日前，最新一期《美国医学会杂志》在线刊登了波士顿布里格姆妇女医院的心血管专家Jessica Mega博士的研究论文"Dosing Clopidogrel Based on CYP2C19 Genotype and the Effect on Platelet Reactivity in Patients With Stable Cardiovascular Disease "，研究人员通过分析ELEVATE-TIMI 56试验结果，认为基因型分析调整用药剂量，可更有针对性地应用氯吡格雷治疗心血管疾病。
既往研究显示，非功能性等位基因CYP2C19 *2携带者氯吡格雷血浆活性代谢物水平较低，因而体内残留血小板活性提高，并导致支架内血栓形成等心脏事件风险增加。为评估增加氯吡格雷剂量能否提高 CYP2C19 *2携带者的药物作用，前瞻性ELEVATE-TIMI 56试验纳入333例接受CYP2C19等位基因基因型分析的稳定性心血管疾病患者，受试者入组前4周~6个月因心肌梗死和(或)接受经皮冠脉介入治疗而每日服用75 mg氯吡格雷。
基于基因型分析，86例CYP2C19*2等位基因携带者(80例杂合子，6例纯合子)随机接受每日75 mg、150 mg、225 mg和300 mg氯吡格雷4个14 d疗程治疗，而247例非CYP2C19*2等位基因携带者接受每日75 mg和150 mg氯吡格雷各2个14 d疗程治疗。每个疗程结束后测定血管扩张剂刺激磷蛋白(VASP)血小板反应性指数(PRI)，并应用Verify Now P2Y12即时监测系统(Accumetrics)测定血小板功能。
结果显示，CYP2C19*2等位基因携带者血小板反应性显著高于非携带者。携带者和非携带者平均VASP PRI分别为70%和58%，而平均P2Y12反应单位(PRU)分别为226和164。CYP2C19*2杂合子携带者达到非携带者75 mg标准剂量的血小板反应性需要3倍每日维持剂量(225 mg)。具体而言，CYP2C19*2杂合子携带者接受150 mg剂量治疗后对标准剂量无反应比例由52%降至26%，而该比例降至10%则至少需要接受225 mg氯吡格雷治疗。占研究人群2%的CYP2C19*2纯合子患者，即使氯吡格雷剂量达到4倍标准剂量(300 mg)，仍达不到最佳血小板抑制程度。75 mg、150 mg、225 mg和300 mg剂量组患者的依从率分别为97.3%、98.1%、98.6%和98.3%。未见死亡、脑血管事件或心肌梗死溶栓治疗(TIMI)重大或轻微出血事件。
研究者指出，虽然目前已有血小板抑制作用较强的替代药物可供选用，但随着明年氯吡格雷仿制药的上市，仍将有相当一部分患者继续使用氯吡格雷，通过基因型分析优化氯吡格雷血小板抑制作用将使患者获益。
佛罗里达大学定量药理学和系统药理学中心主任Lawrence Lesko博士评论指出，氯吡格雷黑框警告表明代谢不良者心血管事件风险增加，而该研究结果表明，*1 和*2基因型患者通过提高剂量可达到代谢正常者75 mg剂量的活性代谢物水平，从而填补了药品说明书中有关代谢不良者以及代谢水平中等患者如何用药的空白。现在亟待解决的重要问题是如何将基因型分析应用到日常临床实践中去。对此，研究者回应称，目前已有基因型分析即时检测(即床边检测)方法并可在1小时内报告结果。
该研究由百时美施贵宝和赛诺菲安万特公司资助，Accumetrics和Nanosphere公司提供研究设备。研究者报告接受了美国国立卫生研究院(NIH)基金支持，评论者报告无相关利益冲突。（生物谷 Bioon.com）
doi:10.1001/jama.2011.1703
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Dosing Clopidogrel Based on CYP2C19 Genotype and the Effect on Platelet Reactivity in Patients With Stable Cardiovascular Disease
Jessica L. Mega, MD, MPH; Willibald Hochholzer, MD; Andrew L. Frelinger III, PhD; Michael J. Kluk, MD, PhD; Dominick J. Angiolillo, MD; Dean J. Kereiakes, MD; Steven Isserman, MD; William J. Rogers, MD,et al.
Context Variants in the CYP2C19 gene influence the pharmacologic and clinical response to the standard 75-mg daily maintenance dose of the antiplatelet drug clopidogrel. Objective To test whether higher doses (up to 300 mg daily) improve the response to clopidogrel in the setting of loss-of-function CYP2C19 genotypes. Design, Setting, and Patients ELEVATE-TIMI 56 was a multicenter, randomized, double-blind trial that enrolled and genotyped 333 patients with cardiovascular disease across 32 sites from October 2010 until September 2011. Interventions Maintenance doses of clopidogrel for 4 treatment periods, each lasting approximately 14 days, based on genotype. In total, 247 noncarriers of a CYP2C19*2 loss-of-function allele were to receive 75 and 150 mg daily of clopidogrel (2 periods each), whereas 86 carriers (80 heterozygotes, 6 homozygotes) were to receive 75, 150, 225, and 300 mg daily. Main Outcome Measures Platelet function test results (vasodilator-stimulated phosphoprotein [VASP] phosphorylation and VerifyNow P2Y12 assays) and adverse events. Results With 75 mg daily, CYP2C19*2 heterozygotes had significantly higher on-treatment platelet reactivity than did noncarriers (VASP platelet reactivity index [PRI]: mean, 70.0%; 95% CI, 66.0%-74.0%, vs 57.5%; 95% CI, 55.1%-59.9%, and VerifyNow P2Y12 reaction units [PRU]: mean, 225.6; 95% CI, 207.7-243.4, vs 163.6; 95% CI, 154.4-173.9; P < .001 for both comparisons). Among CYP2C19*2 heterozygotes, doses up to 300 mg daily significantly reduced platelet reactivity, with VASP PRI decreasing to 48.9% (95% CI, 44.6%-53.2%) and PRU to 127.5 (95% CI, 109.9-145.2) (P < .001 for trend across doses for both). Whereas 52% of CYP2C19*2 heterozygotes were nonresponders (≥230 PRU) with 75 mg of clopidogrel, only 10% were nonresponders with 225 or 300 mg (P < .001 for both). Clopidogrel, 225 mg daily, reduced platelet reactivity in CYP2C19*2 heterozygotes to levels achieved with standard clopidogrel, 75 mg, in noncarriers (mean ratios of platelet reactivity, VASP PRI, 0.92; 90% CI, 0.85-0.99, and PRU, 0.94; 90% CI, 0.84-1.04). In CYP2C19*2 homozygotes, even with 300 mg daily of clopidogrel, mean VASP PRI was 68.3% (95% CI, 44.9%-91.6%) and mean PRU, 287.0 (95% CI, 170.2-403.8). Conclusion Among patients with stable cardiovascular disease, tripling the maintenance dose of clopidogrel to 225 mg daily in CYP2C19*2 heterozygotes achieved levels of platelet reactivity similar to that seen with the standard 75-mg dose in noncarriers; in contrast, for CYP2C19*2 homozygotes, doses as high as 300 mg daily did not result in comparable degrees of platelet inhibition.
