CHARISMA 试验并未证实氯吡格雷和他汀类药物的相互作用
Lack of Evidence of a Clopidogrel–Statin Interaction in the CHARISMA TrialJacqueline Saw, MD*, Danielle M. Brennan, MS, Steven R. Steinhubl, MD, Deepak L. Bhatt, MD, Koon-Hou Mak, MD, Keith Fox, MB, ChB||, Eric J. Topol, MD#,* on behalf of the CHARISMA Investigators
JACC 2007 50: 23-24.
Objectives: The purpose of this study was to evaluate the potential impact of clopidogrel and statin interaction in a randomized, placebo-controlled trial with long-term follow-up.
Background: There are conflicting data regarding whether statins predominantly metabolized by CYP3A4 reduce the metabolism of clopidogrel to its active metabolite and diminish its clinical efficacy.
Methods: The CHARISMA trial was a randomized trial comparing long-term 75 mg/day clopidogrel versus placebo in patients with cardiovascular disease or multiple risk factors on aspirin. The primary end point was a composite of myocardial infarction, stroke, or cardiovascular death at median follow-up of 28 months. We performed a secondary analysis evaluating the interaction of clopidogrel versus placebo with statin administration, categorizing baseline statin use to those predominantly CYP3A4 metabolized (atorvastatin, lovastatin, simvastatin; CYP3A4-MET) or others (pravastatin, fluvastatin; non–CYP3A4-MET).
Results: Of 15,603 patients enrolled, 10,078 received a statin at baseline (8,245 CYP3A4-MET, 1,748 non–CYP3A4-MET) and 5,496 did not. For the overall population, the primary end point was 6.8% with clopidogrel and 7.3% with placebo (hazard ratio [HR] 0.93; p = 0.22). This was similar among patients on CYP3A4-MET (5.9% clopidogrel, 6.6% placebo, HR 0.89; p = 0.18) or non–CYP3A4-MET statin (5.7% clopidogrel, 7.2% placebo, HR 0.78; p = 0.19). There was no interaction between statin types and randomized treatment (p = 0.69). Patients on atorvastatin (n = 4,127) (5.7% clopidogrel, 7.1% placebo, HR 0.80; p = 0.06) or pravastatin (n = 1,440) (5.1% clopidogrel, 7.0% placebo, HR 0.72; p = 0.13) had similar event rates.
Conclusions: Despite theoretic concerns and ex vivo testing suggesting a potential negative interaction with concomitant clopidogrel and CYP3A4-MET statin administration, there was no evidence of an interaction clinically in a large placebo-controlled trial with long-term follow-up.
[url]http://content.onlinejacc.org/cgi/content/abstract/50/4/291[/url] 转贴
CHARISMA 试验并未证实氯吡格雷和他汀类药物的相互作用
最近发表在《美国心脏病学会杂志》（JACC 2007 50: 23-24）上的一篇文章报道，虽然理论上和体外实验都表明，氯吡格雷和经细胞色素P450酶3A4（CYP3A4）代谢的他汀类药物可能存在负面的相互作用，但是在一项大规模安慰剂对照长期随访试验中并未提供这样的证据。
CHARISMA试验是一项关于心血管疾病患者或对阿司匹林有多重危险因素的患者长期服用氯吡格雷75mg/d与安慰剂比较的随机试验。研究共纳入15603名患者，平均随访28个月，主要终点事件包括心肌梗死、卒中或心血管性死亡。将基线水平服用的他汀类药物分为主要经CYP3A4代谢的他汀(阿托伐他汀, 洛伐他汀, 辛伐他汀; 称为CYP3A4-MET) 和不经CYP3A4代谢的他汀（普伐他汀、氟伐地汀；称为非CYP3A4-MET）。共有10078名患者在基线水平接受他汀类药物治疗（8,245名服用 CYP3A4-MET, 1,748 名服用非CYP3A4-MET），5496名患者未服用他汀类药物。
结果显示，从总体来看，主要终点事件在氯吡格雷组和安慰剂组的发生率分别为 6.8% 和7.3% （危险比[HR]0.93；p = 0.22），两组无显著差异。在服用CYP3A4-MET的患者中，氯吡格雷组和和安慰剂组的主要终点事件发生率分别为5.9%和6.6% （HR 0.89； p = 0.18)，在服用非 CYP3A4-MET 的患者中，氯吡格雷组和安慰剂组主要终点事件的发生率分别为5.7%和7.2% （HR 0.78；p = 0.19)，均无显著差异。他汀类型和随机治疗之间没有相互影响（p = 0.69）。在服用阿托伐他汀的患者(n = 4,127) (氯吡格雷组5.7%, 安慰剂组7.1% , HR 0.80; p = 0.06)或服用普伐他汀的患者(n = 1,440)中主要终点事件的发生情况(氯吡格雷组5.7% , 安慰剂组7.1% , HR 0.80; p = 0.06) 也类似。
研究人员称，大多数他汀类药物由细胞色素P450酶3A4代谢，与氯吡格雷合用时可能会减少氯吡格雷代谢为活性代谢物，并降低其临床效应，但从现有的研究数据来看还存在争论。这项大规模安慰剂对照长期随访试验并不支持他汀类药物会影响氯吡格雷的效应。
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