日前，最新一期《美國醫(yī)學(xué)會雜志》在線刊登了波士頓布里格姆婦女醫(yī)院的心血管專家Jessica Mega博士的研究論文"Dosing Clopidogrel Based on CYP2C19 Genotype and the Effect on Platelet Reactivity in Patients With Stable Cardiovascular Disease ",，研究人員通過分析ELEVATE-TIMI 56試驗結(jié)果,，認(rèn)為基因型分析調(diào)整用藥劑量，可更有針對性地應(yīng)用氯吡格雷治療心血管疾病,。
既往研究顯示,，非功能性等位基因CYP2C19 *2攜帶者氯吡格雷血漿活性代謝物水平較低，因而體內(nèi)殘留血小板活性提高,，并導(dǎo)致支架內(nèi)血栓形成等心臟事件風(fēng)險增加,。為評估增加氯吡格雷劑量能否提高 CYP2C19 *2攜帶者的藥物作用，前瞻性ELEVATE-TIMI 56試驗納入333例接受CYP2C19等位基因基因型分析的穩(wěn)定性心血管疾病患者,，受試者入組前4周~6個月因心肌梗死和(或)接受經(jīng)皮冠脈介入治療而每日服用75 mg氯吡格雷,。
基于基因型分析，86例CYP2C19*2等位基因攜帶者(80例雜合子,，6例純合子)隨機接受每日75 mg,、150 mg、225 mg和300 mg氯吡格雷4個14 d療程治療,，而247例非CYP2C19*2等位基因攜帶者接受每日75 mg和150 mg氯吡格雷各2個14 d療程治療,。每個療程結(jié)束后測定血管擴張劑刺激磷蛋白(VASP)血小板反應(yīng)性指數(shù)(PRI),，并應(yīng)用Verify Now P2Y12即時監(jiān)測系統(tǒng)(Accumetrics)測定血小板功能。
結(jié)果顯示,，CYP2C19*2等位基因攜帶者血小板反應(yīng)性顯著高于非攜帶者,。攜帶者和非攜帶者平均VASP PRI分別為70%和58%，而平均P2Y12反應(yīng)單位(PRU)分別為226和164,。CYP2C19*2雜合子攜帶者達(dá)到非攜帶者75 mg標(biāo)準(zhǔn)劑量的血小板反應(yīng)性需要3倍每日維持劑量(225 mg),。具體而言，CYP2C19*2雜合子攜帶者接受150 mg劑量治療后對標(biāo)準(zhǔn)劑量無反應(yīng)比例由52%降至26%,，而該比例降至10%則至少需要接受225 mg氯吡格雷治療,。占研究人群2%的CYP2C19*2純合子患者，即使氯吡格雷劑量達(dá)到4倍標(biāo)準(zhǔn)劑量(300 mg),，仍達(dá)不到最佳血小板抑制程度,。75 mg、150 mg,、225 mg和300 mg劑量組患者的依從率分別為97.3%,、98.1%、98.6%和98.3%,。未見死亡,、腦血管事件或心肌梗死溶栓治療(TIMI)重大或輕微出血事件。
研究者指出,，雖然目前已有血小板抑制作用較強的替代藥物可供選用,，但隨著明年氯吡格雷仿制藥的上市，仍將有相當(dāng)一部分患者繼續(xù)使用氯吡格雷,，通過基因型分析優(yōu)化氯吡格雷血小板抑制作用將使患者獲益,。
佛羅里達(dá)大學(xué)定量藥理學(xué)和系統(tǒng)藥理學(xué)中心主任Lawrence Lesko博士評論指出，氯吡格雷黑框警告表明代謝不良者心血管事件風(fēng)險增加,，而該研究結(jié)果表明,，*1 和*2基因型患者通過提高劑量可達(dá)到代謝正常者75 mg劑量的活性代謝物水平，從而填補了藥品說明書中有關(guān)代謝不良者以及代謝水平中等患者如何用藥的空白?，F(xiàn)在亟待解決的重要問題是如何將基因型分析應(yīng)用到日常臨床實踐中去。對此,，研究者回應(yīng)稱,，目前已有基因型分析即時檢測(即床邊檢測)方法并可在1小時內(nèi)報告結(jié)果。
該研究由百時美施貴寶和賽諾菲安萬特公司資助,，Accumetrics和Nanosphere公司提供研究設(shè)備,。研究者報告接受了美國國立衛(wèi)生研究院(NIH)基金支持，評論者報告無相關(guān)利益沖突,。（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.
