FDA发布的达比加群与华法林安全性比较数据令人欣慰

美国食品药品管理局（FDA）5月13日宣布，基于一项针对联邦医疗保险患者开展的比较达比加群酯与华法令治疗风险的大规模观察性队列研究结果，有关达比加群酯使用的现行推荐指南和说明书内容将不作修订。

据FDA声明，这项最近完成、结果尚未发表的研究表明，与华法令相比，达比加群酯治疗患者缺血性卒中、颅内出血以及死亡风险较低，但胃肠道（GI）大出血风险相对较高，而心梗（MI）风险相似。

声明指出，除MI外，该研究的其他结果与RE-LY（长期抗凝治疗随机评价研究）试验结果相一致。后者发现，达比加群酯治疗患者MI风险高于华法令治疗者。基于RE-LY试验结果，达比加群酯于2010年获准用于减少非瓣膜性房颤患者卒中和全身性栓塞风险。达比加群酯由勃林格殷格翰公司以商品名Pradaxa上市销售。

FDA声明称：“鉴于这项最新研究结果，我们仍然认为Pradaxa具有良好的获益风险特征，对现行说明书和推荐指南无需修订。重要的是，与此前FDA对上市后数据评价所基于的研究相比，这项新的研究纳入了更多老年患者，对所关注事件数据采用了更为精确收集和分析方法。”

作为正在开展的达比加群酯评价研究的一部分，该研究对134,000余例达比加群酯和华法令新近使用者的风险进行了评估。患者年龄＞65岁，在用药前6个月确诊为房颤。数据来自2010~2012年，通过住院和保险索赔资料确定患者结局，数据代表了超过37,500人-年的随访情况。

以华法令为对照组，合并达比加群酯2个批准剂量（75 mg 和 150 mg）数据后的分析结果如下：达比加群酯与华法令组每1,000人-年缺血性卒中发生率（IR）分别为11.3和13.9 [风险比（HR），0.80）]，颅内出血IR分别为3.3和9.6（HR，0.34），GI大出血IR分别为34.2和26.5（HR，1.28），急性MI IR分别为15.7和16.9（HR，0.92），死亡IR分别为32.6和37.8（HR，0.86）。

FDA声明指出，该研究GI大出血结果不同于2012年FDA对约10,600例达比加群酯和华法令新近使用者的分析结果。后者发现达比加群酯治疗者GI和颅内出血发生率低于华法令治疗者。不过，后者纳入了年龄<65岁的患者（64%为65岁以上患者），上述差异“可能反映了两组患者年龄的差异。”

Sanjay Kaul博士

加州大学洛杉矶分校医学教授Sanjay Kaul博士在接受采访时称，这项研究数据令人欣慰，“这表明在获批前的随机对照RE-LY试验中所观察到的令人满意的受益-风险特点可外推至现实临床实践中。”

Kaul博士指出，由于没有设立安慰剂对照， RE-LY试验中MI指标升高的原因不明确，但这项最新研究解决了这一问题。不过，增加GI出血的确切原因尚不得而知。通过服用H₂阻断剂或质子泵抑制剂等胃保护药物将无法降低这一风险，因此，有下消化道出血史的患者最好还是避免服用这一药物。

Deepak Bhatt博士

此外，他还指出，这些数据进一步表明，这一新型口服抗凝药物对于没有禁忌症、可支付得起的患者而言是一个更好选择。哈佛大学医学教授、布里格姆妇女医院心血管中心介入心血管项目执行主任Deepak Bhatt博士也认为FDA研究结果令人欣慰。他指出，这项研究提供了真实世界中大规模患者的数据，是对RE-LY试验结果的补充和真实反映。“我认为这些有关死亡、卒中和GI出血的所有数据都是真实的，因为这是来自随机临床试验的数据，很高兴看到这些数据在现实临床实践中也是真实的。”

Bhatt博士称，总体上，获准用于非瓣膜性房颤适应症的3种口服抗凝新药达比加群酯、Xa因子抑制剂阿哌沙班以及利伐沙班，似乎均可减少卒中和死亡风险，并且均显示可显著减少颅内出血。“达比加群酯等具有较低颅内出血风险药物的上市，确是是一个利好消息，有望使更多的AF患者得到最适治疗，避免因担心脑内出血而没能得到治疗。”

FDA计划发表该项最新研究结果，并将继续评估抗凝药物出血风险。

目前，达比加群酯还获准用于已经接受注射用抗凝药物治疗5~10年患者的深静脉血栓形成（DVT）和肺栓塞（PE）治疗，以及用于降低已经接受治疗患者DVT 和PE复发风险。

FDA于2011年和2012年已分别发布了两项有关达比加群酯出血风险的安全警告。

Kaul博士担任勃林格殷格翰公司顾问，并持有强生公司的股权。Bhatt博士称他得到来自阿斯利康等多家制药公司的研究基金，他还是即将开始的大规模AF支架患者达比加群酯与华法令比较研究RE-DUAL PCI试验的执委会成员。

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By: ELIZABETH MECHCATIE, Cardiology News Digital Network

VITALS

Major finding: The risks of ischemic stroke, intracranial hemorrhage, and death associated with dabigatran treatment were lower than with warfarin, but the risks of MI were similar and the risk of major GI bleeding was increased among those on dabigatran.

Data source: An observational cohort study of more than 134,000 Medicare beneficiaries with atrial fibrillation compared the rates of different outcomes of interest among patients treated with dabigatran and those treated with warfarin.

Disclosures: The FDA conducted the study.

Current recommendations and labeling regarding the use of dabigatran will not change, based on the results of a large observational cohort study comparing the risks of the direct thrombin inhibitor and warfarin in Medicare recipients, the Food and Drug Administration announced on May 13.

The study, which was completed recently and has not been published, found that dabigatran, compared with warfarin, was associated with a lower risk of ischemic stroke, intracranial hemorrhage, and death, according to the FDA’s statement on the findings. The risk of major gastrointestinal bleeding, however, was higher with dabigatran, and the risk of myocardial infarction was similar in both groups.

The statement points out that other than the MI finding, the results are consistent with the results of the RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) trial, which found the MI risk was higher among those on dabigatran than with warfarin. Approval of dabigatran in 2010 for reducing the risk of stroke and systemic embolism in patients with nonvalvular AF was based on the results of the RE-LY study. Dabigatran is marketed as Pradaxa by BoehringerIngelheim.

"As a result of our latest findings, we still consider Pradaxa to have a favorable benefit to risk profile and have made no changes to the current label or recommendations for use," the FDA statement said. "Importantly, the new study is based on a much larger and older patient population than those used in FDA’s earlier review of postmarket data, and employed a more sophisticated analytical method to capture and analyze the events of concern."

The study, part of an ongoing review of dabigatran, evaluated the risks of more than 134,000 new users of dabigatran and warfarin, who were over age 65 years and had been diagnosed with atrial fibrillation during the 6 months before the medication was dispensed. The data were from 2010-2012. Patient outcomes were identified in administrative and insurance claims, and the study represented more than 37,500 person-years of follow-up.

The results were as follows, with warfarin as the reference group, and dabigatran results based on the analysis of both approved doses (75 mg and 150 mg) combined:

• For ischemic stroke, the incidence rates (IR) per 1,000 person-years were 11.3 for dabigatran, vs. 13.9 for warfarin (hazard ratio, 0.80).

• For intracranial hemorrhage, the incidence rates were 3.3 for dabigatran, vs. 9.6 for warfarin (HR, 0.34).

• For major GI bleeding, the incidence rates were 34.2 for dabigatran, vs. 26.5 for warfarin (HR, 1.28).

• For acute MI, the incidence rates were 15.7 for dabigatran, vs. 16.9 for warfarin (HR, 0.92).

• For mortality, the incidence rates were 32.6 for dabigatran vs. 37.8 for warfarin (HR, 0.86).

The FDA statement points out that the results for major GI bleeding in this study are different from a previous FDA analysis of about 10,600 new users of dabigatran and warfarin, reported in 2012, which found that GI and intracranial hemorrhage rates were lower among patients treated with dabigatran, compared with those on warfarin. However, that study included patients under age 65 years (64% were older than age 65 years), and this disparity "may reflect the age differences in the two patient populations," the FDA statement said.

In an interview, Dr. Sanjay Kaul, professor of medicine at University of California Los Angeles, said the data in the Medicare study were reassuring, “and indicate that the favorable benefit-risk balance observed in the pre-approval randomized controlled trial, RE-LY, are generalizable in real world clinical practice.”

Without a placebo control, he added, “it is unclear what to make of the MI signal observed in RE-LY, but not in this study.” And while the exact cause of increased GI bleeding remains unclear, Dr. Kaul pointed out that this risk cannot be mitigated by gastroprotective medications such as H2 blockers or proton pump inhibitors, and that “it is best to avoid this medication in patients with history of lower-GI bleeding.”

Dr. Deepak Bhatt, professor of medicine at Harvard University in Boston, also described the results of the FDA study as reassuring. The study provides real world data in a large number of patients that complement and largely mirror the results in RE-LY, he said in an interview.

 “I think that all those findings regarding death, stroke, and GI bleeding are all true because they were true in the randomized clinical trial dataset, and it is good to see they also appear to be true in real life clinical practice,” he commented. 

In addition, the data “further support the idea that the novel oral anticoagulants in patients who don’t have contraindications for them, and can afford them, [are] a better option than warfarin,” said Dr. Bhatt, the executive director of Interventional Cardiovascular Programs, at Brigham and Women’s Hospital Heart and Vascular Center, Boston.

He pointed out that overall, the three novel oral anticoagulants – dabigatran and the factor Xa inhibitors, apixaban and rivaroxaban – approved for the nonvalvular AF indication, appear to reduce the risk of stroke and death, “and across the board, they all show significantly less intracranial hemorrhage.”

 “The availability of agents that have a lower intracranial hemorrhage risk, such as dabigatran, really is an advantage and will hopefully lead to more patients with atrial fibrillation being appropriately treated, instead of being undertreated  because of fear of bleeding into the brain,” he said. 

The FDA plans to publish the Medicare study and will continue to review the risks of bleeding with anticoagulants.

Dabigatran is now also approved for the treatment of deep venous thrombosis (DVT) and pulmonary embolism (PE) in patients who have been treated with a parenteral anticoagulant for 5-10 days, and to reduce the risk of recurrence of DVT and PE in patients who have been previously treated.

The FDA has issued two previous safety alerts regarding the bleeding risks associated with dabigatran, in 2011 and 2012.

Dr. Kaul is a consultant to BoehringerIngelheim and has equity interest in Johnson and Johnson. Dr. Bhatt said he has research grants with Amarin, AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Medtronic, Roche, Sanofi Aventis, and the Medicines Company. He is also on the executive committee for the RE-DUAL PCI trial, a large study comparing dabigatran to warfarin in stented patients with AF, which will be starting soon.

The FDA notice is available here. Serious adverse events associated with dabigatran and warfarin should be reported to the FDA at 800-332-1088 or at .