Official reprint from UpToDate®
www.uptodate.com ©2015 UpToDate®

ACE inhibitors in heart failure due to systolic dysfunction: Therapeutic use

Wilson S Colucci, MD
Section Editor
Stephen S Gottlieb, MD
Deputy Editor
Susan B Yeon, MD, JD, FACC


Randomized trials have shown that angiotensin converting enzyme (ACE) inhibitor therapy leads to symptomatic improvement, reduced hospitalization, and enhanced survival in patients with heart failure (HF) and systolic dysfunction [1-8]. Therefore, ACE inhibitors are an important component of standard HF therapy in patients with current or prior symptoms of HF and depressed left ventricular systolic function.

The clinical data supporting the use of ACE inhibitors in patients with HF will be reviewed here. The mechanisms of action of these agents in HF, their role in patients with diastolic dysfunction, their use in patients with asymptomatic systolic dysfunction, and the efficacy of angiotensin II receptor blockers are discussed separately. (See "Angiotensin converting enzyme inhibitors and receptor blockers in heart failure: Mechanisms of action" and "Treatment and prognosis of diastolic heart failure" and "Evaluation and management of asymptomatic left ventricular systolic dysfunction" and "Use of angiotensin II receptor blocker and neprilysin inhibitor therapy in heart failure with reduced ejection fraction".)

An overview of the treatment of HF due to systolic dysfunction is discussed separately [9]. (See "Overview of the therapy of heart failure due to systolic dysfunction".)


General efficacy — Angiotensin converting enzyme (ACE) inhibitors are recommended to treat heart failure (HF) due to systolic dysfunction because multiple, large, prospective, randomized trials have consistently demonstrated a significant reduction in mortality (table 1) [1-5] as well as alleviation of symptoms and improvement in clinical status [6-8]. The benefit of ACE inhibitors has been demonstrated in all severities of symptomatic HF and in patients with asymptomatic left ventricular (LV) dysfunction; a benefit has also been demonstrated after myocardial infarction (MI).

A meta-analysis evaluated five trials (three starting during the first one to three weeks post-MI) involving 12,763 patients with LV ejection fraction (LVEF) ≤35 percent or <40 percent and/or clinical HF. ACE inhibition had the following benefits [10]:


Subscribers log in here

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information or to purchase a personal subscription, click below on the option that best describes you:
Literature review current through: Jul 2015. | This topic last updated: Sep 17, 2014.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2015 UpToDate, Inc.
  1. 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.
  2. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. The SOLVD Investigators. N Engl J Med 1991; 325:293.
  3. Cohn JN, Johnson G, Ziesche S, et al. A comparison of enalapril with hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failure. N Engl J Med 1991; 325:303.
  4. Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions. The SOLVD Investigattors. N Engl J Med 1992; 327:685.
  5. 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. The SAVE Investigators. N Engl J Med 1992; 327:669.
  6. Sharpe DN, Murphy J, Coxon R, Hannan SF. Enalapril in patients with chronic heart failure: a placebo-controlled, randomized, double-blind study. Circulation 1984; 70:271.
  7. Cleland JG, Dargie HJ, Ball SG, et al. Effects of enalapril in heart failure: a double blind study of effects on exercise performance, renal function, hormones, and metabolic state. Br Heart J 1985; 54:305.
  8. Erhardt L, MacLean A, Ilgenfritz J, et al. Fosinopril attenuates clinical deterioration and improves exercise tolerance in patients with heart failure. Fosinopril Efficacy/Safety Trial (FEST) Study Group. Eur Heart J 1995; 16:1892.
  9. Hunt SA, Abraham WT, Chin MH, et al. 2009 focused update incorporated into the ACC/AHA 2005 Guidelines for the Diagnosis and Management of Heart Failure in Adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines: developed in collaboration with the International Society for Heart and Lung Transplantation. Circulation 2009; 119:e391.
  10. Flather MD, Yusuf S, Køber 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. ACE-Inhibitor Myocardial Infarction Collaborative Group. Lancet 2000; 355:1575.
  11. Swedberg K, Kjekshus J, Snapinn S. 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.
  12. 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 follow-up study. Lancet 2003; 361:1843.
  13. Carson P, Ziesche S, Johnson G, Cohn JN. Racial differences in response to therapy for heart failure: analysis of the vasodilator-heart failure trials. Vasodilator-Heart Failure Trial Study Group. J Card Fail 1999; 5:178.
  14. Sin DD, McAlister FA. The effects of beta-blockers on morbidity and mortality in a population-based cohort of 11,942 elderly patients with heart failure. Am J Med 2002; 113:650.
  15. Havranek EP, Abrams F, Stevens E, Parker K. Determinants of mortality in elderly patients with heart failure: the role of angiotensin-converting enzyme inhibitors. Arch Intern Med 1998; 158:2024.
  16. Masoudi FA, Rathore SS, Wang Y, et al. National patterns of use and effectiveness of angiotensin-converting enzyme inhibitors in older patients with heart failure and left ventricular systolic dysfunction. Circulation 2004; 110:724.
  17. Ahmed A, Kiefe CI, Allman RM, et al. Survival benefits of angiotensin-converting enzyme inhibitors in older heart failure patients with perceived contraindications. J Am Geriatr Soc 2002; 50:1659.
  18. Ahmed A, Centor RM, Weaver MT, Perry GJ. A propensity score analysis of the impact of angiotensin-converting enzyme inhibitors on long-term survival of older adults with heart failure and perceived contraindications. Am Heart J 2005; 149:737.
  19. Packer M, Poole-Wilson PA, 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. ATLAS Study Group. Circulation 1999; 100:2312.
  20. Heart Failure Society of America, Lindenfeld J, Albert NM, et al. HFSA 2010 Comprehensive Heart Failure Practice Guideline. J Card Fail 2010; 16:e1.
  21. Shekelle PG, Rich MW, Morton SC, et al. Efficacy of angiotensin-converting enzyme inhibitors and beta-blockers in the management of left ventricular systolic dysfunction according to race, gender, and diabetic status: a meta-analysis of major clinical trials. J Am Coll Cardiol 2003; 41:1529.
  22. Keyhan G, Chen SF, Pilote L. Angiotensin-converting enzyme inhibitors and survival in women and men with heart failure. Eur J Heart Fail 2007; 9:594.
  23. Dries DL, Exner DV, Gersh BJ, et al. Racial differences in the outcome of left ventricular dysfunction. N Engl J Med 1999; 340:609.
  24. Exner DV, Dries DL, Domanski MJ, Cohn JN. Lesser response to angiotensin-converting-enzyme inhibitor therapy in black as compared with white patients with left ventricular dysfunction. N Engl J Med 2001; 344:1351.
  25. Materson BJ, Reda DJ, Cushman WC, et al. Single-drug therapy for hypertension in men. A comparison of six antihypertensive agents with placebo. The Department of Veterans Affairs Cooperative Study Group on Antihypertensive Agents. N Engl J Med 1993; 328:914.
  26. Weir MR, Gray JM, Paster R, Saunders E. Differing mechanisms of action of angiotensin-converting enzyme inhibition in black and white hypertensive patients. The Trandolapril Multicenter Study Group. Hypertension 1995; 26:124.
  27. Dries DL, Strong MH, Cooper RS, Drazner MH. Efficacy of angiotensin-converting enzyme inhibition in reducing progression from asymptomatic left ventricular dysfunction to symptomatic heart failure in black and white patients. J Am Coll Cardiol 2002; 40:311.
  28. Farquharson CA, Struthers AD. Gradual reactivation over time of vascular tissue angiotensin I to angiotensin II conversion during chronic lisinopril therapy in chronic heart failure. J Am Coll Cardiol 2002; 39:767.
  29. Lapointe N, Rouleau JL. Activation of vascular tissue angiotensin-converting enzyme (ACE) in heart failure. Effects of ACE inhibitors. J Am Coll Cardiol 2002; 39:776.
  30. Tang WH, Vagelos RH, Yee YG, et al. Neurohormonal and clinical responses to high- versus low-dose enalapril therapy in chronic heart failure. J Am Coll Cardiol 2002; 39:70.
  31. Rochon PA, Sykora K, Bronskill SE, et al. Use of angiotensin-converting enzyme inhibitor therapy and dose-related outcomes in older adults with new heart failure in the community. J Gen Intern Med 2004; 19:676.
  32. Clinical outcome with enalapril in symptomatic chronic heart failure; a dose comparison. The NETWORK Investigators. Eur Heart J 1998; 19:481.
  33. Nanas JN, Alexopoulos G, Anastasiou-Nana MI, et al. Outcome of patients with congestive heart failure treated with standard versus high doses of enalapril: a multicenter study. High Enalapril Dose Study Group. J Am Coll Cardiol 2000; 36:2090.
  34. Rydén L, Armstrong PW, Cleland JG, et al. Efficacy and safety of high-dose lisinopril in chronic heart failure patients at high cardiovascular risk, including those with diabetes mellitus. Results from the ATLAS trial. Eur Heart J 2000; 21:1967.
  35. Exner DV, Dries DL, Waclawiw MA, et al. Beta-adrenergic blocking agent use and mortality in patients with asymptomatic and symptomatic left ventricular systolic dysfunction: a post hoc analysis of the Studies of Left Ventricular Dysfunction. J Am Coll Cardiol 1999; 33:916.
  36. Sliwa K, Norton GR, Kone N, et al. Impact of initiating carvedilol before angiotensin-converting enzyme inhibitor therapy on cardiac function in newly diagnosed heart failure. J Am Coll Cardiol 2004; 44:1825.
  37. McNamara DM, Holubkov R, Janosko K, et al. Pharmacogenetic interactions between beta-blocker therapy and the angiotensin-converting enzyme deletion polymorphism in patients with congestive heart failure. Circulation 2001; 103:1644.
  38. Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med 1999; 341:709.
  39. Pitt B, Remme W, Zannad F, et al. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med 2003; 348:1309.
  40. Zannad F, McMurray JJ, Krum H, et al. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med 2011; 364:11.
  41. Stys T, Lawson WE, Smaldone GC, Stys A. Does aspirin attenuate the beneficial effects of angiotensin-converting enzyme inhibition in heart failure? Arch Intern Med 2000; 160:1409.
  42. Hall D, Zeitler H, Rudolph W. Counteraction of the vasodilator effects of enalapril by aspirin in severe heart failure. J Am Coll Cardiol 1992; 20:1549.
  43. Spaulding C, Charbonnier B, Cohen-Solal A, et al. Acute hemodynamic interaction of aspirin and ticlopidine with enalapril: results of a double-blind, randomized comparative trial. Circulation 1998; 98:757.
  44. Guazzi M, Melzi G, Agostoni P. Comparison of changes in respiratory function and exercise oxygen uptake with losartan versus enalapril in congestive heart failure secondary to ischemic or idiopathic dilated cardiomyopathy. Am J Cardiol 1997; 80:1572.
  45. Nguyen KN, Aursnes I, Kjekshus J. Interaction between enalapril and aspirin on mortality after acute myocardial infarction: subgroup analysis of the Cooperative New Scandinavian Enalapril Survival Study II (CONSENSUS II). Am J Cardiol 1997; 79:115.
  46. Al-Khadra AS, Salem DN, Rand WM, et al. Antiplatelet agents and survival: a cohort analysis from the Studies of Left Ventricular Dysfunction (SOLVD) trial. J Am Coll Cardiol 1998; 31:419.
  47. Guazzi M, Brambilla R, Reina G, et al. Aspirin-angiotensin-converting enzyme inhibitor coadministration and mortality in patients with heart failure: a dose-related adverse effect of aspirin. Arch Intern Med 2003; 163:1574.
  48. Leor J, Reicher-Reiss H, Goldbourt U, et al. Aspirin and mortality in patients treated with angiotensin-converting enzyme inhibitors: a cohort study of 11,575 patients with coronary artery disease. J Am Coll Cardiol 1999; 33:1920.
  49. McAlister FA, Ghali WA, Gong Y, et al. Aspirin use and outcomes in a community-based cohort of 7352 patients discharged after first hospitalization for heart failure. Circulation 2006; 113:2572.
  50. Ezekowitz J, McAlister FA, Humphries KH, et al. The association among renal insufficiency, pharmacotherapy, and outcomes in 6,427 patients with heart failure and coronary artery disease. J Am Coll Cardiol 2004; 44:1587.
  51. Smith NL, Psaty BM, Pitt B, et al. Temporal patterns in the medical treatment of congestive heart failure with angiotensin-converting enzyme inhibitors in older adults, 1989 through 1995. Arch Intern Med 1998; 158:1074.
  52. McDermott MM, Feinglass J, Lee P, et al. Heart failure between 1986 and 1994: temporal trends in drug-prescribing practices, hospital readmissions, and survival at an academic medical center. Am Heart J 1997; 134:901.
  53. Stafford RS, Saglam D, Blumenthal D. National patterns of angiotensin-converting enzyme inhibitor use in congestive heart failure. Arch Intern Med 1997; 157:2460.
  54. Bart BA, Ertl G, Held P, et al. Contemporary management of patients with left ventricular systolic dysfunction. Results from the Study of Patients Intolerant of Converting Enzyme Inhibitors (SPICE) Registry. Eur Heart J 1999; 20:1182.
  55. Echemann M, Zannad F, Briançon S, et al. Determinants of angiotensin-converting enzyme inhibitor prescription in severe heart failure with left ventricular systolic dysfunction: the EPICAL study. Am Heart J 2000; 139:624.
  56. Luzier AB, Forrest A, Adelman M, et al. Impact of angiotensin-converting enzyme inhibitor underdosing on rehospitalization rates in congestive heart failure. Am J Cardiol 1998; 82:465.
  57. Arnold JM, Yusuf S, Young J, et al. Prevention of Heart Failure in Patients in the Heart Outcomes Prevention Evaluation (HOPE) Study. Circulation 2003; 107:1284.
  58. Pedersen OD, Bagger H, Kober L, Torp-Pedersen C. Trandolapril reduces the incidence of atrial fibrillation after acute myocardial infarction in patients with left ventricular dysfunction. Circulation 1999; 100:376.
  59. Vermes E, Tardif JC, Bourassa MG, et al. Enalapril decreases the incidence of atrial fibrillation in patients with left ventricular dysfunction: insight from the Studies Of Left Ventricular Dysfunction (SOLVD) trials. Circulation 2003; 107:2926.
  60. Dickstein K, Cohen-Solal A, Filippatos G, et al. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2008: the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2008 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association of the ESC (HFA) and endorsed by the European Society of Intensive Care Medicine (ESICM). Eur Heart J 2008; 29:2388.
  61. Kostis JB, Shelton BJ, Yusuf S, et al. Tolerability of enalapril initiation by patients with left ventricular dysfunction: results of the medication challenge phase of the Studies of Left Ventricular Dysfunction. Am Heart J 1994; 128:358.
  62. Lang RM, DiBianco R, Broderick GT, et al. First-dose effects of enalapril 2.5 mg and captopril 6.25 mg in patients with heart failure: a double-blind, randomized, multicenter study. The Enalapril-Captopril Investigators. Am Heart J 1994; 128:551.
  63. Delahaye F, de Gevigney G. Is the optimal dose of angiotensin-converting enzyme inhibitors in patients with congestive heart failure definitely established? J Am Coll Cardiol 2000; 36:2096.
  64. Ljungman S, Kjekshus J, Swedberg K. Renal function in severe congestive heart failure during treatment with enalapril (the Cooperative North Scandinavian Enalapril Survival Study [CONSENSUS] Trial). Am J Cardiol 1992; 70:479.
  65. Packer M, Lee WH, Medina N, et al. Functional renal insufficiency during long-term therapy with captopril and enalapril in severe chronic heart failure. Ann Intern Med 1987; 106:346.
  66. Packer M, Lee WH, Kessler PD, et al. Identification of hyponatremia as a risk factor for the development of functional renal insufficiency during converting enzyme inhibition in severe chronic heart failure. J Am Coll Cardiol 1987; 10:837.
  67. Testani JM, Kimmel SE, Dries DL, Coca SG. Prognostic importance of early worsening renal function after initiation of angiotensin-converting enzyme inhibitor therapy in patients with cardiac dysfunction. Circ Heart Fail 2011; 4:685.