Abstract
ACE inhibitors have significantly decreased cardiovascular mortality, myocardial infarction (MI), and hospitalizations for heart failure (HF) in patients with asymptomatic or symptomatic left ventricular (LV) systolic dysfunction. Furthermore, the extended 12-year study of the SOLVD (Studies Of Left Ventricular Dysfunction) Prevention and Treatment trials (X-SOLVD) demonstrated a significant benefit with a reduction of cumulative all-cause death compared with placebo (50.9% vs 56.4%) [hazard ratio (HR) 0.86; 95% CI 0.79, 0.93; p < 0.001]. The survival benefits and significant reductions in cardiovascular morbidity related to treatment with ACE inhibitors are likely achieved by titrating the dose of ACE inhibitors to the target dose achieved in clinical trials. Although the ATLAS (Assessment of Treatment with Lisinopril And Survival) study, which randomly allocated HF patients to low- or high-dose lisinopril, showed no significant difference between groups for the primary outcome of all-cause mortality (HR 0.92; 95% CI 0.82, 1.03), the predetermined secondary combined outcome of all-cause mortality and HF hospitalization was reduced by 15% for the patients receiving high-dose lisinopril compared with low-dose (p < 0.001) with a 24% reduction in HF hospitalization (p = 0.002).
Despite the use of ACE inhibitors, blockade of the renin angiotensin aldosterone system (RAAS) remains incomplete, with evidence of continued production of angiotensin II by non-ACE-dependent pathways. The safety and potential benefits of angiotensin receptor antagonists (angiotensin receptor blockers [ARBs]) in patients with impaired systolic function have been assessed in moderate to large clinical trials. In patients with impaired LV systolic function and HF, combination therapy with ARBs with recommended HF therapy including ACE inhibitors in patients who remain symptomatic may be considered for its morbidity benefit. Based on the CHARM (Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity)-Added data, candesartan cilexetil in addition to standard HF therapy results in a further reduction of cardiovascular mortality. Close monitoring of renal function and serum potassium levels is needed in this setting. The VALIANT (VALsartan In Acute myocardial iNfarction Trial) results suggest that valsartan is as effective as captopril in patients following an acute MI with HF and/or LV systolic dysfunction and may be used as an alternative treatment in ACE inhibitor-intolerant patients. There was no survival benefit with valsartan-captopril combination compared with captopril alone in this trial. Despite these results, ACE inhibitors remain the first-choice therapeutic agent in post-MI patients, and ARBs can be used in patients with clear intolerance. Although the use of ACE inhibitors may be appealing in patients with HF and preserved LV systolic function, there is currently no evidence from large clinical trials to support this.
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Notes
The NETWORK, comprising 82 hospital centers and 610 general practitioners, is not an acronym.
References
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). N Engl J Med 1987; 316(23): 1429–35.
The SOLVD Investigators. Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions [published erratum appears in N Engl J Med 1992; 327 (24): 1768]. N Engl J Med 1992; 327(10): 685–91.
The 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(5): 293–302.
Cohn JN, Johnson G, Ziesche S, et al. A comparison of enalapril with hydralazineisosorbide dinitrate in the treatment of congestive heart failure. N Engl J Med 1991; 325: 302–10.
Fiather MD, Yusuf S, Kober L, et al. Long-term ACE inhibitor therapy in patients with heart failure or left-ventricular dysfunction: a systematic overview of data from individual patients. Lancet 2000; 355: 1575–81.
Swedberg K, Kjekshus J, Snapinn S, et al. Long-term survival in severe heart failure in patients treated with enalapril: ten year follow-up of CONSENSUS I. Eur Heart J 1999; 20: 136–9.
Yusuf S, Pepine CJ, Garces C, et al. Effect of enalapril on myocardial infarction and unstable angina in patients with low ejection fractions. Lancet 1992; 340: 1173–8.
Garg R, Yusuf S. Overview of randomized trials of angiotensin-converting enzyme inhibitors on mortality and morbidity in patients with heart failure. JAMA 1995; 273: 1450–6.
Jong P, Yusuf S, Rousseau MF, et al. Effect of enalapril on 12-year survival and life expectancy in patients with left ventricular systolic dysfunction: a followup study. Lancet 2003; 361: 1843–8.
Wolny A, Clozel JP, Rein J, et al. Functional and biochemical analysis of angiotensin II-forming pathways in the human heart. Circ Res 1997; 80: 219–27.
Petrie MC, Padmanabhan N, McDonald JE, et al. Angiotensin converting enzyme (ACE) and non-ACE dependent angiotensin II generation in resistance arteries from patients with heart failure and coronary heart disease. J Am Coll Cardiol 2001; 37: 1056–61.
Jorde UP, Ennezat PV, Lisker J, et al. Maximally recommended doses of angiotensin-converting enzyme (ACE) inhibitors do not completely prevent ACE-mediated formation of angiotensin II in chronic heart failure. Circulation 2000; 101: 1805–8.
McKelvie RS, Yusuf S, Pericak D, et al. Comparison of candesartan, enalapril, and their combination in congestive heart failure: Randomized Evaluation of Strategies for Left Ventricular Dysfunction (RESOLVD) pilot study. The RESOLVD Pilot study investigators. Circulation 1999; 100: 1056–64.
McMurray JJV, Östergren J, Swedberg K, et al. 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: 767–71.
Tsutsami Y, Matsubara H, Masaki H, et al. Angiotensin II type 2 receptor overexpression activates the vascular kinin system and causes vasodilatation. J Clin Invest 1999; 104: 925–35.
Re R. Tissue renin angiotensin systems. Med Clin North Am 2004; 88: 19–38.
Nozawa Y, Haruno A, Oda N, et al. Angiotensin II receptor subtypes in bovine and human ventricular myocardium. J Pharmacol Exp Ther 1994; 270: 566–71.
Mizuno Y, Yoshimura M, Yasue H, et al. Aldosterone production is activated in failing ventricle in humans. Circulation 2001; 103: 72–7.
Struthers A, MacDonald T. Review of aldosterone- and angiotensin II-induced target organ damage and prevention. Cardiovasc Res 2003; 61: 663–70.
Tsikouris JP, Cox CD. Pharmacologic blockade of the rennin-angiotensin system: vascular benefits beyond commonly understood pharmacologic actions. Pharmacotherapy 2003; 23: 1141–52.
Higgins J. Can angiotensin-converting enzyme inhibitors reverse atherosclerosis? South Med J 2003; 96: 569–79.
Dunlap M, Peterson R. ACE inhibitors vs ARBs: is one class better for heart failure? Clev Clinic J Med 2002; 69: 433–8.
Harris P. Congestive cardiac failure: central role of the arterial blood pressure. Br Heart J 1987; 58: 190–203.
Tan LB, Williams SG, Goldspink DF. From CONSENSUS to CHARM: how do ACEI and ARB produce clinical benefits in CHF? Int J Cardiol 2004; 94: 137–41.
Sander G, James J, McKinnie J, et al. Angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists in the treatment of heart failure caused by left ventricular systolic dysfunction. Prog Cardiovasc Dis 1999; 41: 265–300.
Pfeffer MA, Braunwald E, Moyé 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. N Engl J Med 1992; 327: 669–77.
Kober L, Torp-Pedersen C, Carlsen JE, et al. A clinical trial of the angiotensin converting enzyme inhibitor trandolapril in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med 1995; 333: 1670–6.
The Acute Infarction Ramipril Efficacy (AIRE) Study investigators. Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure. Lancet 1993; 342: 821–8.
Hall AS, Murray GD, Ball SG, et al. Follow-up study of patients randomly allocated ramipril or placebo for heart failure after acute myocardial infarction: AIRE Extension (AIREX) study. Lancet 1997; 349: 1493–7.
The NETWORK Investigators. Clinical outcome with enalapril in symptomatic chronic heart failure: a dose comparison. Eur Heart J 1998; 19: 481–9.
Packer M, Poole-Wilson A, Armstrong PW, et al. Comparative effects of low and high doses of the angiotensin-converting enzyme inhibitor, lisinopril, on morbidity and mortality in chronic heart failure: the ATLAS Study Group. Circulation 1999; 100: 2312–8.
Dickstein K, Chang K, Willenheimer R, et al. Comparison of the effects of losartan and enalapril on clinical status and exercise performance in patients with moderate or severe chronic heart failure. J Am Coll Cardiol 1995; 26: 438–45.
Pitt B, Segal R, Martinez FA, et al. Randomised trial of losartan versus captopril in patients over 65 with heart failure: the ELITE Study investigators. Lancet 1997; 349: 747–52.
Lang RM, Elkayam U, Yellen LG, et al. Comparative effects of losartan and enalapril on exercise capacity and clinical status in patients with heart failure: the Losartan Pilot Exercise Study investigators. J Am Coll Cardiol 1997; 30: 983–91.
Mazayev VP, Fomina IG, Kazakov EN, et al. Valsartan in heart failure patients previously untreated with an ACE inhibitor. Int J Cardiol 1998; 65: 239–46.
Pitt B, Poole-Wilson PA, Segal R, et al. Effect of losartan compared with captopril on mortality in patients with symptomatic heart failure: randomized trial. Losartan Heart Failure Survival Study ELITE II: the ELITE II investigators. Lancet 2000; 355: 1582–7.
Dunselman PH. Effects of the replacement of the angiotensin converting enzyme inhibitor enalapril by the angiotensin II receptor blocker telmisartan in patients with congestive heart failure: the REPLacement of Angiotensin Converting Enzyme inhibition (REPLACE) investigators. Int J Cardiol 2001; 77: 131–8.
Willenheimer R, Helmers C, Pantev E, et al. Safety and efficacy of valsartan versus enalapril in heart failure patients. Int J Cardiol 2002; 85: 261–70.
Jong P, Demers C, McKelvie RS, et al. Angiotensin receptor blockers in heart failure: meta-analysis of randomized controlled trials. J Am Coll Cardiol 2002; 39: 463–70.
Lee VC, Rhew DC, Dylan M, et al. Meta-analysis: angiotensin-receptor blockers in chronic heart failure and high-risk acute myocardial infarction. Ann Intern Med 2004; 141: 693–704.
Hamroff G, Katz SD, Mancini D, et al. Addition of angiotensin II receptor blockade to maximal angiotensin-converting enzyme inhibition improves exercise capacity in patients with severe congestive heart failure. Circulation 1999; 99: 990–2.
Baruch L, Anand I, Cohen IS, et al. Augmented short- and long-term hemodynamic and hormonal effects of an angiotensin receptor blocker added to angiotensin converting enzyme inhibitor therapy in patients with heart failure: Vasodilator Heart Failure Trial (V-HeFT) study group. Circulation 1999; 99: 2658–64.
Tonkon M, Awan N, Niazi I, et al. A study of the efficacy and safety of irbesartan in combination with conventional therapy including ACE inhibitors, in heart failure: Irbesartan Heart Failure Group. Int J Clin Pract 2000; 54: 11–8.
Murdoch DR, McDonagh TA, Farmer R, et al. ADEPT: addition of the AT1 receptor antagonist eprosartan to ACE inhibitor therapy in chronic heart failure trial. Hemodynamic and neurohormonal effects. Am Heart J 2001; 141: 800–7.
Cohn JN, Tognoni G, et al. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure: Valsartan Heart Failure Trial investigators. N Engl J Med 2001; 345: 1667–75.
Dickstein K, Kjekshus J, et al. Effects of losartan and captopril on mortality and morbidity in high-risk patients after acute myocardial infarction: the OPTIMAAL randomized trial. OPTIMAAL Steering Committee of the OPTIMAAL Study Group. Lancet 2002; 360: 752–60.
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: 1893–906.
Acknowledgments
Drs C. Demers, A. Mody, K.K. Teo, and R.S. McKelvie have no conflict of interest to declare. Dr Catherine Demers holds a Ministry of Health and Long Term Care of Ontario Career Scientist Award.
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Demers, C., Mody, A., Teo, K.K. et al. ACE Inhibitors in Heart Failure. Am J Cardiovasc Drugs 5, 351–359 (2005). https://doi.org/10.2165/00129784-200505060-00002
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DOI: https://doi.org/10.2165/00129784-200505060-00002