氯吡格雷治疗冠心病的几个问题与对策魏盟

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 UFH ADP ADP受体抑制剂 斑块破裂 血管壁受损 白血栓途径 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 LMWH Xa 纤维蛋白原 纤维蛋白 TXA2 阿司匹林 纤溶 抗栓治疗 GP IIb/IIIa 受体拮抗剂 Platelet Stimuli GP GP IIb/IIIaIIb/IIIa integrinintegrin ADP Epinephrine Collagen Thrombin Platelet AggregationPlatelet Aggregation Serotonin Shear rate AA TxA2 COX-1 ThrombinThrombin ThrombinThrombin ThrombinThrombin TxATxA 2 2 TxATxA 2 2 Thrombin ADPADP TXATXA 2 2 ADP P2Y12 ADPADP (fibrinogen(fibrinogen receptor)receptor) GP GP IIb/IIIaIIb/IIIa Activation COX-1 clopidogrel bisulfate aspirin cAMP Oral Anti-PAR-1 receptors SCH 530348 E 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 (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):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 RandomizationPPI Use at Randomization n=4529, 33% of study populationn=4529, 33% of study population Type of PPIFrequency Pantoprazole1844 (40%) Omeprazole1675 (37%) Esomeprazole613 (14%) Lansoprazole441 (9.7%) Rabeprazole 66 (1.5%) ODonoghue ML, Braunward et al ESC，2009，Lancet，2009，online CV death, MI or stroke 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 Type of PPI Clopidogrel HR (95% CI) CV death, MI or stroke Prasugrel HR (95% CI) CV death, MI or stroke Omeprazole (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) Risk of CV events with different types of Risk of CV events with different types of PPIsPPIs 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 药物PPI(%)No PPI(%) P值 氯吡格雷23.335.20.02 普拉格雷69.676.70.054 Principle TIMI 44，Lancet，2009，online .n=201 The COGENT TrialThe COGENT Trial Deepak L. Bhatt et al ESC 2009 3627 patients (above the initial target of 3200) 393 sites Median follow-up 133 days (maximum 362 days) 136 adjudicated cardiovascular events (preliminary) 105 adjudicated GI events (preliminary) Adjustment through Cox Proportional Hazards Model Adjusted to Positive NSAID Use and Positive H. Pylori Status HR = 1.02 95% CI = 0.70; 1.51 Placebo: 67 events, 1821 at risk Treated: 69 events, 1806 at risk Days Survival Probability 0306090120150180210240270300330360390 0.900.920.940.960.981.00 Placebo Treated Survival Curves for PPI Treated vs Placebo Composite Cardiovascular Events HR = 0.55 95% CI = 0.36; 0.85 p=0.007 (preliminary) Placebo: 67 events, 1895 at risk Treated: 38 events, 1878 at risk CVDcardiovascular disease; Cerecerebrovascular disease; ASAaspirin; PPIproton pump inhibitorsl; UN unclear; M month; Wweek; Dday; OCLA studyOmeprazole CLopidogrel Aspirin Study Tab.1. Characteristics of the 8 Included Studies Fig.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 gastrointestinal 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 0.24 0.97) 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. 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 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 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 omeprazole groups (p 1.5，或计划住院期间应用口服抗凝药 3.在随机分组前10日内使用过氯吡格雷 4.有使用氯吡格雷和/或ASA的禁忌症 5.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，增生性糖尿病视网膜病变） 6.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 7.疑似或确诊恶性肿瘤 8.未控制的高血压（DBP120mmHg，或SBP180 mmHg） 9.血小板减少（对照 氯吡格雷组 P0.01 4两组服药2小时后、服药第3天较服药前 4ADP介导的血小板聚集抑制率加权平均值比较 4P=0.68 4P=0.0095 4血小板聚集抑制率% 4国产氯吡格雷 4对照 4国产氯吡格雷4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%) 总计12674 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 治疗疗用 药药 首次服药药后2h ADP介导导血小板聚集率（% ） 二次服药药后2h ADP介导导血小板聚集率（%） 发发生率 国产氯 吡格雷 组 5144 3/104 (2.9%) 5144 5248 对照 氯吡 格雷 组 5212 6/101 (6.0%) 5143 5045 5836 8733 5352 4需服用负荷剂量2次（共计600mg)的例数及血小板聚集率情况 4国产氯吡格雷组需多次服用负荷量的例数更少 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