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Superior safety of dual therapy with dabigatran and clopidogrel vs. triple therapy with warfarin, aspirin and clopidogrel in the RE-DUAL PCI trial: What is key, the strategy or the drug?

  • Andrea Rubboli
    Correspondence
    Division of Cardiology - Laboratory of Interventional Cardiology, Ospedale Maggiore, Largo Nigrisoli 2, 40133 Bologna, Italy.
    Affiliations
    Division of Cardiology - Laboratory of Interventional Cardiology, Ospedale Maggiore, Bologna, Italy
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Published:October 05, 2017DOI:https://doi.org/10.1016/j.ejim.2017.10.001
      In line with the results of the PIONEER AF-PCI trial with rivaroxaban [
      • Gibson C.M.
      • Mehran R.
      • Bode C.
      • Halperin J.
      • Verheugt F.W.
      • Wildgoose P.
      • et al.
      Prevention of bleeding in patients with atrial fibrillation undergoing PCI.
      ], those of the recent RE-DUAL PCI trial with dabigatran [
      • Cannon C.P.
      • Bhatt D.L.
      • Oldgren J.
      • Lip G.Y.H.
      • Ellis S.G.
      • Kimura T.
      • RE-DUAL PCI Steering Committee and Investigators
      • et al.
      Dual antithrombotic therapy with dabigatran after PCI in atrial fibrillation.
      ] further support the superior safety on bleeding events of dual therapy with a non-vitamin K-antagonist oral anticoagulant (NOAC) plus clopidogrel over conventional triple therapy with warfarin, aspirin and clopidogrel in patients with atrial fibrillation (AF) undergoing percutaneous coronary intervention with stent (PCI) (Table 1). From the RE-DUAL PCI trial [
      • Cannon C.P.
      • Bhatt D.L.
      • Oldgren J.
      • Lip G.Y.H.
      • Ellis S.G.
      • Kimura T.
      • RE-DUAL PCI Steering Committee and Investigators
      • et al.
      Dual antithrombotic therapy with dabigatran after PCI in atrial fibrillation.
      ] some additional considerations regarding the independent role of the strategy (i.e., dual vs. triple therapy) and the drug (i.e., dabigatran vs. warfarin), and its dose (i.e., dabigatran 110 vs. 150 mg), on the incidence of the primary safety end-point of major or clinically relevant non-major bleeding can be made. Whereas in the PIONEER AF-PCI trial [
      • Gibson C.M.
      • Mehran R.
      • Bode C.
      • Halperin J.
      • Verheugt F.W.
      • Wildgoose P.
      • et al.
      Prevention of bleeding in patients with atrial fibrillation undergoing PCI.
      ] the duration of aspirin in the conventional triple therapy arm of warfarin, aspirin and clopidogrel was at the discretion of, and therefore potentially biased by, the operator, in the RE-DUAL PCI trial [
      • Cannon C.P.
      • Bhatt D.L.
      • Oldgren J.
      • Lip G.Y.H.
      • Ellis S.G.
      • Kimura T.
      • RE-DUAL PCI Steering Committee and Investigators
      • et al.
      Dual antithrombotic therapy with dabigatran after PCI in atrial fibrillation.
      ] aspirin was to be interrupted in all cases at 3 months maximum after PCI, thereby leaving all patients exposed to dual therapy with dabigatran 110/150 mg or warfarin plus single antiplatelet therapy with clopidogrel for the remaining 9 months. Therefore, the initial comparison of two different treatment strategies (dual vs. triple) turned into a comparison of two different drugs (dabigatran vs. warfarin) after the first 3 months [
      • Cannon C.P.
      • Bhatt D.L.
      • Oldgren J.
      • Lip G.Y.H.
      • Ellis S.G.
      • Kimura T.
      • RE-DUAL PCI Steering Committee and Investigators
      • et al.
      Dual antithrombotic therapy with dabigatran after PCI in atrial fibrillation.
      ]. Upon examination of the Kaplan-Meier curves of the probability of the primary safety end-point with dabigatran 110 and 150 mg in comparison with warfarin, it is apparent that the separation of the curves between dual and triple therapy mostly occurs during the first 3 months of treatment (Fig. 1), supporting that is indeed the (dual) strategy of omitting aspirin that carries most of the benefit in reducing the occurrence of bleeding events. Following the first 3 months, the curves keep separating with dabigatran 110 mg suggesting that when the same (dual) strategy is applied, the drug dabigatran at the dose of 110 mg provides by itself a safety benefit over warfarin. This appears not to be the case with dabigatran 150 mg for which the Kaplan-Meier curves after the first 3 months run largely parallel or even tend to converge (Fig. 1). Of note, the above trends are consistent with the results of the RE-LY trial [
      • Connolly S.J.
      • Ezekowitz M.D.
      • Yusuf S.
      • Eikelboom J.
      • Oldgren J.
      • Parekh A.
      • RE-LY Steering Committee and Investigators
      • et al.
      Dabigatran versus warfarin in patients with atrial fibrillation.
      ] in patients with AF where dabigatran 110 mg was significantly safer on major bleeding than warfarin as opposed to dabigatran 150 mg which was comparably safe. Thus, dabigatran at the dose of 110 mg BID may be considered over warfarin (and dabigatran 150 mg BID as well) whenever an indication for single (but also dual) antiplatelet therapy co-exists. Whether this holds true for the other NOACs, and especially apixaban and edoxaban for which superior safety on bleeding events compared to warfarin has been shown in the ARISTOTLE [
      • Granger C.B.
      • Alexander J.H.
      • McMurray J.J.
      • Lopes R.D.
      • Hylek E.M.
      • Hanna M.
      • ARISTOTLE Committees and Investigators
      • et al.
      Apixaban versus warfarin in patients with atrial fibrillation.
      ] and ENGAGE AF-TIMI 48 [
      • Giugliano R.P.
      • Ruff C.T.
      • Braunwald E.
      • Murphy S.A.
      • Wiviott S.D.
      • Halperin J.L.
      • ENGAGE AF-TIMI 48 Investigators
      • et al.
      Edoxaban versus warfarin in patients with atrial fibrillation.
      ] trials in AF patients, remains currently unproven. Nonetheless, it is of note that in the recent focused update on dual antiplatelet therapy in coronary artery disease of the European Society of Cardiology [
      • Valgimigli M.
      • Bueno H.
      • Byrne R.A.
      • Collet J.P.
      • Costa F.
      • Jeppsson A.
      • et al.
      2017 ESC focused update on dual antiplatelet therapy in coronary artery disease developed in collaboration with EACTS: the Task Force for dual antiplatelet therapy in coronary artery disease of the European Society of Cardiology (ESC) and of the European Association for Cardio-Thoracic Surgery (EACTS).
      ] consideration of a NOAC over warfarin is recommended for the first time when combination with (single or dual) antiplatelet therapy is required. Thus, the choice of the proper, that is, safer, oral anticoagulant, namely a NOAC, may be regarded by now as an additional bleeding avoiding strategy in patients with AF undergoing PCI.
      Table 1Hazard ratio (95% Confidence Intervals) of primary safety end-point with dual therapy with dabigatran and clopidogrel vs. triple therapy with warfarin, aspirin and clopidogrel.
      PIONEER AF-PCI
      • Gibson C.M.
      • Mehran R.
      • Bode C.
      • Halperin J.
      • Verheugt F.W.
      • Wildgoose P.
      • et al.
      Prevention of bleeding in patients with atrial fibrillation undergoing PCI.
      RE-DUAL PCI
      • Cannon C.P.
      • Bhatt D.L.
      • Oldgren J.
      • Lip G.Y.H.
      • Ellis S.G.
      • Kimura T.
      • RE-DUAL PCI Steering Committee and Investigators
      • et al.
      Dual antithrombotic therapy with dabigatran after PCI in atrial fibrillation.
      Rivaroxaban 15/10
      In patients with moderate renal impairment (i.e., creatinine clearance of 30–50ml/min). OD: once daily; BID: twice daily.
       mg OD
      Dabigatran 110 mg BID Dabigatran 150 mg BID
      0.59 (0.47–0.76) 0.52 (0.42–0.63) 0.72 (0.58–0.88)
      p < 0.001 p <  0.001 p = 0.002
      a In patients with moderate renal impairment (i.e., creatinine clearance of 30–50 ml/min). OD: once daily; BID: twice daily.
      Fig. 1
      Fig. 1Trend of Kaplan-Meier curves of the probability of the primary safety end-point of major or clinically relevant non-major bleeding before and after the first 90 days of treatment with dabigatran 110 (left) and 150 (right) mg BID vs. warfarin. BID: twice daily.
      (Modified from ref. [
      • Cannon C.P.
      • Bhatt D.L.
      • Oldgren J.
      • Lip G.Y.H.
      • Ellis S.G.
      • Kimura T.
      • RE-DUAL PCI Steering Committee and Investigators
      • et al.
      Dual antithrombotic therapy with dabigatran after PCI in atrial fibrillation.
      ].)
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