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Brief Report
October 2018

Association of Natriuretic Peptides With Cardiovascular Prognosis in Heart Failure With Preserved Ejection Fraction: Secondary Analysis of the TOPCAT Randomized Clinical Trial

Author Affiliations
  • 1Brigham and Women’s Hospital, Boston, Massachusetts
  • 2Akershus University Hospital, Lørenskog, Norway
  • 3Veterans Affairs Medical Center, Minneapolis, Minnesota
  • 4University of Minnesota, Minneapolis
  • 5University of Arizona, Tucson
  • 6University of Utah, Salt Lake City
  • 7Montreal Heart Institute and University of Montreal, Montreal, Quebec, Canada
  • 8Northwestern University, Chicago, Illinois
  • 9University of Michigan School of Medicine, Ann Arbor
JAMA Cardiol. 2018;3(10):1000-1005. doi:10.1001/jamacardio.2018.2568
Key Points

Question  How do age, race/ethnicity, obesity, renal function, and atrial fibrillation influence natriuretic peptides (NP) in heart failure with preserved ejection fraction and does the prognostic significance of NPs vary in these clinically important subgroups?

Findings  In this secondary analysis of the Americas region of the Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial (TOPCAT), 1057 participants had available NP concentrations that varied markedly across key subgroups and were consistently associated with excess cardiovascular risk.

Meaning  Natriuretic peptides represent important biomarkers of prognosis, even in populations with lower distributions of levels; single, absolute NP thresholds for inclusion in contemporary heart failure with preserved ejection fraction trials may lead to an underrepresentation of certain demographic and clinical subgroups.

Abstract

Importance  Contemporary clinical trials of heart failure with preserved ejection fraction (HFpEF) apply natriuretic peptide (NP) thresholds to identify patients who are more likely to have the disease of interest and to enrich the baseline risk of the enrolled cohort.

Objective  To determine whether age, race/ethnicity, obesity, renal function, and atrial fibrillation (AF) affect the levels of NPs in HFpEF and whether the prognostic significance of NPs varies in these clinically important subgroups.

Design, Setting, and Participants  This secondary analysis of the Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial (TOPCAT) evaluated the distribution and prognostic significance of NPs across 6 subgroups comprising 1057 adult patients (60%) in the Americas region of TOPCAT with symptomatic heart failure (HF) and a left ventricular ejection fraction of 45% or more with available NPs at baseline.

Exposures  Natriuretic peptides were log-transformed and standardized (expressed per 1 SD, z score) and assessed in 6 subgroups: age (cutoff, 70 years), black race, body mass index (BMI; calculated as weight in kilograms divided by height in meters squared; cutoff, 30 kg/m2), waist circumference (cutoff, 102 cm for men, 88 cm for women), estimated glomerular filtration rate (cutoff, 60 mL/min/1.73 m2), and a history of AF.

Main Outcomes and Measures  Time to composite cardiovascular death, hospitalization for HF, or aborted cardiac arrest at mean (SD) 2.4-year (1.5) follow-up.

Results  Of 1057 participants, the mean (SD) age was 72 (10) years, 183 (17.3%) were black, the mean (SD) BMI was 33.4 (8.6) kg/m2, the mean (SD) estimated glomerular filtration rate was 64.6 (21.8) mL/min/1.73 m2, and 472 (45%) had a history of AF. Median B-type NP (n = 698) and N-terminal pro-B-type NP concentrations (n = 359) were 257 (interquartile range, 149-443) ng/L and 959 (interquartile range, 554-2015) ng/L, respectively. Natriuretic peptide concentrations varied by up to 0.5 SD within the 6 subgroups, being higher in older patients with nonblack race, a lower BMI, a lower waist circumference, a lower estimated glomerular filtration rate, and a history of AF. Elevated NP levels (per 1-SD increase) were independently associated with an increased risk of the primary outcome (adjusted hazard ratio, 1.36; 95% CI, 1.22-1.54; P < .001) consistently across all investigated subgroups (interaction P > .05). In TOPCAT Americas (n = 1767), 791 (45%) were enrolled based on elevated NP levels as the qualifying criterion (as opposed to a history of HF hospitalization). This proportion was 31% (93 of 302), 34% (258 of 760), and 39% (443 of 1144) for black race, younger than 70 years, and a BMI of 30 kg/m2 or greater, respectively.

Conclusions and Relevance  Natriuretic peptides remain important biomarkers of prognosis in HFpEF, even in subgroups who tend to have lower NP levels. A single, absolute NP threshold for inclusion in contemporary HFpEF trials may lead to an underrepresentation of certain demographic and clinical subgroups.

Trial Registration  ClinicalTrials.gov Identifier: NCT00094302

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