血小板GPIIbIIIa受体拮抗剂临床应用进展ppt课件

1、1,血小板GP IIb/IIIa受体拮抗剂临床应用新视点,上海交通大学附属胸科医院心内科 仇兴标,2,IIb/IIIa受体拮抗剂的作用机制,3,Pharmacologic Intervention in Thrombosis,4,5,三类 GPIIb/IIIa受体拮抗剂的化学结构,6,三类 GP IIb/IIIa受体拮抗剂的特点,7,IIb/IIIa受体拮抗剂的循证依据,8,GP IIb/IIIa Inhibitors,Coronary Intervention EPIC RESTORE CAPTURE EPILOG RAPPORT IMPACT II EPISTENT ESPRIT CADI

2、LLAC TARGET,24,141 Patients,Unstable Angina Non-Q Wave MI PURSUIT PRISM PRISM PLUS PARAGON A PARAGON B GUSTO-IV,31,056 Patients,Oral IIb/IIIa PCI - ACS EXCITE OPUS 1st SYMPHONY 2nd SYMPHONY,33,340 Patients,ST-Elevation Acute MI GUSTO-V ASSENT-3,22,683 Patients,Completed early Large RCTs,9,IIb/IIIa受体

3、拮抗剂在PCI患者中的应用,10,Kong D, et al. Am J Cardiol. 2003; 92:651-655.,Placebo Better,IIb/IIIa Better,Trial,Control,Treatment,N,0.1,1,10,RESTORE,1.1%,0.9%,12,940,EPILOG,1.2%,0.9%,4891,RAPPORT,1.3%,1.0%,5374,CAPTURE,1.3%,1.0%,6639,EPIC,1.7%,1.5%,2099,1.3%,IMPACT I,1.0%,6789,1.2%,IMPACT II,0.9%,10,799,ESPRIT

4、,1.0%,0.8%,17,403,ISAR-2,1.1%,0.8%,17,804,ADMIRAL,1.2%,0.8%,18,104,EPISTENT,1.1%,0.8%,15,339,1.3%,CADILLAC,0.9%,20,186,Odds Ratio and 95% CI,0.73 (0.55, 0.96) P=0.024,Meta-analysis of Survival with Platelet GP IIb/IIIa Antagonists for PCI,11,Favors Control,Favors Treatment,Year,CAPTURE,1997,RESTORE,

5、1998,EPISTENT,1999,1997,CADILLAC-P,2002,ADMIRAL,2001,RAPPORT,1998,Petronio,2002,CADILLAC-S,2002,0.01,0.1,1,10,100,Study,ERASER,1999,ISAR-2,2000,EPIC,Risk Ratio and 95% CI,RR 0.79 Z=-2.27 2P=0.023,EPILOG,1999,ESPRIT,2002,Overall,Tamburino,2002,N,1265,2141,1603,2099,1046,300,483,89,1036,225,401,2792,2

6、064,15,651,107,Karvouni E, et al. J Am Coll Cardiol. 2003;41:26-32.,Intravenous GP IIb/IIIa Receptor Antagonists Reduce Mortality after PCI,12,ISAR-REACT,600 mg Clopidogrel load 2 hours before PCI,Low-risk PCI, 30-Day Ischemic and Bleeding Events ,European and 1 US Center,Placebo,Abciximab,Design,Pa

7、tients Excluded: IDDM ACS or recent MI Vein grafts Thrombotic lesions LVEF 30%,13,p=NS,p=NS,p=NS,p=NS,NEJM 2004;350:232-8,ISAR-REACT low-risk PCI- 30 days outcome,14,p=0.06,p=0.03,p=0.34,p=0.64,JAMA 2006;295:1531-38,ISAR-REACT 2 high-risk PCI- 30 days outcome,15,In patients undergoing elective PCI t

8、reated with UFH and not pretreated with clopidogrel, it is reasonable to administer a GP IIb/IIIa inhibitor (abciximab, double-bolus eptifibatide, or high-bolus dose tirofiban).,Intravenous Antiplatelet Therapy: SIHD,B,2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention,16,In patient

9、s undergoing elective PCI with stent implantation treated with UFH and adequately pretreated with clopidogrel, it might be reasonable to administer a GP IIb/IIIa inhibitor (abciximab, double-bolus eptifibatide, or high-bolus dose tirofiban).,Intravenous Antiplatelet Therapy: SIHD (cont.),B,2011 ACCF

10、/AHA/SCAI Guideline for Percutaneous Coronary Intervention,17,IIb/IIIa受体拮抗剂在NSTE- ACS患者中的应用,18,STEMI,Clinical finding,EKG,Serum markers,Risk assessment,Non-cardiacchest pain,Stableangina,UA,NSTEMI,Negative,Positive,ST-T wave changes,ST elevation,Lowprobability,Medium-high risk,ThrombolysisPrimary PC

11、I,Aspirin + GP IIb/IIIa inhibitor clopidogrel + heparin/ LMWH + anti-ischemic RxEarly invasive Rx,Discharge,Negative,Diagnostic rule out MI/ACS pathway,STEMI,Negative,Atypical pain,Low risk,Aspirin, heparin/low-molecular-weight heparin (LMWH) + clopidogrelAnti-ischemic Rx Early conservative therapy,

12、Ongoing pain,DM=diabetes mellitus. Cannon, Braunwald. Heart Disease. 2001.,Rest pain, Post-MI, DM, Prior Aspirin,Exertional pain,The Spectrum of ACS,19,PRISM (3232)7.1%5.8% 0.800.60-1.06 PRISM-PLUS (1915)12.0%8.7% 0.700.50-0.98 PARAGON-A (2282) 11.7%(l)10.3% 0.870.58-1.29(h)12.3% 1.060.72-1.55 PURSU

13、IT (10,948)15.7%14.2% 0.890.79-1.00 PARAGON-B (5225)11.4%10.6% 0.920.77-1.09 GUSTO-IV (7800)8.0%(24h)8.2% 1.020.83-1.24 (48h)9.1% 1.150.94-1.39,Odds Ratio,Placebo,IV GP IIb/IIIa,95% CI,*With/without heparin. Without heparin. (l)=low dose. (h)=high-dose. Adapted from: Boersma E, et al. Lancet. 2002;3

14、59:189-198.,Placebo Better,GP IIb/IIIa Better,Odds Ratio (95% CI),0.0,1.0,2.0,Study (n),GP IIb/IIIa Inhibitors in UA/NSTEMI: Death or MI at 30 Days,20,Benefit of GP IIb/IIIa Blockade in ACS Meta-Analysis of Six Major Trials (31,402 Patients),All patients with ACS Patients with ACS, undergoing PCI wi

15、thin 5 days,Boersma E et al. Lancet 2002,0.5,0.6,0.7,1.1,Anti GPIIb/IIIa better,0.8,0.9,1.0,Relative 30-Day Risk of Death and MI,21,IIb/IIIa ACS Meta-analysis,30-Day Death or MI,Boersma et al. Lancet 2002;359:189-98,OR=0.95 (0.87-1.02),OR=0.77 (0.64-0.92),22,IIb/IIIa ACS 30-day Death or MI Early PCI

16、,23,IIb/IIIa ACS 30-day Death or MI No Early PCI,24,ACUITY: Ischemic Composite Endpoint,Stone GW. ACC 2007 presentation,*Death, MI, unplanned revascularization for ischemia,25,26,EARLY-ACS study,27,ACC/AHA 2012年UA/NSTEMI指南,预行PCI的中、高危UA/NSTEMI患者，与阿司匹林联合应用GPb/受体拮抗剂，开始于术前(I/B)或术中(I/A) Bivalirudin作为术中抗凝

17、时可不用GPb/a受体拮抗剂 对于选择保守策略的UA/NSTEMI患者，可应用依替巴肽或替罗非班进行抗栓治疗(b/B) 预行PCI的高危UA/NSTEMI且非高出血风险患者，与双联抗血小板药联合上游应用GPb/受体拮抗剂(b/B) 阿昔单抗不应当应用于不准备行PCI的患者（/A） 预行PCI的低危UA/NSTEMI患者或高出血风险患者，不推荐与双联抗血小板药联合上游应用GPb/受体拮抗剂(/B),28,In UA/NSTEMI patients with high-risk features (e.g., elevated troponin level) not treated with bi

18、valirudin and not adequately pretreated with clopidogrel, it is useful at the time of PCI to administer a GP IIb/IIIa inhibitor (abciximab, double-bolus eptifibatide, or high-bolus dose tirofiban) in patients treated with UFH.,Intravenous Antiplatelet Therapy : UA/NSTEMI,A,2011 ACCF/AHA/SCAI Guideli

19、ne for Percutaneous Coronary Intervention,29,In UA/NSTEMI patients with high-risk features (e.g., elevated troponin level) treated with UFH and adequately pretreated with clopidogrel, it is reasonable at the time of PCI to administer a GP IIb/IIIa inhibitor (abciximab, double-bolus eptifibatide, or

20、high-bolus dose tirofiban).,Intravenous Antiplatelet Therapy : UA/NSTEMI (cont.),B,2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention,30,IIb/IIIa受体拮抗剂在AMI患者中的应用,31,早期研究IIb/III受体拮抗剂对AMI直接PCI的作用,32,Relative Risk of Death+MI+TVR Abciximab vs Control,GP IIb/IIIa受体拮抗剂在AMI患者PCI中的应用,33,33,

21、FINESSE: Study design,Ellis et al. N Eng J Med. 2008;358:2205-2217.,34,34,Ellis et al. N Eng J Med. 2008;358:2205-2217,35,FINESSE 90-Day Endpoints,Ellis S. ESC 2007 Vienna,36,FINESSE 90-Day Bleeding,Ellis S. ESC 2007 Vienna,37,CARESS Abciximab with 1/2 Dose Reteplase,Di Mario C. ESC 2007 Vienna,38,3

22、8,OnTIME 2: Study design,Acute myocardial infarction diagnosed in ambulance or referral center ASA+600 mg Clopidogrel,Angiogram,Tirofiban *,Placebo,Transportation,PCI centre,Angiogram,Tirofiban provisional,Tirofiban contd,PCI,vant Hof et al. Lancet 2008;372:537-46.,*Bolus 25 g/kg 372:537-46,Residual

23、 ST Deviation after PCI,p=0.003 3.6 4.6mm4.8 6.3mm,41,On-TIME 2: Results Event-free Survival,survival free from death, recurrent myocardial infarction, urgent target vessel revascularisation, or blinded bail-out use of study drug,42,On-TIME 2: Results,vant Hof et al. Lancet 2008;372:537-46.,Event-fr

24、ee Survival at 30 days,Death at 1 yr. in primary PCI group: Tirofiban (2.4%) vs. Placebo (5.5%) (p=0.007, RR=0.44 (0.24-0.81),43,In patients undergoing primary PCI treated with UFH, it is reasonable to administer a GP IIb/IIIa inhibitor (abciximab, double-bolus eptifibatide, or high-bolus dose tirof

25、iban), whether or not pretreated with clopidogrel. For GP IIb/IIIa inhibitor administration in patients not pretreated with clopidogrel. For GP IIb/IIIa inhibitor administration in patients who are pretreated with clopidogrel.,Intravenous Antiplatelet Therapy: STEMI,A,2011 ACCF/AHA/SCAI Guideline fo

26、r Percutaneous Coronary Intervention,44,44,It is reasonable to start treatment with glycoprotein IIb/IIIa receptor antagonists at the time of primary PCI (with or without stenting) in selected patients with STEMI: abciximab tirofiban and eptifibatide,Use of Glycoprotein IIb/IIIa Receptor Antagonists

27、 in STEMI,45,45,Use of Glycoprotein IIb/IIIa Receptor Antagonists in STEMI,The usefulness of glycoprotein IIb/IIIa receptor antagonists (as part of a preparatory pharmacologic strategy for patients with STEMI prior to arrival in the cardiac catheterization laboratory for angiography and PCI) is unce

28、rtain.,46,BRAVE 3: Study design,Mehilli et al. Circ. 2009;119:1933-1940,TREATMENT: pre-PCI treatment with clopidogrel (600 mg), followed by abciximab vs. placebo INCLUSION: suspected acute MI (ST change or LBBB) within 24 h of symptom onset EXCLUSION:high risk for bleeding, prior stroke,shock, traum

29、a, thrombolytics, hypertension, relevant hematologic deviations 1 OUTCOMES: infarct size, death, stroke, urgent revascularization of affected artery,47,Effects of Abciximab,Mehilli et al. Circ. 2009;119:1933-1940,No significant difference in infarct size or major bleeding,P= 0.47,P= 0.40,48,Routine

30、precatheterization laboratory (e.g., ambulance or emergency room) administration of GP IIb/IIIa inhibitors as part of an upstream strategy for patients with STEMI undergoing PCI is not beneficial.,Intravenous Antiplatelet Therapy: STEMI (cont.),B,No Benefit,2011 ACCF/AHA/SCAI Guideline for Percutane

31、ous Coronary Intervention,49,冠脉内注射IIb/IIIa受体拮抗剂,50,Meta-Analysis I All ACS + GpIIb/IIIa-Inh.,Friedman et al. Am J Cardiol 2011;108:1244-1251,TIMI-3-Flow after PCI,0.569,1,1.76,Favors IV route,Favors IC route,Risk ratio,Deibele Gu Iversen Dominguez-Rodriguez Wu Thiele Yang Bellandi Overall (I-squared

32、=20.1%; p=0.27),1.07 (0.89, 1.28) 8.66 1.03 (0.97, 1.10) 34.90 1.10 (0.98, 1.24) 17.43 1.29 (0.95, 1.76) 3.27 1.22 (1.01, 1.48) 7.96 0.98 (0.86, 1.12) 14.25 1.27 (0.98, 1.64) 4.60 1.15 (0.96, 1.37) 8.92 1.08 (1.02, 1.15) 100.00,Study,RR (95% CI),Weight,51,Meta-Analysis I All ACS + GpIIb/IIIa-Inh.,Fr

33、iedman et al. Am J Cardiol 2011;108:1244-1251,Short-term Mortality,Gu Iversen Wu Thiele Yang Bellandi Overall (I-squared=0.0%; p=0.772),Study,RR (95% CI),Weight,0.69 (0.22, 2.16) 28.34 0.20 (0.04, 0.93) 37.42 0.49 (0.05, 5.27) 8.05 0.67 (0.11, 3.68) 11.97 0.19 (0.01, 3.71) 10.33 1.05 (0.07, 15.70) 3

34、.90 0.45 (0.23, 0.90) 100.00,0.0936,1,107,Risk ratio,52,Meta-Analysis II STEMI + Abciximab,Navarese et al. Platelets 2011;1-8,53,Piccolo, Thiele et al. Submitted,Individual Patient-based Meta-Analysis III,5 randomized trials (n = 1198); individual patient-based meta-analysisIC Abciximab n = 611 IV A

35、bciximab n = 587,Death + Reinfarction,IV Abciximab 587 572 568 552 559 555IC Abciximab 611 603 597 595 594 594,0,0,6,12,18,24,30,0,2,4,6,8,HR 0.54 (95% CI 0.30; 0.95); p=0.03,Days after Randomization,Probability of deathor reinfarction (%),Patients at risk:,IC Abciximab,IV Abciximab,54,Piccolo, Thie

36、le et al. Submitted,Individual Patient-based Meta-Analysis III,5 randomized trials (n = 1198); individual patient-based meta-analysisIC Abciximab n = 611 IV Abciximab n = 587,Mortality,IV Abciximab 587 577 574 572 570 567IC Abciximab 611 606 603 602 602 602,0,0,6,12,18,24,30,0,2,4,6,8,HR 0.43 (95% C

37、I 0.20; 0.94); p=0.03,Days after Randomization,Probability of death (%),Patients at risk:,IC Abciximab,IV Abciximab,55,In patients undergoing primary PCI with abciximab, it may be reasonable to administer intracoronary abciximab.,Intravenous Antiplatelet Therapy : STEMI (cont.),B,2011 ACCF/AHA/SCAI

38、Guideline for Percutaneous Coronary Intervention,56,不同IIb/IIIa受体拮抗剂的比较,57,57,Use of Glycoprotein IIb/IIIa Receptor Antagonists in STEMI,Grum et al. Small Molecule GP IIb/IIIa Inhibitors primary PCI.Circ Cardiovas Intervent. 2009;2:230-2236.,0.1 0.2 0.5 1 2 5,Favors SM GPI Favors Abciximab,OR and 95% CI of 30-day Mortality,58,High-Dose Bolus Tirofiban vs. Abciximab,Pooled Analysis of 5 Studies,Abciximab Tirofiban Study 0.25 mg/kg bolus 25 g/kg bolus 0.125 g/kg/min infusion0.15 g/kg/min infusion Bolognese3130 Danzi280274 Gunasekara110 109 TEN