Official reprint from UpToDate®
www.uptodate.com ©2017 UpToDate®

Triple antithrombotic therapy in patients with cardiovascular disease

Nikolaus Sarafoff, MD
David R Holmes, Jr, MD
Section Editors
Christopher P Cannon, MD
Donald Cutlip, MD
Deputy Editor
Gordon M Saperia, MD, FACC


Some patients with cardiovascular disease have indications for anticoagulant and dual antiplatelet therapy. It is estimated that between 5 and 10 percent of patients scheduled for coronary artery stenting, and who thus require dual antiplatelet therapy, are receiving oral anticoagulation (OAC), most often for atrial fibrillation [1,2]. The concomitant use of dual antiplatelet therapy using aspirin and a platelet P2Y12 receptor blocker and OAC is referred to as triple oral antithrombotic therapy (triple therapy). While the use of three antithrombotic agents reduces the rate of ischemic events, the risk of bleeding is significantly increased compared to one or two antithrombotic agents.

Formulating recommendations for the duration of antithrombotic therapy in patients with indications for triple therapy is a complicated process, in part because there is a broad range for the benefit (prevention of ischemic events) to risk (bleeding) ratio. Since the evidence base upon which recommendations can be made is weak, our recommendations represent consensus of our experts in some cases and a range of approaches in others.

This topic will provide the rationale for the use of triple therapy and will discuss its clinical use. Indications for either dual antiplatelet therapy (DAPT) or OAC in patients with cardiovascular disease are discussed extensively elsewhere:

DAPT after stent implantation. (See "Antithrombotic therapy for elective percutaneous coronary intervention: General use".)

DAPT after an acute coronary syndrome. (See "Antiplatelet agents in acute non-ST elevation acute coronary syndromes", section on 'Summary and recommendations' and "Antiplatelet agents in acute ST elevation myocardial infarction", section on 'Summary and recommendations'.)


Subscribers log in here

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information or to purchase a personal subscription, click below on the option that best describes you:
Literature review current through: Dec 2016. | This topic last updated: Wed Jul 13 00:00:00 GMT+00:00 2016.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2017 UpToDate, Inc.
  1. Schömig A, Sarafoff N, Seyfarth M. Triple antithrombotic management after stent implantation: when and how? Heart 2009; 95:1280.
  2. Holmes DR Jr, Kereiakes DJ, Kleiman NS, et al. Combining antiplatelet and anticoagulant therapies. J Am Coll Cardiol 2009; 54:95.
  3. Dewilde WJ, Oirbans T, Verheugt FW, et al. Use of clopidogrel with or without aspirin in patients taking oral anticoagulant therapy and undergoing percutaneous coronary intervention: an open-label, randomised, controlled trial. Lancet 2013; 381:1107.
  4. Karjalainen PP, Porela P, Ylitalo A, et al. Safety and efficacy of combined antiplatelet-warfarin therapy after coronary stenting. Eur Heart J 2007; 28:726.
  5. Sambola A, Ferreira-González I, Angel J, et al. Therapeutic strategies after coronary stenting in chronically anticoagulated patients: the MUSICA study. Heart 2009; 95:1483.
  6. Lamberts M, Gislason GH, Olesen JB, et al. Oral anticoagulation and antiplatelets in atrial fibrillation patients after myocardial infarction and coronary intervention. J Am Coll Cardiol 2013; 62:981.
  7. Ruiz-Nodar JM, Marín F, Hurtado JA, et al. Anticoagulant and antiplatelet therapy use in 426 patients with atrial fibrillation undergoing percutaneous coronary intervention and stent implantation implications for bleeding risk and prognosis. J Am Coll Cardiol 2008; 51:818.
  8. Sarafoff N, Ndrepepa G, Mehilli J, et al. Aspirin and clopidogrel with or without phenprocoumon after drug eluting coronary stent placement in patients on chronic oral anticoagulation. J Intern Med 2008; 264:472.
  9. Fiedler KA, Maeng M, Mehilli J, et al. Duration of Triple Therapy in Patients Requiring Oral Anticoagulation After Drug-Eluting Stent Implantation: The ISAR-TRIPLE Trial. J Am Coll Cardiol 2015; 65:1619.
  10. Hansen ML, Sørensen R, Clausen MT, et al. Risk of bleeding with single, dual, or triple therapy with warfarin, aspirin, and clopidogrel in patients with atrial fibrillation. Arch Intern Med 2010; 170:1433.
  11. D'Ascenzo F, Taha S, Moretti C, et al. Meta-analysis of randomized controlled trials and adjusted observational results of use of clopidogrel, aspirin, and oral anticoagulants in patients undergoing percutaneous coronary intervention. Am J Cardiol 2015; 115:1185.
  12. Sørensen R, Hansen ML, Abildstrom SZ, et al. Risk of bleeding in patients with acute myocardial infarction treated with different combinations of aspirin, clopidogrel, and vitamin K antagonists in Denmark: a retrospective analysis of nationwide registry data. Lancet 2009; 374:1967.
  13. Rubboli A, Halperin JL, Airaksinen KE, et al. Antithrombotic therapy in patients treated with oral anticoagulation undergoing coronary artery stenting. An expert consensus document with focus on atrial fibrillation. Ann Med 2008; 40:428.
  14. Porter A, Konstantino Y, Iakobishvili Z, et al. Short-term triple therapy with aspirin, warfarin, and a thienopyridine among patients undergoing percutaneous coronary intervention. Catheter Cardiovasc Interv 2006; 68:56.
  15. Hermosillo AJ, Spinler SA. Aspirin, clopidogrel, and warfarin: is the combination appropriate and effective or inappropriate and too dangerous? Ann Pharmacother 2008; 42:790.
  16. Khurram Z, Chou E, Minutello R, et al. Combination therapy with aspirin, clopidogrel and warfarin following coronary stenting is associated with a significant risk of bleeding. J Invasive Cardiol 2006; 18:162.
  17. Orford JL, Fasseas P, Melby S, et al. Safety and efficacy of aspirin, clopidogrel, and warfarin after coronary stent placement in patients with an indication for anticoagulation. Am Heart J 2004; 147:463.
  18. Nguyen MC, Lim YL, Walton A, et al. Combining warfarin and antiplatelet therapy after coronary stenting in the Global Registry of Acute Coronary Events: is it safe and effective to use just one antiplatelet agent? Eur Heart J 2007; 28:1717.
  19. Ndrepepa G, Berger PB, Mehilli J, et al. Periprocedural bleeding and 1-year outcome after percutaneous coronary interventions: appropriateness of including bleeding as a component of a quadruple end point. J Am Coll Cardiol 2008; 51:690.
  20. Roy P, Bonello L, Torguson R, et al. Impact of "nuisance" bleeding on clopidogrel compliance in patients undergoing intracoronary drug-eluting stent implantation. Am J Cardiol 2008; 102:1614.
  21. Jolly SS, Pogue J, Haladyn K, et al. Effects of aspirin dose on ischaemic events and bleeding after percutaneous coronary intervention: insights from the PCI-CURE study. Eur Heart J 2009; 30:900.
  22. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2014; 64:e1.
  23. Authors/Task Force members, Windecker S, Kolh P, et al. 2014 ESC/EACTS Guidelines on myocardial revascularization: The Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS)Developed with the special contribution of the European Association of Percutaneous Cardiovascular Interventions (EAPCI). Eur Heart J 2014; 35:2541.
  24. Rossini R, Musumeci G, Lettieri C, et al. Long-term outcomes in patients undergoing coronary stenting on dual oral antiplatelet treatment requiring oral anticoagulant therapy. Am J Cardiol 2008; 102:1618.
  25. Schulz S, Schuster T, Mehilli J, et al. Stent thrombosis after drug-eluting stent implantation: incidence, timing, and relation to discontinuation of clopidogrel therapy over a 4-year period. Eur Heart J 2009; 30:2714.
  26. Ruiz-Nodar JM, Marín F, Sánchez-Payá J, et al. Efficacy and safety of drug-eluting stent use in patients with atrial fibrillation. Eur Heart J 2009; 30:932.
  27. Lamberts M, Olesen JB, Ruwald MH, et al. Bleeding after initiation of multiple antithrombotic drugs, including triple therapy, in atrial fibrillation patients following myocardial infarction and coronary intervention: a nationwide cohort study. Circulation 2012; 126:1185.
  28. Kiviniemi T, Puurunen M, Schlitt A, et al. Bare-metal vs. drug-eluting stents in patients with atrial fibrillation undergoing percutaneous coronary intervention. Circ J 2014; 78:2674.
  29. Valgimigli M, Patialiakas A, Thury A, et al. Zotarolimus-eluting versus bare-metal stents in uncertain drug-eluting stent candidates. J Am Coll Cardiol 2015; 65:805.
  30. You JJ, Singer DE, Howard PA, et al. Antithrombotic therapy for atrial fibrillation: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141:e531S.
  31. Dans AL, Connolly SJ, Wallentin L, et al. Concomitant use of antiplatelet therapy with dabigatran or warfarin in the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial. Circulation 2013; 127:634.
  32. Lip GY, Windecker S, Huber K, et al. Management of antithrombotic therapy in atrial fibrillation patients presenting with acute coronary syndrome and/or undergoing percutaneous coronary or valve interventions: a joint consensus document of the European Society of Cardiology Working Group on Thrombosis, European Heart Rhythm Association (EHRA), European Association of Percutaneous Cardiovascular Interventions (EAPCI) and European Association of Acute Cardiac Care (ACCA) endorsed by the Heart Rhythm Society (HRS) and Asia-Pacific Heart Rhythm Society (APHRS). Eur Heart J 2014; 35:3155.
  33. Heidbuchel H, Verhamme P, Alings M, et al. Updated European Heart Rhythm Association practical guide on the use of non-vitamin-K antagonist anticoagulants in patients with non-valvular atrial fibrillation: Executive summary. Eur Heart J 2016.