GEMINI-ACS-1: Rivaroxaban vs ASA added to P2Y12 inhibitor following ACS

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Ohman EM, et al. Clinically significant bleeding with low-dose rivaroxaban versus aspirin, in addition to P2Y12 inhibition, in acute coronary syndromes (GEMINI-ACS-1): A double-blind, multicentre, randomised trial. Lancet 2017 (epub ahead of print)

Bottom-line:

  • In patients with ACS, low-dose rivaroxaban produces a similar or greater risk of clinically-significant or major bleed compared to ASA (potential NNH 100), with unclear effect on efficacy outcomes.

  • Although this trial is insufficient to change practice, it provides preliminary evidence that will guide further trials refining antithrombotic regimens in various ACS subpopulations.

 

Context

  • The ATLAS trial demonstrated that adding low-dose rivaroxaban to clopidogrel-based DAPT reduces CV events and death following PCI, offset by an increase in major bleeds
  • The PIONEER trial and other studies have investigated various anticoagulation-based regimens in patients with AF who undergo PCI

Patients (n=3037)

  • Included:
    • Age > 18 years
    • ACS (unstable angina, NSTEMI or STEMI)
    • If age <55 years, at least 1 of the following:
      • Diabetes
      • Previous MI
    • If unstable angina, at least 1 of the following:
      • TIMI score 4+
      • Ischemic changes on EKG
      • Revascularization for this event
  • Key exclusion criteria:
    • Hx of bleeding, ICH or GI bleed within past year
    • CrCl <20 mL/min
    • Need for full-dose anticoagulation
  • Typical study patient
    • Age 62 years
    • Male 75%
    • ACS type: unstable angina 11%, NSTEMI 40%, STEMI 49%
    • Procedure for ACS: Cath 94%, PCI 87% (DES 67%, BMS 33%), CABG <1%
    • Randomized median 5.5 days after ACS
    • Previous MI 22%
    • Previous PCI/CABG 20%/4%
    • PAD 5%
    • CV risk factors
      • Smoker 33%
      • HTN 73%
      • Dyslipidemia 56%
      • Diabetes 30%
    • Meds
      • ACEI/ARB 63%
      • Beta-blocker 64%
      • Statins 69%

Interventions

  • I: Rivaroxaban 2.5 mg PO BID for a minimum 180 days
  • C: ASA 100 mg PO daily for a minimum 180 days
  • Median duration of study drug 9.6 months
  • Co-interventions:
    • Clopidogrel 75 mg daily (44%) or ticagrelor 90 mg BID (56%) based on investigator preference (i.e. choice of P2Y12 inhibitor not randomized)
      • Prematurely discontinued in 4%

Results @ median 10.7 months

  • Primary outcome (TIMI non-CABG clinically significant bleeding): 5% in both groups, hazard ratio (HR) 1.09 (0.80-1.50)
  • Results vary based on bleeding definition
    • ISTH major bleeding: Rivaroxaban 2% versus ASA 1% (NNH 100), HR 1.83 (1.01-3.31)
    • BARC 3a or higher: 1% in both groups, HR 1.70 (0.85-3.37)
    • GUSTO life-threatening or severe: <1% in both groups, HR 1.50 (0.25-8.95)
    • TIMI major bleeding: 1% in both groups, HR 1.25 (0.49-3.17)
  • Efficacy outcomes
    • Death: Rivaroxaban 1%, ASA 1.5%, HR 0.95 (0.53-1.71)
    • CV death, MI, stroke or definite stent thrombosis: 5% in both groups, HR 1.06 (0.77-1.46)
    • Any stent thrombosis: 1% in both groups, HR 1.06 (0.54-2.11)

Internal validity

  • Low risk of bias (including allocation, performance, detection, attrition and reporting biases)
    • Computer-generated randomization
    • Centralized, electronic allocation (allocation concealment)
    • Blinding using identical placebos
    • <0.5% (1 patient) lost to follow-up

Generalizability & applicability

  • Excluded patients with an indication for full-dose anticoagulation (e.g. AF, LV thrombus, VTE)
  • Rivaroxaban dose is dose found to be efficacious in ACS in ATLAS trial, but only 25% of dose demonstrated to have efficacy in AF & VTE
  • Majority used ticagrelor as P2Y12 inhibitor
  • Phase 2 trial:
    • Not powered to compare low-dose rivaroxaban to ASA for: Death, major bleed, and efficacy (including MI, stroke or stent thrombosis)
    • Not formally designed as a non-inferiority trial, but primary analysis met wide pre-defined non-inferiority margin (HR <2.0)