What Is the Optimal Regimen for Triple Antithrombotic Therapy?
Dual antiplatelet (DAT) therapy with aspirin and an ADP-receptor antagonist is the standard therapy after coronary stenting. It is assumed that approximately 5-10% of patients undergoing coronary stenting have an additional indication for oral anticoagulation (OAC)(1) and will thus require a so called “triple therapy” consisting of aspirin, an ADP-receptor antagonist and OAC. The most common combination currently consists of aspirin, clopidogrel and a vitamin K antagonist.
ACS: acute coronary syndrome; BMS: bare-metal stent; DES: drug-eluting stent ; OAC: oral anticoagulation.
Currently there is one consensus document by the European Society of Cardiology (ESC) working group of thrombosis(10) which has been implemented in the recent ESC atrial fibrillation guidelines,(11) and another consensus document giving the “North-American perspective”(12) on indication and duration of triple therapy.
In general these recommendations all advocate triple therapy in patients on OAC undergoing coronary stent implantation. In patients with a low bleeding risk bare-metal stents (BMS) as well as drug-eluting stents (DES) are feasible options whereas in patients with a high bleeding risk DES implantation is not recommended by either document because of the need of prolonged clopidogrel therapy. After BMS implantation triple therapy shall be prescribed for 2-4 weeks followed by OAC plus one antiplatelet alone (aspirin or clopidogrel) whereas there is currently no overall consensus upon duration of triple therapy in patients who have received DES. The ESC recommends 3 months triple therapy in patients with –olimus-eluting stents, and 6 months with paclitaxel-eluting stents (Table 1),(11) while the North American perspective favours 6-12 months (Table 2)(12) of triple therapy according to the patients’ stent thrombosis risk.
To further evaluate the optimal duration of triple therapy in patients receiving DES, we are currently undertaking the randomized ISAR-TRIPLE trial (NCT00776633) which compares 6 weeks vs. 6 months of triple therapy followed by aspirin and OAC. Other ongoing randomized trials in this field are evaluating efficacy and safety of a combination of clopidogrel plus OAC as compared to triple therapy (WOEST, NCT00769938), or DAT with aspirin and clopidogrel as compared to triple therapy in patients with a CHADS2 Score ≤2 (MUSICA-2, NCT01141153).
All guidelines agree that due to the increased bleeding risk the INR should be monitored closely(11,13,14) and the recommended INR range shall be lowered to 2.0 to 2.5 in patients with atrial fibrillation requiring triple therapy after PCI.(13) In this high-risk population, gastric acid suppressing agents, preferably a PPI other than omeprazole, should be given,(12) and DES implantation should be restricted to patients with an expected high risk of restenosis such as diabetes or complex lesions.(1)
Is a NEW-TRIPLE Therapy with Either Prasugrel/Ticagrelor or Dabigatran/Rivaroxaban/Apixaban an Option?
The newer P2Y12 inhibitors prasugrel and ticagrelor have both shown to reduce cardiovascular events as compared to clopidogrel in patients with acute coronary syndromes.(15,16) The downside of this therapy however is a significant increase in bleeding events in patients undergoing PCI, so we do not recommend the routine use of these agents in patients requiring additional OAC. Although the relevance of platelet function testing in the guidance of antiplatelet therapy is still not established, clopidogrel resistant patients might be considered for the use of newer P2Y12 inhibitors.
In the setting of atrial fibrillation the direct thrombin inhibitor dabigatran and the factor Xa inhibitors rivaroxaban and apixaban have all been studied as compared to warfarin(17-19) because these agents may overcome the limitations of vitamin K antagonists such as the narrow therapeutic window of adequate anticoagulation and the highly variable dose-response relation among individuals that requires monitoring by laboratory testing.
AP: antiplatelet agent; BMS: bare-metal stent; DAT: dual antiplatelet therapy; DES: drug-eluting stent; OAC: oral anticoagulation.
These studies have shown that (i) dabigatran 110 mg BID as well as apixaban 5mg BID are associated with lower rates of major haemorrhages;(17,19) (ii) dabigatran 150 mg BID as well as apixaban 5mg BID are associated with lower rates of stroke and systemic embolism;(17,19) and (iii) rivaroxaban 20mg QD is noninferior for the prevention of stroke or systemic embolism without a significant between group difference in the rates of major bleeding.(18) All three agents significantly reduce the rates of intracranial bleeding,(17-19) and apixaban significantly reduces the rate of death.(19)
All of these agents have also been assessed against placebo in patients with acute coronary syndromes (>78 % on DAT with aspirin and clopidogrel). It has to be noted however that the patients included in these trials did not have an indication for OAC. The results may be summarized as follows: (i) dabigatran, rivaroxaban and apixaban significantly increase the rates of major bleeding in a dose dependent manner;(20-22) (ii) apixaban and dabigatran are not associated with a significant reduction in ischemic outcomes;(20,21) and as recently shown, (iii) rivaroxaban at a dose of 2.5mg to 5mg BID reduces ischemic outcomes.(22) However, the doses used in this trial are ¼ to ½ lower as compared to the tested dose of 20mg rivaroxaban QD in patients with atrial fibrillation.(18)
Data concerning outcomes with the newer anticoagulants as compared to warfarin in patients on concomitant dual antiplatelet therapy are very limited. An abstract presented at the recent ESC congress 2011 has revealed that concomitant use of antiplatelets did not affect the efficacy and safety of dabigatran in the RE-LY trial.(23) In patients on either one or two antiplatelet agents, dabigatran 110mg was non-inferior and dabigatran 150mg was superior to warfarin in the reduction of stroke and systemic embolism. There was an 1.6 times increase in the risk of major bleeding with concomitant antiplatelet use in all treatment groups, but the absolute risks were lowest with dabigatran 110mg. Major bleeding events were comparable to warfarin in patients receiving a dose of 150mg/d. The authors state that the results were unaffected by duration of use or number of antiplatelets used. Similar findings have been observed with apixaban. In the subgroup analysis of the ARISTOTLE trial it was shown that the better antiischemic and bleeding profile of apixaban was not changed whether patients received aspirin at baseline or not.(19) However, no information is available upon the use of antiplatelet therapy during the whole trial or upon the use of clopidogrel.
Triple therapy with warfarin has been used for several years now and data upon its efficacy and safety is available while there is currently no published data upon the use of triple therapy with the newer oral anticoagulants. Although it seems promising that some of the newer anticoagulants may lower the risk of bleeding as compared to conventional OAC in patients receiving triple therapy, further studies are needed to evaluate this therapy before recommendation may be given whether these agents may be used in addition to DAT. We believe however that for patients needing DAT and anticoagulation, dabigatran 110mg or apixaban 5mg may be an alternative to conventional OAC in a subset of patients such as those who are unable to take warfarin because of difficulties in INR monitoring or patients with an excessive bleeding risk.
- Schomig A, Sarafoff N, Seyfarth M. Triple antithrombotic management after stent implantation: when and how? Heart 2009;95:1280-5.
- Karjalainen PP, Porela P, Ylitalo A, et al. Safety and efficacy of combined antiplatelet-warfarin therapy after coronary stenting. Eur Heart J 2007.
- 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;28:1717-22.
- Ruiz-Nodar JM, Marin 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;51:818-25.
- 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;264:472-80.
- Hansen ML, Sorensen 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;170:1433-41.
- Sorensen 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;374:1967-74.
- Holmes DR, Jr., Kereiakes DJ, Kleiman NS, Moliterno DJ, Patti G, Grines CL. Combining antiplatelet and anticoagulant therapies. J Am Coll Cardiol 2009;54:95-109.
- Zhao HJ, Zheng ZT, Wang ZH, et al. "Triple therapy" rather than "triple threat": a meta-analysis of the two antithrombotic regimens after stent implantation in patients receiving long-term oral anticoagulant treatment. Chest 2011;139:260-70.
- Lip GY, Huber K, Andreotti F, et al. Antithrombotic management of atrial fibrillation patients presenting with acute coronary syndrome and/or undergoing coronary stenting: executive summary--a Consensus Document of the European Society of Cardiology Working Group on Thrombosis, endorsed by the European Heart Rhythm Association (EHRA) and the European Association of Percutaneous Cardiovascular Interventions (EAPCI). Eur Heart J 2010;31:1311-8.
- Camm AJ, Kirchhof P, Lip GY, et al. Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Eur Heart J 2010;31:2369-429.
- Faxon DP, Eikelboom JW, Berger PB, et al. Consensus Document: Antithrombotic therapy in patients with atrial fibrillation undergoing coronary stenting. A North-American perspective. Thromb Haemost 2011;106.
- King SB, 3rd, Smith SC, Jr., Hirshfeld JW, Jr., et al. 2007 focused update of the ACC/AHA/SCAI 2005 guideline update for percutaneous coronary intervention: a report of the American College of Cardiology/American Heart Association Task Force on Practice guidelines. J Am Coll Cardiol 2008;51:172-209.
- Van de Werf F, Bax J, Betriu A, et al. Management of acute myocardial infarction in patients presenting with persistent ST-segment elevation: the Task Force on the Management of ST-Segment Elevation Acute Myocardial Infarction of the European Society of Cardiology. Eur Heart J 2008;29:2909-45.
- Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007;357:2001-15.
- Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009;361:1045-57.
- Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139-51.
- Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus Warfarin in Nonvalvular Atrial Fibrillation. N Engl J Med 2011;365;883-881.
- Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus Warfarin in Patients with Atrial Fibrillation. N Engl J Med 2011;365:981-992.
- Oldgren J, Budaj A, Granger CB, et al. Dabigatran vs. placebo in patients with acute coronary syndromes on dual antiplatelet therapy: a randomized, double-blind, phase II trial. Eur Heart J 2011.
- Alexander JH, Lopes RD, James S, et al. Apixaban with antiplatelet therapy after acute coronary syndrome. N Engl J Med 2011;365:699-708.
- Mega JL, Braunwald E, Wiviott SD, et al. Rivaroxaban in Patients with a Recent Acute Coronary Syndrome. N Engl J Med 2011; Nov 13;[Epub ahead of print].
- Dans AL, Connolly S, Brückmann M, et al. Concomitant use of Antiplatelet Therapy with Warfarin or Dabigatran. 2011; http://spo.escardio.org/eslides/view.aspx?eevtid=48&fp=1161
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