Spironolactone for heart failure with preserved ejection fraction.
BACKGROUND
Mineralocorticoid-receptor antagonists improve the prognosis for patients with heart failure and a reduced left ventricular ejection fraction. We evaluated the effects of spironolactone in patients with heart failure and a preserved left ventricular ejection fraction.


METHODS
In this randomized, double-blind trial, we assigned 3445 patients with symptomatic heart failure and a left ventricular ejection fraction of 45% or more to receive either spironolactone (15 to 45 mg daily) or placebo. The primary outcome was a composite of death from cardiovascular causes, aborted cardiac arrest, or hospitalization for the management of heart failure.


RESULTS
With a mean follow-up of 3.3 years, the primary outcome occurred in 320 of 1722 patients in the spironolactone group (18.6%) and 351 of 1723 patients in the placebo group (20.4%) (hazard ratio, 0.89; 95% confidence interval [CI], 0.77 to 1.04; P=0.14). Of the components of the primary outcome, only hospitalization for heart failure had a significantly lower incidence in the spironolactone group than in the placebo group (206 patients [12.0%] vs. 245 patients [14.2%]; hazard ratio, 0.83; 95% CI, 0.69 to 0.99, P=0.04). Neither total deaths nor hospitalizations for any reason were significantly reduced by spironolactone. Treatment with spironolactone was associated with increased serum creatinine levels and a doubling of the rate of hyperkalemia (18.7%, vs. 9.1% in the placebo group) but reduced hypokalemia. With frequent monitoring, there were no significant differences in the incidence of serious adverse events, a serum creatinine level of 3.0 mg per deciliter (265 μmol per liter) or higher, or dialysis.


CONCLUSIONS
In patients with heart failure and a preserved ejection fraction, treatment with spironolactone did not significantly reduce the incidence of the primary composite outcome of death from cardiovascular causes, aborted cardiac arrest, or hospitalization for the management of heart failure. (Funded by the National Heart, Lung, and Blood Institute; TOPCAT ClinicalTrials.gov number, NCT00094302.).
From the University of Michigan School of Medicine, Ann Arbor (B.P.); the Cardiovascular Division, Brigham and Women's Hospital, Boston (M.A.P., B.C., A.S.D., E.F.L., S.D.S.); New England Research Institutes, Watertown, MA (S.F.A., B.H., C.T.K., S.M.M.); National Heart, Lung, and Blood Institute, Bethesda, MD (R.B., J.L.F., S.Y.); Veterans Affairs Medical Center and University of Minnesota, Minneapolis (I.S.A.); Hospital de Clinicas de Porto Alegre, Porto Alegre, Brazil (N.C.); Estudios Clinicos Latinoamerica, Rosario, Argentina (R.D.); Pirogov Russian National Research Medical University, Moscow (I.G.); New York Methodist Hospital, Brooklyn (J.F.H.); Montreal Heart Institute, Montreal (E.O.); University of Washington Medical Center, Seattle (J.L.P.); Diagnostic Services Clinic, Tbilisi, Georgia (T.S.); Northwestern University, Chicago (S.J.S.); and the University of Wisconsin, Madison (N.K.S.).
Bertram
B
Pitt
Marc A
MA
Pfeffer
Susan F
SF
Assmann
Robin
R
Boineau
Inder S
IS
Anand
Brian
B
Claggett
Nadine
N
Clausell
Akshay S
AS
Desai
Rafael
R
Diaz
Jerome L
JL
Fleg
Ivan
I
Gordeev
Brian
B
Harty
John F
JF
Heitner
Christopher T
CT
Kenwood
Eldrin F
EF
Lewis
Eileen
E
O'Meara
Jeffrey L
JL
Probstfield
Tamaz
T
Shaburishvili
Sanjiv J
SJ
Shah
Scott D
SD
Solomon
Nancy K
NK
Sweitzer
Song
S
Yang
Sonja M
SM
McKinlay
D000368:Aged; D000369:Aged, 80 and over; D002318:Cardiovascular Diseases / Q000401:mortality; D004311:Double-Blind Method; D005260:Female; D005500:Follow-Up Studies; D006333:Heart Failure / Q000188:drug therapy* / Q000401:mortality / Q000503:physiopathology; D006760:Hospitalization / Q000706:statistics & numerical data; D006801:Humans; D015994:Incidence; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D000451:Mineralocorticoid Receptor Antagonists / Q000009:adverse effects / Q000627:therapeutic use*; D013148:Spironolactone / Q000009:adverse effects / Q000627:therapeutic use*; D013318:Stroke Volume; D017211:Treatment Failure
D000451:Mineralocorticoid Receptor Antagonists; D013148:Spironolactone