新型口服抗凝药预防房颤患者卒中有差异

《美国心脏病学会杂志》8月刊发的一项间接比较分析显示，达比加群、利伐沙班和阿哌沙班这3种新型口服抗凝药，用于房颤患者预防卒中时的相对疗效和安全性存在一些差异。不过，研究者认为这3种药物的相似性大于差异性，并且未建议临床医生根据这些差异在3者中做取舍(J. Am. Coll. Cardiol. 2012;60:738-46)。

这项分析由英国伯明翰大学的Gregory Y.H. Lip博士及其同事进行，采用的数据来自纳入50,000多例患者的多项Ⅲ期随机对照研究，这些研究分别将这3种药物中的某1种(其中达比加群有2种不同剂量：150 mg b.i.d.和110 mg b.i.d.)与华法林进行比较。

总体而言，分析显示这些新型药物明显优于华法林。与使用华法林的患者相比，使用新型药物的患者发生卒中或全身性栓塞的风险降低21%；卒中风险降低23%；出血性卒中风险降低53%；全因死亡风险降低12%；大出血风险降低13%。

阿哌沙班与任一剂量的达比加群之间，以及利伐沙班与达比加群110 mg之间，均无显著疗效差异。达比加群150 mg对部分终点的疗效(卒中或全身性栓塞风险降低26%，出血性卒中风险降低56%)优于利伐沙班。

在安全性终点方面也观察到一些显著差异。阿哌沙班组的大出血风险比利伐沙班组低34%，比达比加群150 mg组低26%，但与达比加群110 mg组相比无显著差异。与利伐沙班组相比，达比加群110 mg组的大出血风险降低23%，颅内出血风险降低54%。

该分析的局限性在于并非直接比较，并且无法校正不同研究人群的人口学因素和卒中风险，而且也无法解释不同研究之间在华法林对照方面的差异(一些研究的平均治疗窗内时间优于另一些研究)。

研究者表示，尽管间接比较分析仍被视为可靠的统计学工具，但只有直接比较才能全面回答这些新药用于房颤患者预防卒中的疗效/安全性差异问题。

随刊述评：必须非常谨慎地看待研究结果

波士顿布里格姆妇女医院的Christopher P. Cannon博士和加州大学旧金山分校的Payal Kohli博士指出，在解读此类分析结果时应非常谨慎，并且该分析的结果颇令人困惑。例如，该分析显示各药在心肌梗死发生率方面无显著差异，然而具体分析各项研究时却发现，达比加群组的心肌梗死发生率高于华法林组，而利伐沙班组或阿哌沙班组与华法林组相比无此结果。这些不一致的结果提示，此类间接比较方法的准确性欠佳，所观察到的差异缺乏鲁棒性，不足以用于指导临床治疗。只有直接比较得出的证据才具有临床指导意义(J. Am. Coll. Cardiol. 2012;60:747-8)。

Christopher Cannon博士

研究者声明是拜耳等公司的顾问和讲师。Cannon博士声明与阿尔尼拉姆等公司存在多种利益关系。Kohli博士声明是第一三共公司的顾问。

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By: JENNIE SMITH, Cardiology News Digital Network

A study indirectly comparing three oral anticoagulant drugs – dabigatran, rivaroxaban, and apixaban – has revealed potential differences among the agents in their relative efficacy and safety when used for stroke prevention in atrial fibrillation.

However, its authors found more similarities than differences overall, and stopped short of saying that the differences they found should have meaning for clinicians in choosing one over another. Only a head-to-head trial comparing the new agents could do that, they said.

The study, published in the August issue of the Journal of the American College of Cardiology, used data from phase III, randomized, controlled trials that had enrolled more than 50,000 patients (J. Am. Coll. Cardiol. 2012;60:738-46). The authors, led by Dr. Gregory Y.H. Lip of the University of Birmingham (England) compared each of the agents – including two different doses of dabigatran, 150 mg b.i.d. and 110 mg b.i.d. – with warfarin.

Overall, the investigators found that the newer agents offered significant advantages over warfarin, with 21% reduced risk of stroke or systemic embolism; 23% reduced risk of stroke; 53% lower risk of hemorrhagic stroke; and 12% less risk of all-cause mortality. The risk of major bleeding was 13% lower with the new agents, compared with warfarin.

Dr. Lip and his colleagues reported that they found no profound significant differences in efficacy between apixaban and dabigatran at either dose, or between rivaroxaban and dabigatran 110 mg; dabigatran 150 mg was seen as superior to rivaroxaban for some end points, with a 26% lower risk of stroke or systemic embolism and a 56% lower risk of hemorrhagic stroke.

Some significant differences were also seen for safety end points. The risk of major bleeding was 34% lower for apixaban than for rivaroxaban, and 26% lower for apixaban than for dabigatran 150 mg, but not significantly different between apixaban and dabigatran 110 mg. Compared with rivaroxaban, dabigatran 110 mg was associated with 23% less risk of major bleeding and 54% less intracranial bleeding.

Dr. Lip and his colleagues acknowledged that their study, because it was an indirect comparison analysis, had automatic limitations, such as the fact that it could not adjust for patient demography and stroke risk of the different trial populations; nor could it account for differences in warfarin control between the trials, with mean time in therapeutic range better in some trials than others.

Although indirect comparison "is still considered a reasonable statistical tool to qualify a comparison of effects that have not yet been investigated head to head," only head-to-head comparison, they concluded, would "fully answer the question of efficacy/safety differences between the new drugs for stroke prevention in AF."

Dr. Lip disclosed having served as a consultant for Bayer, Astellas, and other companies; and having been a speaker for Bayer, Pfizer, and other companies. Two of Dr. Lip’s coauthors on the study, Dr. Torben Bjerregaard Larsen and Dr. Lars Hvilsted Rasmussen, disclosed having been speakers for BMS/Pfizer and Boehringer Ingelheim.
 
View On the News: Study Should Be Approached "With Extreme Caution"

Dr. Christopher P. Cannon and Dr. Payal Kohli argued that studies such as this one should be approached “with extreme caution,” and that “the picture remains a bit confusing” for the individual agents relative to one other. For example, they noted, Dr. Lip and colleagues reported no significant differences in myocardial infarction rates among the agents, whereas within the individual trials, the rate of myocardial infarction was higher with dabigatran, but not with either rivaroxaban or apixaban, as compared with warfarin. “These conflicting results lend support to the conclusion that such methods for indirect comparisons may not be the most accurate due to several sources of confounding.” The statistical limitations of the methods used in this analysis mean that the reported differences “are not robust enough to be relied upon for the clinical care of patients,” Dr. Cannon and Dr. Kohli wrote.
 
Barring head-to-head comparison evidence, they argued, “we would turn to direct evidence from trials and the indications put forth by the FDA [U.S. Food and Drug Administration] to select the appropriate agent, at the dose tested, for use in the patient population studied within the trial.”

DR. CANNON is with Brigham and Women’s Hospital in Boston and DR. KOHLI is with the University of California, San Francisco. These remarks were taken from an editorial accompanying Dr. Lip’s report (J. Am. Coll. Cardiol. 2012;60:747-8). Dr. Cannon disclosed advisory relationships with Alnylam, Bristol-Myers Squibb, and Pfizer; equity in Automedics Medical Systems; and grant support from Accumetrics, AstraZeneca, and other companies. Dr. Kohli disclosed an advisory relationship with Daiichi Sankyo.