Bleeding Risk with Long-Term Low-Dose Aspirin: A Systematic Review of Observational Studies

BackgroundLow-dose aspirin has proven effectiveness in secondary and primary prevention of cardiovascular events, but is also associated with an increased risk of major bleeding events. For primary prevention, this absolute risk must be carefully weighed against the benefits of aspirin; such assessments are currently limited by a lack of data from general populations.MethodsSystematic searches of Medline and Embase were conducted to identify observational studies published between 1946 and 4 March 2015 that reported the risks of gastrointestinal (GI) bleeding or intracranial hemorrhage (ICH) with long-term, low-dose aspirin (75–325 mg/day). Pooled estimates of the relative risk (RR) for bleeding events with aspirin versus non-use were calculated using random-effects models, based on reported estimates of RR (including odds ratios, hazard ratios, incidence rate ratios and standardized incidence ratios) in 39 articles.FindingsThe incidence of GI bleeding with low-dose aspirin was 0.48–3.64 cases per 1000 person-years, and the overall pooled estimate of the RR with low-dose aspirin was 1.4 (95% confidence interval [CI]: 1.2–1.7). For upper and lower GI bleeding, the RRs with low-dose aspirin were 2.3 (2.0–2.6) and 1.8 (1.1–3.0), respectively. Neither aspirin dose nor duration of use had consistent effects on RRs for upper GI bleeding. The estimated RR for ICH with low-dose aspirin was 1.4 (1.2–1.7) overall. Aspirin was associated with increased bleeding risks when combined with non-steroidal anti-inflammatory drugs, clopidogrel and selective serotonin reuptake inhibitors compared with monotherapy. By contrast, concomitant use of proton pump inhibitors decreased upper GI bleeding risks relative to aspirin monotherapy.ConclusionsThe risks of major bleeding with low-dose aspirin in real-world settings are of a similar magnitude to those reported in randomized trials. These data will help inform clinical judgements regarding the use of low-dose aspirin in prevention of cardiovascular events.【背景】低剂量阿司匹林已被证实可有效用于心血管事件（cardiovascular events）的二级预防（secondary prevention）与一级预防（primary prevention），但同时也会增加大出血事件（major bleeding events）的发生风险。在一级预防场景中，需审慎权衡阿司匹林的绝对出血风险与获益；但当前此类评估受限于普通人群相关数据的匮乏。【方法】本研究系统检索了Medline与Embase数据库，以筛选1946年至2015年3月4日期间发表的、报告了长期服用低剂量阿司匹林（75~325 mg/日）相关胃肠道（gastrointestinal, GI）出血或颅内出血（intracranial hemorrhage, ICH）风险的观察性研究（observational studies）。基于39篇文献中报道的相对危险度（relative risk, RR）相关估计值（包括比值比（odds ratios）、风险比（hazard ratios）、发病密度比（incidence rate ratios）及标准化发病比（standardized incidence ratios）），采用随机效应模型（random-effects models）计算阿司匹林与未使用阿司匹林相比时出血事件的合并相对危险度。【结果】低剂量阿司匹林使用者的胃肠道出血发生率为0.48~3.64例/1000人年，其总体合并相对危险度为1.4（95%置信区间（confidence interval, CI）：1.2~1.7）。其中上消化道出血与下消化道出血的合并相对危险度分别为2.3（2.0~2.6）与1.8（1.1~3.0）。阿司匹林的给药剂量与服用时长均未对上消化道出血的相对危险度产生一致影响。低剂量阿司匹林相关颅内出血的总体合并相对危险度为1.4（95%置信区间：1.2~1.7）。与阿司匹林单药治疗相比，阿司匹林联合非甾体类抗炎药（non-steroidal anti-inflammatory drugs）、氯吡格雷（clopidogrel）或选择性5-羟色胺再摄取抑制剂（selective serotonin reuptake inhibitors）时，出血风险会进一步升高。与之相反，联合使用质子泵抑制剂（proton pump inhibitors）可降低阿司匹林单药治疗时的上消化道出血风险。【结论】真实世界中低剂量阿司匹林相关大出血风险的水平与随机对照试验（randomized trials）中的报道结果相近。本研究数据可为临床判断低剂量阿司匹林用于心血管事件预防的用药方案提供参考依据。