Reviews for Primary Care - Fall 2007 - (Page 38) The Renin-Angiotensin System and Cardiovascular Diseases continued significant scope for testing whether increased and more comprehensive RAS suppression could produce additional clinical benefits. Aliskiren, the first in a new class of orally effective renin inhibitors, quite apart from its benefits as a single agent offers the potential to enhance the organ protection and outcome benefits of existing RAS inhibitors. Further trials investigating the effects of aliskiren and future renin inhibitors on cardiovascular and renal outcomes are getting underway. Renin inhibition may offer an important opportunity to examine whether the cardiovascular benefits of inhibiting the RAS can be fully realized. Dr. Weber discloses that he provides speaking and consulting services for Boehringer-Ingelheim, Novartis, Bristol-Myers Squibb, Pfizer, Merck, Sanofi-Aventis, and Sankyo. 5. 6. 7. 8. 9. 10. References 1. Volpe M, Savoia C, De Paolis P, et al. The reninangiotensin system as a risk factor and therapeutic target for cardiovascular and renal disease. J Am Soc Nephrol. 2002;13(suppl 3):S173-S178. Weir MR, Dzau VJ. The renin-angiotensin-aldosterone system: a specific target for hypertension management. Am J Hypertens. 1999;12:205S213S. Hanes DS, Nahar A, Weir MR. The tissue reninangiotensin-aldosterone system in diabetes mellitus. Curr Hypertens Rep. 2004;6:98-105. Engeli S, Schling P, Gorzelniak K, et al. The adipose-tissue renin-angiotensin-aldosterone system: 11. 2. 12. 3. 13. 4. role in the metabolic syndrome? Int J Biochem Cell Biol. 2003;35:807-825. Alderman MH, Ooi WL, Cohen H, et al. Plasma renin activity: a risk factor for myocardial infarction in hypertensive patients. Am J Hypertens. 1997;10:1-8. Turnbull F, Neal B, Algert C, et al. Effects of different blood pressure-lowering regimens on major cardiovascular events in individuals with and without diabetes mellitus: results of prospectively designed overviews of randomized trials. Arch Intern Med. 2005;165:1410-1419. Yusuf S, Sleight P, Pogue J, et al. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med. 2000;342:145-153. Fox KM. Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: randomised, doubleblind, placebo-controlled, multicentre trial (the EUROPA study). Lancet. 2003;362:782-788. Braunwald E, Domanski MJ, Fowler SE, et al. Angiotensin-converting-enzyme inhibition in stable coronary artery disease. N Engl J Med. 2004;351:2058-2068. Nissen SE, Tuzcu EM, Libby P, et al. Effect of antihypertensive agents on cardiovascular events in patients with coronary disease and normal blood pressure: the CAMELOT study: a randomized controlled trial. JAMA. 2004;292: 2217-2225. The CONSENSUS Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). The CONSENSUS Trial Study Group. N Engl J Med. 1987;316:1429-1435. Cohn JN, Tognoni G. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med. 2001;345: 1667-1675. Pfeffer MA, Swedberg K, Granger CB, et al. Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. CHARM-Overall programme. Lancet. 2003;362: 759-766. Pfeffer MA, Braunwald E, Moye LA, et al. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. Results of the survival and ventricular enlargement trial. The SAVE Investigators. N Engl J Med. 1992;327:669-677. Pfeffer MA, McMurray JJ, Velazquez EJ, et al. Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. N Engl J Med. 2003;349:1893-1906. Lewis EJ, Hunsicker LG, Bain RP, Rohde RD. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The Collaborative Study Group. N Engl J Med. 1993;329:1456-1462. Lewis EJ, Hunsicker LG, Clarke WR, et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med. 2001; 345:851-860. Brenner BM, Cooper ME, de Zeeuw D, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med. 2001;345:861-869. National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification and stratification. Am J Kidney Dis. 2002;39(2 suppl 1):S1-S266. Casas JP, Chua W, Loukogeorgakis S, et al. Effect of inhibitors of the renin-angiotensin system and other antihypertensive drugs on renal outcomes: systematic review and meta-analysis. Lancet. 2005;366:2026-2033. Collins R, MacMahon S. Blood pressure, antihypertensive drug treatment and the risks of stroke and of coronary heart disease. Br Med Bull. 1994;50:272-298. PROGRESS Investigators. Randomised trial of a perindopril-based blood-pressure-lowering regimen among 6,105 individuals with previous stroke or transient ischaemic attack. Lancet. 2001;358:1033-1041. Schrader J, Luders S, Kulschewski A, et al. Morbidity and Mortality After Stroke, Eprosartan Main Points • Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) have not delivered the major reductions in cardiovascular outcomes that were predicted given the broad role of renin-angiotensin system (RAS) activation in the pathophysiology of cardiovascular disease. • Increased RAS suppression may improve organ protection. Increasing the dosage of ARBs beyond current recommended levels in patients with diabetes can lead to modest but significantly greater renoprotective effects, despite no further reduction in blood pressure. Another approach to enhancing RAS suppression is to combine ACE inhibitor therapy and ARB therapy. • ACE inhibitor and ARB combination therapy lacks the excellent tolerability of the monotherapies, with hyperkalemia emerging as a particular problem in patients with advanced disease. • Inhibiting the action of renin stands out as a logical approach to improving the completeness of RAS suppression. • Blood pressure values alone represent an incomplete indicator of the presence of target organ damage and overall cardiovascular risk. 38 VOL. 1 NO. 1 2007 REVIEWS FOR PRIMARY CARE
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