Efficacy and Safety of Non-Vitamin-K Antagonist Oral Anticoagulants Versus Warfarin Across the Spectrum of Body Mass Index and Body Weight: An Individual Patient Data Meta-Analysis of 4 Randomized Clinical Trials of Patients With Atrial Fibrillation.

Background: The efficacy and safety of non-vitamin-K antagonist oral anticoagulants (NOACs) across the spectrum of body mass index (BMI) and body weight (BW) remain uncertain.
Methods: We analyzed data from COMBINE AF (A Collaboration Between Multiple Institutions to Better Investigate Non-Vitamin K Antagonist Oral Anticoagulant Use in Atrial Fibrillation), which pooled patient-level data from the 4 pivotal randomized trials of NOAC versus warfarin in patients with atrial fibrillation. The primary efficacy and safety outcomes were stroke or systemic embolic events (stroke/SEE) and major bleeding, respectively; secondary outcomes were ischemic stroke/SEE, intracranial hemorrhage, death, and the net clinical outcome (stroke/SEE, major bleeding, or death). Each outcome was examined across BMI and BW. Because few patients had a BMI <18.5 kg/m ² (n=598), the primary analyses were restricted to those with a BMI ≥18.5 kg/m ² .
Results: Among 58 464 patients, the median BMI was 28.3 (interquartile range, 25.2-32.2) kg/m ² , and the median BW was 81.0 (interquartile range, 70.0-94.3) kg. The event probability of stroke/SEE was lower at a higher BMI irrespective of treatment, whereas the probability of major bleeding was lower at a higher BMI with warfarin but relatively unchanged across BMI with NOACs. NOACs reduced stroke/SEE overall (adjusted hazard ratio [HR _adj ], 0.80 [95% CI, 0.73-0.88]; P <0.001), with a generally consistent effect across BMI ( P _trend across HRs, 0.48). NOACs also reduced major bleeding overall (HR _adj , 0.88 [95% CI, 0.82-0.94]; P <0.001), but with attenuation of the benefit at a higher BMI (trend test across BMI [ P _trend ], 0.003). The overall treatment effects of NOACs versus warfarin for secondary outcomes were consistent across BMI, with the exception of the net clinical outcome and death. While these outcomes were overall reduced with NOACs (net clinical outcome, HR _adj , 0.91 [95% CI, 0.87-0.95]; P <0.001; death, HR _adj , 0.91 [95% CI, 0.86-0.97]; P =0.003), these benefits were attenuated at higher BMI ( P _trend , 0.001 and 0.08, respectively). All findings were qualitatively similar when analyzed across BW.
Conclusions: The treatment effect of NOACs versus warfarin in atrial fibrillation is generally consistent for stroke/SEE across the spectrum of BMI and BW, whereas the reduction in major bleeding is attenuated in those with higher BMI or BW. Death and the net clinical outcome are overall reduced with NOACs over warfarin, although there remain uncertainties for these outcomes at a very high BMI and BW.
Competing Interests: S.M.P. reports consulting fees from Janssen. E.B. has received consulting fees from Amgen, Boehringer Ingelheim/Lilly, Cardurion, MyoKardia, NovoNordisk, and Verve. J.S. has received consultant or speaker fees from Abbott, Alexion, Amgen, AstraZeneca, Bayer, Berlin-Chemie, Biosense Webster, Biotronik, Boehringer Ingelheim, Boston Scientific, BMS, Daiichi Sankyo, Medscape, Medtronic, Menarini, Merck/MSD, Organon, Pfizer, SAJA, Servier, and WebMD. He reports ownership of Swiss EP and CorXL. G.B. reports speaker fees of small amounts from Bayer, Boehringer Ingelheim, Boston Scientific, Daiichi Sankyo, and Janssen, outside the submitted work. E.A.B. reports consulting fees from Novo Nordisk, Esperion, PriMed, Medscape, Amgen and Servier, and participation on clinical end point committees for studies sponsored by Kowa Pharmaceuticals. S.J.C. reports personal fees from BMS, Bayer, Boehringer Ingelheim, Daiichi Sankyo, and Portola during the conduct of the study. J.E. reports honoraria and grant support from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb/Pfizer, Daiichi-Sankyo, GlaxoSmithKline, Janssen, Sanofi Aventis, and Eli Lilly as well as a personnel award from the Heart and Stroke Foundation. C.B.G. reports personal fees from Bayer and Boston Scientific; grants and personal fees from Boehringer Ingelheim, Bristol Myers Squibb, Janssen, and Pfizer; and grants from Daiichi-Sankyo during the conduct of the study; personal fees from AbbVie, Espero, Medscape, Medtronic Inc, Merck, the National Institutes of Health, Novo Nordisk, Roche, Rho Pharmaceuticals, CeleCor, Correvio, Philips, Abiomed, and Anthos Therapeutics; grants from Akros, AstraZeneca, the US Food and Drug Administration, Glaxo Smith Kline, Medtronic Foundation, and Apple; and grants and personal fees from Novartis and The Medicines Company outside the submitted work. D.A.M. reports consulting fees from Abbott Laboratories, ARCA Biopharma, InCarda, Inflammatix, Merck & Co, Novartis, and Roche Diagnostics. M.R.P. reports grants from Astra Zeneca, Bayer, Janssen, Procyrion, and Heartflow; and personal fees from Bayer, Janssen, Mytonomy, and Procyrion outside the submitted work. L.W. reports grants from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb/Pfizer, GlaxoSmithKline, Merck & Co, and Roche Diagnostics and personal fees from Abbott outside the submitted work. R.P.G. reports grant support to his institution from Anthos and Daiichi-Sankyo, and personal fees from Artivion, Bayer, Daiichi-Sankyo, Medical Education Resources, Medscape, Menarini, Pfizer, SAJA Pharmaceuticals, Sanofi, and Servier. S.M.P., E.B., M.G.P., E.M.A., E.A.B., D.A.M., C.T.R., and R.P.G. report being members of the TIMI (Thrombolysis in Myocardial Infarction) 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. The other authors report no conflicts.