阿司匹林或可使老年性黄斑变性风险倍增

《美国医学会内科学杂志》1月21日在线发表的蓝山眼研究(Blue Mountain Eye Study)的二次分析显示，阿司匹林可使10~15年内发生老年性黄斑变性(AMD)的风险增加1倍(JAMA Intern. Med. 2013 Jan. 21 [doi:10.1001/jamainternmed.2013.1583])。

这项迄今规模最大且随访时间最长的前瞻性人群队列研究由悉尼大学眼科视觉研究中心的Gerald Liew博士及其同事进行，纳入2,389例年龄≥49岁的澳大利亚城市居民。基线时通过问卷收集阿司匹林使用情况。研究者表示，尽管未收集阿司匹林剂量信息，但澳大利亚的阿司匹林用量主要为150 mg/d。

共257例(10.8%)受试者使用阿司匹林。随访15年时，63例受试者发生新生血管性(湿性)AMD。在使用阿司匹林的受试者中，新生血管性AMD的5年累计发生率为1.9%，10年为7%，15年为9.3%。而在未经常使用阿司匹林的受试者中，新生血管性AMD的5年、10年和15年累计发生率分别为0.8%、1.6%和3.7%。研究者表示，发生率的增加在10~15年后才变得明显，提示累计剂量在新生血管性AMD的发病机制中发挥着重要作用。另外，这么长的提前期或许可以解释为什么既往一些随访时间较短的研究未能发现阿司匹林与新生血管性AMD发生率增加相关。

校正受试者年龄、性别和吸烟状态后发现，阿司匹林与新生血管性AMD发生率增加显著相关，比值比为2.37。在进一步校正心血管病史、体重指数(BMI)和血压等因素后，这一关联未发生改变。

阿司匹林与地图状(干性)AMD风险无关。新生血管性AMD发生率随阿司匹林使用的增加而增加，在从未使用阿司匹林的受试者中，发生率为2.2%，在偶尔使用者中，发生率为2.9%，在经常使用者中，发生率为5.8%。

对多个危险因素和保护性因素(如白细胞计数、膳食因素、胆固醇水平和有无糖尿病)进行校正后进一步分析发现，阿司匹林与新生血管性AMD之间的关联仍较显著，比值比为2.05。

由于阿司匹林与疼痛性疾病和心血管疾病强烈相关，因此研究者也探讨了其他与这些疾病相关的药物是否与新生血管性AMD存在类似关联。结果显示，对乙酰氨基酚、β受体阻滞剂和其他药物与AMD无显著关联。

研究者表示，尽管阿司匹林是最有效的心血管疾病治疗药物之一，可使复发性心血管疾病事件减少1/5，但一些Meta分析对阿司匹林在心血管疾病一级预防中的效果产生质疑，并强调了阿司匹林的显著不良反应，如胃肠道、颅内和颅外出血增加等。从该研究结果来看，在使用阿司匹林时，还需考虑新生血管性AMD风险。

研究者表示，除了对于具有AMD显著危险因素的患者之外，目前尚无充分证据支持改变临床实践。

该研究获澳大利亚国家卫生与医学研究理事会支持。研究者声明无经济利益冲突。

随刊述评：“轻微”关联不支持改变临床实践


Sanjay Kaul博士

洛杉矶西奈山医疗中心心脏病科的Sanjay Kaul博士和George A. Diamond博士表示，该研究观察到的阿司匹林与AMD的关联强度仅为“轻微”，目前的证据尚不足以改变临床阿司匹林治疗实践。该研究结果最多可用于产生假说，而在用于指导临床实践或患者行为之前还有待于在前瞻性随机研究中加以验证。

维持现状是最明智的做法，特别是在二级预防中，在二级预防中，阿司匹林的获益明显大于风险。医生最好应根据患者的病史和价值判断来权衡阿司匹林的风险和获益，进而再决定是否使用该药(JAMA Intern. Med. 2013 Jan. 21 [doi:10.1001/jamainternmed.2013.2530])。

Kaul博士和Diamond博士均声明无经济利益冲突。

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By: MARY ANN MOON, Internal Medicine News Digital Network

The use of aspirin therapy approximately doubled the risk that age-related macular degeneration would develop over a period of 10-15 years in a secondary analysis of data in the Blue Mountain Eye Study, which was published online Jan. 21 in JAMA Internal Medicine.

The regular use of aspirin was significantly associated with an increased incidence of neovascular (wet) age-related macular degeneration (AMD), with an odds ratio of 2.37, independently of cardiovascular disease (CVD), smoking status, and numerous potentially confounding factors. However, "this potential risk appears to be small (3.7% after 15 years) and should be balanced with the significant morbidity and mortality of suboptimally treated CVD," said Gerald Liew, Ph.D., of the center for vision research, department of ophthalmology, University of Sydney, and his associates.

"Given the widespread use of aspirin, any increased risk of disabling conditions and morbidity will be significant and affect many people," they noted.

Several previous studies have examined the relationship between aspirin therapy and AMD, but the findings have been inconsistent. Dr. Liew and his colleagues performed a prospective study using the largest cohort and the longest follow-up to date. Their study subjects were 2,389 participants in the Blue Mountain Eye Study, a population-based cohort study of eye disease in urban Australians aged 49 years or older.

Aspirin use was determined from the subjects’ responses to a detailed questionnaire at baseline. "Although we did not collect information on aspirin dosage, most aspirin use in Australia is prescribed at 150 mg daily," the researchers said.

A total of 257 subjects (10.8%) used aspirin therapy.

At 15-year follow-up, 63 subjects had developed neovascular AMD.

Among subjects taking aspirin therapy, the cumulative rate of neovascular AMD was 1.9% at 5 years, 7% at 10 years, and 9.3% at 15 years. In comparison, these rates were 0.8% at 5 years, 1.6% at 10 years, and 3.7% at 15 years among subjects who did not take aspirin regularly.

The increase in risk became significant only after 10-15 years, "suggesting that cumulative dosage is important in pathogenesis" of neovascular AMD, the investigators said.

This long lead time also may explain why several previous studies that had shorter follow-up failed to detect the association, they added.

After the data were adjusted to account for subject age, sex, and smoking status, aspirin therapy was significantly associated with an increased incidence of neovascular AMD, with an odds ratio of 2.37. This association remained unchanged after further adjustment for history of CVD, BMI, and blood pressure.

Aspirin therapy was not associated with the risk of geographic (dry) AMD.

The rate of neovascular AMD rose with increasing use of aspirin, from 2.2% among people who never took aspirin to 2.9% among occasional users to 5.8% among regular users, Dr. Liew and his associates said (JAMA Intern. Med. 2013 Jan. 21 [doi:10.1001/jamainternmed.2013.1583]).

The correlation between aspirin therapy and neovascular AMD remained robust in a further analysis of the data that adjusted for numerous risk factors and protective factors, such as white blood cell count, dietary factors, cholesterol levels, and the presence or absence of diabetes. The odds ratio was 2.05 in this analysis.

"Because aspirin use is strongly associated with painful conditions and CVD, we examined whether other medications associated with these conditions had a similar association with neovascular AMD," the investigators wrote. Acetaminophen, beta-blockers, and other drugs showed no significant associations with AMD.

"Although aspirin is one of the most effective CVD treatments and reduces recurrent CVD events by one-fifth, some meta-analyses have called into question the efficacy of aspirin use in CVD primary prevention and highlighted the significant adverse effects, such as increased gastrointestinal, intracerebral, and extracranial hemorrhage. Our study now raises the possibility that the risk of neovascular AMD may also need to be considered," Dr. Liew and his associates wrote.

At this time "there is insufficient evidence to recommend changing clinical practice, except perhaps in patients" who have strong risk factors for AMD, they added.

This study was supported by the National Health and Medical Research Council Australia. No financial conflicts of interest were reported.

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‘Modest’ association does not support change in practice

The evidence is not yet sufficiently robust to change clinical practice regarding aspirin therapy, particularly since the strength of the association with AMD was only "modest" in this study. "These findings are, at best, hypothesis generating and should await validation in prospective randomized studies before guiding clinical practice or patient behavior.    

"Maintaining the status quo" is the most prudent approach, particularly in the setting of secondary prevention, "where the benefits of aspirin are indisputable and greatly exceed the risk," they said.

"In the final analysis, decisions about aspirin use are best made by balancing the risks against the benefits in the context of each individual’s medical history and value judgments."

Dr. Sanjay Kaul and Dr. George A. Diamond are in the division of cardiology at Cedars-Sinai Medical Center, Los Angeles. They reported no financial conflicts of interest. These remarks were taken from their invited commentary accompanying Dr. Liew’s report (JAMA Intern. Med. 2013 Jan. 21 [doi:10.1001/jamainternmed.2013.2530]).