Reviews for Primary Care - Fall 2007 - (Page 33) The Renin-Angiotensin System and Cardiovascular Diseases 0 2 4 6 8 10 RENAAL IDNT Mean rate of decline in GFR (mL/min/1.73 m2/yr) Placebo (no RAS suppression) RAS suppression with ARB Normal rate of decline due to aging Figure 1. Decline in renal function in patients with type 2 diabetic nephropathy in the Reduction of Endpoints in Non-Insulin Dependent Diabetes Mellitus with the Angiotensin II Antagonist Losartan (RENAAL) study and the Irbesartan in Diabetic Nephropathy Trial (IDNT). Figure indicates the annual rate of decline in the glomerular filtration rate (GFR) in patients receiving placebo or angiotensin receptor blocker (ARB) treatment with losartan (the RENAAL study) or irbesartan (the IDNT), as compared with the average loss due to aging specified by National Kidney Foundation guidelines.19 RAS, renin-angiotensin system. www.medreviews.com with ACE inhibitors or ARBs compared with other antihypertensive classes. As with other meta-analyses, however, this study could be faulted for pooling heterogeneous trial results and possibly obscuring important effects in key subgroups of patients. Still, it is reasonable to argue that further benefits might occur with more fully effective blockade of the RAS. What about cardiovascular endpoints? Neither the RENAAL nor the IDNT results demonstrated a significant benefit of ARB treatment on cardiovascular morbidity and mortality,17,18 although there were some interesting positive trends. As well, it could be argued that these studies were not adequately powered to examine such endpoints. The BPLTTC meta-analysis of subgroups of patients with diabetes in antihypertensive clinical trials indicated that ACE inhibitor or ARB treatment in these patients did not provide significantly greater benefits on cardiovascular events compared with other drug classes.6 Again, however, caution should be exercised in interpreting subgroup data derived from metaanalyses. Post-Stroke Patients BP is recognized as an important determinant of the risk of stroke, and systematic reviews of randomized trials of antihypertensive agents have clearly shown that reductions in BP decrease the risk of stroke, with little or no difference observed among the effects of different drug classes.21 The effects of ACE inhibitors in poststroke patients were evaluated in the Perindopril Protection Against Recurrent Stroke Study (PROGRESS). This study examined the effects of perindopril, with the diuretic indapamide added at the discretion of the investigators, on the incidence of stroke in patients with a history of stroke or transient ischemic attack. Although perindopril therapy alone as well as by suppression of the RAS by perindopril. It should be noted that results strongly in favor of specific benefits of RAS blockade in post-stroke patients were achieved in the Morbidity and Mortality After Stroke, Eprosartan Compared with Nitrendipine for Secondary Prevention (MOSES) study. MOSES was the first trial to compare an ARB (eprosartan) with a calcium channel blocker (nitrendipine) in the secondary prevention of stroke in hypertensive patients. Results showed that with the same level of BP-reduction, an eprosartan-based treatment regimen significantly reduced the incidence of mortality and all cardiovascular and cerebrovascular events by 21% (P .014) compared with a nitrendipine-based regimen.23 These results indicate that ARB therapy may provide stroke protection beyond BP lowering in patients with hypertension, although MOSES remains the only major outcome study to demonstrate such a benefit. It is possible that the differential blocking effects of ARBs on angiotensin II type 1 and type 2 receptors (AT1 and AT2)—rather than overall inhibition of the RAS— could explain this benefit. Furthermore, it should be noted that the In a study of post-stroke patients, treatment with perindopril alone did not provide a significant benefit, but the combination of perindopril and indapamide significantly reduced the risk of stroke by 43%. did not provide a significant benefit, perindopril combined with indapamide significantly reduced the risk of stroke by 43% (P .0001) compared with placebo.22 Given that the combination treatment also provided significantly greater BP reductions (P .001) compared with perindopril alone, it is possible that the outcome benefits of therapy in PROGRESS were influenced by reductions in BP analyses were not performed on the time to first event, as is more conventional, but rather on all the events that occurred, so as to enhance the power of the study. High-Risk Hypertension Patients The Losartan Intervention For Endpoint Reduction in hypertension (LIFE) study is widely considered to be a landmark trial showing the outcome VOL. 1 NO. 1 2007 REVIEWS FOR PRIMARY CARE 33 http://www.medreviews.com
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