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Response by Chan and Weitz to Letter Regarding Article, “Antithrombotic Agents: New Directions in Antithrombotic Therapy”

Originally published Research. 2019;124:e119

    In Response:

    Antithrombotic therapy in atrial fibrillation (AF) patients undergoing percutaneous coronary intervention (PCI) is complicated. Anticoagulant therapy is more effective than single or dual antiplatelet therapy for stroke prevention in AF, but dual antiplatelet therapy is more effective than treatment with a vitamin K antagonist such as warfarin for prevention of stent thrombosis after PCI. This conundrum prompted the combination of dual antiplatelet therapy with an anticoagulant—so-called triple therapy—for prevention of thrombotic events in AF patients undergoing PCI. The problem with triple therapy is that it is associated with an increased risk of bleeding.1

    The results of the WOEST (What Is the Optimal Antiplatelet and Anticoagulant Therapy in Patients With Oral Anticoagulation and Coronary Stenting), PIONEER-AF (Open-Label, Randomized, Controlled, Multicenter Study Exploring Two Treatment Strategies of Rivaroxaban and a Dose-Adjusted Oral Vitamin K Antagonist Treatment Strategy in Subjects With Atrial Fibrillation Who Undergo Percutaneous Coronary Intervention), and REDUAL-PCI (Randomized Evaluation of Dual Antithrombotic Therapy With Dabigatran Versus Triple Therapy With Warfarin in Patients With Nonvalvular Atrial Fibrillation Undergoing Percutaneous Coronary Intervention) trials indicated that dual therapy with a P2Y12 inhibitor plus an anticoagulant was safer than triple therapy in AF patients undergoing PCI, but the studies were underpowered to assess efficacy.2–4 The PIONEER-AF study also showed that with triple therapy, there was less bleeding with very low dose rivaroxaban (2.5 mg twice daily) than with warfarin.3 However, Laine et al correctly point out that under dosing of direct oral anticoagulants (DOACs) in AF patients may compromise efficacy and that there are limited data on the efficacy of 2.5 mg twice daily dose of rivaroxaban for stroke prevention in AF. We agree with Laine et al that because of these concerns, the very low dose rivaroxaban regimen should not be used in AF patients undergoing PCI.

    The results of the recent AUGUSTUS trial add to the evidence that DOACs are safer than vitamin K antagonists in AF patients with acute coronary syndrome or in those undergoing PCI.5 Using a 2×2 factorial design, this study randomized 4600 such patients to either apixaban 5 mg twice daily (or 2.5 mg twice daily for those having at least 2 of the 3 dose reduction criteria) or a vitamin K antagonist in the first randomization and to aspirin or placebo in the second. The primary outcome was major or clinically relevant nonmajor bleeding, and secondary outcomes included death and hospitalization and death and ischemic events.

    Compared with warfarin, apixaban was associated with a 31% reduction in bleeding, and compared with dual antiplatelet therapy, dropping aspirin was associated with a 47% reduction in bleeding. Therefore, this trial shows a clear advantage of apixaban over a vitamin K antagonist. Because the trial was not powered to detect differences in coronary ischemic events, however, it remains unclear whether aspirin may be of benefit in patients at high risk of coronary ischemic events.

    In summary, physicians now have the luxury of a choice of various DOAC doses to optimize efficacy and safety in AF patients undergoing PCI. The optimal choice is informed by balancing the risks of cardioembolic and coronary ischemic events with the risk of bleeding. In those at high risk of both ischemic and bleeding events, it is reasonable to reduce the DOAC dose, but not by too much as highlighted by Laine et al. For those at high risk of stroke who are not at high risk of bleeding, a full-dose DOAC regimen is preferred.


    Letters to the Editor will be published, if suitable, as space permits. They should not exceed 1000 words (typed double-spaced) in length and may be subject to editing or abridgment.


    • 1. Chan NC, Weitz JI. Antithrombotic agents: new directions in antithrombotic therapy.Circ Res. 2019; 124:426–436. doi: 10.1161/CIRCRESAHA.118.313155LinkGoogle Scholar
    • 2. Dewilde WJ, Oirbans T, Verheugt FW, Kelder JC, De Smet BJ, Herrman JP, Adriaenssens T, Vrolix M, Heestermans AA, Vis MM, Tijsen JG, van ‘t Hof AW, ten Berg JM; WOEST study investigators. 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; 381:1107–1115. doi: 10.1016/S0140-6736(12)62177-1CrossrefMedlineGoogle Scholar
    • 3. Gibson CM, Mehran R, Bode C, et al. Prevention of bleeding in patients with atrial fibrillation undergoing PCI.N Engl J Med. 2016; 375:2423–2434. doi: 10.1056/NEJMoa1611594CrossrefMedlineGoogle Scholar
    • 4. Cannon CP, Bhatt DL, Oldgren J, et al; RE-DUAL PCI Steering Committee and Investigators. Dual antithrombotic therapy with dabigatran after PCI in atrial fibrillation.N Engl J Med. 2017; 377:1513–1524. doi: 10.1056/NEJMoa1708454CrossrefMedlineGoogle Scholar
    • 5. Lopes RD, Heizer G, Aronson R, et al; AUGUSTUS Investigators. Antithrombotic therapy after acute coronary syndrome or PCI in atrial fibrillation.N Engl J Med. 2019; 380:1509–1524. doi: 10.1056/NEJMoa1817083CrossrefMedlineGoogle Scholar


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