Effects of ACE Inhibition on Cardiovascular Events in High-Risk Patients
abstract & commentary
Synopsis: Treatment with ramipril appears to have protective effects on both the vasculature and the myocardium.
Source: Yusuf S, et al. N Engl J Med 2000;342:145-153.
Epidemiologic and experimental data have clearly demonstrated that activation of the renin-angiotensin-aldosterone system plays an important role in increasing the risk of developing symptomatic and asymptomatic cardiovascular events.1 Reduction of recurrent cardiovascular events has been clearly demonstrated in patients with known coronary artery disease (CAD)1-3 independent of the ejection fraction, the etiology of the heart disease, diabetic status, concomitant use of medications, and regardless of whether hypertension was present. However, an adequately powered study evaluating the benefits of ACE inhibition in patients who are at high risk for cardiovascular events but who were not afflicted with left ventricular systolic dysfunction or heart failure had not been previously performed.
A double-blind, two-by-two factorial, randomized study was performed by 281 medical centers in Canada, the United States, western Europe, Argentina, Brazil, and Mexico. Yusuf and colleagues studied a total of 9297 high-risk patients who possessed evidence of vascular disease or diabetes plus one other cardiovascular risk factor (e.g., hypertension, elevated total serum cholesterol level, low high-density lipoprotein cholesterol levels, cigarette smoking, or documented microalbuminuria) and were not known to have a low ejection fraction or heart failure. These patients were randomized to receive either ramipril (10 mg once daily orally) or matching placebo for a mean of five years. The two-by-two factorial study evaluated both ramipril and vitamin E on the primary outcomes, which consisted of a composite of myocardial infarction (MI), stroke, or death from cardiovascular causes. The study was stopped early by the data and safety monitoring board because of the obvious benefits of ramipril and by the magnitude of the treatment effect. An overall reduction of 22% in the primary outcome of MI, stroke, or death from cardiovascular causes in patients who were not known to have a low ejection fraction or heart failure occurred. Treatment with ramipril appeared to have protective effects on both the vasculature and the myocardium and the benefit could not be ascribed solely to a rather small reduction in blood pressure that occurred.
Comment by Harold L. Karpman, MD, FACC, FACP
The renin, angiotensin, aldosterone system historically was thought to have important endocrine functions on salt and water retention, vasocontriction, release of aldosterone, and thirst. Although the system is activated in response to a decrease in intravascular volume or inadequate perfusion as a way of maintaining adequate blood flow, it is now recognized that this system operates in concert with an even more fundamentally complex tissue-based molecular signaling pathway involving angiotensin II. It now appears that the tissue activities of this system rather than the endocrine function alone are probably responsible for many of the structural and functional abnormalities that occur in the heart, vasculature, and kidneys during continued stimulation.4 Inhibition of this system by first generation ACE inhibitors has clearly been demonstrated in numerous trials to significantly reduce the risk of future cardiovascular events.5,6 The HOPE study demonstrates that the benefits of ACE inhibition exceed even our previous expectations. The beneficial effects on the vasculature, heart, and kidneys apparently go much beyond the rather small blood pressure-lowering effect of these drugs, suggesting that the pharmacological ability to block the untoward effects of the renin-angiotensin-aldosterone system permits the vasculature, heart, and kidneys to escape some of the ravages produced by long-term exposure to angiotensin and aldosterone. Precisely how these myocardial, vascular, and renal benefits occur will almost certainly be elucidated in future studies but, for the time being, there appears to be little question that ACE inhibition produced by ramipril in the HOPE study was successful in dramatically decreasing rates of death, MI, and stroke even in patients who were not afflicted with serious cardiovascular problems.
It now appears reasonable to consider prescribing ramipril for high-risk patients with a history of CAD, peripheral vascular disease, stroke, or diabetes mellitus since most of these patients will have at least one additional cardiovascular risk factor as required by patients enrolled in the HOPE study. This approach will greatly broaden the spectrum of patients who can be treated effectively with ACE inhibition assuming there are no clear contraindications to these agents or signs of drug intolerance. There are currently additional large-scale studies taking place such as the Prevention of Events with ACE Inhibition (PEACE) study and the European Trial of Reduction of Cardiac Events with Perindopril in Stable Coronary Artery Disease (EUROPA) studies. These two large clinical trials are somewhat similar to the HOPE study, however, unless the results of these studies absolutely contradict the HOPE results, the results of this landmark study of 9000 patients will be difficult to ignore and will almost certainly lead to an increase in the appropriate use of ACE inhibition in high-risk patients without manifest CAD.
References
1. Lonn EM, et al. Circulation 1994;90:2056-2069.
2. Yusuf S, et al. Lancet 1992;340:1173-1178.
3. Pfeffer MA, et al. N Engl J Med 1992;327:669-677.
4. Dzua VI, Re R. Circulation 1994;89:493-498.
5. Yusuf S, et al. Lancet 1992;340:1173-1178.
6. Rutherford JD, et al. Circulation 1994;90:1731-1738.
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