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

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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

  • Unadjusted bleed rates from a subgroup analysis by choice of P2Y12 inhibitor (clopidogrel vs ticagrelor) suggest that risk of bleeding increases gradually with number of antithrombotic agents as well as potency of the inhibitor, e.g. ISTH major bleed over mean 14 months from Figure 2:

    • Clopidogrel + dabigatran: ~5%

    • Clopidogrel + ASA + warfarin OR ticagrelor + dabigatran: ~8%

    • Ticagrelor + ASA + warfarin: ~16.5%