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Anticoagulation

Efficacy and Safety Considerations With Dose-Reduced Direct Oral AnticoagulantsA Review

To identify the key insights or developments described in this article
1 Credit CME
JAMA Cardiology
Published Online: June 1, 2022
Review
Behnood Bikdeli, MD, MS1,2,3,4;
Farbod Zahedi Tajrishi, MD5;
Parham Sadeghipour, MD6,7;
Azita H. Talasaz, PharmD8,9;
John Fanikos, RPH, MBA10;
Giuseppe Lippi, MD11;
Deborah M. Siegal, MD, MSc12;
John W. Eikelboom, MBBS13;
Manuel Monreal, MD, PhD14;
David Jimenez, MD, PhD15;
Jean M. Connors, MD16;
Walter Ageno, MD, PhD17;
Geoffrey D. Barnes, MD, MSc18;
Gregory Piazza, MD, MS1,2;
Dominick J. Angiolillo, MD, PhD19;
Sahil A. Parikh, MD4,20;
Ajay J. Kirtane, MD, SM4,20;
Renato D. Lopes, MD, PhD21,22;
Deepak L. Bhatt, MD, MPH1;
Jeffrey I. Weitz, MD23,24;
Roxana Mehran, MD25;
Harlan M. Krumholz, MD, SM3,26,27;
Samuel Z. Goldhaber, MD1,2;
Gregory Y. H. Lip, MD28,29
Author Affiliations
  • 1Cardiovascular Medicine Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
  • 2Thrombosis Research Group, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
  • 3Yale New Haven Hospital/Yale Center for Outcomes Research and Evaluation, New Haven, Connecticut
  • 4Cardiovascular Research Foundation, New York, New York
  • 5Cardiac Primary Prevention Research Center, Tehran Heart Center, Tehran University of Medical Sciences, Tehran, Iran
  • 6Cardiovascular Intervention Research Center, Rajaie Cardiovascular, Medical, and Research Center, Iran University of Medical Sciences, Tehran, Iran
  • 7Clinical Trial Center, Rajaie Cardiovascular, Medical, and Research Center, Iran University of Medical Sciences, Tehran, Iran
  • 8Tehran Heart Center, Tehran University of Medical Sciences, Tehran, Iran
  • 9Virginia Commonwealth University, Richmond
  • 10Department of Pharmacy, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
  • 11Section of Clinical Biochemistry, University of Verona, Verona, Italy
  • 12Division of Hematology, Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada
  • 13Population Health Research Institute, Hamilton Health Sciences, McMaster University, Hamilton, Ontario, Canada
  • 14Department of Internal Medicine, Hospital Universitari Germans Trials i Pujol, Universidad Católica San Antonio de Murcia, Barcelona, Spain
  • 15Respiratory 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, Madrid, Spain
  • 16Hematology Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
  • 17Department of Medicine and Surgery, University of Insubria, Varese, Italy
  • 18Frankel Cardiovascular Center, Department of Internal Medicine, University of Michigan, Ann Arbor
  • 19Division of Cardiology, University of Florida College of Medicine, Jacksonville, Florida
  • 20Division of Cardiology, New York-Presbyterian Hospital/Columbia University Irving Medical Center, New York
  • 21Duke Clinical Research Institute, Duke University Medical Center, Durham, North Carolina
  • 22Brazilian Clinical Research Institute, São Paulo, Brazil
  • 23McMaster University, Hamilton, Ontario, Canada
  • 24Thrombosis and Atherosclerosis Research Institute, Hamilton, Ontario, Canada
  • 25Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, New York
  • 26Department of Health Policy and Management, Yale School of Public Health, New Haven, Connecticut
  • 27Section of Cardiovascular Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut
  • 28Liverpool Centre for Cardiovascular Science, Liverpool Heart and Chest Hospital, University of Liverpool, Liverpool, United Kingdom
  • 29Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
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Abstract

Importance  Dose-reduced regimens of direct oral anticoagulants (DOACs) may be used for 2 main purposes: dose-adjusted treatment intended as full-intensity anticoagulation (eg, for stroke prevention in atrial fibrillation [AF] in patients requiring dose reduction) or low-intensity treatment (eg, extended-duration treatment of venous thromboembolism [VTE]). We reviewed randomized clinical trials (RCTs) to understand the scenarios in which dose-adjusted or low-intensity DOACs were tested and reviewed the labeled indications by regulatory authorities, using data from large registries to assess whether the use of dose-reduced DOACs in routine practice aligned with the findings of RCTs.

Observations  Among 4191 screened publications, 35 RCTs that used dose-adjusted DOACs were identified for dabigatran, apixaban, rivaroxaban, and edoxaban. Of these 35 RCTs, 29 were related to stroke prevention in AF. Efficacy and safety results for dose-adjusted DOACs in large RCTs of AF were similar to those found for full-dose DOACs. To our knowledge, dabigatran, apixaban, and rivaroxaban have not been studied as dose-adjusted therapy for acute VTE treatment. Low-intensity DOACs were identified in 37 RCTs. Low-intensity DOACs may be used for extended-duration treatment of VTE (apixaban and rivaroxaban), primary prevention in orthopedic surgeries (dabigatran, apixaban, and rivaroxaban), primary prevention in ambulatory high-risk cancer patients (apixaban and rivaroxaban) or (postdischarge) high-risk medical patients (rivaroxaban), in stable atherosclerotic vascular disease, or after a recent revascularization for peripheral artery disease in conjunction with aspirin (rivaroxaban). Minor variations exist between regulatory authorities in different regions regarding criteria for dose adjustment of DOACs. Data from large registries indicated that dose-reduced DOACs were used occasionally with doses or for clinical scenarios different from those studied in RCTs or recommended by regulatory authorities.

Conclusions and Relevance  Dose adjustment and low-intensity treatment are 2 different forms of dose-reduced DOACs. Dose adjustment is mostly relevant for AF and should be done based on the approved criteria. Dose adjustment of DOACs should not be used for acute VTE treatment in most cases. In contrast, low-intensity DOACs may be used for primary or secondary VTE prevention for studied and approved indications. Attention should be given to routine practice patterns to align the daily clinical practice with existing evidence of safety and efficacy.

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CME Disclosure Statement: Unless noted, all individuals in control of content reported no relevant financial relationships. If applicable, all relevant financial relationships have been mitigated.

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Cardiology Venous Thromboembolism Anticoagulation Pharmacy and Clinical Pharmacology
Article Information

Accepted for Publication: April 12, 2022.

Published Online: June 1, 2022. doi:10.1001/jamacardio.2022.1292

Correction: This article was corrected on July 1, 2022, to fix the logos in the Figure.

Corresponding Author: Behnood Bikdeli, MD, MS, Cardiovascular Medicine Division, Brigham and Women’s Hospital, 75 Francis St, Boston, MA 02115 (bbikdeli@bwh.harvard.edu; Behnood.bikdeli@yale.edu).

Author Contributions: Drs Bikdeli and Zahedi Tajrishi had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Bikdeli, Zahedi Tajrishi, Sadeghipour, Talasaz, Fanikos, Lippi, Eikelboom, Connors, Parikh, Lopes, Mehran, Lip.

Acquisition, analysis, or interpretation of data: Bikdeli, Zahedi Tajrishi, Sadeghipour, Talasaz, Fanikos, Lippi, Siegal, Eikelboom, Monreal, Jimenez, Ageno, Barnes, Piazza, Angiolillo, Kirtane, Lopes, Bhatt, Weitz, Mehran, Krumholz, Goldhaber.

Drafting of the manuscript: Bikdeli, Zahedi Tajrishi, Sadeghipour, Talasaz, Fanikos, Lippi, Siegal, Parikh, Lip.

Critical revision of the manuscript for important intellectual content: Bikdeli, Zahedi Tajrishi, Sadeghipour, Talasaz, Fanikos, Siegal, Eikelboom, Monreal, Jimenez, Connors, Ageno, Barnes, Piazza, Angiolillo, Parikh, Kirtane, Lopes, Bhatt, Weitz, Mehran, Krumholz, Goldhaber, Lip.

Statistical analysis: Eikelboom, Jimenez.

Administrative, technical, or material support: Bikdeli, Zahedi Tajrishi, Fanikos.

Supervision: Bikdeli, Fanikos, Monreal, Ageno, Barnes, Piazza, Angiolillo, Mehran, Goldhaber, Lip.

Conflict of Interest Disclosures: Dr Bikdeli is supported by the IGNITE Award from the Mary Horrigan Connors Center for Women’s Health and Gender Biology at Brigham and Women’s Hospital and a Career Development Award from the American Heart Association outside the submitted work and is a consulting expert on behalf of the plaintiff for litigation related to 2 specific brand models of inferior vena cava filters. Dr Siegal reported honoraria paid to institution for educational presentation from Bristol Myers Squibb/Pfizer, Servier, and Roche and personal fees from Portola outside the submitted work. Dr Eikelboom reported grant support and personal fees from Bayer, Boehringer Ingelheim, Bristol Myers Squibb/Pfizer, Daiichi Sankyo, Janssen, Sanofi, and Eli Lilly and personal fees from AstraZeneca, Merck, and GlaxoSmithKline during the conduct of the study; personal fees from AstraZeneca, Daiichi Sankyo, and GlaxoSmithKline; and grant support and personal fees from Bayer, Boehringer Ingelheim, Bristol Myers Squibb/Pfizer, Janssen, Sanofi, Merck, and Eli Lilly outside the submitted work. Dr Monreal reported grants from Sanofi, Rovi, and Leo Pharma and personal fees from Pfizer during the conduct of the study and grants from Sanofi, Rovi, and Leo Pharma outside the submitted work. Dr Jimenez reported personal fees from Bayer and Bristol Myers Squibb and grants from Daiichi Sankyo, Leo Pharma, Rovi, and Sanofi during the conduct of the study. Dr Connors reported personal fees from Bristol Myers Squibb, Abbott, Anthos, Alnylam, Pfizer, Roche, and Sanofi and grants from CSL Behring paid to institution outside the submitted work. Dr Ageno reported grants from Bayer and personal fees from Bristol Myers Squibb/Pfizer, Norgine, Sanofi, Leo Pharma, and Werfen outside the submitted work. Dr Barnes reported personal fees from Pfizer, Bristol Myers Squibb, and Janssen during the conduct of the study and personal fees from Acelis and grants from Boston Scientific outside the submitted work. Dr Piazza reported grants from Bristol Myers Squibb/Pfizer, Janssen, Boston Scientific, Bayer, Alexion, and Amgen outside the submitted work. Dr Angiolillo reported individual consulting fees or honoraria from Abbott, Amgen, AstraZeneca, Bayer, Biosensors, Boehringer Ingelheim, Bristol Myers Squibb, Chiesi, Daiichi Sankyo, Eli Lilly, Haemonetics, Janssen, Merck, PhaseBio, PLx Pharma, Pfizer, and Sanofi and institutional grants from Amgen, AstraZeneca, Bayer, Biosensors, CeloNova, CSL Behring, Daiichi Sankyo, Eisai, Eli Lilly, Gilead, Idorsia, Janssen, Matsutani Chemical Industry Co, Merck, Novartis, Osprey Medical, Renal Guard Solutions, and the Scott R. MacKenzie Foundation. Dr Parikh reported grants from Abbott Vascular, Boston Scientific, Surmodics, TriReme, Veryan, Shockwave, and Acotec and personal fees from Janssen, Medtronic, Philips, Cordis, Terumo, Abiomed, Penumbra, and Inari outside the submitted work. Dr Kirtane reported institutional funding to Columbia University and/or Cardiovascular Research Foundation from Medtronic, Boston Scientific, Abbott Vascular, Amgen, Cardiovascular Systems, Inc, Philips, ReCor Medical, Neurotronic, Biotronik, Chiesi, Bolt Medical, Magenta Medical, Canon, and SoniVie and personal fees from Interventional Medical Device Solutions, Medtronic, Boston Scientific, Abbott Vascular, Cardiovascular Systems, Inc, Siemens, Philips, ReCor Medical, Chiesi, OpSens, Zoll, and Regeneron. Dr Bhatt reported grants from Amarin, AstraZeneca, Bristol Myers Squibb, Eisai, Ethicon, Medtronic, Sanofi Aventis, The Medicines Company, Roche, Pfizer, Forest Laboratories/AstraZeneca, Ischemix, PhaseBio, Boston Scientific, Amgen, Eli Lilly, Chiesi, Ironwood, Merck, Abbott, Regeneron, Idorsia, Synaptic, Boehringer Ingelheim, Novo Nordisk, Fractyl, Cereno Scientific, Afimmune, Ferring Pharmaceuticals, Lexicon, Contego Medical, CellProthera, MyoKardia/BMS, Owkin, HLS Therapeutics, Janssen, 89Bio, Novo Nordisk, Garmin, Novartis, NirvaMed, Stasys, Faraday Pharmaceuticals, Javelin, Reid Hoffman Foundation, Moderna, Beren, Aker Biomarine, Recardio, and Acesion Pharma; other support from FlowCo, PLx Pharma, Takeda, American College of Cardiology, Regado Biosciences, Boston Veteran Administration Research Institute, Society of Cardiovascular Patient Care, American Heart Association, Clinical Cardiology, Veterans Affairs Administration, St Jude Medical (now Abbott), Biotronik, Svelte, Cardiovascular Systems, Inc, and Philips; and personal fees from Duke Clinical Research Institute, Mayo Clinic, Population Health Research Institute, Belvoir Publications, Slack Publications, WebMD, Elsevier, Medscape Cardiology, HMP Global, Harvard Clinical Research Institute (now Baim Institute for Clinical Research), Journal of the American College of Cardiology, Cleveland Clinic, Mount Sinai School of Medicine, Cardax, TobeSoft, Bayer, Medtelligence/ReachMD, CSL Behring, MJH Life Sciences, Level Ex, K2P, Canadian Medical and Surgical Knowledge Translation Research Group, Arnold and Porter Law Firm, Piper Sandler, and Cowen and Company, Doctors Linq, Assistance Publique-Hôpitaux de Paris, and Rutgers University outside the submitted work. Dr Weitz reported personal fees from Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Ionis, Janssen, Merck, Novartis, and Pfizer outside the submitted work. Dr Mehran reports institutional research payments from Abbott, Abiomed, Alleviant Medical, AM-Pharma, Applied Therapeutics, Arena, AstraZeneca, Bayer, Biosensors, Biotronik, Boston Scientific, Bristol-Myers Squibb, CardiaWave, CellAegis, CeloNova, Chiesi, Concept Medical, CSL Behring, Cytosorbents, Daiichi Sankyo, Element Science, Faraday, Humacyte, Idorsia, Magenta, Medtronic, Novartis, OrbusNeich, Philips, RenalPro, Vivasure, Zoll; personal fees from Cine-Med Research, WebMD; consulting fees paid to the institution from Abbott, Janssen, Medtronic, Novartis; Equity <1% in Applied Therapeutics, Elixir Medical, Stel, ControlRad (spouse); Scientific Advisory Board service for the American Medical Association, American College of Cardiology (board of trustees member), Society of Cardiovascular Angiography and Interventions (Women in Innovations Committee Member), JAMA Cardiology associate editor; and faculty Cardiovascular Research Foundation (no fee) outside the submitted work. Dr Krumholz reported received expenses and/or personal fees from UnitedHealth, Element Science, Aetna, Reality Labs, Tesseract/4Catalyst, F-Prime, the Siegfried and Jensen Law Firm, Arnold and Porter Law Firm, and Martin/Baughman Law Firm. He is a co-founder of Refactor Health and HugoHealth, and is associated with contracts from the Centers for Medicare & Medicaid Services and from Johnson & Johnson through Yale University. Dr Goldhaber reported grants from Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Boston Scientific, Daiichi Sankyo, Janssen, the National Heart, Lung, and Blood Institute, and the Thrombosis Research Institute and personal fees from Bayer, Agile, Boston Scientific, and Boehringer Ingelheim outside the submitted work. Dr Lip reported serving as a consultant and speaker for Bristol Myers Squibb/Pfizer, Boehringer Ingelheim, and Daiichi Sankyo. No fees are received personally. No other disclosures were reported.

Additional Contributions: We thank Fatemeh Esmaieli, MS, Tehran Heart Center, for help with the figure design. No compensation was received.

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