PCl圍手術(shù)期藥物治療兒科學(xué)

1、1會計學(xué)PCl圍手術(shù)期藥物治療兒科學(xué)圍手術(shù)期藥物治療兒科學(xué)蛋白蛋白C/蛋白蛋白S凝血與抗凝系統(tǒng)凝血與抗凝系統(tǒng)內(nèi)源性凝血系統(tǒng)內(nèi)源性凝血系統(tǒng)外源性凝血系統(tǒng)外源性凝血系統(tǒng)Va纖維蛋白VIIIaXIIaXIaIXaVIIa-IIIXaIIa纖維蛋白原組織因子組織因子途徑抑制物途徑抑制物抗凝血酶抗凝血酶啟動階段啟動階段少量凝血酶少量凝血酶IXIIIXIXaIIaVIIIXVIIaTFVVaXXa損傷部位損傷部位成纖維細(xì)胞成纖維細(xì)胞vWF血小板血小板活化活化血小板激活通道血小板激活通道血小板肝素與凝血因子的作用肝素與凝血因子的作用l由于與血漿蛋白的結(jié)合和通過由于與血漿蛋白的結(jié)合和通過網(wǎng)狀內(nèi)皮系統(tǒng)來清除，生

2、物利網(wǎng)狀內(nèi)皮系統(tǒng)來清除，生物利用度差用度差 (除大劑量除大劑量)l不能抑制結(jié)合于血栓的凝血酶不能抑制結(jié)合于血栓的凝血酶l抗凝效果不確定，劑量響應(yīng)差抗凝效果不確定，劑量響應(yīng)差l有天然抑制劑有天然抑制劑 (PF4)l需需 ACT 監(jiān)測監(jiān)測l療效反跳，停藥后缺血事件增療效反跳，停藥后缺血事件增加加l血小板減少癥血小板減少癥Braunwald Atlas. Vol VIII Figure 10-18低分子肝素低分子肝素1長長固定固定高高無需無需低低小小抗抗 Xa:IIa 活性比值活性比值血漿半衰期血漿半衰期清除速率清除速率生物利用度生物利用度ACT 監(jiān)測監(jiān)測對對 PF4 的敏感性的敏感性對血小板抑制作

3、用對血小板抑制作用普通肝素普通肝素=1短短不固定不固定低低需要需要高高大大Antman 19981. Antithrombotic Trialists Collaboration. BMJ 2002; 324: 7186. 2. Fisher LD et al. Am Heart J 2001; 141: 2632.所有試驗所有試驗195144,051251任何阿司匹林劑量任何阿司匹林劑量6459,395231潘生丁潘生丁155,430161抵克立得抵克立得425,430271氯吡格雷氯吡格雷*119,185302有數(shù)據(jù)的試驗數(shù)有數(shù)據(jù)的試驗數(shù)病人數(shù)病人數(shù)%比值下降比值下降(心肌梗死、腦卒中或者

4、血心肌梗死、腦卒中或者血管性死亡管性死亡)治療治療*氯吡格雷的 % 比值下降是使用Antithrombotic Trialists Collaboration和 CAPRIE試驗估計氯吡格雷比較安慰劑的效果的資料統(tǒng)計分析的結(jié)果“阿斯匹林失敗阿斯匹林失敗”N=20N=20N=21N=30N=21N=11N=22N=20N=20N=19N=24N=19N=17N=20第第7天天第第28天天氯吡格雷氯吡格雷安慰劑安慰劑10 mg25 mg50 mg75 mg100 mg 250 mg b.i.d.-20-100102030405060平均平均I抑制抑制 % 噻氯匹定噻氯匹定8.7

5、相對危險度降低相對危險度降低1. CAPRIE Steering Committee. Lancet 1996; 348: 132939. 2. Jarvis B, Simpson K. Drugs 2000; 60: 34777. 事件率事件率(心肌梗死、缺血性腦卒中或者血管性死亡心肌梗死、缺血性腦卒中或者血管性死亡)(n = 8,854)(n = 4,496)15.2%20.0%23.8%14.1%17.2%20.4%05%10%15%20%25%30%所有所有 CAPRIE病人病人1(n = 19,185)先前任何缺血先前任何缺血事件病史事件病史2先前嚴(yán)重急性事件病史先前嚴(yán)重急性事件病史

6、 (心肌梗死或腦卒中心肌梗死或腦卒中)2事件率事件率 (%)阿司匹林氯吡格雷11*28*34* 每1000個病人每年比阿司匹林多預(yù)防的事件數(shù) 隨訪3年累積發(fā)生事件病人的比例 3年事件率1. CAPRIE Steering Committee. Lancet 1996; 348: 132939. 2. Harker LA et al. Drug Safety 1999; 21: 32535.*排除排除ASA不能耐受的病人不能耐受的病人病情嚴(yán)重或提前停藥病情嚴(yán)重或提前停藥不良事件不良事件腹瀉腹瀉 (嚴(yán)重嚴(yán)重)1胃炎胃炎2胃腸道潰瘍胃腸道潰瘍2胃腸道出血胃腸道出血(嚴(yán)重嚴(yán)重)1顱內(nèi)出血顱內(nèi)出血1皮疹

7、皮疹 (嚴(yán)重嚴(yán)重)1中性粒細(xì)胞減少中性粒細(xì)胞減少2ASA(n = 9,586)波立維波立維(n = 9,599) p 值值 NS 0.0010.001 0.05NS 0.05NS0.11%1.32%1.15% 0.71%0.49%0.10%0.17%0.23%0.75%0.68% 0.49%0.35%0.26%0.10%27% RRRp = 0.02阿司匹林波立維阿司匹林安慰劑心梗，中風(fēng)或死亡(%)隨機(jī)化后的月數(shù)0369128.5%11.5% All patients received 波立維 post PCI up to day 28051015Steinhubl S, et al. JAM

8、A, November 20, 2002 Vol 288, No 19: 2411 2420 早期 隨著時間增加 治療良好的病人 20% RRRp=0.00009n=12,562獲益在用藥數(shù)小時內(nèi)即可出獲益在用藥數(shù)小時內(nèi)即可出現(xiàn)，并在現(xiàn)，并在12月內(nèi)持續(xù)增加月內(nèi)持續(xù)增加0123456789101112隨訪月數(shù)隨訪月數(shù)復(fù)發(fā)缺血事件的病例復(fù)發(fā)缺血事件的病例% *01014124862標(biāo)準(zhǔn)治療標(biāo)準(zhǔn)治療波立維波立維 + 標(biāo)準(zhǔn)治療標(biāo)準(zhǔn)治療The CURE Investigators. N Eng J Med August 2001Data on file包括阿斯匹林包括阿斯匹林*心血管死亡，心肌梗死，或

9、腦卒中心血管死亡，心肌梗死，或腦卒中P=0.003P=0.0001P=0.03(2 + units)%P=NSP=NSP=NSThe CURE Investigators. Lancet August 2001051015202530隨訪天數(shù)隨訪天數(shù)0.00.020.040.060.08累積事件率累積事件率標(biāo)準(zhǔn)治療標(biāo)準(zhǔn)治療 波立維波立維 + 標(biāo)準(zhǔn)治療標(biāo)準(zhǔn)治療包括阿司匹林6.4%4.5%30 天心血管死亡、心肌梗死、或緊急血運(yùn)重建（%）30% RRRp=0.03N=2658COX (環(huán)氧化酶)ADP (二磷酸腺苷)TXA2 (血栓素 A2)氯吡格雷氯吡格雷ASACOXADPADPCGPllb/l

10、lla(纖維蛋白原受體纖維蛋白原受體)膠原、凝血酶膠原、凝血酶TXA2激活激活TXA21. Schafer AI. Am J Med 1996; 101: 199209.阿司匹林阿司匹林1. Herbert JM et al. Thromb Haemost 1998; 80: 51218.-100-80-60-40-20005101520253035404550時間時間 (分鐘分鐘)血流血流 (降低降低%)氯吡格雷+ ASA (10 mg/kg +10 mg/kg)氯吡格雷 (10 mg/kg)ASA (10 mg/kg)安慰劑實驗?zāi)Ｐ蛯嶒災(zāi)Ｐ?. Makkar RR et al. Eur H

11、eart J 1998; 19: 153846.對照 (未灌注的)血栓重量 20 mg阿司匹林 10 mg/kg IV血栓重量 18 mg氯吡格雷 5 mg/kg IV血栓重量 8 mg氯吡格雷 5 mg/kg IV 加阿司匹林 10 mg/kg IV，血栓重量 1 mg支架模型支架模型RR=risk reduction.The PRISM-PLUS Study Investigators. N Engl J Med. 1998;338:1488-1497.RR=66%P=0.012 Days7 DaysRR=43%P=0.006RR=30%P=0.0330 Days4.91

12、1.98.7Patients (%)051015Heparin (n=797)Tirofiban + Heparin (n=773)PTCA=percutanueous transluminal coronary angioplasty.The PRISM-PLUS Study Investigators. N Engl J Med. 1998;338:1488-1497.2 414212870.120.080.040.00Heparin onlyRR=44%475 Patients Undergoing PTCA0.0300.0250.0200.0150.0100.0050.00063001

13、2 18 2436 42 48Heparin onlyTirofiban + HeparinRR=66%All 1570 Patients EvaluatedHoursDaysMean Duration of Study Drug Infusion: 71.3+20 hoursProbability of Death or MITirofiban + HeparinTnI=troponin I. Januzzi JL, et al. Am J Cardiol. 2000;86:713-717.Heparin (n=52)Tirofiban + Heparin (n=53)TnI (ng/mL)

14、Baseline LevelsPeak Levels1.6P=NSP=0.01706121801020304050Heparin(n=622)LargeTirofiban + Heparin(n=608)PossibleSmallModeratePossibleSmallModerateOverallOdds Ratio: 0.77P=0.02217.1%24.1%LargeRecent OcclusionRecent OcclusionZhao X-Q, et al. Circulation. 1999;100:1609-1615.Cumulative (%)TIMI=T

15、hrombolysis in Myocardial Infarction.Zhao X-Q, et al. Circulation. 1999;100:1609-1615.0510152025Cumulative (%)MinimalPerfusion(TIMI 1)Tirofiban + Heparin(n=570)Heparin(n=580)TotalOcclusion(TIMI 0)PartialPerfusion(TIMI 2)TotalOcclusion(TIMI 0)PartialPerfusion(TIMI 2)OverallOdds Ratio:0.65P=0.00218.1%

16、25.5%PlaceboIIb/IIIa+24 hours+48 hours+72 hours6%4%2%0%+24 hours+48 hours+72 hoursPURSUITN=9461Heparin vsEptifibatide/HeparinPRISM-PLUSN=1570Heparin vsTirofiban/HeparinP=0.0033.2%4.4%3.8%P=0.0161.8%Boersma E, et al. Circulation. 1999;100:2045-2048.Reversible GP IIb/IIIa in ACS:Death and MI Prior to

17、Catheterization6%4%2%0%Death/MIPRISM-PLUSPURSUIT16.7%15.6%14.5%11.6%0%5%10%15%20%PCI 72 hr (n=1228)No early PCI(n=8233)Heparin 31%6% 10.2%10.1%7.8%5.9%0%5%10%15%PCI 72 hr (n=287) No early PCI(n=1283)Heparin Tirofiban + Heparin42% 23% Boersma E, et al. Circulation. 1999;100:2045-2048.Eptifibatide + H

18、eparinDeath/MI at 30 DaysDeath/MI at 30 Days3.9%8.0%35%8.2%3.4%33%4.3%9.1%36%0%10%20%30%40%DeathDeath, MIDeath, MI, RevascularizationPlaceboAbciximab, 24 hourAbciximab, 48 hourP=NSP=NSP=NSSimoons ML. GUSTO IV-ACS Investigators. Lancet. 2001;357:1915-1924. 0123456Time (months)048121620Patients(%)OR 0

19、.7895% CI (0.62 to 0.97)P=0.02519.4%15.9%Cannon C, et al. N Engl J Med. 2001;344:1879-1887.Conservative + tirofibanEarly Intervention + tirofibanCooling OffEarly Intervention0 02 24 46 68 8101012121414Death/Nonfatal MI within 30 Days (%)11.6%5.9%Neumann FJ, et al. JAMA. 2003;290:1593-1599.Absolute R

20、eduction in 30-day Death or MI with Eptifibatide vs Placebo (%)(n=2522)(n=2041)(n=3803)(n=1105)1.7% 0%2.3% Time from Onset of SymptomsBhatt D, Topol E. JAMA. 2000;284:1549-1558. 0.00.51.01.52.02.53.0 24 hours 1.7% 2.3% 2.8%4F Coronary AngioscopeIntracoronary UltrasoundCommon in Patients with Diabete

21、sSchoenhagen P, et al. Arterioscler Thromb Vasc Biol. 2003;23:1895-1900.Asakura M, et al. J Am Coll Cardiol. 2001;37:1284-1288.EPIC. N Engl J Med. 1994;330:956-961.EPILOG. N Engl J Med. 1997;336:1589-1596.Patients (%)EPIC151050CAPTUREEPILOGEPISTENTEPICCAPTUREEPILOGEPISTENTLow-doseHeparinAbciximab +

22、StentLow-doseHeparinAbciximab + StentAny Major BleedNon-CABG Major Bleed14.04.12.01.50.8Internal Data, Centrocor.EPISTENT. Lancet. 1998;352:87-92.* TIMI Criteria: Either an intracranial hemorrhage or a decrease in hemoglobin 5 g/dL. EventHeparin + GP BivalirudinP-value IIb/IIIa Inhibitor (

23、n=2994) (n=3008) Major bleeding*123 (4.1%)71 (2.4%)0.001Minor bleeding 772 (25.7%)400 (13.4%)0.001Lincoff AM, et al. JAMA. 2003;289:853-863.* Major bleeding was defined as intracranial, intraocular, or retroperitoneal hemorrhage, clinically overt blood loss resulting in a decrease in hemoglobin of more than 3 g/dL, any decrease in hemoglobin of more than 4 g/dL, or transfusion of 2 or more units of packed red blood cells or whole blood. Ferguson J, et al. Am Heart J. 1998;135:S77-S89.Internal Data, Centrocor.Patients (%)EPIC3210CAPTUREEPILOGEPISTENT0.01.60.01.60.7Inci