全髋关节成形术后预防VTE：阿司匹林优于肝素

根据6月3日《内科学年鉴》在线发表的一篇报告，在全髋关节成形术后的延长期血栓预防中，阿司匹林是低分子量肝素的安全、有效、方便且价廉的替代药物。

主要研究者、Dalhousie大学的David R. Anderson博士介绍，EPCAT(低分子量肝素与阿司匹林用于全髋关节成形术后延长预防的比较)研究是一项多中心随机试验，共招募了3年间786例接受择期全髋关节置换的加拿大患者。结果显示，口服阿司匹林组28天时预防静脉血栓栓塞(VTE)的疗效不逊于皮下注射达肝素钠组，而且同样安全。

参与EPCAT研究的患者在12家大学附属医院接受了择期全髋关节置换术，并连续10天皮下注射达肝素钠以预防血栓。然后这些患者被随机分组，一部分(n=400)继续注射达肝素钠和服用实为安慰剂的阿司匹林，其余患者(n=386)注射安慰剂和服用阿司匹林(81 mg/d)，治疗28天。患者、医生、研究协调员和医疗小组成员均不了解分组情况。两组患者在人口统计学、内外科特征方面均具有可比性。

在这项试验进行时，新的口服抗凝药物利伐沙班在加拿大获准用于这一适应证，在临床上激起了从使用达肝素钠转向使用这一新药的热潮。利伐沙班的上市严重影响了受试者招募工作，原因是在有新型口服药物可供选择的情况下，医生和患者都越来越不愿意参加要求连续38天注射药物的研究。鉴于预定的招募工作无法完成，EPCAT研究提前结束，中期分析显示主要目标——确定阿司匹林的非劣效性——已经达到。

主要疗效终点为随机化后90天内经客观检查证实发生症状性近端深静脉血栓(DVT)或肺栓塞(PE)。结果显示，阿司匹林组和达肝素钠组的主要疗效终点发生率分别为0.3%和1.3%，证实阿司匹林治疗具有非劣效性。阿司匹林组发生了1例近端DVT，而达肝素钠组发生了2例近端DVT和3例PE。达肝素钠组还有1例患者发生了症状性远端DVT，栓塞部位为小腿，“不过并未被判定为终点事件”。

阿司匹林组未发生大出血事件，而达肝素钠组发生了1例(0.3%)。两组分别发生了2例(0.5%)和4例(1.0%)临床显著的非大出血事件，分别发生了8例(2.1%)和18例(4.5%)微出血事件。综合考虑VTE和有临床意义的大出血、非大出血并发症的净临床获益分析显示，阿司匹林组有0.8%的患者达到了这一复合终点，而达肝素钠组为2.5%。

两组在伤口感染、动脉血管事件、心肌梗死、卒中或死亡等次要终点方面无显著差异。

EPCAT研究者表示，接下来有必要比较阿司匹林与新型口服抗凝药物在全髋关节置换术后延长期预防中的作用。这项研究还提示，可以进一步探索在其他情境下使用阿司匹林预防VTE的获益。

EPCAT试验获得了加拿大卫生研究所的支持。阿司匹林由拜耳公司提供，达肝素钠由辉瑞公司提供，但这两家公司均未参与该试验的设计、实施或分析。

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By: MARY ANN MOON, Internal Medicine News Digital Network

Aspirin is an effective, safe, convenient, and inexpensive alternative to low-molecular-weight heparin for extended thromboprophylaxis after total hip arthroplasty, according to a report published online June 3 in Annals of Internal Medicine.

In a multicenter randomized trial involving 786 patients undergoing elective total hip replacement in Canada during a 3-year period, 28 days of oral aspirin prophylaxis was noninferior to and as safe as 28 days of subcutaneous dalteparin injections for preventing venous thromboembolism (VTE), according to Dr. David R. Anderson, who is professor of medicine, pathology, and community health and epidemiology of Dalhousie University, Halifax, N.S., and his associates in the EPCAT (Extended Prophylaxis Comparing Low-Molecular-Weight Heparin to Aspirin in Total Hip Arthroplasty) study.

During this trial, the novel oral anticoagulant rivaroxaban was approved for this indication in Canada, which prompted "a major shift" away from using dalteparin and toward using the new drug in clinical practice. In light of this development, it will be important to "evaluate the benefits and risks of aspirin as extended prophylaxis after [total hip replacement], compared with the new oral anticoagulant agents," noted the EPCAT investigators.

Their findings on the benefits of aspirin also indicate that its role for venous thromboprophylaxis in other settings should now be reconsidered as well, Dr. Anderson and his colleagues added.

In the EPCAT study, patients underwent elective unilateral total hip replacement at 12 university-affiliated tertiary medical centers and received thromboprophylaxis in the form of subcutaneous injections of dalteparin for 10 days. They were randomly assigned to continue receiving dalteparin injections and take placebo oral aspirin tablets (400 patients) or to receive placebo injections and begin taking oral aspirin (81 mg) every day for 28 days (386 patients).

The demographic, medical, and surgical characteristics of the two study groups were comparable. Patients, physicians, study coordinators, and members of the health care teams all were blinded to study assignment.

The introduction of rivaroxaban during the course of the study severely affected ongoing recruitment of subjects, because both patients and orthopedic surgeons became increasingly reluctant to participate in a study requiring daily injections for 38 days when a new oral agent was available. The EPCAT study was terminated early when completion of the intended enrollment appeared "unfeasible" and an interim analysis showed that the primary objective – establishing the noninferiority of aspirin – had been reached.

The primary efficacy outcome was the development of symptomatic proximal deep vein thrombosis (DVT) or pulmonary embolism (PE), confirmed by objective testing, during the 90 days after randomization. This outcome occurred in only 0.3% of the aspirin group, compared with 1.3% of the dalteparin group, establishing the noninferiority of aspirin therapy.

There was a single case of proximal DVT in the aspirin group, compared with two cases of proximal DVT and three of PE in the dalteparin group. Another patient in the dalteparin group developed a symptomatic distal DVT in her calf, "but this was not considered an outcome event," the investigators said.

No major bleeding events developed in the aspirin group, but there was one such event in the dalteparin group for an overall rate of 0.3%. Similarly, there were two clinically significant nonmajor bleeding events for aspirin (0.5% rate), compared with four for dalteparin (1.0% rate). And there were eight minor bleeding events for aspirin (2.1% rate), compared with 18 for dalteparin (4.5% rate).

"In a composite analysis of net clinical benefit that combined VTE and clinically relevant major and nonmajor bleeding complications as outcomes," 0.8% of patients receiving aspirin had complications, compared with 2.5% of patients receiving dalteparin.

There were no differences between the two study groups in secondary outcomes such as wound infections, arterial vascular events, MI, stroke, or deaths.

The EPCAT trial was supported by the Canadian Institutes for Health Research. Aspirin was provided by Bayer HealthCare and dalteparin by Pfizer Pharmaceuticals, but neither Bayer nor Pfizer was involved in the design, conduct, or analysis of the study.