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Study Summary

The ELDERCARE-AF trial was developed to assess the safety and efficacy of low-dose anticoagulation in Japanese octogenarians at higher risk of bleeding. This phase 3 double-blind, placebo controlled, event-driven, superiority trial included a population of 984 patients aged >80 years, randomized to placebo or edoxaban 15mg (one-quarter the standard dose for stroke thromboprophylaxis in atrial fibrillation [AF]). Patients had documented nonvalvular AF, CHADS2 score of ≥2, and were not candidates for oral anticoagulants at doses approved for stroke prevention because of co-morbidities or bleeding risk (low creatinine clearance, bleeding history, weight ≤ 45kg, NSAID use, or antiplatelet use). Over the 36-month follow-up, the primary efficacy end point (ischemic or hemorrhagic stroke or systemic embolism) was 2.3% in the edoxaban group versus 6.7% in the placebo group (HR 0.34, 95%CI 0.19-0.61, P <0.001; see accompanying Hurst's Central Illustration). The primary safety end points, including major bleeding (3.3% versus 1.8% [HR 1.87, 95% CI 0.90-3.89]) and intracranial bleeding (0.3% versus 0.6% [HR 0.50, 95% CI 0.09-2.72]), were not different between groups, although there was a significant increase in gastrointestinal bleeding (2.3% versus 0.8%, 95% CI 1.03-7.88).

Commentary

Study Strengths: This was a well-designed, double-blind, randomized, controlled study with the intent to study anticoagulation in the frail, elderly population. The mean age (86.6 years) was significantly higher than the average age (70-73 years) in previous landmark direct oral anticoagulant (DOAC) trials. Additionally, patients had a high frailty score, with nearly 35% having had a documented fall in the past year. Nearly 50% of patients had paroxysmal AF, and the CHADS2 and CHADS2VASc scores were 3 and 5, respectively. Both placebo and edoxaban groups were similar, with good female representation (57.4%).

Study Limitations: All of the participants were of East Asian descent, which may limit generalizability to other populations. Importantly, in previous trials (ENGAGE AF-TIMI 48), East Asian patients with AF treated with lower-dose edoxaban had higher rates of stroke or systemic embolism and overt bleeding than did patients who were not East Asian. Furthermore, while no patients were lost to follow-up, a substantial number of patients withdrew from the trial (156/982 patients randomized; 16%).

Next Steps/Clinical Perspective: The mean age of participants in the landmark DOAC trials (70-73 years old) was 5-10 years younger than the average age of the AF population. ELDERCARE AF demonstrated a substantial reduction in ischemic events with very-low-dose anticoagulation in older elderly patients (mean age 86.6 years) with a high risk of events based on higher CHADS2VASc scores, without increase in rates of major bleeding or intracranial hemorrhage. Next steps should include a multinational study to investigate if the benefit of low-dose anticoagulation is seen in populations who are otherwise not candidates for standard dose anticoagulation because of bleeding risks. Additionally, subgroup analysis suggested less benefit of anticoagulation in paroxysmal (versus persistent) AF and in those with prior strokes; these hypothesis-generating results should be assessed in further trials.

Trial Reference

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Okumura  K, Akao  M, Yoshida  T,  et al. Low-dose edoxaban in very elderly patients with atrial fibrillation. N. Engl. J. Med. doi:10.1056/NEJMoa2012883.

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