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 IIb/IIIa integrin ADP Epinephrine Collagen Thrombin Platelet Aggregation Serotonin Shear rate AA TxA2 COX-1 Thrombin Thrombin Thrombin TxA2 TxA2 Thrombin ADP TXA2 ADP P2Y12 ADP (fibrinogen receptor) GP IIb/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 Randomization n=4529, 33% of study population Type of PPI Frequency Pantoprazole 1844 (40%) Omeprazole 1675 (37%) Esomeprazole 613 (14%) Lansoprazole 441 (9.7%) Rabeprazole 66 (1.5%) ODonoghue ML, Braunward et al ESC， 2009， Lancet， 2009， online CV death,MI or strokeDays CLOPIDOGREL PPI vs no PPI: Adj HR 0.94, 95% CI 0.80-1.11 PPI use at randomization (n= 4529) Clopidogrel Prasugrel PRASUGREL PPI 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 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 药物 PPI(%) No PPI(%) P值 氯吡格雷 23.3 35.2 0.02 普拉格雷 69.6 76.7 0.054 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 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 Probability0 30 60 90 120 150 180 210 240 270 300 330 360 390 0.90 0.92 0.94 0.96 0.98 1.00 Placebo Treated Survival Curves for PPI Treated vs Placebo Composite Cardiovascular Events D a y sSurvivalProbability0 30 60 90 120 150 180 210 240 270 300 330 360 3900.900.920.940.960.981.00P l a ce b oT r e a t e dSu r v i v a l C u r v e s fo r PPI T r e a te d v s Pl a c e b oC o m p o s i te G I Ev e n tsHR = 0.55 95% CI = 0.36; 0.85 p=0.007 (preliminary) Placebo: 67 events, 1895 at risk Treated: 38 events, 1878 at risk CVD cardiovascular disease; Cere cerebrovascular disease; ASA aspirin; PPI proton pump inhibitorsl; UN unclear; M month; W week; D day; OCLA study Omeprazole 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 SBP 180 mmHg） 9. 血小板减少 （ 对照氯吡格雷组 P0.01 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 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%） 6.7871 0.0092 对照组（ 101例） 70（ 72.16%） 27(27.84%) 总计 126 74 有效性分析 : 国产氯吡格雷组血小板