Heart Failure Risk Assessment Using Biomarkers in Patients With Atrial Fibrillation: Analysis From COMBINE-AF.

Background: Heart failure (HF) is common among patients with atrial fibrillation (AF), and accurate risk assessment is clinically important.
Objectives: The goal of this study was to investigate the incremental prognostic performance of N-terminal pro-B-type natriuretic peptide (NT-proBNP), high-sensitivity cardiac troponin T (hs-cTnT), and growth differentiation factor (GDF)-15 for HF risk stratification in patients with AF.
Methods: Individual patient data from 3 large randomized trials comparing direct oral anticoagulants (DOACs) with warfarin (ARISTOTLE [Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation], ENGAGE AF-TIMI 48 [Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis In Myocardial Infarction 48], and RE-LY [Randomized Evaluation of Long-Term Anticoagulation Therapy]) from the COMBINE-AF (A Collaboration Between Multiple Institutions to Better Investigate Non-Vitamin K Antagonist Oral Anticoagulant Use in Atrial Fibrillation) cohort were pooled; all patients with available biomarkers at baseline were included. The composite endpoint was hospitalization for HF (HHF) or cardiovascular death (CVD), and secondary endpoints were HHF and HF-related death. Cox regression was used, adjusting for clinical factors, and interbiomarker correlation was addressed using weighted quantile sum regression analysis.
Results: In 32,041 patients, higher biomarker values were associated with a graded increase in absolute risk for CVD/HHF, HHF, and HF-related death. Adjusting for clinical variables and all biomarkers, NT-proBNP (HR per 1 SD: 1.68; 95% CI: 1.59-1.77), hs-cTnT (HR: 1.39; 95% CI: 1.33-1.44), and GDF-15 (HR: 1.20; 95% CI: 1.15-1.25) were significantly associated with CVD/HHF. The discrimination of the clinical model improved significantly upon addition of the biomarkers (c-index: 0.70 [95% CI: 0.69-0.71] to 0.77 [95% CI: 0.76-0.78]; likelihood ratio test, P < 0.001). Using weighted quantile sum regression analysis, the contribution to risk assessment was similar for NT-proBNP and hs-cTnT for CVD/HHF (38% and 41%, respectively); GDF-15 provided a statistically significant but lesser contribution to risk assessment. Results were similar for HHF and HF-related death, individually, and across key subgroups of patients based on a history of HF, AF pattern, and reduced or preserved left ventricular ejection fraction.
Conclusions: NT-proBNP, hs-cTnT, and GDF-15 contributed significantly and independently to the risk stratification for HF endpoints in patients with AF, with hs-cTnT being as important as NT-proBNP for HF risk stratification. Our findings support a possible future use of these biomarkers to distinguish patients with AF at low or high risk for HF.
Competing Interests: Funding Support and Author Disclosures Dr Haller is supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)–10086/1-1. Dr S.M. Patel is supported by a T32 postdoctoral training grant from the National Heart, Lung, and Blood Institute (NHLBI) (T32HL007604). RE-LY was funded by Boehringer Ingelheim, ARISTOTLE was funded by Bristol Myers Squibb and Pfizer, and ENGAGE AF-TIMI 48 was funded by Daiichi-Sankyo. No outside funding was obtained to support the creation of the COMBINE AF database or for these analyses. Dr Haller has received travel grants from the German Center of Cardiovascular Research (DZHK); and has received funding by the German Foundation for Heart Research and the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)–10086/1-1. Dr Jarolim has received research support through BWH from Abbott Laboratories, Amgen, Inc, AstraZeneca, LP, Daiichi-Sankyo, Roche Diagnostic Corporation, and Siemens Healthineers. Dr Antman received grants from Daiichi-Sankyo during the conduct of the study. Mr Eikelboom has received honoraria and/or research support from Anthos, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Idorsia, Janssen, Merck, and Pfizer. Dr Granger has received consulting fees from AbbVie, Abiomed, Alnylam Pharmaceuticals, Amgen, Anthos, Bayer Corporation, Boehringer Ingelheim, Boston Scientific Corporation, Bristol Myers Squibb, Cardionomic, CeleCor Therapeutics, Janssen Pharmaceutical, Merck, Novo Nordisk, Novartis, Pfizer, Philips, and Roche; has salary funded by Duke grants sponsored by Alnylam Pharmaceuticals, Boehringer Ingelheim, Bristol Myers Squibb, Janssen Pharmaceuticals, NHLBI, Novartis, Pfizer, and Philips; and has equity in tenac.io. Dr Healey has received research grants and speaking fees from Boston Scientific, Medtronic, Bristol Myers Squibb/Pfizer, and Servier; and has been a consultant for Bayer. Dr Hijazi has received lecture and consulting fees from Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Pfizer, and Roche Diagnostics; and has received research support from Hjärt-Lungfonden (The Swedish Heart-Lung Foundation and Uppsala University Hospital). Dr M.R. Patel has received consulting fees from Bayer, Janssen, and Novartis; and has received research grants from the NHLBI, Bayer, Novartis, and Philips. Dr S.M. Patel has received consulting fees from Janssen. Dr Ruff has received research grants through Brigham and Women’s Hospital from Anthos, AstraZeneca, Daiichi-Sankyo, Janssen, and Novartis; and has received honoraria for scientific advisory boards and consulting from Anthos, Bayer, Bristol Myers Squibb, Daiichi-Sankyo, Janssen, and Pfizer. Dr Wallentin has received institutional research grants from Bristol Myers Squibb/Pfizer, AstraZeneca, GlaxoSmithKline, Boehringer Ingelheim, and Roche Diagnostics; and is a patent holder on GDF-15 for prognostication in acute coronary syndrome. Dr Braunwald has received research grants through his institution from AstraZeneca, Daiichi-Sankyo, Merck, and Novartis; and has consulted for Amgen, Bristol Myers Squibb, Boehringer Ingelheim, Cardurion, Edgewise, and Verve. Dr Giugliano has received research support from Anthos Therapeutics and Daiichi-Sankyo; has received honoraria for lectures from Daiichi-Sankyo, Medical Education Resources (MER), Menarini, Pfizer, SAJA Pharmaceuticals, Servier, and Shanghai Medical Telescope; and has received consulting fees from Artivion, Inc, AstraZeneca, Bayer, Daiichi-Sankyo, Perosphere, PhaseBio Pharmaceuticals, Samsung, Sanofi, Syneos Health, and Thrombosis Research Institute. Dr Morrow has received consulting fees from Abbott Laboratories, ARCA Biopharma, InCarda, Inflammatix, Merck & Co, Novartis, and Roche Diagnostics. Dr Haller, Dr Morrow, Mr Palazzolo, Dr Bellavia, Dr Ruff, Dr Braunwald, and Dr Giugliano are members of the TIMI Study Group, which has received institutional research grant support through Brigham and Women’s Hospital from Abbott, Amgen, Anthos Therapeutics, AstraZeneca, Bayer HealthCare Pharmaceuticals, Inc, Daiichi-Sankyo, Eisai, Intarcia, MedImmune, Merck, Novartis, Pfizer, Quark Pharmaceuticals, Regeneron Pharmaceuticals, Inc, Roche, Siemens Healthcare Diagnostics, Inc, The Medicines Company, and Zora Biosciences. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
(Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)