血栓形成机制与抗栓药物展望.

1、血栓形成机制与抗栓药物展望血栓形成机制与抗栓药物展望 首都医科大学附属北京同仁医院首都医科大学附属北京同仁医院史旭波史旭波FibrinPlateletsRBCs血栓的构成血栓的构成 RBCs, red blood cells.血栓是机体维护血管壁结构完整的一种防护性反应正常内皮细胞有强烈抑血作用正常内皮细胞有强烈抑血作用内皮损伤诱发血栓形成示意图内皮损伤诱发血栓形成示意图Pollack CV, et al. The Journal of Emergency Medicine. 2008(34)4: 417-42835 X 109典型血管的剪切率典型血管的剪切率血管类型血管类型剪切率剪切率 (

2、(s s-1-1) )静脉静脉20 -20020 -200大动脉大动脉300 - 800300 - 800小动脉小动脉500 - 1,600500 - 1,600狭窄冠状动脉狭窄冠状动脉800 - 10,000800 - 10,000动脉血栓形成动脉血栓形成高流速、高流速、高度依赖血小板高度依赖血小板动动脉脉 预防和治疗动脉系统血栓预防和治疗动脉系统血栓 抗血小板抗血小板+ +抗凝治疗抗凝治疗静脉血栓形成静脉血栓形成 低流速低流速 对血小板依赖程度很低对血小板依赖程度很低静静脉脉预防和治疗静脉系统血栓预防和治疗静脉系统血栓抗凝治疗为主抗凝治疗为主 动脉系统血栓形成动脉系统血栓形成高度依赖血小板

3、高度依赖血小板抗血小板抗血小板+抗凝治疗抗凝治疗 心腔内血栓形成心腔内血栓形成对血小板依赖介入动静脉之间对血小板依赖介入动静脉之间高危患者抗凝治疗为主，低危患者抗血小板治疗高危患者抗凝治疗为主，低危患者抗血小板治疗 静脉系统血栓形成静脉系统血栓形成对血小板依赖较低对血小板依赖较低抗凝治疗为主抗凝治疗为主Brass, L. F. Chest 2003;124:18-25S血小板的作用血小板的作用 抗血小板药物抗血小板药物 血栓素血栓素 A A2 2 抑制剂抑制剂阿司匹林阿司匹林 ( (ASA)ASA) ADP-ADP-受体拮抗剂受体拮抗剂氯吡格雷氯吡格雷 噻氯匹啶噻氯匹啶 糖蛋白糖蛋白 ( (G

4、P) IIb/IIIa GP) IIb/IIIa 阻滞剂阻滞剂abciximab, eptifibatide, tirofibanabciximab, eptifibatide, tirofiban阿司匹林的抗血小板作用阿司匹林的抗血小板作用胶原胶原 5-羟色氨羟色氨 ADP凝血酶凝血酶 TXA2刺激传刺激传递系统递系统肾上腺素肾上腺素 cAMPCa+释放反应释放反应GP IIbGP IIIaCa+GP IIIaGP IIb纤维蛋白原纤维蛋白原聚集聚集AspirinAntithrombotic Trialists Collaboration. BMJ. 2002;324:71-86.00.51

5、.01.52.05001500 mg34 19160325 mg19 2675150 mg12 3275 mg 3 13Any aspirin65 23Antiplatelet BetterAntiplatelet WorseAspirin Dose # Trials OR* (%)*Odds reduction. Treatment effect P 0.0001.Odds Ratio氯吡格雷作用机制氯吡格雷作用机制 胶原胶原 5-羟色氨羟色氨 ADP凝血酶凝血酶 TXA2刺激传刺激传递系统递系统肾上腺素肾上腺素 cAMPCa+释放反应释放反应GP IIbGP IIIaCa+GP IIIaG

6、P IIb纤维蛋白原纤维蛋白原聚集聚集X药药 代代 动动 力力 学学 肠道吸收，肝脏代谢，肠道吸收，肝脏代谢，2.2% 2.4% 尿中排泄尿中排泄 半减期为半减期为 7.2 7.5 小时小时 75mg/d, 4 5天天; 300mg/d, 4-6h; 600mg/d, 2h 停药后作用可延续到停药后作用可延续到 7 10到稳定天，洗脱期长到稳定天，洗脱期长 （氯吡格雷）血小板血小板 GPb / a 拮抗剂作用机制拮抗剂作用机制 胶原胶原 5-羟色氨羟色氨 ADP凝血酶凝血酶 TXA2刺激传刺激传递系统递系统肾上腺素肾上腺素 cAMPCa+释放反应释放反应GP IIbGP IIIaCa+GP I

7、IIaGP IIb纤维蛋白原纤维蛋白原聚集聚集X西洛他唑西洛他唑 潘生丁作用机制潘生丁作用机制 胶原胶原 5-羟色氨羟色氨 ADP凝血酶凝血酶 TXA2刺激传刺激传递系统递系统肾上腺素肾上腺素 cAMPCa+释放反应释放反应GP IIbGP IIIaCa+GP IIIaGP IIb纤维蛋白原纤维蛋白原聚集聚集X奥扎格雷钠的抗血小板作用奥扎格雷钠的抗血小板作用胶原胶原 5-羟色氨羟色氨 ADP凝血酶凝血酶 TXA2刺激传刺激传递系统递系统肾上腺素肾上腺素 cAMPCa+释放反应释放反应GP IIbGP IIIaCa+GP IIIaGP IIb纤维蛋白原纤维蛋白原聚集聚集奥扎格雷钠安步乐克作用机制

8、安步乐克作用机制 胶原胶原 5-羟色氨羟色氨 ADP凝血酶凝血酶 TXA2刺激传刺激传递系统递系统肾上腺素肾上腺素 cAMPCa+释放反应释放反应GP IIbGP IIIaCa+GP IIIaGP IIb纤维蛋白原纤维蛋白原聚集聚集XNew Antiplatelet Agents P 2 Y 12 antagonists Prasugrel Ticagrelor Cangrelor Thrombin receptor antagonists SCH 530348 E 5555Prasugrel 抑制 P 2 Y 12 药代动力学 迅速起效（ 2 h） 不可逆的结合 与氯吡格雷激活的代谢途径不同

9、 比氯吡格雷更有效的抑制 ADP 引起的血小板激活TicagrelorPrimary endpoint: CV death, MI or stroke005101560120180240300360Days after randomizationK-M estimated rate (% per year)HR: 0.84 (95% CI = 0.750.94), p=0.00259.0210.65ClopidogrelTicagrelorNo. at riskClopidogrelTicagrelor6,6766,7326,1296,2366,0346,1345,8814,8154,8893

10、,6803,7352,9653,0485,972K-M = Kaplan-Meier; HR = hazard ratio; CI = confidence interval TicagrelorClopidogrelNSNSNS0K-M estimated rate (% per year)PLATO major bleeding12345678910121113TIMI major bleeding11.511.68.08.02.93.2GUSTO severe bleeding*4.74.12.82.31.91.7Non-CABG and CABG-related major bleed

11、ingNon-CABGCABG*Preliminary from eCRF凝血酶受体拮抗剂凝血酶受体拮抗剂 TRA SCH 530348 第一种此类药 口服，长效 阻断血小板 PAR 1 受体 不干扰纤维蛋白形成 对出血时间或 PT / aPTT 无影响抗血小板药物 血栓素 A2 抑制剂阿司匹林 (ASA) ADP-受体拮抗剂氯吡格雷 噻氯匹啶 糖蛋白 (GP) IIb/IIIa 阻滞剂abciximab, eptifibatide, tirofibanOralParenteral 磺达肝癸钠磺达肝癸钠Idrabiotaparinux利伐沙班利伐沙班艾吡沙班艾吡沙班Dabigatran口服制剂

12、口服制剂静脉制剂静脉制剂XaIIaTF/VIIaXIXIXaVIIIaVaIIFibrinFibrinogenATAdapted from Weitz & Bates, J Thromb Haemost 2005XimelagatranDabigatran口服制剂口服制剂静脉制剂静脉制剂Adapted from Weitz & Bates, J Thromb Haemost 2005BivalirudinXaIIaTF/VIIaXIXIXaVIIIaVaIIFibrinFibrinogenDavie EW. THE JOURNAL OF BIOLOGICAL CHEMISTRY

13、.2003;278;51:5081950832Monroe DM, et al. Arterioscler Thromb Vasc Biol. 2006;26:41-48XimelagatranDabigatran口服制剂口服制剂静脉制剂静脉制剂Adapted from Weitz & Bates, J Thromb Haemost 2005BivalirudinXaIIaTF/VIIaXIXIXaVIIIaVaIIFibrinFibrinogenDabigatranCompanyBoehringer IngelheimBrand namePradaxa Mechanism of ac

14、tionDirect anti-IIa (Anti-Thrombin)ProdrugYesHalf-Life14-17 hours (Stangier publi)Anti-doteNo. Not NovoSeven, but off labelFormulationHard capsule, 75 and 110 mgRenal excretion80%Biliary excretionLowDrug InteractionInteraction with ASA in higher doses. No interaction with cytochrome P450.NSAID exclu

15、ded in clinical trials. P-glycoprotein inhibitors and enhancers. Quinidne CI. Amiodarone: dose reductionFood InteractionDelayed absorption with foodBioavailabilityLow 6%Spinal anesthesiaContra-indication, while indwelling catheter in place. Start 2 hours after removalSide effectsVomiting 17% (Lancet

16、). Venous thrombosis.IndicationName (Phase)ComparatorDoseEndpointsCompletionResultsACSREDEEM (Ph II)PlaceboDabigatran 4 doses bidcomposite of major and clinically relevant minor bleeding events during six months of treatment Q3 2009AHA 2009 o r A C C 2010SPAFRELYwarfarinDab 110mg, 150mg bidIncidence

17、 of stroke and systemic embolismEnd Q1 2009ESC 2009Dabigatran临床研究临床研究 已完成的骨科领域研究：已完成的骨科领域研究： 一项与美国克赛常用剂量一项与美国克赛常用剂量(30mg BD) 的对照研究失败；的对照研究失败； 两项与克赛对照的研究证实为两项与克赛对照的研究证实为“非劣效性非劣效性” 剂量用法复杂剂量用法复杂 几项进展中的临床研究（心血管领域）几项进展中的临床研究（心血管领域）, 包括包括:RE-LY: A Non-inferiority TrialAtrial fibrillation 1 Risk FactorAbse

18、nce of contra-indications951 centers in 44 countriesRWarfarinadjusted (INR 2.0-3.0)N=6000Dabigatran Etexilate 110 mg BIDN=6000Dabigatran Etexilate 150 mg BIDN=6000Blinded Event Adjudication.OpenBlindedStroke or Systemic Embolism0.500.751.001.251.50Dabigatran 110 vs. WarfarinDabigatran 150 vs. Warfar

19、inSuperiorityp-value 0.340.001HR (95% CI)Warfarin betterDabigatran betterBleedingD 110mgD 150mgwarfarinD 110mg vs. WarfarinD 150mg vs. WarfarinTotal14.6%16.4%18.2%0.780.74-0.830.0010.910.86-0.970.002Major 2.7 %3.1 %3.4 %0.800.69-0.930.0030.930.81-1.070.31Life-Threatening major1.2 %1.5 %1.8 %0.680.55

20、-0.830.0010.810.66-0.990.04Gastro-intestinalMajor1.1 %1.5 %1.0 %1.100.86-1.410.431.501.19-1.890.001磺达肝癸钠磺达肝癸钠Idrabiotaparinux利伐沙班利伐沙班艾吡沙班艾吡沙班口服制剂口服制剂静脉制剂静脉制剂XaIIaTF/VIIaXIXIXaVIIIaVaIIFibrinFibrinogenATAdapted from Weitz & Bates, J Thromb Haemost 2005Fondaparinus 磺达肝癸钠磺达肝癸钠IdrabiotaparinuxRivaro

21、xaban 利伐沙班利伐沙班Apixaban 艾吡沙班艾吡沙班Features利伐沙班利伐沙班艾吡沙班艾吡沙班Molecular weight436460TargetFactor XaFactor XaProdrugNoNoCYP450 metabolismMinimalMinimalTime to peak drug level (h)33Half-life (h)99- 14Biliary excretion (%)3575Renal excretion (%)6525直接直接 Xa 抑制剂抑制剂 (口服口服)Knee replacementRivaroxaban 10 mg o.d.fo

22、r 12 2 daysvs.Enoxaparin 30 mg b.i.d.for 12 2 days N = 3148 Rivaroxaban 10 mg o.d. administered 68 hours post surgery compared with enoxaparin Same efficacy and safety outcomes Same independent, blinded adjudication committeesHip replacementRivaroxaban 10 mg o.d.for 35 4 daysvs.Enoxaparin 40 mg o.d.

23、for 35 4 daysN = 4541Hip replacementRivaroxaban 10 mg o.d.for 35 4 days vs.Enoxaparin 40 mg o.d.for 12 2 days followed by placeboN = 2509Knee replacementRivaroxaban 10 mg o.d.for 12 2 days vs.Enoxaparin 40 mg o.d.for 12 2 days N = 2531Data from Eriksson BI et al. N Engl J Med 2008;358:276575; Kakkar

24、 AK et al. Lancet 2008;372:319; Lassen MR et al. N Engl J Med 2008;358:277686; Turpie AGG et al. Pathophysiol Haemost Thromb 2007/2008;36:A14. - VTE Treatnent- Atrial Fibrillation- ACS treatmentIndicationName (Phase)ComparatorDoseEndpointsTimeline/ResultsCommentsACSAPPRAISE Ph1PlaceboApixaban 2.5mg

25、bid, 10mg odBleeding - ISTHLinear dose response with higher bleeding /better efficacy with 10mg qd2.5mg bid to be tested in phase IIIIndicationTrialComparatorDoseEndpointsCompletionResultsSPAF ARISTOTLE 15000 ptsAVERROES 5600 ptsWarfarin 2mg INR 2.5ASA 81-324 mg qd upto 36 moApi 2.5mg, 5mg bidconfir

26、med stroke or systemic embolismQ3 2010Q4 2010ACSAPPRAISE-2 /10800 ptsplaceboApi 5mg bid Time to first occurrence of cardiovascular death, MI, strokeQ4 2011Q1 2012已完成的临床试验已完成的临床试验进行中的临床试验进行中的临床试验FeaturesLMWH 磺达磺达肝癸钠肝癸钠IdrabiotaparinuxRoute of administrationSubcutaneous or intravenousSubcutaneousSubcu

27、taneousTargetFactor Xa and IIaFactor XaFactor XaBioavailability (%)90100100Half-life (h)417120Plasma protein-bindingLowNoneNoneRenal excretionYesYesYesRisk of heparin- induced thrombocytopeniaYesNoNoSafe in pregnancyYesUnknownUnknownNeutralized by protamine sulfatePartialNoyes间接间接 CASSIOPEAProduct ProfileAnticoag