VTE后延长阿哌沙班、达比加群治疗安全有效

《新英格兰医学杂志》2月21日在线发表的3项随机临床研究显示，阿哌沙班和达比加群这两种口服抗凝剂可有效用于静脉血栓栓塞(VTE)的延长治疗。此外，这两种药物均可降低出血并发症风险。

在AMPLIFY-EXT研究中，Giancarlo Agnelli博士及其同事3年内在28个国家的328个医学中心纳入2,486例已完成6~12个月标准抗凝治疗但其医生不确定是否应停止还是继续抗凝治疗的VTE患者。这些患者以双盲方式随机接受阿哌沙班维持剂量2.5 mg(840例)、阿哌沙班治疗剂量5 mg(813例)或匹配安慰剂(829例)治疗，每天给药2次，持续1年。主要疗效终点是症状性复发性VTE或全因死亡复合终点事件。阿哌沙班维持剂量组和治疗剂量组该疗效终点事件的发生率分别为3.8%和4.2%，均显著低于安慰剂组(11.6%)。因此，阿哌沙班的治疗剂量和维持剂量均可显著降低复发性VTE的发生率。主要安全性终点是大出血。阿哌沙班维持剂量组和治疗剂量组该安全性终点事件的发生率分别为0.2%和0.1%，与安慰剂组(0.5%)相似。阿哌沙班维持剂量组和治疗剂量组具有临床意义的非大出血的发生率分别为3.0%和4.2%，显著高于安慰剂组(2.3%)。在患者需治数方面，阿哌沙班每治疗14例患者可预防1起复发性VTE事件。相比之下，阿哌沙班每治疗200例患者可引起1起大出血或具有临床意义的非大出血(N. Engl. J. Med. 2013 Feb. 21 [doi10.1056/NEJMoa1207541])。

研究者表示，对于不确定长期抗凝治疗的获益和风险的VTE患者而言，该研究结果支持患者继续接受额外12个月的抗凝治疗。但需指出的是，该研究中仅15%患者的年龄大于75岁，而且少数患者的体重低于60 kg或存在中度或重度肾功能损害。因此，需要更多的数据才能进一步明确阿哌沙班在此类患者中的获益和风险，特别是出血方面。此外，还需进行进一步研究，以确定超过12个月的长期抗凝治疗的获益和风险。

在RE-MEDY和RE-SONATE研究中，加拿大安大略省麦克马斯特大学血栓与动脉粥样硬化研究所的Sam Schulman博士及其同事达比加群长期抗凝治疗进行了研究(N. Engl. J. Med. 2013 Feb. 21 [doi:10.1056/NEJMoa1113697])。

在RE-SONATE研究中，研究者在33个国家的265个医学中心纳入2,866例完成至少3个月抗凝治疗且被认为复发风险较高的VTE患者，这些患者随机接受固定剂量达比加群2次/d(1430例)或华法林(1426例)治疗36个月。

在RE-MEDY研究中，研究者在21个国家的147个医学中心纳入1,343例完成至少3个月抗凝治疗但复发风险不高的VTE患者，这些患者接受固定剂量达比加群(681例)或匹配安慰剂(662例)治疗。在RE-SONATE和RE-MEDY研究中，主要疗效终点为复发性症状性VTE或VTE相关死亡。

结果显示，在RE-SONATE研究中，达比加群组和华法林组该疗效终点事件的发生率分别为1.8%和1.3%，因此达比加群在预防复发性或致死性VTE方面达到非劣效于华法林的标准。在RE-MEDY研究中，达比加群组和安慰剂组该疗效终点事件的发生率分别为0.4%和5.6%，表明达比加群预防复发性或致死性VTE的作用显著强于安慰剂。达比加群组大出血事件(0.9% vs. 1.8%)和具有临床意义的出血事件(5.6% vs. 10.2%)的发生率显著低于华法林组。然而，达比加群组大出血和具有临床意义的出血事件的发生率均高于安慰剂组(5.3% vs 1.8%)。此外，达比加群组急性冠脉事件(0.9%)高于华法林组(0.2%)，尽管受累患者数量不多。近期一项对7项非劣效性研究进行的meta分析也显示，达比加群的相关心肌梗死或急性冠脉综合征风险显著高于对照药物。Schulman博士表示，尚不清楚达比加群是否增加心肌梗死风险。

AMPLIFY-EXT研究获百时美施贵宝和辉瑞公司资助；Agnelli博士及其同事声明与拜耳等多家药企存在联系。RE-MEDY和RE-SONATE研究获勃林格殷格翰公司资助；Schulman博士及其同事声明与多家药企存在联系。

随刊述评：权衡长期抗凝治疗的风险和获益

布里格姆妇女医院血液科的Jean M. Connors博士表示，权衡长期抗凝治疗的风险和获益较为困难，并且是否停止或何时停止治疗也是难以决定的事情(N. Engl. J. Med. 2013 Feb. 21 [doi:10.1056/NEJMe1215678])。

阿哌沙班和达比加群均未获准用于VTE的短期和长期治疗。利伐沙班是首个获得此类批准的新抗凝药。然而，研究显示，小剂量阿哌沙班的疗效与全治疗剂量相同，并且出血风险相同，表明小剂量阿哌沙班用于VTE患者长期治疗的风险-获益比较好。

在临床实践中应用新口服抗凝药的关键在于选择合适的患者。与临床上的常见患者相比，这些研究中的患者年龄更轻(平均56岁)、合并症更少且出血风险更低，并且没有癌症或抗磷脂综合征等需要长期抗凝治疗的明显适应证。

VTE复发风险最高的患者从长期抗凝治疗获益最大。需建立更佳的风险分层策略，以识别这些患者。

Connors博士声明无经济利益冲突。

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By: MARY ANN MOON, Cardiology News Digital Network

Two oral anticoagulants, apixaban and dabigatran, were found to be effective for the extended treatment of venous thromboembolism in three industry-sponsored randomized clinical trials. The results were published online Feb. 21 in the New England Journal of Medicine.

Both medications also reduced the risk of bleeding complications, the investigators said.

In the first trial, two doses of apixaban were compared against placebo in 2,486 patients with venous thromboembolism who had finished 6-12 months of standard anticoagulation therapy and whose physicians were uncertain whether to stop or continue anticoagulation treatment, said Dr. Giancarlo Agnelli and his associates in the Apixaban after the Initial Management of Pulmonary Embolism and DVT with First-Line Therapy–Extended Treatment (AMPLIFY-EXT) study.

Apixaban is an oral factor Xa inhibitor that is administered in fixed doses and doesn’t require laboratory monitoring. The 5-mg (treatment) dose of apixaban has proved effective at preventing stroke in patients with atrial fibrillation, and the 2.5-mg (maintenance) dose has proved effective for thromboprophylaxis after major orthopedic surgery, said Dr. Agnelli of the department of internal and cardiovascular medicine-stroke unit at the University of Perugia (Italy) and his colleagues.

The study subjects were enrolled over a 3-year period at 328 medical centers in 28 countries. They were randomly assigned in double-blind fashion to receive the 2.5-mg dose (840 subjects), the 5-mg dose (813 subjects), or a matching placebo (829 subjects) twice daily for 1 year.

The primary efficacy outcome measure was a composite of symptomatic recurrent VTE or death from any cause. This occurred in 3.8% of the maintenance-dose group and 4.2% of the treatment-dose group, both significantly lower rates than in the placebo group (11.6%). Thus, both doses of apixaban significantly decreased the incidence of recurrent VTE, Dr. Agnelli and his associates said (N. Engl. J. Med. 2013 Feb. 21 [doi10.1056/NEJMoa1207541]).

The primary safety outcome measure was major bleeding, which occurred in 0.2% of the maintenance-dose group and 0.1% of the treatment-dose group, compared with 0.5% of the placebo group. Thus, both doses of apixaban were comparable to placebo in rates of major bleeding.

Clinically relevant nonmajor bleeding occurred in 3.0% of subjects taking 2.5 mg of apixaban and 4.2% of those taking 5 mg of apixaban, which were significantly higher than the 2.3% rate in subjects taking placebo.

The number of patients who would need to be treated with apixaban to prevent a single episode of recurrent VTE was 14. In contrast, the number who would need to be treated to cause an episode of major or clinically relevant nonmajor bleeding was 200, the investigators noted.

"For patients with venous thromboembolism for whom there is uncertainty about the benefits and risks of continued therapy, the results of this study provide a rationale for continuing anticoagulation therapy for an additional 12 months," they said.

"It should be noted, however, that only 15% of the patients in this study were older than 75 years of age, and few had a body weight below 60 kg or moderate or severe renal impairment. Consequently, more data are needed to better determine the benefit-to-risk profile of apixaban with respect to bleeding in such patients," the researchers said.

Further research also is needed to determine the risks and benefits of extending anticoagulation therapy beyond the 12-month mark examined in this study, they added.

In a separate report, Dr. Sam Schulman and his associates in the RE-MEDY and RE-SONATE studies examined the direct thrombin inhibitor dabigatran as a long-term anticoagulation treatment. These trials were extensions of two previous studies of short-term anticoagulation after venous thromboembolism (N. Engl. J. Med. 2013 Feb. 21 [doi:10.1056/NEJMoa1113697]).

In RE-SONATE, 2,866 VTE patients who had completed at least 3 months of anticoagulation therapy and were considered to be at increased risk for recurrence were randomly assigned to receive either fixed-dose dabigatran twice daily (1,430 subjects) or warfarin (1,426 subjects) for up to 36 months. They were followed at 265 medical centers in 33 countries, said Dr. Schulman of McMaster University Thrombosis and Atherosclerosis Research Institute, Hamilton, Ont., and his colleagues.

The RE-MEDY trial, in contrast, involved 1,343 VTE patients who had completed at least 3 months of anticoagulation therapy but were not considered to be at increased risk of recurrence, so it was ethical to assess the effect of dabigatran vs. placebo in these patients. The subjects were randomly assigned to receive either fixed-dose dabigatran (681 patients) or a matching placebo (662 patients) and were followed at 147 medical centers in 21 countries.

In both RE-SONATE and RE-MEDY, the primary efficacy outcome measure was recurrent symptomatic VTE or VTE-related death.

In RE-MEDY, this outcome occurred in 1.8% of the dabigatran group and 1.3% of the warfarin group, thus meeting the criteria for noninferiority to warfarin in preventing recurrent or fatal VTE.

In RE-SONATE, this outcome occurred in 0.4% of the dabigatran group, compared with 5.6% of the placebo group, so the drug was significantly more effective than placebo at preventing recurrent or fatal VTE.

Dabigatran was associated with markedly fewer major bleeding events (0.9% vs. 1.8%) and clinically relevant bleeding events (5.6% vs. 10.2%) than was warfarin. However, the drug was associated with more major or clinically relevant bleeding events than was placebo (5.3% vs 1.8%).

In addition, there was a higher rate of acute coronary events with dabigatran (0.9%) than with warfarin (0.2%), although the number of affected patients was small. A recent meta-analysis of seven noninferiority trials also showed a significantly higher risk of MI or acute coronary syndromes with dabigatran than with the comparators. "Whether dabigatran increases the risk of MI is therefore still unclear," Dr. Schulman and his associates said.

AMPLIFY-EXT was funded by Bristol-Myers Squibb (BMS) and Pfizer; Dr. Agnelli reported ties to Bayer, Boehringer Ingelheim (BI), Daiichi Sankyo, BMS, and Sanofi-Aventis, and his associates reported ties to numerous industry sources. RE-MEDY and RE-SONATE were funded by BI; Dr. Schulman and his associates reported ties to numerous industry sources.

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Weigh risks, benefits of extended anticoagulation

Balancing the risks and benefits of extended anticoagulation is difficult, and deciding whether or when to stop the treatment remains a challenge, said Dr. Jean M. Connors.

Neither apixaban nor dabigatran are approved for short-term or extended treatment of VTE; rivaroxaban is the first of the new anticoagulants to gain such approval. However, the finding that apixaban was as effective in a low dose as it was at the full therapeutic dose, with the same bleeding risk, "may tip the risk-to-benefit ratio in favor of extended treatment for this patient population."

"The crux of using the new oral anticoagulants in clinical practice ... lies in the selection of appropriate patients. Patients in these studies were younger (average age, 56 years), with fewer coexisting diseases and a lower bleeding risk than patients typically seen in practice," and they had no strong indications for continuing anticoagulation, such as cancer or antiphospholipid syndrome.

Patients at the greatest risk of VTE recurrence are the ones who stand to benefit most from extended anticoagulation. Better risk-stratification strategies are needed to identify these patients, she said.

Dr. Connors is in the hematology division, department of medicine, at Brigham and Women’s Hospital, Boston. She reported no financial conflicts of interest. These remarks were taken from her editorial accompanying Dr. Agnelli’s and Dr. Schulman’s reports (N. Engl. J. Med. 2013 Feb. 21 [doi:10.1056/NEJMe1215678]).