N Engl J Med 2010;363: CAMS PUMCH Shen zhujun, MD

试验设计背景： - 已往研究大多入组简单病变, 非临床实际情况 - 目前 1 代支架的不足 : 涂层即使生物相容性好，仍有过 敏、炎症、内皮化不全至血栓形成

第二代 DES 背景 Resolute DESXience V DES 支架平台 Driver BMS 钴合金 模块设计 支架丝厚度 91 µm Multi-Link Vision BMS 钴合金 管状雕刻 支架丝厚度 81 µm 药物佐它莫司依维莫司 药物密度 1.6 µg/mm²1.0 µg/mm² 药物完全释放时间 180 天 120 天 多聚物涂层 BioLinx – 亲脂内层 C10 – 亲水外层 C19 – Polyvinyl pyrrolidinone Fluoropolymer （氟聚合物） Polyvinylidene fluoride

purpose of this study Resolute All Comers trial, --- was to compare the Resolute zotarolimus- eluting stent with an everolimus eluting stent in an unrestricted, multicenter, open-label, randomized, controlled, noninferiority trial in patients undergoing percutaneous coronary intervention (PCI) in everyday clinical practice.

N = 2,300 名患者 17 个中心 (100% monitored) 西欧 主要终点 : TLF ( 复合终点包括： Cardiac Death, Target Vessel MI, Clinically driven 12mo) 次要终点 : 30d, 6mo, 2 – 5 yr; angiographic & optical coherence tomography (OCT) 13 mo. 双重抗血小板治疗 : ASA and clopidogrel/ticlid >6 months (per guidelines) 主要终点 : TLF ( 复合终点包括： Cardiac Death, Target Vessel MI, Clinically driven 12mo) 次要终点 : 30d, 6mo, 2 – 5 yr; angiographic & optical coherence tomography (OCT) 13 mo. 双重抗血小板治疗 : ASA and clopidogrel/ticlid >6 months (per guidelines) 30d 6mo 4yr 3yr 2yr 12mo 13mo 5yr 临床 /TLF 造影 /OCT Resolute Stent n  1,150 Resolute Stent n  1,150 Control Xience V Stent n  1,150 Control Xience V Stent n  1,150 Co-PIs: Profs. Serruys, Silber, Windecker Clinical Endpoints 460 (20%) QCA subset 50 (2%) OCT Subset = 主要终点观测点 = 次要终点观测点 试验设计

入组条件 冠脉疾病 Stable angina Silent ischemia ACS 包括 UA, NSTEMI 和 STEMI 病变特征 病变数量 : 无限制 血管数量 : 无限制 病变长度 : 无限制 签署知情同意书 排除条件 有以下过敏反应 阿司匹林，氯吡格雷，肝素，造影剂 钴铬合金，依维莫司，佐它莫司 多聚物涂层 6 个月内有计划搭桥手术 怀孕 参与其他临床试验 入组条件 试验入组条件

17 17 个参与中心 S. Windecker Bern, Switzerland P. Serruys Rotterdam, Netherlands G. Richardt Bad Segeberg, Germany P. Buszman Bielsko Biala/ Kedzierzyn Kozle, Poland H. Kelbaek Copenhagen, Denmark A. van Boven Leeuwarden, Netherlands A. Linke Leipzig, Germany V. Klauss Munich, Germany W. Wijns Aalst, Belgium C. Macaya Madrid, Spain P. Garot Quincy/Massy, France C. DiMario London, UK G. Manoharan Belfast, UK R. Kornowski Petach Tikva, Israel A. Bartorelli Milan, Italy S. Silber Munich, Germany T. Ischinger Munich, Germany

6个月全部入组完成 Apr 08 May 08 JunJulAugSeptOct 08

临床和造影随访 Randomised 1:1 Angiographic F/U 13 mths 62.3% 2292 patients (N L = 3366) Enrolled and randomised Resolute ZES N = 1140 pts Randomised to Angio F/U N = 228 pts Randomised to Angio F/U N = 228 pts Randomised to Angio F/U N = 227 pts Randomised to Angio F/U N = 227 pts Xience V EES N = 1152 pts Xience V EES N = 1152 pts Clinical F/U 12 mths 98.2% Clinical F/U 12 mths 97.7% Angiographic F/U 13 mths 57.3%

病人基线特征 Resolute ZES (N = 1140) Xience V EES (N = 1152)P value Age (yr)64.4 ± ± Men (%) Diabetes mellitus (%) IDDM ACS (%) AMI (within 12 hr) (%) AMI (within 72 hr) (%) Multivessel disease (%) Small vessel (RVD ≤2.75 mm) Long lesion (length >18 mm) Bifurcation/trifurcation (%) Total occlusion (%) In-stent restenosis (%) Complex Patients 1 (%) Complex patient definition: Bifurcation, SVG, ISR, AMI 2 vessels stented, renal insufficiency or failure (creatinine >140 µmol/L), lesion length >27 mm, >1 lesion per vessel, lesion with thrombus or TO (preprocedure TIMI = 0). With the exception of long lesions (treatable with a single 38-mm length stent), Resolute DES currently is not specifically approved for the patient subsets noted in this complex patient definition.

病变治疗情况 Resolute ZES N = 1140 patients, 1661 Lesions Xience V EES N = 1152 patients, 1705 LesionsP value Lesions treated per patient1.46 ± ± Lesion length (mm)11.89 ± ± No. of stents per patient1.9 ± ± Stent length per patient (mm)34 ± 2437 ± Pre-stent balloon dilatation69.5%70.2%0.75 Implantation of study stent only98.0%96.9%0.11 Lesion success98.9%99.1%0.62 Device success97.0%96.6%0.52 Procedure success94.6%94.2%0.78

8.3% Cumulative incidence of events [%] Time after initial procedure [days] Resolute ZES (N = 1140) Xience V EES (N = 1152) No. at risk ZES EES % 主要终点 : TLF (CD 、 TVMI 、 ID- TLR) at 1 year Log-Rank P = 0.92 Error bars indicate a point-wise two-sided 95% confidence interval (±1.96*SE) Standard Error based on the Greenwood Formula Resolute ZES 8.2% vs. Xience V EES 8.3% P non-inferiority <0.001 Resolute ZES 8.2% vs. Xience V EES 8.3% P non-inferiority <0.001

主要临床终点 :12 个月 TLF 分项 n = 1119n = 1126 心源性死亡 (%) n = 1119n = 1126 P = Resolute ZESXience V EES 靶血管心梗 (%) n = 1119n = 1126 P = ID-TLR (%) P = Resolute ZESXience V EESResolute ZESXience V EES

从器械到患者 器械 患者 TVF CD TV MI ID- TVR TLF CD TV MI ID- TLR MACE All D All MI e-CABG ID- TLR Patient Composite All lD All MI All Revasc 标准的复合终点可以告诉我们更多的器械和患者信息 不同复合终点的影响因素

器械 患者 从器械到患者 不同复合终点分析 P = 1.00 Patient Composite (%) (D, All MI, All Revasc) n = 1119n = 1126n = 1119n = 1126 TLF (%) (CD, TV MI, CI-TLR) P = 0.94 TVF (%) (CD, TV MI, TVR) n = 1119n = 1126 P = 0.42 n = 1119n = 1126 MACE (%) (D, MI, eCABG, TLR) P = 0.66

次要终点：13个月造影结果 Noninferiority P values calculated based on a prespecified noninferiority margin of 5%. Other listed P values are based on t-test and are unadjusted for multiple comparisons. RESOLUTE All Comers was not specifically designed or powered to compare late loss at 13 months. Resolute ZES Xience V EES In-Stent Late Loss (mm) Cumulative Frequency (%) P = 0.21 n = 191n = 186 In-Stent Diameter Stenosis (%) 有效力的次要终点 In-Stent Late Loss and Distribution In-stent Late Loss: Resolute 0.27 mm vs. Xience V 0.19 mm (P = 0.08) P nonInferiority = ZESEES

p-values are based on Fisher's Exact Test. p-values for outcome differences are unadjusted for multiple comparisons. RESOLUTE All Comers was not specifically designed or powered to individually compare endpoints shown above. p = NS p = 0.04 p = NS n = 1119n = 1126 安全终点： 30 天

n = 1119n = 1126 p-values are based on Fisher's Exact Test. p-values for outcome differences are unadjusted for multiple comparisons. RESOLUTE All Comers was not specifically designed or powered to individually compare endpoints shown above. p = NS 安全终点：1年

For distribution only in markets where Resolute DES has been approved. Not for distribution in the USA or Japan. © 2010 Medtronic, Inc. All rights reserved. UC EE 5/10 70% 的复杂病变患者

(Cardiac death, Target vessel MI, and clinically driven TLR) 9.8% 8.9% P = 0.59 N = 698 patients Cumulative incidence of events [%] Time after initial procedure [days] Resolute (ZES) Xience V (EES) 复杂病患复合终点 TLF Complex patient definition: Bifurcation, SVG, ISR, AMI 2 vessels stented, renal insufficiency or failure (creatinine >140 µmol/L), lesion length >27 mm, >1 lesion per vessel, lesion with thrombus or TO (preprocedure TIMI = 0). With the exception of long lesions (treatable with a single 38-mm length stent), Resolute DES currently is not specifically approved for the patient subsets noted in this complex patient definition. P values are based on Fisher's Exact Test. P values for outcome differences are unadjusted for multiple comparisons. RESOLUTE All Comers was not specifically designed or powered for complex patient subset analysis.

P = 0.80P = 0.24P = 0.90 % : Components of TLF 复杂病患中 : Components of TLF Complex patient definition: Bifurcation, SVG, ISR, AMI 2 vessels stented, renal insufficiency or failure (creatinine >140 µmol/L), lesion length >27 mm, >1 lesion per vessel, lesion with thrombus or TO (preprocedure TIMI = 0). With the exception of long lesions (treatable with a single 38-mm length stent), Resolute DES currently is not specifically approved for the patient subsets noted in this complex patient definition. P values are based on Fisher's Exact Test. P values for outcome differences are unadjusted for multiple comparisons. RESOLUTE All Comers was not specifically designed or powered for complex patient subset analysis. TLR Cardiac death MI ZES EES

TLF (%) (CD, TV MI, CI-TLR) MACE (%) (D, MI, eCABG, TLR) TVF (%) (CD, TV MI, TVR) P = 0.67 n = 764n = 756n = 764n = 756n = 764n = 756 P = 0.15P = 0.45 复杂病患中的复合事件率 Complex patient definition: Bifurcation, SVG, ISR, AMI 2 vessels stented, renal insufficiency or failure (creatinine >140 µmol/L), lesion length >27 mm, >1 lesion per vessel, lesion with thrombus or TO (preprocedure TIMI = 0). With the exception of long lesions (treatable with a single 38-mm length stent), Resolute DES currently is not specifically approved for the patient subsets noted in this complex patient definition. P values are based on Fisher's Exact Test. P values for outcome differences are unadjusted for multiple comparisons. RESOLUTE All Comers was not specifically designed or powered for complex patient subset analysis.

复杂病变患者 : ST and Death Error bars indicate a point-wise two-sided 95% confidence interval (1.96 ± SD) Standard Error based on the Greenwood Formula 1.5% 3.4%

RESOLUTE All Comers 试验 1 年结论 RESOLUTE-AC 试验设计充分反映了日常真实的临床 情况，其结果具有重要的临床意义 Resolute 达到主要终点 TLF 、各个临床终点均表现优 异, 并不比 Xience V 支架弱 与既往第 1 代 DES 临床试验结果相比，新一代支架为 临床提供了一个非常好的选择 In conclusion, the new-generation zotarolimus-eluting stent was found to be as safe and effective as the everolimus-eluting stent in a group of patients for whom the procedure was considered to be predominantly off-label.

讨论 1. 与第一代支架比的优势 2.All comers 设计的意义 3.TVF 作为一级终点的意义 4. 支架内血栓事件的差别与临床终点事件如总死亡、心 脏性死亡差别在研究中的细微不一致

对比同样真实世界试验： ( 第一代 Vs. 第二代 ) N = 2,300 patients 17 sites (100% monitored) Western Europe 1º Endpoint: TLF – Cardiac Death, TV-MI, clinically driven 12-mo 2º Endpoints: 30d, 6mo, 2 – 5 yr; angiographic & optical coherence tomography (OCT) 13 mo Drug Therapy: ASA and clopidogrel/ticlid >6 months (per guidelines) 1º Endpoint: TLF – Cardiac Death, TV-MI, clinically driven 12-mo 2º Endpoints: 30d, 6mo, 2 – 5 yr; angiographic & optical coherence tomography (OCT) 13 mo Drug Therapy: ASA and clopidogrel/ticlid >6 months (per guidelines) RESOLUTE All Comers Co-PIs: Profs. Serruys, Silber, Windecker Resolute Stent n  1,150 Resolute Stent n  1,150 Xience V Stent n  1,150 Xience V Stent n  1,150 Real World All Comers with symptomatic coronary artery disease Real World All Comers with symptomatic coronary artery disease 460 (20%) QCA subset 50 (2%) OCT subset 30d 6mo 4yr 3yr 2yr 12mo 13mo 5yr Clinical/TLF Angio/OCT 1º Endpoint: Cardiac Death, MI, clinically-driven 9-mo 2º Endpoints: Death, Cardiac Death, MI, TLR, TVR, ARC ST Drug Therapy: ASA and clopidogrel/ticlid recommended  12 months 1º Endpoint: Cardiac Death, MI, clinically-driven 9-mo 2º Endpoints: Death, Cardiac Death, MI, TLR, TVR, ARC ST Drug Therapy: ASA and clopidogrel/ticlid recommended  12 months 420 (25%) QCA subset 46 (3%) OCT subset N = 1,700 patients 10 sites (100% monitored) Western Europe BioMatrix Flex n  850 BioMatrix Flex n  850 Cypher Select n  850 Cypher Select n  850 Stable and ACS Patients undergoing PCI LEADERS PI: Prof. Windecker 30d 6mo 4yr 3yr 2yr 9mo 12mo 5yr Clinical Angio/OCT

RESOLUTE-AC 和 LEADERS 病人基线： 69%68% Small vessel (RVD ≤2.75 mm) 37%36%32.1%31.8%Prior PCI 33%32%30.4%28.9% Prior myocardial infarction 1.4   ± ±0.73 Lesions treated per patient 22% 55%  11 LEADERS BioMatrix Flex DES N = % Unstable Angina (%) RESOLUTE All Comers Resolute DES N = 1140 RESOLUTE All Comers Xience V DES N = 1152 LEADERS Cypher Select DES N = 850 Age (yr)64.4 ± ±  11 Men (%) Diabetes mellitus (%) ACS (%) %

12 个月真实世界所有患者事件率对比： 第一代 Vs. 第二代 Data come from different trials and could differ in a head-to-head comparison. TVF (%) CD, MI, ID-TVR ID-TLR (%) ST (%) ARC Def/Prob LEADERS RESOLUTE All Comers RESOLUTE All Comers RESOLUTE All Comers BioMatrixFlex DES (n=857) CypherSelect DES (n=850) XienceV DES (n=1126) Resolute DES (n=1119)

累积 1 年的 ARC 肯定和可能的血栓 % (n) R-Zotarolimus stent n = 1119 Everolimus stent n = 1126 P Definite ST Acute: (0 – 1 day) Acute: (0 – 1 day) 0.4% (4) 0.1% (1) NS Sub-Acute: (2 – 30 days) Sub-Acute: (2 – 30 days) 0.4% (5)* † 0.4% (5)* † 0.0% (0) 0.03 Late: (31 days – 360 days) Late: (31 days – 360 days) 0.4% (5)* 0.4% (5)* 0.2% (2) NS All: (0 days – 360 days) All: (0 days – 360 days) 1.2% (13) 1.2% (13) 0.3% (3) 0.01 Definite/Probable ST Acute: (0 – 1 day) Acute: (0 – 1 day) 0.4% (5) † 0.2% (2) NS Sub-Acute: (2 – 30 days) Sub-Acute: (2 – 30 days) 0.7% (8) *† 0.7% (8) *† 0.4% (4) NS Late: (31 days – 360 days) Late: (31 days – 360 days) 0.6% (7)* 0.2% (2) NS All: (0 days – 360 days) All: (0 days – 360 days) 1.6% (18) 0.7% (8) NS *One patient had a definite ST at day 4 and 31 † One patient had a probable ST on day 0 and a definite ST on day 5

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