利伐沙班致颅内出血的风险低于华法林

NEW ORLEANS (EGMN) – Compared with warfarin, the new-generation anticoagulant rivaroxaban was associated with a 40% lower risk of intracranial hemorrhage in patients with atrial fibrillation who were taking the agents to prevent stroke.

Since its approval by the U.S. Food and Drug Administration last fall, rivaroxaban has been deemed an alternative to warfarin, especially among those patients who have trouble maintaining a stable international normalized ratio, who have warfarin side effects, or who find the constant warfarin monitoring untenable, Dr. Graeme Hankey said at an international stroke conference.

Rivaroxaban also doesn’t involve the medication and food interactions that can make warfarin problematic, said Dr. Hankey, head of the stroke unit at Royal Perth Hospital, Western Australia.

“Many patients don’t want to take warfarin for these reasons,” he said in an interview. “Rivaroxaban doesn’t have these interactions. It has a stable, predictable effect with once-a-day dosing and doesn’t require this constant monitoring.”

Dr. Hankey’s subanalysis of the pivotal ROCKET-AF study, which compared rivaroxaban with warfarin, also determined that some patients had up to a fourfold increased risk of an intracranial bleed while taking either of the anticoagulants.

The initial study – Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation or ROCKET AF – included 14,264 patients with atrial fibrillation; a history of stroke, TIAs, or systemic embolism; and at least two of the following stroke risk factors: heart failure or a left ventricular ejection fraction of 35% or less; hypertension, an age of 75 years or more; or the presence of diabetes mellitus. Patients were randomized to receive dose-adjusted warfarin or rivaroxaban. Those with normal creatinine clearance received 20 mg daily of the study drug; those with a decreased clearance received 15 mg rivaroxaban daily.

The study’s main end point – a combination of stroke or systemic embolism – was similar in both groups (about 2% per year). The rates of myocardial infarction, and major bleeding also were not significantly different. Vascular mortality and all-cause mortality were nearly identical. However, there was a significant difference in intracranial hemorrhage, favoring rivaroxaban (0.8%; 55 vs. 1.2%; 84). (N. Engl. J. Med 2011;365:883-91). Fatal bleeding occurred in less than 1% of each group.

Dr. Hankey’s subanalysis examined the drug’s effect on intracranial hemorrhage, “probably the most-feared complication of anticoagulation,” according to the investigator. It also examined independent risk factors for intracranial hemorrhage regardless of which drug the study patients took.

He and his colleagues found 172 intracranial hemorrhages in ROCKET-AF – a rate of about 7% per year. Of these bleeds, 128 were intracerebral, 5 subarachnoid, 38 subdural, and 1 extradural. Patients taking rivaroxaban were 40% less likely to have an intracranial hemorrhage than were those taking warfarin.

The subanalysis identified factors that significantly increased the risk of an intracranial bleed. The largest by far were race and concomitant use of clopidogrel. Compared with whites, blacks were more than 400% more likely to have a brain bleed (odds ratio, 4.2), while Asians were 200% more likely. Those taking clopidogrel plus either warfarin or rivaroxaban were 250% more likely to have a bleed than were those not taking an additional anticoagulant (OR, 2.50).

Other significant associations with brain bleeds were as follows:

• High diastolic blood pressure – 21% increased risk for every 10 mm/Hg above normal.

• Poor kidney function – 10% increased risk for every 10 mL/min decrease in creatinine clearance.

• History of stroke or transient ischemic attack – 55% increased risk.

• Low platelets – 8% increased risk;

• Low albumin – 37% increased risk.

The FDA approved rivaroxaban in 2011, to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation.

Dr. José Biller, chairman of neurology at Loyola University, Maywood, Illinois, said that although rivaroxaban is another tool in the armamentarium for patients at risk of stroke, he thinks it’s premature to make a paradigm shift away from warfarin.

“Clearly, ROCKET-AF showed us that rivaroxaban was noninferior to warfarin,” said Dr. Biller, the lead author on a recently published review of the new-generation anticoagulation drugs (Expert Rev. Neurother. 2012;12:179-90). “This subanalysis showed that rivaroxaban also had a decreased rate of intracranial hemorrhage, compared with warfarin, but we must keep in mind that the drug did not affect the ROCKET-AF trial’s primary end points of stroke or systemic embolism, nor did it decrease mortality, compared with warfarin.

“One of the biggest concerns about rivaroxaban and some of the other new antithrombotic agents is that we have no established protocol to deal with bleeding, should it occur, as we do with warfarin. At this point, we really don’t know the best way to deal with a bleed. This is something we will learn only with more time,” he said. And compared with the other new-generation anticoagulants apixaban and dabigatran, rivaroxaban seems to have a few more side effects, such as nausea and increased liver enzymes.

“Rivaroxaban and these other drugs do have benefit of being fixed-dose medications taken once or twice a day, and which don’t require the monitoring that warfarin does. But they are going to be more expensive.

“If a patient is under treatment with warfarin and is stable, and if the monitoring schedule is acceptable and there are no major INR fluctuations, I don’t think there is any indication to shift treatment. If the patient has difficulty maintaining a therapeutic INR or if the monitoring is inconvenient, then I suspect patients might welcome the use of one of these fixed-dose agents,” Dr. Biller said.

ROCKET-AF was supported by Johnson & Johnson Pharmaceutical Researchand Development and by Bayer HealthCare. Dr. Hankey was an investigator on the trial and has received honoraria for speaking on the study drug. He is also a consultant for Boehringer Ingelheim and Bayer, which make dabigatran and rivaroxaban, respectively.

Dr. Biller had no disclosures.

Copyright (c) 2010 Elsevier Global Medical News. All rights reserved. This material may not be published, broadcast, rewritten, or redistributed.

新奥尔良(EGMN)——在国际卒中大会上，西澳皇家珀斯医院卒中单元负责人Graeme Hankey博士报告称，服用新一代抗凝剂利伐沙班以预防卒中的房颤患者发生颅内出血的风险比服用华法林的患者低40%。

自去年秋季经美国食品药品管理局(FDA)批准用于非瓣膜性房颤患者预防卒中和全身性栓塞以来，利伐沙班就被视为华法林的替代药物，尤其是对于国际标准化比值(INR)难以维持稳定、服用华法林后出现了副作用以及难以坚持接受频繁的华法林用药监测的患者。而且，与华法林不同，利伐沙班不存在药物与食物之间发生相互作用的问题。

关键性试验ROCKET AF(比较每日1次口服Ⅹa因子直接抑制剂利伐沙班与维生素K拮抗剂预防房颤患者发生卒中和栓塞的效果)共纳入了14,264例房颤患者。纳入标准包括：确诊为心房颤动；既往有卒中、一过性脑缺血发作(TIA)或全身性栓塞病史；至少存在2个卒中危险因素：心衰或左室射血分数≤35%、高血压、年龄≥75岁、或者合并糖尿病。患者随机分组接受校正剂量的华法林或利伐沙班治疗。肌酐清除率正常的患者每日服用20 mg利伐沙班；肌酐清除率偏低的患者则每日服用15 mg利伐沙班。

该试验的主要终点为卒中或全身性栓塞的复合发生率，结果显示两组发生率相似，均为每年2%左右。心肌梗死和大出血的发生率也无显著的组间差异。两组的血管性死亡率和全因死亡率也很接近。然而，利伐沙班组的颅内出血发生率却显著低于华法林组(0.8% vs. 1.2%) (N. Engl. J. Med 2011;365:883-91)。两组致命性出血的发生率均不足1%。

Hankey博士及其同事基于ROCKET-AF试验开展了亚分析，评估了利伐沙班对颅内出血的影响，因为颅内出血很可能是抗凝剂最令人担忧的一种并发症。此外，还分析了颅内出血的独立危险因素，无论受试者服用的是哪种抗凝剂。结果显示，ROCKET-AF试验中共出现了172例颅内出血病例，发生率约为每年7%。其中128例为大脑内出血，5例为蛛网膜下腔出血，38例为硬膜下出血，还有1例为硬膜外出血。利伐沙班组患者出现颅内出血的风险比华法林组低40%。

这项亚分析还确定了会使颅内出血风险显著增加的主要危险因素：种族以及伴随使用氯吡格雷。具体来说，黑人出现颅内出血的风险比白人高400%以上(OR，4.2)，亚裔的风险也比白人高200%。在服用华法林或利伐沙班的同时还使用了氯吡格雷的患者出现颅内出血的风险比没有服用氯吡格雷者高250%(OR，2.50)。

此外，与颅内出血相关的其他显著危险因素包括：

• 舒张压高——相比正常值每增加10 mmHg，风险增加21%。

• 肾功能差——肌酐清除率每降低10 ml/min，风险增加10%。

• 既往卒中或TIA病史——风险增加55%。

• 血小板少——风险增加8%。

• 白蛋白低——风险增加37%。

美国伊利诺伊州洛约拉大学神经病学系主任José Biller博士则认为，虽然利伐沙班也可降低房颤患者卒中风险，但现在就更改华法林治疗模式还为时过早。Biller博士最近发表了一篇关于新一代抗凝药物的综述文章(Expert Rev. Neurother. 2012;12:179-90)。

Biller博士称：“显然，ROCKET-AF试验表明利伐沙班不劣于华法林。这项亚分析提示，利伐沙班较之华法林还能降低患者发生颅内出血的风险，但值得注意的是，利伐沙班对ROCKET-AF试验的主要终点卒中或全身性栓塞的发生率并无影响，而且与华法林相比也没能降低患者的死亡率。”“利伐沙班以及其他一些新型抗血栓形成药物最令人担忧的问题之一是没有确立一旦发生出血事件应如何处理的方案，但华法林却有这样的方案。从这点上讲，我们并不清楚处理出血事件的最佳方法是什么，还需要更多的时间来积累经验。”此外，与其他新一代抗凝剂阿哌沙班和达比加群相比，利伐沙班的副作用似乎要多一些，比如恶心和肝酶升高。

“利伐沙班以及其他新型抗凝药物作为固定剂量制剂，只需每日服用1次或2次，而且也无需像华法林那样频繁监测，这的确是一种优势。不过这些新药的价格也更加昂贵。”“如果患者正在接受华法林治疗并且情况稳定，而且监测方案也被患者所接受，INR没有大的波动，那么我认为没有必要更改治疗。如果患者的INR难以维持稳定，或者监测方案给患者带来不便，那么患者可能会愿意使用这类固定剂量制剂。”

ROCKET-AF试验由强生药物研发公司和拜耳医药共同资助。Hankey博士是该试验的研究者之一，接受了有关该药宣讲的讲课费。他同时还担任了达比加群生产商勃林格-殷格翰以及利伐沙班生产商拜耳的顾问。Biller博士声明无相关利益冲突。

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