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ENSURE-AF: Edoxaban noninferior to standard anticoagulation before cardioversion in patients with AF
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In patients with atrial fibrillation undergoing cardioversion, edoxaban conferred similar outcomes to the standard care of warfarin plus enoxaparin, according to findings from the ENSURE-AF study presented at the European Society of Cardiology Congress.
“At a practical level, our study results show that newly diagnosed nonanticoagulated AF patients can start edoxaban as early as 2 hours prior to their cardioversion procedure if they have access to transesophageal echocardiography (TEE) or 3 weeks prior without,” Andreas Goette, MD, from the departments of cardiology and intensive care medicine, St. Vincenz-Hospital, Paderborn, Germany, said in a press release.
Andreas Goette
Goette and colleagues performed a randomized, open-label, phase 3b trial of 2,199 patients at 239 centers in 19 countries requiring cardioversion for nonvalvular AF (mean age, 64 years; mean CHA2DS2-VASc score, 2.6; standard deviation, 1.4). Patients were randomly assigned edoxaban (Savaysa, Daiichi Sankyo) 60 mg per day (reduced to 30 mg per day in cases of low body weight, low creatinine clearance or P-glycoprotein inhibitor use) or warfarin plus enoxaparin.
The primary efficacy endpoint was a composite of stroke, systemic embolic event, MI and CV death. The primary safety endpoint was major and clinically relevant nonmajor bleeding in patients receiving at least one dose of the study drug. Follow-up was for 28 days on the study drug after cardioversion plus an additional 30 days for safety evaluation. The results were simultaneously published in The Lancet.
Among those assigned warfarin, mean time in therapeutic range was 70.8% (standard deviation, 27.4). Unlike warfarin, edoxaban, an oral Factor Xa inhibitor, does not require regular monitoring, Goette said in the release.
During the study period, the primary efficacy endpoint occurred in five (< 1%) patients assigned edoxaban vs. 11 (1%) assigned warfarin plus enoxaparin (OR = 0.46; 95% CI, 0.12-1.43), according to the researchers.
The primary safety endpoint occurred in 16 (1%) of those who took at least one dose of edoxaban vs. 11 (1%) of those who took at least one dose of warfarin plus enoxaparin (OR = 1.48; 95% CI, 0.64-3.55).
“Edoxaban had similar rates of major bleeding and thromboembolism compared to well-managed, optimized enoxaparin/warfarin therapy,” Goette said in the release. “The results were similar whether TEE guidance was used or not, whether patients had received prior anticoagulation or not, and in patients with a broad range of associated comorbidities.”
Howard Rutman, MD, vice president of medical affairs for Daiichi Sanyko, told Cardiology Today that the results “may have important clinical implications for newly diagnosed nonanticoagulated [patients with AF] needing to undergo cardioversion. … We are pleased with the results from ENSURE-AF, which expand our understanding of the use of once-daily edoxaban” in that population.
While ENSURE-AF was the largest randomized trial of a non-vitamin K antagonist oral anticoagulant in patients with AF undergoing cardioversion, “it’s important to broaden scientific knowledge about the safety and efficacy of non-vitamin K antagonist oral anticoagulants in AF procedures undergoing a range of [CV] procedures,” Rutman said. – by Erik Swain
References:
Goette A, et al. Hot Line: Preventive strategies 2. Presented at: European Society of Cardiology Congress; Aug. 27-31, 2016; Rome.
Goette A, et al. Lancet. 2016;doi:10.1016/S0140-6736(16)31474-X.
Disclosure: The study was funded by Daiichi Sankyo. Goette reports consulting for Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo and Pfizer, and speaking for AstraZeneca, Bayer, Berlin Chemie, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Medtronic, Pfizer and Sanofi Aventis. Rutman is an employee of Daiichi Sankyo.
Perspective
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Jagmeet Singh, MD, PhD
ENSURE-AF was a well-conducted trial in over 2,000 patients which showed that the entire period of anticoagulation in the patient with AF prior to a cardioversion can be abbreviated. The study demonstrated that one does not have to wait for a 3-week period of anticoagulation prior to the cardioversion. Instead, administering edoxaban 2 hours earlier can suffice in proceeding with electrically converting the individual to normal sinus rhythm. These patients did just as well in terms of the primary endpoint, freedom from stroke, MI, CV mortality or bleeding.
These findings absolutely have the potential to impact clinical practice. Data suggesting that a short pre-procedural period with a direct oral anticoagulant prior to cardioversion is similar to warfarin will impact the way we treat new-onset nonvalvular AF. Just having to take a pill orally 2 hours prior to the cardioversion obviates the need for a cumbersome approach of using warfarin and the concomitant overlapping use of heparin plus enoxaparin. However, it is important to note that the study was not powered for adequately showing differences in the safety or efficacy endpoints.
I think it would be interesting to understand the patient population a little better. A subanalysis to determine if there is a subset of patients that we can eliminate the need for a TEE prior to cardioversion would be very useful. Understanding the impact of the duration of AF, the left atrial size and the CHA2DS2-VASc score in this patient population and using this to help risk-stratify patients that may not need a TEE prior to cardioversion may further enhance the adoption of this approach.
The X-VERT study examined the same clinical issue using another factor Xa inhibitor (rivaraxoban; Xarelto, Janssen Pharmaceuticals) and found similar results. That study was also not adequately powered. The incidence of stroke is so small that that we may have to make our inferences off these two studies, as trying to put into place an adequately powered noninferiority study may involve several thousands of patients.
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