title: Incidence, predictors, and outcomes related to hypo- and hyperkalemia in patients with severe heart failure treated with a mineralocorticoid receptor antagonist.
abstract: BACKGROUND
  Mineralocorticoid receptor antagonists reduce morbidity and mortality in patients with heart failure but can cause hyperkalemia, which contributes to reduced use of these drugs. Hypokalemia also leads to worse outcomes in patients with heart failure and may be attenuated by mineralocorticoid receptor antagonists.
  
  
  RESULTS
  We assessed incidence and predictors of hyperkalemia (potassium ≥5.5 mmol/L) and hypokalemia (potassium <3.5 mmol/L) and the relationship to outcomes in 1663 patients with class III or IV heart failure and left ventricular ejection fraction <35% randomized to treatment with spironolactone 25 mg or placebo in the Randomized Aldactone Evaluation Study (RALES) trial. All-cause mortality rates and the influence of potassium levels on the effectiveness of spironolactone were assessed in a landmark analysis and in relation to time-varying potassium levels. After 1 month, mean potassium levels increased in the spironolactone group but not in the placebo group (4.54±0.49 versus 4.28±0.50 mmol/L; P<0.001) and remained elevated during the trial. Although the extremes of hypokalemia and hyperkalemia at 4 weeks were associated with increased risk of mortality in both treatment arms, participants in the spironolactone arm had lower mortality rates at all potassium levels throughout the duration of the trial. The treatment benefit of spironolactone was maintained at least until potassium exceeded 5.5 mmol/L.
  
  
  CONCLUSIONS
  With appropriate surveillance of potassium and creatinine, the use of spironolactone was associated with less hypokalemia and improved survival in patients with severe heart failure even in the setting of moderate hyperkalemia.
authors.affiliation: From the Department of Pharmacy, University of Wisconsin School of Pharmacy, Madison, WI (O.V.); Department of Medicine, Brigham and Women's Hospital, Boston, MA (B.C., A.S.D., S.D.S.); VA Medical Center and University of Minnesota, Minneapolis (I.A.); INSERM, Centre d'Investigations Cliniques-9501 and INSERM U1116, Nancy, France (P.R., F.Z.); Department of Cardiology (F.Z.) and Department of Nephrology (P.R.), Université de Lorraine, Nancy, France; and Department of Medicine, University of Michigan, Ann Arbor (B.P.). ovardeny@pharmacy.wisc.edu.
authors.forename: Orly
authors.initials: O
authors.lastname: Vardeny
authors.affiliation: From the Department of Pharmacy, University of Wisconsin School of Pharmacy, Madison, WI (O.V.); Department of Medicine, Brigham and Women's Hospital, Boston, MA (B.C., A.S.D., S.D.S.); VA Medical Center and University of Minnesota, Minneapolis (I.A.); INSERM, Centre d'Investigations Cliniques-9501 and INSERM U1116, Nancy, France (P.R., F.Z.); Department of Cardiology (F.Z.) and Department of Nephrology (P.R.), Université de Lorraine, Nancy, France; and Department of Medicine, University of Michigan, Ann Arbor (B.P.).
authors.forename: Brian
authors.initials: B
authors.lastname: Claggett
authors.affiliation: From the Department of Pharmacy, University of Wisconsin School of Pharmacy, Madison, WI (O.V.); Department of Medicine, Brigham and Women's Hospital, Boston, MA (B.C., A.S.D., S.D.S.); VA Medical Center and University of Minnesota, Minneapolis (I.A.); INSERM, Centre d'Investigations Cliniques-9501 and INSERM U1116, Nancy, France (P.R., F.Z.); Department of Cardiology (F.Z.) and Department of Nephrology (P.R.), Université de Lorraine, Nancy, France; and Department of Medicine, University of Michigan, Ann Arbor (B.P.).
authors.forename: Inder
authors.initials: I
authors.lastname: Anand
authors.affiliation: From the Department of Pharmacy, University of Wisconsin School of Pharmacy, Madison, WI (O.V.); Department of Medicine, Brigham and Women's Hospital, Boston, MA (B.C., A.S.D., S.D.S.); VA Medical Center and University of Minnesota, Minneapolis (I.A.); INSERM, Centre d'Investigations Cliniques-9501 and INSERM U1116, Nancy, France (P.R., F.Z.); Department of Cardiology (F.Z.) and Department of Nephrology (P.R.), Université de Lorraine, Nancy, France; and Department of Medicine, University of Michigan, Ann Arbor (B.P.).
authors.forename: Patrick
authors.initials: P
authors.lastname: Rossignol
authors.affiliation: From the Department of Pharmacy, University of Wisconsin School of Pharmacy, Madison, WI (O.V.); Department of Medicine, Brigham and Women's Hospital, Boston, MA (B.C., A.S.D., S.D.S.); VA Medical Center and University of Minnesota, Minneapolis (I.A.); INSERM, Centre d'Investigations Cliniques-9501 and INSERM U1116, Nancy, France (P.R., F.Z.); Department of Cardiology (F.Z.) and Department of Nephrology (P.R.), Université de Lorraine, Nancy, France; and Department of Medicine, University of Michigan, Ann Arbor (B.P.).
authors.forename: Akshay S
authors.initials: AS
authors.lastname: Desai
authors.affiliation: From the Department of Pharmacy, University of Wisconsin School of Pharmacy, Madison, WI (O.V.); Department of Medicine, Brigham and Women's Hospital, Boston, MA (B.C., A.S.D., S.D.S.); VA Medical Center and University of Minnesota, Minneapolis (I.A.); INSERM, Centre d'Investigations Cliniques-9501 and INSERM U1116, Nancy, France (P.R., F.Z.); Department of Cardiology (F.Z.) and Department of Nephrology (P.R.), Université de Lorraine, Nancy, France; and Department of Medicine, University of Michigan, Ann Arbor (B.P.).
authors.forename: Faiez
authors.initials: F
authors.lastname: Zannad
authors.affiliation: From the Department of Pharmacy, University of Wisconsin School of Pharmacy, Madison, WI (O.V.); Department of Medicine, Brigham and Women's Hospital, Boston, MA (B.C., A.S.D., S.D.S.); VA Medical Center and University of Minnesota, Minneapolis (I.A.); INSERM, Centre d'Investigations Cliniques-9501 and INSERM U1116, Nancy, France (P.R., F.Z.); Department of Cardiology (F.Z.) and Department of Nephrology (P.R.), Université de Lorraine, Nancy, France; and Department of Medicine, University of Michigan, Ann Arbor (B.P.).
authors.forename: Bertram
authors.initials: B
authors.lastname: Pitt
authors.affiliation: From the Department of Pharmacy, University of Wisconsin School of Pharmacy, Madison, WI (O.V.); Department of Medicine, Brigham and Women's Hospital, Boston, MA (B.C., A.S.D., S.D.S.); VA Medical Center and University of Minnesota, Minneapolis (I.A.); INSERM, Centre d'Investigations Cliniques-9501 and INSERM U1116, Nancy, France (P.R., F.Z.); Department of Cardiology (F.Z.) and Department of Nephrology (P.R.), Université de Lorraine, Nancy, France; and Department of Medicine, University of Michigan, Ann Arbor (B.P.).
authors.forename: Scott D
authors.initials: SD
authors.lastname: Solomon
mesh_terms: D002423:Cause of Death / Q000639:trends; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004452:Echocardiography; D005500:Follow-Up Studies; D014943:Global Health; D006333:Heart Failure / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000401:mortality; D006352:Heart Ventricles / Q000000981:diagnostic imaging / Q000503:physiopathology*; D006947:Hyperkalemia / Q000097:blood / Q000139:chemically induced / Q000453:epidemiology*; D007008:Hypokalemia / Q000097:blood / Q000139:chemically induced / Q000453:epidemiology*; D015994:Incidence; D000451:Mineralocorticoid Receptor Antagonists / Q000008:administration & dosage / Q000009:adverse effects*; D011188:Potassium / Q000097:blood; D012189:Retrospective Studies; D012307:Risk Factors; D012720:Severity of Illness Index; D013148:Spironolactone / Q000008:administration & dosage / Q000009:adverse effects*; D013318:Stroke Volume; D015996:Survival Rate / Q000639:trends; D016896:Treatment Outcome; D016277:Ventricular Function, Left / Q000187:drug effects*
chemical_list: D000451:Mineralocorticoid Receptor Antagonists; D013148:Spironolactone; D011188:Potassium
keywords: heart failure; pharmacology; potassium; spironolactone