Review

. 2024 Jan 23;83(3):444-465.

doi: 10.1016/j.jacc.2023.10.038.

When Direct Oral Anticoagulants Should Not Be Standard Treatment: JACC State-of-the-Art Review

Antoine Bejjani¹, Candrika D Khairani², Ali Assi³, Gregory Piazza⁴, Parham Sadeghipour⁵, Azita H Talasaz⁶, John Fanikos⁷, Jean M Connors⁸, Deborah M Siegal⁹, Geoffrey D Barnes¹⁰, Karlyn A Martin¹¹, Dominick J Angiolillo¹², Dawn Kleindorfer¹³, Manuel Monreal¹⁴, David Jimenez¹⁵, Saskia Middeldorp¹⁶, Mitchell S V Elkind¹⁷, Christian T Ruff¹⁸, Samuel Z Goldhaber², Harlan M Krumholz¹⁹, Roxana Mehran²⁰, Mary Cushman²¹, John W Eikelboom²², Gregory Y H Lip²³, Jeffrey I Weitz²⁴, Renato D Lopes²⁵, Behnood Bikdeli²⁶

Affiliations

¹ Thrombosis Research Group, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA; Cardiovascular Medicine Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA; Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.
² Thrombosis Research Group, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA; Cardiovascular Medicine Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
³ Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
⁴ Thrombosis Research Group, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA; Cardiovascular Medicine Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA; Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
⁵ Rajaie Cardiovascular, Medical, and Research Center, Iran University of Medical Sciences, Tehran, Iran; Clinical Trial Center, Rajaie Cardiovascular, Medical, and Research Center, Iran University of Medical Sciences, Tehran, Iran.
⁶ Tehran Heart Center, Tehran University of Medical Sciences, Tehran, Iran; Virginia Commonwealth University, Richmond, Virginia, USA.
⁷ Department of Pharmacy, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
⁸ Hematology Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
⁹ Division of Hematology, Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada.
¹⁰ Frankel Cardiovascular Center, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.
¹¹ Division of Hematology/Oncology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
¹² Division of Cardiology, University of Florida College of Medicine, Jacksonville, Florida, USA.
¹³ University of Cincinnati, Cincinnati, Ohio, USA.
¹⁴ Cátedra de Enfermedad Tromboembólica, Universidad Católica San Antonio de Murcia, Spain.
¹⁵ Respiratory Department, Hospital Ramón y Cajal and Medicine Department, Universidad de Alcalá (Instituto de Ramón y Cajal de Investigación Sanitaria), Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), Madrid, Spain.
¹⁶ Department of Internal Medicine, Radboud University Medical Center, Nijmegen, the Netherlands.
¹⁷ Department of Neurology, Vagelos College of Physicians and Surgeons, New York, New York, USA; Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, New York, USA.
¹⁸ Cardiovascular Medicine Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
¹⁹ Yale New Haven Hospital/Yale Center for Outcomes Research and Evaluation, New Haven, Connecticut, USA; Department of Health Policy and Management, Yale School of Public Health, New Haven, Connecticut, USA; Section of Cardiovascular Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut, USA.
²⁰ Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
²¹ Department of Medicine, Larner College of Medicine at the University of Vermont, Burlington, Vermont, USA; Department of Pathology and Laboratory Medicine, Larner College of Medicine at the University of Vermont, Burlington, Vermont, USA.
²² Population Health Research Institute, Hamilton Health Sciences, McMaster University, Hamilton, Ontario, Canada.
²³ Liverpool Centre for Cardiovascular Science at University of Liverpool, Liverpool John Moores University and Liverpool Heart and Chest Hospital, Liverpool, United Kingdom; Danish Center for Clinical Health Services Research, Department of Clinical Medicine, Aalborg University, Aalborg, Denmark.
²⁴ McMaster University, Hamilton, Ontario, Canada; Thrombosis and Atherosclerosis Research Institute, Hamilton, Ontario, Canada.
²⁵ Duke Clinical Research Institute, Duke University Medical Center, Durham, North Carolina, USA; Brazilian Clinical Research Institute, São Paulo, Brazil.
²⁶ Thrombosis Research Group, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA; Cardiovascular Medicine Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA; Department of Internal Medicine, Radboud University Medical Center, Nijmegen, the Netherlands; Cardiovascular Research Foundation, New York, New York, USA. Electronic address: bbikdeli@bwh.harvard.edu.

PMID: 38233019
DOI: 10.1016/j.jacc.2023.10.038

Free article

Review

When Direct Oral Anticoagulants Should Not Be Standard Treatment: JACC State-of-the-Art Review

Antoine Bejjani et al. J Am Coll Cardiol. 2024.

Free article

. 2024 Jan 23;83(3):444-465.

doi: 10.1016/j.jacc.2023.10.038.

Authors

Affiliations

¹ Thrombosis Research Group, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA; Cardiovascular Medicine Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA; Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.
² Thrombosis Research Group, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA; Cardiovascular Medicine Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
³ Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
⁴ Thrombosis Research Group, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA; Cardiovascular Medicine Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA; Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
⁵ Rajaie Cardiovascular, Medical, and Research Center, Iran University of Medical Sciences, Tehran, Iran; Clinical Trial Center, Rajaie Cardiovascular, Medical, and Research Center, Iran University of Medical Sciences, Tehran, Iran.
⁶ Tehran Heart Center, Tehran University of Medical Sciences, Tehran, Iran; Virginia Commonwealth University, Richmond, Virginia, USA.
⁷ Department of Pharmacy, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
⁸ Hematology Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
⁹ Division of Hematology, Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada.
¹⁰ Frankel Cardiovascular Center, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.
¹¹ Division of Hematology/Oncology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
¹² Division of Cardiology, University of Florida College of Medicine, Jacksonville, Florida, USA.
¹³ University of Cincinnati, Cincinnati, Ohio, USA.
¹⁴ Cátedra de Enfermedad Tromboembólica, Universidad Católica San Antonio de Murcia, Spain.
¹⁵ Respiratory Department, Hospital Ramón y Cajal and Medicine Department, Universidad de Alcalá (Instituto de Ramón y Cajal de Investigación Sanitaria), Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), Madrid, Spain.
¹⁶ Department of Internal Medicine, Radboud University Medical Center, Nijmegen, the Netherlands.
¹⁷ Department of Neurology, Vagelos College of Physicians and Surgeons, New York, New York, USA; Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, New York, USA.
¹⁸ Cardiovascular Medicine Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
¹⁹ Yale New Haven Hospital/Yale Center for Outcomes Research and Evaluation, New Haven, Connecticut, USA; Department of Health Policy and Management, Yale School of Public Health, New Haven, Connecticut, USA; Section of Cardiovascular Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut, USA.
²⁰ Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
²¹ Department of Medicine, Larner College of Medicine at the University of Vermont, Burlington, Vermont, USA; Department of Pathology and Laboratory Medicine, Larner College of Medicine at the University of Vermont, Burlington, Vermont, USA.
²² Population Health Research Institute, Hamilton Health Sciences, McMaster University, Hamilton, Ontario, Canada.
²³ Liverpool Centre for Cardiovascular Science at University of Liverpool, Liverpool John Moores University and Liverpool Heart and Chest Hospital, Liverpool, United Kingdom; Danish Center for Clinical Health Services Research, Department of Clinical Medicine, Aalborg University, Aalborg, Denmark.
²⁴ McMaster University, Hamilton, Ontario, Canada; Thrombosis and Atherosclerosis Research Institute, Hamilton, Ontario, Canada.
²⁵ Duke Clinical Research Institute, Duke University Medical Center, Durham, North Carolina, USA; Brazilian Clinical Research Institute, São Paulo, Brazil.
²⁶ Thrombosis Research Group, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA; Cardiovascular Medicine Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA; Department of Internal Medicine, Radboud University Medical Center, Nijmegen, the Netherlands; Cardiovascular Research Foundation, New York, New York, USA. Electronic address: bbikdeli@bwh.harvard.edu.

PMID: 38233019
DOI: 10.1016/j.jacc.2023.10.038

Erratum in

Correction.
[No authors listed] [No authors listed] J Am Coll Cardiol. 2024 Apr 9;83(14):1351. doi: 10.1016/j.jacc.2024.02.032. J Am Coll Cardiol. 2024. PMID: 38569766 No abstract available.

Abstract

For most patients, direct oral anticoagulants (DOACs) are preferred over vitamin K antagonists for stroke prevention in atrial fibrillation and for venous thromboembolism treatment. However, randomized controlled trials suggest that DOACs may not be as efficacious or as safe as the current standard of care in conditions such as mechanical heart valves, thrombotic antiphospholipid syndrome, and atrial fibrillation associated with rheumatic heart disease. DOACs do not provide a net benefit in conditions such as embolic stroke of undetermined source. Their efficacy is uncertain for conditions such as left ventricular thrombus, catheter-associated deep vein thrombosis, cerebral venous sinus thrombosis, and for patients with atrial fibrillation or venous thrombosis who have end-stage renal disease. This paper provides an evidence-based review of randomized controlled trials on DOACs, detailing when they have demonstrated efficacy and safety, when DOACs should not be the standard of care, where their safety and efficacy are uncertain, and areas requiring further research.

Keywords: arterial thrombosis; bleeding; direct oral anticoagulants; randomized controlled trial; standard of care; venous thromboembolism.

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Conflict of interest statement

Funding Support and Author Disclosures Dr Piazza has received research support paid to his institution from Bristol Myers Squibb/Pfizer Alliance, Bayer, Janssen, Alexion, Amgen, and Boston Scientific Corporation; and has received consulting fees from Pfizer, Boston Scientific Corporation, Janssen, and Amgen. Dr Fanikos has served as a consultant to AstraZeneca, Mallinckrodt, and Pfizer. Dr Connors has received research funding to her institution from CSL Behring; has received consulting fees from Abbott; has received honoraria for lectures from Bristol Myers Squibb, Roche, and Sanofi; and has participated on the advisory board of Abbott, Alnylam, Anthos, Bristol Myers Squibb, Sanofi, and Takeda, outside of the submitted work. Dr Siegal is supported by a Tier 2 Canada Research Chair in Anticoagulant Management of Cardiovascular Disease; declares that she has received honoraria paid indirectly to her research institute from AstraZeneca, Bristol Myers Squibb-Pfizer, Roche, and Servier. Dr Barnes has served as a consultant for Pfizer, Bristol Myers Squibb, Janssen, Bayer, AstraZeneca, Sanofi, Anthos, Boston Scientific, and Abbott Vascular; and has received grant funding from Boston Scientific. Dr Martin is supported by National Institutes of Health K23HL157758; and has received research support paid to her institution from Janssen Scientific Affairs. Dr Angiolillo has received consulting fees or honoraria from Abbott, Amgen, AstraZeneca, Bayer, Biosensors, Boehringer Ingelheim, Bristol Myers Squibb, Chiesi, CSL Behring, Daiichi-Sankyo, Eli Lilly, Haemonetics, Janssen, Merck, Novartis, PhaseBio, PLx Pharma, Pfizer, Sanofi, and Vectura; and his institution has received research grants from Amgen, AstraZeneca, Bayer, Biosensors, CeloNova, CSL Behring, Daiichi-Sankyo, Eisai, Eli Lilly, Gilead, Idorsia, Janssen, Matsutani Chemical Industry Co, Merck, Novartis, and the Scott R. MacKenzie Foundation. Dr Kleindorfer has received other support from the University of Michigan College of Medicine. Dr Monreal has received unrestricted grants for research from Sanofi, Leo and Rovi; and has participated in advisory meetings sponsored by Sanofi. Dr Jimenez has served as an advisor or consultant for Pfizer and Sanofi; and has served as a speaker or a member of a Speakers Bureau for Bristol Myers Squibb, Pfizer and Sanofi. Dr Middeldorp has received grants and personal fees from Daiichi-Sankyo, Bayer, Pfizer, and Boehringer Ingelheim; and has received personal fees from Portola/Alexion, Abbvie, Pfizer/Bristol Myers Squibb, Norgine, Viatris, and Sanofi, all paid to her institution and outside of the submitted work. Dr Elkind has received study drug in kind from the Bristol Myers Squibb-Pfizer Alliance; has received ancillary research funding from Roche for a National Institutes of Health-funded trial of stroke prevention; and has received royalties from UpToDate for chapters on stroke. Dr Elkind has received study drug in kind from the Bristol Myers Squibb-Pfizer Alliance and ancillary research funding from Roche for a National Institutes of Health-funded trial of stroke prevention, and royalties from UpToDate for chapters on stroke. Dr Ruff is a member of the TIMI Study Group, which has received institutional research grant support through Brigham and Women’s Hospital from Abbott, Amgen, Anthos Therapeutics, ARCA Biopharma, Inc, AstraZeneca, Bayer HealthCare Pharmaceuticals, Inc, Daiichi-Sankyo, Eisai, Intarcia, Ionis Pharmaceuticals, Inc, Janssen Research and Development, LLC, MedImmune, Merck, Novartis, Pfizer, Quark Pharmaceuticals, Regeneron Pharmaceuticals, Inc, Roche, Siemens Healthcare Diagnostics, Inc, Softcell Medical Limited, The Medicines Company, and Zora Biosciences. Dr Goldhaber has received research support from Bayer, Bristol Myers Squibb, Boston Scientific BTG EKOS, Janssen, National Heart, Lung, and Blood Institute, and Pfizer; and has received consulting fees from Agile, Bayer, and Pfizer, outside of the submitted work. In the past 3 years, Dr Krumholz has received expenses and/or personal fees from UnitedHealth, Element Science, Eyedentifeye, and F-Prime; is a co-founder of Refactor Health and HugoHealth; and is associated with contracts, through Yale New Haven Hospital, from the Centers for Medicare and Medicaid Services and through Yale University from Janssen, Google, and Pfizer. Dr Mehran has received institutional research payments from Abbott, Abiomed, Alleviant Medical, Amgen, AM-Pharma, Arena, AstraZeneca, AtriCure Inc, Biosensors, Biotronik, Boston Scientific, Bristol Myers Squibb, CardiaWave, CeloNova, Chiesi, Concept Medical, Cytosorbents, Daiichi-Sankyo, Element Science, Faraday, Humacyte, Idorsia Pharmaceuticals, Janssen, Magenta, MedAlliance, Mediasphere, Medtelligence, Medtronic, MJH Healthcare, Novartis, OrbusNeich, Penumbra, PhaseBio, Philips, Pi-Cardia, PLx Pharma, Protembis, RenalPro, RM Global, Shockwave, Vivasure, Zoll; has received personal fees from Ionis Pharmaceuticals, J-CalC, Novartis, NovoNordisk, Vectura, VoxMedia, WebMD, IQVIA, McVeigh Global, Overcome, Primer Healthcare of New Jersey, Radcliffe, SL Solutions, TARSUS Cardiology, and Esperion Science/Innovative Biopharma; has received honoraria from JAMA Cardiology (Associate Editor) and the ACC (BOT Member, SC Member CTR Program); and has equity <1% in Applied Therapeutics, Elixir Medical, Stel, ControlRad (spouse). Dr Eikelboom has received fees, honoraria and/or research support from Anthos, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, DSI, Janssen, Pfizer, Servier, and Takeda. Dr Lip is a consultant and speaker for Bristol Myers Squibb/Pfizer, Boehringer Ingelheim, Daiichi-Sankyo, and Anthos, no fees are received personally; and is coprincipal investigator of the AFFIRMO project on multimorbidity in AF, which has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement #899871. Dr Weitz has served as a consultant and has received honoraria from Alnylam, Anthos, Bayer, Bristol Myers Squibb, Ionis, Janssen, Merck, Pfizer, Regeneron, and Servier. Dr Lopes reports research grants or contracts from Amgen, Bristol Myers Squibb, GlaxoSmithKline, Medtronic, Pfizer, Sanofi; funding for educational activities or lectures from Pfizer, Bristol Myers Squibb, Novo Nordisk, and AstraZeneca; and has received funding for consulting from Bayer, Boehringer Ingelheim, Bristol Myers Squibb, NovoNordisk, and AstraZeneca. Dr Bikdeli is supported by a Career Development Award from the American Heart Association and VIVA Physicians (#938814); was supported by the Scott Schoen and Nancy Adams IGNITE Award; is supported by the Mary Ann Tynan Research Scientist award from the Mary Horrigan Connors Center for Women’s Health and Gender Biology at Brigham and Women’s Hospital, and the Heart and Vascular Center Junior Faculty Award from Brigham and Women’s Hospital; is a consulting expert, on behalf of the plaintiff, for litigation related to 2 specific brand models of IVC filters; has not been involved in the litigation in 2022 or 2023 nor has he received any compensation in 2022 or 2023; is a member of the Medical Advisory Board for the North American Thrombosis Forum; and serves in the Data Safety and Monitory Board of the NAIL-IT trial funded by the National Heart, Lung, and Blood Institute, and Translational Sciences. All other authors have reported that they have no relationships related to the contents of this paper to disclose.

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When Direct Oral Anticoagulants Should Not Be Standard Treatment: JACC State-of-the-Art Review

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When Direct Oral Anticoagulants Should Not Be Standard Treatment: JACC State-of-the-Art Review

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Erratum in

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Conflict of interest statement

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