1、介入术后抗血小板治疗,一抗血小板药物作用机制和阿司匹林抵抗,不同的抗血小板药物作用机制,胶原凝血酶TXA2,阿司匹林,ADP,(纤维蛋白原受体）,氯吡格雷,TXA2,ADP,双嘧达莫,磷酸二酯酶,ADP,Gp IIb/IIIa,激活,COX,盐酸噻氯匹定,ADP = adenosine diphosphate, TXA2 = thromboxane A2, COX = cyclooxygenase.Schafer AI. Am J Med. 1996;101:199209.,Category % ORAcute MIAcute stroke Prior MI Prior stroke/TIAO
2、ther high riskCoronary artery disease(unstable angina, heart failure)Peripheral arterial disease(intermittent claudication) 22 2 %High risk of embolism (atrial fibrillation)Other (diabetes mellitus)All trials,1.0,0.5,0.0,1.5,2.0,Control Better,Antiplatelet Better,Antithrombotic Trialists Collaborati
3、on (ATC): Efficacy of Antiplatelet Therapy on Vascular Events*,*Vascular events = MI, stroke, or vascular death.OR, odds reduction; MI, myocardial infarction; TIA, tranient ischemic attack.Antithrombotic Trialists Collaboration. BMJ. 2002;324:71-86. (with permission),Aspirin Resistance: More Than Ju
4、st a Laboratory Curiosity?,Bhatt DL. J Am CollCardiol.2004;43:1127-1129.,Genetic PolymorphismsCOX-1 GP IIIa receptor Collagen receptor vWF receptor,Cellular FactorsInsufficient suppression of COX-1Overexpression of COX-2 mRNAErythrocyte-induced platelet activation Increased norepinephrine Generation
5、 of 8-iso-PGF2,Clinical FactorsFailure to prescribe Noncompliance Nonabsorption Interaction with ibuprofenInteraction with naproxen,Aspirin Resistance,Aspirin Resistance and the Risk ofCardiovacular Events in High Risk Patients,5529 pts from HOPE study with baseline urine samples,Case (n=488)Pts wit
6、h CV events after randomization,Controls (n=488)Pts without CV events after randomization,Urinary 11-dehydro Thromboxane B2 (ng/mmol creatinine),33.8,1.0,1.3,1.4,1.8,MI, stroke or CV death (P=.01),Odd Ratio,Hypothesis: Incomplete inhibition of thromboxane B2 increases risk of cardiovascular event,Ad
7、apted from Eikelboom JW, et al. Circulation. 2002;105:1650-1655.,VerifyNowASA, ASA/clopidogrel (n=464), 26.9% ASA resistant,Aspirin-resistant,Aspirin-sensitive,n=125,P=0.007,n=339,CV DeathMICVA/TIAHospUA,Cumulative incidence of composite end point(%),Follow-up time (days),ASA Response and Long-Term
8、CV Events,二、氯吡格雷的早期和长期应用什么时间用？用多长时间？,CLARITY 急救亚组研究: 住院前氯吡格雷对比安慰剂(加溶栓治疗),ECG显示ST段恢复的患者 (%),在救护车上给予氯吡格雷的患者伴ST段恢复,Verheugt F et al. J Thromb Thrombolysis 2006;Dec 6 epub,p=0.02,p=0.05,给予负荷剂量后的时间,3,491名 76岁的 STEMI患者，接受溶栓治疗，随机分组接受氯吡格雷或安慰剂，在救护车或入院时给药,STEMI, ST段抬高型心肌梗死; ECG, 心电图,47.2,37,63.2,52.7,90分钟,180
9、分钟,试验,PCI后至30天的心血管死亡或心梗,Sabatine, et al. JAMA. 2005;294:1224-1232,PCI 预处理(300 mg负荷量) 事件,1.0,0.25,2.0,0.5,预处理更优,不预处理更优,OR (95% CI),PCI前3-24小时氯吡格雷 300mg预处理给予负荷剂量的时间越早，受益越大,UTVR: 紧急目标血管血运重建,Steinhubl S, et al. JAMA, 2002 288 2411 2420, JACC 2006; 47:939-943,氯吡格雷预处理对PCI显著有益,4,160名计划行 PCI的患者接受氯吡格雷 300 mg
10、,PCI前氯吡格雷预处理的益处,引自: Szuk T et al. Am Heart J 2007;153:289295.,ARR, 绝地风险降低; TVR, 目标血管血运重建; PCI, 经皮冠脉介入术; CI, 可信区间; MI, 心肌梗死,ARR: 1.97(95% CI, 0.813.13) p=0.02,重大不良事件发生的时间 (天),负荷量预处理,p=0.001,植入支架后给予负荷量,0.05,0.04,0.03,0.02,0.01,0.00,0,5,10,15,20,25,30,死亡、心梗或反复TVR的累积风险,早期使用氯吡格雷表现为使STR增多,血管造影前接受治疗的患者 (%)
11、,Spontaneous STR,p=0.045,p=94,p=0.33,p=0.96,p=0.70,206名因STEMI入院的连续患者，在 PCI前，18%的患者ST段自动恢复 (STR),Jabaren M et al. Am J Cardiol 2006;98:14351438,PCI术前早期使用氯吡格雷,PCI, 经皮冠脉介入术; STEMI, ST段抬高型心肌梗死,氯吡格雷可降低NSTEMI患者1年严重心脑血管不良事件发生率,1年事件率 (%),p0.001,*,*MACCE = 重大心脑血管不良事件 (死亡、非致命性再梗、脑卒中)Zeymer U et al: 私人沟通,20.8,
12、8.5,2,28.1,9.4,5.8,1.9,15.6,0,5,10,15,20,25,30,死亡,再梗,脑卒中,MACCE,阿司匹林,阿司匹林 + 氯吡格雷,NSTEMI后给予氯吡格雷ACOS登记研究,ACOS Registry-Antiplatelet Therapy and 1-Year Mortality in ST-elevation MI,Mortality (%),ASA aloneASA + Clopidogrel,*P12个月(n=252) : DES + 氯吡格雷12个月(n=276),0%,-3.5%P=0.004,3.5%,DES术后氯吡格雷治疗长期疗效 Duke Re
13、gistry*,Endpoint (%),校正的死亡和心梗发生率（2年）,Eisenstein EL, et al. JAMA. 2007; 297(2):159-168,*DES=1501例, BMS=3165例,无论置入何种支架，氯吡格雷应用越久，获益越多,J Am Coll Cardiol 2008;51:22207,未来双联抗血小板治疗更长的疗程？,Dual Antiplatelet Therapy Trial (DAPT): 30个月vs 12个月双重抗血小板在支架患者中的疗效8个厂家出资10亿美元，入组2万例患者,FDA Townhall Meeting, TCT Oct 15,
14、2008,开放DAPT治疗,DAPT研究设计,双盲安慰剂随机对照(RCT):12个月时明确符合入组条件12个月和30个月DAPT组的患者联合主要终点：支架血栓和MACCE；次要终点：严重出血33个月的随访包括3个月“反弹期”BMS组12个月vs30个月同期进行研究参与者自行决定支架类型和噻氯匹啶药物的选择（氯吡格雷或普扎格雷）,DES n=15,245BMS n=5,400,RDES n=12,196BMS n=4,320,30 个月 DAPT 组,观察期,12个月 DAPT 组,观察期,初步阶段：入组,随机化：所有符合入组条件的患者,0 月,6个 月,12个 月,15个 月,30个 月,治疗
15、结束,随访结束,33个 月,有MACCE*或严重出血的患者随访至12 个月，但是不符12个月时入组的入组条件,MACCE*: Major Adverse Cardiac and Cerebrovascular event 严重心脑血管不良反应,FDA Townhall Meeting, TCT Oct 15, 2008,三、氯吡格雷负荷量及相关问题用什么样的剂量及三联抗血小板,Relation of Platelet Inhibition to Periprocedural Necrosis and MACE,DUAL RESISTANCE Study (N=150),% Patients w
16、ith CK-MB Elevation,Myocardiol infarct Platelet Inhibition Major Adverse Cardiac Events,Lev et al. J Am Coll Cardiol.2006.Chen et al. J Am Coll Cardiol.2004.,ASAresistant,ASAsensitive,Clopidogrel resistant,Clopidogrel sensitive,Dualresistant,Dualsensitive,Relation of Platelet Inhibition to Periproce
17、dural Necrosis and MACE,ASPIRIN Myonecrosis Study (n=151),% Patients with CK-MB and troponin I elevation,Magnitude of CK-MB elevation,Myocardiol infarct Platelet Inhibition Major Adverse Cardiac Events,P=0.006,P=0.012,Lev et al. J Am Coll Cardiol.2006.Chen et al. J Am Coll Cardiol.2004.,ISAR-CHOICE(
18、300,600,900mg),von Beckerath et al. Circulation.2005.,ALBION: 氯吡格雷 600 Mg 可以更迅速地抑制血小板聚集,抑制血小板聚集 (%),更高剂量的负荷量伴更快速的抑制,103名非ST段抬高的ACS患者随机分配接受300、600或900 mg 氯吡格雷,0,Montalescot et al. JACC 2006;48:931-8,0,50,10,20,30,40,1,2,3,4,5,6,时间(小时),5 mol/L ADP,*p0.05 与300 mg相比,900 mg,600 mg,300 mg,600 mg,300 mg,*,
19、900 mg,*,ARMYDA-2 Trial,Primary Endpoint: death, MI, or TVR at 30 days,4%,0%,2%,4%,6%,8%,10%,12%,14%,High Dose,Standard Dose,12%,Clopidogrel Loading Dose 600 mgPre-PCI,Clopidogrel Loading Dose 300 mgPre-PCI,255 patients with stable CAD or NSTEMI prior to PCI 13% GP IIb/IIIa inhibitors20% DES,Randomi
20、zed 4-8 hrs Pre-PCI,p=0.041,Circulation 2005;111:2099-2106,600mg的氯吡格雷负荷剂量可降低后续事件的发生率,292名接受300或600 mg 氯吡格雷负荷剂量的支架植入的NSTE ACS连续患者,ST = 支架血栓形成Cuisset et al. J Am Coll Cardiol 2006; 48:133945,无心血管事件生存 (%),100,80,90,95,p0.03 g/L),0,5,10,15,20,25,30,Days After Randomization,Placebo Group (N=1010)Abcixima
21、b Group (N=1012),Troponin 0.03 g/LLog-Rank p = 0.02,Troponin 0.03 g/LLog-Rank p = 0.98,JAMA 2006; 295:1531-38,%,0,2,4,6,8,10,12,Follow-up duration (months),%,No. at risk,Log-Rank, P=0.0192,0,1,2,3,4,5,0.8%,0.1%,Triple group 965 957 953Dual group 965 948 942,The DECREASE RegistryCumulative incidence
22、of stent thrombosis,Dual antiplatelet therapy (n=965)Triple antiplatelet therapy (n=965),0,2,4,6,8,10,12,Follow-up duration (months),%,No. at risk,Log-Rank, P=0.0744,0,1,2,3,4,5,2.6%,1.4%,Triple group 965 955 950Dual group 965 948 940,Cumulative incidence of Death or MI,Dual antiplatelet therapy (n=
23、965)Triple antiplatelet therapy (n=965),研究设计,氯吡格雷高剂量组氯吡格雷 600 mg负荷剂量第1天，接第2-7天150 mg; 第8-30天75 mg,氯吡格雷标准剂量组氯吡格雷 300 mg (+安慰剂) 第1天，接第2-7天75 mg (+安慰剂);第8-30天75 mg,随机分组,随机分组,ASA 低剂量组第1天至少 300 mg;D2 - D30 75100 mg,ASA 高剂量组第1天至少 300 mg;D2- D30 300 mg325 mg,ASA高剂量组第1天至少 300 mg;D2- D30 300 mg325 mg,ASA低剂量组
24、第1天至少 300 mg;D2 - D30 75100 mg,计划早期介入治疗的 UA/NSTEMI患者，即有意在24小时内尽早行PCI的患者,随机分组,PCI: 经皮冠脉介入术UA/NSTEMI: 不稳定心绞痛/非ST段抬高型心梗,CURRENT,四、新型抗血小板药物的研究,JUMBO-TIMI 26 three doses of prasugrel vs clopidogrel in elective or urgent PCI (safety evaluation),Circulation 2005; 11:3366-73,1.7,1.2,%,7.2,9.4,%,Significant
25、non-CABGBleeding at 30daysP=0.77,MACE at 30 daysHR 0.76P=0.26,PRINCIPLE TIMI 44(Planned Elective PCI)PRIMARY EP Acute Phase: IPA 20 uM ADP,Prasugrel 60 mg,P0.0001 for each,IPA (%; 20 mM ADP),Hours,Circulation 2007;116:2923-32,Prasugrel 10 mg,Prasugrel 10 mg,Difference Between Treatments: 14.9 95% CI
26、 10.6 19.3, P0.0001,IPA (%; 20 mM ADP),Days,Circulation 2007;116:2923-32,PRINCIPLE TIMI 44,PRIMARY EP Chronic Phase: IPA 20 uM ADP,Days,Primary Endpoint(%),30,Prasugrel,Clopidogrel,60,90,180,270,360,450,HR 0.77P=0.0001,HR 0.80P=0.0003,12.1(781),9.9(643),HR 0.81(0.73-0.90)P=0.0004NNT=46,ITT=13,608 LT
27、FU=14(0.1%),TRITON TIMI-38ACS (STEMI or UA NSTEMI) & Planned PCI Primary Endpoint : CV Death, MI, Stroke,N Engl J Med 2007; 357: 2001-15,ARD 0.6HR 1.32P =0.03NNH =167,ARD 0.5HR 1.52P =0.01,ARD 0.2P =0.23,ARD 0.3P =0.002,ARD 0%P =0.74,TRITON TIMI-38 Bleeding EventsSafety Cohort (n=13,457),ICH in Pts
28、wPrior Stroke/ TIA(N=518)Clop 0(0) %Pras 6(2.3)%(P=0.02),N Engl J Med 2007; 357: 2001-15,Days,Endpoint(%),30,Prasugrel,Clopidogrel,60,90,180,270,360,450,12.1,9.9,TRITON TIMI 38Balance of Efficacy and Safety,CV Death / MI / Stroke,2.4,1.8,TIMI MajorNonCABG Bleeds,138 eventsHR 0.81(0.73-0.90)P =0.0004
29、NNT =46,35 eventsHR 1.32(1.03-1.68)P =0.03NNH =167,N Engl J Med 2007; 357: 2001-15,Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the benefit: risk balance,SafetySignificantincrease inserious bleeding(32% increase)Avoid in ptswith priorCVA/ TIA,Efficaency1. A
30、 significant reduction in: CV Death/ MI/ Stroke 19% Stent Thrombosis 52% uTVR 34% MI 24%2. An early and sustained benefit3. Across ACS spectrum,Net clinical benefit significant favored Prasugrel,TRITON TIMI-38 Higher IPA to Support PCI,Prasugrel 60 mg LD/ 10mg MD vs Clopidogrel 300 mg LD/ 75 mg LD,N
31、 Engl J Med 2007; 357: 2001-15,2007年ESC NSTE-ACS指南对氯吡格雷的推荐,I IIa IIb III,所有患者立即给予300mg负荷剂量氯吡格雷，再以每天75mg维持剂量治疗。 除非有极高出血风险，否则应维持使用12个月阿司匹林禁忌，改用氯吡格雷考虑进行介入或PCI治疗的患者，可采用600mg负荷剂量以更快达到抑制血小板功能,B,A,A,2007年AHA/ACC NSTE-ACS 指南对氯吡格雷的推荐,B,A,A,如对阿司匹林过敏或胃肠道不耐受，应服用氯吡格雷（负荷剂量300600mg，维持剂量75mg/天） 采用介入治疗的患者在冠脉造影诊断之前应在
32、阿司匹林的基础上联合使用氯吡格雷（负荷剂量300600mg，维持剂量75mg/天）或静脉GP IIb/IIIa受体抑制剂。采用保守治疗患者，应在其入院后尽早联合使用氯吡格雷（负荷剂量300600mg，维持剂量75mg/天）阿司匹林和抗凝治疗，至少持续1个月，最好持续1年,A,I IIa IIb III,2007年国际权威指南推荐对所有ACS患者都应从急性期到长期持续使用氯吡格雷,2009年中国PCI治疗指南阿司匹林推荐,2009年中国PCI治疗指南氯吡格雷PCI术前推荐,2009年中国PCI治疗指南氯吡格雷PCI术后推荐,I IIa IIb III,置入DES的患者，如无高出血风险，PCI术后服用氯吡格雷75 mg/d至少12个月。接受BMS的患者，氯吡格雷75 mg/d至少1个月，最好12个月（如患者出血风险增高，最少应用2周）置入DES的患者，可考虑将氯吡格雷服用时间延至1年以上对阿司匹林禁忌的患者，应在PCI术前至少6h给予300 mg负荷剂量的氯吡格雷和（或）PCI时加用血小板糖蛋白b/a受体拮抗剂,C,B,C,谢谢,
