A New Strategy for Discontinuation of Dual Antiplatelet Therapy: Real Safety and Efficacy of 3-Month...
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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 Cardiovascular Hospital

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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,

Severance Cardiovascular Hospital

Yonsei University College of Medicine, Seoul, Korea

RESET ClinicalTrials.gov identifier: NCT01145079


Funding sources

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).


Background i

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 ii

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.


Background iii

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.


Hypothesis objective

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.


Randomization

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;


Inclusion criteria

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

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

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

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).


Myeong ki hong md ph d on behalf of reset investigators professor division of cardiology severance cardiovascula

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


Myeong ki hong md ph d on behalf of reset investigators professor division of cardiology severance cardiovascula

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


Baseline clinical characteristics

Baseline clinical characteristics


Baseline angiographic characteristics

Baseline angiographic characteristics


Quantitative angiographic analysis

Quantitative Angiographic analysis


Clinical follow up at 1 year

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

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


Any death mi or stent thrombosis

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


Individual component of primary endpoint itt

Individual component of primary endpoint (ITT)


Subgroup analysis

Subgroup analysis

Favor E-ZES + 3mo DAPT

Favor Standard therapy


Duration of dual antiplatelet therapy

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 analysis

Clinical outcomes of both groups, *per protocol analysis

* Analysis after exclusion of the patients with interrupting 3-month DAPT


Summary

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

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

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

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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