从2007年NSTE-ACS指南看 抗血小板治疗的进展

Pathophysiology of ACS

NSTEMI 有增加的趋势

虽然STEMI的院内死亡率较高 但NSTEMI长期危险与STEMI相当 生存率 NSTEMI STEMI 尽管NSTEMI的院内死亡率低于STEMI， 但远期预后（>1年）不比STEMI好，甚至可能更差 Several reports have shown that over time, the annual incidence of Q-wave infarction per 100,000 inhabitants was gradually declining, and that conversely, the frequency of non-Q wave infarction was increasing, with the rate now higher than for Q-wave MI. In addition, initial mortality in ST elevation MI is higher during the first month of evolution than in non-ST elevation MI. After hospital discharge, the rate of events is greater with non-ST elevation MI, with the result that the death rate at 1 year is equal in both clinical presentations of ACS. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 ACS后的时间（月） Courtesy A Gitt

NSTE-ACS的治疗： 抗缺血药物 抗凝药物 抗血小板药物 阿司匹林 氯吡格雷 糖蛋白IIb/IIIa受体抑制剂 血运重建

阿司匹林显著降低NSTE ACS患者的 死亡或心梗发生率 4个随机研究的Meta分析： 死亡/心梗相对降低 53％ Theroux P, et al. N Engl J Med 1988;319:1105–1111. Theroux P, et al. Circulation 1993;88:2045–2048. Cairns JA, et al. Can J Cardiol 1989;5:239–246. Antithrombotic Trialists Collaboration. BMJ 2002;324:71–86 ECS NSTEACS guideline 2007.

增加ASA剂量不能进一步减少心血管事件发生率 阿司匹林剂量 研究数 OR*(%) Odds Ratio 500-1500 mg 34 19 160-325 mg 19 26 75-150 mg 12 32 <75 mg 3 13 Any aspirin 65 23 The Antithrombotic Trialists’ Collaboration compared data from 65 aspirin trials to examine the effects of aspirin dose on vascular events in high-risk patients (in some trials, the aspirin dose was used in more than one of the comparisons).1 Serious vascular events (the primary measure of outcome) included nonfatal myocardial infarction, nonfatal stroke, death from vascular causes, and death from unknown causes. They found that all doses of aspirin studied reduced the risk of vascular events. The greatest number of trials (34) examined high aspirin doses (500- 1500 mg) and revealed a proportional reduction in vascular events of 19%. Aspirin doses of 160 to 325 mg were associated with a 26% proportional reduction in vascular events, whereas 75 to 150 mg and <75 mg were associated with reductions of 32% and 13%, respectively. 0.5 1.0 1.5 2.0 抗血小板更好 抗血小板更差 * Odds reduction. Treatment effect P<.0001. Antithrombotic Trialists’ Collaboration. BMJ. 2002;324:71-86. References 1 Antithrombotic Trialists’ Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ. 2002;324:71-86.

但严重出血发生率随阿司匹林剂量增加而升高 严重出血发生率% CURE研究结果还显示增加ASA的剂量不会增加治疗效果，但会增加出血的危险。 100mg n=5320 101-199mg n=3109 200mg n=4110 阿司匹林剂量 Peters. Circulation 2003;108:1682

2007年ESC NSTE-ACS指南对阿司匹林的建议 2007年AHA/ACC NSTE-ACS指南对阿司匹林的建议 I IIa IIb III 如无禁忌，所有患者都应服用阿司匹林，起始负荷剂 量160-325 mg (非肠溶) ，长期维持剂量为75–100 mg A 2007年AHA/ACC NSTE-ACS指南对阿司匹林的建议 I IIa IIb III 患者应尽早服用阿司匹林75-162mg/天，如无禁忌，应长期服用 A

氯吡格雷显著降低NSTE-ACS患者的 死亡/心梗/卒中发生率 CURE研究： 12,563 例病人 RRR 20%, p<0.001 0.14 安慰剂 (11.4%) 0.12 0.10 氯吡格雷 (9.3%) 0.08 死亡、心梗和卒中 0.06 根据CURE研究结果，NSTE－ACS的患者需要接受9－12个月的两联抗血小板治疗。 0.04 0.02 0.0 3 6 9 12 随访时间 （月） 所有患者都接受阿司匹林做为标准治疗 NEJM 2001; 345: 494

在采用不同治疗策略的NSTEMI/UA患者中 氯吡格雷治疗的1年终点事件*发生率均明显降低 0.20 0.15 0.10 0.05 0.0 0.20 0.15 0.10 0.05 0.0 药物治疗患者 血运重建 RR: 0.80 (0.69-0.92) Placebo 累积风险 (%) Placebo Clopidogrel Clopidogrel RR: 0.82 (0.69-0.96) 0 100 200 300 0 100 200 300 氯吡格雷在NSTE ACS的证据 Fox et al sought to further explore the benefits of antiplatelet therapy in reducing the risk of cardiac events in patients with acute coronary syndrome and the risks of this therapy in increasing the risk of bleeding by analyzing results from the Clopidogrel in Unstable angina to prevent Recurrent ischemic Events (CURE) trial. The CURE trial randomized 12,562 patients to receive clopidogrel or placebo in addition to aspirin. Primary outcomes were cardiovascular (CV) death, myocardial infarction (MI), or stroke. The benefits of clopidogrel vs placebo were consistent among patients undergoing percutaneous coronary intervention (PCI) [9.6% for clopidogrel, 13.2% for placebo; relative risk (RR), 0.72; 95% confidence interval (CI), 0.57 to 0.90], patients undergoing coronary artery bypass grafting (CABG) surgery (14.5% for clopidogrel, 16.2% for placebo; RR, 0.89; 95% CI, 0.71 to 1.11), and medical therapy only (8.1% for clopidogrel, 10.0% for placebo; RR, 0.80; 95% CI, 0.69 to 0.92; test for interaction among strata, 0.53). Of the 12,562 patients enrolled in the CURE trial, 2,072 underwent CABG. Of these, 1,061 were randomized to placebo and 1,011 to clopidogrel. The time to CABG for those undergoing the procedure during the initial hospitalization (n=1,013) was 12 days (interquartile range, 8 to 19 days) for the group randomized to placebo and 13 days (interquartile range, 8 to 21 days) for the group randomized to clopidogrel. For the patients undergoing the CABG procedure later (n=1,057), time to CABG for the placebo group was 73 days (interquartile range, 36 to 129) and 67.5 days (interquartile range, 38 to 141 days) for those randomized to clopidogrel. The primary outcomes occurred in 16.2% of placebo patients and 14.5% of clopidogrel patients (RR, 0.89; 95% CI, 0.71 to 1.11) undergoing CABG at any time. For those undergoing surgical revascularization during the initial hospitalization period (n=530 for placebo, n=485 for clopidogrel), 16.4% of the placebo patients and 13.4% of the clopidogrel patients experienced a primary outcome (RR, 0.81; 95% CI, 0.59 to 1.12), findings that are consistent with the treatment effect observed in the entire CURE trial (RR, 0.80; 95% CI, 0.72 to 0.90). The number of patients who underwent PCI (1,345 placebo patients and 1,313 clopidogrel patients) was 21.2% of the study population. The primary outcome occurred in 9.6% of clopidogrel patients and in 13.2% of placebo patients (RR, 0.72; 95% CI, 0.57 to 0.90; P=.004). The authors concluded that the relative risk reduction in the primary end point is consistent in those undergoing CABG revascularization, those undergoing PCI, and those who did not undergo revascularization procedures. PCI 0.20 0.15 0.10 0.05 0.0 0.20 0.15 0.10 0.05 0.0 CABG Placebo 累积风险 (%) Placebo Clopidogrel Clopidogrel RR: 0.89 (0.71-1.11) RR: 0.72 (0.57-0.90) 0 100 200 300 0 100 200 300 随访时间 (天) 随访时间 (天) * 主要终点事件:死亡/MI/卒中 Fox et al. Circulation 2004; 110(10):1202-8. Reference: Fox KAA, Mehta SR, Peters R, et al. Benefits and risks of the combination of clopidogrel and aspirin in patients undergoing surgical revascularization for nonST-elevation acute coronary syndrome. The Clopidogrel in Unstable angina to prevent Recurrent ischemic Events (CURE) trial. Circulation. 2004;110:TK-TK.

2007年NSTE ACS指南 对氯吡格雷的推荐进一步加强和明确 尽早使用 对600mg 负荷剂量的推荐 持续用药的时间 特殊情况的建议：如外科手术、停药、与他汀类合用、血小板抑制率的检测等等

* 随机分组后24小时内的CV死亡/MI/卒中/严重缺血事件发生率 氯吡格雷减少严重缺血事件的作用 在24小时内就显现 * 随机分组后24小时内的CV死亡/MI/卒中/严重缺血事件发生率 0.025 事件发生率 0.020 Placebo+ ASA 2.1％ 34% RRR 0.015 RR= 0.66 p =0.003 0.010 有些医生倾向在ACS患者接受冠脉造影检查，明确不需要行CABG术后，在PCI开始前再开始两联抗血小板治疗。 但是，CURE研究的结果显示，患者接受两联抗血小板治疗后，在24小时内既可显示出获益，晚期给药将减少患者的获益程度。 Clopidogrel+ASA 1.4％ 0.005 0.0 2 4 6 8 10 12 14 16 18 20 22 24 随机分组后时间 （小时） Yusuf S. Circulation 2003;107:966

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 10 9 8 7 6 5 4 3 2 1 无波立维预处理 8.3% 7.9% 38.6 % RRR p = 0.05 提前3-6小时给予负荷剂量 5.8% 提前6-24 小时给予负荷剂量 死亡/心梗/UTVR(%) 58.8 % RRR p = 0.0028 Looking at the per protocol population of those patients who underwent a PCI, pretreatment with a 300mg loading dose of 波立维 led to an 18.5% relative reduction in the risk of 死亡, MI, and urgent target vessel revascularization at 28 days that did not achieve statistical significance (95% CI, 14.2 – 41.8, p=0.23).1 The relative risk reduction for the per protocol endpoints (MI, 死亡, TVR or MI, 死亡) also showed similar risk reductions. The results observed in the early phase were consistent with those of other trials in the area: EPISTENT, TARGET, PCI-CURE. In CREDO, good standard of care in the overall study population led to a lower than expected overall event rate in the trial (8.3% actual vs 13.4% planned) which may have contributed to the observed results. The time to PCI in the CREDO trial was much shorter than in previous trials in patients undergoing PCI (mean: 9.8 hours). For example, in the PCI-CURE2 trial, the mean time between randomization and PCI was 10 days. References: Steinhubl SR, Berger PB, Tift Mann III J, et al. JAMA, November 20, 2002 – Vol 288, No 19: 2411 – 2420. Mehta SR et al. Lancet. 2001: 358: 527–33. 提前15-24 小时给予负荷剂量 3.5% 7 14 21 28 随机化后天数 Steinhubl S, et al. JAMA, 2002 288 2411 – 2420, JACC 2006; 47:939-943 UTVR: 紧急目标血管血运重建

高负荷剂量氯吡格雷提供更强的血小板抑制作用 600mg负荷剂量在服药2小时后即达到300mg5小时后的血小板抑制率 并且更迅速抑制血小板聚集 103 名 NSTE ACS患者随机接受300, 600 or 900 mg氯吡格雷治疗 5 mmol/L ADP 50 40 30 20 10 1 2 3 4 5 6 *p<0.05 vs 300 mg 300 mg 600 mg 900 mg 时间 (小时) * 血小板聚集抑制率 (%) 600mg负荷剂量在服药2小时后即达到300mg5小时后的血小板抑制率 Montalescot G et al.ABION study. JACC 2006;48:931-8

Meta分析结果显示 高负荷剂量的临床效果更好 评价终点：1个月内的心血管死亡/MI 高负荷剂量 标准负荷剂量 OR 研究项目 目前还无大规模的临床研究评价高负荷剂量的临床效果（CURRENT研究在进行中），对已发表的数个小规模设计氯吡格雷负荷剂量的研究进行META分析的结果提示，高负荷剂量的氯吡格雷与标准剂量相比，能降低30天的心血管死亡和MI发生， 高负荷剂量更好 标准负荷剂量更好

2007年ESC NSTE-ACS指南对氯吡格雷的推荐 2007年AHA/ACC NSTE-ACS 指南对氯吡格雷的建议 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 A A B 2007年AHA/ACC NSTE-ACS 指南对氯吡格雷的建议 I IIa IIb III 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 300～600mg，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阿司匹林的基础上 联合使用氯吡格雷（负荷剂量300～600mg，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300～600mg，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 A A B

氯吡格雷+ASA改善NSTE-ACS预后的作用 的近期和远期都存在 每治疗1000例患者可减少12 例事件发生(p=0.002) 每治疗1000例患者增加3例出血 (p=0.10) 发生率 % 急性期 (<30 天) 1 2 3 4 5 6 7 8 死亡/MI/卒中 危及生命的出血 每治疗1000例患者增加 1 例出血(p=0.66) 每治疗1000例患者可减少10例事件发生(p=0.01) 长期 (30 天-1年) 1 2 3 4 5 6 7 8 死亡/MI/卒中 危及生命的出血 氯吡格雷＋阿司匹林 安慰剂＋阿司匹林 CURE研究结果显示不论在治疗早期（<30天）还是长期治疗（30天－12 月），氯吡格雷＋ASA 治疗ACS的临床益处均超过出血的风险。 Yusuf Circulation 2003;107:966 Courtesy G Montalescot

氯吡格雷的临床净获益高于出血的风险 减少的事件数 （心血管死亡/心梗/卒中） 增加的危及生命的出血例数 3 6 9 12 - 5 5 10 15 20 25 预防或增加的事件数（每10000 例) 减少的事件数 （心血管死亡/心梗/卒中） Most of the incremental bene.t of clopidogrel in CURE occurred within the .rst 1 to 3 months, but favorable results were observed over the entire trial period, which averaged 9 months, and for up to 1 year undertaken by experienced surgeons at acceptable incremental bleeding risk (135). Figure 3. Primary efficacy (events prevented) and excess in life-threatening bleeding in clopidogrel group compared with placebo group. Difference between 2 curves is indication of net absolute benefit of clopidogrel. CV indicates cardiovascular. 增加的危及生命的出血例数 随访时间（月） * 氯吡格雷每治疗1000例 Yusuf Circulation 2003;107:966

CURE试验中停止服用试验药物（退出研究）的患者分析 停用氯吡格雷后原有的临床获益逐渐消失 安慰剂 CURE研究中，对中途撤回知情同意退出试验的患者（不包括因不良反应退出研究的患者）进行随访，两组中该部分患者均近600例，平均治疗时间（退出试验的时间）为3个月左右。 结果显示，虽然两组间差异在3个月时最明显，但停药后氯吡格雷组患者逐渐丧失其从最初两联抗血小板治疗中的获益，在12个月时两组患者的事件发生率几乎相等。 因此，我们有理由认为，NSTE ACS的患者需要长期接受两联抗血小板治疗。但到底应治疗多长期，目前还没有研究可以回答这个问题。 1st Co-Primary Outcome: Subgroup of Patients Who Permanently Discontinued Study Drug Due to “Withdrawal of Consent” (N=596 Clop, 561 Plac): ITT Analysis of First Primary Event in Study 氯吡格雷 安慰剂 - 氯吡格雷组的患者平均用药时间为3个月 Bertrand. In press.

CABG 术前5天停用氯吡格雷，可有效避免大出血 安慰剂 氯吡格雷 RR p CABG前5天内停药或继续用药 N = 565 N = 519 大出血/危及生命出血 5.7% 8.5% 1.50 0.07 CABG前5天以上停药 N = 454 N = 456 5.3% 4.4% 0.83 0.53

2007年ESC NSTE-ACS 指南对中止抗血小板治疗的建议 I IIa IIb III 不主张症状初现后12个月内暂停双重抗血小板治疗 （阿司匹林＋氯吡格雷） 由于大的出血、或威胁生命的出血、或因为需要行 某些即使小出血也可能引发严重后果的外科手术（ 如颅脑或脊柱手术），应暂时停药。CABG应提前5 天停药。 除非有临床指针，不主张在治疗期内长期、或提前 撤除阿司匹林、氯吡格雷或两者治疗。如欲停药、 应对再发缺血事件的风险（取决于基线的风险、是 否植入/ 植入何种支架、以及计划停药与初发事件 和/或血运重建之间的时间窗）作慎重考量 C C C

CREDO研究证实：BMS后使用氯吡格雷 1 年可 明显减少严重缺血事件的发生 15 已接受良好治疗的病人 11.5% 27% RRR p = 0.02 10 8.5% 心梗，中风或死亡(%) 5 The CREDO results demonstrate the significant benefits of long-term (1 year) administration of 波立维 in patients undergoing PCI.1 For the entire study population, long-term 波立维 treatment was associated with a 27% reduction in the relative risk of the combined endpoint of death, MI, and stroke at 1 year. This result was statistically significant (95% CI, 3.9 – 44.4, p=0.02). Reference: Steinhubl SR, Berger PB, Tift Mann III J, et al. JAMA, November 20, 2002 – Vol 288, No 19: 2411 – 2420. 受益随着时间增加 安慰剂*# 氯吡格雷* 3 6 9 12 随机化后的月数 * On top of standard therapy including ASA # All patients received 氯吡格雷 post PCI up to day 28 Steinhubl S, et al. JAMA, November 20, 2002 – Vol 288, No 19: 2411 – 2420

早期停用氯吡格雷后DES的死亡/MI增加 BASKET-LATE 死亡 / MI (%) 0.07 A 0.06 DES 0.05 0.04 0.03 BMS 0.02 0.01 P=0.06 0.00 2 4 6 8 10 12 14 16 18 随访 (月) TVR (%) 0.14 B BMS 0.12 0.10 0.08 0.06 0.04 DES 0.02 P=0.02 0.00 2 4 6 8 10 12 14 16 18 随访 (月) * TVR＝因再狭窄的靶血管血运重建 J. Am. Coll. Cardiol., 2006, 48(1), CS7-CS8

过早停用氯吡格雷是 DES迟发性血栓的重要危险因素 迟发性支架内血栓 风险比 P 提前终止抗血小板治疗 57.13 <0.001 分叉病变 8.11 0.001 LVEF每降低 10% 1.06 0.03 而血栓事件发生后的死亡率可高达45％。 迟发性血栓的绝对发生率虽然很低，但一旦发生对病人的危害巨大 Table 3. Independent Predictors of Stent Thrombosis Incidence, Predictors, and Outcome of Thrombosis After Successful Implantation of Drug-Eluting Stents Iakovou, Ioannis MD; Schmidt, Thomas MD; Bonizzoni, Erminio PhD; Ge, Lei MD; Sangiorgi, Giuseppe M. MD; Stankovic, Goran MD; Airoldi, Flavio MD; Chieffo, Alaide MD; Montorfano, Matteo MD; Carlino, Mauro MD; Michev, Iassen MD; Corvaja, Nicola MD; Briguori, Carlo MD; Gerckens, Ulrich MD; Grube, Eberhard MD; Colombo, Antonio MD JAMA 2005; 293(17):2126–2130 Abstract: Context: Traditionally, stent thrombosis has been regarded as a complication of percutaneous coronary interventions during the first 30 postprocedural days. However, delayed endothelialization associated with the implantation of drug-eluting stents may extend the risk of thrombosis beyond 30 days. Data are limited regarding the risks and the impact of this phenomenon outside clinical trials. Objective: To evaluate the incidence, predictors, and clinical outcome of stent thrombosis after implantation of sirolimus-eluting and paclitaxel-eluting stents in routine clinical practice. Design, Setting, and Patients: Prospective observational cohort study conducted at 1 academic hospital and 2 community hospitals in Germany and Italy. A total of 2229 consecutive patients underwent successful implantation of sirolimus-eluting (1062 patients, 1996 lesions, 2272 stents) or paclitaxel-eluting (1167 patients, 1801 lesions, 2223 stents) stents between April 2002 and January 2004. Interventions: Implantation of a drug-eluting stent (sirolimus or paclitaxel). All patients were pretreated with ticlopidine or clopidogrel and aspirin. Aspirin was continued indefinitely and clopidogrel or ticlopidine for at least 3 months after sirolimus-eluting and for at least 6 months after paclitaxel-eluting stent implantation. Main Outcome Measures: Subacute thrombosis (from procedure end through 30 days), late thrombosis (>30 days), and cumulative stent thrombosis. Results: At 9-month follow-up, 29 patients (1.3%) had stent thrombosis (9 [0.8%] with sirolimus and 20 [1.7%] with paclitaxel; P = .09). Fourteen patients had subacute thrombosis (0.6%) and 15 patients had late thrombosis (0.7%). Among these 29 patients, 13 died (case fatality rate, 45%). Independent predictors of stent thrombosis were premature antiplatelet therapy discontinuation (hazard ratio [HR], 89.78; 95% CI, 29.90–269.60; P<.001), renal failure (HR, 6.49; 95% CI, 2.60–16.15; P<.001), bifurcation lesions (HR, 6.42; 95% CI, 2.93–14.07; P<.001), diabetes (HR, 3.71; 95% CI, 1.74–7.89; P = .001), and a lower ejection fraction (HR, 1.09; 95% CI, 1.05–1.36; P<.001 for each 10% decrease). Conclusions: The cumulative incidence of stent thrombosis 9 months after successful drug-eluting stent implantation in consecutive “real-world” patients was substantially higher than the rate reported in clinical trials. Premature antiplatelet therapy discontinuation, renal failure, bifurcation lesions, diabetes, and low ejection fraction were identified as predictors of thrombotic events. 支架内血栓的死亡率为 45% Iakovou. JAMA 2005;293:2126

DES + 氯吡格雷>12个月(n=252) : DES + 氯吡格雷<12个月(n=276) 药物支架后应用氯吡格雷的长期临床效益 DES + 氯吡格雷>12个月(n=252) : DES + 氯吡格雷<12个月(n=276) 死亡率 药物洗脱支架 裸金属支架 使用氯吡格雷 未使用氯吡格雷 使用氯吡格雷 未使用氯吡格雷 3.5% 累计事件率 -3.5% P=0.004 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). 0% 月 Eisenstein, JAMA. 2007;297:(doi:10.1001/jama.297.2.joc60179)

2007年AHA/ACC NSTE-ACS 指南对支架患者的建议 I IIa IIb III B 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。

GRACE研究 氯吡格雷与他汀联合使用使临床益处增加 院外死亡率（％） GRACE 登记研究 four groups on the basis of medications prescribed at discharge: group I (aspirin alone); group II (aspirin + clopidogrel); group III (aspirin + statin); group IV (aspirin + clopidogrel + statin). 时间 （月） 阿司匹林＋氯吡格雷 阿司匹林＋氯吡格雷＋他汀 EHJ 2005; 26:1063–1069

CHARISMA结果 缺乏氯吡格雷与他汀相互作用的证据 Saw et al. JACC 2007;50:291–5

2007年ESC NSTE-ACS指南对氯吡格雷于他汀联用的推荐 I IIa IIb III B 氯吡格雷可以同所有的他汀类降脂药合用

2007年NSTE ACS指南 对氯吡格雷的推荐进一步加强和明确 所有患者都应尽早给予双联抗血小板治疗 所有患者都应给氯吡格雷负荷剂量，如需迅速抑制血小板可给600mg 负荷剂量 如果无出血风险，最好持续用氯吡格雷用1年。特别是DES患者应至少12个月。 如CABG等外科手术前停药>5天。 氯吡格雷可以和任何他汀类药物合用

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