PDF: AFIRE
(2019)Objective
To determine whether rivaroxaban monotherapy is noninferior to combination therapy with rivaroxaban plus an antiplatelet agent in patients with atrial fibrillation and stable coronary artery disease
Study Summary
• Rivaroxaban monotherapy was noninferior for efficacy (4.14% vs 5.75% per patient-year, HR 0.72, P<0.001)
• Monotherapy superior for safety with lower major bleeding (1.62% vs 2.76%, HR 0.59, P=0.01)
Intervention
Rivaroxaban monotherapy (10-15 mg once daily based on creatinine clearance) versus rivaroxaban plus single antiplatelet agent (aspirin or P2Y12 inhibitor)
Inclusion Criteria
Age ≥20 years, atrial fibrillation, stable coronary artery disease (PCI or CABG >1 year prior OR angiographically confirmed CAD not requiring revascularization), CHADS2 score ≥1
Study Design
Arms: Rivaroxaban monotherapy vs Rivaroxaban + antiplatelet combination therapy
Patients per Arm: 1107 monotherapy, 1108 combination therapy
Outcome
• All-cause death: 1.85% vs 3.37% (HR 0.55, 95% CI 0.38-0.81)
• Major bleeding: 1.62% vs 2.76% (HR 0.59, 95% CI 0.39-0.89, P=0.01)
Bottom Line
In patients with atrial fibrillation and stable coronary artery disease, rivaroxaban monotherapy was noninferior to combination therapy for efficacy and superior for safety. The trial was stopped early due to increased mortality in the combination therapy group. Rivaroxaban monotherapy is the preferred approach in this population based on both efficacy and safety.
Major Points
- First adequately powered randomized trial of oral anticoagulant monotherapy vs combination therapy in AF patients with stable CAD >1 year after revascularization
- Trial stopped early due to increased mortality in combination therapy group
- 2236 patients randomized (1107 monotherapy, 1108 combination therapy); mean age 74 years, 79% male
- 70.6% had previous PCI, 11.4% had previous CABG; median CHADS2 score 2
- Primary efficacy endpoint (CV events or death): 4.14% vs 5.75% per patient-year (HR 0.72, 95% CI 0.55-0.95, P<0.001 for noninferiority)
- Post-hoc superiority analysis: P=0.02 for primary efficacy endpoint
- All-cause mortality significantly lower with monotherapy: 1.85% vs 3.37% (HR 0.55, 95% CI 0.38-0.81)
- Cardiovascular death: 1.17% vs 1.99% (HR 0.59); noncardiovascular death: 0.68% vs 1.39% (HR 0.49)
- Primary safety endpoint (major bleeding): 1.62% vs 2.76% per patient-year (HR 0.59, 95% CI 0.39-0.89, P=0.01)
- Net adverse clinical events lower with monotherapy: 3.90% vs 6.28% (HR 0.62, 95% CI 0.47-0.82)
- Benefits consistent across subgroups including age, sex, diabetes, renal function, stroke/bleeding risk scores
- Among combination therapy patients: 70.2% received aspirin, 26.8% received P2Y12 inhibitor
Study Design
- Study Type
- Multicenter, randomized, open-label, parallel-group, noninferiority trial
- Randomization
- Yes
- Blinding
- Open-label for treatment; blinded independent clinical events committee for endpoint adjudication. Independent data and safety monitoring committee reviewed data.
- Sample Size
- 2215
- Follow-up
- Median 24.1 months (IQR 17.3-31.5); median treatment duration 23.0 months (IQR 15.8-31.0). Planned follow-up 24-45 months.
- Centers
- 294
- Countries
- Japan
Primary Outcome
Definition: Composite of stroke, systemic embolism, myocardial infarction, unstable angina requiring revascularization, or death from any cause. Originally included only cardiovascular death but changed to all-cause death in August 2015.
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 121 of 1108 (5.75% per patient-year) | 89 of 1107 (4.14% per patient-year) | 0.72 (0.55-0.95) | P<0.001 for noninferiority; P=0.02 for superiority (post-hoc analysis) |
Limitations & Criticisms
- Trial stopped early due to increased mortality in combination therapy group, which may overestimate efficacy data
- Open-label design has potential to introduce bias, though all events were adjudicated by blinded independent committee
- Relatively high rates of withdrawal and loss to follow-up (though within anticipated 5% and balanced between groups)
- Rivaroxaban dose used was Japan-approved dose (10-15 mg daily) rather than global dose (20 mg daily), though pharmacokinetic modeling showed similar blood levels
- Choice of antiplatelet agent (aspirin vs P2Y12 inhibitor) at physician discretion creates heterogeneity; unclear if benefit applies equally to both combinations
- Reductions in ischemic events and all-cause death with monotherapy were unanticipated and difficult to explain biologically; may be due to chance
- Only Japanese patients enrolled; generalizability to other populations uncertain
- Conducted in stable CAD patients >1 year post-revascularization; does not address immediate post-PCI period
- Sample size calculation based on 2200 patients and 219 events; early termination may have affected power
- Noninferiority margin of HR 1.46 is relatively wide
- 25% of patients had angiographically confirmed CAD not requiring revascularization, different population from typical post-PCI patients
- High cardiovascular and bleeding risk population (mean CHADS2 2.5, 52% age ≥75 years)
- Multiple causes of death differences (cardiovascular, noncardiovascular, cancer) difficult to attribute to antithrombotic regimen
- Some heterogeneity in stent types (drug-eluting 69-70%, bare-metal 23-24%, both types 2.6-5%)
- Follow-up assessments only at baseline, 6 months, and end of trial (plus routine clinical care as needed)
Citation
N Engl J Med 2019;381:1103-13