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  • Review Article
  • Published:

Optimizing antithrombotic therapy in patients with coexisting cardiovascular and gastrointestinal disease

Abstract

Balancing the safety and efficacy of antithrombotic agents in patients with gastrointestinal disorders is challenging because of the potential for interference with the absorption of antithrombotic drugs and for an increased risk of bleeding. In this Review, we address considerations for enteral antithrombotic therapy in patients with cardiovascular disease and gastrointestinal comorbidities. For those with gastrointestinal bleeding (GIB), we summarize a general scheme for risk stratification and clinical evidence on risk reduction approaches, such as limiting the use of concomitant medications that increase the risk of GIB and the potential utility of gastrointestinal protection strategies (such as proton pump inhibitors or histamine type 2 receptor antagonists). Furthermore, we summarize the best available evidence and potential gaps in our knowledge on tailoring antithrombotic therapy in patients with active or recent GIB and in those at high risk of GIB but without active or recent GIB. Finally, we review the recommendations provided by major medical societies, highlighting the crucial role of teamwork and multidisciplinary discussions to customize the antithrombotic regimen in patients with coexisting cardiovascular and gastrointestinal diseases.

Key points

  • Balancing the safety and efficacy of antithrombotic therapy in patients with gastrointestinal disorders is challenging because of the potential for interference with the absorption of antithrombotic drugs or for an increased risk of bleeding.

  • Various clinical states, including malabsorption syndromes, bariatric surgery, short-bowel syndrome or enteral tube feeding, can influence the absorption and bioavailability of oral antithrombotic agents.

  • Bleeding events are an essential prognosticator in patients with cardiovascular diseases — at times as important as thrombotic events — and using antithrombotic agents in patients at high risk of gastrointestinal bleeding (GIB) is very challenging.

  • Most of the existing models to predict the risk of bleeding in patients with coronary artery disease do not estimate the risk of GIB specifically.

  • Identifying patients at high risk of GIB, modifying the bleeding risk by using gastroprotective agents, and determining the appropriate antithrombotic therapy regimen have crucial roles in preventing GIB.

  • After an episode of acute GIB, determining the duration of antithrombotic therapy interruption and the regimen for re-initiation requires consideration of the balance between the bleeding severity and the risk of thrombotic events.

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Fig. 1: Pharmacokinetics and pharmacodynamics of antithrombotic agents in patients with malabsorption, bariatric surgery or small-intestine resection or with delivery by different types of enteral tube.
Fig. 2: Management of antithrombotic agents in patients at risk of GIB, stratified according to thrombotic risk and bleeding severity.
Fig. 3: Management of antithrombotic agents in patients with recent GIB, stratified according to thrombotic risk and bleeding severity.

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Acknowledgements

The authors thank L. Laine (Yale School of Medicine, New Haven, CT, USA) for reviewing this manuscript before submission and for his insightful comments.

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A.H.T., H.K., M.A. and B.B. researched data for the article. All the authors discussed its content. A.H.T., P.S., L.O.-P., C.B., J.F., D.M.S., L.A.C., A.C., G.D.B., J.M.C., E.A.S., R.D.C., J.E.K., A.A., G.P. and B.B. wrote the manuscript. All the authors reviewed/edited it before submission.

Corresponding author

Correspondence to Behnood Bikdeli.

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Competing interests

J.F. has served as a consultant for AstraZeneca, Mallinckrodt and Pfizer. J.W.E. holds the Jack Hirsh/Population Health Research Chair in Thrombosis and Atherosclerosis and has received honoraria, fees or research support from Anthos, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, DSI, Idorsia, Janssen, Pfizer and Servier. D.M.S. is supported by a Tier 2 Canada Research Chair in Anticoagulant Management of Cardiovascular Disease and has received honoraria paid indirectly to her institution from AstraZeneca, BMS–Pfizer, Roche and Servier. M.M. has participated in advisory meetings sponsored by Sanofi. D.J. has served as a speaker or a member of a speakers’ bureau for Bristol Myers Squibb, Pfizer and Sanofi, and has served as an adviser or consultant for Pfizer and Sanofi. M.V. has received research grant support, served on advisory boards or had speaker engagements with American Regent, Amgen, AstraZeneca, Bayer AG, Baxter Healthcare, Boehringer Ingelheim, Chiesi, Cytokinetics, Lexicon Pharmaceuticals, Merck, Novatis, Novo Nordisk, Pharmacosmos, Relypsa, Roche Diagnostics, Sanofi and Tricog Health, and participates on clinical trial committees for studies sponsored by AstraZeneca, Bayer AG, Impulse Dynamics, Novartis and Occlutech. L.A.C. holds a Tier 2 research Chair in Thrombosis and Anticoagulation Safety from the University of Ottawa, and her research institution has received honoraria from The Academy for Continued Advancement in Healthcare Education, Amag Pharmaceutical, Bayer, BMS-Pfizer Alliance, LEO Pharma, Sanofi, Servier and Valeo Pharma. A.C. has served as a consultant for MingSight Pharmaceuticals, the New York Blood Center, Sanofi and Synergy, and has received authorship royalties from UpToDate. G.D.B. has received consulting fees from Abbott Vascular, Anthos, AstraZeneca, Bayer, Boston Scientific, Bristol Myers Squibb, Janssen, Pfizer and Sanofi; research funding from Boston Scientific; serves on the clinical adjudication committee for Translational Sciences and serves on the board of directors for the Anticoagulation Forum. J.M.C. reports consulting fees or scientific advisory board honoraria from Abbott Laboratories, Anthos Pharmaceuticals, Bristol Myers Squibb, Pfizer, Roche, Sanofi and Werfen, and research funding to the institution from C.S.L. Behring. E.A.S. has received funding from NIH/NHLBI K23HL150290, Food & Drug Administration, SCAI; grants to his institution from Abbott, BD, Boston Scientific, Cook, Medtronic and Philips; and speaking/consulting fee from Abbott, BD, Boston Scientific, Cagent, Conavi, Cook, Cordis, InfraRedx, Medtronic, Philips, Recor, Shockwave, VentureMed and Verya. B.W.V.T. has received research funding from Novartis, R-Pharm and Serpin Pharma, and was a consultant for Implicit Biosciences. R.D.C. reports grants, personal consulting fees and non-financial support from AstraZeneca, Boehringer Ingelheim, Bayer, BMS–Pfizer, Daiichi Sankyo, Guidotti, Janssen, Menarini, Merck, Milestone, Novartis, Portola, Roche and Sanofi. A.A. has received research grant and speaking honorarium from Ethicon and Medtronic. G.P. has research grants from Alexion, Amgen, Bayer, BMS–Pfizer, BSC, Esperion, Janssen and the NIH (1R01HL164717-01) and an advisory role with Amgen, BCRI, BMS, BSC, Janssen, NAMSA, PERC and Regeneron. S.Z.G. has received research support from Bayer, BMS, Boston Scientific, EKOS, Janssen and NHLBI. S.M. reports grants and personal fees from Bayer, Boehringer-Ingelheim, Daiichi-Sankyo and Pfizer, and personal fees from Abbvie, Pfizer–Bristol-Meyers Squibb, Portola/Alexion, Norgine, Sanofi and Viatris, all paid to her institution. A.J.K. reports institutional funding to Columbia University and/or Cardiovascular Research Foundation from Abbott Vascular, Amgen, Biotronik, Bolt Medical, Boston Scientific, Canon, CathWorks, Chiesi, CSI, Magenta Medical, Medtronic, Neurotronic, Philips, ReCor Medical, Shockwave Medical and SoniVie. In addition to research grants, institutional funding includes fees paid to Columbia University and/or Cardiovascular Research Foundation for consulting and/or speaking engagements in which A.J.K. controlled the content. A.J.K received personal funding for travel expenses/meals from Abbott Vascular, Abiomed, Amgen, Biotronik, Boston Scientific, CathWorks, Chiesi, CSI, Edwards, Medtronic, Novartis, Philips, ReCor Medical, Regeneron, Shockwave and Zoll. M.S.V.E. receives salary as the Chief Clinical Science Officer of the American Heart Association, received study drug in kind from the BMS–Pfizer Alliance for Eliquis, ancillary funding from Roche for an HIH-funded trial of apixaban for stroke prevention, royalties from UpToDate for chapters on stroke, and honoraria for lectures on stroke from the Atria Academy of Science and Medicine. D.J.A. reports 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, Pfizer, PhaseBio, PLx Pharma, Sanofi and Vectura; and research grants to his institution from Amgen, AstraZeneca, Bayer, Biosensors, Celo-Nova, CSL Behring, Daiichi-Sankyo, Eisai, Eli Lilly, Gilead, Idorsia, Janssen, Matsutani Chemical Industry Co., Merck, Novartis and the Scott R. MacKenzie Foundation. S.K. reports consulting fees from Bayer, Boston Scientific, Daiichi Sankyo and Penumbra, lecture honoraria from Boston Scientific, Bristol Myers Squibb–Pfizer, MSD and Penumbra, and research grants to his institution from Bayer, Boston Scientific, Daiichi Sankyo, LumiraDx and Penumbra. G.Y.H.L. is a consultant and speaker for Anthos, BMS–Pfizer, Boehringer Ingelheim and Daiichi-Sankyo; no fees are received personally. G.Y.H.L. is co-principal investigator of the AFFIRMO project on multimorbidity in atrial fibrillation, which has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement no. 899871. G.W.S. has received speaker honoraria from Abiomed, Amgen, Boehringer Ingelheim, Infraredx, Medtronic and Pulnovo; is a consultant to Abbott, Abiomed, Ablative Solutions, Adona Medical, Ancora, Apollo Therapeutics, Cardiac Success, Cardiomech, CorFlow, Daiichi Sankyo, Elucid Bio, Gore, HeartFlow, HighLife, Impulse Dynamics, Millennia Biopharma, Miracor, Neovasc, Occlutech, Oxitope, Robocath, TherOx, Vectorious and Valfix; and holds equity/options from Ancora, Applied Therapeutics, Aria, Biostar family of funds, Cagent, Cardiac Success, Orchestra Biomed, SpectraWave, Valfix and Xenter. G.W.S.’s employer, Mount Sinai Hospital, receives research grants from Abbott, Abiomed, Biosense-Webster, Bioventrix, Cardiovascular Systems Inc., Philips, Pulnovo, Shockwave, Vascular Dynamics and V-wave. G.W.S.’s daughter is an employee at IQVIA. H.M.K. has received expenses and/or personal fees from Element Science, Eyedentify, F-Prime and UnitedHealth. H.M.K. is a co-founder of Ensight-AI, Hugo Health and Refactor Health. H.M.K. is the editor of Journal Watch: Cardiology of the Massachusetts Medical Society and is a section editor of UpToDate. H.M.K. is associated with contracts, through Yale New Haven Hospital, from the Centers for Medicare & Medicaid Services and through Yale University from Janssen, Johnson & Johnson Consumer and Pfizer. R.M. reports institutional research payments from Abbott, Abiomed, Affluent Medical, Alleviant Medical, Amgen, AM-Pharma, Arena, AstraZeneca, AtriCure, Biosensors, Biotronik, Boston Scientific, Bristol Myers Squibb, CardiaWave, CeloNova, Chiesi, Concept Medical, Cytosorbents, Daiichi Sankyo, Duke, 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 and Zoll; personal fees from Affluent Medical, Cardiovascular Research Foundation (CRF), Daiichi Sankyo Brasil, E.R. Squibb & Sons, Esperion Science/Innovative Biopharma, Europa Group/Boston Scientific, Gaffney Events, Educational Trust, Ionis Pharmaceuticals, IQVIA, McVeigh Global, Novartis, Novo Nordisk, Primer Healthcare of New Jersey, Radcliffe, TARSUS Cardiology, Vectura, VoxMedia and WebMD; no fees from AMA (Scientific Advisory Board) and SCAI (Women in Innovations Committee Member); Faculty CRF honorarium from JAMA Cardiology (Associate Editor), ACC (BOT Member, SC Member CTR Program); equity <1% in Applied Therapeutics, Elixir Medical, Stel and ControlRad (spouse). D.L.B. discloses the following relationships — Advisory Board: Angiowave, Bayer, Boehringer Ingelheim, Cardax, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, High Enroll, Janssen, Level Ex, McKinsey, Medscape Cardiology, Merck, MyoKardia, NirvaMed, Novo Nordisk, PhaseBio, PLx Pharma, Stasys; Board of Directors: American Heart Association New York City, Angiowave (stock options), Bristol Myers Squibb (stock), DRS.LINQ (stock options), High Enroll (stock); Consultant: Broadview Ventures, Hims; Data Monitoring Committees: Acesion Pharma, Assistance Publique-Hôpitaux de Paris, Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St. Jude Medical, now Abbott), Boston Scientific (Chair, PEITHO trial), Cleveland Clinic, Contego Medical (Chair, PERFORMANCE 2), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi Sankyo; for the ABILITY-DM trial, funded by Concept Medical), Novartis, Population Health Research Institute; Rutgers University (for the NIH-funded MINT trial); Honoraria: American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org; Chair, ACC Accreditation Oversight Committee), Arnold and Porter law firm (work related to Sanofi/Bristol Myers Squibb clopidogrel litigation), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE-DUAL PCI clinical trial steering committee funded by Boehringer Ingelheim; AEGIS-II executive committee funded by CSL Behring), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Canadian Medical and Surgical Knowledge Translation Research Group (clinical trial steering committees), CSL Behring (AHA lecture), Cowen and Company, Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE trial, funded by Ferring Pharmaceuticals), HMP Global (Editor in Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), K2P (Co-Chair, interdisciplinary curriculum), Level Ex, Medtelligence/ReachMD (CME steering committees), MJH Life Sciences, Oakstone CME (Course Director, Comprehensive Review of Interventional Cardiology), Piper Sandler, Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee, and USA national co-leader, funded by Bayer), WebMD (CME steering committees), Wiley (steering committee); Other: Clinical Cardiology (Deputy Editor); Patent: sotagliflozin (named on a patent for sotagliflozin assigned to Brigham and Women’s Hospital who assigned to Lexicon; neither D.L.B. nor Brigham and Women’s Hospital receives any income from this patent); Research Funding: Abbott, Acesion Pharma, Afimmune, Aker Biomarine, Alnylam, Amarin, Amgen, AstraZeneca, Bayer, Beren, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cardax, CellProthera, Cereno Scientific, Chiesi, CinCor, Cleerly, CSL Behring, Eisai, Ethicon, Faraday Pharmaceuticals, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Garmin, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Janssen, Javelin, Lexicon, Lilly, Medtronic, Merck, Moderna, MyoKardia, NirvaMed, Novartis, Novo Nordisk, Otsuka, Owkin, Pfizer, PhaseBio, PLx Pharma, Recardio, Regeneron, Reid Hoffman Foundation, Roche, Sanofi, Stasys, Synaptic, The Medicines Company, Youngene, 89Bio; Royalties: Elsevier (Editor, Braunwald’s Heart Disease); Site Co-Investigator: Abbott, Biotronik, Boston Scientific, CSI, Endotronix, St. Jude Medical (now Abbott), Philips, SpectraWAVE, Svelte, Vascular Solutions; Trustee: American College of Cardiology; Unfunded Research: FlowCo, Takeda. B.B. is supported by a Career Development Award from the American Heart Association and VIVA Physicians (938814). B.B. was supported by the Scott Schoen and Nancy Adams IGNITE Award and 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. B.B. reports that he was a consulting expert, on behalf of the plaintiff, for litigation related to two specific brand models of IVC filters. B.B. has not been involved in the litigation in 2022 or 2023 nor has he received any compensation in 2022 or 2023. B.B. reports that he 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. The other authors declare no competing interests.

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Nature Reviews Cardiology thanks Anna Falanga, Marco Valgimigli and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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A diverse group of experts was convened (cardiologists, haematologists, gastroenterologists, bariatric surgeons, neurologists, internists, pharmacists and epidemiologists). A protocol outline was agreed ahead of the literature search. A series of comprehensive literature searches were performed to address several questions. These topics included pharmacokinetics and pharmacodynamics of antithrombotic agents with respect to gastrointestinal absorption impairment with motility problems, oral administration difficulties and tube feeding, and gastrointestinal resection surgery. Separate systematic search queries were prepared for strategies to reduce the risk of gastrointestinal bleeding (GIB) in patients receiving antithrombotic agents, including acid-suppressive medications and modifying antithrombotic regimens. Additional search queries were devised for the management of antithrombotic agents in patients with acute GIB, in those with recent GIB, and in those at high risk of GIB without active or recent bleeding (such as patients with inflammatory bowel disease or gastrointestinal cancer). The patient population, interventions, comparators, outcomes and type of study (PICOS) model was used as a search strategy tool. For efficacy or comparative effectiveness questions, randomized controlled trials and, where appropriate, pooled analyses from randomized controlled trials were prioritized. Medline with the PubMed interface was searched. In addition, a systematic search was conducted with respect to existing guidelines or major society recommendations related to the key questions. The date of the last search was 21 January 2023. Existing recent guidelines were referred to if they addressed a question, instead of duplicating them. Cost-effectiveness is not covered in this Review.

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Talasaz, A.H., Sadeghipour, P., Ortega-Paz, L. et al. Optimizing antithrombotic therapy in patients with coexisting cardiovascular and gastrointestinal disease. Nat Rev Cardiol 21, 574–592 (2024). https://doi.org/10.1038/s41569-024-01003-3

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