Use of angiotensin II receptor blocker in heart failure with reduced ejection fraction
- Wilson S Colucci, MD
Wilson S Colucci, MD
- Section Editor — Heart Failure
- Professor of Medicine
- Boston University School of Medicine
Blockade of the renin-angiotensin-aldosterone system (RAAS) is a key component of treatment of patients with heart failure (HF) with reduced ejection fraction (HFrEF, also known as systolic HF or HF due to systolic dysfunction) [1-3]. (See "Overview of the therapy of heart failure with reduced ejection fraction".)
This topic will discuss the clinical evidence on and use of ARB therapy in HFrEF. The role of angiotensin receptor-neprilysin inhibitor therapy in HFrEF, an overview of pharmacologic treatment of HFrEF, and mechanisms of action of ARB therapy are discussed separately. (See "Use of angiotensin receptor-neprilysin inhibitor in heart failure with reduced ejection fraction" and "Pharmacologic therapy of heart failure with reduced ejection fraction" and "Angiotensin converting enzyme inhibitors and receptor blockers in heart failure: Mechanisms of action".)
ANGIOTENSIN II RECEPTOR BLOCKER
Mechanism of action — Angiotensin II receptor blockers (ARBs) and angiotensin converting enzyme (ACE) inhibitors reduce the stimulation of angiotensin II (AT) receptors via different mechanisms (figure 1). Given the difference in mechanisms, it was previously postulated that ARB therapy would provide an advantage over ACE inhibitor therapy but the evidence has shown that ARB therapy is not superior to ACE inhibitor therapy for heart failure (HF).
ACE inhibitors block the formation of angiotensin II, thereby decreasing the amount of angiotensin available to both AT type 1 (AT1) and AT type 2 (AT2) receptors. ARBs selectively block the binding of angiotensin II to the AT1 receptor, but do not affect the AT2 receptor . The clinical importance of this is uncertain, since the AT1 receptor seems to dominate. (See "Actions of angiotensin II on the heart" and "Differences between angiotensin-converting enzyme inhibitors and receptor blockers".)
Another difference is that ACE inhibitors, but not ARBs, reduce kinin degradation, since ACE is also a kininase (figure 1). The accumulation of kinins may mediate some of the benefits as well as the adverse effects of ACE inhibitors. One important clinical consequence resulting from the lack of kinin accumulation is that the ARBs do not induce cough, a complication that occurs in 3 to 20 percent of patients treated with ACE inhibitors. (See "Major side effects of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers".)
- WRITING COMMITTEE MEMBERS, Yancy CW, Jessup M, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation 2013; 128:e240.
- Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC)Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J 2016; 37:2129.
- Yancy CW, Jessup M, Bozkurt B, et al. 2016 ACC/AHA/HFSA Focused Update on New Pharmacological Therapy for Heart Failure: An Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. J Am Coll Cardiol 2016; 68:1476.
- Goldsmith DJ. Angiotensin receptor antagonists. Lancet 1997; 349:1255.
- WRITING COMMITTEE MEMBERS, Yancy CW, Jessup M, et al. 2016 ACC/AHA/HFSA Focused Update on New Pharmacological Therapy for Heart Failure: An Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. Circulation 2016; 134:e282.
- Heran BS, Musini VM, Bassett K, et al. Angiotensin receptor blockers for heart failure. Cochrane Database Syst Rev 2012; :CD003040.
- 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.
- 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.
- Dickstein K, Chang P, 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.
- 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.
- 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.
- Cohn JN, Tognoni G, 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.
- McMurray JJ, Ostergren 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.
- 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.
- Weir RA, McMurray JJ, Puu M, et al. Efficacy and tolerability of adding an angiotensin receptor blocker in patients with heart failure already receiving an angiotensin-converting inhibitor plus aldosterone antagonist, with or without a beta blocker. Findings from the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM)-Added trial. Eur J Heart Fail 2008; 10:157.
- http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/020838s031lbl.pdf (Accessed on July 22, 2015).
- http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/021283s033lbl.pdf (Accessed on July 22, 2015).
- Palmer BF. Managing hyperkalemia caused by inhibitors of the renin-angiotensin-aldosterone system. N Engl J Med 2004; 351:585.
- Eklind-Cervenka M, Benson L, Dahlström U, et al. Association of candesartan vs losartan with all-cause mortality in patients with heart failure. JAMA 2011; 305:175.
- Konstam MA, Neaton JD, Dickstein K, et al. Effects of high-dose versus low-dose losartan on clinical outcomes in patients with heart failure (HEAAL study): a randomised, double-blind trial. Lancet 2009; 374:1840.
- ANGIOTENSIN II RECEPTOR BLOCKER
- Mechanism of action
- Indications for use of angiotensin II receptor blocker
- Evidence on angiotensin II receptor blocker
- - Intolerant of ACE inhibitor
- - Compared with ACE inhibitor
- - Use MRA rather than ARB with ACE inhibitor
- Addition of MRA to ACE inhibitor improves survival
- Addition of ARB to ACE inhibitor does not improve survival
- - Avoid combination of ARB with ACE inhibitor and MRA
- Adverse effects
- Agent and dose
- SUMMARY AND RECOMMENDATIONS