Advances in Therapy

, Volume 24, Issue 6, pp 1290–1304 | Cite as

Reducing cardiovascular risk by blockade of the renin-angiotensin-aldosterone system

Article

Abstract

Many factors contribute to the overall risk of cardiovascular disease (CVD) in a given patient. Activation of the renin-angiotensin-aldosterone system (RAAS) is pivotal in the pathophysiology of CVD and renal disease and appears to place individuals at high risk for cardiovascular (CV) and renal events. Results from many large-scale, long-term clinical trials have demonstrated that RAAS blockade with an angiotensin-converting-enzyme inhibitor (ACEI) or an angiotensin receptor blocker (ARB) can significantly decrease CV and renal morbidity and mortality in a wide range of patients. Some of the clinical benefits derived from use of these agents appears to be independent of their ability to lower blood pressure. The combined use of an ACEI and an ARB for antihypertensive therapy has begun to receive considerable attention. Such an approach may seem counterintuitive, but ACEIs and ARBs have distinct and potentially complementary pharmacologic effects. Results from clinical trials thus far suggest that combination therapy with an ACEI plus an ARB may be a rational choice in patients with chronic activation of the RAAS, including those with heart failure or impaired left ventricular systolic function, diabetes, proteinuria, impaired renal function, recent myocardial infarction, or multiple CV risk factors. Results from ongoing, large-scale, clinical endpoint trials will provide important additional information about the benefits of dual RAAS inhibition in patients at high risk for CV morbidity and mortality.

Keywords

angiotensin-converting enzyme renin-angiotensin-aldosterone system angiotensin receptor blocker cardiovascular myocardial infarction 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Rosamond W, Flegal K, Friday G, et al. Heart disease and stroke statistics—2007 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee.Circulation. 2007;115:e69-e171.PubMedCrossRefGoogle Scholar
  2. 2.
    Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III).JAMA. 2001;285:2486–2497.CrossRefGoogle Scholar
  3. 3.
    Erdine S, Aran SN. Current status of hypertension control around the world.Clin Exp Hypertens. 2004;26:731–738.PubMedCrossRefGoogle Scholar
  4. 4.
    Bonora E. The metabolic syndrome and cardiovascular disease.Ann Med. 2006;38:64–80.PubMedCrossRefGoogle Scholar
  5. 5.
    Volpe M, Savoia C, De Paolis P, Ostrowska B, Tarasi D, Rubattu S. The renin-angiotensin system as a risk factor and therapeutic target for cardiovascular and renal disease.J Am Soc Nephrol. 2002;13(suppl 3):S173-S178.PubMedCrossRefGoogle Scholar
  6. 6.
    Unger T, Li J. The role of the renin-angiotensin-aldosterone system in the development of cardiovascular disease.Am J Cardiol. 2002;89(suppl):3A-10A.PubMedCrossRefGoogle Scholar
  7. 7.
    Dendorfer A, Dominiak P, Schunkert H. ACE inhibitors and angiotensin II receptor antagonists.Handb Exp Pharmacol. 2005;170:407–442.PubMedCrossRefGoogle Scholar
  8. 8.
    Paul M, Poyan Mehr A, Kreutz R. Physiology of local renin-angiotensin systems.Physiol Rev. 2006;86:747–803.PubMedCrossRefGoogle Scholar
  9. 9.
    SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure.N Engl J Med. 1991;325:293–302.Google Scholar
  10. 10.
    SOLVD Investigators. Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions.N Engl J Med. 1992; 327:685–691.Google Scholar
  11. 11.
    CONSENSUS Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure: results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS).N Engl J Med. 1987;316:1429–1435.Google Scholar
  12. 12.
    Pfeffer MA, Braunwald E, Moye LA, et al, the SAVE Investigators. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction: results of the survival and ventricular enlargement trial.N Engl J Med. 1992;327:669–677.PubMedGoogle Scholar
  13. 13.
    Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G, for the Heart Outcomes Prevention Evaluation Study Investigators. Effects of an angiotensin-converting enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients.N Engl J Med. 2000;342:145–153.PubMedCrossRefGoogle Scholar
  14. 14.
    Fox KM, for the European Trial on Reduction of Cardiac Events With Perindopril in Stable Coronary Artery Disease Investigators. Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: randomised, double-blind, placebo-controlled, multicentre trial (the EUROPA study).Lancet. 2003;362:782–788.PubMedCrossRefGoogle Scholar
  15. 15.
    Granger CB, McMurray JJ, Yusuf S, et al. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerant to angiotensin-converting enzyme inhibitors: the CHARM-Alternative trial.Lancet. 2003;362:772–776.PubMedCrossRefGoogle Scholar
  16. 16.
    Cohn JN, Tognoni G, for the Valsartan Heart Failure Trial Investigators. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure.N Engl J Med. 2001;345: 1667–1675.PubMedCrossRefGoogle Scholar
  17. 17.
    Solomon SD, Wang D, Finn P, et al. Effect of candesartan on cause-specific mortality in heart failure patients: the Candesartan in Heart failure Assessment of Reduction in Mortality and morbidity (CHARM) program.Circulation. 2004;110:2180–2183.PubMedCrossRefGoogle Scholar
  18. 18.
    Dickstein K, Kjekshus J, OPTIMAAL Steering Committee of the OPTIMAAL Study Group. Effects of losartan and captopril on mortality and morbidity in high-risk patients after acute myocardial infarction: the OPTIMAAL randomised trial.Lancet. 2002;360:752–760.PubMedCrossRefGoogle Scholar
  19. 19.
    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.PubMedCrossRefGoogle Scholar
  20. 20.
    Wright JT Jr, Bakris G, Greene T, et al. Effect of blood pressure lowering and antihypertensive drug class on progression of hypertensive kidney disease: results from the AASK trial.JAMA. 2002;288:2421–2431.PubMedCrossRefGoogle Scholar
  21. 21.
    Maschio G, Alberti D, Locatelli F, et al, ACE Inhibition in Progressive Renal Insufficiency (AIPRI) Study Group. Angiotensin-converting enzyme inhibitors and kidney protection: the AIPRI trial.J Cardiovasc Pharmacol. 1999;33(suppl 1):S16-S20.PubMedCrossRefGoogle Scholar
  22. 22.
    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.PubMedCrossRefGoogle Scholar
  23. 23.
    Barnett AH, Bain SC, Bouter P, et al. Angiotensin-receptor blockade versus converting-enzyme inhibition in type 2 diabetes and nephropathy.N Engl J Med. 2004;351:1952–1961.PubMedCrossRefGoogle Scholar
  24. 24.
    Staessen JA, Li Y, Thijs L, Wang JG. Blood pressure reduction and cardiovascular prevention: an update including the 2003–2004 secondary prevention trials.Hypertens Res. 2005;28:385–407.PubMedCrossRefGoogle Scholar
  25. 25.
    Cohn JN. Is it the blood pressure or the blood vessel?J Am Soc Hypertens. 2007;1:5–16.CrossRefGoogle Scholar
  26. 26.
    Bosch J, Yusuf S, Pogue J, et al. Use of ramipril in preventing stroke: double blind randomised trial.BMJ. 2002;324:699–702.PubMedCrossRefGoogle Scholar
  27. 27.
    Bosch J, Lonn E, Pogue J, et al. Long-term effects of ramipril on cardiovascular events and on diabetes: results of the HOPE study extension.Circulation. 2005;112:1339–1346.PubMedCrossRefGoogle Scholar
  28. 28.
    Wing LM, Reid CM, Ryan P, et al. A comparison of outcomes with angiotensin-converting enzyme inhibitors and diuretics for hypertension in the elderly.N Engl J Med. 2003;348:583–592.PubMedCrossRefGoogle Scholar
  29. 29.
    Dahlof B, Sever PS, Poulter NR, et al. Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethi- azide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA): a multicentre randomised controlled trial.Lancet. 2005;366:895–906.PubMedCrossRefGoogle Scholar
  30. 30.
    Dahlof B, Devereux RB, Kjeldsen SE, et al. Cardiovascular morbidity and mortality in the losartan intervention for endpoint reduction in hypertension study (LIFE)—a randomised trial against atenolol.Lancet. 2002;359:995–1003.PubMedCrossRefGoogle Scholar
  31. 31.
    Papademetriou V, Farsang C, Elmfeldt D, et al. Stroke prevention with the angiotensin II type 1 receptor blocker candesartan in elderly patients with isolated systolic hypertension: the Study on Cognition and Prognosis in the Elderly (SCOPE).J Am Coll Cardiol. 2004;44:1175–1180.PubMedGoogle Scholar
  32. 32.
    Schrader J, Luders S, Kulschewski A, et al. Morbidity and mortality after stroke, eprosartan compared with nitrendipine for secondary prevention: principal results of a prospective randomized controlled study (MOSES).Stroke. 2005;36:1218–1226.PubMedCrossRefGoogle Scholar
  33. 33.
    Bakris G, Burgess E, Weir M, et al. Comparative long-term effects of two AT1 receptor blockers on proteinuria in patients with type-2 diabetes and overt nephropathy and hypertension: results of the AMADEO trial.J Clin Hypertens (Greenwich). 2007;9(suppl A):A5.Google Scholar
  34. 34.
    van de Wal RM, van Veldhuisen DJ, van Gilst WH, Voors AA. Addition of an angiotensin receptor blocker to full-dose ACE-inhibition: controversial or common sense?Eur Heart J. 2005;26:2361–2367.PubMedCrossRefGoogle Scholar
  35. 35.
    Gottlieb SS, Dickstein K, Fleck E, et al. Hemodynamic and neurohormonal effects of the angiotensin II antagonist losartan in patients with congestive heart failure.Circulation. 1993;88:1602–1609.PubMedGoogle Scholar
  36. 36.
    Azizi M, Linhart A, Alexander J, et al. Pilot study of combined blockade of the renin- angiotensin system in essential hypertensive patients.J Hypertens. 2000;18:1139–1147.PubMedCrossRefGoogle Scholar
  37. 37.
    Ruilope LM, Aldigier JC, Ponticelli C, Oddou-Stock P, Botteri F, Mann JF, for the European Group for the Investigation of Valsartan in Chronic Renal Disease. Safety of the combination of valsartan and benazepril in patients with chronic renal disease.J Hypertens. 2000;18:89–95.PubMedGoogle Scholar
  38. 38.
    Mogensen CE, Neldam S, Tikkanen I, et al. Randomised controlled trial of dual blockade of renin-angiotensin system in patients with hypertension, microalbuminuria, and non-insulin dependent diabetes: the candesartan and lisinopril microalbuminuria (CALM) study.BMJ. 2000;321:1440–1444.PubMedCrossRefGoogle Scholar
  39. 39.
    Azizi M, Guyene TT, Chatellier G, Wargon M, Menard J. Additive effects of losartan and enalapril on blood pressure and plasma active renin.Hypertension. 1997;29:634–640.PubMedGoogle Scholar
  40. 40.
    Horita Y, Tadokoro M, Taura K, et al. Low-dose combination therapy with temocapril and losartan reduces proteinuria in normotensive patients with immunoglobulin A nephropathy.Hypertens Res. 2004;27:963–970.PubMedCrossRefGoogle Scholar
  41. 41.
    Jacobsen P, Andersen S, Jensen BR, Parving HH. Additive effect of ACE inhibition and angiotensin II receptor blockade in type I diabetic patients with diabetic nephropathy.J Am Soc Nephrol. 2003;14:992–999.PubMedCrossRefGoogle Scholar
  42. 42.
    Tylicki L, Rutkowski P, Renke M, Rutkowski B. Renoprotective effect of small doses of losartan and enalapril in patients with primary glomerulonephritis: short-term observation.Am J Nephrol. 2002;22:356–362.PubMedCrossRefGoogle Scholar
  43. 43.
    Doulton TW, He FJ, MacGregor GA. Systematic review of combined angiotensin-converting enzyme inhibition and angiotensin receptor blockade in hypertension.Hypertension. 2005;45: 880–886.PubMedCrossRefGoogle Scholar
  44. 44.
    Solomon SD, Skali H, Anavekar NS, et al. Changes in ventricular size and function in patients treated with valsartan, captopril, or both after myocardial infarction.Circulation. 2005;111:3411- 3419.PubMedCrossRefGoogle Scholar
  45. 45.
    Krum H, Carson P, Farsang C, et al. Effect of valsartan added to background ACE inhibitor ther- apy in patients with heart failure: results from Val-HeFT.Eur J Heart Fail. 2004;6:937–945.PubMedCrossRefGoogle Scholar
  46. 46.
    McMurray JJ, Ostergren J, Swedberg K, et al for the Charm Investigators and Committees. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function taking angiotensin-converting enzyme inhibitors: the CHARM-Added trial.Lancet. 2003;362:767–771.PubMedCrossRefGoogle Scholar
  47. 47.
    Dayi SU, Akbulut T, Akgoz H, et al. Long-term combined therapy with losartan and an angiotensin-converting enzyme inhibitor improves functional capacity in patients with left ventricular dysfunction.Acta Cardiol. 2005;60:373–377.PubMedCrossRefGoogle Scholar
  48. 48.
    Cice G, Di Benedetto A, D’Isa S, et al. Effect of telmisartan in addition to angiotensin converting enzyme inhibitors on mortality and morbidity in haemodialysis patients with chronic heart failure: a double-blind placebo-controlled trial.Nephrol Dial Transplant. 2005;20(suppl 5):187.Google Scholar
  49. 49.
    Nakao N, Yoshimura A, Morita H, Takada M, Kayano T, Ideura T. Combination treatment of angiotensin-II receptor blocker and angiotensin-converting enzyme inhibitor in non-diabetic renal disease (COOPERATE): a randomised controlled trial.Lancet. 2003;361:117–124.PubMedCrossRefGoogle Scholar
  50. 50.
    Nakao N, Seno H, Kasuga H, Toriyama T, Kawahara H, Fukagawa M. Effects of combination treatment with losartan and trandolapril on office and ambulatory blood pressures in non- diabetic renal disease: a COOPERATE-ABP substudy.Am J Nephrol. 2004;24:543–548.PubMedCrossRefGoogle Scholar
  51. 51.
    MacKinnon M, Shurraw S, Akbari A, Knoll GA, Jaffey J, Clark HD. Combination therapy with an angiotensin receptor blocker and an ACE inhibitor in proteinuric renal disease: a systematic review of the efficacy and safety data.Am J Kidney Dis. 2006;48:8–20.PubMedCrossRefGoogle Scholar
  52. 52.
    Teo K, Yusuf S, Sleight P, et al. Rationale, design, and baseline characteristics of 2 large, simple, randomized trials evaluating telmisartan, ramipril, and their combination in high-risk patients: the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial/Telmisartan Randomized Assessment Study in ACE Intolerant Subjects with Cardiovascular Disease (ONTARGET/TRANSCEND) trials.Am Heart J. 2004;148:52–61.PubMedCrossRefGoogle Scholar
  53. 53.
    Diener HC, Sacco R, Yusuf S. Rationale, design and baseline data of a randomized, double- blind, controlled trial comparing two antithrombotic regimens (a fixed-dose combination of extended-release dipyridamole plus ASA with clopidogrel) and telmisartan versus placebo in patients with strokes: the Prevention Regimen for Effectively Avoiding Second Strokes Trial (PRoFESS).Cerebrovasc Dis. 2007;23:368–380.PubMedCrossRefGoogle Scholar
  54. 54.
    Hollenberg NK. The renin system: is direct renin inhibition different from blockade at the AT1 receptor or the ACE step?Rev Cardiovasc Med. 2007;8(suppl 2):S7-S13.PubMedGoogle Scholar
  55. 55.
    O’Brien E, Barton J, Nussberger J, et al. Aliskiren reduces blood pressure and suppresses plasma renin activity in combination with a thiazide diuretic, an angiotensin-converting enzyme inhibitor, or an angiotensin receptor blocker.Hypertension. 2007;49:276–284.PubMedCrossRefGoogle Scholar
  56. 56.
    Pool JL, Schmieder RE, Azizi M, et al. Aliskiren, an orally effective renin inhibitor, provides antihypertensive efficacy alone and in combination with valsartan.Am J Hypertens. 2007;20:11–20.PubMedCrossRefGoogle Scholar

Copyright information

© Health Communications Inc 2007

Authors and Affiliations

  1. 1.Cardiovascular DivisionUniversity of Minnesota Medical SchoolMinneapolis
  2. 2.Rasmussen Center for Cardiovascular Disease PreventionUniversity of Minnesota Medical SchoolMinneapolis

Personalised recommendations