Additional subgroup analysis revealed a higher absolute incidence of endpoints in hypertensive patients when compared to those without hypertension. Subjects with microalbuminuria also had a higher absolute event rate compared with nonalbuminuric participants. The relative risk reduction for the primary composite outcome persisted despite these differences.

IV. Clinical Implications of the HOPE Trial

The HOPE study showed that ramipril therapy produced dramatic survival benefits and improved clinical outcomes in high risk patients with and without established cardiovascular disease. The authors of this study have attributed the improved clinical outcomes and decreased mortality specifically to ACE inhibitors and blockade of the renin-angiotensin system rather than blood pressure reduction. The magnitude of blood pressure reduction in this trial (3/2 mmHg) was modest. According to the HOPE investigators, this degree of blood pressure reduction appeared to have played only a minor role and likely accounted for less than half of the risk reduction reported. Like others, they have postulated that the ACE inhibitor, ramipril, may have a direct protective effect on the endothelium, vasculature and myocardium. However, this trial was not designed to answer this mechanistic question.

These results clearly support the use of an ACE inhibitor as essential therapy for high risk patients with cardiovascular disease. Using strict evidence-based medicine, JNC VI currently recommends the use of ACE inhibitors as initial drug therapy only for hypertensive patients with diabetes mellitus and proteinuria, heart failure, or myocardial infarction with systolic dysfunction. The striking results of the HOPE trial should compel physicians to include high cardiovascular risk (defined as a history of stroke, myocardial infarction, peripheral arterial disease, or diabetes plus an additional independent risk factor) as a compelling indication for ACE inhibitors as initial therapy.

Concern remains about the possible adverse effects of ACE inhibitor therapy. In the HOPE trial, the most commonly encountered adverse effect was cough, which occurred in about 7% of ramipril treated participants. More serious adverse reactions such as angioedema were quite rare and occurred in only 0.4% of ramipril treated subjects. Adverse reactions do occur but in a small minority of patients and should not dissuade the clinician from using ACE inhibitors in these high-risk vascular disease patients who stand to gain a substantial benefit.

There may also be additional benefits from ACE inhibitor therapy as compared to other agents. Patients treated with ramipril in the HOPE Trial had a significantly lower incidence of new diagnosis of diabetes when compared to those who received placebo. This stands in sharp contrast to data with other anti-hypertensive agents, especially diuretics and beta-blockers. For example, a recent retrospective analysis of beta-blocker therapy (ARIC) revealed a 28% increase in the incidence of new diabetes as compared to other agents.

In the past, questions have been raised about a possible negative interaction between aspirin and ACE inhibitors. This concern likely stemmed from some observations from the SOLVD study where there was a trend for less benefit of the ACE inhibitor in a subgroup of patients on aspirin. In the HOPE study more than 70% of patients were on aspirin and no negative interaction between the two drugs was perceived. The addition of ACE inhibitors to aspirin therapy in this patient population may actually produce an additive beneficial effect as has been observed in the post-myocardial infarction studies.

The HOPE study has convincingly demonstrated that ACE inhibitor therapy can be used safely in combination with standard medical therapy for high risk cardiovascular disease patients with or without coexistent hypertension. ACE inhibitors should not replace other therapies, but should be used in combination with them in order to achieve the highest possible survival benefit for patients at risk. High-risk vascular disease patients stand to benefit considerably from the concerted efforts of physicians to employ the knowledge gained from the HOPE trial.

Selected References:

1. 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 Jan 20;342(3):145-53.

2. The 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. Lancet. 2000 Jan 22;355(9200):253-9.

3. National Institutes of Health. The Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Bethesda, MD: National Heart, Lung, and Blood Institute;November 1997. NIH Publication No. 98-4080.