临床病例分析 PCI术后支架内血栓形成及预防

ARC 对支架血栓的定义 1 month 1 year 0 天 到1天 急性支架血栓 >1天 到1个月 亚急性支架血栓 INT.CLO.04.02.01 NOT FOR DISTRIBUTION/ FOR INTERNAL USE ONLY ARC 对支架血栓的定义 1 month 1 year 早期血栓 ≤ 1 个月 1个月< 晚期血栓 ≤ 1年 晚晚期血栓 > 1年 急性 ≤1天 亚急性 >1天 - ≤1个月 美国学术研究联合会(ARC,Academic Research Consortium) 0 天 到1天 急性支架血栓 >1天 到1个月 亚急性支架血栓 >1个月 到1年 晚期支架血栓 >1年 晚晚期支架血栓 Cutlip D et al. Circulation. 2007;115:2344-2351 Please note that neither Sanofi-Synthelabo nor Bristol-Myers Squibb recommends the use of clopidogrel in any manner inconsistent with that described in the full prescribing information.

DES与BMS相比支架的内皮化延迟 该图显示，在术后1年BMS的内皮化已达到90％以上，但DMS低于50％ INT.CLO.04.02.01 NOT FOR DISTRIBUTION/ FOR INTERNAL USE ONLY DES与BMS相比支架的内皮化延迟 该图显示，在术后1年BMS的内皮化已达到90％以上，但DMS低于50％ 内皮化延迟可能是DES发生迟发性血栓的原因之一 Please note that neither Sanofi-Synthelabo nor Bristol-Myers Squibb recommends the use of clopidogrel in any manner inconsistent with that described in the full prescribing information.

INT.CLO.04.02.01 NOT FOR DISTRIBUTION/ FOR INTERNAL USE ONLY Please note that neither Sanofi-Synthelabo nor Bristol-Myers Squibb recommends the use of clopidogrel in any manner inconsistent with that described in the full prescribing information.

支架血栓 早期停用抗血小板药物的危险因素 ( 6个月内) INT.CLO.04.02.01 NOT FOR DISTRIBUTION/ FOR INTERNAL USE ONLY 支架血栓 早期停用抗血小板药物的危险因素 ( 6个月内) 总体支架血栓发生率 = 1.3% (P=0.09, N=2229) 发生率 (%) Premature discontinuation of antiplatelet therapy was a major significant univariate predictor of stent thrombosis. The cumulative incidence of thrombosis was 29% (5 of 17 patients), with a hazard ratio of 152 (95% Confidence interval; 52 to 442; P<0.001); clopidogrel was discontinued in one patient. Other significant univariate predictors included prior brachytherapy, renal failure, bifurcation with 2 stents, bifurcation lesions, and diabetes, with respective cumulative thrombosis rates of 8.7%, 6.2%, 3.9%, 3.6%, and 2.5% (P<0.05). Unstable angina, thrombus, and unprotected left main were not significant univariate predictors of thrombosis. UA 血栓 糖尿病 未受保护的左主干 分叉病变 肾衰 Prior brachy Rx 过早停用抗血小板药物 Iakovou et al. JAMA. 2005;293:2126. Iakovou I, Schmidt T, Bonizzoni E, et al. Incidence, predictors, and outcome of thrombosis after successful implantation of drug-eluting stents. JAMA. 2005;293:2126-2130. Please note that neither Sanofi-Synthelabo nor Bristol-Myers Squibb recommends the use of clopidogrel in any manner inconsistent with that described in the full prescribing information.

PREMIER登记研究显示： 早期停用氯吡格雷，患者死亡率增加 INT.CLO.04.02.01 NOT FOR DISTRIBUTION/ FOR INTERNAL USE ONLY PREMIER登记研究显示： 早期停用氯吡格雷，患者死亡率增加 早期停用氯吡格雷与死亡率增加有关 (7.5% vs 0.7%, p<0.0001) 停用氯吡格雷 持续使用氯吡格雷 P<0.01 死亡率 持续用药的人数 停止用药的人数 月 The Science Advisory addressed strategies that have the potential to reduce premature discontinuation of thienopyridine therapy, including:  Before implantation of a stent, the physician should discuss the need for dual antiplatelet therapy. In patients not expected to comply with 12 months of thienopyridine therapy, whether for economic or other reasons, strong consideration should be given to avoiding a DES.  In patients who are undergoing preparation for percutaneous coronary intervention and are likely to require invasive or surgical procedures within the next 12 months, consideration should be given to implantation of a BMS or performance of balloon angioplasty with provisional stent implantation instead of the routine use of a DES.  A greater effort by health care professionals must be made before patient discharge to ensure patients are properly and thoroughly educated about the reasons they are prescribed thienopyridines and the significant risks associated with prematurely discontinuing such therapy. Reference: Grines CL, Bonow RO, Casey DE, et al. Prevention of premature discontinuation of dual antiplatelet therapy in patients with coronary artery stents: A science advisory. J Am Coll Cardiol 2007;49:734-39.   月 Spertus JA et al. Circulation. 2006; 113:2803-2809 Please note that neither Sanofi-Synthelabo nor Bristol-Myers Squibb recommends the use of clopidogrel in any manner inconsistent with that described in the full prescribing information.

INT.CLO.04.02.01 NOT FOR DISTRIBUTION/ FOR INTERNAL USE ONLY 2006年在西班牙巴塞罗那召开的世界心脏病学大会（WCC）和欧洲心脏病学年会（ESC）上，Camenzind报告了一项关于第一代DES—CYPHER和TAXUS安全性的汇总分析，该研究汇总了已发表或公布结果的DES与BMS的随机对照研究，结果表明，在支架置入3年内死亡和MI发生率在CYPHER支架组较BMS对照组有请读但有意义的增加（6.3%vs.3.9%,p=0.03）,而TAXUS与BMS对比差异无统计学意义（2.6%vs2.3%）.Nordmann报告的另一项汇总分析则表明，心脏死亡及支架血栓发生率在DES和BMS组差异无统计学意义，但CYPHER支架组在2年和3年事件非心源性死亡明显高于BMS对照组，而TAXUS支架组未见明显差别。 Please note that neither Sanofi-Synthelabo nor Bristol-Myers Squibb recommends the use of clopidogrel in any manner inconsistent with that described in the full prescribing information.

Basel Stent Cost-effectiveness Trial –Late Thrombotic Events INT.CLO.04.02.01 NOT FOR DISTRIBUTION/ FOR INTERNAL USE ONLY BASKET-LATE Basel Stent Cost-effectiveness Trial –Late Thrombotic Events 药物支架成本-效果研究– 迟发性血栓事件研究 2006年ACC年会上报告 Please note that neither Sanofi-Synthelabo nor Bristol-Myers Squibb recommends the use of clopidogrel in any manner inconsistent with that described in the full prescribing information.

BASKET-LATE研究 n=826 PCI BASKET: 比较BMS与DES 6个月内的临床效果 氯吡格雷＋ASA 停止使用氯吡格雷 n=244 使用BMS者 BASKET BASKET-LATE 6个月 12个月 *: 药物支架包括Cypher®和Taxus®支架两组 Christoph Kaiser, et al. Lancet 2005; 366: 921–29 J. Am. Coll. Cardiol., 2006, 48(1), CS7-CS8

研究背景 BASKET 是一项比较裸支架（BMS）与药物支架（DES）的临床效果和经济学效益的随机对照研究。 826例PCI患者随机分入BMS组(281例), Cypher支架(264例)和 Taxus支架(281例) 所有患者均接受6个月的氯吡格雷治疗，同时应用 ASA、调脂剂. 术后6个月内： DES 组的主要终点事件(心血管死亡/MI/TVR)*的发生率明显低于BMS组（7.2％ vs. 12.1％， p=0.02）

BASKET-LATE : 6个月后停用氯吡格雷（PCI后7-18月） DES组心源性死亡／心梗的发生率明显升高 INT.CLO.04.02.01 BASKET-LATE : 6个月后停用氯吡格雷（PCI后7-18月） DES组心源性死亡／心梗的发生率明显升高 NOT FOR DISTRIBUTION/ FOR INTERNAL USE ONLY MACE:　Major Adverse Cardiac Events 虽然总体而言, 严重的心血管不良事件发生率, 两组无明显差异, 但药物涂层支架组心源性死亡／心梗的发生率明显升高, 而再狭窄率较低. Please note that neither Sanofi-Synthelabo nor Bristol-Myers Squibb recommends the use of clopidogrel in any manner inconsistent with that described in the full prescribing information.

BASKET-LATE : 大多数事件由血栓引起 INT.CLO.04.02.01 NOT FOR DISTRIBUTION/ FOR INTERNAL USE ONLY BASKET-LATE : 大多数事件由血栓引起 并且大多数事件由血拴形成引起, 意味着抗血小板治疗的必要性. 与血栓相关的事件 Please note that neither Sanofi-Synthelabo nor Bristol-Myers Squibb recommends the use of clopidogrel in any manner inconsistent with that described in the full prescribing information.

BASKET-LATE 结论 停用氯吡格雷之后, 在药物支架患者中心梗和猝死的发生率高于裸金属支架 INT.CLO.04.02.01 NOT FOR DISTRIBUTION/ FOR INTERNAL USE ONLY BASKET-LATE 结论 停用氯吡格雷之后, 在药物支架患者中心梗和猝死的发生率高于裸金属支架 在药物支架组中迟发支架内血栓相关事件的发生率是裸支架的 2-3倍. 停用氯吡格雷后一年, 仍有事件发生 在临床实际操作中 ,药物支架患者可以多避免 5 起靶血管血运重建。但如果术后6个月停用氯吡格雷，可能反而增加 3.3 起迟发的死亡或MI。 BASKET-LATE 结果提示：对植入药物支架的患者，仅使用6个月的氯吡格雷是不够的. BASKET-LATE 研究的结果确认了一个结果, 那就是, 如果PCI术6个月即停用氯吡格雷,相对于裸金属支架, DES的植入虽然可以减少再狭窄的发生,但是会在很长一段时间内增加由于迟发性血栓形成而引起的死亡和心梗. Please note that neither Sanofi-Synthelabo nor Bristol-Myers Squibb recommends the use of clopidogrel in any manner inconsistent with that described in the full prescribing information.

INT.CLO.04.02.01 NOT FOR DISTRIBUTION/ FOR INTERNAL USE ONLY Christopher Cannon MD Staff cardiologist Brigham and Women's Hospital Boston, MA 2006年ACC专题讨论会专家相关言论 “ BASKET-LATE 的研究设计提供了一个很好的机会, 让我们斟酌支架植入后6个月停用氯吡格雷的做法.这个研究将延长药物涂层支架植入后氯吡格雷的用药时间. 仅对近100个患者进行了研究, 不能断言, 但这些数据的确令人 瞩目.许多介入医生正在采用 氯吡格雷2年的给药方法以预防与药物涂层支架植入相关的支架内血栓形成.” 在2006年ACC的专题讨论会上,案有关专家就BASKET-LATE 研究发表了评述. Please note that neither Sanofi-Synthelabo nor Bristol-Myers Squibb recommends the use of clopidogrel in any manner inconsistent with that described in the full prescribing information.

Valentin Fuster MD Director, Cardiovascular Institute Mount Sinai Medical Center New York, NY INT.CLO.04.02.01 NOT FOR DISTRIBUTION/ FOR INTERNAL USE ONLY 专家观点 “ 在BASKET LATE研究中,血栓形成相关的心梗和猝死在植入药物涂层支架的患者中的发生率高于裸金属支架；当采用药物涂层支架时,氯吡格雷可能应维持应用18-24个月。任何1年内做过支架的患者都应该使用氯吡格雷＋阿司匹林。既往有脑血管疾病史/复发的患者，可能多个血管床受影响，需要使用联合氯吡格雷＋阿司匹林治疗。” Please note that neither Sanofi-Synthelabo nor Bristol-Myers Squibb recommends the use of clopidogrel in any manner inconsistent with that described in the full prescribing information.

DES后 双重抗血小板治疗多久为最佳？ 至少1年 1年以上 ? 终身 ? INT.CLO.04.02.01 NOT FOR DISTRIBUTION/ FOR INTERNAL USE ONLY DES后 双重抗血小板治疗多久为最佳？ 至少1年 1年以上 ? 终身 ? Please note that neither Sanofi-Synthelabo nor Bristol-Myers Squibb recommends the use of clopidogrel in any manner inconsistent with that described in the full prescribing information.

药物支架后应用氯吡格雷的长期临床效益 DES至少使用6个月氯吡格雷的患者，长期死亡率/MI低于未用者 INT.CLO.04.02.01 NOT FOR DISTRIBUTION/ FOR INTERNAL USE ONLY 药物支架后应用氯吡格雷的长期临床效益 DES至少使用6个月氯吡格雷的患者，长期死亡率/MI低于未用者 最新发表的包括4666例PCI支架病人的随访研究结果显示： 在术后6个月无事件的病人中，至少使用波立维6月的DES患者（637例）24月死亡率明显低于未使用波立维6个月的DES（579例）患者（(2.0% vs 5.3%; difference, −3.3%; 95% CI, −6.3% to −0.3%; P=.03)，死亡和MI的联合终点也低于未用波立维患者 (3.1% vs 7.2%; difference, −4.1%; 95% CI： −7.6% to −0.6%; P=.02)。但在BMS患者的24月预后，使用波立维患者（417例）的预后虽然有较未使用者（1976例）好的趋势，死亡率为3.7% vs 4.5%; 死亡/MI为5.5% vs 6.0%， 但未达到统计学意义 Context Recent studies of drug-eluting intracoronary stents suggest that current antiplatelet regimens may not be sufficient to prevent late stent thrombosis. Objective To assess the association between clopidogrel use and long-term clinical outcomes of patients receiving drug-eluting stents (DES) and bare-metal stents (BMS) for treatment of coronary artery disease. Design, Setting, and Patients An observational study examining consecutive patients receiving intracoronary stents at Duke Heart Center, a tertiary care medical center in Durham, NC, between January 1, 2000, and July 31, 2005, with follow-up contact at 6, 12, and 24 months through September 7, 2006. Study population included 4666 patients undergoing initial percutaneous coronary intervention with BMS (n=3165) or DES (n=1501). Landmark analyses were performed among patients who were eventfree (no death, myocardial infarction [MI], or revascularization) at 6- and 12-month follow-up. At these points, patients were divided into 4 groups based on stent type and self-reported clopidogrel use: DES with clopidogrel, DES without clopidogrel, BMS with clopidogrel, and BMS without clopidogrel. Main Outcome Measures Death, nonfatal MI, and the composite of death or MI at 24-month follow-up. Results Among patients with DES who were event-free at 6 months (637 with and 579 without clopidogrel), clopidogrel use was a significant predictor of lower adjusted rates of death (2.0% with vs 5.3% without; difference, −3.3%; 95% CI, −6.3% to −0.3%; P=.03) and death or MI (3.1% vs 7.2%; difference, −4.1%; 95% CI, −7.6% to −0.6%; P=.02) at 24 months. However, among patients with BMS (417 with and 1976 without clopidogrel), there were no differences in death (3.7% vs 4.5%; difference, −0.7%; 95% CI, −2.9% to 1.4%; P=.50) and death or MI (5.5% vs 6.0%; difference, −0.5%; 95% CI, −3.2% to 2.2%; P=.70). Among patients with DES who were event-free at 12 months (252 with and 276 without clopidogrel), clopidogrel use continued to predict lower rates of death (0% vs 3.5%; difference, −3.5%; 95% CI, −5.9% to −1.1%; P=.004) and death or MI (0% vs 4.5%; difference, −4.5%; 95% CI, −7.1% to −1.9%; P.001) at 24 months. However, among patients with BMS (346 with and 1644 without clopidogrel), there continued to be no differences in death (3.3% vs 2.7%; difference, 0.6%; 95% CI, −1.5% to 2.8%; P=.57) and death or MI (4.7% vs 3.6%; difference, 1.0%; 95% CI, −1.6% to 3.6%; P=.44). Conclusions The extended use of clopidogrel in patients with DES may be associated with a reduced risk for death and death or MI. However, the appropriate duration for clopidogrel administration can only be determined within the context of a largescale randomized clinical trial. JAMA. 2007;297:(doi:10.1001/jama.297.2.joc60179) Eisenstein, JAMA. 2007;297:(doi:10.1001/jama.297.2.joc60179) Please note that neither Sanofi-Synthelabo nor Bristol-Myers Squibb recommends the use of clopidogrel in any manner inconsistent with that described in the full prescribing information.

药物支架后应用氯吡格雷的长期临床效益 DES至少使用12个月氯吡格雷的患者，长期死亡率/MI低于未用者 INT.CLO.04.02.01 NOT FOR DISTRIBUTION/ FOR INTERNAL USE ONLY 药物支架后应用氯吡格雷的长期临床效益 DES至少使用12个月氯吡格雷的患者，长期死亡率/MI低于未用者 在术后12个月无事件的病人中，至少使用波立维12个月的患者（252例）24月死亡率明显低于未使用波立维不足12个月的DES（276例）患者(0% vs 3.5%; difference, −3.5%; 95% CI, −5.9% to −1.1%; P=.004)，死亡和MI的联合终点也低于未用波立维12个月患者 (0% vs 4.5%; difference, −4.5%; 95% CI, −7.1% to −1.9%; P.001)。但在BMS患者中使用和未用波立维至少12个月的患者间，24个月的预后差别 但未达到统计学意义 Among patients with DES who were event-free at 12 months (252 with and 276 without clopidogrel), clopidogrel use continued to predict lower rates of death (0% vs 3.5%; difference, −3.5%; 95% CI, −5.9% to −1.1%; P=.004) and death or MI (0% vs 4.5%; difference, −4.5%; 95% CI, −7.1% to −1.9%; P.001) at 24 months. However, among patients with BMS (346 with and 1644 without clopidogrel), there continued to be no differences in death (3.3% vs 2.7%; difference, 0.6%; 95% CI, −1.5% to 2.8%; P=.57) and death or MI (4.7% vs 3.6%; difference, 1.0%; 95% CI, −1.6% to 3.6%; P=.44). Eisenstein, JAMA. 2007;297:(doi:10.1001/jama.297.2.joc60179) Please note that neither Sanofi-Synthelabo nor Bristol-Myers Squibb recommends the use of clopidogrel in any manner inconsistent with that described in the full prescribing information.

2007年美国心脏协会、美国心脏病学院、心血管血管造影和介入学会、美国外科学院和美国牙科协会以及美国医师协会代表 联合推出的科学建议 这项建议强调，药物洗脱支架植入后双重抗血小板治疗至少持续12个月的重要性 Circulation. 2007;115:813-818

支架植入(特别是DES )后 双重抗血小板治疗至少持续12个月 INT.CLO.04.02.01 NOT FOR DISTRIBUTION/ FOR INTERNAL USE ONLY 支架植入(特别是DES )后 双重抗血小板治疗至少持续12个月 2007年AHA/ACC NSTE-ACS 指南 2007年ACC/AHA重点更新的PCI指南 I IIa IIb III 置入BMS的患者，阿司匹林162～325mg应至少持 续1个月，然后维持剂量75~162mg. 氯吡格雷75mg/ 天应至少使用1个月，最好持续1年。 所有置入DES的PCI患者，氯吡格雷75mg/天应至少 持续使用12个月。 B B 新！ 2007年ACC/AHA重点更新的PCI指南 C 置入DES的患者，可以考虑延长氯吡格雷治疗超过1年 2007年ESC NSTE-ACS指南 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 A Please note that neither Sanofi-Synthelabo nor Bristol-Myers Squibb recommends the use of clopidogrel in any manner inconsistent with that described in the full prescribing information.

CONCLUSION Indication for DES stenting INT.CLO.04.02.01 NOT FOR DISTRIBUTION/ FOR INTERNAL USE ONLY CONCLUSION Long-term efficacy of DES is persistent and the safety of DES is confirmed by meta-analysis based on patients level Late stent thrombosis after DES implantation has emerged as a concerning entity Indication for DES stenting Proper dual antiplatelet therapy, at least 1year For high risk patients or lesions, dual antiplatelet therapy may be longer than 1 year gs Please note that neither Sanofi-Synthelabo nor Bristol-Myers Squibb recommends the use of clopidogrel in any manner inconsistent with that described in the full prescribing information.

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