氯吡格雷治疗冠心病的几个问题与对策魏盟

1、会计学1氯吡格雷治疗冠心病的几个问题与对策氯吡格雷治疗冠心病的几个问题与对策魏盟魏盟UFHADPADP受体抑制剂斑块破裂斑块破裂血管壁受损血管壁受损白血栓途径白血栓途径红血栓途径红血栓途径Von Willebrand 因子、胶原血小板黏附血小板激活纤维蛋白原结合血小板聚集血栓凝血酶（IIa）组织因子/ VIIa因子复合物LMWHXa纤维蛋白原纤维蛋白TXA2阿司匹林纤溶纤溶抗栓治疗GP IIb/IIIa受体拮抗剂受体拮抗剂Platelet StimuliADPEpinephrineCollagenThrombinSerotoninShear rateAATxA2COX-1ThrombinADP

2、 P2Y12ActivationCOX-1clopidogrel bisulfateaspirincAMPOral Anti-PAR-1 receptorsSCH 530348E 5555adapted from Schafer AI. Am J Med. 1996;101:199-209.25,087 ACS Patients (UA/NSTEMI 70.8%, STEMI 29.2%)Planned Early (奥美拉唑埃索美拉唑泮托拉唑雷贝拉唑Drug Safety 2006,29:769-784Fig.3. PPI和氯吡格雷的药代动力学影响Tab.2PPI和氯吡格雷的药代动力学影响F

3、ig .5. A population-based study of the drug interaction between proton pump inhibitors and clopidogrelDavid NJ, Tara GM, Dennis TK, et al. CMAJ 2009; 180(7):713-738.Primary endpoints: Recurrent infarction within 90 days and 1 year following hospital discharge after treatment of acute myocardial infa

4、rction不同的制酸药对氯吡格雷的影响不相同不同的制酸药对氯吡格雷的影响不相同 Type of PPIFrequencyPantoprazole1844 (40%)Omeprazole1675 (37%)Esomeprazole613 (14%)Lansoprazole441 (9.7%)Rabeprazole 66 (1.5%)ODonoghue ML, Braunward et al ESC，2009，Lancet，2009，onlineCV death, MI or strokeDaysCLOPIDOGREL PPI vs no PPI: Adj HR 0.94, 95% CI 0.8

5、0-1.11PPI use at randomization (n= 4529)ClopidogrelPrasugrelPRASUGRELPPI vs no PPI: Adj HR 1.00, 95% CI 0.84-1.20Primary endpoint stratified by use of a PPIODonoghue ML, Braunward et al ESC，2009，Lancet，2009，onlineType of PPIClopidogrelHR (95% CI)CV death, MI or strokePrasugrelHR (95% CI)CV death, MI

6、 or strokeOmeprazole(n=1675)0.91 (0.72-1.15)1.04 (0.81-1.34)Pantoprazole(n=1844)0.94 (0.74-1.18)1.09 (0.86-1.39)Esomeprazole(n=613)1.07 (0.75-1.52)0.86 (0.55-1.33)Lansoprazole(n=441)1.00 (0.63-1.59)0.98 (0.61-1.57)Rabeprazole not included due to small sample size (n=66)药物PPI(%)No PPI(%)P值氯吡格雷23.335.

7、20.02普拉格雷69.676.70.054Principle TIMI 44，Lancet，2009，online .n=201Deepak L. Bhatt et al ESC 2009Adjustment through Cox Proportional Hazards ModelAdjusted to Positive NSAID Use and Positive H. Pylori StatusHR = 1.0295% CI = 0.70; 1.51Placebo: 67 events, 1821 at riskTreated: 69 events, 1806 at riskDays

8、Survival Probability03060901201501802102402703003303603900.900.920.940.960.981.00PlaceboTreatedSurvival Curves for PPI Treated vs PlaceboComposite Cardiovascular EventsDaysSurvival Probability03060901201501802102402703003303603900.900.920.940.960.981.00PlaceboTreatedSurvival Curves for PPI Treated v

9、s PlaceboComposite GI EventsHR = 0.5595% CI = 0.36; 0.85p=0.007(preliminary)Placebo: 67 events, 1895 at riskTreated: 38 events, 1878 at riskCVDcardiovascular disease; Cerecerebrovascular disease; ASAaspirin; PPIproton pump inhibitorsl; UNunclear; Mmonth; Wweek; Dday; OCLA studyOmeprazole CLopidogrel

10、 Aspirin Study Tab.1. Characteristics of the 8 Included StudiesFig.6. Pooled rate 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 gastrointest

11、inal bleeding (OR 5.96, 95%CI 1.31 to 21.70, P=0.02) in aspirin-plus-PPI group. The other 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-PPIMetaMet

12、a分析结果分析结果Kam CL,et al, (N Engl J Med 2002;346:2033-8. Francis KL, et al. N Engl J Med 2001;344: 967-73.Clopidogrel-plus-PPI versus aspirin-plus-PPIThere was no difference on the rate of treatment success between two groups (P=0.34), indicating that early conversion from aspirin to clopidogrel does n

13、ot appear superiority over the continuation of low-dose aspirin in the presence of PPI administration group. End points: Recurrent ulcer complications including bleeding, perforation and obstruction MetaMeta分析结果分析结果FH NG, et al. Aliment Pharmacol Ther 2004; 19: 359365.Clopidogrel and aspirin versus

14、dual clopidogrel and aspirin plus PPIMean PRI on Days 1 and 7 in the Two GroupsFig. 8. On Day 1, mean platelet reactivity 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 omep

15、razole groups (p 0.0001). VASP vasodilator -stimulated phosphoprotein.MetaMeta分析结果分析结果Martine Gilard, et al. OCLA study. JACC2008; 51: 256260.Placebo-plus-PPI versus aspirin-plus-PPITo evaluate the effect of reintroduction of aspirin as soon as the endoscopic control of active bleeding in the condit

16、ion 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% in 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 ra

17、te of recurrent ulcer bleeding within 30 days MetaMeta分析结果分析结果Sung J, et al. Gastroenterology 2006;130:A44PPI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小结小结 较低的血小

18、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4Thromb Haemost 2007; 98: 838843安贞1301安贞2中日协和北京华信宣武石景山复兴4取得受试者取得受试者4知情同意知情同意测定基线ADP介导的血小板聚集率采集人口动力学和基线资料4入选/排除4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。4本研究为随机、活性对照、多中心

19、开放临床试验4 不合格 4不合格4 不合格 4 不合格 不入组4不合格4不合格 不入组4合格4合格4合格4合格4合格4合格统计分析指标及统计分析方法由第统计分析指标及统计分析方法由第3 3方完成方完成一. 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

20、照组间差别 置信限水平取双侧=0.05。 主要有效性指标一般临床资料4服药2h、服药3日血小板聚集抑制率（意向治疗分析集）4 4 观察指标 国产氯吡格雷组 对照组 统计量 P44基线 PLA聚集率(%) 104 42.85 12.76 101 39.36 15.28 t= 3.16 0.0780442h PLA聚集率(%) 104 32.35 11.45 98 28.55 11.87 42h: 聚集率差值 104 10.50 11.35 98 10.49 12.75 t= 0.00 0.9952 42h: 聚集抑制率4 加权平均值（%） 104 13.58 91.29 98 16.86 55.

21、18 Z=0.1758 0.8604443d PLA聚集率(%) 103 24.30 10.56 97 24.88 9.37 43d: 聚集率差值 103 18.46 14.49 97 14.20 14.73 t= 4.25 0.040543d: 聚集抑制率4 加权平均值（%） 103 32.04 77.44 97 13.27 112.58 Z=-2.5936 0.00954国产氯吡格雷组国产氯吡格雷组 4对照氯吡格雷组对照氯吡格雷组 4服药前4服药后2小时4服药后3天442.8512.76432.3511.45424.3010.56439.3615.28428.5511.87424.889.

22、374两组两组2h及第及第3天天与服药前均有差异与服药前均有差异P对照对照氯吡格雷组氯吡格雷组 P0.014两组服药两组服药2小时后、服药第小时后、服药第3天较服药前天较服药前4ADP介导的血小板聚集抑制率加权平均值比较介导的血小板聚集抑制率加权平均值比较4P=0.684P=0.00954血小板聚集抑制率血小板聚集抑制率%4国产氯吡格雷 4对照对照4国产氯吡格雷 4对照对照组别血小板聚集抑制率50%(3d后）血小板聚集抑制率50%(3d后）x2值 P国产氯吡格雷组（104例）56（54.37%）47（45.63%）6.78710.0092对照组（101例）70（72.16%）27(27.84%

23、)总计1261267474有效性分析有效性分析: : 国产氯吡格雷组血小板抑制率国产氯吡格雷组血小板抑制率50%50%例数更多例数更多 p0.01治疗用治疗用药药首次服药后首次服药后2h2hADPADP介导血小板聚集率（介导血小板聚集率（% %）二次服药后二次服药后2h2hADPADP介导血小板聚集率（介导血小板聚集率（% %）发生率发生率国产氯吡格雷组51443/104(2.9%)51445248对照氯吡格雷组52126/101(6.0%)514350455836873353524需服用负荷剂量需服用负荷剂量2 2次（共计次（共计600mg)600mg)的例数及血小板聚集率情况的例数及血小板

24、聚集率情况4国产氯吡格雷组需多次服用负荷量的例数更少国产氯吡格雷组需多次服用负荷量的例数更少0.2 0.5 1 2 5AOR(95%CI)1.25(1.11-1.41)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 ClopidogrelPrimary endpoints: Death or rehospitalization for ACS occurred Fig.3. Risk of Adverse Outcomes Associated With Concomitant Use of Clopidogrel and Proton Pump Inhibitors Following Ac