依度沙班与华法林对房颤患者疗效相似

Robert P. Giugliano医生在美国心脏协会(AHA)年会上报告的Ⅲ期ENGAGE AF-TIMI 48试验显示，对于心房颤动患者，每日1次口服Ⅹa因子抑制剂依度沙班共2次治疗预防卒中或全身栓塞的疗效不劣于华法林。该研究结果同期发表在《新英格兰医学杂志》上(N. Engl. J. Med. 2013 Nov. 19 [doi:10.1056/NEJMoa1310907])。


Robert Giugliano医生

依度沙班目前已在日本(Lixiana)获准用于在大型骨科手术后预防静脉血栓栓塞(VTE)事件，但在近期关于治疗和预防复发性有症状VTE的Ⅲ期试验得出阳性结果后，预期将于2014年在美国、欧洲和日本监管备案。

ENGAGE AF-TIMI 48试验中纳入21,105例中度至高度风险的心房颤动患者。其中1/4有阵发性心房颤动，中位随访时间为2.8年，治疗期间，华法林组有中位68.4%的时间处于治疗范围之内。主要终点为卒中或栓塞事件。

结果显示，在控制良好的华法林、依度沙班60 mg[关于非劣效性，危险比(HR)0.79；P<0.001]和依度沙班 30 mg组（关于非劣效性，HR：1.07；P=0.005），主要终点每年的发生率分别为1.50%、1.18%和1.61%。小剂量依度沙班仅在对主要终点的意向治疗分析中符合非劣效性标准（95%可信区间上限为1.34；非劣效性边界为1.38），并且缺血性卒中的发生率显著高于华法林组（分别为每年1.77%和1.25%；HR：1.41; P<0.001）。大剂量依度沙班组的缺血性卒中发生率与华法林组相同，均为1.25%。关于出血性卒中，华法林、大剂量依度沙班 (HR：0.54)和小剂量依度沙班(HR：0.33;均P<0.001)组的每年发生率分别为0.47%、0.26%和0.16%。

在预先设定的意向治疗分析中，关于主要终点，大剂量依度沙班组也未达到相对于华法林的优效性标准（分别为1.57%和1.80%；HR：0.87；P=0.08），因此，无法明确优效性。关于研究的主要安全性终点大出血，依度沙班的表现也优于口服华法林，依度沙班组显著减少出血和心血管原因导致的死亡。华法林、依度沙班 60 mg(HR：0.80)和依度沙班 30 mg (HR：0.47；均P<0.001)组大出血的发生率分别为每年3.43%、2.75%和1.61%，波士顿市Brigham妇女医院和哈佛医学院的Giugliano医生报告。三组对应的心血管原因死亡率分别为每年3.17%、2.74%和2.71%，均无统计学差异。关键复合次要终点为卒中、全身栓塞或心血管原因死亡，华法林、大剂量依度沙班(HR：0.87%；P=0.005)和低剂量依度沙班组(HR：0.95；P=0.32)的发生率分别为4.43%、3.85%和4.23%，小剂量依度沙班组未达到统计学意义。

Giugliano医生及其合作者披露接受了研究申办方日本第一制药三共公司提供的资金支持并有其他利益关系。

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By: PATRICE WENDLING, Cardiology News Digital Network

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]).

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.