1887
Volume 2013, Issue 3
  • ISSN: 2305-7823
  • EISSN:

Abstract

The renin-angiotensin-aldosterone system (RAAS) regulates the body's hemodynamic equilibrium, circulating volume, and electrolyte balance, and is a key therapeutic target in hypertension, the world's leading cause of premature mortality. Hypertensive disorders are strongly linked with an overactive RAAS, and RAAS inhibitors, like angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs), are routinely used to treat high blood pressure (BP). BP reduction is one of the main goals of current European hypertension guidelines. Oral ACE inhibitors, the oldest category of RAAS inhibitor, were commercially released over 30 years ago in the early 1980s, over a decade before the first ARBs became available. The introduction of ACE inhibitors heralded major changes in the way hypertension and cardiovascular disease were treated. Although the decision of the medical community to replace older ACE inhibitors with more modern ARBs in the 1990s was debatable, it did nevertheless allow scientists to learn more about the angiotensin receptors involved in RAAS stimulation. This and much else of value have been discovered since RAAS inhibitors first became available, but some surprising gaps in our knowledge exist. Until recently, the effect of RAAS inhibition on mortality in hypertension was unknown. This question was recently addressed by a meta-analysis of randomized controlled trials in populations who received contemporary antihypertensive medication. The results of this meta-analysis have helped elucidate the long-term consequences of treatment with RAAS inhibitors on mortality in hypertension. This article will consider the differences between RAAS inhibitors in terms of pharmacological and clinical effects and analyze the impact of the main types of RAAS inhibitor, ACE inhibitors and ARBs, on mortality reduction in hypertensive patients with reference to this latest meta-analysis.

Loading

Article metrics loading...

/content/journals/10.5339/gcsp.2013.34
2014-02-01
2024-12-26
Loading full text...

Full text loading...

/deliver/fulltext/gcsp/2013/3/gcsp.2013.34.html?itemId=/content/journals/10.5339/gcsp.2013.34&mimeType=html&fmt=ahah

References

  1. Kearney PM, Whelton M, Reynolds K, Muntner P, Whelton PK, He J. Global burden of hypertension: analysis of worldwide data. Lancet 2005; 365::217223.
    [Google Scholar]
  2. Atlas SA. The renin-angiotensin aldosterone system: pathophysiological role and pharmacologic inhibition. J Manag Care Pharm. 2007; 13::920.
    [Google Scholar]
  3. Wong ND, Dede J, Chow VH, Wong KS, Franklin SS. Global cardiovascular risk associated with hypertension and extent of treatment and control according to risk group. Am J Hypertens. 2012; 25::561567.
    [Google Scholar]
  4. Mancia G, De Backer G, Dominiczak A, Cifkova R, Fagard R, Germano G, Grassi G, Heagerty AM, Kjeldsen SE, Laurent S, Narkiewicz K, Ruilope L, Rynkiewicz A, Schmieder RE, Struijker Boudier HA, Zanchetti A, Vahanian A, Camm J, De Caterina R, Dean V, Dickstein K, Filippatos G, Funck-Brentano C, Hellemans I, Kristensen SD, McGregor K, Sechtem U, Silber S, Tendera M, Widimsky P, Zamorano JL, Kjeldsen SE, Erdine S, Narkiewicz K, Kiowski W, Agabiti-Rosei E, Ambrosioni E, Cifkova R, Dominiczak A, van Zwieten P, Viigimaa M, Waeber B, Williams B, Zamorano JL. Guidelines for the management of arterial hypertension: The Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). Eur Heart J. 2007; 28::14621536.
    [Google Scholar]
  5. Sica DA. The evolution of renin-angiotensin blockade: angiotensin-converting enzyme inhibitors as the starting point. Curr Hypertens Rep. 2010; 12::6773.
    [Google Scholar]
  6. van Vark LC, Bertrand M, Akkerhuis KM, Brugts JJ, Fox K, Mourad JJ, Boersma E. Angiotensin-converting enzyme inhibitors reduce mortality in hypertension - a meta-analysis of randomized clinical trials of renin-angiotensin-aldosterone-system inhibitors involving 158,998 patients. Eur Heart J. 2012; 33::20882097.
    [Google Scholar]
  7. Unger T, Stoppelhaar M. Rationale for double renin-angiotensin-aldosterone system blockade. Am J Cardiol. 2007; 100::25J31J.
    [Google Scholar]
  8. Probstfield JL, O'Brien KD. Progression of cardiovascular damage: the role of renin-angiotensin system blockade. Am J Cardiol. 2010; 105::10A20A.
    [Google Scholar]
  9. Ferrari R, Fox K. Insight into the mode of action of ACE inhibition in coronary artery disease: The ultimate ‘EUROPA’ story. Drugs 2009; 69::265277.
    [Google Scholar]
  10. Athyros VG, Mikhailidis DP, Kakafika AI, Tziomalos K, Karagiannis A. Angiotensin II reactivation and aldosterone escape phenomena in renin-angiotensin-aldosterone system blockade: is oral renin inhibition the solution? Expert Opin Pharmacother. 2007; 8::529535.
    [Google Scholar]
  11. Hollenberg NK, Fisher ND. Renal circulation and blockade of the renin-angiotensin system. Is angiotensin-converting enzyme inhibition the last word? Hypertension 1995; 26::602609.
    [Google Scholar]
  12. Comini L, Bachetti T, Cargnoni A, Bastianon D, Gitti GL, Ceconi C, Ferrari R. Therapeutic modulation of the nitric oxide pathway: are all ACE inhibitors equivalent? Pharmacol Res. 2007; 56::4248.
    [Google Scholar]
  13. Ceconi C, Francolini G, Olivares A, Comini L, Bachetti T, Ferrari R. Angiotensin-converting enzyme (ACE) inhibitors have different selectivity for bradykinin binding sites of human somatic ACE. Eur J Pharmacol. 2007; 577::16.
    [Google Scholar]
  14. Strauss MH, Hall AS. Angiotensin receptor blockers may increase risk of myocardial infarction: unraveling the ARB-MI paradox. Circulation 2006; 114::838854.
    [Google Scholar]
  15. Wolf G, Ritz E. Combination therapy with ACE inhibitors and angiotensin II receptor blockers to halt progression of chronic renal disease: pathophysiology and indications. Kidney Int. 2005; 67::799812.
    [Google Scholar]
  16. Chrysant SG, Chrysant GS, Chrysant C, Shiraz M. The treatment of cardiovascular disease continuum: focus on prevention and RAS blockade. Curr Clin Pharmacol. 2010; 5::8995.
    [Google Scholar]
  17. Yusuf S, Teo KK, Pogue J, Dyal L, Copland I, Schumacher H, Dagenais G, Sleight P, Anderson C, ONTARGET Investigators. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med. 2008; 358::15471559.
    [Google Scholar]
  18. Barnett AH, Bain SC, Bouter P, Karlberg B, Madsbad S, Jervell J, Mustonen J. Angiotensin-receptor blockade versus converting-enzyme inhibition in type 2 diabetes and nephropathy. N Engl J Med. 2004; 351::19521961.
    [Google Scholar]
  19. Lithell H, Hansson L, Skoog I, Elmfeldt D, Hofman A, Olofsson B, Trenkwalder P, Zanchetti A, SCOPE Study Group . The Study on Cognition and Prognosis in the Elderly (SCOPE): principal results of a randomized double-blind intervention trial. J Hypertens. 2003; 21::875886.
    [Google Scholar]
  20. Yusuf S, Diener HC, Sacco RL, Cotton D, Ounpuu S, Lawton WA, Palesch Y, Martin RH, Albers GW, Bath P, Bornstein N, Chan BP, Chen ST, Cunha L, Dahlöf B, De Keyser J, Donnan GA, Estol C, Gorelick P, Gu V, Hermansson K, Hilbrich L, Kaste M, Lu C, Machnig T, Pais P, Roberts R, Skvortsova V, Teal P, Toni D, Vander Maelen C, Voigt T, Weber M, Yoon BW, PRoFESS Study Group . Telmisartan to prevent recurrent stroke and cardiovascular events. N Engl J Med. 2008; 359::12251237.
    [Google Scholar]
  21. Yusuf S, Teo K, Anderson C, Pogue J, Dyal L, Copland I, Schumacher H, Dagenais G, Sleight P, Telmisartan Randomised AssessmeNt Study in ACE iNtolerant subjects with cardiovascular Disease (TRANSCEND) Investigators. Effects of the angiotensin-receptor blocker telmisartan on cardiovascular events in high-risk patients intolerant to angiotensin-converting enzyme inhibitors: a randomised controlled trial. Lancet 2008; 372::11741183.
    [Google Scholar]
  22. McDonald MA, Simpson SH, Ezekowitz JA, Gyenes G, Tsuyuki RT. Angiotensin receptor blockers and risk of myocardial infarction: systematic review. BMJ 2005; 331::873.
    [Google Scholar]
  23. Verdecchia P, Angeli F, Gattobigio R, Reboldi GP. Do angiotensin II receptor blockers increase the risk of myocardial infarction? Eur Heart J. 2005; 26::23812386.
    [Google Scholar]
  24. Volpe M, Mancia G, Trimarco B, Angiotensin II . receptor blockers and myocardial infarction: deeds and misdeeds. J Hypertens. 2005; 23::21132118.
    [Google Scholar]
  25. Turnbull F, Neal B, Pfeffer M, Kostis J, Algert C, Woodward M, Chalmers J, Zanchetti A, MacMahon S, Blood Pressure Lowering Treatment Trialists' Collaboration. Blood pressure-dependent and independent effects of agents that inhibit the renin-angiotensin system. J Hypertens. 2007; 25::951958.
    [Google Scholar]
  26. Bangalore S, Kumar S, Wetterslev J, Messerli FH. Angiotensin receptor blockers and risk of myocardial infarction: meta-analyses and trial sequential analyses of 147 020 patients from randomised trials. BMJ 2011; 342::d2234.
    [Google Scholar]
  27. Wing LM, Reid CM, Ryan P, Beilin LJ, Brown MA, Jennings GL, Johnston CI, McNeil JJ, Macdonald GJ, Marley JE, Morgan TO, West MJ, Second Australian National Blood Pressure Study Group . A comparison of outcomes with angiotensin-converting–enzyme inhibitors and diuretics for hypertension in the elderly. N Engl J Med. 2003; 348::583592.
    [Google Scholar]
  28. Yui Y, Sumiyoshi T, Kodama K, Hirayama A, Nonogi H, Kanmatsuse K, Origasa H, Iimura O, Ishii M, Saruta T, Arakawa K, Hosoda S, Kawai C, Japan Multicenter Investigation for Cardiovascular Diseases-B Study Group . Comparison of nifedipine retard with angiotensin converting enzyme inhibitors in Japanese hypertensive patients with coronary artery disease: the Japan Multicenter Investigation for Cardiovascular Diseases-B (JMIC-B) randomized trial. Hypertens Res. 2004; 27::181191.
    [Google Scholar]
  29. ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA 2002; 288::29812997.
    [Google Scholar]
  30. Bulpitt CJ, Beckett NS, Cooke J, Dumitrascu DL, Gil-Extremera B, Nachev C, Nunes M, Peters R, Staessen JA, Thijs L, Hypertension in the Very Elderly Trial Working Group . Results of the pilot study for the Hypertension in the Very Elderly Trial. J Hypertens. 2003; 21::24092417.
    [Google Scholar]
  31. Dahlöf B, Sever PS, Poulter NR, Wedel H, Beevers DG, Caulfield M, Collins R, Kjeldsen SE, Kristinsson A, McInnes GT, Mehlsen J, Nieminen M, O'Brien E, Ostergren J, ASCOT Investigators . Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA): a multicentre randomised controlled trial. Lancet 2005; 366::895906.
    [Google Scholar]
  32. Patel A, MacMahon S, Chalmers J, Neal B, Woodward M, Billot L, Harrap S, Poulter N, Marre M, Cooper M, Glasziou P, Grobbee DE, Hamet P, Heller S, Liu LS, Mancia G, Mogensen CE, Pan CY, Rodgers A, Williams B, ADVANCE Collaborative Group. Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial. Lancet 2007; 370::829840.
    [Google Scholar]
  33. Beckett NS, Peters R, Fletcher AE, Staessen JA, Liu L, Dumitrascu D, Stoyanovsky V, Antikainen RL, Nikitin Y, Anderson C, Belhani A, Forette F, Rajkumar C, Thijs L, Banya W, Bulpitt CJ, HYVET Study Group . Treatment of hypertension in patients 80 years of age or older. N Engl J Med. 2008; 358::18871898.
    [Google Scholar]
  34. Ogihara T, Fujimoto A, Nakao K, Saruta T, CASE-J Trial Group . ARB candesartan and CCB amlodipine in hypertensive patients: the CASE-J trial. Expert Rev Cardiovasc Ther. 2008; 6::11951201.
    [Google Scholar]
  35. Kasanuki H, Hagiwara N, Hosoda S, Sumiyoshi T, Honda T, Haze K, Nagashima M, Yamaguchi J, Origasa H, Urashima M, Ogawa H, HIJ-CREATE Investigators . Angiotensin II receptor blocker-based vs. non-angiotensin II receptor blocker-based therapy in patients with angiographically documented coronary artery disease and hypertension: the heart institute of Japan candesartan randomized trial for evaluation in coronary artery disease (HIJ-CREATE). Eur Heart J. 2009; 30::12031212.
    [Google Scholar]
  36. Schrader J, Lüders S, Kulschewski A, Hammersen F, Plate K, Berger J, Zidek W, Dominiak P, Diener HC, MOSES Study Group . Morbidity and Mortality After Stroke, Eprosartan Compared with Nitrendipine for Secondary Prevention: principal results of a prospective randomized controlled study (MOSES). Stroke 2005; 36::12181226.
    [Google Scholar]
  37. Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB, Ritz E, Atkins RC, Rohde R, Raz I, Collaborative Study Group . Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med. 2001; 345::851860.
    [Google Scholar]
  38. Brenner BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE, Parving HH, Remuzzi G, Snapinn SM, Zhang Z, Shahinfar S, RENAAL Study Investigators . Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med. 2001; 345::861869.
    [Google Scholar]
  39. Dahlöf B, Devereux RB, Kjeldsen SE, Julius S, Beevers G, de Faire U, Fyhrquist F, Ibsen H, Kristiansson K, Lederballe-Pedersen O, Lindholm LH, Nieminen MS, Omvik P, Oparil S, Wedel H, LIFE Study Group . Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet. 2002; 359::9951003.
    [Google Scholar]
  40. Julius S, Kjeldsen SE, Weber M, Brunner HR, Ekman S, Hansson L, Hua T, Laragh J, McInnes GT, Mitchell L, Plat F, Schork A, Smith B, Zanchetti A, VALUE trial group . Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomised trial. Lancet 2004; 363::20222031.
    [Google Scholar]
  41. Mochizuki S, Dahlöf B, Shimizu M, Ikewaki K, Yoshikawa M, Taniguchi I, Ohta M, Yamada T, Ogawa K, Kanae K, Kawai M, Seki S, Okazaki F, Taniguchi M, Yoshida S, Tajima N, Jikei Heart Study group . Valsartan in a Japanese population with hypertension and other cardiovascular disease (Jikei Heart Study): a randomised, open-label, blinded endpoint morbidity-mortality study. Lancet 2007; 369::14311439.
    [Google Scholar]
  42. Sawada T, Yamada H, Dahlöf B, Matsubara H. Effects of valsartan on morbidity and mortality in uncontrolled hypertensive patients with high cardiovascular risks: KYOTO HEART Study. Eur Heart J. 2009; 30::24612469.
    [Google Scholar]
  43. McMurray JJ, Holman RR, Haffner SM, Bethel MA, Holzhauer B, Hua TA, Belenkov Y, Boolell M, Buse JB, Buckley BM, Chacra AR, Chiang FT, Charbonnel B, Chow CC, Davies MJ, Deedwania P, Diem P, Einhorn D, Fonseca V, Fulcher GR, Gaciong Z, Gaztambide S, Giles T, Horton E, Ilkova H, Jenssen T, Kahn SE, Krum H, Laakso M, Leiter LA, Levitt NS, Mareev V, Martinez F, Masson C, Mazzone T, Meaney E, Nesto R, Pan C, Prager R, Raptis SA, Rutten GE, Sandstroem H, Schaper F, Scheen A, Schmitz O, Sinay I, Soska V, Stender S, Tamás G, Tognoni G, Tuomilehto J, Villamil AS, Vozár J, Califf RM, NAVIGATOR Study Group . Effect of valsartan on the incidence of diabetes and cardiovascular events. N Engl J Med. 2010; 362::14771490.
    [Google Scholar]
  44. Manisty CH, Zambanini A, Parker KH, Davies JE, Francis DP, Mayet J, McG Thom SA, Hughes AD, Anglo-Scandinavian Cardiac Outcome Trial Investigators . Differences in the magnitude of wave reflection account for differential effects of amlodipine- versus atenolol-based regimens on central blood pressure: an Anglo-Scandinavian Cardiac Outcome Trial substudy. Hypertension. 2009; 54::724730.
    [Google Scholar]
  45. Williams B, Lacy PS, Thom SM, Cruickshank K, Stanton A, Collier D, Hughes AD, Thurston H, O'Rourke M, CAFE Investigators; Anglo-Scandinavian Cardiac Outcomes Trial Investigators; CAFE Steering Committee and Writing Committee . Differential impact of blood pressure-lowering drugs on central aortic pressure and clinical outcomes: principal results of the Conduit Artery Function Evaluation (CAFE) study. Circulation. 2006; 113::12131225.
    [Google Scholar]
  46. Dolan E, Stanton AV, Thom S, Caulfield M, Atkins N, McInnes G, Collier D, Dicker P, O'Brien E, ASCOT Investigators . Ambulatory blood pressure monitoring predicts cardiovascular events in treated hypertensive patients–an Anglo-Scandinavian cardiac outcomes trial substudy. J Hypertens. 2009; 27::876885.
    [Google Scholar]
  47. Guo W, Turlapaty P, Shen Y, Dong V, Batchelor A, Barlow D, Lagast H. Clinical experience with perindopril in patients nonresponsive to previous antihypertensive therapy: a large US community trial. Am J Ther. 2004; 11::199205.
    [Google Scholar]
  48. Julius S, Cohn JN, Neutel J, Weber M, Turlapaty P, Shen Y, Dong V, Batchelor A, Lagast H. Antihypertensive utility of perindopril in a large, general practice-based clinical trial. J Clin Hypertens (Greenwich). 2004; 6::1017.
    [Google Scholar]
  49. Physicians' Desk Reference (58th ed.) Thompson Healthcare (2004) ISBN: 9781563634710.
  50. Ferrari R. Angiotensin-converting enzyme inhibition in cardiovascular disease: evidence with perindopril. Expert Rev Cardiovasc Ther. 2005; 3::1529.
    [Google Scholar]
  51. Louis WJ, Conway EL, Krum H, Workman B, Drummer OH, Lam W, Phillips P, Howes LG, Jackson B. Comparison of the pharmacokinetics and pharmadocynamics of perindopril, cilazapril and enalapril. Clin Exp Pharmacol Physiol Suppl. 1992; 19::5560.
    [Google Scholar]
  52. Tsoukas G, Anand S, Yang K. Dose-dependent antihypertensive efficacy and tolerability of perindopril in a large, observational, 12-week, general practice-based study. Am J Cardiovasc Drugs. 2011; 11::4555.
    [Google Scholar]
  53. Ceconi C, Fox KM, Remme WJ, Simoons ML, Bertrand M, Parrinello G, Kluft C, Blann A, Cokkinos D, Ferrari R, EUROPA Investigators; PERTINENT Investigators and the Statistical Committee . ACE inhibition with perindopril and endothelial dysfunction. Results of a substudy of the EUROPA study: PERTINENT. Cardiovasc Res. 2007; 73::237246.
    [Google Scholar]
  54. Cangiano E, Marchesini J, Campo G, Francolini G, Fortini C, Carrà G, Miccoli M, Ceconi C, Tavazzi L, Ferrari R. ACE inhibition modulation of endothelial apoptosis and renewal via endothelial progenitor cells in patients with acute coronary syndromes. Am J Cardiovasc Drugs. 2011; 11::189198.
    [Google Scholar]
  55. Yazawa H, Miyachi M, Furukawa M, Takahashi K, Takatsu M, Tsuboi K, Ohtake M, Murase T, Hattori T, Kato Y, Murohara T, Nagata K. Angiotensin-converting enzyme inhibition promotes coronary angiogenesis in the failing heart of Dahl salt-sensitive hypertensive rats. J Card Fail. 2011; 17::10411050.
    [Google Scholar]
  56. Asmar R, Topouchian J, Pannier B, Benetos A, Safar M. Scientific, Quality Control, Coordination and Investigation Committees of the Complior Study. Pulse wave velocity as endpoint in large-scale intervention trial. The Complior study. Scientific, Quality Control, Coordination and Investigation Committees of the Complior Study. J Hypertens. 2001; 19::813818.
    [Google Scholar]
  57. Ruschitzka F, Taddei S. Angiotensin-converting enzyme inhibitors: first-line agents in cardiovascular protection? Eur Heart J. 2012; 33::19961998.
    [Google Scholar]
/content/journals/10.5339/gcsp.2013.34
Loading
/content/journals/10.5339/gcsp.2013.34
Loading

Data & Media loading...

Supplements

Supplementary File 1

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error