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/systemic embolism
• High-dose edoxaban showed 21% reduction in stroke (HR 0.79) during treatment period
• Both edoxaban doses significantly reduced major bleeding and cardiovascular death compared to warfarin
• High-dose edoxaban showed 21% reduction in stroke (HR 0.79) during treatment period
• 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: Approximately 7,000 patients per arm
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, 95% CI 0.63–0.99, p<0.001 for noninferiority, p=0.02 for superiority). In overall study period (including post-drug transition): HR 0.87, p=NS for superiority.
- Low-dose edoxaban (30 mg) met noninferiority but had numerically more ischemic strokes: stroke/SE 1.61% vs 1.50%/yr (HR 1.07, p=0.005 for noninferiority). Ischemic stroke specifically: 1.77% vs 1.25%/yr (HR 1.41, p<0.001) — unacceptable in most patients. The 30mg dose was not approved for AF in the US.
- Most impressive bleeding reduction of any DOAC trial — high-dose: major bleeding 2.75% vs 3.43%/yr (HR 0.80, p<0.001); low-dose: 1.61%/yr (HR 0.47, 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.
- Best warfarin TTR of any DOAC trial: 68.4% — making this the fairest comparison against well-managed warfarin. Centers with TTR >66.4% (upper 2 quartiles) still showed noninferiority for high-dose edoxaban, validating the result even against optimal warfarin care.
- Built-in dose-reduction algorithm: 50% dose reduction for CrCl 30–50 mL/min, body weight ≤60 kg, or concomitant verapamil/quinidine/dronedarone (potent P-gp inhibitors). 25.4% received reduced dose at randomization. This protocol-mandated reduction was validated — reduced-dose patients maintained efficacy with less bleeding.
- Transition-to-warfarin analysis revealed a critical finding: at trial end, patients switching from edoxaban to warfarin had an excess of stroke events during the transition period. This led to an FDA boxed warning about abrupt discontinuation without anticoagulant coverage — a warning unique to edoxaban among DOACs.
- GI bleeding was higher with high-dose edoxaban (1.51% vs 1.23%/yr, p=0.03) — consistent with the GI bleeding signal seen with rivaroxaban and dabigatran 150mg, but NOT with the low-dose edoxaban (0.82%, p<0.001 for reduction). 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
- 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), 1.80% per year (overall study period) | 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: 0.63-0.99 (treatment), 0.73-1.04 (overall); Low-dose: 0.87-1.31 (treatment), 0.96-1.34 (overall)) | High-dose: P<0.001 for noninferiority, P=0.02 for superiority (treatment); Low-dose: P=0.005 for noninferiority |
Limitations & Criticisms
- Post-trial transition period: abrupt switch from edoxaban to warfarin caused an excess of stroke events (bridging gap), leading to a unique FDA boxed warning. This operationally complicated real-world use — clinicians must ensure adequate anticoagulant overlap when stopping edoxaban.
- Low-dose edoxaban (30 mg) showed 41% MORE ischemic stroke than warfarin (HR 1.41, p<0.001) — an unacceptable trade-off despite dramatically less bleeding. This arm was not approved in the US and should not be used as primary stroke prevention dose.
- High-dose GI bleeding excess (1.51% vs 1.23%/yr, 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.
- Edoxaban was the last DOAC to market (FDA approved 2015) and has the smallest market share — clinical experience and post-marketing safety data are less extensive than for apixaban or rivaroxaban.
- 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).
- FDA's unusual stance: approved only the 60 mg dose for AF, with a labeling note that the 30 mg dose should NOT be used. Also added a boxed warning about transitions — more warnings than any other DOAC label.
- Best TTR (68.4%) means the warfarin comparator was strongest, which supports edoxaban's noninferiority but also means the absolute benefit over warfarin was smallest — in settings with poor TTR, edoxaban would show larger benefit.
- Industry-sponsored (Daiichi Sankyo) — the smallest DOAC manufacturer, with less academic and clinical infrastructure supporting real-world implementation and post-marketing surveillance.
Citation
N Engl J Med 2013;369:2093-104