PIONEER AF-PCI - Antithrombotics in patients with AF after PCI

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Bottom line: In patients with AF undergoing PCI, a novel antithrombotic regimen (reduced-dose rivaroxaban + P2Y12 inhibitor, or ATLAS trial-like triple therapy regimen) reduces the risk of hospitalization, bleeding requiring medical attention and study discontinuation (NNT ~10-15 each).

This trial does not answer whether these novel regimens retain stroke efficacy for AF (either regimen versus full anticoagulation) or MI/stent thrombosis efficacy for CAD (modified double therapy versus DAPT). While ongoing trials will provide further guidance on the ideal regimen and dose, the best available evidence suggests that dual therapy with clopidogrel plus full-dose anticoagulation provides the best balance of benefit and safety.

 

Patients (n=2124)

  • Inclusion
    • Age 18+ y
    • AFib (documented within 1 y before enrolment or taking OAC for at least 3 months before PCI)
    • Underwent PCI with stent placement (randomized within 3 days of PCI)
  • Exclusion
    • Prior stroke/TIA
    • Significant GI bleed within 1 year
    • Anemia of unknown cause with Hb <100 g/L
    • "Any other condition known to increase bleed risk"
    • CrCl <30 mL/min
  • Screened 2236 -> randomized 2124 -> analyzed 2099
  • "Average" patient
    • Age 71 y (36% 75+ y)
    • Female 26%
    • White 94%
    • Indication for PCI: Unstable angina (21%), NSTEMI (18%), STEMI (12%), non-ACS (49%)
    • Drug-eluting (2/3), bare-metal (1/3) stent
    • CHA2DS2-VASc score: 0 (<2%), 1 (9%), 2 (15%), 3 (18%), 4 (20%), 5 (20%), 6 (13%), 7 (3%)
    • CrCl 78 mL/min
    • P2Y12 inhibitor: Clopidogrel (93%), prasugrel (<2%), ticagrelor (~5%)
    • PPI used in ~40%

Generalizability

  • Represents the target population at the time when the decision on antithrombotics would be made.
  • Similar to WOEST and ISAR-TRIPLE, ACS was the indication for PCI in <50% of patients
    • Due to their higher risk of MI, stent thrombosis & CV death, thes benefit-risk profile of different antithrombotic regimens (& DAPT duration) likely differs in this subgroup. This trial is underpowered to evaluate this subgroup.
  • ~90% of patients had a CHA2DS2-VASc of 2 or more, corresponding to a risk of stroke or systemic thromboembolism of >1.5%/year & indication for anticoagulation by all major guidelines (AHA, CCS, ESC).
  • This trial included only patients without major bleeding risk factors (i.e. no recent GI bleed, intracranial hemorrhage, eGFR <30 mL/min, or chronic NSAID use)
    • The bleeding rates in this trial therefore represent a minimum risk that would be expected to increase substantially in the presence of any of these risk factors.

 

Interventions & co-interventions

  • I 1: Modified "double therapy" for trial duration
    • Rivaroxaban 15 mg daily + P2Y12 inhibitor at standard dose
      • If CrCl 30-50: Decrease rivaroxaban to 10 mg daily
    • Comments about this intervention:
      • Rivaroxaban dose 75% of the 20 mg/d dose determined to be non-inferior to warfarin in ROCKET-AF trial of non-valvular AF. It is unclear if the addition of 1 antiplatelet drug to this reduced dose provides similar ischemic stroke risk reduction compared to full-dose anticoagulation monotherapy
      • Full-dose apixaban may have been a better option, since it has demonstrated similar risk of major bleeding compared to ASA, with greater reduction in ischemic stroke in non-valvular AF (AVERROES)
  • I 2: Rivaroxaban 2.5 mg BID + DAPT (ATLAS trial regimen)
    • DAPT consisted of ASA 75-100 mg/d indefinitely + a standard dose of any of clopidogrel, prasugrel, ticagrelor x1 to 12 months (decided before randomization)
    • Comments about this intervention:
      • Rivaroxaban dose 25% of the 20 mg/d dose determined to be non-inferior to warfarin in ROCKET-AF trial. There is no prior evidence suggesting that this dose is adequate to reduce the risk of stroke in AF, nor is there evidence that adding DAPT to this reduced dose will reduce the risk of ischemic stroke.
  • C: Warfarin-based triple therapy
    • Warfarin to INR 2.0-3.0 (mean time in the therapeutic range 65%) + ASA 75-100 mg/d + P2Y12 inhibitor
      • Warfarin & ASA continued for trial duration
      • P2Y12 inhibitor continued x1 to 12 months (decided before randomization)

 

Outcomes @ 1 year

  • Efficacy
    • Death or hospitalization: Modified double therapy 35%, ATLAS regimen 32%, triple therapy 42%
      • Modified double therapy vs triple therapy: Hazard ratio (HR) 0.79 (95% confidence interval 0.66-0.94), NNT 10
      • ATLAS regimen vs triple therapy: HR 0.75 (0.62-0.90), NNT 15
      • Note: The lower risk of hospitalization in the 2 rivaroxaban-based regimens vs triple therapy were due to reductions in both CV- and bleeding-related hospitalizations
    • Death: 2.3-2.7% (no statistically significant differences)
    • Composite CV death, MI or stroke: 6.5% vs 5.6% vs 6.0%
      • Double vs triple therapy: HR 1.08 (0.69-1.68)
      • ATLAS regimen vs triple therapy: HR 0.93 (0.59-1.48)
    • Stent thrombosis: 0.8% vs 0.9% vs 0.7%
      • Double vs triple therapy: HR 1.20 (0.32-4.45)
      • ATLAS regimen vs triple therapy: HR 1.44 (0.40-5.09)
    • Stroke: 1.3% vs 1.5% vs 1.2%
      • Double vs triple therapy: HR 1.07 (0.39-2.96)
      • ATLAS regimen vs triple therapy: HR 1.36 (0.52-3.58)
  • Safety
    • Primary outcome (major + minor bleeding based on TIMI criteria or bleeding requiring medical attention): 16.8% vs 18.0% vs 26.7%
      • Double vs triple therapy: HR 0.59 (0.47-0.76), NNT 11
      • ATLAS regimen vs triple therapy: HR 0.63 (0.50-0.80), NNT 12
    • Major bleeding: 2.1% vs 1.9% vs 3.3%
      • Double vs triple therapy: HR 0.66 (0.33-1.31)
      • ATLAS regimen vs triple therapy: HR 0.57 (0.28-1.16)
  • Discontinuation before study termination: 21.0% vs 21.1% vs 29.4% (NNT ~12 for either double therapy or the ATLAS regimen versus triple therapy)

 

Context

 

Internal validity

  • Low risk of allocation bias (central randomization)
  • Unclear risk of certain biases
    • Performance bias
      • Open-label
      • Anticipated DAPT duration selected & recorded prior to randomization
      • PPI/H2RA use for gastroprotection encouraged but not mandated for all trial participants
    • Detection bias:
      • Open-label
      • Most outcomes included in the primary safety outcome were subjective "soft" outcomes ("bleeding requiring medical attention" accounted for >90% of bleeding outcomes reported) & prone to biased reporting from patients, and subsequently from the treating clinician
      • The more important & objective outcomes such as major hemorrhage or death occurred infrequently (~2-3%), with too few events to provide firm conclusions about differences or lack thereof
      • Blinded adjudication: All efficacy endpoints & a portion of bleeding events reported by patients & their clinicians were subsequently adjudicated by investigators blind to assigned intervention
    • Attrition bias:
      • Analyzed only patients who took at least 1 dose of the study drug (modified intention-to-treat [mITT] population)
      • None in the mITT population were lost-to-follow-up, but more patients in the triple therapy group discontinued the study regimen prematurely
  • Low risk of reporting bias (all clinically-important outcomes reported)

 

 

    Interpretation of study outcomes

    • Study underpowered to demonstrate superiority or non-inferiority of any intervention to each other for the outcomes of cardiovascular events or major hemorrhage
      • Could not rule out a 3-fold increased risk of stroke in the double therapy/ATLAS regimen versus triple therapy.
    • Contrary to WOEST, PIONEER did not demonstrate a lower risk of death with the modified double therapy regimen vs triple therapy. Due to the low number of events, either finding could be due to chance (false-negative in PIONEER or false-positive in WOEST).
    • The risk of major hemorrhage over 1 year with triple therapy (3.3%) was comparable to that in the ISAR-TRIPLE trial (2.4% at 9 months), & substantially lower than in the Danish registry (12.2%) and the WOEST trial (5.6%).