title: Interaction Between Spironolactone and Natriuretic Peptides in Patients With Heart Failure and Preserved Ejection Fraction: From the TOPCAT Trial.
abstract: The aims of this study were to explore the relationship of baseline levels of natriuretic peptides (NPs) with outcomes and to test for an interaction between baseline levels of NPs and the effects spironolactone.
  
  
  
  Plasma NPs are considered to be helpful in the diagnosis of heart failure (HF) with preserved ejection fraction (HFpEF), and elevated levels are associated with adverse outcomes. Levels of NPs higher than certain cutoffs are often used as inclusion criteria in clinical trials of HFpEF to increase the likelihood that patients have HF and to select patients at higher risk for events. Whether treatments have a differential effect on outcomes across the spectrum of NP levels is unclear.
  
  
  
  The TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial) trial randomized patients with HFpEF and either prior hospitalization for HF or elevated natriuretic peptide levels (B-type NP [BNP] ≥100 pg/ml or N-terminal proBNP ≥360 pg/ml) to spironolactone or placebo. Baseline BNP (n = 430) or N-terminal proBNP (n = 257) levels were available in 687 patients enrolled from the Americas in the elevated-NP stratum of TOPCAT.
  
  
  
  Higher levels of NPs were independently associated with an increased risk for TOPCAT's primary endpoint of cardiovascular mortality, aborted cardiac arrest, or hospitalization for HF when analyzed either continuously or grouped by terciles, adjusting for region of enrollment, age, sex, atrial fibrillation, diabetes, renal function, body mass index, and heart rate. There was a significant interaction between the effect of spironolactone and baseline NP terciles for the primary outcome (p = 0.017), with greater benefit of the drug in the lower compared with higher NP terciles.
  
  
  
  Similar to the effects of irbesartan in the I-PRESERVE (Irbesartan in Heart Failure With Preserved Ejection Fraction) trial, a greater benefit of spironolactone was observed in the group with lower levels of NPs and overall risk in TOPCAT. Elevated NPs in HFpEF identify patients at higher risk for events but who may be less responsive to treatment. The mechanism of this apparent interaction between disease severity and response to therapy requires further exploration. (Aldosterone Antagonist Therapy for Adults With Heart Failure and Preserved Systolic Function [TOPCAT]; NCT00094302).
authors.affiliation: VA Medical Center and University of Minnesota, Minneapolis, Minnesota. Electronic address: anand001@umn.edu.
authors.forename: Inder S
authors.initials: IS
authors.lastname: Anand
authors.affiliation: Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Brian
authors.initials: B
authors.lastname: Claggett
authors.affiliation: Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Jiankang
authors.initials: J
authors.lastname: Liu
authors.affiliation: Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Amil M
authors.initials: AM
authors.lastname: Shah
authors.affiliation: VA Medical Center and University of Minnesota, Minneapolis, Minnesota.
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Rector
authors.affiliation: Cardiology Division, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
authors.forename: Sanjiv J
authors.initials: SJ
authors.lastname: Shah
authors.affiliation: Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Akshay S
authors.initials: AS
authors.lastname: Desai
authors.affiliation: Montreal Heart Institute, Montreal, Quebec, Canada.
authors.forename: Eileen
authors.initials: E
authors.lastname: O'Meara
authors.affiliation: National Heart, Lung, and Blood Institute, Bethesda, Maryland.
authors.forename: Jerome L
authors.initials: JL
authors.lastname: Fleg
authors.affiliation: Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Marc A
authors.initials: MA
authors.lastname: Pfeffer
authors.affiliation: University of Michigan School of Medicine, Ann Arbor, Michigan.
authors.forename: Bertram
authors.initials: B
authors.lastname: Pitt
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; D000369:Aged, 80 and over; D002318:Cardiovascular Diseases / Q000401:mortality; D005260:Female; D006323:Heart Arrest / Q000453:epidemiology; D006333:Heart Failure / Q000097:blood* / Q000188:drug therapy / Q000503:physiopathology; D006760:Hospitalization / Q000706:statistics & numerical data; D006801:Humans; D008297:Male; D008875:Middle Aged; D000451:Mineralocorticoid Receptor Antagonists / Q000627:therapeutic use*; D020097:Natriuretic Peptide, Brain / Q000097:blood*; D010446:Peptide Fragments / Q000097:blood*; D011379:Prognosis; D016032:Randomized Controlled Trials as Topic; D013148:Spironolactone / Q000627:therapeutic use*; D013318:Stroke Volume
chemical_list: D000451:Mineralocorticoid Receptor Antagonists; D010446:Peptide Fragments; C109794:pro-brain natriuretic peptide (1-76); D020097:Natriuretic Peptide, Brain; D013148:Spironolactone
keywords: biomarkers; heart failure; natriuretic peptides; preserved ejection fraction; prognosis