血小板GPIIbIIIa受体拮抗剂临床应用新视点

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iib/iiia受体拮抗剂的作用机制pharmacologic intervention in thrombosisufh=unfractionated heparin.lmwh=low-molecular-weight heparinadp=adenosine diphosphate.tfpi=tissue factor pathway inhibitor selwyn a. am j cardiol. 2003;91:3h-11h.coagulation cascadeplateletslmwhthie

2、nopyridinesgp iib/iiia inhibitorsthrombolyticslmwhufhlmwhufhdirect thrombininhibitorstissue factorfactor xaprothrombinthrombinplateletsa2 vwf adpactivated plateletsfibrinogen cross-linkingplatelet aggregationaspirinfibrinogenfibrinfibrindegradationcollagenleukocytestfpianti-thrombinanti-thrombinthro

3、mboxaneplasminthrombuspharmahalf-liferenal adj.dosageabciximab(reopro)fab portion ofchimeric monoclonalantibody30minsno0.25 mcg/kg bolusfollowed by0.125 mcg/kg/min drip(max 10 mcg/min) forup to 12 hourstirofiban(aggrastat)synthetic non-peptide1.8hrsyes0.4 mcg/kg/min for 30minutes followed by0.1 mcg/

4、kg/min dripfor 48-96 hours25 mcg/kg for 3minutes followed by0.15 mcg/kg/min dripfor up to 18 hourseptifibatide(integrilin)cyclic heptapeptide2.5hrsyes180 mcg/kg bolus (x2)followed by 2.0mcg/kg/min drip for12-18 hoursgp iib/iiia inhibitorsiib/iiia受体拮抗剂在pci患者中的应用kong d, et al. am j cardiol. 2003; 92:6

5、51-655.placebo betteriib/iiia bettertrialcontroltreatmentn0.1110restore1.1%0.9%12,940epilog1.2%0.9%4891rapport1.3%1.0%5374capture1.3%1.0%6639epic1.7%1.5%20991.3%impact i1.0%67891.2%impact ii0.9%10,799esprit1.0%0.8%17,403isar-21.1%0.8%17,804admiral1.2%0.8%18,104epistent1.1%0.8%15,3391.3%cadillac 0.9%

6、20,186odds ratio and 95% ci0.73 (0.55, 0.96)p=0.024meta-analysis of survival with platelet gp iib/iiia antagonists for pcifavors controlfavors treatmentyearcapture1997restore1998epistent19991997cadillac-p2002admiral2001rapport1998petronio2002cadillac-s20020.010.1110100studyeraser1999isar-22000epicri

7、sk ratio and 95% cirr 0.79z=-2.272p=0.023epilog1999esprit2002overalltamburino2002n126521411603209910463004838910362254012792206415,651107karvouni e, et al. j am coll cardiol. 2003;41:26-32.intravenous gp iib/iiia receptor antagonists reduce mortality after pciisar-reactp=nsp=nsp=nsp=ns0.3%3.8%4.0%0.

8、6%0.3%3.7%4.0%0.9%0%5%10%deathmideath/miurg revacplaceboabciximabisar-react low-risk pci- 30 days outcomep=0.06p=0.03p=0.34p=0.641.6%10.5%11.5%1.2%1.1%8.1%8.6%1.0%0%5%10%deathmideath/miurg revacplaceboabciximabisar-react 2 high-risk pci- 30 days outcomein patients undergoing elective pci treated wit

9、h ufh and , it is reasonable to administer a gp iib/iiia inhibitor (abciximab, double-bolus eptifibatide, or high-bolus dose tirofiban).i iia iib iii in patients undergoing elective pci it might be reasonable to administer a gp iib/iiia inhibitor (abciximab, double-bolus eptifibatide, or high-bolus

10、dose tirofiban).i iia iib iiiiib/iiia受体拮抗剂在nste- acs患者中的应用stemiclinical findingekgserum markersrisk assessmentnon-cardiacchest painstableanginauansteminegativepositivest-t wave changesst elevationlowprobabilitymedium-high riskthrombolysisprimary pciaspirin + gp iib/iiia inhibitor clopidogrel + hepar

11、in/lmwh + anti-ischemic rxearly invasive rxdischargenegativediagnostic rule out mi/acs pathwaystemi negativeatypical painlow riskaspirin, heparin/low-molecular-weight heparin (lmwh) + clopidogrelanti-ischemic rx early conservative therapyongoing paindm=diabetes mellitus.cannon, braunwald. heart dise

12、ase. 2001.rest pain, post-mi, dm, prior aspirinexertional painthe spectrum of acsprism (3232)7.1%5.8% 0.800.60-1.06prism-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% 1.060.72-1.55pursuit (10,948)15.7%14.2% 0.890.79-1.00 paragon-b (5225)11.4%10.6% 0.920.77-

13、1.09gusto-iv (7800)8.0% (24h)8.2% 1.020.83-1.24 (48h)9.1% 1.150.94-1.39odds ratioplaceboiv gp iib/iiia95% ci*with/without heparin.without heparin.(l)=low dose.(h)=high-dose.adapted from: boersma e, et al. lancet. 2002;359:189-198.placebo bettergp iib/iiia betterodds ratio (95% ci)0.01.02.0study (n)g

14、p iib/iiia inhibitors in ua/nstemi: death or mi at 30 daysbenefit of gp iib/iiia blockade in acsmeta-analysis of six major trials (31,402 patients)all patients with acspatients with acs, undergoing pci within 5 daysboersma e et al. lancet 2001.1anti gpiib/iiia betterrelative 30-da

15、y risk of death and miiib/iiia acs meta-analysisiib/iiia acs 30-day death or mi early pciiib/iiia acs 30-day death or mi no early pciacuity: ischemic composite endpointearly-acs studyacc/aha 2012年ua/nstemi指南n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)nbivalirudin作为术中抗凝时可不用gpb/a受体拮抗剂n

16、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)n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)n阿昔单抗不应当应用于不准备行pci的患者（/a）n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) in ua/nstemi patients (e.g., elevated troponin level) and , it is useful to administer a gp iib/iiia inhibitor (abc

17、iximab, double-bolus eptifibatide, or high-bolus dose tirofiban) in patients treated with ufh.i iia iib iii in ua/nstemi patients (e.g., elevated troponin level) treated with ufh and adequately pretreated with clopidogrel, it is reasonable to administer a gp iib/iiia inhibitor (abciximab, double-bol

18、us eptifibatide, or high-bolus dose tirofiban).i iia iib iiiiib/iiia受体拮抗剂在ami患者中的应用早期研究iib/iii受体拮抗剂对ami直接pci的作用relative risk of death+mi+tvrabciximab vs control00.511.530 days6 months rapport, brener et al.(ptca)circulation 1999isar-2neumann et al. (stent)j am coll cardiol 2000admiralmontalescot et

19、al(stent) n engl j med, 2001cadillacstone et al.(stent/ptca) n engl j med, 2002aceantoniucci et al.(stent) j am coll cardiol 2003pooledabciximab for pci in ami00.511.5gp iib/iiia受体拮抗剂在受体拮抗剂在ami患者患者pci中的应用中的应用33: study designellis et al. n eng j med. 2008;358:2205-2217. pre-pci treatment with -dose l

20、ytic plus abciximab, pre-pci abciximab alone, and abciximab at time of pcisuspected acute mi (st change or lbbb) within 6 h of symptom onsetlow risk (3mm) 1 hour after pcikey clinical secondarycombined occurrence of death, recurrent mi, urgent tvr or thrombotic bailout at 30 days follow-upsafety (ma

21、jor bleeding)death at 1 year follow-up40vant hof et al. lancet 2008;372:537-46residual st deviation after pcip=0.003 3.6 4.6mm4.8 6.3mmon-time 2: results event-free survivalsurvival free from death, recurrent myocardial infarction, urgent target vessel revascularisation, or blinded bail-out use of s

22、tudy drugtime (days)302520151050event free survival90%80%70%60%50%40%tirofibanplacebop value 0,012on-time 2: resultsvant hof et al. lancet 2008;372:537-46.event-free survival at 30 daysndeath at 1 yr. in primary pci group: tirofiban (2.4%) vs. placebo (5.5%) (p=0.007, rr=0.44 (0.24-0.81)in patients

23、undergoing primary pci treated with ufh, it is reasonable to administer a gp iib/iiia inhibitor (abciximab, double-bolus eptifibatide, or high-bolus dose tirofiban), whether or not pretreated with clopidogrel.i iia iib iiii iia iib iii44it is reasonable to start treatment with glycoprotein iib/iiia

24、receptor antagonists at the time of primary pci (with or without stenting) in selected patients with stemi:abciximabtirofiban and eptifibatideuse of glycoprotein iib/iiia receptor antagonists in stemii i iiiaiiaiia iibiibiib iiiiiiiiii i iiiaiiaiia iibiibiib iiiiiiiiii i iiiaiiaiia iibiibiib iiiiiii

25、iiiiaiiaiia iibiibiib iiiiiiiiii i iiiaiiaiia iibiibiib iiiiiiiiii i iiiaiiaiia iibiibiib iiiiiiiiii i iiiaiiaiia iibiibiib iiiiiiiiiiiaiiaiia iibiibiib iiiiiiiiimodified recommendation45use of glycoprotein iib/iiia receptor antagonists in stemii i iiiaiiaiia iibiibiib iiiiiiiiii i iiiaiiaiia iibiib

26、iib iiiiiiiiii i iiiaiiaiia iibiibiib iiiiiiiiiiiaiiaiia iibiibiib iiiiiiiiithe usefulness of glycoprotein iib/iiia receptor antagonists (as part of a preparatory pharmacologic strategy for patients with stemi prior to arrival in the prior to arrival in the cardiac catheterization laboratorycardiac

27、catheterization laboratory for angiography and pci) is uncertain. modified recommendation: study designmehilli et al. circ. 2009;119:1933-1940treatment: pre-pci treatment with clopidogrel (600 mg), followed by abciximab vs. placeboinclusion: suspected acute mi (st change or lbbb) within 24 h of symp

28、tom onsetexclusion:high risk for bleeding, prior stroke,shock,trauma, thrombolytics, hypertension,relevant hematologic deviations1effects of abciximabmehilli et al. circ. 2009;119:1933-1940no significant difference in infarct size or major bleedingp= 0.47p= 0.40routine precatheterization laboratory

29、(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.i iia iib iiino benefit冠脉内注射iib/iiia受体拮抗剂friedman et al. am j cardiol 2011;108:1244-1251timi-3-flow after pci0.56911.76favors iv route

30、favors ic routerisk ratiodeibeleguiversendominguez-rodriguezwuthieleyangbellandioverall (i-squared=20.1%; p=0.27)1.07 (0.89, 1.28) 8.661.03 (0.97, 1.10) 34.901.10 (0.98, 1.24) 17.431.29 (0.95, 1.76) 3.271.22 (1.01, 1.48) 7.960.98 (0.86, 1.12) 14.251.27 (0.98, 1.64) 4.601.15 (0.96, 1.37) 8.921.08 (1.

31、02, 1.15) 100.00studyrr (95% ci) weightbleedingguiversendominguez-rodriguezwuthieleyangoverall (i-squared=0.0%; p=0.562)risk ratio0.122 18.22reduced risk by ic routereduced risk by iv route1.11 (0.68, 1.81) 35.690.69 (0.41, 1.17) 38.010.67 (0.12, 3.65) 3.690.76 (0.31, 1.91) 11.820.80 (0.22, 2.87) 6.

32、512.17 (0.63, 7.51) 4.050.92 (0.68, 1.24) 100.00rr (95% ci) weightstudyfriedman et al. am j cardiol 2011;108:1244-1251short-term mortalityguiversenwuthieleyangbellandioverall (i-squared=0.0%; p=0.772)studyrr (95% ci) weight0.69 (0.22, 2.16) 28.340.20 (0.04, 0.93) 37.420.49 (0.05, 5.27) 8.050.67 (0.1

33、1, 3.68) 11.970.19 (0.01, 3.71) 10.331.05 (0.07, 15.70) 3.900.45 (0.23, 0.90) 100.000.0936 1107risk rationavarese et al. platelets 2011;1-8cicero 2010crystal ami 2010dominguez-rodriguez 2009easy-mi 2010iversen 2011thiele 2008500022271252553185777100932632325521707733.7%7.4%44.8%14.1%0.690.29 (0.01;7

34、.59)not estimablenot estimable0.20 (0.04;0.92)0.66 (0.11;4.05)study or subgroupintracoronary abciximabintravenous abciximabodds ratioeventstotaleventstotal weight m-h, fixed 95%total (95%)total events636610100.0%0.43 (0.20;0.94)920heterogeneity: chi2 =1.88, df=3 (p=0.60);i2=0%test for overall effect

35、: z=2.11 (p=0.03)30-day mortalitym-h, fixed 95%odds ratiofavors icfavors iv0.01 0.1 1 10 100favors icfavors ivcicero 2010easy-mi 2010iversen 2011thiele 200830-day myocardial infarction305027153185774082263521707727.5%55.5%17.0%study or subgroupintracoronary abciximabintravenous abciximabodds ratioev

36、entstotaleventstotal weight m-h, fixed 95%total (95%)total events636562 100.0%0.54 (0.23;1.28)814heterogeneity: chi2 =0.58, df=2 (p=0.75);i2=0%test for overall effect: z=1.39 (p=0.17)m-h, fixed 95%odds ratio0.01 0.1 1 10 1000.72 (0.16;3.27)not estimable0.56 (0.18;1.75)0.19 (0.01;4.13)586cicero 2010e

37、asy-mi 2010iversen 2011thiele 200830-day target vessel revascularization90702715318577100162263521707727.5%55.5%17.0%study or subgroupintracoronary abciximabintravenous abciximabodds ratioeventstotaleventstotal weight m-h, fixed 95%total (95%)total events636562100.0%0.53 (0.29;0.99)1628heterogeneity

38、: chi2 =2.58, df=2 (p=0.36);i2=2%test for overall effect: z=2.00 (p=0.05)m-h, fixed 95%odds ratiofavors icfavors iv0.01 0.1 1 10 1000.87 (0.35;2.17)not estimable0.38 (0.15;0.94)0.19 (0.01;4.13)586piccolo, thiele et al. submittedindividual patient-based meta-analysis iii5 randomized trials (n = 1198)

39、; individual patient-based meta-analysisic abciximab n = 611iv abciximab n = 587death + reinfarctioniv abciximab 587 572 568 552 559 555ic abciximab 611 603 597 595 594 5940061218243002468hr 0.54 (95% ci 0.30; 0.95); p=0.03days after randomizationprobability of deathor reinfarction (%)patients at ri

40、sk:ic abciximabiv abciximabpiccolo, thiele et al. submittedindividual patient-based meta-analysis iii5 randomized trials (n = 1198); individual patient-based meta-analysisic abciximab n = 611iv abciximab n = 587mortalityiv abciximab 587 577 574 572 570 567ic abciximab 611 606 603 602 602 60200612182

41、43002468hr 0.43 (95% ci 0.20; 0.94); p=0.03days after randomizationprobability of death (%)patients at risk:ic abciximabiv abciximab in patients undergoing primary pci with abciximab, it may be reasonable to administer intracoronary abciximab.i iia iib iii不同iib/iiia受体拮抗剂的比较57use of glycoprotein iib/iiia receptor antagonists in stemigrum et al. small molecule gp iib/iiia inhibitors primary pci.circ cardiovas intervent. 2009;2:230-2236. smgpiabcix