PDF: ENGAGE AF-TIMI 48
(2013)Objective
To compare two once-daily regimens of edoxaban with warfarin for stroke prevention in patients with atrial fibrillation
Study Summary
• Both edoxaban regimens were noninferior to warfarin for preventing stroke or systemic embolism
• High-dose edoxaban reduced stroke/systemic embolism by 21% during treatment (HR 0.79, 97.5% CI 0.63–0.99); stroke alone HR 0.88 (95% CI 0.75–1.03), P=0.11
• Both edoxaban doses significantly reduced major bleeding and cardiovascular death compared to warfarin
• High-dose edoxaban reduced stroke/systemic embolism by 21% during treatment (HR 0.79, 97.5% CI 0.63–0.99); stroke alone HR 0.88 (95% CI 0.75–1.03), P=0.11
• Both edoxaban doses significantly reduced major bleeding and cardiovascular death compared to warfarin
Intervention
Edoxaban (high-dose 60mg or low-dose 30mg once daily) versus warfarin (INR 2.0-3.0)
Inclusion Criteria
Age ≥21 years, atrial fibrillation documented within 12 months, CHADS2 score ≥2, planned anticoagulation therapy
Study Design
Arms: Three arms: warfarin, high-dose edoxaban, low-dose edoxaban
Patients per Arm: Warfarin N=7,036; high-dose edoxaban N=7,035; low-dose edoxaban N=7,034 (total 21,105)
Outcome
• Primary endpoint (stroke/systemic embolism): 1.50% warfarin vs 1.18% high-dose vs 1.61% low-dose edoxaban per year
• Major bleeding: 3.43% warfarin vs 2.75% high-dose vs 1.61% low-dose edoxaban per year
• Cardiovascular death significantly lower with both edoxaban regimens
• Major bleeding: 3.43% warfarin vs 2.75% high-dose vs 1.61% low-dose edoxaban per year
• Cardiovascular death significantly lower with both edoxaban regimens
Bottom Line
Both once-daily edoxaban regimens were noninferior to warfarin for preventing stroke or systemic embolism and were associated with significantly lower rates of bleeding and cardiovascular death.
Major Points
- ENGAGE AF-TIMI 48 was the fourth and largest DOAC trial in AF (21,105 patients), completing the quartet after RE-LY (dabigatran), ROCKET AF (rivaroxaban), and ARISTOTLE (apixaban). It tested edoxaban, a once-daily factor Xa inhibitor.
- Unique three-arm design: high-dose edoxaban (60 mg), low-dose edoxaban (30 mg), and warfarin — the only DOAC trial to test two clinically distinct doses against warfarin in the same trial, providing a dose-response relationship.
- High-dose edoxaban (60 mg) met noninferiority AND showed superiority during treatment period: stroke/SE 1.18% vs 1.50%/yr (HR 0.79, 97.5% CI 0.63–0.99, P<0.001 for noninferiority, P=0.02 for superiority). In the intention-to-treat analysis over the overall study period (randomization to end of double-blind treatment): HR 0.87 (97.5% CI 0.73–1.04), P=0.08 for superiority.
- Low-dose edoxaban (30 mg, reduced to 15 mg when dose-reduction criteria met) met noninferiority but had numerically more ischemic strokes: stroke/SE 1.61% vs 1.50%/yr (HR 1.07, 97.5% CI 0.87–1.31, P=0.005 for noninferiority; P=0.44 for superiority). Ischemic stroke specifically: 1.77% vs 1.25%/yr (HR 1.41, 95% CI 1.19–1.67, P<0.001).
- Most impressive bleeding reduction of any DOAC trial — high-dose: major bleeding 2.75% vs 3.43%/yr (HR 0.80, 95% CI 0.71–0.91, P<0.001); low-dose: 1.61%/yr (HR 0.47, 95% CI 0.41–0.55, P<0.001). A 53% reduction in major bleeding with low-dose was unprecedented.
- Both doses significantly reduced hemorrhagic stroke (HR 0.54 and 0.33), intracranial bleeding (HR 0.47 and 0.30), life-threatening bleeding (HR 0.51 and 0.32), and cardiovascular death (HR 0.86 and 0.85, both P≤0.01) — edoxaban had the most consistent CV mortality benefit among DOACs.
- Well-managed warfarin comparator: median warfarin TTR 68.4% (IQR 56.5–77.4), mean 64.9±18.7%; INR was between 1.8 and 3.2 for 83.1% of the treatment period — providing a rigorous benchmark against which noninferiority was demonstrated.
- Built-in dose-reduction algorithm: 50% dose reduction for CrCl 30–50 mL/min, body weight ≤60 kg, or concomitant verapamil/quinidine (dronedarone added by Dec 22, 2010 protocol amendment). Overall, 5,330 of 21,105 patients (25.3%) received a reduced dose at randomization (arm-level ~25.4%). Reduced-dose patients maintained efficacy with less bleeding.
- During the 30-day transition from blinded study drug to open-label anticoagulation at trial end, primary-endpoint events were evenly distributed: 7 in each of the three treatment groups. Rates of major bleeding and death were also similar across groups during the transition period, suggesting no rebound activation of coagulation after edoxaban discontinuation.
- GI bleeding was higher with high-dose edoxaban (1.51% vs 1.23%/yr, HR 1.23, 95% CI 1.02–1.50, P=0.03) — consistent with the GI bleeding signal seen with rivaroxaban and dabigatran 150mg — but NOT with low-dose edoxaban (0.82%, HR 0.67, 95% CI 0.53–0.83, P<0.001). The low-dose arm uniquely reduced GI bleeding.
Study Design
- Study Type
- Randomized controlled trial
- Randomization
- Yes
- Blinding
- Double-blind, double-dummy - patients and investigators blinded to treatment assignment
- Sample Size
- 21105
- Follow-up
- Median 2.8 years (1022 days)
- Centers
- 1393
- Countries
- 46 countries including North America, Latin America, Western Europe, Eastern Europe, Asia-Pacific region, South Africa
Primary Outcome
Definition: Time to first adjudicated stroke (ischemic or hemorrhagic) or systemic embolic event
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 1.50% per year (treatment period, modified ITT); 1.80% per year (overall study period, ITT) | High-dose: 1.18% per year (treatment), 1.57% per year (overall); Low-dose: 1.61% per year (treatment), 2.04% per year (overall) | High-dose vs warfarin: 0.79 (treatment), 0.87 (overall); Low-dose vs warfarin: 1.07 (treatment), 1.13 (overall) | High-dose: P<0.001 for noninferiority, P=0.02 for superiority (treatment period), P=0.08 for superiority (overall ITT); Low-dose: P=0.005 for noninferiority, P=0.44 for superiority (treatment period), P=0.10 for superiority (overall ITT) |
Limitations & Criticisms
- Low-dose edoxaban (30 mg) showed 41% MORE ischemic stroke than warfarin (HR 1.41, 95% CI 1.19–1.67, P<0.001) — an unacceptable trade-off despite dramatically less bleeding.
- High-dose GI bleeding excess (1.51% vs 1.23%/yr, HR 1.23, P=0.03) — consistent class effect with other DOACs (except low-dose edoxaban and apixaban). Limits use in patients with GI bleeding risk factors.
- No head-to-head comparison with other DOACs — the largest DOAC trial but still compared only to warfarin. Cross-trial DOAC comparisons are indirect and fraught with population differences.
- Complex dose-reduction algorithm (3 criteria: CrCl, weight, P-gp inhibitors) may lead to errors in clinical practice — incorrect dose selection could lead to either stroke (underdosing) or bleeding (overdosing).
- The well-managed warfarin comparator (median TTR 68.4%) provided a rigorous test but also means the absolute benefit over warfarin was smallest — in settings with poor TTR, edoxaban would likely show a larger benefit.
- Industry-sponsored (Daiichi Sankyo Pharma Development) — potential for sponsor influence on trial conduct and reporting, though endpoints were independently adjudicated.
Citation
N Engl J Med 2013;369:2093-104