title: Reduced Risk of Hyperkalemia During Treatment of Heart Failure With Mineralocorticoid Receptor Antagonists by Use of Sacubitril/Valsartan Compared With Enalapril: A Secondary Analysis of the PARADIGM-HF Trial.
abstract: Consensus guidelines recommend the use of mineralocorticoid receptor antagonists (MRAs) for selected patients with symptomatic heart failure and reduced ejection fraction (HFrEF) to reduce morbidity and mortality; however, the use of MRAs in combination with other inhibitors of the renin-angiotensin-aldosterone system increases the risk of hyperkalemia.
  
  
  
  To determine whether the risk of hyperkalemia associated with use of MRAs for patients with HFrEF is reduced by sacubitril/valsartan in comparison with enalapril.
  
  
  
  The PARADIGM-HF (Prospective Comparison of ARNI With an ACE-Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial randomly assigned 8399 patients with chronic HF, New York Heart Association class II to IV symptoms, and a left ventricular EF of 40% or less to treatment with enalapril 10 mg twice daily or sacubitril/valsartan 97/103 mg twice daily (previously known as LCZ696 [200 mg twice daily]) in addition to guideline-directed medical therapy. Use of MRAs was encouraged but left to the discretion of study investigators. Serum potassium level was measured at every study visit. The incidence of hyperkalemia (potassium level >5.5 mEq/L) and severe hyperkalemia (potassium level >6.0 mEq/L) among patients treated or not treated with an MRA at baseline and the risk of subsequent hyperkalemia for those newly treated with an MRA during study follow-up were defined in time-updated Cox proportional hazards models. Analyses were conducted between August 1 and October 15, 2016.
  
  
  
  Incident hyperkalemia and severe hyperkalemia.
  
  
  
  In comparison with the 3728 patients (44.4% of enrolled participants [21.6% female]) not taking an MRA at baseline, the 4671 patients (55.6% [22.0% female]) taking an MRA tended to be younger, with a lower EF, lower systolic blood pressure, and more advanced HF symptoms. Among those taking an MRA at baseline, the overall rates of hyperkalemia were similar between treatment groups, but severe hyperkalemia was more common in patients randomly assigned to enalapril than to sacubitril/valsartan (3.1 vs 2.2 per 100 patient-years; HR, 1.37 [95% CI, 1.06-1.76]; P = .02). In analyses including patients who newly started taking MRAs during the PARADIGM-HF trial, severe hyperkalemia remained more common in those randomly assigned to enalapril than to those randomly assigned to sacubitril/valsartan (3.3 vs 2.3 per 100 patient-years; HR, 1.43 [95% CI, 1.13-1.81]; P = .003).
  
  
  
  Among MRA-treated patients with symptomatic HFrEF, severe hyperkalemia is more likely during treatment with enalapril than with sacubitril/valsartan. These data suggest that neprilysin inhibition attenuates the risk of hyperkalemia when MRAs are combined with other inhibitors of the renin-angiotensin-aldosterone system in patients with HF.
  
  
  
  clinicaltrials.gov Identifier: NCT01035255.
authors.affiliation: Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Akshay S
authors.initials: AS
authors.lastname: Desai
authors.affiliation: Pharmacy Practice Division, University of Wisconsin School of Pharmacy, Madison.
authors.forename: Orly
authors.initials: O
authors.lastname: Vardeny
authors.affiliation: Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Brian
authors.initials: B
authors.lastname: Claggett
authors.affiliation: British Heart Foundation Cardiovascular Research Centre, University of Glasgow, Glasgow, Scotland.
authors.forename: John J V
authors.initials: JJ
authors.lastname: McMurray
authors.affiliation: Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas, Texas.
authors.forename: Milton
authors.initials: M
authors.lastname: Packer
authors.affiliation: Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden6National Heart and Lung Institute, Imperial College, London, England.
authors.forename: Karl
authors.initials: K
authors.lastname: Swedberg
authors.affiliation: Montreal Heart Institute, Université de Montréal, Montréal, Quebec, Canada.
authors.forename: Jean L
authors.initials: JL
authors.lastname: Rouleau
authors.affiliation: Medical University of South Carolina, Charleston9Ralph H. Johnston Veterans Administration Medical Center, Charleston, South Carolina.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Zile
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, New Jersey.
authors.forename: Martin
authors.initials: M
authors.lastname: Lefkowitz
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, New Jersey.
authors.forename: Victor
authors.initials: V
authors.lastname: Shi
authors.affiliation: Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Scott D
authors.initials: SD
authors.lastname: Solomon
mesh_terms: D000368:Aged; D000613:Aminobutyrates / Q000009:adverse effects* / Q000627:therapeutic use; D001713:Biphenyl Compounds; D004338:Drug Combinations; D004656:Enalapril / Q000009:adverse effects* / Q000627:therapeutic use; D005260:Female; D006333:Heart Failure / Q000188:drug therapy* / Q000503:physiopathology; D006801:Humans; D006947:Hyperkalemia / Q000139:chemically induced / Q000453:epidemiology*; D015994:Incidence; D008297:Male; D008875:Middle Aged; D000451:Mineralocorticoid Receptor Antagonists / Q000009:adverse effects*; D017410:Practice Guidelines as Topic; D011446:Prospective Studies; D013318:Stroke Volume; D013777:Tetrazoles / Q000009:adverse effects* / Q000627:therapeutic use; D016896:Treatment Outcome; D000068756:Valsartan
chemical_list: D000613:Aminobutyrates; D001713:Biphenyl Compounds; D004338:Drug Combinations; D000451:Mineralocorticoid Receptor Antagonists; D013777:Tetrazoles; D004656:Enalapril; D000068756:Valsartan; C549068:sacubitril and valsartan sodium hydrate drug combination