Wang Thomas H, Bhatt Deepak L, Fox Keith A A, Steinhubl Steven R, Brennan Danielle M, Hacke Werner, Mak Koon-Hou, Pearson Thomas A, Boden William E, Steg P Gabriel, Flather Marcus D, Montalescot Gilles, Topol Eric J
Cleveland Clinic, Cleveland, OH, USA.
Eur Heart J. 2007 Sep;28(18):2200-7. doi: 10.1093/eurheartj/ehm274. Epub 2007 Aug 2.
To examine the unanticipated, excess mortality observed in patients randomized to clopidogrel and aspirin vs. aspirin alone in the prespecified 'asymptomatic' subgroup of CHARISMA, we investigated whether dual-antiplatelet therapy may be associated with adverse cardiovascular (CV) events in a primary prevention population.
Of 15 603 patients enrolled, 3284 were initially categorized as asymptomatic with CV risk factors, but 995 had a prior CV event, leaving 2289 patients to represent the primary prevention cohort. This subset was compared with 13 148 symptomatic patients with established vascular disease and both were evaluated for CV death and bleeding. A multivariate analysis analysed predictors of CV death in this group. No post mortem data were available. Compared with aspirin alone, a significant increase in CV death (P = 0.01) was observed in patients receiving dual-antiplatelet therapy in the asymptomatic population. Within the primary prevention cohort, this excess CV death was not significant (P = 0.07). Multivariate analysis of the primary prevention group showed a trend towards excess CV death (P = 0.054; HR 1.72; CI 0.99-2.97) with dual-antiplatelet therapy (aspirin plus clopidogrel). Other independent predictors of CV death included increasing age, hypertension, atrial fibrillation, and a history of heart failure. There was a non-significant increase in moderate or severe bleeding (P = 0.218) with dual-antiplatelet therapy; thus, bleeding was an unlikely explanation for the excess event rate.
These findings do not support the use of dual-antiplatelet therapy with clopidogrel and aspirin in a primary prevention population. In this subgroup analysis, CV death occurred more frequently than anticipated. The cause of this apparent harm is not elucidated, may represent play of chance, but requires further prospective evaluation.
为研究在CHARISMA预先设定的“无症状”亚组中，随机接受氯吡格雷与阿司匹林联合治疗的患者与单独接受阿司匹林治疗的患者相比出现的意外的额外死亡率，我们调查了双重抗血小板治疗是否可能与一级预防人群中的不良心血管（CV）事件相关。
在纳入的15603例患者中，3284例最初被归类为有CV危险因素的无症状患者，但其中995例曾有过CV事件，因此2289例患者代表一级预防队列。将该亚组与13148例有确诊血管疾病的有症状患者进行比较，并对两者的CV死亡和出血情况进行评估。采用多变量分析该组中CV死亡的预测因素。未获得尸检数据。在无症状人群中，与单独使用阿司匹林相比，接受双重抗血小板治疗的患者CV死亡显著增加（P = 0.01）。在一级预防队列中，这种额外的CV死亡不显著（P = 0.07）。对一级预防组的多变量分析显示，双重抗血小板治疗（阿司匹林加氯吡格雷）有导致CV死亡增加的趋势（P = 0.054；HR 1.72；CI 0.99 - 2.97）。CV死亡的其他独立预测因素包括年龄增加、高血压、心房颤动和心力衰竭病史。双重抗血小板治疗导致中度或重度出血有非显著性增加（P = 0.218）；因此，出血不太可能是事件发生率过高的原因。
这些发现不支持在一级预防人群中使用氯吡格雷与阿司匹林的双重抗血小板治疗。在该亚组分析中，CV死亡的发生比预期更频繁。这种明显危害的原因尚未阐明，可能是偶然因素，但需要进一步的前瞻性评估。
