J-ROCKET AF

Japanese Rivaroxaban Once daily oral direct factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial
Fibrillation (2012)

Condition

Prevention of VTE in Japanese patients with non-valvular AF and increased risk for stroke

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Objective

To compare the the safety of a Japan-specific rivaroxaban dose with warfarin administered according to Japanese guidelines in Japanese patients with AF

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Trial design

Randomized, double-blind, double-dummy phase III study
Active treatment: rivaroxaban 15 mg once daily plus warfarin placebo for 30 months (n=639)
Control treatment: warfarin dose-adjusted to a target INR of 2.0–3.0 in patients aged <70 years, or a reduced INR of 1.6–2.6 in patients aged ≥70 years (according to Japanese guidelines), plus rivaroxaban placebo for 30 months (n=639)

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Endpoints

Primary safety endpoint: composite of major and non-major clinically relevant bleeding
Primary efficacy endpoint: composite of adjudicated all-cause stroke (ischemic or hemorrhagic) and non-CNS systemic embolism
Secondary efficacy endpoints: composite of stroke, systemic embolism, and vascular death and composite of stroke, systemic embolism, vascular death, and MI

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Trial participants

1280 Japanese patients aged ≥20 years (mean age 71.1 years) with non-valvular AF, documented electrocardiographically ≤30 days before randomization, and with ≥2 risk factors for thromboembolism. The safety population (n=1278, 639 in each group) included all patients who received ≥1 dose of study drug. 1274 patients without major protocol violations were included in the per-protocol population (637 in each group)

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Results

Safety outcome: The composite of major bleeding and non-major clinically relevant bleeding events, evaluated in the safety population (on-treatment analysis), occurred in 138 patients in the rivaroxaban group (18.0% per year) compared with 124 patients in the warfarin group (16.4% per year) (HR 1.11; p for non-inferiority<0.001). The observed rate of major bleeding events was 3.0% per year in the rivaroxaban group compared with 3.6% per year in the warfarin group (HR 0.85). Non-major clinically relevant bleeding event rates were 15.4% per year in rivaroxaban-treated patients compared with 13.0% per year in warfarin-treated patients (HR 1.20)
Efficacy outcome: In the per-protocol population, while on treatment, stroke or non-CNS systemic embolism occurred at a rate of 1.3% per year in the rivaroxaban arm, compared with 2.6% per year in the warfarin arm (RRR 51%; p=0.050). All-cause stroke occurred at a lower rate in patients treated with rivaroxaban than with warfarin (10/637 patients vs. 21/637 patients; HR 0.46), as did primary ischemic stroke (7/637 patients vs. 17/637 patients; HR 0.40). Primary hemorrhagic stroke occurrence was similar in both treatment arms (3/637 Patients vs. 4/637 patients; HR 0.73). The numbers of MI, vascular death, and all-cause mortality were also low in both treatment groups.

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Summary

Safety: The oral direct factor XA inhibitor rivaroxaban was non-inferior to warfarin dose-adjusted according to Japanese guideline recommendations with respect to the primary safety outcome of major plus non-major clinically relevant bleeding. Although no significant differences in overall bleeding rates were observed, rivaroxaban use was associated with a non-significant lower major bleeding rate and a slightly higher non-major clinically relevant bleeding rate than treatment with warfarin
Efficacy: Compared with warfarin therapy, there was a strong trend towards reduction in stroke and non-CNS systemic embolism with rivaroxaban. The findings of J-ROCKET AF support bridging of the broader safet and efficacy data from the larger, global ROCKET AF study to Japanese patients with AF

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Reference

Hori M, Matsumoto M, Tanahashi N, Momomura SI, Uchiyama S, Goto S, Izumi T, Koretsune Y, Kajikawa M, Kato M, Ueda H, Iwamoto K, Tajiri M, on behalf of the J-ROCKET AF study investigators. Rivaroxaban vs. warfarin in Japanese patients with atrial fibrillation. Circ J 2012 Jun 5. [Epub ahead of print]

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Corresponding author

Masatsugu Hori, MD, PhD, Osaka Medical Center for Cancer and Cardiovascular Diseases, 1-3-3 Nakamichi, Higashinari-ku, Osaka 357-8511, Japan, e-mail: hori-ma@mc.pref.osaka.jp

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