Dual Antithrombotic Therapy with Dabigatran after PCI in Atrial Fibrillation (RE-DUAL PCI)

Dual Antithrombotic Therapy with Dabigatran after PCI in Atrial Fibrillation (RE-DUAL PCI)
Thakul Rattanasuwan, PharmD, CentraCare Health-Paynesville 

Background: Among patients with atrial fibrillation who have CHA2DS2-VASc score of 2 or greater, the 2014 AHA guideline recommends long-term use of an oral anticoagulant to prevent thromboembolic events. In patients with coronary artery disease (CAD) following coronary revascularization including percutaneous coronary intervention (PCI) with stent, dual-antiplatelet therapy (DAPT), which includes aspirin and a P2Y12 inhibitor, is recommended to prevent stent thrombosis. Therefore, in patients with atrial fibrillation who underwent coronary stenting, guidelines recommended triple therapy consisting of DAPT and an oral anticoagulant. Studies have shown, however, that triple therapy can increase major and minor bleeding risk and should be avoided.  In order to avoid this bleeding risk, the safety and efficacy of an alternative combination of an anticoagulant and one antiplatelet was studied. 

Objective: Compare the use of two regimens of dabigatran and a P2Y12 inhibitor with triple therapy (warfarin-based regimen) among atrial fibrillation patients who underwent PCI. 

Study Design: An open-label noninferiority design was conducted at 414 sites in 41 countries. Despite having unblinded participants, primary and secondary endpoints were analyzed by an independent committee who were not aware of treatment groups. Adult patients with nonvalvular atrial fibrillation who underwent successful PCI with bare-metal or drug-eluting stent were included in this study. Patients with renal insufficiency (CrCl <30) or a heart valve complication were excluded. A total of 2725 participants were eligible for this study and randomized to either dabigatran 110 mg twice daily plus a P2Y12 inhibitor, dabigatran 150 mg twice daily plus a P2Y12 inhibitor or triple therapy (warfarin, aspirin and a P2Y12 inhibitor). The primary endpoint was the first major or clinically relevant nonmajor bleeding event. The secondary end-point was a composite efficacy of thromboembolic events, including myocardial infarction, stroke, systemic embolism, death or unplanned revascularization. The endpoints were analyzed by cox-proportional hazard model with noninferiority margin of 1.38 for upper boundary. 

Results: A total of 2,725 eligible participants were assigned to one of the treatment groups: 981 participants in dual therapy with dabigatran 110 mg and a P2Y12 inhibitor, 761 participants in dual therapy with dabigatran 150 mg and P2Y12 inhibitor, and 981 participants in triple therapy. The mean duration was 12.3 months. The mean age was 70.8 years. In triple therapy, the mean percentage of in-range INR was 64%.

  • Primary endpoint: With statistical significance, the incidence of major or clinically nonmajor bleeding events were lower in both groups of dual therapies when compared to the triple therapy group (HR 0.52 [95% CI 0.42-0.63] p<0.001) in dabigatran 110 mg and (HR 0.72 [95% CI 0.58-0.88] p<0.001) in dabigatran 150 mg).

  • Secondary endpoint: The incidence of composite thromboembolic events was 13.7% in combined dual therapy groups compared with 13.4% in the triple therapy group (HR 1.04 [95% CI 0.84-1.29] p=0.005). In subgroup analysis there was no statistical significance in composite thromboembolic events in either dabigatran 110 mg (HR 1.13 [95% CI 0.90-1.43] p=0.30) or dabigatran 150 mg (HR 0.89 [95% CI 0.67-1.19] p=0.44) when compared with triple therapy.

  • Serious adverse effects:  Serious adverse events were reported in 42.7% of dual therapy patients taking dabigatran 110 mg, 39.6% in dual therapy with dabigatran 150 mg and 41.8% in the triple therapy group. 

Conclusion: Dual therapy with dabigatran (either 110 mg twice daily or 150 mg twice daily) and a P2Y12 inhibitor showed a significantly lower rate of major and clinically relevant nonmajor bleeding events when compared to triple therapy with warfarin. In addition, the results showed that the incidence of composite thromboembolic events of dual therapies were noninferior to triple therapy with warfarin. 

Limitations: There were multiple limitations of this study:

  1. The noninferiority margin used in this trial was set by FDA for registration trial on non-vitamin K anticoagulation to evaluate its efficacy on stroke and embolism prevention. However, the authors used this margin to calculate sample size and evaluate for safety of the treatments.

  2. The original protocol was amended. The composite efficacy endpoint was set as the primary endpoint in the original protocol; however, to adjust sample size number, the protocol was amended and the composite efficacy endpoint was changed to a secondary endpoint. Furthermore, efficacy was inconclusive due to underpower.

  3. P2Y12 inhibitors were limited to clopidogrel and ticagrelor in this trial. Additionally, some elderly patients outside the United States were not eligible for dabigatran 150 mg according to their countries’ label.

  4. This study included both patients with bare-metal stents and drug-eluting stents in PCI, in which patients with bare-metal stents had a shorter time period on triple therapy than those with drug-eluting stents. Subgroup analysis should be performed. 

Key Point: Dual therapy with dabigatran could minimize risk of major and clinically relevant nonmajor bleeds in patients with atrial fibrillation who underwent PCI.  However, the conclusion from this study should be carefully interpreted based on the study’s limitations. 

Cannon CP, Bhatt DL, Oldgren J, et al. Dual antithrombotic therapy with dabigatran after PCI in atrial fibrillation. N Engl J Med. 2017;377(16): 1513-1524.