Very elderly AF patients fare well on low-dose edoxaban

Elderly patients with nonvalvular atrial fibrillation (AF) aged ≥80 years who cannot receive oral anticoagulants at recommended doses may do well instead on low-dose edoxaban, which prevents stroke without increasing the incidence of bleeding, according to the results of the phase III ELDERCARE-AF trial.

“Clinical guidelines recommend the use of direct oral anticoagulants (DOACS) for the prevention of stroke in patients with nonvalvular AF, including in elderly patients. [However], the mean or median age of the patients enrolled in previous landmark clinical trials of DOACs was 70–73 years, which is 5–10 years younger than the average age in the general AF population,” according to the investigators. [N Engl J Med 2013;369:2093-2104; N Engl J Med 2009;361:1139-1151; N Engl J Med 2011;365:883-891; N Engl J Med 2011;365:981-992]

“Therefore, the findings in [those] major trials cannot be easily generalized to older patients,” they added.

Conducted in Japan, ELDERCARE-AF broke new ground by including patients who were aged ≥80 years and had additional risk factors for bleeding, such as a low creatinine clearance (15–30 ml per minute), a history of bleeding from a critical area or organ or gastrointestinal bleeding, low body weight (≤45 kg), continuous use of nonsteroidal anti-inflammatory drugs, or current use of an antiplatelet drug.

In total, 984 elderly Japanese patients (mean age, 86.6 years; 42.6 percent male) were randomized to receive a daily dose of 15-mg edoxaban (n=492 patients) or placebo (n=492). The annualized rate of the composite of stroke or systemic embolism was lower on the DOAC (2.3 percent vs 6.7 percent; hazard ratio [HR], 0.34, 95 percent confidence interval [CI], 0.19–0.61; p<0.001). [N Engl J Med 2020;383:1735-1745]

Meanwhile, the annualized rate of major bleeding on edoxaban was higher than on placebo, although the difference was not meaningful (3.3 percent vs 1.8 percent; HR, 1.87, 95 percent CI, 0.90–3.89; p=0.09). Gastrointestinal bleeding occurred more frequently in the edoxaban group, whereas no between-group difference was seen in death from any cause (9.9 percent vs 10.2 percent; HR, 0.97, 95 percent CI, 0.69–1.36).

A total of 681 patients completed the trial, and the proportion of those who did not (158 withdrew, 135 died, and 10 had other reasons) were similar in the two treatment groups.

“We used a 15-mg dose of edoxaban in this trial on the basis of data from the ENGAGE AF-TIMI 48 trial, which compared two doses of edoxaban (60 mg and 30 mg) with warfarin. If patients in either edoxaban group met criteria for dose reductions, the 60-mg dose was reduced to 30 mg, and the 30-mg dose was reduced to 15 mg,” the investigators said.

“The annualized rates of major bleeding (3.3 percent) and intracranial haemorrhage (0.3 percent) among patients in the current trial who received 15 mg of edoxaban were similar to those among patients ≥80 years of age in the ENGAGE AF-TIMI 48 trial who received a 30-mg regimen of edoxaban (2.6 percent and 0.5 percent, respectively) and lower than the rates among patients [of the same age] in the warfarin group (6.2 percent and 1.6 percent, respectively),” they added. [J Am Heart Assoc 2016;5:e003432]

Why the efficacy and safety results are similar in patients who received 15-mg edoxaban in ELDERCARE-AF and those who received 60-mg and 30-mg doses in ENGAGE AF-TIMI 48 may be partly explained by comparable plasma concentrations of the DOAC in these patients, as reflected in a previous study of elderly Japanese patients with AF. [Circ J 2015;79:1486-1495]

Finally, the investigators pointed out that the ELDERCARE-AF results may not be applicable to other populations, as East Asian AF patients treated with the lower-dose regimen of edoxaban in ENGAGE AF-TIMI 48 trial had higher rates of stroke or systemic embolism and higher rates of overt bleeding of any kind than those who were not East Asian. [Circ J 2016;80: 860-869]