AFIRE - Antithrombotics for AF + stable CAD
Bottom Line:
Among Japanese patients with AF warranting OAC & stable CAD, using OAC monotherapy reduced the risk of dying (3% fewer) & having a major bleed (2% fewer) without increasing thrombotic risk compared with OAC plus an antiplatelet at 2 years.
These results are likely generalizable to non-Japanese patients & to other DOACs using approved doses.
Participants (n=2246 randomized, n=2215 analyzed)
Setting: Japan, enrolled 2015-2017
Included
Age >20 y
AF with CHADS2 score 1-6
Stable CAD (prior PCI or CABG >1 y ago, coronary stenosis 50%+ on angiography)
Key exclusion
Prior stent thrombosis
Active tumor
Poorly-controlled HTN
Baseline
Age 74 y, female 21%
AF: Paroxysmal 53%, persistent 15%, permanent 32%
CHADS2=2, CHA2DS2-VASc=4, HASBLED=2 (medians)
Previous stroke 15%, MI 35%, PCI 71% (drug-eluting stent 65-70%, mostly everolimus-eluting)
Current smoker 13%, diabetes 42%
CrCl <50 mL/min 34%
Intervention: Oral anticoagulant (OAC) monotherapy
Rivaroxaban 15 mg/d if CrCl 50+ (standard dose in Japan)
If CrCl 15-49: 10 mg/d (equivalent to 15 mg/d in non-Japanese)
3.5% used antiplatelet
Control: OAC + antiplatelet
Rivaroxaban (as above) + antiplatelet (ASA or P2Y12 inhibitor at clinician’s discretion)
Antiplatelet used: ASA 70%, P2Y12 inhibitor 27%, other 2%, none <1%
Outcomes @ median 24 months
Primary outcome (death, stroke, systemic embolism, MI, unstable angina requiring PCI/CABG):
OAC 8.0% vs OAC+antiplatelet 10.9% (ARR 2.9%, NNT 35)
Hazard ratio (HR) 0.72 (95% confidence interval 0.55-0.95)
Death: 3.7% vs 6.6% (HR 0.55, 0.38-0.81; ARR 2.9%, NNT 35)
Ischemic stroke: 1.9% vs 2.5%
MI: 1.2% vs 0.7%
Major bleed (ISTH definition): 3.2% vs 5.2% (HR 0.59, 0.39-0.89; ARR 2%, NNT 50)
Hemorrhagic stroke: 0.4% vs 1.2% (HR 0.30, 0.10-0.92)
Internal Validity: Low risk of bias overall
Allocation bias: Low risk
Randomization using computer-generated minimization algorithm
Allocation concealed via web-based response system
Performance bias: Unclear risk
Open-label (patients & clinicians aware of allocated intervention)
Potential for crossover, differential management of antithrombotics & other cardiovascular risk factor modification
Detection bias: Low risk
Difference in outcomes driven by mortality; hard outcome with little opportunity to “game”
Outcomes assessed by blinded adjudication committee
Attrition bias: Low risk
Analyzed modified intention-to-treat (mITT) population & per-protocol (for non-inferiority)
Loss-to-follow-up: OAC monotherapy 2.5%, OAC+antiplatelet 1.8%
Other biases: Low risk
Stopped early for safety (higher risk of death in comparator group)
Other Considerations
Non-inferiority trial
Non-inferiority margin HR<1.46
Non-inferiority (and superiority) of OAC monotherapy met in both mITT & per-protocol analyses
Lower dose of rivaroxaban than used in North America
The approved “full dose” of rivaroxaban for stroke prophylaxis in AF in Japan is 15 mg/d (rather than 20 mg/d outside Asia) based on the J-ROCKET AF trial, as well as supporting pharmacokinetic-pharmacodynamic data
The 20 mg/d dose should be used among non-Asians. It is unclear what dose we should use in non-Japanese Asians & South Asians.