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
“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).
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.