氯吡格雷治疗冠心病的几个问题与对策_魏盟.ppt
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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,A
2、ctivation,COX-1,clopidogrel bisulfate,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 (24 h) Invasive Management with intended P
3、CI Ischemic ECG (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
4、Dose (300-325 mg/d) vs Low dose (75-100 mg/d),Efficacy Outcomes: CV Death, MI or stroke at day 30 Stent Thrombosis at day 30 Safety Outcomes: CURRENT defined Major/Severe and TIMI Major Key Subgroup: PCI v No PCI,Clop in 1st 7d (median) 7d 7 d 2 d 7d,Complete Followup 99.8%,Compliance:,Days,Cumulati
5、ve Hazard,0.0,0.004,0.008,0.012,0,3,6,9,12,15,18,21,24,27,30,Clopidogrel Standard Dose,Clopidogrel Double Dose,42% RRR,HR 0.58 95% CI 0.42-0.79 P=0.001,Clopidogrel: Double vs Standard Dose Definite 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,Clopidogr
6、el: Double vs Standard Dose Primary Outcome: PCI Patients,Clopidogrel Standard,Clopidogrel Double,HR 0.85 95% CI 0.74-0.99 P=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,
7、C Standard, A Low,C Standard, A High,C Double, A Low,C Double, 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
8、 no increase in fatal, CABG-related or TIMI major bleeds. Patients 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=0.022 P=0.012 Multivariabl
9、e analyses,RR(95%CI),4 weeks 1year (n=176 vs 877),Favors PPI+Clopidogrel+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 o
10、f Clopidogrel in the CREDO Trial,Steven PD, Trancy EM, Danielle BM, et al. Circulation. 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=452
11、1 vs 9862),Favors PPI+Clopidogrel Favors Clopidogrel,Primary endpoints: one-year incidence 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 X
12、ia , 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(1.11-1.41) 1.86(1.57-2.20) 1.49(1.30-1.71) 0.91(0.80-1.05) Multivariable analyses,AOR(95%CI),Primary endpoints Hospitalization for recurrent ACS Revascularization procedures All cause mortality (n=5244 vs 29
13、16),Favors PPI+Clopidogrel Favors Clopidogrel,Primary endpoints: Death or rehospitalization for ACS occurred,Fig.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
14、; 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: Formation 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 stud
15、y 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
16、 Use at Randomization n=4529, 33% of study population,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,PRASUGREL PPI vs no PPI: Adj HR 1.00, 95% CI 0
17、.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 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
18、,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 N
19、SAID 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,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
20、disease; ASAaspirin; PPIproton pump inhibitorsl; UNunclear; 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
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