Two doses of the once-daily, oral factor Xa inhibitor edoxaban were noninferior to warfarin in preventing stroke or systemic embolism in patients with atrial fibrillation in the phase III ENGAGE AF-TIMI 48 trial.
The primary endpoint of stroke or embolic events was seen in 1.50% of patients per year on well-controlled warfarin vs. 1.18% with edoxaban 60 mg (hazard ratio, 0.79; P less than .001 for noninferiority) and 1.61% with edoxaban 30 mg (HR, 1.07; P = .005 for noninferiority), Dr. Robert P. Giugliano reported at the American Heart Association scientific sessions.
Edoxaban also bested oral warfarin on the study’s principal safety endpoint of major bleeding and significantly reduced bleeding and death from cardiovascular causes in the study, published simultaneously with the presentation (N. Engl. J. Med. 2013 Nov. 19 [doi:10.1056/NEJMoa1310907]).
Dr. Robert Giugliano
Edoxaban is currently approved only in Japan (Lixiana) for venous thromboembolism (VTE) prevention after major orthopedic surgery, although regulatory filings are expected in the United States, Europe, and Japan in 2014 following recent positive results phase III results for the treatment and prevention of recurrent symptomatic VTE.
Though positive, the results of ENGAGE AF-TIMI 48 (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation – Thrombolysis in Myocardial Infarction 48) do little to distinguish edoxaban from other novel oral anticoagulants entering the market, including the factor Xa inhibitors rivaroxaban (Xarelto) and apixaban (Eliquis), and the twice-daily direct thrombin inhibitor dabigatran (Pradaxa).
Approval of the lower dose of edoxaban is unlikely as it barely meets noninferiority for the primary endpoint in the intention-to-treat analysis (upper 95% confidence interval bound of 1.34; noninferiority margin of 1.38) – and ischemic stroke was significantly worse than warfarin (1.77% per year vs. 1.25% per year; HR, 1.41; P less than .001), observed cardiologist Dr. Sanjay Kaul of Cedars-Sinai Medical Center, Los Angeles.
High-dose edoxaban had the same ischemic stroke rate as warfarin, 1.25%.
Annualized rates of hemorrhagic stroke were 0.47% with warfarin, compared with 0.26% with high-dose edoxaban (HR, 0.54) and 0.16% with low-dose edoxaban (HR, 0.33; both P less than .001).
High-dose edoxaban also failed to meet superiority over warfarin for the primary endpoint in a prespecified intention-to-treat analysis (1.57% vs. 1.80%; HR, 0.87; P = .08), so a superiority claim won’t be allowed.
"Marketability might be an issue, as the treatment advantage is not overwhelming," Dr. Kaul said in an interview. "Being the fourth kid on the block with no unique advantage might challenge its acceptability in clinical practice and marketability."
ENGAGE AF-TIMI 48 enrolled 21,105 patients with moderate- to high-risk atrial fibrillation. One-quarter had paroxysmal atrial fibrillation, median follow-up was 2.8 years, and the warfarin group was in the therapeutic range for a median of 68.4% of the treatment period.
Major bleeding occurred in 3.43% of patients per year with warfarin vs. 2.75% with edoxaban 60 mg (HR, 0.80) and in 1.61% with edoxaban 30 mg (HR, 0.47; both P less than .001), reported Dr. Giugliano of Brigham and Women’s Hospital and Harvard Medical School, in Boston. The corresponding annualized rates of death from cardiovascular causes were, respectively, 3.17% vs. 2.74% and 2.71%, both nonsignificant differences.
Rates of the key composite secondary endpoint of stroke, systemic embolism, or death from cardiovascular causes were 4.43% with warfarin vs. 3.85% with high-dose edoxaban (HR, 0.87%; P = .005) and 4.23% for low-dose edoxaban, which failed to reach statistical significance (HR, 0.95; P = .32), he noted.
Dr. Giugliano and his coauthors reported grant support and other financial relationships with Daiichi Sankyo, the study sponsor. Dr. Kaul reported stock in Johnson & Johnson and consultancy for Boehringer Ingelheim.