Natriuretic Peptides and Spironolactone Effect in TOPCAT

Study Questions:

What is the relationship of baseline levels of natriuretic peptides (NPs) with outcomes, and the interaction between baseline levels of NPs and the effects of spironolactone?


TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial) was a randomized, placebo-controlled, double-blind, multicenter trial designed to evaluate the efficacy and safety of the aldosterone antagonist spironolactone to reduce cardiovascular morbidity in patients with symptomatic heart failure with preserved ejection fraction (HFpEF). This study randomized patients with HFpEF and either prior hospitalization for HF or elevated NP levels (B-type NP [BNP] ≥100 pg/ml or N-terminal proBNP ≥360 pg/ml) to spironolactone or placebo. Of the 3,445 patients enrolled in the TOPCAT trial, 2,464 (72%) were enrolled in the hospitalization stratum and 981 (28%) in the elevated NP stratum. 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. The combined NP was related to each study endpoint using Cox proportional hazards and Poisson regression models adjusting for region, age, sex, atrial fibrillation, diabetes, estimated glomerular filtration rate, body mass index, and heart rate.


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.


The authors concluded that a greater benefit of spironolactone was observed in the group with lower levels of NPs and overall risk in TOPCAT.


This post hoc analysis of patients with HFpEF enrolled in the TOPCAT trial shows that NP levels are independently associated with an increased risk for the primary endpoint, all-cause mortality, and hospitalization for HF, confirming previous findings that NPs are important prognostic markers in patients with HFpEF. Furthermore, there was a significant interaction between the effect of spironolactone treatment and NP levels, with most of the beneficial effects of spironolactone seen in patients with low levels of NPs and no effect in the patients with high NP levels. Given the post hoc, subgroup nature of the current analysis, additional prospective studies are required to test the interaction between biomarker levels and treatment effect. In addition, novel treatment strategies need to be developed for higher risk patients where established therapies may be less effective.

Clinical Topics: Anticoagulation Management, Arrhythmias and Clinical EP, Heart Failure and Cardiomyopathies, Anticoagulation Management and Atrial Fibrillation, Implantable Devices, SCD/Ventricular Arrhythmias, Atrial Fibrillation/Supraventricular Arrhythmias, Acute Heart Failure, Heart Failure and Cardiac Biomarkers

Keywords: Atrial Fibrillation, Biological Markers, Body Mass Index, Diabetes Mellitus, Glomerular Filtration Rate, Heart Arrest, Heart Failure, Hospitalization, Natriuretic Peptide, Brain, Natriuretic Peptides, Peptide Fragments, Spironolactone, Stroke Volume

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