Reviews for Primary Care - Fall 2007 - (Page 34) The Renin-Angiotensin System and Cardiovascular Diseases continued benefits of ARB treatment. In LIFE, losartan-based treatment significantly reduced the risk of the primary coronary and stroke composite endpoint by 13% (P .021) compared with atenolol-based therapy, a result driven largely by the 25% reduction in the relative risk of stroke with losartan compared with atenolol.24 It should be recalled, though, that ARB treatment in LIFE was originally expected to test whether the inability of older antihypertensive therapies to reduce the risk of coronary events reflected a need to more effectively of the RAS inhibitor was not demonstrated. ACE inhibition and diuretics were also compared in the Second Australian National Blood Pressure Study (ANBP2), which enrolled hypertensive patients ages 65 to 84 years.27 In ANBP2, ACE-inhibitor therapy provided a modest 11% reduction (P .05) in the risk of cardiovascular events or all-cause mortality compared with diuretic therapy, with the benefit being stronger in men than in women. ANBP2, therefore, showed benefits of RAS blockade, but failed One study showed that a treatment regimen based on the calcium channel blocker amlodipine, with the addition of the ACE inhibitor perindopril, significantly reduced the incidence of stroke, total cardiovascular events, and all-cause mortality compared with an atenolol-diuretic regimen. block the RAS.25 In fact, losartan did not significantly reduce the risk of cardiovascular mortality compared with atenolol in the overall cohort, whereas the rate of MI in the losartan group was definitely not lower than in patients receiving atenolol.24 The Antihypertensive and LipidLowering Treatment to Prevent Heart Attack Trial (ALLHAT) compared the effects on cardiovascular outcomes of treatment with amlodipine, the ACE inhibitor lisinopril, or the thiazide diuretic chlorthalidone in hypertensive patients aged 55 years or older with one or more risk factors for coronary heart disease. Although the stated conclusions of ALLHAT remain highly controversial, the study found that neither lisinopril nor amlodipine provided significantly greater cardiovascular benefits than the diuretic chlorthalidone.26 Criticisms can be made that the problems inherent in the design of ALLHAT put the ACE inhibitor group at a clear BP disadvantage, but the fact remains that the expected superiority to demonstrate a compelling advantage of treatment with an ACE inhibitor. More recently, the BP-lowering arm of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) showed that a treatment regimen based on the calcium channel blocker amlodipine, with the addition of the ACE inhibitor perindopril, significantly reduced the .0003), total incidence of stroke (P cardiovascular events (P .0001), and all-cause mortality (P .025) compared with an atenolol-diuretic regimen.28 The primary coronary endpoint, however, failed to achieve statistical significance due to the early termination of the trial. Since this trial was essentially a comparison of combination therapies, it is unclear whether the superior outcomes in the amlodipine/perindopril group were due to the calcium channel blocker, the ACE inhibitor, or the combination of the 2. The Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial was specifically designed to test in high-risk hypertensive patients whether the ARB valsartan would provide cardioprotective benefits beyond BP-lowering compared with amlodipine.29 In the VALUE trial, the incidence of the primary composite cardiac endpoint was virtually identical in the valsartan and amlodipine groups. Amlodipine was associated with a lower incidence of MI compared with valsartan, although heart failure endpoints tended to be lower with valsartan.29 The study authors noted that BP control in VALUE was better in the amlodipine arm, and the unequal BP reductions may have confounded the interpretation of the results. What is more, valsartan was not administered at its optimal RASblocking dose. Overall, however, VALUE does not appear to provide strong evidence for the cardiovascular superiority of an ARB over a calcium channel blocker. ACE Inhibitors and ARBs: Can We Do Better? Taken together, the picture that emerges from these outcome trials is far from clear. Although some studies of ACE inhibitors or ARBs have demonstrated outcome benefits over other antihypertensive drug classes, the results as a whole have been somewhat equivocal. If ACE inhibitors and ARBs have not provided the full measure of outcome benefits that we might expect from inhibitors of a system with such pathophysiological importance as the RAS, it is important that we understand why. The RAS can be considered a classic feedback loop, because angiotensin II acts to inhibit the release of renin from the kidney.30 RAS activity is governed by the ratelimiting step of the cycle, which is the action of renin on its substrate.31 Inhibition of angiotensin II production (by ACE inhibitors) or action (by ARBs) disrupts the feedback loop by 34 VOL. 1 NO. 1 2007 REVIEWS FOR PRIMARY CARE
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