The direct-acting oral anticoagulant benefitted prevention of adverse clinical events, but was associated with worse major bleeding.
Edoxaban (Savaysa) showed non-inferiority to vitamin K antagonist (warfarin) therapy for the treatment of atrial fibrillation in patients who had underwent successful transcatheter aortic-valve replacement (TAVR), according to new findings presented at the European Society of Cardiology (ESC) 2021 Congress this weekend.
Investigators from the ENVISAGE-TAVI AF trial confirmed the direct oral anticoagulant (DOAC), previously approved for the prevention of stroke and non-CNS systemic embolism, provided noninferior benefit for composite adverse event prevention to standard-care vitamin K antagonist in the observed patient population.
Approximately one-third of all patients to undergo TAVR experience atrial fibrillation, investigators explained, with non–vitamin K oral anticoagulants being the primary method of treatment.
"The effects of various antithrombotic strategies to prevent thromboembolic events with atrial fibrillation after TAVR have not been well studied," they wrote. "An exploratory subgroup analysis involving 191 patients with previous implantation of a bioprosthetic valve, the results of which are reported in a separate article, suggested that clinical outcomes may have been better with edoxaban than with warfarin."
The multicenter, prospective, randomized, open-label, adjudicator-masked assessment compared edoxaban to the competing drug class in patients with prevalent or incident atrial fibrillation.
Led by George Dangas, MD, PhD, Professor of Medicine at Icahn School of Medicine at Mount Sinai, the investigators sought a primary efficacy outcome of composite adverse events associated with post-TAVR atrial fibrillation, including:
The ENVISAGE-TAVI AF team also sought a primary safety outcome of major bleeding. The efficacy and safety outcomes were tested sequentially for noninferiority; edoxaban noninferiority was established in the upper boundary of the 95% confidence interval for a hazard ratio (HR) of composite events not exceeding 1.38.
Through the hierarchal testing, superiority testing for the DOAC therapy versus vitamin K antagonist would be conducted if edoxaban achieved noninferiority and superiority for major bleeding risk.
The trial population included 1426 patients enrolled 1:1 to either edoxaban (n = 713) or vitamin K antagonist (n = 713). Mean patient age was 82.1 years, with 47.5% of the population being women. Atrial fibrillation was prevalent in most patients prior to TAVR procedure.
Dangas and colleagues observed the composite primary efficacy outcome 17.3 times per 100 person-years among patients treated with edoxaban, versus 16.5 timers per 100 person-years among patients treated with vitamin K antagonist, indicating an HR of 1.05 (95% CI, 0.85 – 1.31; P = .01) and showing noninferiority of the DOAC.
Major bleeding rates were 9.7 per 100 person-years and 7.0 per 100 person-years in the 2 groups, respectively, indicating an HR of 1.40 (95% CI, 1.03 – 1.91; P = .93). Edoxaban did not achieve noninferiority in the primary safety outcome, primarily due to the significantly increase rate of gastrointestinal bleeding in patients with edoxaban.
All-cause deaths or stroke prevalence were 10.0 per 100 person-years among edoxaban-treated patients and 11.7 per 100 person-years among vitamin K antagonist-treated patients, showing edoxaban’s potential superiority in the 2 outcomes (HR, 0.85; 95% CI, 0.66 – 1.11).
Dangas and colleagues concluded that edoxaban provided noninferiority to vitamin K antagonist in the reduction of composite adverse clinical events among post-TAVR patients with atrial fibrillation. However, major bleeding incidence was observed to be greater with the DOAC therapy.
"Because of the hierarchical design of our statistical analysis, the failure to show noninferiority for major bleeding precluded formal testing for superiority of edoxaban, but the point estimate for the hazard ratio favored vitamin K antagonists and the confidence interval included 1, indicating that superiority of edoxaban would not have been shown," they wrote.
The study, “Edoxaban versus Vitamin K Antagonist for Atrial Fibrillation after TAVR,” was published online in The New England Journal of Medicine.