从指南到临床实践 ——看ACS的抗栓治疗 高润霖 院士 2007年3月29日 北京

CRUSADE研究结果 与临床试验比较实际的ACS早期死亡率更高 院内死亡率 4.5% 7天死亡率 1.9% 1.8% 1.5% ACS患者发生心血管事件的风险 PURSUIT1 (n = 9,461) PRISM-PLUS2 (n = 1,915) SYNERGY3 (n = 9,975) CRUSADE (n = 165,498) 1.The PURSUIT Trial Investigators. N Engl J Med 1998 2.The PRISM-PLUS Study Investigators. N Engl J Med 1998 3. The Synergy Study JAMA 2004 CRUSADE cumulative data through 12/31/2005

ACS患者6个月死亡率－ ACS患者需要更强化的院内和出院后治疗 10% 8% 6% 6个月死亡率 4% 2% 0% 30 60 90 GUSTO-IIb研究结果 8.9% ST段压低 8% 6.8% ST段抬高 6% 6个月死亡率 4% 3.4% T波倒置 ACS患者发生心血管事件的高风险 Patients who present with ST segment depression have at least as great a six-month risk of mortality as those who present with ST-segment-elevation ACS, emphasizing the importance of aggressive in-hospital and post-discharge therapy. 2% 0% 30 60 90 120 150 180 从随机分组开始的天数 Savonitto S. JAMA. 1999 24;281(8):707-13

Toneja AK. Eur Heart J 2004;25:20:2013-18 ACS的长期风险 UA/NSTEMI 的累积年死亡率 UA/NSTEMI 4年内的死亡原因 10.2 14.4 19.1 22.6 1 2 3 4 年份 25 20 10 15 5 % 死亡率 16 再发心梗 其他心血管疾病 肿瘤 非心血管疾病 15 50 19 ACS患者发生心血管事件的长期风险 70% 的死亡属于心血管疾病 Toneja AK. Eur Heart J 2004;25:20:2013-18

抗血小板治疗对各心脑血管患者亚组均有降低心血管事件的作用 * 包括心肌梗死（MI）脑血管意外（CVA），血管性死亡 抗血栓协作组荟萃分析* 抗血小板治疗对各心脑血管患者亚组均有降低心血管事件的作用 21.4 抗血小板 对照 20 17.8 17 14.2 13.5 13.2 心血管事件* % 10.4 10.2 10.7 9.1 10 8.2 8 P<0.0001 P<0.0001 P<0.0001 P<0.0001 P<0.0001 P<0.0001 抗血小板治疗的证据 既往MI 急性MI 既往CVA/TIA 急性CVA 其他高风险 全部 * 涵盖了至97年9月的所有临床研究（n=135,000, 287项随机对照试验） * 包括心肌梗死（MI）脑血管意外（CVA），血管性死亡 BMJ 2002;324:71-86

CURE研究结果 氯吡格雷75mg用于非ST段抬高ACS的早期和长期疗效 0-30 天 31 天至 12个月 氯吡格雷75mg 100 1.00 氯吡格雷75mg 氯吡格雷75mg 0.98 0.98 0.96 0.96 无事件患者比例 % 安慰剂 安慰剂 0.94 0.94 0.92 0.92 RR： 0.79 (0.87-0.92) P=0.003 RR： 0.82 (0.75-0.95) P=0.003 氯吡格雷75mg在NSTE ACS的证据 0.90 0.90 1 2 3 4 1 4 6 8 10 12 无风险 氯吡格雷75mg 6259 5145 6070 6020 5990 5981 5481 4742 4004 3180 2418 安慰剂 6303 5158 6048 5993 5965 5954 5390 4639 3929 3159 2388 周 月 The CURE Trial Investigators. N Engl J Med 2001; 345: 494–502.

在采用不同治疗策略的NSTEMI/UA患者中 氯吡格雷75mg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75mg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.

CLARITY研究结果 在包括溶栓和ASA标准治疗的基础上 氯吡格雷75mg可使STEMI患者30天临床事件*的风险相对降低20% 15 标准治疗 20%* p=0.03 10 标准治疗+氯吡格雷75mg 终点事件发生率 (%) 5 氯吡格雷75mg在STEMI 的证据 At 30 days, clopidogrel had a significant effect on reducing clinical endpoints1 Clopidogrel reduced the odds of cardiovascular death, recurrent MI or recurrent ischemia leading to urgent revascularization by 20%: 0.80 (95% CI [0.65–0.97]; p=0.03)1 Reference 1. Sabatine MS et al. New Engl J Med 2005; In press. 5 10 15 20 25 30 入组时间 (天) * 心血管事件/MI/再发缺血性事件导致紧急血运重建 Sabatine et al. N Engl J Med 2005;352:1179-1189 1. Sabatine MS et al. New Engl J Med 2005; 352 (available at www.nejm.org)

2007年ESC非ST段抬高ACS指南 急性期/长期抗血小板治疗 A A B B C C C I IIa IIb III 如无禁忌，所有患者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 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，否则氯吡格 雷应维持使用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 如需行CABG，手术应在停用氯吡格雷5天后进行 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） 不主张长期或永久停用阿司匹林和（或）氯吡格雷，除非 有临床停药指征。 A A B B C C C Guidelines for the diagnosis and treatment of non-ST-segment elevation acute coronary syndromes. The European Society of Cardiology 2007. European Heart Journal doi:10.1093/eurheartj/ehm161

ACC/AHA处理UA/NESTEMI的指南 确诊ACS伴插管和PCI, 或高危(IIa) 可能有ACS 低危ACS 阿司匹林 阿司匹林 + SC LMWH* 或 IV 肝素 阿司匹林 + IV 肝素/LMWH* IV 血小板 GP IIb/IIIa 抑制剂 氯吡格雷75mg 1 IIa类: 依诺肝素优于 IV 肝素.§ ACC/AHA Braunwald E, 等. 可以在如下地址下载: http://www.acc.org/clinical/guidelines/unstable/unstable.pdf. 2004年12月9日. 氯吡格雷75mg *无肾衰时使用依诺肝素，除非计划在24小时内行CABG

临床实践与指南的差距

ACS患者急性期药物使用情况 在最初的24小时内，无禁忌症的患者中的比例 临床实践与指南的差距 CRUSADE DATA: January 1, 2005 – December 31, 2005 (n=34,408)

ACS患者出院时的氯吡格雷75mg处方 97 73 氯吡格雷75mg使用% 53 34 100 80 60 40 20 合计 药物治疗的患者 临床实践与指南的差距 非侵入性治疗和CABG治疗的患者，出院时氯吡格雷75mg的处方均很低。 合计 药物治疗的患者 PCI患者 CABG患者 CRUSADE DATA: Quarter 4, 2004-Quarter 3, 2005 (n=35,897) Arch Intern Med 2006;166:806-811

ACS患者出院时药物治疗 在医院间存在很大差别 临床实践与指南的差距 Hospitals that ranked in the top quartile for adherence to ACC/AHA Guidelines have a consistently higher rate of adherence to recommended discharge therapies than do hospitals in the lowest quartile of adherence. Despite the overall higher rate of adherence among those hospitals in the leading quartile, some therapies such as ACE inhibitors and clopidogrel are still underutilized. Peterson et al, ACC 2004 # LVEF < 40% , * Known hyperlipidemia

老年患者出院时处方率较低 （在无禁忌症的患者中） 比例 年龄（年） 100% 90% 80% 70% 60% 50% 40% 30% 20% 阿司匹林 β-受体阻滞药 降脂药物 ACE 抑制剂 氯吡格雷75mg 50% 40% 临床实践与指南的差距 老年人中差距更大，但老年人是高危人群。 30% 20% 50 60 70 80 90 年龄（年） Alexander KA, J Am coll Cardiol 2005;46:1479-87

Provider awareness does not equal successful implementation 心脑血管患者院外治疗的差距 Provider awareness does not equal successful implementation 95 100 百分比(%) 80 60 40 18 20 临床实践与指南的差距 CHD patient treatment gap: community To assess potential reasons behind the treatment gap, in the Lipid Treatment Assessment in Practice (L-TAP) study practicing physicians that considered themselves to be aggressive in their treatment of lipids were invited to participate. By survey 95% of the physicians reported that they were aware of the NCEP guidelines and 65% reported that they follow the guidelines in almost all patients. Yet in patients with documented CHD being cared for by these physicians, only 18% were treated to an LDL-C of <100 mg/dl. This study shows that provider awareness of the guidelines alone does not translate into successful treatment implementation. Reference: Pearson TA, Laurora I, Chu H, Kafonek S. The Lipid Treatment Assessment Project (L-TAP): a multicenter survey to evaluate the percentages of dyslipidemic patients receiving lipid-lowering therapy and achieving low-density lipoprotein cholesterol goals. Arch Intern Med 2000;160:459-467. 医生对指南(NCEP)的了解率 病人治疗的达标率 NCEP=National Cholesterol Education Program. Pearson TA et al. Arch Intern Med. 2000;160:459-467.

患者出院后治疗率下降, 二级医院治疗率较三级医院低 我国ACS患者抗血小板和调脂药治疗情况 患者出院后治疗率下降, 二级医院治疗率较三级医院低 入院时或住院期间 出院时 出院后6个月随访时 3级医院 2级医院 98% 96% ASA 氯吡格雷75mg 他汀类 100% 80% 60% 40% 20% 0% 93% 88% 94% 89% 63% 54% 43% 37% 31% 21% 71% 84% 79% 57% 78% 临床实践与指南的差距 数据来自中国ACS登记研究(CPACS) 住院期间较出院后好 三级医院较二级医院好 高润霖等. 中国ACS登记研究CPACS

接受侵入性治疗的患者出院时的用药 Percentage Use Early Cath No Early Cath 100 90 80 70 92.6 90 85.2 82.3 80 76 70.2 70 63.4 64.8 59.5 58.5 60 50.1 47.5 Percentage Use 50 38.9 40 27.8 30 20 10 Aspirin Clopidogrel B-Blocker ACE-l Statin Smoking Cessation Cardiac Rehab Bhatt DL.JAMA 2004;292:2096- 104.

遵循指南对临床结果的影响

接受到100%指南推荐的药物治疗的患者比率 100% Q1 Q4 Q8 Q11 75% 48% 50% 46% 47% 50% 36% 33% 34% 31% 30% 30% 21% 25% 16% 0% Overall 100% Correct Medication Acute 100% Correct Medication Discharge 100% Correct Medication * In patients without contraindications. Mehta et al, AHA 2005.

Hospital Link Between Overall Guidelines Adherence and Mortality 对指南依从性越高，临床结果改善越好 Hospital Link Between Overall Guidelines Adherence and Mortality 7 6.31 Adjusted Unadjusted 5.95 6 5.16 5.06 4.97 5 4.63 4.16 4.15 4 % In-Hosp Mortality 3 2 Every 10%↑in guidelines adherence → 10%↓in mortality （OR=0.90.95% CI: 0.84-0.97） 1 <=25% 25 - 50% 50 - 75% >=75% Hospital Composite Quality Quartiles Peterson et al.JAMA 2006.295.1863- 1912

Multivariate Logistic Regression Analysis * “遵从指南”对降低院内死亡率 Multivariate Logistic Regression Analysis * 0.94 * Adjusted for age. gender. prior MI. prior stroke. renal failure. PHD 1997-1998 0.80 1999-2000 0.55 根据欧洲心脏协会的数据，可以看出随着临床治疗指南的建立和推动，AMI的院内死亡率逐渐下降 2001-2002 0,2 0,4 0,6 0,8 1 1,2 1,4 1,6 1,8 Odds Ratio Lower Hospital Mortality Higher Hospital Mortality as compared to 1994-96 E u r o H e a r t S u r v e y P r o g r a m m e ESC Quality Assurance Programme to Improve Cardiac Care in Europe

影响 STEMI远期死亡率的因素 肾衰 2.64 MI史 1.62 糖尿病 1.50 卒中史 1.26 年龄(每增加1岁) 1.07 女性 0.94 ACEI 0.91 他汀类 0.62 再灌注 0.58 ASA和/或氯吡格雷75mg 0.58 Beta阻滞剂 0.52 0,1 1 10 远期死亡率降低 远期死亡率增高 OR E u r o H e a r t S u r v e y P r o g r a m m e ESC Quality Assurance Programme to Improve Cardiac Care in Europe

合并治疗药物: 抗血小板制剂 / ß 阻滞剂 / ACEI / 他汀类 Months after Discharge “遵从指南”的药物使用对1年死亡率的影响 合并治疗药物: 抗血小板制剂 / ß 阻滞剂 / ACEI / 他汀类 存活出院的STEMI 患者 1 4 Drugs No Drug 2 Drugs 1 Drug 3 Drugs 0,9 0,8 0,7 按指南推荐用1种药（抗血小板制剂 / ß 阻滞剂 / ACEI / 他汀类）比不用以上任何一种的生存率大大提高，用其中2种的患者生存率更高，使用4种药物的患者预后最好 p-log-rank < 0.0001 0,6 2 4 6 8 10 12 Months after Discharge E u r o H e a r t S u r v e y P r o g r a m m e ESC Quality Assurance Programme to Improve Cardiac Care in Europe

氯吡格雷75mg对STEMI出院存活者1年死亡率的影响 – ACOS 注册研究 MACEs @ 1年随访 从德国进行的ACOS注册研究的结果来看，AMI存活出院的患者，接受两联抗血小板治疗能明显提高患者1年的生存率 。 Aims We sought to assess the effect of clopidogrel on clinical events 1 year after discharge in survivors of ST-elevation myocardial infarction (STEMI) in clinical practice. Methods and results We analysed data of consecutive survivors of acute STEMI and either concomitant therapy with aspirin or aspirin plus clopidogrel at discharge, who were prospectively enrolled in the Acute Coronary Syndromes (ACOS) registry between July 2000 and November 2002. A total of 5886 (3795 with and 2091 without clopidogrel) patients were included into this analysis. Patients were divided into three groups according to the initial reperfusion therapy: no reperfusion therapy (n=1445), fibrinolysis (n=1734), or primary PCI (n=2707). The multivariable analysis for 12+2 month mortality after discharge using the propenstiy score with adjustment for baseline characteristics and treatments (age, sex, diabetes mellitus, hypertension, prior MI, hyperlipidaemia, renal insufficiency, cardiogenic shock, heart rate, systolic blood pressure, anterior infarct location, reduced left ventricular function, elective revascularization, beta-blockers, statins, ACE-inhibitors) showed that mortality was significantly lower in the aspirin plus clopidogrel group compared with the aspirin group in the total group and patients with reperfusion therapy [total group odds ratio (OR) 0.48, 95% confidence interval (CI) 0.48–0.61; no reperfusion therapy OR 0.96, 95% CI 0.65–1.45; fibrinolysis OR 0.53, 95% CI 0.32–0.87; primary percutaneous coronary intervention OR 0.38, 95% CI 0.23–0.62]. Conclusion In clinical practice, adjunctive therapy with clopidogrel, in addition to aspirin, in survivors after STEMI is associated with a reduction in 1-year mortality in patients treated with early reperfusion therapy. Zeymer Eur Heart J 2006; 27: 2661-2666

氯吡格雷75mg治疗降低STEMI出院存活者1年死亡率 – ACOS 注册研究 MACEs @ 1 year FU 无论是否接受再灌注治疗，该治疗效果均存在。 虽然这个结论是从注册研究中得到，而并非来自RCT，但仍然能够说明双重抗血小板治疗对ST段抬高ACS的长期效果。 Zeymer Eur Heart J 2006; 27: 2661-2666

搭建科学研究和临床实践的桥梁 Science Practice SYSTEMS Science Practice Guidelines not followed in the real world Outpatient Hospital Community Guidelines followed under ideal circumstances Clinical Trials Community Trials This slide is taken from a presentation made by Dr. Gray Elrodt from Berkshire Medical Center in western Massachusetts. At Berkshire Medical Center, their goal is 100% implementation of the interventions. They view anything less than 100% as a “medical error,” and that patient’s treatment is discussed at mortality and morbidity rounds – just like any other medical mistake. In Massachusetts, the GWTG intervention team estimated that if the interventions were implemented with every patient, every time, they estimated that they would save 782 patients annually from death or another coronary event. We have all the evidence that demonstrates what will impact efficacy, and the development of guidelines. Effectiveness is where it really happens. There is a “big gulf” between the two as demonstrated in this slide – and how do we bridge the gap between efficacy and effectiveness. The alligators represent what can happen – and who, and what, are impacted if we don’t effectively implement the guidelines. Our patients are impacted; third party payors, HCFA and accreditation agencies like JCAHO will be looking at how hospitals improve quality of patient care. This is a process-change. Systems to Translate Science to Practice