JAMA：小剂量阿司匹林增加出血风险

美国医学会杂志(JAMA)6月6日在线发表的一项大型意大利人群队列研究显示，小剂量阿司匹林使用者的大出血事件风险是未用药者的50%以上。然而，该研究首次发现，使用阿司匹林的糖尿病患者的出血风险仅轻微增加，间接提示阿司匹林抑制血小板功能的疗效在该患者人群中降低(JAMA 2012;307:2286-94)。

在这项研究中，意大利Consorzio Mario Negri Sud 临床药理学和流行病学科的Giorgia De Berardis及其同事采用意大利普利亚区12个地方卫生管理部门的行政数据，将来自出院病历、处方数据库(包括阿司匹林相关信息，阿司匹林在意大利是用于心血管预防的处方药)和民事登记处的数据进行关联。研究者比较了2003~2008年186,425名小剂量阿司匹林(≤300 mg)使用者与未曾用过阿司匹林的匹配对照者的胃肠道大出血或脑出血住院情况。在该队列中，女性比例略超过50%，平均年龄为69岁。

随访6年(中位数)期间，阿司匹林组发生5.58次血液学事件/1,000人-年，而对照组为3.60次事件/1,000人-年，前者风险增加55%。与对照组相比，阿司匹林组的胃肠道出血风险增加55%，颅内出血风险增加54%。

在阿司匹林使用者中，多数亚组中观察到出血风险增加，在50岁以下的阿司匹林使用者中观察到的出血风险特别高，发生率比值(incidence rate ratio)为1.93，出血风险是50岁以下对照者的3倍。在未接受过降压治疗的阿司匹林使用者中也观察到出血风险增加。出血风险增加的情况见于所评价的大部分亚组，除了糖尿病患者和既往因胃肠道或心血管问题而入院的患者之外，这可能与使用质子泵抑制剂(PPI)有关。

未使用阿司匹林的糖尿病患者的胃肠道出血风险增加59%，颅内出血风险增加64%。但在使用阿司匹林的糖尿病患者中，出血风险仅轻微增加。

该研究的一个重要发现是，他汀类药物的使用与胃肠道出血(35%)和颅内出血(31%)发生率显著降低有关。研究者表示，该研究观察到的阿司匹林相关大出血事件发生率比随机前瞻性研究报道的发生率要高得多。阿司匹林使用者的大出血风险相对未使用阿司匹林者增加55%，这意味着每对1,000患者治疗1年，就新增2例大出血病例。换言之，与使用阿司匹林相关的新增大出血事件数量，与10年风险10%~20%者通过一级预防可避免的主要心血管事件数量，处于同一量级。

该研究的局限性在于未能校正所有可能影响出血的潜在因素，包括非处方阿司匹林的使用。

在随刊述评中，维也纳医科大学心脏病科的Jolanta Siller-Matula博士指出，由于有证据显示阿司匹林在一级预防方面的风险获益比不佳，因此最新的欧洲指南不建议使用阿司匹林进行一级预防，而该研究结果也支持这一建议。该研究强调，在治疗决策过程中，应仔细考虑潜在的出血风险(JAMA 2012;307:2318-20)。

一些研究者声明从百时美施贵宝和拜耳公司获得研究资金。Siller-Matula博士从礼来和阿斯利康公司获得讲课费。

The risk of major bleeding events in Italians taking low-dose aspirin was more than 50% higher than in those not on the regimen in a large population-based cohort study.

However, those with diabetes had showed no increase in bleeding risk.

“Weighing the benefits of aspirin therapy against the potential harms is of particular relevance in the primary prevention setting, in which benefits seem to be lower than expected based on results in high risk populations,�� concluded Giorgia De Berardis of the department of clinical pharmacology and epidemiology, Consorzio Mario Negri Sud, S. Maria Imbaro, Italy, and her associates. The study was published online on June 6 (JAMA 2012;307:2286-94).

Although low-dose aspirin was associated with an increased risk of major bleeding in people with hypertension and most other subgroups they identified, it was not independently associated with such a risk in people with diabetes, a finding that indicates that “diabetes might represent a different population in terms of both expected benefits and risks associated with antiplatelet therapy,” they wrote.

In the study, the investigators used administrative data on people living in 12 local health authorities in Puglia, Italy, which is in the southeastern part of the country, linking data from hospital discharge records, prescription databases (including information on aspirin, which in Italy is prescribed for CV prevention), and the civil registry. They compared hospitalizations for major gastrointestinal bleeding or cerebral hemorrhage among 186,425 users of low-dose aspirin (300 mg or less) during 2003-2008, to matched controls who had never used aspirin. A little over half were women; the mean age was about 69 years.

Over a median follow-up of almost 6 years, 5.58 hemorrhagic events/1,000 person-years occurred in persons on aspirin, compared with 3.60 events/1,000 person-years in those who had never used aspirin, for an increased risk of 55%. Among those on aspirin, the risk of GI bleeding was increased by 55% and the risk of intracranial bleed was increased by 54%, compared with those who had never used aspirin.

Among those on aspirin, the risk of bleeding was increased in most of the subgroups evaluated, and was “particularly high” among those younger than age 50 years(an incidence rate ratio of 1.93 – about a threefold greater risk when compared with people under 50 years who were not on aspirin). It was also increased in aspirin users who had not been treated for hypertension. They pointed out that this increased risk was seen in most of the subgroups they evaluated, except for patients with diabetes and those who had previously been admitted to the hospital for GI or CV problems, which they said could be “partially” attributed to the use of proton pump inhibitors (PPIs).

Those with diabetes who were not taking aspirin had a 59% increased risk for GI bleeding and a 64% increase risk for intracranial bleeding. But among those with diabetes who were on aspirin, the risk of bleeding was only slightly elevated. “Our study shows, for the first time, to our knowledge, that aspirin therapy only marginally increases the risk of bleeding in individuals with diabetes,” the authors wrote, adding that these results “can represent indirect evidence that the efficacy of aspirin in suppressing platelet function is reduced in this population.”

A notable finding, they said, was that the use of statins was associated with a significant reduction of gastrointestinal bleeding (35%) and intracranial bleeding (31%).

The authors said that the incidence of major bleeding events associated with aspirin identified in their study was “much higher” than reported in randomized prospective studies. The 55% increase in the relative risk of major bleeding, over no aspirin, “translates to 2 excess cases for 1,000 patients treated per year,” they said. “In other words, the excess number of major bleeding events associated with the use of aspirin is of the same magnitude of the number of major cardiovascular events avoided in the primary prevention setting for individuals with a 10-year risk of between 10% and 20%.”

Limitations of their study include the not being able to adjust for all potential factors that can affect bleeding, including over-the-counter aspirin use, although in Italy, low-dose aspirin for CV prevention in high-risk individuals is available by prescription and is fully covered.

Although the value of aspirin for secondary prevention “is not disputed,” the use of aspirin for primary prevention continues to be debated, because of evidence that “does not support the assumption that the balance of benefits and harms of aspirin is clearly favorable for primary prevention,” Dr. Jolanta Siller-Matula wrote in an accompanying editorial.

The results of this study reinforce the recent European guidelines that do not recommend aspirin for primary prevention because of evidence of “its unfavorable risk-to-benefit profile,” on the basis of clinical data that include a meta-analysis that found that the reduced risk of stroke in women and reduced risk of MI in men associated with aspirin use were offset by an increase in the risk of major bleeding events. Another meta-analysis and a randomized trial indicate that “the magnitude of benefit with aspirin in primary prevention is small and at least partially balanced by the magnitude of harm,” added Dr. Siller-Matula of the department of cardiology, Medical University of Vienna.

Noting that “a decision-making process based on balancing an individual patient’s risk of bleeding and ischemic events is difficult,” she said that the new study “underscores that the potential risk of bleeding should be carefully considered in decision making.” There is a “thin line” between efficacy and safety for aspirin and “future studies investigating the risks and benefits for individual patients appear to be mandatory to help physicians appropriately make recommendations about aspirin use for primary prevention,” she added (JAMA 2012;307:2318-20).

Four of the seven authors, including the lead author, reported no disclosures. One author reported receiving a research grant from Bristol-Myers Squibb, another reported receiving a research grant from Bayer, and another reported receiving a research grant and lecture fees, including service on speakers bureaus from Bayer. Dr. Siller-Matula reported receiving speaker fees from Eli Lilly and AstraZeneca.