Director, Center for Clinical Studies, 100 N Academy Ave, MC 44-00, Danville, PA 17822, USA.
Circulation. 2010 Jun 15;121(23):2575-83. doi: 10.1161/CIRCULATIONAHA.109.895342. Epub 2010 Jun 1.
Uncertainty exists about the frequency, correlates, and clinical significance of bleeding with dual antiplatelet therapy (DAPT), particularly over an extended period in a stable population. We sought to determine the frequency and time course of bleeding with DAPT in patients with established vascular disease or risk factors only; identify correlates of bleeding; and determine whether bleeding is associated with mortality.
We analyzed 15 603 patients enrolled in the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial, a double-blind, placebo-controlled, randomized trial comparing long-term clopidogrel 75 mg/d versus placebo; all patients received aspirin (75 to 162 mg) daily. Patients had either established stable vascular disease or multiple risk factors for vascular disease without established disease. Median follow-up was 28 months. Bleeding was assessed with the use of the Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries (GUSTO) criteria. Severe bleeding occurred in 1.7% of the clopidogrel group versus 1.3% on placebo (P=0.087); moderate bleeding occurred in 2.1% versus 1.3%, respectively (P<0.001). The risk of bleeding was greatest the first year. Patients without moderate or severe bleeding during the first year were no more likely than placebo-treated patients to have bleeding thereafter. The frequency of bleeding was similar in patients with established disease and risk factors only. In multivariable analysis, the relationship between moderate bleeding and all-cause mortality was strong (hazard ratio, 2.55; 95% confidence interval, 1.71 to 3.80; P<0.0001), along with myocardial infarction (hazard ratio, 2.92; 95% confidence interval, 2.04 to 4.18; P<0.0001) and stroke (hazard ratio, 4.20; 95% confidence interval, 3.05 to 5.77; P<0.0001).
In CHARISMA, there was an increased risk of bleeding with long-term clopidogrel. The incremental risk of bleeding was greatest in the first year and similar thereafter. Moderate bleeding was strongly associated with mortality. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00050817.
关于双联抗血小板治疗（DAPT）期间出血的频率、相关性和临床意义，尤其是在稳定人群中延长时间内，目前尚存在不确定性。我们旨在确定在仅有已确立的血管疾病或多种血管疾病风险因素的患者中，DAPT 治疗期间出血的频率和时间进程；确定出血的相关性；并确定出血是否与死亡率相关。
我们分析了 15603 例在氯吡格雷用于高动脉血栓形成风险和缺血稳定性、管理和避免（CHARISMA）试验中入组的患者，这是一项双盲、安慰剂对照、随机试验，比较了长期氯吡格雷 75mg/d 与安慰剂；所有患者每日均接受阿司匹林（75~162mg）。患者要么患有已确立的稳定血管疾病，要么患有多种血管疾病风险因素但无已确立的疾病。中位随访时间为 28 个月。出血使用全球应用链激酶和组织型纤溶酶原激活剂治疗闭塞性冠状动脉疾病（GUSTO）标准进行评估。氯吡格雷组中严重出血发生率为 1.7%，安慰剂组为 1.3%（P=0.087）；中度出血发生率分别为 2.1%和 1.3%（P<0.001）。出血风险在第一年最大。在第一年无中度或重度出血的患者与安慰剂治疗患者相比，此后发生出血的可能性无差异。在仅患有已确立疾病和多种风险因素的患者中，出血频率相似。在多变量分析中，中度出血与全因死亡率之间的关系很强（风险比，2.55；95%置信区间，1.71 至 3.80；P<0.0001），同时与心肌梗死（风险比，2.92；95%置信区间，2.04 至 4.18；P<0.0001）和卒中（风险比，4.20；95%置信区间，3.05 至 5.77；P<0.0001）相关。
在 CHARISMA 中，长期氯吡格雷治疗有出血风险增加。出血的增量风险在第一年最大，此后相似。中度出血与死亡率密切相关。
临床试验注册- URL：http://www.clinicaltrials.gov。独特标识符：NCT00050817。
