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Randomized Controlled Trial
. 2025 Aug 12;86(6):426-439.
doi: 10.1016/j.jacc.2025.05.060.

Outcomes in Older Patients After Switching to a Newer Anticoagulant or Remaining on Warfarin: The COMBINE-AF Substudy

Andre M Nicolau  1 , Robert P Giugliano  2 , Andre Zimerman  3 , Jonathan Afilalo  4 , Baris Gencer  5 , Jan Steffel  6 , Michael G Palazzolo  7 , John W Eikelboom  8 , Christopher B Granger  9 , Manesh R Patel  9 , Renato D Lopes  9 , Bernard J Gersh  10 , Belal Suleiman  9 , Joris R de Groot  11 , Mauricio I Scanavacca  1 , Christian T Ruff  7 , Elliott M Antman  7 , Eugene Braunwald  7 , Lars Wallentin  12
Affiliations
Randomized Controlled Trial

Outcomes in Older Patients After Switching to a Newer Anticoagulant or Remaining on Warfarin: The COMBINE-AF Substudy

Andre M Nicolau et al. J Am Coll Cardiol. .

Abstract

Background: Whether frail, elderly patients with atrial fibrillation (AF) on a vitamin K antagonist (VKA) should switch to a direct-acting oral anticoagulant (DOAC) was studied in the FRAIL-AF trial and remains controversial.

Objectives: The purpose of this study was to evaluate, in the COMBINE-AF data set, the impact on clinical outcomes of switching frail, elderly AF patients from VKA to DOAC.

Methods: COMBINE-AF consists of individual patient-level data from 71,683 patients with AF in 4 randomized clinical trials comparing DOAC vs warfarin. Frailty was evaluated using a frailty index derived from a modified Rockwood's Accumulation Model including 18 age-related conditions. Patients with a frailty index score above the median were considered frail. Prespecified outcomes were stroke or systemic embolic events, bleeding events, death, and a net clinical outcome combining these events.

Results: We identified 5,913 patients who were frail, elderly (age ≥75 years), and VKA-experienced and 52,721 patients who did not meet all 3 of these criteria. Patients were randomized to a standard-dose (SD) DOAC or warfarin. After 27 months median follow-up, there was no heterogeneity in treatment effect with SD-DOAC vs warfarin among those who met all 3 criteria vs those who did not for the endpoints of stroke or systemic embolic events (HR: 0.83 vs 0.81; Pint = 0.75) or for death (HR: 0.95 vs 0.91; Pint = 0.54). Major bleeding was similar with SD-DOAC vs warfarin in frail, elderly, VKA-experienced patients (HR: 1.06 [95% CI: 0.90-1.25]), while it was significantly reduced with SD-DOAC in patients without all 3 criteria (HR: 0.82 [95% CI: 0.76-0.89]; Pint = 0.007). Likewise, the net clinical outcome was similar in the frail, elderly, VKA-experienced patients with SD-DOAC vs warfarin (HR: 1.01 [95% CI: 0.91-1.13]), while significantly reduced with SD-DOAC patients without all 3 criteria (HR: 0.89 [95% CI: 0.85-0.93]; Pint = 0.028). Fatal and intracranial bleeding were significantly reduced with SD-DOAC in both subgroups to a similar degree (both Pint > 0.05), while gastrointestinal bleeding with SD-DOAC was increased to a greater degree in frail, elderly, VKA-experienced patients (HR: 1.83 [95% CI: 1.42-2.36]) compared with those without all 3 criteria (HR: 1.23 [95% CI: 1.09-1.39]; Pint = 0.006).

Conclusions: Frail, elderly, VKA-experienced patients with AF switched to SD-DOAC experienced significant reductions in stroke or systemic embolism, fatal and intracranial bleeding, and death. Gastrointestinal bleeding was increased with SD-DOAC, while major bleeding and the primary net clinical outcome were similar. Based on these findings, SD-DOAC is a reasonable choice for frail, elderly, VKA-experienced patients to reduce stroke and systemic embolism, death, and the most serious types of bleeding.

Keywords: atrial fibrillation; directing acting oral anticoagulant; elderly; frail; vitamin K antagonist.

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Conflict of interest statement

Funding Support and Author Disclosures Dr Giugliano has received research support from Anthos Therapeutics, Daiichi-Sankyo, and Novartis; has received honoraria for lectures from Daiichi-Sankyo, Medical Education Resources, Menarini, SAJA Pharmaceuticals, Shanghai Medical Technology, and SUMMEET; and has received consulting fees from Artivion, Celecor, Daiichi-Sankyo, Novartis, Perosphere, PhaseBio Pharmaceuticals, Samsung, Sanofi, SFJ Pharmaceuticals, and Thrombosis Research Institute. Dr Steffel has received consultant and/or speaker fees from Abbott, Bayer, Berlin-Chemie, Biosense Webster, Biotronik, Boehringer Ingelheim, Boston Scientific, Daiichi-Sankyo, Medscape, Medtronic, Menarini, Pfizer, Saja, Servier, and WebMD; and has ownership of Swiss EP and CorXL. Dr 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, National Heart, Lung, and Blood Institute, Novartis, Pfizer, and Philips; and has equity in tenac.io. Dr Patel has received consulting fees from Bayer, Janssen, and Novartis; and has received research grants from the National Heart, Lung, and Blood Institute, Bayer, Novartis, and Philips. Dr Lopes has received research grants or contracts from Amgen, Bristol Myers Squibb, GlaxoSmithKline, Medtronic, Pfizer, and Sanofi; has received funding for educational activities or lectures from Pfizer, Daiichi-Sankyo, and Novo Nordisk; and has received funding for consulting or other services from Bayer, Boehringer Ingelheim, Bristol Myers Squibb, and Novo Nordisk. 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 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 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. Mr Palazzolo, Dr Ruff, Dr Antman, 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.

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