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

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.

Conflict of interest statement

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Myhre has received speaker fees from Novartis and is supported by a postdoctoral research grant from the South-Eastern Norway Regional Health Authority (Dr Røsjø), Akershus University Hospital (Dr Omland), the Norwegian Medical Association, and the Unger Vetlesen Medical Fund. Dr Vaduganathan is supported by the National Heart, Lung, and Blood Institute (NHLBI) T32 postdoctoral training grant T32HL007604 and receives consulting fees from Bayer AG and Baxter Healthcare. Dr Sweitzer has received research grants from the National Institutes of Health (NIH). Dr Fang is a member of the data and safety monitoring board for Novartis, Amgen, NIH, and Johnson & Johnson. Dr O’Meara has received subventions/research support and consulting fees from Novartis, Bayer, AstraZeneca, Servier, and Amgen. Dr Shah has received research grants from Actelion, AstraZeneca, Corvia, and Novartis and consulting fees from Actelion, Amgen, AstraZeneca, Bayer, Boehringer-Ingelheim, Cardiora, Eisai, Ironwood, Merck, Novartis, Sanofi, and United Therapeutics. Dr Desai has received research grant support from Novartis and consulting fees from Novartis, AstraZeneca, Abbott, Relypsa, and DalCor Pharma. Dr Lewis has received research grants from the NHLBI, Novartis, and Sanofi and consulting fees from Novartis. Dr Rouleau reports receiving consulting fees from Novartis and AstraZeneca. Dr Pitt reports receiving consulting fees and/or stock options from AstraZeneca, Bayer, Sanofi, Stealth Peptides, Relypsa/Vifor, scPharmaceuticals, Sarfez, Tricida, and KBP Pharmaceuticals, reports a patent related to a site-specific delivery of eplerenone to the myocardium (9931412), and is a member of the data and safety monitoring board for Johnson & Johnson. Dr Pfeffer has received consulting fees from Amgen, AstraZeneca, Bayer, DalCor Pharma UK, Genzyme, Lilly, Medicines Company, MedImmune, Medtronic, Merck, Novartis, Novo Nordisk, Relypsa, Salix, Sanderling, Sanofi, Takeda, Teva, Thrasos, and Vericel and has received research grant support from Amgen, Celladon, Novartis, and Sanofi. The Brigham and Women’s Hospital has patents for the use of inhibitors of the renin-angiotensin system in selected survivors of myocardial infarction with Novartis Pharmaceuticals, for which Dr Pfeffer is a coinventor. His share of the licensing agreement is irrevocably transferred to charity. Dr Solomon has received research grants from Alnylam, Amgen, AstraZeneca, Bellerophon, Celladon, Gilead, GlaxoSmithKline, Ionis Pharmaceutics, Lone Star Heart, Mesoblast, MyoKardia, NIH/NHLBI, Novartis, Sanofi Pasteur, and Theracos and has consulted for Alnylam, Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Corvia, Gilead, GlaxoSmithKline, Ironwood, Merck, Novartis, Pfizer, Takeda, and Theracos. No other disclosures are reported.

Figures

Figure 1.. Baseline Natriuretic Peptides and Subsequent Cardiovascular Risk in 6 Subgroups of the Americas Region of the Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial

Overall, 1057 patients had natriuretic peptides (NPs) available for analysis. Multivariate Cox regression models and risk reclassification models accounted for the following covariates: age, sex, race/ethnicity, body mass index (calculated as weight in kilograms divided by height in meters squared), estimated glomerular filtration rate (eGFR), history of atrial fibrillation (AF), enrollment strata, and treatment randomization. BNP indicates B-type natriuretic peptide; HR, hazard ratio; SEM, standard error of the mean.

Figure 2.. Association Between Natriuretic Peptide (NP) Levels and Incidence of Primary Outcome in 6 Subgroups of the Americas Region of the Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial

Restricted cubic splines models with 3 knots were constructed to display the association between log-transformed, standardized NP concentrations as a continuous variable and the incidence of the primary end point for each of the key subgroups. The dotted lines reflect the 95% confidence intervals. BNP indicates B-type natriuretic peptide; eGFR, estimated glomerular filtration rate; NT-proBNP, N-terminal pro-B-type natriuretic peptide. Body mass index is calculated as weight in kilograms divided by height in meters squared.