关键性试验显示依度沙班对VTE安全有效

阿姆斯特丹——据欧洲心脏病学会(ESC)年会上公布的一项关键的国际随机临床试验结果，新型因子Ⅹa抑制剂依度沙班在治疗急性静脉血栓栓塞症（VTE）中所起的作用越来越大，依靠卓越性能从同类药品中脱颖而出(N. Engl. J. Med. 2013;doi:10.1056NEJMoa1306638)。

研究显示，在12个月的随访中，依度沙班非劣效于标准治疗，不仅如此，其安全性还优于后者，与前2个因子Ⅹa直接抑制剂——利伐沙班（Xarelto）和阿哌沙班（Eliquis）治疗静脉血栓栓塞症（VTE）的结局不相上下。依度沙班临床试验也显示了这类药物的一项重要新特征：入选的大约1/3患有重度肺栓塞并导致右室功能障碍的患者经依度沙班治疗后病情好转，与华法林相比具有显著的统计学收益。


Harry Büller博士

这项名为“Hokusai-VTE”的试验将2010年1月~2012年10月间4,921例深静脉血栓形成患者和3,319例肺栓塞患者随机分组，共涉及37个国家的439家诊疗中心。患者平均年龄为56岁，男性略过半数，所有患者均接受了中位时间7天的肝素治疗。在本研究中，所有受试者先接受至少5天的依诺肝素或普通肝素静脉输注治疗，大约在5天后停止这项治疗，采用口服华法林或依度沙班继续进行治疗。这项治疗策略与先前的利伐沙班和阿哌沙班关键性研究相反，后两项研究对急性VTE患者先开始口服药物治疗。

主要疗效终点为VTE复发。1年后，在4,118例随机接受依度沙班的患者中有3.2%、在4,122例随机接受华法林治疗的患者中有3.5%出现了主要疗效终点，结果满足本研究的非劣效标准。在预设的存在较大血凝块和推测有右室功能障碍的肺栓塞患者亚组中，根据他们的血凝块解剖学大小以及血N末端前脑钠肽水平判断，依度沙班治疗组与华法林治疗组随访期间的复发性VTE发生率分别为3.3%和6.2%，具有显著的统计学差异。

本研究的主要安全结局为具有临床意义的大出血或非大出血发生率，这在依度沙班治疗组与华法林治疗组中分别为8.5%和10.3%，依度沙班治疗组的相对危险下降19%，在统计学上显著优效于华法林。安全性数据还表明，依度沙班治疗组患者总共有5次脑内或腹膜后出血，而华法林治疗组有22次出血，以Büller医生的观点看，这种差异是真实的，归因于华法林对凝血因子Ⅶ产生的作用，并且在验证其他新型因子Xa抑制剂的临床试验中也观察到这样的结果。

Hokusai-VTE研究在口服Ⅹa因子抑制剂试验中是独一无二的，是惟一一项允许灵活设定抗凝治疗疗程、对所有患者随访了12个月并使用影像学检查和生物标志物对患者进行风险分层以证实对重度肺栓塞患者疗效的研究。

Zoghbi医生在受访中表示，研究结果显示在最严重的肺栓塞患者中依度沙班的疗效较优，从而使人更确信高危患者使用依度沙班不仅不是劣效的，反而可能有优势。Konstantinides医生表示，迄今所收集的有关这3种口服Ⅹa因子抑制剂的数据表明，这3种药物全都“非劣效于标准的治疗，并且在安全性方面很可能还优于标准治疗”。但他也警告指出，这些新药还需要通过显示患者对治疗及生活质量的满意度提高以及通过减少VTE患者的再住院次数降低整体卫生医疗费用，证明其高昂的费用是物有所值的。

Hokusai-VTE研究得到第一三共制药的赞助，该公司开发了依度沙班。Büller医生称其收到第一三共制药、拜耳、勃林格殷格翰、辉瑞/百时美施贵宝、Isis以及Thrombogenics的酬金，他本人也是利伐沙班和阿哌沙班VTE关键性试验的主要研究者。Zoghbi医生无相关的披露内容。 Konstantinides医生担任勃林格殷格翰、拜耳以及辉瑞/百时美施贵宝的讲者。

专家点评：依度沙班将延续新型口服抗凝药的发展态势

Hokusai-VTE研究的结果似乎证实这样的假设，即依度沙班非劣效于华法林，而且在存在严重肺栓塞的高危患者中依度沙班也有较好的疗效，这一点同样重要。口服因子X抑制剂的出现，给医生们一个全新的治疗理念。这些药物与华法林相比使用更方便，饮食也不会干扰治疗，同时也不必抽血。看起来这类新型的因子Ⅹ抑制剂产生的收益可能属于类效应，这些药物所产生的结果也具有一致性，不过也存在费用相对较高的局限性，希望这种费用差别最终不会成为患者治疗的绊脚石。

美国的医生和患者将逐渐开始常规使用这些药物治疗VTE或将其用在其他场合中，比如抑制血凝块形成以及预防房颤患者发生卒中。在2013年6月份，房颤患者中大约有10%~12%在接受一种新型口服抗凝药治疗，这类药物还包括达比加群（Pradaxa）。随着人们对这类药物的了解增加和接受度的提高，它们的使用率也将逐渐增加，取代华法林。

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William A. Zoghbi医生是休斯顿卫理公会医院DeBakey心血管中心心血管影像学研究所的医学教授兼所长。他本人无相关披露内容。Zoghbi医生在一次受访中发表了上述评论。

By: MITCHEL L. ZOLER, Cardiology News Digital Network

AMSTERDAM – The growing role for the new factor Xa inhibitors in treating acute venous thromboembolism received another boost with sterling performance of a new drug from the class, edoxaban, in a pivotal, randomized, international trial with more than 8,000 patients.

Edoxaban showed noninferior efficacy and superior safety compared with the standard treatment, warfarin, during 12 months of follow-up, performance that closely matched prior results for the first two direct factor Xa inhibitors that were tested for treating venous thromboembolism (VTE), rivaroxaban (Xarelto) and apixaban (Eliquis). The edoxaban trial also showed an important new feature for drugs in this class, a statistically significant benefit compared with warfarin in the roughly one-third of enrolled patients with a severe pulmonary embolism causing right ventricular dysfunction.

"The most interesting observation is that the third of patients [with pulmonary embolism and] with right ventricular dysfunction were better off with edoxaban," Dr. Harry R. Büller said at the European Society of Cardiology Congress 2013.

"A criticism raised with [the pivotal rivaroxaban and apixaban trials treating acute VTE] was that the investigators were reluctant not to use low molecular weight heparin in the patients with large clots. In that group we’ve made a novel observation" in this prespecified subgroup analysis, said Dr. Büller, professor and chairman of vascular medicine at the Academic Medical Center in Amsterdam.
 
Investigators in the edoxaban trial may have been more willing to enroll their severely ill VTE patients because the treatment regimens compared began all patients with at least 5 days of treatment with either enoxaparin or unfractionated heparin. Intravenous treatment stopped after about a week and then continued with either oral warfarin or edoxaban. This treatment strategy contrasted with the prior rivaroxaban (EINSTEIN, N. Engl. J. Med. 2012;366:1287-97 and apixaban (AMPLIFY, N. Engl. J. Med. 2013;369:799-808) pivotal studies that began acute VTE patients on the oral drugs from the start of treatment. In the edoxaban study, participating physicians enrolled "the full spectrum of VTE patients," Dr. Büller said.

Physicians "feel comfortable intervening with heparin in these patients because you have quick, intravenous treatment with an anticoagulant," commented Dr. William A. Zoghbi, professor of medicine and director of the Cardiovascular Imaging Institute at the Debakey Heart and Vascular Center at Methodist Hospital in Houston. The results showing superior efficacy of edoxaban over warfarin in the most severely affected pulmonary embolism patients "makes you more confident that in the higher-risk patients edoxaban was not only not inferior but may even have an advantage," Dr. Zoghbi said in an interview.

The Hokusai-VTE trial randomized 4,921 patients with deep-vein thrombosis and 3,319 patients with pulmonary embolism at 439 centers in 37 countries during January 2010–October 2012. Patients averaged 56 years of age, a bit more than half were men, and they received heparin for a median of 7 days.

After 1 year, the primary efficacy endpoint of recurrent VTE in all patients occurred in 3.2% of the 4,118 patients randomized to received edoxaban and in 3.5% of the 4,122 randomized to receive warfarin, results that meet the study’s criterion for noninferiority.

Among the prespecified subgroup of pulmonary embolism patients with a larger clot and inferred right-ventricular dysfunction – based on both the anatomic size of their clot and on their blood level of N-terminal pro-brain natriuretic peptide – the rate of recurrent VTE during follow-up was 3.3% in the edoxaban group and 6.2% in the warfarin group, a statistically significant difference.

The study’s primary safety outcome was the rate of clinically relevant major or nonmajor bleeds, which occurred in 8.5% of the edoxaban patients and in 10.3% of the warfarin patients, for a relative hazard reduction of 19% by edoxaban that was statistically significant for superiority, reported Dr. Büller. Concurrent with his talk at the meeting a report of the trial results was published online (N. Engl. J. Med. 2013;doi:10.1056NEJMoa1306638).

The safety data also showed that the edoxaban-treated patients had a total of 5 intracranial or retroperitoneal bleeds, compared with 22 in the patients treated with warfarin, a difference that Dr. Büller said he believed was real and due to the effect of warfarin on clotting factor VII, and is something that has also been seen in the trials testing the other new factor Xa inhibitors.

The Hokusai-VTE study is unique among the trials of oral factor Xa inhibitors by being the only study that allowed for a flexible duration of anticoagulation treatment, followed all patients for 12 months, and used imaging and biomarkers to risk-stratify patients to prove efficacy in patients with severe pulmonary embolism, commented Dr. Stavros V. Konstantinides, professor and deputy scientific director of the Center for Thrombosis and Haemostasis of Johannes Gutenberg University in Mainz, Germany.

The data collected on all three oral factor X inhibitors so far suggest that they all are "noninferior to standard treatment and are also not inferior and most likely superior for safety, with apixaban showing the best safety profile so far," said Dr. Konstantinides, who was the designated discussant for Dr. Büller’s report. But Dr. Konstantinides also warned that these new drugs will need to "justify their high cost" by showing improvements in patient satisfaction with their treatment and quality of life, and by lowering overall health-care costs by lowering the number of rehospitalizations in VTE patients.

Hokusai-VTE was sponsored by Daiichi-Sankyo, the company developing endoxaban. Dr. Büller said that he has received honoraria from Daiichi Sankyo, as well as from Bayer, Boehringer Ingelheim, Pfizer/Bristol-Myers Squibb, Isis, and Thrombogenics. Dr. Büller also served as a principal investigator for the VTE pivotal trials of rivaroxaban and apixaban. Dr. Zoghbi said that he had no relevant disclosures. Dr. Konstantinides has been a speaker for and an advisor to Boehringer Ingelheim, Bayer, and Pfizer/Bristol-Myers Squibb.

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Edoxaban continues new oral anticoagulant growth

It appears that the Hokusai-VTE results proved the hypothesis that edoxaban is noninferior to warfarin, and also important was that in higher-risk patients with significant pulmonary embolisms, edoxaban was better.

The emergence of the oral factor X inhibitors is giving physicians a new option for treatment. These drugs are much more convenient to use than warfarin; diet does not interfere with treatment, and blood draws aren’t necessary. It looks like the benefits from the new factor X inhibitors may be class effects; the results have been consistent from one drug to the next. But there is the limitation right now of their relatively high cost. I hope that eventually the cost differential won’t be as prohibitive as it probably is today for some patients.

Physicians and patients in the United States are slowly starting to use these drugs routinely in patients with VTE, and in other settings, such as to prevent clot formation and strokes in patients with atrial fibrillation. In mid-2013, about 10%-12% of patients with atrial fibrillation are being treated with one of the new oral anticoagulants, a group of drugs that also includes dabigatran (Pradaxa). I think there will gradually be increasing use of these drugs in place of warfarin as people grow more familiar and comfortable with them.

Dr. William A. Zoghbi is professor of medicine and director of the Cardiovascular Imaging Institute at the DeBakey Heart and Vascular Center of Methodist Hospital in Houston. He said that he had no relevant disclosures. Dr. Zoghbi made these comments in an interview.