ATLAS - Rivaroxaban in patients with a recent ACS

in

ATLAS ACS 2-TIMI 51: Mega JL, et al. Rivaroxaban in patients with a recent acute coronary syndrome. NEJM 2012;366:9-19.

Bottom line:

  • Over ~13 months of follow-up, the addition of rivaroxaban 2.5 mg BID to ASA+clopidogrel/ticlopidine reduced the risk of CV events, mainly driven by fatal events, which led to lower all-cause mortality (NNT 63) in patients post-ACS. Adding rivaroxaban also reduced stent thrombosis (NNT 143). This came at the cost of a greater risk of major bleeds (NNH 84), including intracranial hemorrhages (NNH 500).

  • Adding rivaroxaban 5 mg BID did not reduce mortality, & further increased the risk of major bleeds.

  • It remains unclear which of the following regimens would have the best balance between efficacy & safety: Ticagrelor-based DAPT, clopidogrel-based DAPT + low-dose rivaroxaban, or ticagrelor-based DAPT + low-dose rivaroxaban.

Patients (n=15,526)

  • Included
    • ACS (within 7 days of admission, after revascularization if planned)
    • Plus either
      • Age >55 y
      • Previous MI
      • Diabetes
    • Excluded
      • Previous intracranial hemorrhage
      • Clinically-significant GI bleed within 12 months
      • CrCl <30 mL/min
      • Hb <100 g/L
      • Platelet count <90
  • Baseline characteristics
    • Age 61.5 y (9.6% 75 y or greater)
    • Female 25%
    • STEMI (~50%), NSTEMI (~25%), UA (~25%)
    • Previous MI 27%
    • CV risk factors: HTN ~67%, diabetes ~32%, dyslipidemia ~50% 
    • CrCl 86 mL/min
    • Meds
      • ASA 99%, P2Y12 inhibitor ~93%
      • ACEI/ARB ~40%
      • Beta-blocker ~66%
      • Statin ~15%

Interventions

  • Intervention1: Rivaroxaban 2.5 mg BID
  • Intervention2: Rivaroxaban 5 mg BID
  • Control: Placebo
  • All groups: ASA + clopidogrel or ticlopidine

Results @ 13.1 months

Considerations

  • Low risk of bias (allocation, performance, detection & attrition)
    • Allocation concealed by central computer/phone allocation
    • Participants, clinicians & investigators blinded to study drug
    • Modified ITT & full ITT analysis
    • 0.3% lost to follow-up, though ~28% in all groups discontinued study drug before end of study
  • Generalizability
    • Patients represented a group of post-ACS patients at very high risk of recurrent ASCVD with very low use of proven secondary prevention therapies
    • Additionally, this trial was performed before approval of more potent P2Y12 inhibitors (prasugrel & ticagrelor), so background DAPT included ASA + clopidogrel/ticlopidine (how many specifically received clopidogrel not reported)
    • Based on the preliminary results from ATLAS ACS-TIMI 46 (see below), the investigators selected 2.5 and 5 mg BID doses of rivaroxaban for this trial; this is pharmacokinetically rational given the 5-13h half-life of rivaroxaban (apixaban & dabigatran have similar half-lives and are generally dosed BID), however, it is a very different regimen than that used for AF/VTE. As a result, it's unclear if this regimen preserves the efficacy of rivaroxaban for these other conditions.

Summary of ATLAS ACS-TIMI 46

  • Dose-ranging study with identical enrolment criteria as ATLAS ACS 2-TIMI 51