COMPASS - ASA + rivaroxaban (or riva alone) vs ASA alone in stable CVD

in

Eikelboom JW, et al. Rivaroxaban with or without aspirin in stable cardiovascular disease. NEJM 2017

Note: This was a factorial trial; the other intervention under study - pantoprazole vs placebo - will be reported later in a separate report.

Bottom line:

  • In patients with stable CAD/PAD, addition of rivaroxaban 2.5 mg PO BID to low-dose ASA resulted in a reduction in cardiovascular events, primarily driven by all-cause mortality & stroke (NNT ~144 each), and an increase in major & minor bleed (NNH 84 & 28, respectively) over an average duration of 1.9 years;

    • In patients with PAD, rivaroxaban + ASA also reduces the risk of major adverse limb events (NNT 100).

  • Monotherapy with rivaroxaban 5 mg PO BID did not reduce events compared to ASA monotherapy, but increased major & minor bleeds (NNH 112 & 39).

Patients (n=27,402)

  • Included either CAD or PAD:
    • CAD (MI within 20 years, multivessel CAD with symptoms or history of angina, multivessel PCI, multivessel CABG), plus
      • Age >65 y
      • Atherosclerosis in at least 2 vascular beds
      • At least 2 more risk factors (current smoking, diabetes, eGFR <60, non-lacunar stroke >1 month earlier)
    • PAD (with either claudication, previous revasc [including carotid], or amputation)
  • Exclusion
    • High bleeding risk
    • Recent stroke, or previous hemorrhagic or lacunar stroke
    • Severe HF
    • eGFR <15
    • Use of DAPT, anticoagulation, or other antithrombotic therapy
  • Baseline characteristics
    • Age 68 y
    • Female 22%
    • CV history
      • Previous MI 62% (mean 7.1 years ago)
      • CAD 90% (multivessel 62%; enrolled within 2 weeks of CABG ~5%)
      • PAD 27%
    • Risk factors: Tobacco use 21%, HTN 75%, diabetes 38%
    • eGFR: <30 (<1%), 30-59 (22%), 60+ (77%)
    • Meds: ACEI/ARB ~70%, BB 70%, lipid-lowering ~90%

Interventions

  • Intervention1: Enteric-coated ASA 100 mg/d + rivaroxaban 2.5 mg PO BID
  • Intervention2: Rivaroxaban 5 mg PO BID
  • Control: Enteric-coated ASA 100 mg/d

Results @ mean 1.9 years (max 3.92 years)

Subgroup analyses published in separate papers:

  • CAD (91% of study population, n=24,824)
    • Of the 69% with prior MI, timing: <1 y (5%), 1-5 y (29%), >5 y (34%)
    • 4-5% received DAPT during trial follow-up, & most in rivaroxaban groups D/Ced rivaroxaban
    • Efficacy & safety results virtually identical to full trial
    • Additional analyses:
      • Post-hoc defined coronary event composite (MI, coronary death, sudden death, resuscitated cardiac arrest, or unstable angina): ASA+riva vs ASA HR 0.83 (0.81-0.98)
      • Stent thrombosis: ASA+riva vs ASA HR 1.08 (0.72-1.61)
      • Coronary revascularization: ASA+riva vs ASA HR 0.95 (0.84-1.07)
      • Post-hoc landmark analysis suggests that efficacy HR consistent between years 1, 2 & >2, whereas bleeding risk is front-loaded & decreases after year 1
      • Further subgroups suggest that relative risk reduction similar across most subgroups, including those with vs without prior PCI, optimal use of 2o CV prevention vs not, & different risk categories. Notably, however, significant p-value for interaction suggesting no/less benefit in patients with history of CABG.
  • PAD or carotid disease (27% of study population, n=7470)
    • Efficacy & safety results virtually identical to full trial
    • Additional analyses:
      • Prespecified limb outcomes - Major adverse limb event or major amputation: ASA+riva 1% vs ASA 2%: HR 0.54 (0.35-0.82)
      • Composite of 1o outcome + limb outcome: ASA+riva 6% vs ASA 9% (NNT 34), HR 0.69 (0.56-0.85)
  • Modified ISTH definition of major bleed included standard ISTH major bleed components (fatal bleed, symptomatic bleed into a critical organ, bleeding into a surgical site requiring re-operation) plus bleeding that led to hospitalization (including ED visits without overnight stay)

Considerations

  • Risk of bias
    • Low for allocation, performance, detection, attrition bias
      • Computer-generated randomization (reported in Lancet substudies)
      • Allocation concealed by using central web-based randomization (reported in Lancet substudies)
      • Blinding of all participants, clinicians & investigators
      • 0.2% lost to follow-up, ~16% discontinued study drug before last follow-up (but continued follow-up)
      • ITT analysis
    • Trial stopped early after 1st interim analysis for efficacy of ASA + rivaroxaban
    • Run-in phase (active ASA & placebo rivaroxaban BID) to ensure patient able to adhere to trial regimen (~8% excluded after run-in)
  • Generalizability
    • This trial applies to patients with previous MI or clear history of angina/ischemia/coronary revascularization + angiographically-proven CAD, or with PAD
      • Unclear how these results may translate to use of higher doses of rivaroxaban once daily (i.e. rivaroxaban 15-20 mg once daily as used in AF +/- PCI)