AUGUSTUS - Antithrombotic regimens including apixaban vs warfarin, & aspirin vs placebo, in patients with AFib plus PCI &/or ACS

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Reference: Lopes RD, et al. Antithrombotic therapy after acute coronary syndrome or PCI in atrial fibrillation. NEJM 2019.

Bottom line: In patients with atrial fibrillation who either undergo PCI and/or have ACS, in combination with a P2Y12 inhibitor (almost always clopidogrel):

  • Apixaban reduces the risk of major or clinically-relevant non-major bleeding (NNT=24), hospitalizations (NNT=27), & stroke (NNT=84) compared to warfarin at 6 months;

  • Aspirin (beyond the first week) increases the risk major or clinically-relevant non-major bleeding (NNH=15), without a clear effect on hospitalization/death or ischemic events compared to placebo at 6 months;

  • Therefore, an antithrombotic regimen of apixaban + clopidogrel (without aspirin) should be routinely considered in these patients. Warfarin should be limited to patients for whom a DOAC is contraindicated, intolerable or unaffordable; & aspirin beyond the first week should be limited to patients with very high risk of stent thrombosis/recurrent coronary events.

Patients (n=4614 from 33 countries)

  • Included if (all of the following):

    • Age 18+ years

    • Known AF (paroxysmal, persistent or permanent) with planned long-term oral anticoagulation

    • Recent (<14 days) ACS &/or PCI with plan for 6+ months of P2Y12 inhibitor

  • Key exclusion criteria:

    • Other indication for anticoagulation (prosthetic valve, VTE, mitral stenosis, etc)

    • History of intracranial hemorrhage, ongoing bleeding or coagulopathy

    • Recent/planned CABG

    • “Severe” renal insufficiency

  • Average baseline characteristics:

    • Age 71 years, male (71%), white (92%)

    • Qualifying event: ACS+PCI (37%), medically-managed ACS (24%), elective PCI (39%)

      • ~6.6 days from ACS/PCI to randomization

    • CHA2DS2-VASc ~4, HAS-BLED ~3

    • Prior stroke/TIA/thromboembolism (14%), HF (43%), HTN (88%), diabetes (36%)

    • SCr >133 (8%)

    • Previous oral anticoagulant (49%)

Interventions x6 months

  • 2x2 factorial design: Patients were simultaneously randomized to apixaban vs warfarin & aspirin vs placebo within 14 days of ACS &/or PCI, so total of 4 different intervention groups.

  • Management prior to randomization: At the discretion of treating physicians according to local standard of care (likely that all at least received DAPT +/- anticoagulation leading up to randomization, though not recorded/reported)

  • Anticoagulation: Apixaban vs warfarin

    • Apixaban arm: 5 mg PO BID

      • Reduced to 2.5 mg PO BID if 2 of the following: Age >80 years, wt <60 kg, SCr >133 umol/L

      • Discontinued study regimen prematurely: 13%

    • Warfarin to target INR 2.0-3.0

      • Median time in therapeutic range (TTR)=59%; INR<2.0 23% of the time, INR>3.0 3% of the time

      • Discontinued study regimen prematurely: 14%

  • Antiplatelet: Aspirin 81 mg PO daily vs matching placebo

    • Discontinued study drug prematurely: 15-17%

  • All: P2Y12 inhibitor left at the discretion of the treating clinicians (clopidogrel 93%, prasugrel 1%, ticagrelor 6%)

  • After 6 months, anticoagulation & antiplatelets were managed according to local standard of care (i.e. not standardized for the trial)

Results @ 6 months

  • Primary outcome: Major or clinically-relevant non-major bleeding, ISTH definition

  • Key secondary outcomes: Composite of death or hospitalization; composite of death or ischemic events (stroke, MI, definite/probable stent thrombosis, or urgent revascularization).

Outcomes at 6 months of apixaban versus warfarin in combination with P2Y12 inhibitor +/- aspirin

Outcomes at 6 months of aspirin versus placebo in combination with P2Y12 inhibitor + apixaban or warfarin

Risk of bias

  • Low risk of: Allocation bias (allocation concealed via interactive voice-response system), attrition bias (low [0.3%] loss to follow-up & analyzed by intention-to-treat), outcome reporting bias (all outcomes of interest defined & reported).

  • Variable risk of performance/detection bias:

    • Apixaban vs warfarin comparison was open-label (i.e. patients & clinicians aware of treatment assignment):

      • All outcomes were adjudicated by a blinded clinical endpoint committee, therefore providing some protection against (but not eliminating) detection bias.

    • Aspirin vs placebo comparison was blinded (patients, clinicians, outcome adjudicators unaware of treatment assignment): Low risk of performance & detection bias.