Reviews for Primary Care - Fall 2007 - (Page 31) The Renin-Angiotensin System and Cardiovascular Diseases The role of the RAS in patients with primary hypertension is not known. However, in conditions such as diabetes mellitus and heart failure, dysregulation of the RAS is clear. It is now accepted that angiotensin II, the chief effector of this system, may play a role in cardiovascular remodeling, leading to structural and functional changes in the myocardium, kidneys, and vasculature.2 Activity of the RAS in the pancreas and adipose tissue could play a big part in creating insulin resistance and diminishing beta cell responsiveness, thus making obese people more susceptible to diabetes.3,4 The organ damage caused by the RAS may be independent of blood pressure (BP); increased plasma renin activity in patients with hypertension is associated with an increased risk of myocardial infarction (MI), even when BP levels are effectively controlled by antihypertensive therapy.5 Given the evidence for the importance of RAS activation in cardiovascular disease, it was widely anticipated that interrupting this system would represent a clear step forward in reducing cardiovascular morbidity and mortality. This article examines whether this outcome has actually occurred, and it looks forward to expected innovations in the area of RAS inhibition. ACE Inhibitors and ARBs: Surveying the Evidence ACE inhibitors and ARBs are very useful antihypertensive drug classes that have been proven to lower BP effectively and with good tolerability. The ARBs in particular have proven to be remarkably well tolerated—consistently demonstrating placebo-like tolerability—and have set a gold standard in safety for future antihypertensive therapies. But, the ultimate aim of drug treatment for hypertension is to reduce morbidity and mortality. Hence the key question in evaluating the success of ACE inhibitors and ARBs is: have these drugs delivered the improved cardiovascular outcomes that were anticipated? In reality, the answer is not completely clear. ACE inhibitors and ARBs have not delivered the major reductions in cardiovascular outcomes that were predicted given the broad role of RAS activation in the pathophysiology of cardiovascular disease. This raises the issue of whether the RAS is as broadly dysregulated in hypertension as previously believed, or alternatively that our current strategies are not fully effective in blocking this system. What is the evidence that ACE inhibitors and ARBs have not fully delivered the hoped-for reductions in cardiovascular outcomes? For instance, a recent meta-analysis of 27 randomized trials involving a total of 158,709 patients conducted by the Blood Pressure Lowering Treatment Trialists’ Collaboration (BPLTTC) showed no significant advantage of ACE inhibitors or ARBs over other antihypertensive classes with regard to major clinical outcomes.6 It might be more valuable, however, to discuss the results of individual clinical trials that have evaluated the effects of ACE inhibitors and ARBs in different clinical conditions, and to critically assess the evidence for benefits of these agents over other drug classes. Landmark Outcome Trials in Patients at High Cardiovascular Risk High-Risk Patients ACE inhibitors in particular have improved outcomes in clinical trials of high-risk cardiovascular patients (in which some patients were not classified as hypertensive). The best known of these trials is the Heart Outcomes Prevention Evaluation (HOPE) study, in which the ACE inhibitor ramipril significantly reduced the incidence of MI, cardiovascular death, or stroke by 22% compared with placebo (P .001) in high-risk patients (patients with a history of cardiovascular disease or with complicated diabetes).7 Similarly, in the European Trial on Reduction of Cardiac Events with Perindopril in Patients with Stable Coronary Artery Disease (EUROPA) study, perindopril significantly reduced cardiovascular events by 20% compared with placebo (P .0003).8 Even so, since in both these studies BP was reduced by the ACE inhibitor treatment, it is likely that at least some of the cardiovascular benefits achieved by the ACE inhibitors were due to reductions in BP. Interestingly, the benefits of ACE inhibitor therapy in HOPE and EUROPA have not been repeated in some other recent trials of high-risk patients. In the Prevention of Events with Angiotensin Converting Enzyme Inhibition (PEACE) trial, adding an ACE inhibitor to conventional therapy did not provide additional cardiovascular benefits in patients with coronary artery disease (CAD). In particular, trandolapril did not reduce the incidence of the primary study endpoint of cardiovascular death, MI, or coronary revascularization compared with conventional therapy alone.9 This study might have been confounded, however, by the beneficial effects of ongoing aggressive therapy with statins, antiplatelet drugs, and other risk-reducing therapies. The Comparison of Amlodipine Versus Enalapril to Limit Occurrences of Thrombosis (CAMELOT) study similarly failed to demonstrate improved outcomes with ACE inhibitor therapy in patients with angiographically documented stable CAD. CAMELOT compared the effects of the ACE inhibitor enalapril or the calcium channel blocker amlodipine with placebo on cardiovascular events in patients VOL. 1 NO. 1 2007 REVIEWS FOR PRIMARY CARE 31
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