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A low dose of the direct oral anticoagulant (DOAC) edoxaban (Savaysa) reduced thrombotic events in elderly atrial fibrillation patients without a significant excess in bleeding, a Japanese trial showed.

Among such patients ages 80 and older considered to be inappropriate candidates for a standard oral anticoagulant regimen, 15 mg of edoxaban daily cut stroke or systemic embolism by a relative 66%, with an annualized rate of 2.3% versus 6.7% with placebo (HR 0.34, 95% CI 0.19-0.61), according to results from the ELDERCARE-AF trial.

As expected, more cases of major bleeding occurred with the anticoagulant, with an annualized rate of 3.3% versus 1.8% in the placebo group. But the difference missed statistical significance (HR 1.87, 95% CI 0.90-3.89, P=0.09).

Net clinical benefit, weighing the safety and efficacy endpoints together, tended to favor edoxaban (HR 0.86, 95% CI 0.65-1.15), reported Ken Okumura, MD, PhD, of Saiseikai Kumamoto Hospital in Kumamoto, Japan, and colleagues at the European Society of Cardiology virtual meeting.

Clinical guidelines recommend DOAC use for stroke prevention in nonvalvular atrial fibrillation, including in elderly patients. However, elderly people were underrepresented in the clinical trials upon which those guidelines were based and face a high risk of both thrombotic and bleeding events.

The magnitude of benefit in Okumura's trial "is about what you see with warfarin versus placebo from previous studies -- in general," commented Elliott Antman, MD, of Brigham and Women's Hospital in Boston and a past president of the American Heart Association. "That's gratifying. ... Typically in very elderly patients, physicians are worried about any form of anticoagulation. They're very worried about warfarin, because of the vagaries of use of warfarin in very elderly patients."

It was also similar to what had been seen with higher-dose edoxaban (2.5% with 60 mg and 2.8% with 30 mg) and with warfarin (2.9%) in the 80-plus subgroup of the in a lower risk population, the researchers pointed simultaneously online in the New England Journal of Medicine.

Antman, who was primary investigator for ENGAGE AF, characterized the tradeoff in bleeding risk as worthwhile. "The benefit is important here, because stroke is an irreversible loss of neurologic function. Gastrointestinal bleeding is something that you can manage clinically, in the infrequent event that it occurs, when it occurs."

GI bleeding accounted for most of the major bleeds (14 vs five cases with edoxaban and placebo, respectively, 2.3% vs 0.8%). All-cause mortality was similar between groups, at 9.9% in the edoxaban group and 10.2% in the placebo group (HR 0.97, 95% CI 0.69-1.36).

The double-blind, randomized trial included 984 patients ages 80 and older with nonvalvular atrial fibrillation and CHADS₂ scores of 2 or higher, but not considered candidates for standard-dose anticoagulation due to low creatinine clearance (15-30 mL/min), prior bleeding events, low body weight, continuous use of a nonsteroidal anti-inflammatory drug, or current use of an antiplatelet.

Because the trial involved only Japanese patients, generalizability to other populations is unclear.

The researchers noted the somewhat different outcomes in East Asian participants on the lower-dose regimen of edoxaban in the ENGAGE AF trial (more stroke or systemic embolism and more overt bleeding of any kind) than in other patients.

Antman noted the lower average body weight of Japanese patients and genetic differences in metabolic pathways in the liver compared with a typical U.S. population. "Those limitations notwithstanding, I believe this information is useful and clinically informative to patients outside of the Japanese population. We cannot be definitive about it... but I find it encouraging."

Generalizability of a similar-low dose approach to other DOACs can't be assumed, he cautioned.

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