Presentation on theme: "The Randomized Comparison of 6-month vs"— Presentation transcript:
1 The Randomized Comparison of 6-month vs The Randomized Comparison of 6-month vs. 12-month Duration of Dual Antiplatelet Therapy after the Implantation of Drug Eluting StentHyeon-Cheol Gwon, Joo Yong Hahn, Young Bin Song,Kyung Woo Park, Yang Soo Jang, Hyo-Soo Kim,On behalf of the EXCELLENT Trial InvestigatorsSamsung Medical Center, Sungkyunkwan University School of Medicine
2 Disclosure Statement of Financial Interest Within the past 12 months, I or my spouse/partner have had a financial interest/arrangement or affiliation with the organization(s) listed below.CONSULTING FEES/HONORARIA:Cordis,Medtronic Asia PacificRESEARCH/RESEARCH GRANTS:Abbott Korea,Medtronic Korea
3 BackgroundCurrent guidelines recommend at least 12 months of dual antiplatelet therapy after DES implantationThis recommendation is not based on any prospectively randomized data.Prolonged duration of clopidogrel therapy in addition to aspirin may be associated with greater cost and higher risk of bleeding.
4 Objective of Study Hypothesis To test the safety and efficacy of 6-month duration compared with 12-month duration of dual antiplatelet therapy (DAT) in addition to aspirin after the implantation of DESHypothesisSix-month DAT is non-inferior to 12-month DATin terms of target vessel failure at 12 months
5 General Exclusion Criteria Angiographic Exclusion Criteria Patient EligibilityInclusion Criteria> 50% stenosis by visual estimationEvidence of myocardial ischemiaStable anginaUnstable anginaRecent infarction, silent ischemia+ functional study or reversible changes in the ECG c/w ischemiaTarget lesion must be located in a native coronary artery2.25mm ≤ RVD ≤ 4.25mmLesion length: no limitationMultiple stenting: no limitationGeneral Exclusion CriteriaGI or GU bleeding ≤3 months, major surgery ≤ 2 monthsHb<10 g/dL, PLT<100KElective surgical procedure planned ≤ 12 monthsLVEF < 25%, or in shockMI ≤ 72 hoursCreatinine level ≥ 3.0mg/dL or dependence on dialysisSevere hepatic dysfunction (AST, ALT ≥ x3 UNL)Patients who have received any stent implantation in the target vessel prior to enrollmentAngiographic Exclusion CriteriaPatients with significant LM stenosisBMS or DES ISRCTOTrue bifurcation lesions requiring two stents
7 EXCELLENT RCT EES vs. SES Presented at LBCT session in TCT 2010 by Dr. HS Kim
8 Study Endpoints Primary Endpoint 12-month target vessel failure (TVF) a composite of cardiac death, MI, or TVRCo-primary endpointIn-segment late luminal loss (LL) at 9 months (for comparison of EES vs. SES)Secondary EndpointsAll death, cardiac deathMyocardial infarction (MI)Cerebrovascular accident (CVA)Target lesion revascularization (TLR)Target vessel revascularization (TVR)Any revascularizationStent thrombosis: definite or probable stent thrombosis by ARC definitionTIMI major bleeding: a drop in Hb > 5 g/dl or in Hct > 15%Safety endpoint: death, MI, CVA, stent thrombosis, or TIMI major bleedingMajor adverse cardiocerebral event (MACCE): death, MI, CVA, or any revasc* Definitions follow the ARC recommendations, if not described.
9 Sample Size Calculation Primary Endpoint12-month Target Vessel Failure (TVF)TVF in 12-month DAT group: 10%Non-inferiority design with non-inferiority margin 4%Type I error 0.05, type II error 0.20Sampling ratio 6-month:12-month = 1:1Estimated drop out rate 5%Total 1,372 patients needed
10 Independence in Trial Coordination Executive Committee(HS Kim, MD, YS Jang, MD, JH Yoon, MD,HC Gwon, MD, IH Chae, MD, TH Ahn, MD)DSMBData SafetyMonitoring BoardMRCCTrialCoordinating CenterCEACClinical Event Adjudication CommitteeSteering Committee19 study investigatorsGrant Support1) Ministry of Health, Welfare, and Family Affairs of Korea2) Abbott Vascular Korea3) Boston Scientific KoreaThe companies were not involved with the protocol development or the study process, including site selection, management, and data collection and analysis.
11 Participating Centers 19 Hospitals in Republic of KoreaSeoul National University HospitalYonsei University Severance HospitalSamsung Medical CenterSeoul National University Bundang HospitalGachon University Gil Medical CenterYonsei University Wonju Christian HospitalHallym University Sacred Heart HospitalKandgong Sacred Heart HospitalChonam National University HospitalGangnam Severance HospitalNHIC Ilsan HospitalInje University Sanggye Paik HospitalKorea University Anan HospitalPusan National University HospitalBoramae Medical CenterKangnam Sacred Heart HospitalUijeongbu St. Mary’s HospitalKeimyung University Dongsan HospitalEwha Womans University Mokdong Hospital
12 Study flow Enrolled and Randomized (n=1,443) Allocated to 6-mo DAT Allocated to 12-mo DAT (n=721)Intention-to-treatment AnalysisFollow-up loss within 395 days n=6Follow-up loss within 395 days n=96-mo DAT with 12-mo FU (n=716)12-mo DAT with 12-mo FU (n=712)12-mo event Analysis
17 Medications Variables ― no. (%) 6-mo DAT (N=722) 12-mo DAT (N=721) p-valueUse of aspirin at 1 year676 (99.9%)667 (99.3%)Duration of clopidogrel therapy190 [ ]375 [ ]Clopidogrel durationLess than due time*Within due time*More than due time*No information16 (2.2%)501 (69.4%)192 (26.6%)13 (1.8%)45 (6.2%)442 (61.3%)219 (30.4%)15 (2.1%)Clopidogrel restart within 1 year34 (4.7%)22 (3.1%)Medications at dischargeAspirin707 (99.4)704 (99.0)0.364Clopidogrel702 (98.7)708 (99.6)0.082Statin604 (85.0)582 (81.9)0.117ACE inhibitor224 (31.5)243 (34.2)0.283ARB244 (34.3)231 (32.5)0.465Beta blocker427 (60.1)445 (62.6)0.327Warfarin6 (0.8)13 (1.8)0.106Calcium channel blocker238 (33.5)249 (35.0)0.539Table 2(*due time: 120~240 days in 6-mo DAT group, 300~420 days in 12-mo DAT group)
19 12-month Target Vessel Failure 1˚ Endpoint12-month Target Vessel Failure(Kaplan-Meier Analysis)Cumulative proportional TVF estimate at 1 year6-mo DAT (N=1067)5.2±0.8%12-mo DAT (N=361)4.3±0.8%Pre-specified non-inferiority margin4.0%Differencep=0.426Non-inferiorityp=0.0031Upper 1-sided 97.5% CIDifferenceTable 4: PP, all lesionsNon-inferior0.9%3.6%-1.5-1.0-0.50.00.51.01.52.02.53.03.54.04.5 %
20 Cumulative incidence rate (%) Months after initial procedure 1˚ EndpointTarget Vessel Failure6-mo DAT12-mo DATP=0.507HR = 1.17 (95% CI )4.7%Cumulative incidence rate (%)4.4%Months after initial procedurePatient Number at Risks6-month72270770169768112-month721710699698680
21 Target Vessel Failure (Landmark Analysis) ~ 6 months 6 months ~ 1˚ EndpointTarget Vessel Failure(Landmark Analysis)6-mo DAT12-mo DAT~ 6 months6 months ~P=0.563HR = 1.25 (95% CI )P=0.699HR = 1.13 (95% CI )Patient Number at Risks6-month72270770112-month721710699Patient Number at Risks701697681699698680
22 Cumulative incidence rate (%) Months after initial procedure Cardiac Death6-mo DAT12-mo DATP=0.533HR = 0.58 (95% CI 0.10 – 3.23)Cumulative incidence rate (%)0.4%0.3%Months after initial procedurePatient Number at Risks6-month72270770169768112-month721710699698680
23 Myocardial Infarction 6-mo DAT12-mo DATP=0.280HR = 1.62 (95% CI 0.67 – 3.93)Cumulative incidence rate (%)1.8%1.1%Months after initial procedurePatient Number at Risks6-month72270770169768112-month721710699698680
24 Cumulative incidence rate (%) Months after initial procedure Stent Thrombosis(Definite or probable stent thrombosis by ARC definition)6-mo DAT12-mo DATP=0.426HR = 1.68 (95% CI 0.47 – 6.06)Cumulative incidence rate (%)0.8%0.4%Months after initial procedurePatient Number at Risks6-month72270770169768112-month721710699698680
25 Cumulative incidence rate (%) Months after initial procedure TIMI Major Bleeding(Overt clinical bleeding with a drop of Hb > 5 g/dl or Hct > 15%)6-mo DAT12-mo DATP=0.419HR = 0.50 (95% CI 0.09 – 2.71)Cumulative incidence rate (%)0.6%0.3%Months after initial procedurePatient Number at Risks6-month72270770169768112-month721710699698680
26 Cumulative incidence rate (%) Months after initial procedure Safety Endpoint(Death, MI, stent thrombosis, CVA, or TIMI major bleeding)6-mo DAT12-mo DATP=0.678HR = 1.13 (95% CI 0.64 – 1.99)Cumulative incidence rate (%)3.4%3.1%Months after initial procedurePatient Number at Risks6-month72270770169768112-month721710699698680
27 Cumulative incidence rate (%) Months after initial procedure MACCE(Death, MI, CVA, or any revascularization)8.4%P=0.896HR = 0.98 (95% CI 0.68 – 1.40)7.5%Cumulative incidence rate (%)6-mo DAT12-mo DATMonths after initial procedurePatient Number at Risks6-month72270770169768112-month721710699698680
28 Subgroup Analysis N 6-mo DAT 12-mo Χ2 p-value Cox HR Cox P for interactionAge< 6576119 (5.0%)12 (3.2%)0.2020.1150.127 6566715 (4.5%)19 (5.7%)0.4650.588ACS*No69421 (6.9%)14 (4.1%)0.2520.1880.301Yes73413 (3.6%)17 (4.6%)0.4740.728Diabetes88410 (2.2%)23 (5.3%)0.0180.0550.00154424 (8.9%)8 (2.9%)0.0030.006LVEF< 50%1233 (3.0%)4 (7.1%)0.2860.5030.330 50%108626 (4.8%)25 (4.6%)0.8330.607Bifurcation95923 (4.7%)20 (4.3%)0.7690.6080.95746911 (4.9%)11 (4.5%)0.8300.668StentEES106725 (4.7%)27 (5.1%)0.7390.9140.305SES3619 (5.0%)4 (2.2%)0.1490.168Multi-stent85414 (3.2%)12 (2.9%)0.8190.8940.59756320 (7.5%)19 (6.4%)0.6010.311*ACS = unstable angina, NSTEMI, or STEMI123Favors 6-mo DATFavors 12-mo DAT
29 12-month TVF in Stent Subgroups (Kaplan-Meier Analysis)Cumulative proportional TVF estimate at 1 yearEverolimus-eluting StentSirolimus-eluting Stent97.5%6-mo DAT (N=540)5.2±1.0%12-mo DAT (N=539)5.1±1.0%Non-inferiorityp=0.00296-mo DAT (N=182)5.0±1.6%12-mo DAT (N=182)2.2±1.1%Non-inferiorityp=0.268Pre-specified non-inferiority margin: 4.0%Upper 1-sided97.5% CIDifferenceTable 4: PP, all lesions0.1%2.9%2.2%6.6%-1123456-1123456
30 Everolimus-eluting Stent Sirolimus-eluting Stent TVF in Stent Subgroups6-mo DAT12-mo DATEverolimus-eluting StentSirolimus-eluting Stentp=0.914HR = 1.03 ( )p=0.168HR = 2.29 ( )5.0%4.9%4.6%2.2%Patient Number at Risks6-mo54053152852451112-mo539521505Patient Number at Risks6-mo18217617417112-mo179178
31 Study flow: Per-protocol analysis Enrolled and Randomized (n=1,443)Allocated to 6-mo DAT(n=722)Allocated to 12-mo DAT (n=721)Intention-to-treatment AnalysisFollow-up loss within 395 days (n=6)Clopidogrel duration less than due time (n=14)Clopidogrel duration more than due time (n=192)No information about clopidogrel (n=13)Follow-up loss within 395 days (n=9)Clopidogrel duration less than due time (n=41)Clopidogrel duration more than due time (n=219)No information about clopidogrel (n=13)DAT 6-mo with 12-mo FU (n=497, 68.8%)DAT 12-mo with 12-mo FU (n=439, 60.9%)Per-protocol Analysis(*due time: 120~240 days in 6-mo DAT group, 300~420 days in 12-mo DAT group)
32 12-month Target Vessel Failure by Per-protocol Analysis Cumulative proportional TVF estimate at 1 year6-mo DAT (N=497)3.6±0.8%12-mo DAT (N=439)4.3±0.8%Pre-specified non-inferiority margin4.0%Differencep=0.158Non-inferiorityp=0.0093Upper 1-sided 97.5% CIDifferenceTable 4: PP, all lesionsNon-inferior1.5%3.6%-1.5-1.0-0.50.00.51.01.52.02.53.03.54.04.5 %
33 Target Vessel Failure by Per-protocol Analysis 6-mo DAT12-mo DATP=0.203HR = 1.66 (95% CI 0.76 – 3.59)Cumulative incidence rate (%)3.2%2.1%Months after initial procedurePatient Number at Risks6-month49749048848748012-month439435433
34 12-month TVF in Stent Subgroups by Per-protocol Analysis Cumulative proportional TVF estimate at 1 yearEverolimus-eluting StentSirolimus-eluting Stent6-mo DAT (N=377)4.4±0.9%12-mo DAT (N=332)2.1±0.8%Non-inferiorityp=0.0136-mo DAT (N=120)4.2±1.8%12-mo DAT (N=107)1.9±1.3%Non-inferiorityp=0.222Pre-specified non-inferiority margin: 4.0%Upper 1-sided97.5% CIDifferenceTable 4: PP, all lesions188.8.131.52.7Non-inferior-1123456-1123456
35 TVF in Stent Subgroups by Per-protocol Analysis Everolimus-eluting StentSirolimus-eluting Stentp=0.286HR=1.65 ( )p=0.332HR=2.25 ( )4.2%2.9%1.9%2.1%Patient Number at Risks6-mo37737337136512-mo332329328Patient Number at Risks120117116115107106105
36 Study LimitationsThe incidence of primary endpoint was lower than expected.Underpowered to test hard endpoints of death, MI, or stent thrombosis.Significant proportion of the patients crossed over to shorter or longer duration of clopidogrel therapy.Longer term duration of follow-up is to be done.
37 ConclusionsSix-month DAT is non-inferior to 12-month DAT with regard to the risk of target vessel failure at 12 months after DES implantation.In particular, the EES subgroup showed very similar event rates between the 6-month and 12-month DAT groups.A larger-scale randomized controlled trial is required to test the impact of shorter duration of clopidogrel therapy on the hard endpoints of death, MI, or stent thrombosis.