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Neprilysin inhibition attenuates the hyperkalaemia risk in HFrEF patients on MRAs

Literature - Desai AS et al., JAMA Cardiol. 2016

Desai AS, Vardeny O, Claggett B, et al.
JAMA Cardiol. 2016;published online ahead of print


Current treatment guidelines recommend additional use of an MRA for most HFrEF patients who remain symptomatic despite treatment with β-blockers and inhibitors of the renin-angiotensin-aldosterone system [1,2]. However, the use of MRAs is limited in clinical practice, due to concerns about the elevated risk of hyperkalaemia, particularly in patients with chronic kidney disease [3,4].
In the PARADIGM-HF trial, patients with symptomatic HFrEF randomly assigned to sacubitril/valsartan had lower rates of death and HF hospitalisation compared to those randomly assigned to enalapril [5].
In this post-randomisation examination of hyperkalaemia in PARADIGM-HF patients, it was evaluated whether treatment with sacubitril/valsartan might reduce the risk of hyperkalaemia associated with the use of MRAs. At baseline, 4671 patients received an MRA. Of those, 2271 received sacubitril/valsartan and 2400 received enalapril.

Main results

  • Compared with participants not taking an MRA at baseline, participants taking an MRA at baseline were younger, had a lower EF, lower SBP, less severe ischemic heart disease, greater likelihood of prior hospitalisation for HF, and more advanced HF symptoms.
  • Treatment with sacubitril/valsartan reduced the risk of CV death regardless of MRA use at baseline (MRA non-users: HR: 0.75; 95% CI: 0.63-0.89; MRA users: HR: 0.84; 95%CI: 0.73-0.98; P = 0.30 for interaction).
  • The incidences of hyperkalaemia (10.0 vs 7.3 per 100 patient-years [PY]; HR: 1.33; 95% CI: 1.19-1.48; P < 0.001) and severe hyperkalaemia (2.7 vs 2.0 per 100 PY; HR: 1.35; 95% CI: 1.11-1.64; P = 0.003) were higher among MRA-treated patients compared with patients not taking MRAs during study follow-up.
  • For patients taking an MRA at baseline, rates of hyperkalaemia were similar between treatment groups (10.6 vs 9.4 per 100 PY; HR: 1.12; 95% CI: 0.98-1.28; P = 0.11; risk difference: 1.2 per 100 PY; 95% CI: −0.1 to 2.6 per 100 PY).
  • Severe hyperkalaemia was more common in patients randomly assigned to enalapril compared with patients randomly assigned to sacubitril/valsartan (3.1 vs 2.2 per 100 PY; HR: 1.37; 95% CI: 1.06-1.76; P = 0.02; risk difference: 1.0 per 100 PY; 95% CI: 0.3-1.6 per 100 PY).
  • Including both patients on MRA at baseline and those who initiated MRA therapy during the trial, the risk of subsequent severe hyperkalaemia was more common among those randomly assigned to enalapril than those assigned to sacubitril/valsartan (3.3 vs 2.3 per 100 PY; HR: 1.43; 95% CI: 1.13-1.81; P = 0.003).


In a post-randomisation analysis of hyperkalaemia in the PARADIGM-HF trial, neprilysin inhibition attenuated the risk of hyperkalaemia when MRAs were combined with other inhibitors of the renin-angiotensin-aldosterone system in patients with HFrEF. These data support the use of sacubitril/valsartan for suitable HFrEF patients on MRAs in clinical practice.

Find this article online at JAMA Cardiology


1. Yancy CW, Jessup M, Bozkurt B, et al; American College of Cardiology Foundation; American Heart Association Task Force on Practice Guidelines. 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. J AmColl Cardiol.2013;62(16):e147-e239.
2. Ponikowski P, Voors AA, Anker SD, et al; Authors/Task Force Members; Document Reviewers. 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 J Heart Fail. 2016;18(8):891-975.
3. Palmer BF. Managing hyperkalemia caused by inhibitors of the renin-angiotensin-aldosterone system. N Engl J Med. 2004;351(6):585-592.
4. Dev S, LacyME, Masoudi FA,WuW-C. Temporal trends and hospital variation in mineralocorticoid receptor antagonist use in veterans discharged with heart failure. J AmHeart Assoc. 2015;4(12):e002268.
5. McMurray JJ, Packer M, Desai AS, et al; PARADIGM-HF Investigators and Committees. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014;371(11):993-1004.

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