Randomized, Parallel Group, Multicenter, Multinational Study Evaluating Safety of DU-176b Compared with Warfarin in Subjects with Non-Valvular Atrial Fibrillation
Randomized, Parallel Group, Multicenter, Multinational Study Evaluating Safety of DU-176b Compared with Warfarin in Subjects with Non-Valvular Atrial Fibrillation
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评估 DU-176b 与华法林在非瓣膜性心房颤动受试者中的安全性的随机、平行组、多中心、跨国研究
DOI：
10.1182/blood.v112.11.33.33
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发表时间：
2008
期刊：
影响因子：
20.3
通讯作者：
Indravadan Patel
中科院分区：
文献类型：
--
作者：
J. Weitz;S. Connolly;S. Kunitada;James Jin;Indravadan Patel
简介：这项 II 期研究的主要目的是评估 DU-176b（一种口服直接 Xa 因子抑制剂）不同剂量方案在非瓣膜性心房颤动 (AF) 患者中的安全性。方法：这是一项针对 AF 患者（CHADS2 指数≥ 2）的随机、平行组、多中心、跨国、双盲 DU-176b 和开放标签华法林安全性研究。患者被随机分配接受 DU-176b 四种固定剂量方案中的一种（30 mg qd、30 mg bid、60 mg qd 或 60 mg bid）或华法林剂量调整至目标国际标准化比率 (INR) 2.0-3.0。 12 周。研究人员、申办者和研究受试者对 DU-176b 剂量不知情，但对 DU-176b 与华法林的身份不知情。研究人员根据当地实验室获得的 INR 值调整华法林剂量。 INR 每周测定一次，持续 4 周，此后每两周测定一次。主要结局是集中判定的重大和/或临床相关的非重大出血事件的发生，以及肝酶和/或胆红素升高。次要结局包括主要不良心血管事件（MACE），即中风、全身性栓塞、急性心肌梗塞、因心血管疾病住院或心血管死亡的复合事件，以及所有其他不良事件，包括所有出血事件。结果：共有 1,146 名患者被随机分组。治疗组之间在人口统计数据和基线特征方面不存在临床相关差异。平均年龄为 65±8.7 岁，63.3% 的患者 CHADS2 指数为 2，64.40% 未接受过华法林治疗。根据独立数据监测委员会 (DMC) 的建议，DU-176b 60 mg bid 治疗组在研究期间提前终止。当时共有 180 名患者被随机分配到该组。 DU-176b 60 mg bid 和 30 mg bid 组的主要和临床相关非主要出血事件的发生率均显着高于服用华法林的组。 DU-176b 30 mg qd 和 60 mg qd 组的主要和临床相关非主要出血事件的发生率与华法林治疗患者相似。使用过华法林的患者的治疗范围时间 (TTR) 为 50.1%，而未使用过华法林的患者为 41.8%。各治疗组中 ALT、AST 或胆红素值持续升高的受试者数量 (%) 没有显着差异。各治疗组的中风发生率相似（表）。结论：DU-176b 30 mg qd 和 60 mg qd 剂量方案在 AF 患者中具有与华法林相似的安全性。使用 DU-176b 30 mg bid 或 60 mg bid 方案治疗的患者比使用华法林治疗的患者发生的出血事件更多。这些结果表明 DU-176b 30 mg qd 或 60 mg qd 方案是安全且耐受性良好的。需要进行 III 期试验来确定 DU-176b 是否可以为 AF 患者提供华法林的合适替代品。 CR，临床相关。 aP
Introduction: The primary objective of this phase II study was to assess the safety of different dose regimens of DU-176b, an oral direct factor Xa inhibitor, in patients with non-valvular atrial fibrillation (AF). Methods: This was a randomized, parallel group, multicenter, multinational, double-blind DU-176b and open-label warfarin safety study in patients with AF (CHADS2 index ≥ 2). Patients were randomly assigned to receive either one of four fixed dose regimens of DU-176b (30 mg qd, 30 mg bid, 60 mg qd or 60 mg bid) or warfarin dose-adjusted to a target international normalized ratio (INR) of 2.0–3.0. for 12 weeks. Investigators, sponsor and study subjects were blinded to DU-176b dose but not to the identity of DU-176b vs. warfarin. Investigators adjusted warfarin doses based on INR values obtained in local laboratories. The INR was determined weekly for 4 weeks and every two weeks thereafter. The primary outcomes were the occurrence of centrally adjudicated major and/or clinically relevant non-major bleeding event, and elevated liver enzymes and/or bilirubin. Secondary outcomes included major adverse cardiovascular events (MACE), a composite of stroke, systemic embolism, acute myocardial infarction, hospitalizations due to cardiovascular condition or cardiovascular death, as well as all other adverse events, including all bleeding events. Results: A total of 1,146 patients were randomized. There were no clinically relevant differences between treatment groups with respect to the demographic data and baseline characteristics. Mean age was 65±8.7 years, 63.3% of patients had a CHADS2 index of 2 and 64.40% were warfarin naive. The DU-176b 60 mg bid treatment arm was prematurely terminated during the study based on a recommendation by the Independent Data Monitoring Committee (DMC). A total of 180 patients were randomized to this group at the time. The incidence of major and clinically relevant non-major bleeding events was significantly higher in both the DU-176b 60 mg bid and 30 mg bid groups than in those given warfarin. The incidence of major and clinically relevant non-major bleeding events in the DU-176b 30 mg qd and 60 mg qd groups was similar to that in warfarin-treated patients. The time in therapeutic range (TTR) for warfarin-experienced patients was 50.1% and for warfarin naive patients was 41.8%. There were no significant differences in the number (%) of subjects with persistently elevated ALT, AST, or bilirubin values across the treatment groups. The incidence of stroke was similar across treatment groups (Table). Conclusions: DU-176b 30 mg qd and 60 mg qd dose regimens had a safety profile similar to warfarin in patients with AF. Patients treated with the DU-176b 30 mg bid or 60 mg bid regimens had more bleeding events than occurred with warfarin. These results suggest that the DU-176b 30 mg qd or 60 mg qd regimens are safe and well tolerated. A Phase III trial is needed to determine whether DU-176b will provide a suitable replacement for warfarin in AF patients. CR, clinically relevant. aP