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  • Review Article
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Optimizing antithrombotic therapy in patients with coexisting cardiovascular and gastrointestinal disease

Nature Reviews Cardiology (2024)Cite this article

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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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References

  1. Mitrov-Winkelmolen, L. et al. The effect of Roux-en-Y gastric bypass surgery in morbidly obese patients on pharmacokinetics of (acetyl) salicylic acid and omeprazole: the ERY-PAO study. Obes. Surg. 26, 2051–2058 (2016).

    Article  PubMed  Google Scholar 

  2. Miedziaszczyk, M., Ciabach, P. & Szałek, E. The effects of bariatric surgery and gastrectomy on the absorption of drugs, vitamins, and mineral elements. Pharmaceutics 13, 2111 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Valgimigli, M. et al. Trade-off of myocardial infarction vs. bleeding types on mortality after acute coronary syndrome: lessons from the Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRACER) randomized trial. Eur. Heart J. 38, 804–810 (2017).

    CAS  PubMed  Google Scholar 

  4. Abraham, N. S. et al. American College of Gastroenterology-Canadian Association of Gastroenterology Clinical Practice Guideline: management of anticoagulants and antiplatelets during acute gastrointestinal bleeding and the periendoscopic period. J. Can. Assoc. Gastroenterol. 5, 100–101 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  5. Mehran, R. et al. Associations of major bleeding and myocardial infarction with the incidence and timing of mortality in patients presenting with non-ST-elevation acute coronary syndromes: a risk model from the ACUITY trial. Eur. Heart J. 30, 1457–1466 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  6. Yasuda, H. et al. Treatment and prevention of gastrointestinal bleeding in patients receiving antiplatelet therapy. World J. Crit. Care Med. 4, 40–46 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  7. Abrignani, M. G. et al. Gastroprotection in patients on antiplatelet and/or anticoagulant therapy: a position paper of National Association of Hospital Cardiologists (ANMCO) and the Italian Association of Hospital Gastroenterologists and Endoscopists (AIGO). Eur. J. Intern. Med. 85, 1–13 (2021).

    Article  CAS  PubMed  Google Scholar 

  8. Kido, K. & Scalese, M. J. Management of oral anticoagulation therapy after gastrointestinal bleeding: whether to, when to, and how to restart an anticoagulation therapy. Ann. Pharmacother. 51, 1000–1007 (2017).

    Article  CAS  PubMed  Google Scholar 

  9. Scott, M. J., Veitch, A. & Thachil, J. Reintroduction of anti‐thrombotic therapy after a gastrointestinal haemorrhage: if and when? Br. J. Haematol. 177, 185–197 (2017).

    Article  PubMed  Google Scholar 

  10. Sengupta, N. et al. Management of patients with acute lower gastrointestinal bleeding: an updated ACG guideline. Am. J. Gastroenterol. 118, 208–231 (2023).

    Article  PubMed  Google Scholar 

  11. Abraham, N. S. et al. American College of Gastroenterology-Canadian Association of Gastroenterology Clinical Practice Guideline: management of anticoagulants and antiplatelets during acute gastrointestinal bleeding and the periendoscopic period. Am. J. Gastroenterol. 117, 542–558 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Tomaselli, G. F. et al. 2020 ACC expert consensus decision pathway on management of bleeding in patients on oral anticoagulants: a report of the American College of Cardiology Solution Set Oversight Committee. J. Am. Coll. Cardiol. 76, 594–622 (2020).

    Article  CAS  PubMed  Google Scholar 

  13. European Association for the Study of the Liver EASL Clinical Practice Guidelines on prevention and management of bleeding and thrombosis in patients with cirrhosis. J. Hepatol. 76, 1151–1184 (2022).

    Article  Google Scholar 

  14. Sandercock, P. A., Counsell, C., Gubitz, G. J. & Tseng, M. C. Antiplatelet therapy for acute ischaemic stroke. Cochrane Database Syst. Rev. 1, CD000029 (2022).

    Google Scholar 

  15. Zafar, M. U., Farkouh, M. E., Fuster, V. & Chesebro, J. H. Crushed clopidogrel administered via nasogastric tube has faster and greater absorption than oral whole tablets. J. Interv. Cardiol. 22, 385–389 (2009).

    Article  PubMed  Google Scholar 

  16. Parodi, G. et al. Ticagrelor crushed tablets administration in STEMI patients: the MOJITO study. J. Am. Coll. Cardiol. 65, 511–512 (2015).

    Article  PubMed  Google Scholar 

  17. Rollini, F. et al. Crushed prasugrel tablets in patients with STEMI undergoing primary percutaneous coronary intervention: the CRUSH Study. J. Am. Coll. Cardiol. 67, 1994–2004 (2016).

    Article  CAS  PubMed  Google Scholar 

  18. Vlachojannis, G. J. et al. Effect of prehospital crushed prasugrel tablets in patients with ST-segment-elevation myocardial infarction planned for primary percutaneous coronary intervention: the randomized COMPARE CRUSH trial. Circulation 142, 2316–2328 (2020).

    Article  CAS  PubMed  Google Scholar 

  19. Gargiulo, G. et `al. Cangrelor, tirofiban, and chewed or standard prasugrel regimens in patients with ST-segment-elevation myocardial infarction: primary results of the FABOLUS-FASTER trial. Circulation 142, 441–454 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Angiolillo, D. J. et al. Bridging antiplatelet therapy with cangrelor in patients undergoing cardiac surgery. JAMA 307, 265–274 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Vaduganathan, M. et al. Cangrelor with and without glycoprotein IIb/IIIa inhibitors in patients undergoing percutaneous coronary intervention. J. Am. Coll. Cardiol. 69, 176–185 (2017).

    Article  CAS  PubMed  Google Scholar 

  22. Ferreira Silva, R. & Rita Carvalho Garbi Novaes, M. Interactions between drugs and drug-nutrient in enteral nutrition: a review based on evidences. Nutr. Hosp. 30, 514–518 (2014).

    PubMed  Google Scholar 

  23. Klang, M., Graham, D. & McLymont, V. Warfarin bioavailability with feeding tubes and enteral formula. JPEN J. Parenter. Enter. Nutr. 34, 300–304 (2010).

    Article  CAS  Google Scholar 

  24. Hankey, G. J. & Eikelboom, J. W. Dabigatran etexilate: a new oral thrombin inhibitor. Circulation 123, 1436–1450 (2011).

    Article  PubMed  Google Scholar 

  25. Peterson, J. J. & Hoehns, J. D. Administration of direct oral anticoagulants through enteral feeding tubes. J. Pharm. Technol. 32, 196–200 (2016).

    Article  CAS  PubMed Central  Google Scholar 

  26. Duchin, K. et al. An open-label crossover study of the pharmacokinetics of the 60-mg edoxaban tablet crushed and administered either by a nasogastric tube or in apple puree in healthy adults. Clin. Pharmacokinet. 57, 221–228 (2018).

    Article  CAS  PubMed  Google Scholar 

  27. Moore, K. T. et al. Rivaroxaban crushed tablet suspension characteristics and relative bioavailability in healthy adults when administered orally or via nasogastric tube. Clin. Pharmacol. Drug. Dev. 3, 321–327 (2014).

    Article  CAS  PubMed  Google Scholar 

  28. Hobl, E. L. et al. Morphine decreases clopidogrel concentrations and effects: a randomized, double-blind, placebo-controlled trial. J. Am. Coll. Cardiol. 63, 630–635 (2014).

    Article  CAS  PubMed  Google Scholar 

  29. McEvoy, J. W. et al. Effect of intravenous fentanyl on ticagrelor absorption and platelet inhibition among patients undergoing percutaneous coronary intervention: the PACIFY randomized clinical trial (Platelet Aggregation With Ticagrelor Inhibition and Fentanyl). Circulation 137, 307–309 (2018).

    Article  CAS  PubMed  Google Scholar 

  30. Iglesias, J. F. et al. Effects of fentanyl versus morphine on ticagrelor-induced platelet inhibition in patients with ST-segment elevation myocardial infarction: the PERSEUS randomized trial. Circulation 142, 2479–2481 (2020).

    Article  CAS  PubMed  Google Scholar 

  31. Tavenier, A. H. et al. Impact of opioids on P2Y12 receptor inhibition in patients with ST-elevation myocardial infarction who are pre-treated with crushed ticagrelor: Opioids aNd crushed Ticagrelor In Myocardial infarction Evaluation (ON-TIME 3) trial. Eur. Heart J. Cardiovasc. Pharmacother. 8, 4–12 (2022).

    Article  PubMed  Google Scholar 

  32. Fernando, H. et al. Effects of lignocaine vs. opioids on antiplatelet activity of ticagrelor: the LOCAL trial. Eur. Heart J. 42, 4025–4036 (2021).

    Article  CAS  PubMed  Google Scholar 

  33. Fernando, H. et al. Lidocine versus opioids in myocardial infarction: the AVOID-2 randomized controlled trial. Eur. Heart J. Acute Cardiovasc. Care 12, 2–11 (2023).

    Article  PubMed  Google Scholar 

  34. Holm, M. et al. The MOVEMENT trial. J. Am. Heart Assoc. 8, e010152 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Franchi, F. et al. Effects of methylnaltrexone on ticagrelor-induced antiplatelet effects in coronary artery disease patients treated with morphine. JACC Cardiovasc. Interv. 12, 1538–1549 (2019).

    Article  PubMed  Google Scholar 

  36. Niezgoda, P. et al. Oral naloxone to overcome the morphine effect in acute coronary syndrome patients treated with ticagrelor – NARCOTIC trial. Cardiol. J. 29, 432–440 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  37. Sikora, J. et al. Metoclopramide administration as a strategy to overcome morpHine-ticagrelor interaction in patients with unstable angina pectorIs – the METAMORPHOSIS trial. Thromb. Haemost. 118, 2126–2133 (2018).

    Article  PubMed  Google Scholar 

  38. Saad, M. et al. Impact of morphine treatment with and without metoclopramide coadministration on ticagrelor-induced platelet inhibition in acute myocardial infarction: the randomized MonAMI trial. Circulation 141, 1354–1356 (2020).

    Article  PubMed  Google Scholar 

  39. Siller-Matula, J. M. et al. Abciximab as a bridging strategy to overcome morphine-prasugrel interaction in STEMI patients. Br. J. Clin. Pharmacol. 82, 1343–1350 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Zwart, B. et al. Use of glycoprotein IIb/IIIa antagonists to prevent stent thrombosis in morphine-treated patients with ST-elevation myocardial infarction. Platelets 31, 174–178 (2020).

    Article  CAS  PubMed  Google Scholar 

  41. Wong, G. C. et al. 2019 Canadian Cardiovascular Society/Canadian Association of Interventional Cardiology guidelines on the acute management of ST-elevation myocardial infarction: focused update on regionalization and reperfusion. Can. J. Cardiol. 35, 107–132 (2019).

    Article  PubMed  Google Scholar 

  42. Byrne, R. A. et al. 2023 ESC Guidelines for the management of acute coronary syndromes. Eur. Heart J. 44, 3720–3826 (2023).

    Article  CAS  PubMed  Google Scholar 

  43. Droppa, M., Karathanos, A., Gawaz, M. & Geisler, T. Individualised dual antiplatelet therapy in a patient with short bowel syndrome after acute myocardial infarction with coronary artery stenting. BMJ Case Rep. 2015, bcr2014205227 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  44. Koltai, K., Kesmarky, G., Feher, G., Tibold, A. & Toth, K. Platelet aggregometry testing: molecular mechanisms, techniques and clinical implications. Int. J. Mol. Sci. 18, 1803 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  45. Yan, H. et al. The relationship among intestinal bacteria, vitamin K and response of vitamin K antagonist: a review of evidence and potential mechanism. Front. Med. 9, 829304 (2022).

    Article  Google Scholar 

  46. Sobieraj, D. M., Wang, F. & Kirton, O. C. Warfarin resistance after total gastrectomy and Roux-en-Y esophagojejunostomy. Pharmacotherapy 28, 1537–1541 (2008).

    Article  PubMed  Google Scholar 

  47. Strong, A. T. et al. Adjustments to warfarin dosing after gastric bypass and sleeve gastrectomy. Surg. Obes. Relat. Dis. 14, 700–706 (2018).

    Article  PubMed  Google Scholar 

  48. Grymonprez, M. et al. Impact of P-glycoprotein and CYP3A4-interacting drugs on clinical outcomes in patients with atrial fibrillation using non-vitamin K antagonist oral anticoagulants: a nationwide cohort study. Eur. Heart J. Cardiovasc. Pharmacother. 9, 722–730 (2023).

    Article  PubMed  Google Scholar 

  49. Cheung, Y. W. et al. Pharmacokinetics of dabigatran etexilate and rivaroxaban in patients with short bowel syndrome requiring parenteral nutrition: the PDER PAN study. Thromb. Res. 160, 76–82 (2017).

    Article  CAS  PubMed  Google Scholar 

  50. Grainger, B. et al. Evidence of impaired dabigatran absorption following laparoscopic Roux-en-Y gastric bypass surgery: the Auckland regional experience (2011-2018). Br. J. Haematol. 191, e67–e69 (2020).

    Article  CAS  PubMed  Google Scholar 

  51. Christensen, L. D., Vinter-Jensen, L., Rasmussen, H. H., Kristensen, S. R. & Larsen, T. B. Rivaroxaban as anticoagulant therapy in short bowel syndrome. Report of three cases. Thromb. Res. 135, 568–570 (2015).

    Article  CAS  PubMed  Google Scholar 

  52. Kröll, D. et al. Pharmacokinetics and pharmacodynamics of single doses of rivaroxaban in obese patients prior to and after bariatric surgery. Br. J. Clin. Pharmacol. 83, 1466–1475 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  53. Steele, K. E. et al. The APB study: apixaban pharmacokinetics in bariatric patients before to 1 year after vertical sleeve gastrectomy or Roux-en-Y gastric bypass. Surg. Obes. Relat. Dis. 18, 594–603 (2022).

    Article  PubMed  Google Scholar 

  54. Hakeam, H. A. & Al-Sanea, N. Effect of major gastrointestinal tract surgery on the absorption and efficacy of direct acting oral anticoagulants (DOACs). J. Thromb. Thrombolysis 43, 343–351 (2017).

    Article  CAS  PubMed  Google Scholar 

  55. Colquitt, J. L., Pickett, K., Loveman, E. & Frampton, G. K. Surgery for weight loss in adults. Cochrane Database Syst. Rev. 2014, CD003641 (2014).

    PubMed  PubMed Central  Google Scholar 

  56. Angrisani, L. et al. Bariatric surgery and endoluminal procedures: IFSO worldwide survey 2014. Obes. Surg. 27, 2279–2289 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Kingma, J. S. et al. Oral drug dosing following bariatric surgery: general concepts and specific dosing advice. Br. J. Clin. Pharmacol. 87, 4560–4576 (2021).

    Article  CAS  PubMed  Google Scholar 

  58. Azran, C. et al. Oral drug therapy following bariatric surgery: an overview of fundamentals, literature and clinical recommendations. Obes. Rev. 17, 1050–1066 (2016).

    Article  PubMed  Google Scholar 

  59. Rocca, B. et al. Antithrombotic therapy and body mass: an expert position paper of the ESC Working Group on Thrombosis. Eur. Heart J. 39, 1672–1686f (2018).

    Article  CAS  PubMed  Google Scholar 

  60. Norgard, N. B., Monte, S. V., Fernandez, S. F. & Ma, Q. Aspirin responsiveness changes in obese patients following bariatric surgery. Cardiovasc. Ther. 35, e12268 (2017).

    Article  Google Scholar 

  61. Caruana, J. A., McCabe, M. N., Smith, A. D., Panemanglore, V. P. & Sette Camara, D. Risk of massive upper gastrointestinal bleeding in gastric bypass patients taking clopidogrel. Surg. Obes. Relat. Dis. 3, 443–445 (2007).

    Article  PubMed  Google Scholar 

  62. Patel, P. H., Ho, T. & Upadhyay, S. M. A systematic review of warfarin use in post-bariatric surgery patients: cases compiled from a literature review. Ann. Pharmacother. 57, 193–197 (2023).

    Article  CAS  PubMed  Google Scholar 

  63. Rottenstreich, A., Barkai, A., Arad, A., Raccah, B. H. & Kalish, Y. The effect of bariatric surgery on direct-acting oral anticoagulant drug levels. Thrombosis Res. 163, 190–195 (2018).

    Article  CAS  Google Scholar 

  64. Leong, R., Chu, D. K., Crowther, M. A. & Mithoowani, S. J. Direct oral anticoagulants after bariatric surgery — what is the evidence? Thromb. Haemost. 20, 1988–2000 (2022).

    Article  CAS  Google Scholar 

  65. Kröll, D. et al. Efficacy and safety of rivaroxaban for postoperative thromboprophylaxis in patients after bariatric surgery. JAMA Netw. Open. 6, e2315241 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  66. Martin, K. A. et al. Use of direct oral anticoagulants in patients with obesity for treatment and prevention of venous thromboembolism: updated communication from the ISTH SSC Subcommittee on Control of Anticoagulation. J. Thromb. Haemost. 19, 1874–1882 (2021).

    Article  PubMed  Google Scholar 

  67. Decousus, H. et al. Factors at admission associated with bleeding risk in medical patients: findings from the IMPROVE investigators. Chest 139, 69–79 (2011).

    Article  PubMed  Google Scholar 

  68. Sostres, C., Gargallo, C. J. & Lanas, A. Nonsteroidal anti-inflammatory drugs and upper and lower gastrointestinal mucosal damage. Arthritis Res. Ther. 15, S3 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  69. Masclee, G. M. et al. Risk of upper gastrointestinal bleeding from different drug combinations. Gastroenterology 147, 784–792.e9 (2014).

    Article  CAS  PubMed  Google Scholar 

  70. Rostom, A. et al. Gastrointestinal safety of cyclooxygenase-2 inhibitors: a Cochrane Collaboration systematic review. Clin. Gastroenterol. Hepatol. 5, 818–828 (2007).

    Article  PubMed  Google Scholar 

  71. Ray, W. A. et al. Association of oral anticoagulants and proton pump inhibitor cotherapy with hospitalization for upper gastrointestinal tract bleeding. JAMA 320, 2221–2230 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Lanas, A., Wu, P., Medin, J. & Mills, E. J. Low doses of acetylsalicylic acid increase risk of gastrointestinal bleeding in a meta-analysis. Clin. Gastroenterol. Hepatol. 9, 762–768.e6 (2011).

    Article  CAS  PubMed  Google Scholar 

  73. Lanza, F. L., Royer, G. L. Jr. & Nelson, R. S. Endoscopic evaluation of the effects of aspirin, buffered aspirin, and enteric-coated aspirin on gastric and duodenal mucosa. N. Engl. J. Med. 303, 136–138 (1980).

    Article  CAS  PubMed  Google Scholar 

  74. Petroski, D. Endoscopic comparison of three aspirin preparations and placebo. Clin. Ther. 15, 314–320 (1993).

    CAS  PubMed  Google Scholar 

  75. Clerici, B. & Cattaneo, M. Pharmacological efficacy and gastrointestinal safety of different aspirin formulations for cardiovascular prevention: a narrative review. J. Cardiovasc. Dev. Dis. 10, 137 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Sleem, A. et al. Effectiveness and safety of enteric-coated vs uncoated aspirin in patients with cardiovascular disease: a secondary analysis of the ADAPTABLE randomized clinical trial. JAMA Cardiol. 8, 1061–1069 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  77. Mehta, S. R. et al. Dose comparisons of clopidogrel and aspirin in acute coronary syndromes. N. Engl. J. Med. 363, 930–942 (2010).

    Article  PubMed  Google Scholar 

  78. Carnicelli, A. P. et al. Direct oral anticoagulants versus warfarin in patients with atrial fibrillation: patient-level network meta-analyses of randomized clinical trials with interaction testing by age and sex. Circulation 145, 242–255 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Xu, Y. & Siegal, D. M. Anticoagulant-associated gastrointestinal bleeding: framework for decisions about whether, when and how to resume anticoagulants. J. Thromb. Haemost. 19, 2383–2393 (2021).

    Article  PubMed  Google Scholar 

  80. Costa, F. et al. Antithrombotic therapy according to baseline bleeding risk in patients with atrial fibrillation undergoing percutaneous coronary intervention: applying the PRECISE-DAPT score in RE-DUAL PCI. Eur. Heart J. Cardiovasc. Pharmacother. 8, 216–226 (2022).

    Article  PubMed  Google Scholar 

  81. Urban, P. et al. Defining high bleeding risk in patients undergoing percutaneous coronary intervention: a consensus document from the Academic Research Consortium for High Bleeding Risk. Eur. Heart J. 40, 2632–2653 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Lv, M. et al. A new score for predicting acute gastrointestinal bleeding in patients administered oral antiplatelet drugs. Front. Pharmacol. 11, 571605 (2020).

    Article  CAS  PubMed  Google Scholar 

  83. Bikdeli, B. et al. Clinical characteristics, time course, and outcomes of major bleeding according to bleeding site in patients with venous thromboembolism. Thromb. Res. 211, 10–18 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Catella, J. et al. Major gastrointestinal bleeding in patients receiving anticoagulant therapy for venous thromboembolism. Thromb. Res. 214, 29–36 (2022).

    Article  CAS  PubMed  Google Scholar 

  85. Mo, C. et al. Proton pump inhibitors in prevention of low-dose aspirin-associated upper gastrointestinal injuries. World J. Gastroenterol. 21, 5382–5392 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Bhatt, D. L. et al. Clopidogrel with or without omeprazole in coronary artery disease. N. Engl. J. Med. 363, 1909–1917 (2010).

    Article  CAS  PubMed  Google Scholar 

  87. Ng, F. H. et al. Famotidine is inferior to pantoprazole in preventing recurrence of aspirin-related peptic ulcers or erosions. Gastroenterology 138, 82–88 (2010).

    Article  CAS  PubMed  Google Scholar 

  88. Ng, F. H. et al. Esomeprazole compared with famotidine in the prevention of upper gastrointestinal bleeding in patients with acute coronary syndrome or myocardial infarction. Am. J. Gastroenterol. 107, 389–396 (2012).

    Article  CAS  PubMed  Google Scholar 

  89. Chan, F. K. et al. Similar efficacy of proton-pump inhibitors vs H2-receptor antagonists in reducing risk of upper gastrointestinal bleeding or ulcers in high-risk users of low-dose aspirin. Gastroenterol 152, 105–110.e1 (2017).

    Article  CAS  Google Scholar 

  90. Levine, G. N. et al. 2016 ACC/AHA guideline focused update on duration of dual antiplatelet therapy in patients with coronary artery disease: a report of the American College of Cardiology/American Heart Association task force on clinical practice guidelines: an update of the ACCF/AHA/SCAI guideline for percutaneous coronary intervention, 2011 ACCF/AHA guideline for coronary artery bypass graft surgery, 2012 ACC/AHA/ACP/AATS/PCNA/SCAI/STS guideline for the diagnosis and management of patients with stable ischemic heart disease, 2013 ACCF/AHA guideline for the management of st-elevation myocardial infarction, 2014 AHA/ACC guideline for the management of patients with non-ST-elevation acute coronary syndromes, and 2014 ACC/AHA guideline on perioperative cardiovascular evaluation and management of patients undergoing noncardiac surgery. Circulation 134, e123–e155 (2016).

    PubMed  Google Scholar 

  91. Virani, S. S. et al. 2023 AHA/ACC/ACCP/ASPC/NLA/PCNA guideline for the management of patients with chronic coronary disease: a report of the American Heart Association/American College of Cardiology Joint Committee on Clinical Practice Guidelines. Circulation 148, e9–e119 (2023).

    Article  PubMed  Google Scholar 

  92. Moayyedi, P. et al. Pantoprazole to prevent gastroduodenal events in patients receiving rivaroxaban and/or aspirin in a randomized, double-blind, placebo-controlled trial. Gastroenterology 157, 403–412.e5 (2019).

    Article  CAS  PubMed  Google Scholar 

  93. Weisz, G. et al. Proton pump inhibitors, platelet reactivity, and cardiovascular outcomes after drug-eluting stents in clopidogrel-treated patients: the ADAPT-DES study. Circ. Cardiovasc. Interv. 8, e001952 (2015).

    Article  CAS  PubMed  Google Scholar 

  94. Dunn, S. P. et al. Impact of proton pump inhibitor therapy on the efficacy of clopidogrel in the CAPRIE and CREDO trials. J. Am. Heart Assoc. 2, e004564 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  95. Charlot, M. et al. Proton-pump inhibitors are associated with increased cardiovascular risk independent of clopidogrel use: a nationwide cohort study. Ann. Intern. Med. 153, 378–386 (2010).

    Article  PubMed  Google Scholar 

  96. Demcsák, A. et al. PPIs are not responsible for elevating cardiovascular risk in patients on clopidogrel – a systematic review and meta-analysis. Front. Physiol. 9, 1550 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  97. Marx, N. et al. 2023 ESC Guidelines for the management of cardiovascular disease in patients with diabetes: developed by the task force on the management of cardiovascular disease in patients with diabetes of the European Society of Cardiology (ESC). Eur. Heart J. 44, 4043–4140 (2023).

    Article  CAS  PubMed  Google Scholar 

  98. Agewall, S. et al. Expert position paper on the use of proton pump inhibitors in patients with cardiovascular disease and antithrombotic therapy. Eur. Heart J. 34, 1708–1713 (2013).

    Article  PubMed  Google Scholar 

  99. Reddy, V. Y. et al. Percutaneous left atrial appendage closure vs warfarin for atrial fibrillation: a randomized clinical trial. JAMA 312, 1988–1998 (2014).

    Article  PubMed  Google Scholar 

  100. Holmes, D. R. Jr. et al. Prospective randomized evaluation of the Watchman left atrial appendage closure device in patients with atrial fibrillation versus long-term warfarin therapy: the PREVAIL trial. J. Am. Coll. Cardiol. 64, 1–12 (2014).

    Article  PubMed  Google Scholar 

  101. Osmancik, P. et al. Left atrial appendage closure versus direct oral anticoagulants in high-risk patients with atrial fibrillation. J. Am. Coll. Cardiol. 75, 3122–3135 (2020).

    Article  CAS  PubMed  Google Scholar 

  102. Caliskan, E. et al. Interventional and surgical occlusion of the left atrial appendage. Nat. Rev. Cardiol. 14, 727–743 (2017).

    Article  PubMed  Google Scholar 

  103. Costa, R. A. et al. Polymer-free biolimus A9-coated stents in the treatment of de novo coronary lesions: 4- and 12-month angiographic follow-up and final 5-year clinical outcomes of the prospective, multicenter biofreedom FIM clinical trial. JACC Cardiovasc. Interv. 9, 51–64 (2016).

    Article  PubMed  Google Scholar 

  104. Hamon, M. et al. Clinical and angiographic experience with a third-generation drug-eluting Orsiro stent in the treatment of single de novo coronary artery lesions (BIOFLOW-I): a prospective, first-in-man study. EuroIntervention 8, 1006–1011 (2013).

    Article  PubMed  Google Scholar 

  105. Bikdeli, B. et al. Inferior vena cava filters to prevent pulmonary embolism: systematic review and meta-analysis. J. Am. Coll. Cardiol. 70, 1587–1597 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  106. Bikdeli B., et al. Developmental or procedural vena cava interruption and venous thromboembolism: a review. Semin. Thromb. Hemost. https://doi.org/10.1055/s-0043-1777991 (2024).

  107. De Caterina, R. et al. Great debate: triple antithrombotic therapy in patients with atrial fibrillation undergoing coronary stenting should be limited to 1 week. Eur. Heart J. 43, 3512–3527 (2022).

    Article  PubMed  Google Scholar 

  108. Gargiulo, G. et al. Safety and efficacy outcomes of double vs. triple antithrombotic therapy in patients with atrial fibrillation following percutaneous coronary intervention: a systematic review and meta-analysis of non-vitamin K antagonist oral anticoagulant-based randomized clinical trials. Eur. Heart J. 40, 3757–3767 (2019).

    Article  CAS  PubMed  Google Scholar 

  109. Alexander, J. H. et al. Risk/benefit tradeoff of antithrombotic therapy in patients with atrial fibrillation early and late after an acute coronary syndrome or percutaneous coronary intervention: insights from AUGUSTUS. Circulation 141, 1618–1627 (2020).

    Article  PubMed  Google Scholar 

  110. Vranckx, P. et al. Edoxaban-based versus vitamin K antagonist-based antithrombotic regimen after successful coronary stenting in patients with atrial fibrillation (ENTRUST-AF PCI): a randomised, open-label, phase 3b trial. Lancet 394, 1335–1343 (2019).

    Article  CAS  PubMed  Google Scholar 

  111. Lopes, R. D. et al. Antithrombotic therapy after acute coronary syndrome or PCI in atrial fibrillation. N. Engl. J. Med. 380, 1509–1524 (2019).

    Article  CAS  PubMed  Google Scholar 

  112. Gibson, C. M. et al. Prevention of bleeding in patients with atrial fibrillation undergoing PCI. N. Engl. J. Med. 375, 2423–2434 (2016).

    Article  CAS  PubMed  Google Scholar 

  113. Cannon, C. P. et al. Dual antithrombotic therapy with dabigatran after PCI in atrial fibrillation. N. Engl. J. Med. 377, 1513–1524 (2017).

    Article  CAS  PubMed  Google Scholar 

  114. Kumbhani, D. J. et al. 2020 ACC expert consensus decision pathway for anticoagulant and antiplatelet therapy in patients with atrial fibrillation or venous thromboembolism undergoing percutaneous coronary intervention or with atherosclerotic cardiovascular disease: a report of the American College of Cardiology Solution Set Oversight Committee. J. Am. Coll. Cardiol. 77, 629–658 (2021).

    Article  PubMed  Google Scholar 

  115. Angiolillo, D. J. et al. Antithrombotic therapy in patients with atrial fibrillation treated with oral anticoagulation undergoing percutaneous coronary intervention: a North American Perspective: 2021 update. Circulation 143, 583–596 (2021).

    Article  CAS  PubMed  Google Scholar 

  116. Schaefer, J. K. et al. Adverse events associated with the addition of aspirin to direct oral anticoagulant therapy without a clear indication. JAMA Intern. Med. 181, 817–824 (2021).

    Article  CAS  PubMed  Google Scholar 

  117. Schaefer, J. K. et al. Association of adding aspirin to warfarin therapy without an apparent indication with bleeding and other adverse events. JAMA Intern. Med. 179, 533–541 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  118. Akao, M. et al. Rivaroxaban monotherapy versus combination therapy according to patient risk of stroke and bleeding in atrial fibrillation and stable coronary disease: AFIRE trial subanalysis. Am. Heart J. 236, 59–68 (2021).

    Article  CAS  PubMed  Google Scholar 

  119. Gragnano, F. et al. P2Y12 inhibitor or aspirin monotherapy for secondary prevention of coronary events. J. Am. Coll. Cardiol. 82, 89–105 (2023).

    Article  CAS  PubMed  Google Scholar 

  120. Patti, G. et al. Outcomes of anticoagulated patients with atrial fibrillation treated with or without antiplatelet therapy – a pooled analysis from the PREFER in AF and PREFER in AF PROLONGATON registries. Int. J. Cardiol. 270, 160–166 (2018).

    Article  PubMed  Google Scholar 

  121. Yasuda, S. et al. Antithrombotic therapy for atrial fibrillation with stable coronary disease. N. Engl. J. Med. 381, 1103–1113 (2019).

    Article  CAS  PubMed  Google Scholar 

  122. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT05627375 (2023).

  123. CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 348, 1329–1339 (1996).

    Article  Google Scholar 

  124. Bhatt, D. L., Hirsch, A. T., Ringleb, P. A., Hacke, W. & Topol, E. J. Reduction in the need for hospitalization for recurrent ischemic events and bleeding with clopidogrel instead of aspirin. CAPRIE investigators. Am. Heart J. 140, 67–73 (2000).

    Article  CAS  PubMed  Google Scholar 

  125. McQuaid, K. R. & Laine, L. Systematic review and meta-analysis of adverse events of low-dose aspirin and clopidogrel in randomized controlled trials. Am. J. Med. 119, 624–638 (2006).

    Article  CAS  PubMed  Google Scholar 

  126. Wallentin, L. et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N. Engl. J. Med. 361, 1045–1057 (2009).

    Article  CAS  PubMed  Google Scholar 

  127. Wiviott, S. D. et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N. Engl. J. Med. 357, 2001–2015 (2007).

    Article  CAS  PubMed  Google Scholar 

  128. Hiatt, W. R. et al. Ticagrelor versus clopidogrel in symptomatic peripheral artery disease. N. Engl. J. Med. 376, 32–40 (2017).

    Article  CAS  PubMed  Google Scholar 

  129. Hochholzer, W. et al. Predictors of bleeding and time dependence of association of bleeding with mortality: insights from the trial to assess improvement in therapeutic outcomes by optimizing platelet inhibition with prasugrel-thrombolysis in myocardial infarction 38 (TRITON-TIMI 38). Circulation 123, 2681–2689 (2011).

    Article  PubMed  Google Scholar 

  130. Guo, C. G. et al. Systematic review with meta-analysis: the risk of gastrointestinal bleeding in patients taking third-generation P2Y12 inhibitors compared with clopidogrel. Aliment. Pharmacol. Ther. 49, 7–19 (2019).

    Article  CAS  PubMed  Google Scholar 

  131. Koo, B. K. et al. Aspirin versus clopidogrel for chronic maintenance monotherapy after percutaneous coronary intervention (HOST-EXAM): an investigator-initiated, prospective, randomised, open-label, multicentre trial. Lancet 397, 2487–2496 (2021).

    Article  CAS  PubMed  Google Scholar 

  132. Nguyen, T. A., Diodati, J. G. & Pharand, C. Resistance to clopidogrel: a review of the evidence. J. Am. Coll. Cardiol. 45, 1157–1164 (2005).

    Article  CAS  PubMed  Google Scholar 

  133. Giugliano, R. P. et al. Edoxaban versus warfarin in patients with atrial fibrillation. N. Engl. J. Med. 369, 2093–2104 (2013).

    Article  CAS  PubMed  Google Scholar 

  134. Patel, M. R. et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N. Engl. J. Med. 365, 883–891 (2011).

    Article  CAS  PubMed  Google Scholar 

  135. Connolly, S. J. et al. Dabigatran versus warfarin in patients with atrial fibrillation. N. Engl. J. Med. 361, 1139–1151 (2009).

    Article  CAS  PubMed  Google Scholar 

  136. Schulman, S. et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N. Engl. J. Med. 361, 2342–2352 (2009).

    Article  CAS  PubMed  Google Scholar 

  137. Schulman, S. et al. Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis. Circulation 129, 764–772 (2014).

    Article  CAS  PubMed  Google Scholar 

  138. Agnelli, G. et al. Oral apixaban for the treatment of acute venous thromboembolism. N. Engl. J. Med. 369, 799–808 (2013).

    Article  CAS  PubMed  Google Scholar 

  139. Young, A. M. et al. Comparison of an oral factor Xa inhibitor with low molecular weight heparin in patients with cancer with venous thromboembolism: results of a randomized trial (SELECT-D). J. Clin. Oncol. 36, 2017–2023 (2018).

    Article  CAS  PubMed  Google Scholar 

  140. Raskob, G. E. et al. Edoxaban for the treatment of cancer-associated venous thromboembolism. N. Engl. J. Med. 378, 615–624 (2018).

    Article  CAS  PubMed  Google Scholar 

  141. Agnelli, G. et al. Apixaban for the treatment of venous thromboembolism associated with cancer. N. Engl. J. Med. 382, 1599–1607 (2020).

    Article  CAS  PubMed  Google Scholar 

  142. Halvorsen, S. et al. Management of antithrombotic therapy after bleeding in patients with coronary artery disease and/or atrial fibrillation: expert consensus paper of the European Society of Cardiology Working Group on Thrombosis. Eur. Heart J. 38, 1455–1462 (2017).

    CAS  PubMed  Google Scholar 

  143. Gralnek, I. M. et al. Diagnosis and management of nonvariceal upper gastrointestinal hemorrhage: European Society of Gastrointestinal Endoscopy (ESGE) guideline. Endoscopy 47, a1–a46 (2015).

    Article  PubMed  Google Scholar 

  144. Ray, W. A. et al. Association of proton pump inhibitors with reduced risk of warfarin-related serious upper gastrointestinal bleeding. Gastroenterology 151, 1105–1112.e10 (2016).

    Article  CAS  PubMed  Google Scholar 

  145. Sung, J. J. et al. Asia-Pacific working group consensus on non-variceal upper gastrointestinal bleeding: an update 2018. Gut 67, 1757–1768 (2018).

    Article  PubMed  Google Scholar 

  146. Qureshi, W. et al. Restarting anticoagulation and outcomes after major gastrointestinal bleeding in atrial fibrillation. Am. J. Cardiol. 113, 662–668 (2014).

    Article  CAS  PubMed  Google Scholar 

  147. Gralnek, I. M. et al. Endoscopic diagnosis and management of nonvariceal upper gastrointestinal hemorrhage (NVUGIH): European Society of Gastrointestinal Endoscopy (ESGE) guideline – update 2021. Endoscopy 53, 300–332 (2021).

    Article  PubMed  Google Scholar 

  148. Gralnek, I. M. et al. Endoscopic diagnosis and management of esophagogastric variceal hemorrhage: European Society of Gastrointestinal Endoscopy (ESGE) guideline. Endoscopy 54, 1094–1120 (2022).

    Article  PubMed  Google Scholar 

  149. Sung, J. J. et al. Continuation of low-dose aspirin therapy in peptic ulcer bleeding: a randomized trial. Ann. Intern. Med. 152, 1–9 (2010).

    Article  PubMed  Google Scholar 

  150. Forrest, J. A., Finlayson, N. D. & Shearman, D. J. Endoscopy in gastrointestinal bleeding. Lancet 2, 394–397 (1974). Aug 17.

    Article  CAS  PubMed  Google Scholar 

  151. de Groot, N. L. et al. Reassessment of the predictive value of the Forrest classification for peptic ulcer rebleeding and mortality: can classification be simplified? Endoscopy 46, 46–52 (2014).

    PubMed  Google Scholar 

  152. Sherwood, M. W. et al. Gastrointestinal bleeding in patients with atrial fibrillation treated with rivaroxaban or warfarin: ROCKET AF trial. J. Am. Coll. Cardiol. 66, 2271–2281 (2015).

    Article  CAS  PubMed  Google Scholar 

  153. Aisenberg, J. et al. Gastrointestinal bleeding with edoxaban versus warfarin: results from the ENGAGE AF-TIMI 48 trial (effective anticoagulation with factor Xa next generation in atrial fibrillation-thrombolysis in myocardial infarction). Circ. Cardiovasc. Qual. Outcomes 11, e003998 (2018).

    Article  PubMed  Google Scholar 

  154. Garcia, D. A. et al. Gastrointestinal bleeding in patients with atrial fibrillation treated with apixaban or warfarin: insights from the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial. Am. Heart J. 221, 1–8 (2020).

    Article  CAS  PubMed  Google Scholar 

  155. Witt, D. M. et al. Risk of thromboembolism, recurrent hemorrhage, and death after warfarin therapy interruption for gastrointestinal tract bleeding. Arch. Intern. Med. 172, 1484–1491 (2012).

    Article  CAS  PubMed  Google Scholar 

  156. Little, D. H. W. et al. Rates of rebleeding, thrombosis and mortality associated with resumption of anticoagulant therapy after anticoagulant-related bleeding. CMAJ 193, E304–E309 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Little, D. et al. Resumption of anticoagulant therapy after anticoagulant-related gastrointestinal bleeding: a systematic review and meta-analysis. Thromb. Res. 175, 102–109 (2019).

    Article  CAS  PubMed  Google Scholar 

  158. Candeloro, M. et al. Recurrent bleeding and thrombotic events after resumption of oral anticoagulants following gastrointestinal bleeding: communication from the ISTH SSC Subcommittee on Control of Anticoagulation. J. Thromb. Haemost. 19, 2618–2628 (2021).

    Article  CAS  PubMed  Google Scholar 

  159. Staerk, L. et al. Stroke and recurrent haemorrhage associated with antithrombotic treatment after gastrointestinal bleeding in patients with atrial fibrillation: nationwide cohort study. BMJ 351, h5876 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  160. Little, D. H. W. et al. Management of antithrombotic therapy after gastrointestinal bleeding: a mixed methods study of health-care providers. J. Thromb. Haemost. 19, 153–160 (2021).

    Article  PubMed  Google Scholar 

  161. Nieto, J. A. et al. Acute venous thromboembolism in patients with recent major bleeding. The influence of the site of bleeding and the time elapsed on outcome. J. Thromb. Haemost. 4, 2367–2372 (2006).

    Article  CAS  PubMed  Google Scholar 

  162. Burnett, A. E. & Barnes, G. D. A call to action for anticoagulation stewardship. Res. Pract. Thromb. Haemost. 6, e12757 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  163. Capodanno, D. et al. Bleeding avoidance strategies in percutaneous coronary intervention. Nat. Rev. Cardiol. 19, 117–132 (2022).

    Article  PubMed  Google Scholar 

  164. Angiolillo, D. J. et al. Pharmacokinetic and pharmacodynamic profile of a novel phospholipid aspirin formulation. Clin. Pharmacokinet. 61, 465–479 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Cryer, B. et al. Low-dose aspirin-induced ulceration is attenuated by aspirin-phosphatidylcholine: a randomized clinical trial. Am. J. Gastroenterol. 106, 272–277 (2011).

    Article  CAS  PubMed  Google Scholar 

  166. Storey, R. F. et al. Pharmacodynamics, pharmacokinetics, and safety of single-dose subcutaneous administration of selatogrel, a novel P2Y12 receptor antagonist, in patients with chronic coronary syndromes. Eur. Heart J. 41, 3132–3140 (2020).

    Article  CAS  PubMed  Google Scholar 

  167. Bhatt, D. L. et al. Antibody-based ticagrelor reversal agent in healthy volunteers. N. Engl. J. Med. 380, 1825–1833 (2019).

    Article  CAS  PubMed  Google Scholar 

  168. Gurbel, P. A., Bliden, K. P., Chaudhary, R. & Tantry, U. S. First in-human experience with inhaled acetylsalicylic acid for immediate platelet inhibition: comparison with chewed and swallowed acetylsalicylic acid. Circulation 142, 1305–1307 (2020).

    Article  CAS  PubMed  Google Scholar 

  169. Vivas, D. et al. Effects of intravenous lysine acetylsalicylate versus oral aspirin on platelet responsiveness in patients with ST-segment elevation myocardial infarction: the ECCLIPSE-STEMI trial. J. Thromb. Thrombolysis 55, 203–210 (2023).

    Article  CAS  PubMed  Google Scholar 

  170. Parodi, G. et al. Orodispersible ticagrelor in acute coronary syndromes: the TASTER study. J. Am. Coll. Cardiol. 78, 292–294 (2021).

    Article  CAS  PubMed  Google Scholar 

  171. Rai, V., Balters, M. W. & Agrawal, D. K. Factors IX, XI, and XII: potential therapeutic targets for anticoagulant therapy in atherothrombosis. Rev. Cardiovasc. Med. 20, 245–253 (2019).

    Article  PubMed  Google Scholar 

  172. Nickel, K. F., Long, A. T., Fuchs, T. A., Butler, L. M. & Renné, T. Factor XII as a therapeutic target in thromboembolic and inflammatory diseases. Arterioscler. Thromb. Vasc. Biol. 37, 13–20 (2017).

    Article  CAS  PubMed  Google Scholar 

  173. Nopp, S., Kraemmer, D. & Ay, C. Factor XI inhibitors for prevention and treatment of venous thromboembolism: a review on the rationale and update on current evidence. Front. Cardiovasc. Med. 9, 903029 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. De Caterina, R., Prisco, D. & Eikelboom, J. W. Factor XI inhibitors: cardiovascular perspectives. Eur. Heart J. 44, 280–292 (2023).

    Article  PubMed  Google Scholar 

  175. Bikdeli, B. et al. Sulodexide versus control and the risk of thrombotic and hemorrhagic events: meta-analysis of randomized trials. Semin. Thromb. Hemost. 46, 908–918 (2020).

    Article  CAS  PubMed  Google Scholar 

  176. Chan, F. K. L. et al. Management of patients on antithrombotic agents undergoing emergency and elective endoscopy: joint Asian Pacific Association of Gastroenterology (APAGE) and Asian Pacific Society for Digestive Endoscopy (APSDE) practice guidelines. Gut 67, 405–417 (2018).

    Article  CAS  PubMed  Google Scholar 

  177. Uchiyama, S., Tanahashi, N. & Minematsu, K. Clopidogrel two doses comparative 1-year assessment of safety and efficacy (COMPASS) study in Japanese patients with ischemic stroke. Cerebrovasc. Dis. 34, 229–239 (2012).

    Article  CAS  PubMed  Google Scholar 

  178. Becker, R. C. et al. Bleeding complications with the P2Y12 receptor antagonists clopidogrel and ticagrelor in the Platelet Inhibition and Patient Outcomes (PLATO) trial. Eur. Heart J. 32, 2933–2944 (2011).

    Article  CAS  PubMed  Google Scholar 

  179. Granger, C. B. et al. Apixaban versus warfarin in patients with atrial fibrillation. N. Engl. J. Med. 365, 981–992 (2011).

    Article  CAS  PubMed  Google Scholar 

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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.

Author information

Authors and Affiliations

  1. Arnold & Marie Schwartz College of Pharmacy and Health Sciences, Department of Pharmacy Practice, Long Island University, New York, NY, USA

    Azita H. Talasaz

  2. Division of Pharmacy, New York-Presbyterian/Columbia University Irvine Medical Center, New York, NY, USA

    Azita H. Talasaz

  3. Department of Pharmacotherapy and Outcome Sciences, Virginia Commonwealth University, Richmond, VA, USA

    Azita H. Talasaz & Benjamin W. Van Tassell

  4. Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran

    Parham Sadeghipour & Hessam Kakavand

  5. Division of Cardiology, University of Florida College of Medicine, Jacksonville, FL, USA

    Luis Ortega-Paz & Dominick J. Angiolillo

  6. Department of Clinical Pharmacy, School of Pharmacy, Iran University of Medical Sciences, Tehran, Iran

    Hessam Kakavand

  7. Tehran Heart Center, Tehran University of Medical Sciences, Tehran, Iran

    Maryam Aghakouchakzadeh

  8. University of Kentucky College of Pharmacy, Lexington, KY, USA

    Craig Beavers

  9. Department of Pharmacy, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    John Fanikos

  10. Population Health Research Institute, Hamilton Health Sciences, McMaster University, Hamilton, Ontario, Canada

    John W. Eikelboom

  11. Division of Hematology, Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada

    Deborah M. Siegal

  12. Department of Internal Medicine, Hospital Universitari Germans Trials i Pujol, Universidad Católica San Antonio de Murcia, Barcelona, Spain

    Manuel Monreal

  13. Respiratory Department, Hospital Ramón y Cajal and Medicine Department, Universidad de Alcalá (IRYCIS), Centro de Investigación Biomédica en Red de Enfermedades Respiratorias, ISCIII, Madrid, Spain

    David Jimenez

  14. Cardiovascular Medicine Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    Muthiah Vaduganathan, Gregory Piazza, Samuel Z. Goldhaber & Behnood Bikdeli

  15. Department of Medicine, Ottawa Hospital Research Institute at the University of Ottawa, Ottawa, Ontario, Canada

    Lana A. Castellucci

  16. Department of Medicine and Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Adam Cuker

  17. Frankel Cardiovascular Center, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA

    Geoffrey D. Barnes

  18. Hematology Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    Jean M. Connors

  19. Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA

    Eric A. Secemsky

  20. Smith Center for Outcomes Research in Cardiology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA

    Eric A. Secemsky

  21. Penn Cardiovascular Outcomes, Quality, & Evaluative Research Center, Cardiovascular Medicine Division, Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Eric A. Secemsky

  22. Cardiology Division, Pisa University Hospital, Pisa, Italy

    Raffaele De Caterina

  23. Fondazione Villa Serena per la Ricerca, Città Sant’Angelo, Pescara, Italy

    Raffaele De Caterina

  24. Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA

    Jacob E. Kurlander

  25. Institute for Healthcare Policy and Innovation, University of Michigan, Ann Arbor, MI, USA

    Jacob E. Kurlander

  26. VA Ann Arbor Center for Clinical Management Research, Ann Arbor, MI, USA

    Jacob E. Kurlander & Behnood Bikdeli

  27. Bariatric and Metabolic Institute, Department of General Surgery, Cleveland Clinic, Cleveland, OH, USA

    Ali Aminian

  28. Thrombosis Research Group, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    Gregory Piazza & Samuel Z. Goldhaber

  29. F. Edward Hébert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD, USA

    Lisa Moores

  30. Department of Internal Medicine, Radboud Institute of Health Sciences (RIHS), Radboud University Medical Center, Nijmegen, Netherlands

    Saskia Middeldorp

  31. Cardiovascular Research Foundation, New York, NY, USA

    Ajay J. Kirtane

  32. Division of Cardiology, New York-Presbyterian Hospital/Columbia University Irving Medical Center, New York, NY, USA

    Ajay J. Kirtane

  33. Department of Neurology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA

    Mitchell S. V. Elkind

  34. Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA

    Mitchell S. V. Elkind

  35. Center for Thrombosis and Hemostasis, Johannes Gutenberg, University of Mainz, Mainz, Germany

    Stavros Konstantinides

  36. Liverpool Centre for Cardiovascular Science at University of Liverpool, Liverpool John Moores University and Liverpool Heart and Chest Hospital, Liverpool, UK

    Gregory Y. H. Lip

  37. Danish Center for Health Services Research, Department of Clinical Medicine, Aalborg University, Aalborg, Denmark

    Gregory Y. H. Lip

  38. Mount Sinai Heart, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Gregg W. Stone, Roxana Mehran & Deepak L. Bhatt

  39. University of Vermont Medical Center, Burlington, VT, USA

    Mary Cushman

  40. Yale New Haven Hospital/Yale Center for Outcomes Research and Evaluation, New Haven, CT, USA

    Harlan M. Krumholz & Behnood Bikdeli

  41. Department of Health Policy and Management, Yale School of Public Health, New Haven, CT, USA

    Harlan M. Krumholz

  42. Section of Cardiovascular Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA

    Harlan M. Krumholz

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  1. Azita H. Talasaz
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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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Review criteria

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 (2024). https://doi.org/10.1038/s41569-024-01003-3

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