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Edoxaban noninferior to warfarin for prevention of stroke, systemic embolism
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DALLAS — New data from the ENGAGE AF-TIMI 48 trial demonstrate that once-daily edoxaban was noninferior to warfarin for the prevention of stroke or systemic embolism, and was associated with significantly lower bleeding and CV death.
Researchers compared high- and low-dose oral edoxaban (Daiichi Sankyo) with warfarin in 21,105 patients with moderate- to high-risk atrial fibrillation and a score of 2 or higher on CHADS2 risk assessment.
“ENGAGE AF-TIMI 48 [is] the largest trial in AF to date,” Robert P. Giugliano, MD, researcher and physician at Brigham and Women’s Hospital, said at a press conference.
The randomized, double blind, double-dummy trial had three treatment arms: edoxaban 60 mg, edoxaban 30 mg or warfarin. The dose was halved if patients had estimated creatinine clearance of 30 to 50 mL per minute, body weight ≤60 mg and concomitant use of verapamil or quinidine.
Robert P. Giugliano
Patients were followed for a median of 2.8 years, making this “the longest trial of a novel [anticoagulant] agent,” Giugliano said.
The annualized rate of stroke or systemic embolism, the primary efficacy endpoint of the trial, was 1.5% with warfarin (median time in therapeutic range, 68.4%) vs. 1.18% with high-dose edoxaban (HR=0.79; 97.5% CI, 0.63-0.99; P<.001 for noninferiority) and 1.61% with low-dose edoxaban (HR=1.07; 95% CI, 0.87-1.31; P<.005 for noninferiority). In a superiority analysis that included all patients randomized, high-dose edoxaban was associated with a 13% reduction (P=.08) in stroke or systemic embolism vs. warfarin and low-dose edoxaban with a 13% excess (P=.10) of stroke or systemic embolism vs. warfarin.
Additionally, “the rate of ischemic stroke was similar with high-dose edoxaban and warfarin, but was higher with the low-dose edoxaban regimen,” researchers wrote in The New England Journal of Medicine. The rate of ischemic stroke was 1.25% with warfarin vs. 1.25% with the high dose (HR=1.00; 95% CI, 0.83-1.19) and 1.77% with the low dose (HR=1.41; 95% CI, 1.19-1.67).
The principal safety endpoint was major bleeding. The annualized rate was 3.43% with warfarin vs. 2.75% with high-dose edoxaban (HR=0.8; 95% CI, 0.71-0.91) and 1.61% with low-dose edoxaban (HR=0.47; 95% CI, 0.41-0.55). The annualized rate of gastrointestinal bleeding was higher with high-dose edoxaban vs. warfarin (1.51% vs. 1.23%), but lowest with low-dose edoxaban (0.82%).
Additionally, “both [edoxaban] regimens significantly reduced hemorrhagic stroke (46% high dose; 67% low dose) and intracranial hemorrhage (53%/70%),” Giugliano said.
The annualized rate of death from CV causes was 3.17% with warfarin vs. 2.74% with high-dose edoxaban (HR=0.86; 95% CI, 0.77-0.97) and 2.71% with low-dose edoxaban (HR=0.85; 95% CI, 0.76-0.96). According to key secondary endpoint data presented, the rate of a composite of stroke/systemic embolism/death from CV causes was 4.43% with warfarin vs. 3.85% with high-dose edoxaban (HR=0.87; 95% CI, 0.78-0.96) and 4.23% with low-dose edoxaban (HR=0.95; 95% CI, 0.86-1.05).
There was no excess in stroke or bleeding during a 30-day transition period from study drug to open-label drug at the end of the trial, he added.
In other results, rates of adverse events were similar between treatment groups and the primary efficacy and safety findings were consistent across major subgroups.
The ENGAGE AF-TIMI 48 trial was conducted at 1,393 centers in 46 countries. It was a “rigorously conducted trial,” Giugliano said. More than 99% of patients enrolled received the study drug and only one patient was lost to follow-up. – by Katie Kalvaitis
For more information:
Giugliano RP. LBCT.05. New strategies for atrial fibrillation patients: Rhythm and thrombosis. Presented at: the American Heart Association Scientific Sessions; Nov. 16-20, 2013; Dallas.
Giugliano RP. N Engl J Med. 2013;doi:10.1056/NEJMoa1310907.
Disclosure: Giugliano reports receiving honoraria from Daiichi Sankyo and Merck; consulting for/serving on an advisory board of Amgen, Beckman-Coulter, Daiichi Sankyo, Janssen, Lexicon, Merck and Sanofi-Aventis; and receiving research grants from Amgen, Daiichi Sankyo and Merck.
Perspective
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Robert Harrington, MD
If you look across the [novel oral anticoagulant] trials, there is remarkable consistency in either being superior to warfarin or at least noninferior to warfarin, and then on the safety side they uniformly look safer than warfarin. It seems to me that this is the perfect construct that we should really demand: a comparative–effectiveness-type trial. A very large, simple trial could and should be done with these drugs be able to answer the question [of which is better] definitively. As Dr. Giugliano notes, there are some little differences that might make a difference, and we just don’t understand it yet.
Perspective
Back to TopMark S. Link, MD
If you look at the four new [oral anticoagulants] they are more similar than different, and when they are compared to warfarin they, in general, look better than warfarin. It is hard to compare, in fact it is impossible to compare the drugs, because they are not compared head to head. We will look for certain patient characteristics that will favor one drug over the other — once a day dosing, renal failure, age. But until there are head-to-head comparisons it is going to be very difficult to say one drug is better than the other.
Perspective
Back to TopMunir Pirmohamed, MD, PhD
From the UK and Swedish perspective, it is going to [be based on] choice, but at the moment there is no clear rationale for deciding which drug to choose. It often depends on which one comes on the market first. A clear issue is the cost. In the United Kingdom, NICE does look at the cost effectiveness; although it is said these new oral anticoagulants are cost effective, the initial cost outlay is much greater than warfarin. Certainly in the United Kingdom and Sweden, warfarin still remains the most widely used drug for initiation of anticoagulation.
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