril group taking either ramipril or an open-label ACE inhibitor at 1 year, and 75.2% of the patients taking an ACE inhibitor at 4 years. In the placebo group, 10.8% of the patients were receiving an open-label ACE inhibitor at year 4.

The primary end point was defined as a combination of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke. The trial was stopped about 1 year early, after 4.5 years of treatment, on the advice of the Data and Safety Monitoring Committee, since the weight of the available evidence strongly supported a more favorable outcome in the ramipril-treated group. During the study period, 17.8% of subjects in the placebo group reached the primary combined end point, compared with 14% in the ramipril-treated group. This difference represented a 22% reduction in relative risk. The individual components of the composite end point were also significantly reduced: by 32% for stroke, 26% for cardiovascular death, and 20% for myocardial infarction. Ramipril also reduced the risk of several other clinical end points, including CHF by 23% and revascularization procedures by 15%. All-cause mortality was reduced by 16%, with divergence of the Kaplan-Meier survival curves by 1 year and continued separation of these curves until the trial was terminated.[7]

Noncardiovascular mortality was equal in the ramipril and placebo treatment groups. A noteworthy feature of the results was the consistency of the findings over a wide range of prespecified subgroup analyses. The results were also the same irrespective of concomitant baseline antihypertensive medications and whether or not patients were taking ß blockers, calcium channel blockers, diuretics, or lipid-lowering agents. In contradistinction to the findings with ramipril, Vitamin E had no positive effects on any of the outcome variables.[9] The reasons why Vitamin E treatment provided no additional benefit are unclear. It is speculated that the study may not have been of sufficient length to show a response to antioxidant therapy and/or that for Vitamin E to show a positive effect it must be given together with other antioxidant therapy, such as Vitamin C. An unexpected finding in the HOPE study was that ramipril-treated patients experienced a 33% reduction in the onset of new diabetes during the 4.5 years of the trial, supporting the similar, though less pronounced, reduction in new-onset diabetes observed in the Captopril Prevention Project (CAPP) study.[10] Since this was not a prespecified end point, this finding requires corroboration in other studies.