N Engl J Med 2010;363:136-46

CAMS PUMCHShen 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 DES Xience 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/mm² 1.0 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

主要终点主要终点 : TLF (: TLF ( 复合终点包括：复合终点包括： Cardiac Death, Target Vessel MI, Clinically driven TLR @ 12mo)Cardiac Death, Target Vessel MI, Clinically driven TLR @ 12mo)次要终点次要终点 : Composite @ 30d, 6mo, 2 – 5 yr; angiographic & optical coherence tomography: Composite @ 30d, 6mo, 2 – 5 yr; angiographic & optical coherence tomography(OCT) parameters @ 13 mo. (OCT) parameters @ 13 mo. 双重抗血小板治疗双重抗血小板治疗 : ASA and clopidogrel/ticlid >6 months (per guidelines): ASA and clopidogrel/ticlid >6 months (per guidelines)

主要终点主要终点 : TLF (: TLF ( 复合终点包括：复合终点包括： Cardiac Death, Target Vessel MI, Clinically driven TLR @ 12mo)Cardiac Death, Target Vessel MI, Clinically driven TLR @ 12mo)次要终点次要终点 : Composite @ 30d, 6mo, 2 – 5 yr; angiographic & optical coherence tomography: Composite @ 30d, 6mo, 2 – 5 yr; angiographic & optical coherence tomography(OCT) parameters @ 13 mo. (OCT) parameters @ 13 mo. 双重抗血小板治疗双重抗血小板治疗 : ASA and clopidogrel/ticlid >6 months (per guidelines): ASA and clopidogrel/ticlid >6 months (per guidelines)

30d30d 6mo6mo 4yr4yr3yr3yr2yr2yr12mo12mo 13mo13mo 5yr5yr临床 /TLF

造影 /OCT

Resolute StentResolute Stentn n 1,150 1,150

Resolute StentResolute Stentn n 1,150 1,150

Control Xience V StentControl Xience V Stentn n 1,150 1,150

Control Xience V StentControl Xience V Stentn n 1,150 1,150

Co-PIs: Profs. Serruys, Silber, WindeckerCo-PIs: Profs. Serruys, Silber, WindeckerCo-PIs: Profs. Serruys, Silber, WindeckerCo-PIs: Profs. Serruys, Silber, Windecker

ClinicalEndpoints

460 (20%) QCA subset50 (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 anginaSilent ischemiaACS 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

试验入组条件入组条件

17 17 个参与中心

S. WindeckerS. WindeckerBern, SwitzerlandBern, Switzerland

P. SerruysP. SerruysRotterdam, NetherlandsRotterdam, Netherlands

G. RichardtG. RichardtBad Segeberg, GermanyBad Segeberg, Germany

P. BuszmanP. BuszmanBielsko Biala/Bielsko Biala/Kedzierzyn Kozle, PolandKedzierzyn Kozle, Poland

H. KelbaekH. KelbaekCopenhagen, DenmarkCopenhagen, Denmark

A. van BovenA. van BovenLeeuwarden,Leeuwarden,NetherlandsNetherlands

A. LinkeA. LinkeLeipzig, GermanyLeipzig, Germany

V. Klauss V. Klauss Munich, GermanyMunich, Germany

W. Wijns W. Wijns Aalst, BelgiumAalst, Belgium

C. MacayaC. MacayaMadrid, SpainMadrid, Spain

P. Garot P. Garot Quincy/Massy, FranceQuincy/Massy, France

C. DiMario C. DiMario London, UKLondon, UK

G. ManoharanG. ManoharanBelfast, UKBelfast, UK

R. KornowskiR. KornowskiPetach Tikva, IsraelPetach Tikva, Israel

A. BartorelliA. BartorelliMilan, ItalyMilan, Italy

S. SilberS. SilberMunich, GermanyMunich, Germany

T. IschingerT. IschingerMunich, GermanyMunich, Germany

0

500

1000

1500

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Apr-08 May-08 Jun-08 Jul-08 Aug-08 Sep-08 Oct-08

Pa

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6 个月全部入组完成

0

500

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Apr 08 May 08 Jun Jul Aug Sept Oct 08

临床和造影随访

Randomised1:1

Angiographic F/U13 mths 62.3%

2292 patients (NL = 3366)Enrolled and randomised

Resolute ZESN = 1140 pts

Randomised to Angio F/UN = 228 pts

Randomised to Angio F/UN = 228 pts Randomised to Angio F/U

N = 227 pts

Randomised to Angio F/UN = 227 pts

Xience V EESN = 1152 pts

Xience V EESN = 1152 pts

Clinical F/U 12 mths 98.2%

Clinical F/U 12 mths 97.7%

Angiographic F/U13 mths 57.3%

病人基线特征Resolute ZES(N = 1140)

Xience V EES(N = 1152) P value

Age (yr) 64.4 ± 10.9 64.2 ± 10.8 0.70

Men (%) 76.7 77.2 0.80

Diabetes mellitus (%) 23.5 23.4 1.00

IDDM 8.4 7.1 0.28

ACS (%) 48.3 47.7 0.80

AMI (within 12 hr) (%) 15.4 17.8 0.13

AMI (within 72 hr) (%) 28.9 28.8 0.96

Multivessel disease (%) 58.4 59.2 0.73

Small vessel (RVD ≤2.75 mm) 67.8 67.4 0.88

Long lesion (length >18 mm) 18.2 21.2 0.11

Bifurcation/trifurcation (%) 16.9 17.7 0.62

Total occlusion (%) 16.3 17.2 0.61

In-stent restenosis (%) 8.1 8.0 0.94

Complex Patients1 (%) 67.0 65.6 0.51

1Complex patient definition: Bifurcation, SVG, ISR, AMI <72 hr, LVEF <30%, unprotected LM, >2 vessels stented, renal insufficiency orfailure (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 approvedfor the patient subsets noted in this complex patient definition.

病变治疗情况Resolute ZES

N = 1140 patients,1661 Lesions

Xience V EESN = 1152 patients,

1705 Lesions P value

Lesions treated per patient 1.46 ± 0.73 1.48 ± 0.77 0.46

Lesion length (mm) 11.89 ± 7.50 12.15 ± 7.86 0.38

No. of stents per patient 1.9 ± 1.2 2.0 ± 1.3 0.02

Stent length per patient (mm) 34 ± 24 37 ± 26 0.02

Pre-stent balloon dilatation 69.5% 70.2% 0.75

Implantation of study stent only 98.0% 96.9% 0.11

Lesion success 98.9% 99.1% 0.62

Device success 97.0% 96.6% 0.52

Procedure success 94.6% 94.2% 0.78

8.3%

0 180 360

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Time after initial procedure [days]

20

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Resolute ZES (N = 1140)

Xience V EES (N = 1152)

No. at risk 0 30 60 90 120 150 180 210 240 270 300 330 360ZES 1140 1110 1084 1076 1070 1062 1060 1058 1051 1042 1038 1037 1025EES 1152 1123 1088 1080 1078 1074 1068 1061 1047 1046 1038 1032 1019

8.2%

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%Resolute ZES 8.2% vs. Xience V EES 8.3%PPnon-inferioritynon-inferiority <0.001 <0.001

Resolute ZES 8.2% vs. Xience V EES 8.3%Resolute ZES 8.2% vs. Xience V EES 8.3%PPnon-inferioritynon-inferiority <0.001 <0.001

主要临床终点主要临床终点 :12:12 个月 个月 TLFTLF 分分项项

n = 1119 n = 1126

心源性死亡 (%)

n = 1119 n = 1126

P = 0.61

1.71.3

Resolute ZES Xience V EES

靶血管心梗 (%)

n = 1119 n = 1126

P = 0.92

4.2 4.1

ID-TLR (%)

P = 0.50

3.93.4

Resolute ZES Xience V EES Resolute ZES Xience V EES

器械患者

从器械到患者不同复合终点分析

P = 1.0014.614.6

Resolute Xience

Patient Composite (%)(D, All MI, All Revasc)

n = 1119 n = 1126n = 1119 n = 1126

8.2 8.3

Resolute Xience

TLF (%)(CD, TV MI, CI-TLR)

P = 0.94

TVF (%)(CD, TV MI, TVR)

n = 1119 n = 1126

9.69.0

Resolute Xience

P = 0.42

n = 1119 n = 1126

8.79.7

Resolute Xience

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)

0.00 1.00 2.00 3.00-1.00

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25

50

75

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21.719.8

Resolute ZES Xience V EES

P = 0.21

n = 191n = 186

In-Stent Diameter Stenosis (%)有效力的次要终点

In-Stent Late Lossand Distribution

In-stent Late Loss: Resolute 0.27 mm vs. Xience V 0.19 mm (P = 0.08)PnonInferiority = 0.035

ZES EES

0.5

0.90.7

3.4

1.1

0.2 0.2

3.7

Arc Def/Prob ST(%) Death (%) CD (%) TVMI (%)

Xience V DES Resolute DES

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 = NS p = 0.04 p = NS

n = 1119n = 1126

安全终点： 30 天

0.7

2.8

1.7

4.1

1.6 1.61.3

4.2

Arc Def/Prob ST(%) Death (%) CD (%) TVMI (%)

Xience V DES Resolute DES

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

p = NS

p = NS

p = NS

安全终点：安全终点： 11 年年

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All PatientsN = 1520/2292

70% 的复杂病变患者

4.4

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2.2

4.4

TLR Cardiac Death MI

Resolute (n= 764)

Xience V (n=756)

P = 0.80 P = 0.24 P = 0.90

%

复杂病患中 : Components of TLF: Components of TLF

Complex patient definition: Bifurcation, SVG, ISR, AMI <72 hr, LVEF <30%, unprotected LM, >2 vessels stented, renal insufficiency orfailure (creatinine >140 µmol/L), lesion length >27 mm, >1 lesion per vessel, lesion with thrombus or TO (preprocedure TIMI = 0). Withthe exception of long lesions (treatable with a single 38-mm length stent), Resolute DES currently is not specifically approved for thepatient subsets noted in this complex patient definition. P values are based on Fisher's Exact Test. P values for outcome differences areunadjusted for multiple comparisons. RESOLUTE All Comers was not specifically designed or powered for complex patientsubset analysis.

TLR Cardiac death MI

ZESEES

4.44.0

1.3

2.2

4.3 4.4

9.2

11.5

Resolute Xience V

8.99.7

Resolute Xience V

TLF (%)(CD, TV MI, CI-TLR)

MACE (%)(D, MI, eCABG, TLR)

TVF (%)(CD, TV MI, TVR)

P = 0.67

n = 764 n = 756 n = 764 n = 756

11.19.8

Resolute Xience Vn = 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 <72 hr, LVEF <30%, unprotected LM, >2 vessels stented, renal insufficiency orfailure (creatinine >140 µmol/L), lesion length >27 mm, >1 lesion per vessel, lesion with thrombus or TO (preprocedure TIMI = 0). Withthe exception of long lesions (treatable with a single 38-mm length stent), Resolute DES currently is not specifically approved for thepatient subsets noted in this complex patient definition. P values are based on Fisher's Exact Test. P values for outcome differences areunadjusted for multiple comparisons. RESOLUTE All Comers was not specifically designed or powered for complex patientsubset 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%

P = 0.19

Stent Thrombosis (ARC Def/Prob)N = 1520 patients

0.9%

5

4

2

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All Death N = 1520 patients

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Resolute ZESXience V EES

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4Resolute ZESXience V EES

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 patients17 sites (100% monitored)

Western Europe

1º Endpoint: TLF – Cardiac Death, TV-MI, clinically driven TLR @ 12-mo2º Endpoints: Composite @ 30d, 6mo, 2 – 5 yr; angiographic & optical

coherence tomography (OCT) parameters @ 13 moDrug Therapy: ASA and clopidogrel/ticlid >6 months (per guidelines)

1º Endpoint: TLF – Cardiac Death, TV-MI, clinically driven TLR @ 12-mo2º Endpoints: Composite @ 30d, 6mo, 2 – 5 yr; angiographic & optical

coherence tomography (OCT) parameters @ 13 moDrug Therapy: ASA and clopidogrel/ticlid >6 months (per guidelines)

RESOLUTE All ComersCo-PIs: Profs. Serruys, Silber, Windecker

Resolute Stentn 1,150

Resolute Stentn 1,150

Xience V Stentn 1,150

Xience V Stentn 1,150

Real WorldAll Comers with symptomatic

coronary artery disease

Real WorldAll Comers with symptomatic

coronary artery disease

460 (20%) QCA subset50 (2%) OCT subset

30d30d 6mo6mo 4yr4yr3yr3yr2yr2yr12mo12mo 13mo13mo 5yr5yr

Clinical/TLF

Angio/OCT

1º Endpoint: Cardiac Death, MI, clinically-driven TVR @ 9-mo1º Endpoint: Cardiac Death, MI, clinically-driven TVR @ 9-mo2º Endpoints: Death, Cardiac Death, MI, TLR, TVR, ARC ST2º Endpoints: Death, Cardiac Death, MI, TLR, TVR, ARC STDrug Therapy: ASA and clopidogrel/ticlid recommendedDrug Therapy: ASA and clopidogrel/ticlid recommended

12 months 12 months

1º Endpoint: Cardiac Death, MI, clinically-driven TVR @ 9-mo1º Endpoint: Cardiac Death, MI, clinically-driven TVR @ 9-mo2º Endpoints: Death, Cardiac Death, MI, TLR, TVR, ARC ST2º Endpoints: Death, Cardiac Death, MI, TLR, TVR, ARC STDrug Therapy: ASA and clopidogrel/ticlid recommendedDrug Therapy: ASA and clopidogrel/ticlid recommended

12 months 12 months

420 (25%) QCA subset46 (3%) OCT subset

N = 1,700 patients10 sites (100% monitored)

Western Europe

BioMatrix FlexBioMatrix Flexn n 850 850

BioMatrix FlexBioMatrix Flexn n 850 850

Cypher SelectCypher Selectn n 850 850

Cypher SelectCypher Selectn n 850 850

Stable and ACS Patients Stable and ACS Patients undergoing PCIundergoing PCI

Stable and ACS Patients Stable and ACS Patients undergoing PCIundergoing PCI

LEADERSPI: Prof. Windecker

30d30d 6mo6mo 4yr4yr3yr3yr2yr2yr9mo9mo 12mo12mo 5yr5yr

Clinical

Angio/OCT

RESOLUTE-AC 和 LEADERS 病人基线：

69%68%67.467.8Small vessel (RVD ≤2.75 mm)

37%36%32.1%31.8%Prior PCI

33%32%30.4%28.9%Prior myocardial infarction

1.4 0.71.5 0.71.48 ±0.771.46 ±0.73Lesions treated per patient

22%

55%

26

75

65 11

LEADERSBioMatrix Flex DESN = 857

20%18.919.4Unstable Angina (%)

RESOLUTE All Comers

Resolute DESN = 1140

RESOLUTE All Comers

Xience V DESN = 1152

LEADERSCypher

Select DESN = 850

Age (yr) 64.4 ±10.9 64.2 ±10.8 65 11

Men (%) 76.7 77.2 75

Diabetes mellitus (%) 23.5 23.4 23

ACS (%) 48.3 47.7 56%

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

10.7

12.1

9.6

9.0

5.1 5.8

3.4 3.9

2.8 2.20.7 1.6

LEADERS LEADERS LEADERSRESOLUTE All Comers

RESOLUTE All Comers

RESOLUTE All Comers

BioMatrix Flex DES (n=857)

Cypher Select DES (n=850)

Xience V DES (n=1126)

Resolute DES (n=1119)Resolute DES (n=1119)

累积 1 年的 ARC 肯定和可能的血栓

% (n)% (n)R-Zotarolimus stentR-Zotarolimus stent

n = 1119n = 1119Everolimus stentEverolimus stent

n = 1126n = 1126 PP

Definite STDefinite ST Acute: (0 – 1 day)Acute: (0 – 1 day) 0.4% (4) 0.4% (4) 0.1% (1)0.1% (1) NSNS

Sub-Acute: (2 – 30 days)Sub-Acute: (2 – 30 days) 0.4% (5)*0.4% (5)*†† 0.0% (0)0.0% (0) 0.030.03

Late: (31 days – 360 days)Late: (31 days – 360 days) 0.4% (5)*0.4% (5)* 0.2% (2)0.2% (2) NSNS

All: (0 days – 360 days)All: (0 days – 360 days) 1.2% (13)1.2% (13) 0.3% (3)0.3% (3) 0.010.01

Definite/Probable STDefinite/Probable ST Acute: (0 – 1 day)Acute: (0 – 1 day) 0.4% (5)0.4% (5)†† 0.2% (2)0.2% (2) NSNS

Sub-Acute: (2 – 30 days)Sub-Acute: (2 – 30 days) 0.7% (8)0.7% (8)**†† 0.4% (4)0.4% (4) NSNS

Late: (31 days – 360 days)Late: (31 days – 360 days) 0.6% (7)*0.6% (7)* 0.2% (2)0.2% (2) NSNS

All: (0 days – 360 days)All: (0 days – 360 days) 1.6% (18)1.6% (18) 0.7% (8)0.7% (8) NSNS

*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

谢谢！