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Myeong-Ki Hong , MD. Ph D, on behalf of RESET investigators Professor, Division of Cardiology, Severance Cardiovascula

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 . Myeong-Ki Hong , MD. Ph D, on behalf of RESET investigators Professor, Division of Cardiology,

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Myeong-Ki Hong , MD. Ph D, on behalf of RESET investigators Professor, Division of Cardiology, Severance Cardiovascula

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  1. 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 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 RESET ClinicalTrials.gov identifier: NCT01145079

  2. Funding sources Supported 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).

  3. 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.

  4. Background - II Recent OCT study reported sufficient strut coverage following E-ZES implantation as early as 3 months post-procedure. Kim JS, et al. J Am Coll Cardiol Intv 2009;2:1240-7.

  5. Background - III 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. Hahn JY, et al. Circ J 2010;74:2314-21.

  6. Hypothesis & Objective Hypothesis; 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.

  7. Study design and patients Randomization • Prospective, open label, randomized trial • Participating centers; conducted at 26 sites in Korea • 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;

  8. 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)

  9. 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

  10. 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%.

  11. 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).

  12. Study organization • 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

  13. Study at a glance & Final Enrollment 2,148 patients enrolled and randomized Divided into 4 subsets and 1:1 randomization was performed. E-ZES + 3-month DAPT Standard Therapy: Other DES with 12-month DAPT 31 patients excluded - 16 Withdrawal of consent - 15 Met exclusion criteria E-ZES + 3-month DAPT (n=1059) Standard therapy (n=1058) Diabetes mellitus subset (N=292) Acute coronary syndrome subset (N=601) Short-length DES Subset (N=681) Long-length DES Subset (N=543) E-ZES (n=146) R-ZES (n=146) E-ZES (n=301) R-ZES (n=300) E-ZES (n=341) SES (n=340) E-ZES (n=271) EES (n=272) R-ZES = Resolute zotarolimus-eluting stent ; SES = sirolimus-eluting stent; EES = everolimus-eluting stents

  14. Baseline clinical characteristics

  15. Baseline angiographic characteristics

  16. Quantitative Angiographic analysis

  17. 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).

  18. Primary endpoint, by Kaplan-Meier method * Primary end-point; A composite of death from CV cause, MI, stent thrombosis, TVR or bleeding at 1 year 8 Standard therapy E-ZES + 3-month DAPT Difference = 0.0% 95% CI, -2.5 to 2.5; p = 0.84 6 4.7% 4.7% p-value for non-inferiority < 0.01 Cumulative event rate (%) 4 2 0 0 6 12 Months

  19. Any death, MI, or stent thrombosis 8 Standard therapy E-ZES + 3-month DAPT p-value by log-rank test = 0.48 6 4 Cumulative event rate (%) 2 1.3% 0.8% 0 0 6 12 Months

  20. Individual component of primary endpoint (ITT)

  21. Subgroup analysis Favor E-ZES + 3mo DAPT Favor Standard therapy

  22. 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)

  23. Clinical outcomes of both groups, *per protocol analysis * Analysis after exclusion of the patients with interrupting 3-month DAPT

  24. 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.

  25. 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.

  26. 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.

  27. 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

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