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: NCT

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. A and A102064), the Korea Health 21 R&D Project, Ministry of Health & Welfare, Republic of Korea (No. A085136).

4. 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:
Pfisterer M, et al. J Am Coll Cardiol 2006;48:
Brar SS, et al. J Am Coll Cardiol 2008;51:
Bhatt DL, et al. N Engl J Med 2006;354:
Grines CL, et al. Circulation 2007;115:813-8.
Stone GW, et al. Am J Cardiol 2008;102:
Fajadet J, et al. Circulation 2006;114:
Meredith IT, et al. Am J Cardiol. 2007;100:S56-S61.
Leon MB, et al. J Am Coll Cardiol 2010;55:

5. 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:

6. 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:

7. Hypothesis & Objective
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.

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

9. Inclusion criteria Exclusion 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)

10. 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

11. 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%.

12. 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; , SAS Institute, NC) and R version (R Development Core Team, Vienna, Austria).

13. 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

14. 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

15. Baseline clinical characteristics
Variables
E-ZES+3-month DAPT
(n=1,059)
Standard therapy
(n=1,058) P
Age (year)
62.4±9.4
62.4±9.8
0.94
Male sex, n (%)
682 (64.4)
665 (62.9)
0.47
Body mass index, kg/m2
25.0±3.2
24.9±3.1
0.50
Hypertension, n (%)
660 (62.3)
650 (61.4)
0.69
Diabetes mellitus, n (%)
316 (29.8)
305 (28.8)
0.63
Dyslipidemia, n (%)
611 (57.7)
634 (59.9)
0.31
Current smoker, n (%)
267 (25.2)
241 (22.8)
0.20
Congestive heart failure, n (%)
120 (11.3)
125 (11.8)
0.74
Ejection fraction, %
64.2±9.4
63.9±9.4
0.45
Prior myocardial infarction, n (%)
19 (1.8)
17 (1.6)
0.87
Prior percutaneous coronary intervention, n (%)
37 (3.5)
32 (3.0)
Prior coronary bypass surgery, n (%)
2 (0.2)
6 (0.6)
0.18
Clinical 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)
0.61
Beta blockers, no. (%)
712 (67.2)
730 (69.0)
0.40
ACE inhibitors, no. (%)
331 (31.3)
349 (33.0)
Angiotensin receptor blockers, no. (%)
323 (30.5)
301 (28.4)
0.32

16. 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)
0.54
ACC/AHA class B2/C C, n (%)
910 (67.9)
932 (69.2)
0.46
Lesion length, mm
19.6±10.1
20.1±10.8
0.21
Type 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)
0.44
Number of lesions per patient
1.27±0.53
1.27±0.68
0.88
Stent diameter, mm
3.18±0.42
3.17 ± 0.83
0.63
Stent length per lesion, mm
22.7±10.1
22.9±10.7
0.35
Adjuvant post-dilation, n (%)
539 (40.2)
540 (40.1)
0.97
Maximum stent pressure, atm
16.2±3.7
16.5±3.6
Use of GP IIb/IIIa inhibitors/patient, n (%)
20 (1.9)
21 (2.0)
0.89
Procedure success, no. (%)
1339 (99.9)
1345 (99.9)

17. 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
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
In-stent
2.7±0.4
0.28
In-segment
2.2±0.5
2.1±0.5
0.58
11.2±7.8
11.1±8.1
0.65
30.7±11.7
0.83

18. 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).

19. 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 6 12
Months
No. at Risk
E-ZES +3-month DAPT
1059
1049
1037
1027
945
Standard therapy
1058
1046
1032
1024
920

20. Any death, MI, or stent thrombosis8
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% 6 12
Months
No. at Risk
E-ZES+ 3-month DAPT
1059
1051
1045
1041
966
Standard therapy
1058
1042
1037
937

21. 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 (%)
-0.2% (-0.7 ~ 0.3)
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 (%)
3 (0.3)
-0.1% (-0.5 – 0.3)
0.65
< 1months 2
1-3 months
3-12 months 3
Bleeding, n (%)
Major or minor
10 (1.0)
-0.5% (-1.2 – 0.2)
0.20
Major
6 (0.6)
-0.4% (-0.9 – 0.1)
0.16
CVA, n (%)
6 (0.7)
0.1% (-0.1 – 1.0)
0.96

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

23. 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)

24. Clinical outcomes of both groups, *per protocol analysis
Characteristics
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)
0.69
Any death, MI, or ST, n (%)
6 (0.6)
11 (1.3)
-0.7% (-1.6–0.3)
0.27
CV Death or MI, n (%)
4 (0.4)
7 (0.7)
-0.3% (-0.9–0.4)
0.42
Each 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)
-0.2% (-0.6–0.3)
0.46
MI, n (%)
-0.2% (-0.7–0.3)
TVR, n (%)
27 (3.7)
0.0% (-2.5–2.4)
0.94
Non-TVR, n (%)
14 (1.5)
11 (1.5)
0.0% (-1.4–1.4)
0.55
Stent thrombosis, n (%)
-0.1% (-0.5–0.3)
0.70
< 1months 2
1-3 months
3-12 months 3
Bleeding, n (%)
Major or minor
5 (0.5)
10 (1.0)
-0.5% (-1.2–0.3)
0.24
Major
-0.4% (-0.9–0.2)
0.18
CVA, n (%)
6 (0.7)
-0.2% (-0.9–0.6)
0.80 ;
* Analysis after exclusion of the patients with interrupting 3-month DAPT

25. 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.

26. 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.

27. 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.

28. 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