Reviews for Primary Care - Fall 2007 - (Page 32) The Renin-Angiotensin System and Cardiovascular Diseases continued with CAD. Although amlodipine significantly reduced the rate of cardiovascular events by 31% compared with placebo (P .003), the effects of enalapril treatment—for the same degree of BP-lowering—were not significant (15% reduction; P .16).10 It is possible that this negative result reflected an inadequate dose of the ACE inhibitor, and, again, the study results could have been influenced by ongoing statin therapy. Heart Failure Patients Neurohormonal activation has been strongly implicated in the progression of heart failure, so RAS inhibitors and aldosterone might be expected to provide particular benefits in heart failure patients. Early trials such as the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS) supported this expectation by demonstrating that enalapril reduced mortality by 27% compared with placebo (P .003) in patients with heart failure.11 Turning to ARBs, the Valsartan Heart Failure Trial (Val-HeFT) assessed the clinical outcome benefits of valsartan treatment in patients with chronic heart failure. In Val-HeFT, adding valsartan to existing therapies (including ACE inhibitors) led to a 13.2% reduction compared with placebo (P .009) in the incidence of the primary study endpoint of mortality and cardiovascular morbidity, which was driven primarily by a reduction in hospitalizations due to heart failure.12 However, in a small subset of patients not receiving ACE inhibitors, the ARB significantly reduced mortality and morbidity. The Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity (CHARM-Overall) trial showed that ARB treatment in chronic heart failure patients significantly reduced the hard endpoints of all-cause mortality by 10% (P .032) and cardiovascular death by 13% (P .006).13 But, despite the interesting and important endpoint benefits observed with candesartan in the CHARM studies, residual mortality remained high (23% and 25% in the candesartan and placebo groups, respectively). The fact that nearly 1 in 4 patients died during the course of the trial despite treatment with an ARB (and, in some patients, an ACE inhibitor) shows that there might still be scope to improve clinical outcomes in the treatment of patients with heart failure. Among the strategies to be considered, alternative methods for inhibiting the RAS could be worth testing. Post-Myocardial Infarction Patients The benefits of ACE inhibitor treatment in patients with acute compromise of left ventricular systolic function following MI were demonstrated in the Survival and Ventricular Enlargement (SAVE) trial. SAVE showed that long-term treatment with the ACE inhibitor captopril significantly reduced mortality by 19% (P .019) and also reduced cardiovascular morbidity compared with placebo.14 The Valsartan in Acute Myocardial Infarction Trial (VALIANT) investigated whether the ARB valsartan alone or in combination with captopril would provide superior cardiovascular outcomes compared with captopril monotherapy in post-MI patients with impaired systolic function.15 Results demonstrated that valsartan was equal to captopril monotherapy in its effects on major endpoints. The ACE inhibitor and ARB combination did not provide improved cardiovascular outcomes compared with the ACE inhibitor alone. The VALIANT data therefore suggest that further progress in this area, at least as far as the RAS is concerned, might require a different approach to inhibition. Diabetic Nephropathy Patients Diabetes mellitus is regarded as a compelling indication for the use of ACE inhibitors or ARBs in treating hypertension. Activation of the RAS is a key step in the progression of diabetic kidney disease, even when plasma levels of renin activity do not appear to be increased. ACE inhibitors and ARBs have demonstrated renoprotective benefits in patients with diabetic nephropathy in trials such as the Captopril Collaborative Study, the Reduction of Endpoints in NIDDM (non-insulin-dependent diabetes mellitus) with the Angiotensin II Antagonist Losartan (RENAAL), and the Irbesartan Diabetic Nephropathy Trial (IDNT).16-18 Despite their very positive outcomes, inspection of the RENAAL and IDNT results reveals even further opportunities for improvement. Although ARB treatment in these trials significantly slowed the decline in renal function in patients with diabetic nephropathy, the absolute mean rate of decline in the glomerular filtration rate in both studies was still higher than the expected loss due to aging specified in guidelines from the National Kidney Foundation (Figure 1).19 Progression of renal disease was delayed, but not halted. Likewise, proteinuria was significantly reduced, but overall it still remained clearly in the macroalbuminuria range. The renoprotective benefits of ACE inhibitors and ARBs in patients with diabetic renal disease were also evaluated in a recent meta-analysis of 127 randomized trials involving a total of 73,514 patients. This study confirmed that ACE inhibitor or ARB treatment provides renoprotective benefits, but indicated that these benefits are probably due to the BP-lowering effects of treatment.20 The analysis also suggested that patients with diabetic nephropathy experienced no significant additional renoprotective benefits 32 VOL. 1 NO. 1 2007 REVIEWS FOR PRIMARY CARE
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