Lower dose DOAC reduces net clinical outcome in patients with AF
Randomized, Double-Blind Comparison of Half-Dose Versus Full-Dose Edoxaban in 14,014 Patients With Atrial FibrillationLiterature - Steffel J, Ruff CT, Yin O, et al. - J Am Coll Cardiol. 2021 Mar 9;77(9):1197-1207. doi: 10.1016/j.jacc.2020.12.053.
Introduction and methods
The ENGAGE AF-TIMI 48 trial has demonstrated non-inferiority for higher dose edoxaban regimen (HDER) and lower dose edoxaban regimen (LDER) compared to well-managed warfarin in the prevention of stroke or systemic embolic events (SEE) in patients with AF . Both regimens, compared to warfarin, reduced the risk of major bleeding and CVD, but LDER increased the incidence for ischemic stroke. This has led to the approval of HDER for the prevention of stroke in patients with AF [2,3]. Although the risk of bleeding is lower with DOACs than with VKAs, the fear of bleeding in some high-risk patients has resulted in an overuse of unstudied underdosing in these patients [4-7].
This study comprehensively compared the pre-defined net clinical outcome (NCO) of LDER (30 mg once daily or dose reduced to 15 mg) vs. HDER (60 mg once daily or dose reduced to 30 mg) in the ENGAGE AF-TIMI 48 trial. The NCO could be a better assessment of efficacy and safety, because it represents a more integrative approach towards overall patient outcome contrary to single events.
The ENGAGE AF-TIMI 48 trial was a phase III, double-blind, double-dummy study that included patients with AF who had a moderate to high risk of stroke (CHADS₂ score ≥2). Patients were randomized to LDER (n=7,002), HDER (n=7,012), or warfarin. The dose of HDER or LDER was reduced by 50% in patients with a creatinine clearing of 30-50 mL/min, body weight ≤60 kg, or in those concomitantly treated with quinidine, verapamil or dronedarone. The efficacy endpoint of the trial was stroke/SEE. The safety endpoints were major bleeding, clinically relevant non-major bleeding and intracranial hemorrhage. The pre-defined primary NCO was a composite of stroke, SEE, major bleeding, or all-cause mortality. The secondary NCO included disabling stroke, life-threatening bleeding, or all-cause mortality and tertiary NCO was defined as stroke, SEE, life-threatening bleeding, or all-cause mortality. Median follow-up was 2.8 years.
- Patients with LDER had a significant risk reduction for the primary NCO stroke/SEE, major bleeding, or death compared to patient with HDER (7.26% vs. 8.01%, respectively; HR 0.90, 95% CI: 0.84-0.98, P=0.014).
- There were no differences in secondary and tertiary NCOs observed between LDER and HDER treatments.
- Patients on LDER had a higher risk of stroke or SEE compared to the ones on HDER (2.04% vs. 1.56%, respectively; HR 1.31, 95% CI: 1.12-1.52, P<0.001). This was mainly caused by a 43% increase in ischemic strokes (1.77% vs. 1.24%, respectively; HR 1.43, 95% CI: 1.21-1.69). Also, all strokes (HR 1.30, 95% CI: 1.11-1.52, P=0.001) and SEE (HR 1.92, 95% CI: 1.03-3.59, P=0.04) were significantly higher in patients with LDER vs HDER.
- Major bleeding (HR 0.64, 95% CI: 0.55-0.74, P<0.001), intracranial hemorrhage (HR 0.65, 95% CI: 0.44-0.97, P=0.035), major gastrointestinal bleeding (HR 0.57, 95% CI: 0.46-0.70, P<0.0001), and fatal and/or life-threatening bleeding (HR 0.61, 95% CI: 0.44-0.84, P=0.002) were less frequently observed with LDER compared to HDER.
- Patients with reduced LDER (15mg) and HDER (30 mg) doses had an even more reduced risk for hemorrhagic or intracranial strokes compared to patients on 30 mg LDER or 60 mg HDER (hemorrhagic stroke P=0.006, intracranial stroke P=0.004).
In the on-treatment population of the ENGAGE AF-TIMI 48 trial, LDER decreased the primary NCO of major bleeding, stroke, and SEE, and mortality in patients with AF compared to HDER. The incidence of bleeding was reduced in patients with LDER and was even further reduced when the dose was reduced by half. However, the incidence of stroke and SEE occurred significantly more often in patients using LDER compared to those with HDER. The secondary and tertiary NCOs were similar between LDER and HDER.
The authors suggest that these results may aid physicians which edoxaban dose to prescribe to patients. However, the approved HDER for the prevention of stroke in patients with AF remains the standard therapy