Cardiovascular Outcomes and Angiotensin Converting Enzyme Inhibitors: Beyond Blood Pressure Control

Abstract

Atherosclerosis and its complications, stroke, coronary artery disease and peripheral arterial disease, remain the leading cause of mortality and morbidity and are increasing in incidence in the developing world [1]. Multiple mechanisms are associated with the development of atherosclerosis but since the discovery of renin by Tigerstedt and Bergman [2] more that 100 years ago, the renin–angiotensin system (RAS) has been focus of intensive investigative efforts. Although our understanding of the RAS and the development of atherosclerosis has grown increasingly complex, inhibition of the RAS with an angiotensinconverting enzyme inhibitor (ACE-I) has become a firmly established therapeutic approach for reducing morbidity and the risk of death across a broad spectrum of cardiovascular diseases based on multiple, well-conducted, randomized clinical outcome trials (RCT) [3–6]. The benefits of ACE-I on clinical outcomes are due in part to blood pressure control but other mechanisms beyond blood pressure lowering, such as their anti-atherosclerotic properties has been postulated in recent clinical trials [7]. These clinical trials have broadened our knowledge of management of cardiovascular risk The Heart Outcome Prevention and Evaluation (HOPE) study [8] demonstrated the benefits of ACE-I on clinical outcomes in patients with established atherosclerosis or diabetes. The HOPE study by excluding patients with left ventricular systolic dysfunction and heart failure made obvious that the ACE-I ramipril not only reduced cardiovascular mortality, but also significantly reduced incidence of myocardial infarction and stroke. Similarly, the European Reduction of Cardiac Events with Perindopril in Stable Coronary Artery Disease (EUROPA) [9] study demonstrated that inhibition of the RAS with an ACE-I perindopril will result in secondary prevention of coronary events in a much broader population, patients with stable coronary disease irrespective of risk profile. The ACE-I perindopril in EUROPA [9] significantly reduced the combined endpoint of cardiovascular death, non-fatal myocardial infarction, and resuscitated sudden cardiac death by 20%. However studies such as PEACE [10] failed to replicate the results of EUROPA and HOPE. In the PEACE trial, patients with coronary artery disease and with preserved left ventricular systolic function treated with ACE-I trandolapril in a dose of 4 mg for several years did not show any reduction in cardiovascular outcomes. The lack of benefits of trandolapril in PEACE may be due to a lower cardiovascular risk population included in the trial and that patients were optimally treated with other evidence based treatments such as statins, beta blockers, antiplatelets and revascularization therefore they do not benefit with additional ACE-I. Cardiovasc Drugs Ther (2009) 23:109–111 DOI 10.1007/s10557-008-6152-5