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1、,氯吡格雷治疗冠心病的几个问题与对策,上海市第六人民医院魏盟,斑块破裂血管壁受损,Von Willebrand 因子、胶原,血小板黏附,血小板聚集,凝血酶（IIa）,组织因子/VIIa因子复合物,Xa,纤维蛋白原,纤维蛋白,抗栓治疗,GP IIb/IIIa受体拮抗剂,Platelet Stimuli,GP IIb/IIIa integrin,ADP,Epinephrine,Collagen,Thrombin,Platelet Aggregation,Serotonin,Shear rate,AA,TxA2,COX-1,Thrombin,ADP,TXA2,ADP P2Y12,ADP,Activa
2、tion,COX-1,clopidogrel bisulfate,cAMP,Oral Anti-PAR-1 receptors,SCH 530348E 5555,adapted from Schafer AI.Am J Med.1996;101:199-209.,氯吡格雷治疗若干问题与对策,用药时间、剂量、抵抗与新药氯吡格雷与PPI国产氯吡格雷循证学依据及其意义,25,087 ACS Patients(UA/NSTEMI 70.8%,STEMI 29.2%)Planned Early(24 h)Invasive Management with intended PCIIschemic ECG(
3、80.8%)or cardiac biomarker(42%),PCI 17,232(70%),Angio 24,769(99%),No PCI 7,855(30%),No Sig.CAD 3,616,CABG 1,809,CAD 2,430,Randomized to receive(2 X 2 factorial):CLOPIDOGREL:Double-dose(600 mg then150 mg/d x 7d then 75 mg/d)vs Standard dose(300 mg then 75 mg/d)ASA:High Dose(300-325 mg/d)vs Low dose(7
4、5-100 mg/d),Efficacy Outcomes:CV Death,MI or stroke at day 30Stent Thrombosis at day 30Safety Outcomes:CURRENT defined Major/Severe and TIMI MajorKey Subgroup:PCI v No PCI,Clop in 1st 7d(median)7d 7 d 2 d 7d,Complete Followup 99.8%,Compliance:,Days,Cumulative Hazard,0.0,0.004,0.008,0.012,0,3,6,9,12,
5、15,18,21,24,27,30,Clopidogrel Standard Dose,Clopidogrel Double Dose,42%RRR,HR 0.5895%CI 0.42-0.79P=0.001,Clopidogrel:Double vs Standard DoseDefinite Stent Thrombosis,Days,Cumulative Hazard,0.0,0.01,0.02,0.03,0.04,0,3,6,9,12,15,18,21,24,27,30,Clopidogrel:Double vs Standard Dose Primary Outcome:PCI Pa
6、tients,Clopidogrel Standard,Clopidogrel Double,HR 0.8595%CI 0.74-0.99P=0.036,15%RRR,CV Death,MI or Stroke,Definite Stent Thrombosis in 4 Groups(Angiographically Proven),Days,Cumulative Hazard,0.0,0.004,0.008,0.012,0,3,6,9,12,15,18,21,24,27,30,C Standard,A Low,C Standard,A High,C Double,A Low,C Doubl
7、e,A High,Clinical Implications,For every 1,000 patients with ACS receiving PCI,using double-dose clopidogrel for 7 days instead of standard dose will prevent an additional 6 MIs and 7 stent thromboses with an excess of 3 severe bleeds and no increase in fatal,CABG-related or TIMI major bleeds.Patien
8、ts not undergoing PCI should continue to use the standard dose regimen of clopidogrel.,处理氯吡格雷反应不良的三板斧,氯吡格雷治疗若干问题与对策,用药时间、抵抗与新药氯吡格雷与PPI国产氯吡格雷循证学依据及其意义,0.2 0.5 1 2 5,RR(95%CI)1.79(0.99-3.23)1.63(1.02-2.63)P=0.022P=0.012Multivariable analyses,RR(95%CI),4 weeks1year(n=176 vs 877),Favors PPI+Clopidogrel+
9、ASA Favors Clopidogrel+ASA,Primary endpoints:Twenty-eight day(Death/MI/UTVR)and 1-year(Death/MI/Stroke),Fig.2.Baseline Proton Pump Inhibitor Use is Associated with Increased Cardiovascular Events With and Without the Use of Clopidogrel in the CREDO Trial,Steven PD,Trancy EM,Danielle BM,et al.Circula
10、tion.2008;118:S-815.,双联抗血小板再加PPI心脏事件增加,0.2 0.5 1 2 5,RR(95%CI)1.79(1.62-1.97)1.86(1.63-2.12)Multivariable analyses,RR(95%CI),Stent patients with no preceding CV events Stent patients with preceding CV events(n=4521 vs 9862),Favors PPI+Clopidogrel Favors Clopidogrel,Primary endpoints:one-year inciden
11、ce of major adverse CV events(hospitalization for stroke,MI,angina or CABG),Fig.4.Proton Pump Inhibitors Effect on Clopidogrel Effectiveness:The Clopidogrel Medco Outcomes Study,Ronald EA,Robert SE,Fang Xia,et al.Circulation.2008;118:S-815.,氯吡格雷加用PPI使PCI患者MACE增加,0.2 0.5 1 2 5,AOR(95%CI)1.25(1.11-1.4
12、1)1.86(1.57-2.20)1.49(1.30-1.71)0.91(0.80-1.05)Multivariable analyses,AOR(95%CI),Primary endpointsHospitalization for recurrent ACSRevascularization proceduresAll cause mortality(n=5244 vs 2916),Favors PPI+Clopidogrel Favors Clopidogrel,Primary endpoints:Death or rehospitalization for ACS occurred,F
13、ig.3.Risk of Adverse Outcomes Associated With Concomitant Use of Clopidogrel and Proton Pump Inhibitors Following Acute Coronary Syndrome,P.Michael H,Thomas M M,Li Wang,et al.JAMA.2009;301(9):937-944.,氯吡格雷加用PPI死亡和在住院增加,N,S,O,Cl,O,CH3,C,Clopidogrel,Pro-drugs,3,N,S,O,C,H,C,O,F,O,Thienopyridines:Format
14、ion of Active Metabolite,Prasugrel,Gut,对CYP2C19的抑制强度：兰索拉唑奥美拉唑埃索美拉唑泮托拉唑雷贝拉唑,Drug Safety 2006,29:769-784,Fig.3.PPI和氯吡格雷的药代动力学影响,Tab.2,PPI和氯吡格雷的药代动力学影响,Fig.5.A population-based study of the drug interaction between proton pump inhibitors and clopidogrel,David NJ,Tara GM,Dennis TK,et al.CMAJ 2009;180(7)
15、:713-738.,Primary endpoints:Recurrent infarction within 90 days and 1 year following hospital discharge after treatment of acute myocardial infarction,不同的制酸药对氯吡格雷的影响不相同,PPI Use at Randomizationn=4529,33%of study population,ODonoghue ML,Braunward et al ESC，2009，Lancet，2009，online,CV death,MI or strok
16、e,Days,CLOPIDOGREL PPI vs no PPI:Adj HR 0.94,95%CI 0.80-1.11,PPI use at randomization(n=4529),Clopidogrel,Prasugrel,PRASUGRELPPI vs no PPI:Adj HR 1.00,95%CI 0.84-1.20,Primary endpoint stratified by use of a PPI,ODonoghue ML,Braunward et al ESC，2009，Lancet，2009，online,Risk of CV events with different
17、 types of PPIs,Rabeprazole not included due to small sample size(n=66),氯吡/普拉格雷与PPI合用对血小板抑制率的影响,Principle TIMI 44，Lancet，2009，online.n=201,The COGENT Trial,Deepak L.Bhatt et al ESC 2009,3627 patients(above the initial target of 3200)393 sitesMedian follow-up 133 days(maximum 362 days)136 adjudicated
18、cardiovascular events(preliminary)105 adjudicated GI events(preliminary),Adjustment through Cox Proportional Hazards ModelAdjusted to Positive NSAID Use and Positive H.Pylori Status,HR=1.0295%CI=0.70;1.51,Placebo:67 events,1821 at riskTreated:69 events,1806 at risk,HR=0.5595%CI=0.36;0.85p=0.007(prel
19、iminary),Placebo:67 events,1895 at riskTreated:38 events,1878 at risk,CVDcardiovascular disease;Cerecerebrovascular disease;ASAaspirin;PPIproton pump inhibitorsl;UNunclear;Mmonth;Wweek;Dday;OCLA studyOmeprazole CLopidogrel Aspirin Study,Tab.1.Characteristics of the 8 Included Studies,Fig.6.Pooled ra
20、te of recurrent upper gastrointestinal bleeding in patients receiving aspirin versus aspirin-plus-PPI.,The combined results showed no statistical heterogeneity(P=0.30,I2=6%)but lower rate of recurrent upper gastrointestinal bleeding(OR 5.96,95%CI 1.31 to 21.70,P=0.02)in aspirin-plus-PPI group.The ot
21、her study reported with a significant reduction of heartburn(OR 0.48,95%CI 0.240.97)but no influence on other aspirin associated symptoms in the group of aspirin-plus-PPI,Aspirin versus aspirin-plus-PPI,Meta分析结果,Kam CL,et al,(N Engl J Med 2002;346:2033-8.Francis KL,et al.N Engl J Med 2001;344:967-73
22、.,Clopidogrel-plus-PPI versus aspirin-plus-PPI,There was no difference on the rate of treatment success between two groups(P=0.34),indicating that early conversion from aspirin to clopidogrel does not appear superiority over the continuation of low-dose aspirin in the presence of PPI administration
23、group.,End points:Recurrent ulcer complications including bleeding,perforation and obstruction,Meta分析结果,FH NG,et al.Aliment Pharmacol Ther 2004;19:359365.,Clopidogrel and aspirin versus dual clopidogrel and aspirin plus PPI,Mean PRI on Days 1 and 7 in the Two Groups,Fig.8.On Day 1,mean platelet reac
24、tivity index(PRI)was 83.2%and 83.9%,respectively,in the placebo and omeprazole groups(nonsignificant).On Day 7,mean PRI was 39.8%and 51.4%,respectively,in the placebo and omeprazole groups(p 0.0001).VASP vasodilator-stimulated phosphoprotein.,Meta分析结果,Martine Gilard,et al.OCLA study.JACC2008;51:2562
25、60.,Placebo-plus-PPI versus aspirin-plus-PPI,To evaluate the effect of reintroduction of aspirin as soon as the endoscopic control of active bleeding in the condition of receiving PPI therapy.Results showed that the rate of endpoint event was similar in two groups(18.9%in aspirin group versus 10.9%i
26、n placebo group,P=0.25).But the aspirin-plus-PPI group had lower mortality than PPI therapy alone(1 patient versus 8 patients,P=0.01).,End points:The rate of recurrent ulcer bleeding within 30 days,Meta分析结果,Sung J,et al.Gastroenterology 2006;130:A44,PPI与阿斯匹林联用相比较阿斯匹林或氯吡格雷单用可明显降低上消化道出血和溃疡并发症的再发生率,阿斯匹
27、林、氯吡格雷分别合用PPI后的临床结果相近，在使用PPI的基础上无需将阿斯匹林更换为氯吡格雷,在阿斯匹林、氯吡格雷联用基础上服用PPI使双重抗血小板的能力减弱,仅用PPI较将PPI与ASA合用使死亡率增高，而后两者合用并不增再出血发生。活动性出血停止后可安全加用ASA,小结,停用氯吡格雷要缓慢减量,PCI后患者突然停用氯吡格雷在一段时期内会导致死亡和再梗危险的反跳性增加(JAMA,2007)临床上停用氯吡格雷可能需缓慢减量,低体重是出血的重要危险因素,按欧美体重标准，95%国人低于中位数体重（美国50百分位体重近似于中国95百分位体重）进口氯吡格雷日剂量75mg加大国人出血危险？prasugr
28、el也以体重标准决定给药剂量,氯吡格雷治疗若干问题与对策,用药时间、抵抗与新药氯吡格雷与PPI国产氯吡格雷循证学依据及其意义,国产氯吡格雷与进口氯吡格雷对择期PCI术患者疗效和安全性的对比研究,目的-评价国产氯吡格雷与进口氢氯吡格雷片对择期PCI患者血小板聚集的影响观察指标-ADP介导的血小板聚集率-PCI三天内患者急性血栓发生率-安全性和不良反应,研究背景,较低的血小板反应与支架置入术后的心血管事件相关ADP介导的血小板聚集率是支架置入术后再发缺血事件的预测因子,Thromb Haemost 2007;98:838843,研究中心,总体设计,取得受试者知情同意,测定基线ADP介导的血小板聚集
29、率采集人口动力学和基线资料,入选/排除,受试者随机分组,试验组（国产氯吡格雷组）和对照组（进口氯吡格雷组）各110例，共220例，给予研究药物（国产氯吡格雷或进口氯吡格雷），分别于用药前、用药两小时后、用药后第3天测血小板聚集率。记录不良事件与合并用药。并在给药前、后进行安全性实验室检查。,本研究为随机、活性对照、多中心开放临床试验,技术路线,用药前测ADP聚集率、血常规、肝功能,首剂300mg国产氯吡格雷,首剂300mg波立维,PCI+75mg国产氯吡格雷,PCI+75mg波立维,30 天门诊随访,华法令+培达,ACS及稳定心绞痛患者随机入选,服药2hrs ADP聚集率,用药3th天ADP聚
30、集率,华法令+培达,患者出院观察血常规、肝功能及不良反应,不合格,不合格,300mg国产氯吡格雷,300mg波立维,服药2hrs ADP聚集率,服药2hrs ADP聚集率,不合格,300mg国产氯吡格雷,服药2hrs ADP聚集率,不合格 不入组,300mg波立维,服药2hrs ADP聚集率,不合格,不合格 不入组,合格,合格,合格,合格,合格,合格,研究方法,血小板聚集率检测所有入组患者血样全部送至安贞医院检验科（从抽取血样至样本检测不得超过两小时）采用真空采血管取血3 ml(1：9抗凝)，以800r/min低速离心10min取上层PRP10l，加入诱导剂ADP（溶度为3毫摩尔/升）10l混
31、匀，再以3 000 rmin离心10 min，取PPP，用PPP作空白对照，用比浊法置入血小板聚集率分析仪中分析，得每份标本的血小板聚集率，结果以聚集百分率表示。,统计分析指标及统计分析方法由第3方完成,入选标准,所有入选患者必须符合下列要求：1.年龄18岁 2.择期行PCI手术的急性冠脉综合征患 者及稳定性心绞痛患者 3.签署知情同意书,排除标准,以下任意一项，不入选：年龄 1.5，或计划住院期间应用口服抗凝药在随机分组前10日内使用过氯吡格雷有使用氯吡格雷和/或ASA的禁忌症活动性出血或有高度出血危险（如接受纤溶治疗及其他被证实有抗血小板聚集作用的中药的患者，严重肝功能不全，消化性溃疡，增
32、生性糖尿病视网膜病变）严重全身性出血史(如消化道出血、肉眼血尿、肉眼出血、出血性卒中、颅内出血)，出血体质及凝血障碍性疾病疑似或确诊恶性肿瘤未控制的高血压（DBP120mmHg，或SBP180 mmHg）血小板减少（10万/dl）哺乳期、妊娠期妇女之前入选其他试验在之前30天内进行过研究性（药物或器械）治疗由于医疗，地理或其他社会因素使患者不能参加本研究，或患者不能提供书面的知情同意,观察指标,血小板聚集率及聚集抑制率 服药前、服药后2小时、服药后第3天早晨测血小板聚集率（送往北京安贞医院统一测定，传统比浊法）ADP介导的血小板聚集率显效达标的标准：ADP介导的血小板聚集率较服药前的基线水平降
33、低50%。心脏标志物 包括CK、CK-MB、TnI 服药前、PCI术后第1天早晨血常规(血色素、白细胞计数、中性粒细胞计数)、血小板计数 用药前、出院前肝功能（ALT、AST）用药前、出院前超声心动图 根据需要,不良事件观察,胃肠道疾病 如腹痛、消化不良、腹泻、恶心等血小板性出血和凝血疾病 如紫癜、鼻出血等皮肤及附属组织疾病 如皮疹、瘙痒等中枢及周围神经系统疾病 如头疼、眩晕等白细胞降低出血 严重出血的定义:危及生命：致命的、症状性颅内出血，导致血红蛋白降低至少 5 g/dl，导致静脉使用正性肌力药物，需要外科手术干预，或需要输血4个单位以上非危及生命：明显的活动障碍，眼内出血导致视力丧失，或
34、需要输血至少2个单位轻微出血的定义：任何其它导致研究用药中断的出血,一.服药后2h及服药后3天血小板聚集抑制率考察血小板聚集率测定值、较基线变化差值和聚集抑制率a)抑制差值=基线血小板聚集率服药后2h或3d血小板聚集率b)聚集抑制率=(基线血小板聚集率服药后血小板聚集率)/基线血小板聚集率二.疗效达标评价显效：血小板聚集抑制率50%非显效：血小板聚集抑制率50%三.需多次负荷量用药比较观察 采用卡方检验、t检验、wilcoxon秩和检验分析试验组、对照组间差别 置信限水平取双侧=0.05。,主要有效性指标,安全性评价,不良事件与不良反应计算不良事件发生例数和发生率。列出发生各种不良事件、不良反
35、应的病例清单。实验检查结果在服药前后的改变包括血液红细胞、白细胞、血小板计数、血红蛋白含量、中性粒细胞比例、AST、ALT、CK、CK-MB和TnI。描述给药前后实验室检查测定结果的例数、均值、标准差、最大值、最小值。,研究进展及结果,本试验计划入组220例受试者。2008年12月9日至今已入组并完成合格病例205例其中1例不符合入选标准，被排除在外，未行治疗；14例受试者未完成入组（试验组9例，对照组5例）。,观察指标 国产氯吡格雷组（104 例）对照组（101例）P年龄 60.57 10.51 59.43 11.01 0.4635性别（男）73(71.57%)62(62.00%)0.148
36、7BMI 24.24 4.46 25.32 3.30 0.1705高血压 55(56.12%)52(56.52%)0.9558糖尿病 21(21.00%)23(25.00%)0.4446血脂异常 20(20.00%)22(23.91%)0.7422吸烟 40(40.00%)30(32.61%)0.363饮酒 22(22.00%)13(14.13%)0.3695基线 PLA聚集率(%)42.85 12.76 39.36 15.28 0.0780,一般临床资料,有效性分析,服药2h、服药3日血小板聚集抑制率（意向治疗分析集）观察指标 国产氯吡格雷组 对照组 统计量 P基线 PLA聚集率(%)104
37、 42.85 12.76 101 39.36 15.28 t=3.16 0.07802h PLA聚集率(%)104 32.35 11.45 98 28.55 11.87 2h:聚集率差值 104 10.50 11.35 98 10.49 12.75 t=0.00 0.9952 2h:聚集抑制率 加权平均值（%）104 13.58 91.29 98 16.86 55.18 Z=0.1758 0.86043d PLA聚集率(%)103 24.30 10.56 97 24.88 9.37 3d:聚集率差值 103 18.46 14.49 97 14.20 14.73 t=4.25 0.04053d:
38、聚集抑制率 加权平均值（%）103 32.04 77.44 97 13.27 112.58 Z=-2.5936 0.0095,国产氯吡格雷组,对照氯吡格雷组,42.8512.76,32.3511.45,24.3010.56,39.3615.28,28.5511.87,24.889.37,两组2h及第3天与服药前均有差异P0.001,两组服药2小时后、服药第3天较服药前ADP介导的血小板聚集率明显降低,43.2%,36.7%,服药后2小时,服药后第3天,13.5891.29,16.8055.18,32.0477.44,13.27112.58,服药后第3天国产氯吡格雷组抑制率对照氯吡格雷组 P0.
39、01,两组服药2小时后、服药第3天较服药前ADP介导的血小板聚集抑制率加权平均值比较,P=0.68,P=0.0095,血小板聚集抑制率%,国产氯吡格雷,对照,国产氯吡格雷,对照,有效性分析:国产氯吡格雷组血小板抑制率50%例数更多 p0.01,有效性分析,有效性分析,需服用负荷剂量2次（共计600mg)的例数及血小板聚集率情况国产氯吡格雷组需多次服用负荷量的例数更少,安全性分析-不良事件,不良事件 国产氯吡格雷组 对照组 肝酶升高 3 3/104(2.9%)4 4/101(4.0%)消化道出血 0 1 1/101(1.0%)妇科出血 0 1 1/101(1.0%)腹泻 1 1/104(1.0%)1 1/101(1.0%)左股动脉穿刺部位出血 0 1 1/101（1.0%）白细胞计数减少 0 0 合计 4 4/104(3.9%)8 8/101(8.0%),结论,以ADP介导的血小板聚集率评价国产氯吡格雷与进口氯吡格雷均有良好的抗血小板作用，两者抗血小板聚集相似两组用药3天时国产氯吡格雷有更好的疗效国产氯吡格雷临床应用安全有效，可应用于PCI患者,氯吡格雷治疗若干问题与对策,用药时间、抵抗与新药氯吡格雷与PPI国产氯吡格雷循证学依据及其意义,
