RE-DUAL PCI - Dabigatran-based dual antithrombotic regimen in patients with AF after PCI

Cannon CP, et al. Dual antithrombotic therapy with dabigatran after PCI in atrial fibrillation. NEJM 2017

Bottom line:

  • RE-DUAL PCI provides further evidence supporting dual therapy with an oral anticoagulant + P2Y12 inhibitor in patients with AF post-PCI instead of triple therapy.

  • Dual therapy with dabigatran 150 mg BID reduced clinically relevant bleeds (NNT 19) as well as major bleeds (NNT 36-56 depending on definition), & was non-inferior in terms of thromboembolic events over approximately 1 year.

  • Dual therapy with dabigatran 110 mg BID showed a possible increase in death, MI & definite stent thrombosis, & was potentially inferior for the composite efficacy outcome. Despite reducing major & clinically-relevant bleeds, this regimen can't be recommended due to inadequate evidence of efficacy in this setting.

    • Notably, the PIONEER trial did not assess for non-inferiority of rivaroxaban-based dual therapy regimens to triple therapy, but if it had, it would not have met the non-inferiority criteria from RE-DUAL PCI. However, the PIONEER results did not show the concerning numerical trends seen here with dabigatran 110 mg BID.

Patients (n=2725)

  • Included
    • Non-valvular AFib (paroxysmal, persistent or permanent)
    • PCI (bare-metal or drug-eluting stent) within 120h for stable CAD or ACS
  • Exclusion
    • Bioprosthetic or mechanical heart valve
    • CrCl <30 mL/min
    • "Other major coexisting conditions"
  • Baseline characteristics
    • ~72 y
    • Female ~24%
    • AF characteristics
      • Paroxysmal (~50%), persistent (~17%), permanent (33%)
      • CHA2DS2-VASc score ~4, HAS-BLED score ~3
      • Previous stroke 10%
    • PCI characteristics
      • Previous: MI ~25%, PCI ~33%, CABG ~10%
      • Indication for PCI: ACS (~50%), stable angina/+ stress test (44%), other (~6%)
      • Drug eluting stent 85%

Interventions

  • Intervention1: Dabigatran 150 mg BID + clopidogrel/ticagrelor
    • Note: Elderly outside the US not eligible for this group due to dabigatran labeling
  • Intervention2: Dabigatran 110 mg BID + clopidogrel/ticagrelor
  • Control ("triple therapy"): Warfarin (INR 2-3) + clopidogrel/ticagrelor + low-dose ASA
    • ASA D/Ced after 1 month with bare-metal stent or 3 months with drug-eluting stent
    • Time in therapeutic INR: 64%
  • In all groups
    • P2Y12 inhibitor was continued for at least 12 months
    • P2Y12 inhibitor chosen: Clopidogrel 88%, ticagrelor 12%
    • Mean duration of trial anticoagulant: 12.3 months

Results @ mean 14 months

Dabigatran 150 mg BID vs triple therapy (control group excludes elderly outside US not eligible for higher dabigatran dose)

  • Primary outcome (major or clinically relevant non-major bleed, ISTH definition):
    • Dabi150 20.2%, control 25.7%, NNT 19
    • HR 0.72 (0.58-0.88), p<0.001 for non-inferiority
  • Major bleed:
    • ISTH definition: Dabi150 5.6%, control 8.4%, HR 0.64 (0.43-0.94), NNT 36
    • TIMI definition: Dabi150 2.1%, control 3.9%, HR 0.51 (0.28-0.93), NNT 56
    • Intracranial hemorrhage: Dabi150 0.1%, control 1.0%, p=0.047
  • Composite efficacy outcome (death, MI, stroke, or systemic embolism, or unplanned PCI/CABG): Dabi150 11.8%, control 12.8%, HR 0.89 (0.67-1.19)

Dabigatran 110 mg BID vs triple therapy

  • Primary outcome:
    • Dabi110 15.4%, control 26.9%, NNT 9
    • HR 0.52 (0.42-0.63), p<0.001 for non-inferiority
  • Major bleed:
    • ISTH definition: Dabi110 5.0%, control 9.2%, HR 0.52 (0.37-0.74), NNT 24
    • TIMI definition: Dabi110 1.4%, control 3.8%, HR 0.37 (0.20-0.68), NNT 42
    • Intracranial hemorrhage: Dabi110 0.3%, control 1.0%, p=0.06
  • Composite efficacy outcome: Dabi110 15.2%, control 13.4%, HR 1.13 (0.90-1.43) - did not meet non-inferiority criteria
    • Thromboembolic events or death: Dabi110 11.0%, control 8.5%, HR 1.30 (0.98-1.73)
      • Death Dabi110 5.6%, control 4.9%
      • MI: Dabi110 4.5%, control 3.0%
      • Definite stent thrombosis: Dabi110 1.5%, control 0.8%

Considerations

  • Low to unclear risk of bias
    • Unclear randomization & allocation concealment (not adequately reported)
    • Open-label design - low risk of performance bias, but high risk of detection bias for softer outcomes (ie clinically significant non-major bleeds)
    • Low risk of attrition bias (ITT analysis that included all randomized patients regardless of receipt of study intervention; 0.2% lost to follow-up, <4% withdrew consent with no vital status available at end of study)
  • Non-inferiority trial
    • Non-inferiority margin 1.38 for HR upper end of 95% confidence interval for both efficacy & safety outcomes
    • Primary analysis using ITT population with sensitivity on-treatment analysis
    • Dual therapy with dabi150 met non-inferiority for both bleeding & thromboembolic outcomes, but dabi110 only met non-inferiority criteria for bleeding
  • Excellent generalizability due to broad eligibility criteria & enrolment of a representative, relatively elderly population