血管事件和VTE复发：阿司匹林一箭双雕

在美国心脏协会(AHA)年会和《新英格兰医学杂志》上同时发表的一项研究显示，每日服用100 mg阿司匹林即可显著降低主要血管事件风险，但是在减少静脉血栓栓塞(VTE)复发方面的效果不够显著(N. Engl. J. Med. 2012 Nov. 4 [doi: 10.1056/NEJMoa1210384])。

澳大利亚悉尼大学的Timothy A. Brighton博士指出，为了降低治疗的复杂性和出血风险，发生不明原因VTE的患者常常会停止抗凝治疗。Brighton博士及其同事在ASPIRE(阿司匹林预防静脉血栓栓塞复发)研究中，评估了阿司匹林100 mg/d对于有首次不明原因VTE病史且已接受了初步抗凝治疗的患者的效果。

这项研究于2003~2011年从5个国家的56家医院招募了822例成人患者，将其随机分为安慰剂组和阿司匹林组。约半数患者为男性，56%的患者曾发生近端深静脉血栓事件，29%曾发生肺栓塞，14%兼有这两种事件史。

结果显示，阿司匹林组共有57例患者(14%)出现VTE复发，安慰剂组为73例(18%)，年复发率分别为5%和7%，差异无统计学意义。

然而，在两项次要复合终点方面，阿司匹林组患者的发生率显著低于安慰剂组：(1)包含VTE、心肌梗死、卒中或心血管死亡的复合终点，阿司匹林组的发生率降低34%(5%/年 vs. 8%/年)；(2)包含VTE、心肌梗死、卒中、主要出血或任何原因死亡的复合终点，阿司匹林组的发生率降低33%(6%/年 vs. 9%/年)。

两组在严重不良事件或明显出血/有临床意义的不明显出血方面均无明显差异。

研究者承认，该研究的局限性在于患者数量少于原计划招募量，仅凭ASPIRE数据尚不足以显示VTE复发率的明显下降。

不过，当把ASPIRE数据与招募相似患者(402例)的WARFASA(华法林与阿司匹林)研究的数据合并分析时，研究者发现“VTE复发率高度显著地降低32%，主要血管事件发生率降低34%且无额外出血”。因此，合并分析结果支持首次发生不明原因VTE的患者采用小剂量阿司匹林预防VTE复发和主要血管事件。

主要作者Brighton博士披露称为辉瑞、葛兰素史克等公司提供咨询服务。这项研究获得了澳大利亚国立卫生与医学研究委员会、新西兰卫生研究委员会、澳大利亚国立心脏基金会、拜耳医疗(德国)及澳大利亚血液学与血栓形成学会的资金支持。

随刊述评：临床实践中的阿司匹林用法

抗凝药物预防术后VTE的效果或许优于阿司匹林，但是ASPIRE和WARFASA这两项研究的结果却支持临床上采用阿司匹林来预防VTE。加拿大麦克马斯特大学的Warkentin博士强调了已首次发生不明原因VTE 的患者的VTE复发长期风险。“阿司匹林是否代表了无限期抗凝和停止抗凝这两种极端做法的中间选项呢？”

ASPIRE和WARFASA的合并分析结果提示，阿司匹林具有一箭双雕的作用：既能显著降低VTE复发率，又能明显减少主要血管事件的复合发生率。基于这一结果，Warkentin博士就如何在临床上使用阿司匹林的问题提出了建议：“在考虑对已出现急性不明原因VTE的患者使用阿司匹林之前，很重要的一点是要给予至少3个月的有效抗凝治疗，以避免早期复发的高风险。如果此后患者希望中止抗凝治疗，不妨转为阿司匹林100 mg/d，这样可使VTE复发、动脉性心血管事件风险降低1/3，而且可能有助于避免停用口服抗凝药物之后短期内的血栓复发高风险。”

此外，阿司匹林还具有成本效益、不需要监测以及在肾功能不全患者体内无蓄积等额外优势(N. Engl. J. Med. 2012 Nov. 4 [doi: 10.1056/NEJMe1211480])。

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By: HEIDI SPLETE, Cardiology News Digital Network

A 100-mg daily dose of aspirin significantly reduces the rate of major vascular events, but had no significant impact on reducing the rate of recurrence of venous thromboembolism, based on data from 822 patients.

The findings were simultaneously published in the New England Journal of Medicine and presented at the annual meeting of the American Heart Association in Los Angeles.

Patients who have had an episode of unprovoked venous thromboembolism (VTE) often discontinue anticoagulant therapy due to inconvenience and the risk of bleeding, and low-dose aspirin has been proposed as an alternative, said Dr. Timothy A. Brighton of the University of Sydney, Australia, and his colleagues.

The ASPIRE (Aspirin to Prevent Recurrent Venous Thromboembolism) study examined the effect of a 100-mg daily dose of aspirin in patients who had a history of a first-ever unprovoked VTE and had completed initial anticoagulation therapy.

The study population included 822 adults who were randomized to a placebo or aspirin at 56 sites in five countries from May 2003 and August 2011. Roughly half of the patients were male; 56% had a proximal deep-vein thrombosis as an index event; 29% had pulmonary embolism as an index event, and 14% had both conditions as an index event (N. Engl. J. Med. 2012 Nov. 4 [doi: 10.1056/NEJMoa1210384]).

Overall, VTE recurred in 57 patients (14%) in the aspirin group, compared with 73 patients (18%) in the placebo group (rates of 5% and 7% per year, respectively, a nonsignificant difference).

However, the rates of two secondary composite outcomes were significantly reduced in patients who took aspirin compared with those on placebo, the researchers noted.

The rate of a composite outcome including VTE, myocardial infarction, stroke, or cardiovascular death was reduced by 34% in aspirin patients (5% per year for aspirin vs. 8% per year for placebo). The rate of a composite outcome including VTE, myocardial infarction, stroke, major bleeding, or death from any cause was reduce by 33% in aspirin patients (6% per year for aspirin vs. 9% per year for placebo).

No significant differences in serious adverse events or in the rates of major or clinically relevant nonmajor bleeding were observed between the aspirin and placebo groups, the researchers noted.

The findings were limited by the lower number of patients in the study than originally planned, and the ASPIRE data alone were not enough to show a significant reduction in the recurrence of VTE, they said.

However, when the ASPIRE data were combined with data from a similar patient population of 402 adults in the WARFASA (Warfarin and Aspirin) study, the researchers found "a highly significant reduction of 32% in the rate of recurrence of venous thromboembolism and a reduction of 34% in the rate of major vascular events with no excess of bleeding."

Therefore, the combined results of the two studies support the use of low-dose aspirin to prevent both recurrent VTE and major vascular events in patients who have had a first episode of unprovoked VTE, the researchers said.

Lead author Dr. Brighton disclosed serving as a consultant for Pfizer, GlaxoSmithKline, and other companies. The study was supported by grants from the National Health and Medical Research Council (Australia), the Health Research Council (New Zealand), the National Heart Foundation of Australia, Bayer HealthCare (Germany), and the Australasian Society of Haematology and Thrombosis.

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Prescribing Aspirin in Clinical Practice

Anticoagulants may trump aspirin in efficacy for preventing VTE after surgery, but the findings from the ASPIRE and WARFASA studies support a clinical role for aspirin in preventing VTE, Dr. Theodore Warkentin wrote.

Dr. Warkentin noted the long-term risk of a recurrence of VTE in patients who have had a first unprovoked VTE.

"Could aspirin represent a reasonable intermediate option between the extremes of indefinite anticoagulation and no ongoing anticoagulation, particularly from the additional perspective of concomitant prevention of arterial thrombosis?" he asked.

The combined data from the WARFASA and ASPIRE studies suggest that aspirin has the double benefit of significantly reducing not only the rate of VTE recurrence, but also the rate of a composite of major vascular events, Dr. Warkentin said.

On the basis of the findings, Dr. Warkentin explained how aspirin could fit into clinical practice.

"Before physicians consider prescribing aspirin for patients who have had acute unprovoked venous thromboembolism, it is important that they treat the patients with effective anticoagulation for at least 3 months, to avoid the high risk of early recurrence," he said.

"For patients who then wish to stop anticoagulation, a switch to aspirin at a dose of 100 mg daily will reduce by one-third the risk of recurrent venous thromboembolism, as well as of arterial cardiovascular events, and may also attenuate the early burst of thrombosis recurrence after cessation of oral anticoagulation," he said.

Aspirin has the added benefits of being cost-effective, requiring no monitoring, and not accumulating in patients with renal insufficiency, Dr. Warkentin added.

DR. WARKENTIN is a professor of pathology and molecular medicine at McMaster University in Hamilton, Ont. These remarks were taken from his accompanying editorial (N. Engl. J. Med. 2012 Nov. 4 [doi: 10.1056/NEJMe1211480]).