Myeong-Ki Hong, MD. Ph D, on behalf of RESET investigators
Professor, Division of Cardiology, Severance Cardiovascular Hospital
Yonsei University College of Medicine, Seoul, Korea
A New Strategy for Discontinuation of Dual Antiplatelet Therapy: Real Safety and Efficacy of 3-Month Dual Antiplatelet Therapy Following Zotarolimus-Eluting Stent Implantation: RESET Trial
RESET ClinicalTrials.gov identifier: NCT01145079
Funding sourcesSupported by the Cardiovascular Research Center, Seoul, Korea, Medtronic Inc. and grants from the Korea Healthcare Technology R&D Project, Ministry for Health, Welfare & Family Affairs, Republic of Korea (No. A085012 and A102064), the Korea Health 21 R&D Project, Ministry of Health & Welfare, Republic of Korea (No. A085136).
Background - I• Because one of strong predictor for stent thrombosis is early
discontinuation of clopidogrel, prolonged dual antiplatelet therapy (DAPT) is highly recommended.
• However, prolonged use of clopidogrel is associated with many potential risks; bleeding, higher cost, and poor patient compliance or premature discontinuation.
• Reports from several trials of the Endeavor zotarolimus-eluting stent (E-ZES) have shown beneficial efficacy and safety, despite a relatively short duration of DAPT.
Iakovou I, et al. JAMA 2005;293:2126-30.Pfisterer M, et al. J Am Coll Cardiol 2006;48:2584-91.
Brar SS, et al. J Am Coll Cardiol 2008;51:2220-7.
Bhatt DL, et al. N Engl J Med 2006;354:1706-17.Grines CL, et al. Circulation 2007;115:813-8.
Stone GW, et al. Am J Cardiol 2008;102:1017-22.
Fajadet J, et al. Circulation 2006;114:798-806. Meredith IT, et al. Am J Cardiol. 2007;100:S56-S61.Leon MB, et al. J Am Coll Cardiol 2010;55:543-54.
Background - IIKim JS, et al. J Am Coll Cardiol Intv 2009;2:1240-7.
Recent OCT study reported sufficient strut coverage following E-ZES implantation as early as 3 months post-procedure.
Background - III
Hahn JY, et al. Circ J 2010;74:2314-21.
A recent registry study reported that low-risk patients with E-ZES + 3-month DAPT (n=661) showed a favorable long-term clinical outcomes after cessation of clopidogrel 3 months post intervention.
Hypothesis & ObjectiveHypothesis;
Three-month DAPT after E-ZES implantation (E-ZES+3-month DAPT) may be non-inferior to 12-month DAPT after implantation with other DES (standard therapy).
Objectives;To compare the safety and efficacy between patients treated with E-ZES+3-month DAPT and patients treated with the standard therapy, in the RESET (REal Safety and Efficacy of a 3-month dual antiplatelet Therapy following E-ZES implantation) trial.
Randomization• Using an interactive web-based response system, study
participants were randomly assigned in a 1:1 ratio to receive either the E-ZES or another currently available DES.
• Stratified by participating center and four clinical or lesion characteristics;
Study design and patients • Prospective, open label, randomized trial • Participating centers; conducted at 26 sites in Korea
Inclusion criteria • Patients with stable angina, unstable angina, or acute MI• Diameter stenosis ≥ 50% and reference vessel diameter of 2.5 to 4.0
mm by visual estimation• Elective PCI, eligible for participation
Exclusion criteria • Prior history of cerebral vascular accidents, peripheral artery diseases,
thromboembolic disease or stent thrombosis • Left ventricular ejection fraction < 40% • Lesions with in-stent restenotic lesion, chronic total occlusion, or
significant left main disease requiring intervention• Cardiogenic shock• Acute ST-elevation MI within 48 hours after onset of symptoms• Contraindication to antiplatelet agents• Severe hepatic (≥3 times normal values) or renal dysfunction (serum
creatinine >2.0 mg/dl)
Primary end-points• A composite of 1) death from cardiovascular cause, 2)
myocardial infarction, 3) stent thrombosis *, 4) ischemia-driven target-vessel revascularization or 5) bleeding † at 1 year post-procedure.
* Stent thrombosis, defined as definite or probable stent thrombosis by ARC definition† Bleeding, defined as TIMI-defined major or minor bleeding
• Post-procedure clinical follow-up; in-hospital, and after 1, 3, 6 and 12 months either by clinic visit or by telephone interview
Sample size calculation• A non-inferiority comparison
• Overall incidence of the primary endpoint of two groups; E-ZES+3-month DAPT; 10% Standard therapy; 11%
We hypothesized that the clinical outcome of E-ZES+3-month DAPT would be non-inferior to the other group with a non-inferiority margin of 4% for the absolute difference in risk at 12 months.
Assuming a 10% drop out rate, this required an estimated sample size of 2,120 patients (1,060 for each group) to achieve 80% power for non-inferiority test and a one-sided type I error of 5%.
Statistical analysis• All comparisons, according to the intention-to-treat allocations. • Cumulative event rates, estimated by the Kaplan-Meier
method (using log-rank test) and calculated the absolute differences and 95% confidence intervals (CI).
• P-value <0.05 were considered statistically significant. • Statistical Analysis System software (SAS; 9.1.3., SAS
Institute, NC) and R version 2.12.2 (R Development Core Team, Vienna, Austria).
Principal investigator;Professor Myeong-Ki Hong, MD, Ph D, Yonsei University College of Medicine, Seoul, Korea
Steering committee;• Myeong-Ki Hong, MD, Yonsei University College of Medicine, Seoul, Korea • Yangsoo Jang, MD, Yonsei University College of Medicine, Seoul, Korea • Joo-Young Yang, MD, National Health Insurance Corporation Ilsan Hospital, Goyang, Korea• Hyuck-Moon Kwon, MD, Kangnam Severance Hospital, Seoul, Korea• Jung-Han Yoon, MD, Yonsei University Wonju College of Medicine, Wonju, Korea• Dong-Woon Jeon, MD, National Health Insurance Corporation Ilsan Hospital, Goyang, Korea• Seung-Whan Lee, MD, Wonju Christian Hospital, Wonju, Korea• Byung-Ok Kim, MD, Sanggye Paik Hospital, Inje University College of Medicine, Seoul, Korea• Bum-Kee Hong, MD, Kangnam Severance Hospital, Seoul, Korea
Coordinating center; Cardiovascular Research Center, Seoul Korea
Data safety monitoring board (DSMB);• Chul-Min Ahn, MD, Korea University College of Medicine, Seoul, Korea• Hyuck-Jai Chang, MD, Yonsei University College of Medicine, Seoul, Korea • Seong-Hoon Choi, MD, Hallym University College of Medicine, Seoul, Korea• Deok-Kyu Cho, MD, Kwandong University College of Medicine, Goyang, Korea
Clinical event committee (CEC);• Eui-Young Choi, MD, Kangnam Severance Hospital, Seoul, Korea• Ji-Young Shim, MD, Yonsei University College of Medicine, Seoul, Korea • Se-Jung Yoon, MD, NHIC Ilsan Hospital, Koyang, Korea • Jang Young Kim, MD, Wonju Christian Hospital, Wonju, Korea
Data management and biostatistical analysis;• Jung Mo Nam, Ph D, Department of Preventive Medicine and Biostatistics, Yonsei University College of Medicine, Seoul,
Korea• Dong-Ho Shin, MD, MPH, Yonsei University College of Medicine, Seoul, Korea
Study organization
E-ZES(n=146
)
E-ZES(n=301
)
E-ZES(n=341
)
E-ZES(n=271
)
R-ZES(n=146
)
R-ZES(n=300
)
SES(n=340
)
EES(n=272
)
Diabetes mellitus
subset (N=292)
Acute coronary syndrome
subset (N=601)
Short-length DES
Subset (N=681)Long-length DES Subset (N=543)
2,148 patients enrolled and randomized
31 patients excluded - 16 Withdrawal of consent - 15 Met exclusion criteria
Divided into 4 subsets and 1:1 randomization was performed.
E-ZES + 3-month DAPT (n=1059) Standard therapy (n=1058)
E-ZES + 3-month DAPTStandard Therapy:Other DES with 12-month DAPT
Study at a glance & Final Enrollment
R-ZES = Resolute zotarolimus-eluting stent ; SES = sirolimus-eluting stent; EES = everolimus-eluting stents
Baseline clinical characteristicsVariables E-ZES+3-month DAPT
(n=1,059)Standard therapy
(n=1,058) P
Age (year) 62.4±9.4 62.4±9.8 0.94Male sex, n (%) 682 (64.4) 665 (62.9) 0.47Body mass index, kg/m2 25.0±3.2 24.9±3.1 0.50Hypertension, n (%) 660 (62.3) 650 (61.4) 0.69Diabetes mellitus, n (%) 316 (29.8) 305 (28.8) 0.63Dyslipidemia, n (%) 611 (57.7) 634 (59.9) 0.31Current smoker, n (%) 267 (25.2) 241 (22.8) 0.20Congestive heart failure, n (%) 120 (11.3) 125 (11.8) 0.74Ejection fraction, % 64.2±9.4 63.9±9.4 0.45Prior myocardial infarction, n (%) 19 (1.8) 17 (1.6) 0.87Prior percutaneous coronary intervention, n (%) 37 (3.5) 32 (3.0) 0.63Prior coronary bypass surgery, n (%) 2 (0.2) 6 (0.6) 0.18Clinical presentation, n (%) 0.66
Stable angina 471 (44.5) 490 (46.3) Unstable angina 432 (40.8) 422 (39.9) Acute myocardial infarction 156 (14.7) 146 (13.8)
Medications at discharge Statins, no. (%) 923 (87.2) 914 (86.4) 0.61Beta blockers, no. (%) 712 (67.2) 730 (69.0) 0.40ACE inhibitors, no. (%) 331 (31.3) 349 (33.0) 0.40Angiotensin receptor blockers, no. (%) 323 (30.5) 301 (28.4) 0.32
Baseline angiographic characteristics
Variables E-ZES+3-month DAPT(n=1,059)
Standard therapy(n=1,058) P
No. of lesions 1341 1346 Treated vessel, LAD, n (%) 707 (52.7) 722 (53.6) 0.54ACC/AHA class B2/C C, n (%) 910 (67.9) 932 (69.2) 0.46Lesion length, mm 19.6±10.1 20.1±10.8 0.21Type of drug-eluting stent, n (%)
Endeavor zotarolimus-eluting stents 1341 (100.0) - Cypher sirolimus-eluting stents - 383 (28.5) Xience everolimus-eluting stents - 404 (30.0) Resolute zotarolimus-eluting stents - 559 (41.5)
Multi-vessel intervention / patients, n (%) 233 (22.0) 248 (23.4) 0.44Number of lesions per patient 1.27±0.53 1.27±0.68 0.88Stent diameter, mm 3.18±0.42 3.17 ± 0.83 0.63Stent length per lesion, mm 22.7±10.1 22.9±10.7 0.35Adjuvant post-dilation, n (%) 539 (40.2) 540 (40.1) 0.97Maximum stent pressure, atm 16.2±3.7 16.5±3.6 0.35Use of GP IIb/IIIa inhibitors/patient, n (%) 20 (1.9) 21 (2.0) 0.89Procedure success, no. (%) 1339 (99.9) 1345 (99.9) 0.63
Quantitative Angiographic analysis
Variables E-ZES+3-month DAPT(n=1,059)
Standard therapy(n=1,058) P
No. of lesions 1341 1346
Pre-intervention
Reference vessel diameter, mm 3.0±0.5 3.0±0.5 0.13
Minimum luminal diameter, mm 1.1±0.5 1.0±0.5 0.23
Percent diameter stenosis, % 65.0±14.1 65.5±13.8 0.36
Post-intervention
Minimum luminal diameter, mm
In-stent 2.7±0.4 2.7±0.4 0.28
In-segment 2.2±0.5 2.1±0.5 0.58
Percent diameter stenosis, %
In-stent 11.2±7.8 11.1±8.1 0.65
In-segment 30.7±11.7 30.7±11.7 0.83
Clinical follow-up at 1 year
• Clinical follow-up at 1 year was completed for 2,086 of 2,117 patients (98.5%):
1,044 of 1,059 patients (98.6%) in E-ZES+3-month DAPT vs. 1,042 of 1,058 patients (98.5%) in standard therapy group (p=0.99).
Primary endpoint, by Kaplan-Meier method
No. at Risk E-ZES +3-month
DAPT 1059 1049 1037 1027 945
Standard therapy 1058 1046 1032 1024 920
* Primary end-point; A composite of death from CV cause, MI, stent thrombosis, TVR or bleeding at 1 year
0
2
8
6
4
Cum
ulat
ive
even
t rat
e (%
)
0 6 12
Standard therapyE-ZES + 3-month DAPT
4.7%
p-value for non-inferiority < 0.01
Months
Difference = 0.0% 95% CI, -2.5 to 2.5; p = 0.84
4.7%
Any death, MI, or stent thrombosis
0
2
8
6
4
Cum
ulat
ive
even
t rat
e (%
)
0 6 12
Standard therapyE-ZES + 3-month DAPT
1.3%
0.8%
p-value by log-rank test = 0.48
MonthsNo. at Risk
E-ZES+ 3-month DAPT 1059 1051 1045 1041 966
Standard therapy 1058 1051 1042 1037 937
Individual component of primary endpoint (ITT)
Variables E-ZES+3-month DAPT (n=1,059)
Standard therapy(n=1,058)
Difference(95% CI) p
Death, n (%)
From any cause 5 (0.5) 8 (1.0) -0.5% (-1.4 – 0.4) 0.39
From cardiovascular cause 2 (0.2) 4 (0.4) -0.2% (-0.6 – 0.3) 0.41
MI, n (%) 2 (0.2) 4 (0.4) -0.2% (-0.7 ~ 0.3) 0.41
TVR, n (%) 31 (3.9) 27 (3.7) 0.2% (-2.3 – 2.6) 0.70
Non-TVR, n (%) 15 (1.5) 11 (1.5) 0.0% (-1.3 – 1.4) 0.52
Stent thrombosis, n (%) 2 (0.2) 3 (0.3) -0.1% (-0.5 – 0.3) 0.65
< 1months 2 0
1-3 months 0 0
3-12 months 0 3
Bleeding, n (%)
Major or minor 5 (0.5) 10 (1.0) -0.5% (-1.2 – 0.2) 0.20
Major 2 (0.2) 6 (0.6) -0.4% (-0.9 – 0.1) 0.16
CVA, n (%) 6 (0.6) 6 (0.7) 0.1% (-0.1 – 1.0) 0.96
Subgroup analysis
Duration of dual antiplatelet therapy • Mean duration of DAPT;
- E-ZES+3-month DAPT group: 93±28 days (median, 93 day) - Standard therapy group: 364±31 days (median, 363 day)
• Interruption of DAPT regimen in E-ZES + 3-month DAPT group occurred in 62 / 1,059 patients (5.9%) (mean duration of
DAPT, 196±63 days; median, 173 day for the 62 patients).
• Reasons for interruption of the DAPT regimen; physicians’ mistake or failure of monitoring (n=26) physicians’ discretion (n=22) patients’ disagreement (n=13) repeat revascularization (n=1)
Clinical outcomes of both groups, *per protocol analysisCharacteristics E-ZES+3-month
DAPT (n=997)Standard therapy
(n=1,058)Difference(95% CI) p
Primary endpoint, n (%) 36 (4.6) 41 (4.7) -0.1% (-2.7–2.4) 0.69Any death, MI, or ST, n (%) 6 (0.6) 11 (1.3) -0.7% (-1.6–0.3) 0.27CV Death or MI, n (%) 4 (0.4) 7 (0.7) -0.3% (-0.9–0.4) 0.42Each components Death, n (%) From any cause 3 (0.3) 8 (1.0) -0.7% (-1.5–0.2) 0.15 From cardiovascular cause 2 (0.2) 4 (0.4) -0.2% (-0.6–0.3) 0.46MI, n (%) 2 (0.2) 4 (0.4) -0.2% (-0.7–0.3) 0.46TVR, n (%) 27 (3.7) 27 (3.7) 0.0% (-2.5–2.4) 0.94Non-TVR, n (%) 14 (1.5) 11 (1.5) 0.0% (-1.4–1.4) 0.55Stent thrombosis, n (%) 2 (0.2) 3 (0.3) -0.1% (-0.5–0.3) 0.70
< 1months 2 0 1-3 months 0 0 3-12 months 0 3
Bleeding, n (%) Major or minor 5 (0.5) 10 (1.0) -0.5% (-1.2–0.3) 0.24Major 2 (0.2) 6 (0.6) -0.4% (-0.9–0.2) 0.18
CVA, n (%) 5 (0.5) 6 (0.7) -0.2% (-0.9–0.6) 0.80
* Analysis after exclusion of the patients with interrupting 3-month DAPT
Summary• E-ZES+3-month DAPT was non-inferior to the standard
therapy for the primary endpoint (defined as a composite of death from CV cause, MI, stent thrombosis, TVR or bleeding at 1 year).
• The occurrence of stent thrombosis was similar between the two groups: From 3 months through 12 months following the index procedure, there were no stent thrombosis events in the E-ZES+3-month DAPT group.
• There were no significant difference of the other composite events or individual component of primary endpoint.
Limitations• One year of clinical follow-up may not be sufficient to assess
the fatal late outcomes (e.g, very late stent thrombosis).
• Because the patients with very high risks were not included, the generalized application of these results to the entire population demands careful attention.
• The comparator group was not treated with a single DES type.
• There was no 3-month vs. 12-month DAPT either within E-ZES or within other DES. - However, hypothesis of protection by E-ZES was the main
objective of this trial and the 1:1 matched randomization between E-ZES and the comparative DES was performed.
Conclusion
• E-ZES + 3-month DAPT could be safe and beneficial for the selected patients with coronary artery disease who may need to stop DAPT early after DES implantation.
Clinical implications• As an alternative PCI strategy, E-ZES + 3-month
DAPT could be useful for the selected patients, • those at risk for bleeding complications • those at risk of poor compliance with
medication, especially in the elderly population
• those with a high probability of unexpected non-cardiac surgery or invasive procedures
• those with a low risk of stent thrombosis
