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
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
•
Because one of strong predictor for stent thrombosis is early
discontinuation of clopidogrel, prolonged dual antiplatelet therapy (DAPT)
is highly recommended.
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.
•
However, prolonged use of clopidogrel is associated with many potential
risks; bleeding, higher cost, and poor patient compliance or premature
discontinuation.
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.
•
Reports from several trials of the Endeavor zotarolimus-eluting stent (EZES) have shown beneficial efficacy and safety, despite a relatively short
duration of DAPT.
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
Recent OCT study reported sufficient strut coverage following E-ZES implantation
Kim JS, et al. J Am Coll Cardiol Intv 2009;2:1240-7.
as early as 3 months post-procedure.
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
Hahn JY, et al. Circ J 2010;74:2314-21.
clopidogrel 3 months post intervention.
Hypothesis & Objective
Hypothesis;
Three-month DAPT after E-ZES implantation (E-ZES+3month 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.
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;
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) ischemiadriven 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+3month 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).
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
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:
31 patients excluded
- 16 Withdrawal of consent
- 15 Met exclusion criteria
Other DES with 12-month DAPT
E-ZES + 3-month DAPT (n=1059)
Diabetes mellitus
subset (N=292)
E-ZES
(n=146)
R-ZES
(n=146)
Acute coronary syndrome
subset (N=601)
E-ZES
(n=301)
R-ZES
(n=300)
Standard therapy (n=1058)
Short-length DES
Subset (N=681)
E-ZES
(n=341)
SES
(n=340)
Long-length DES
Subset (N=543)
E-ZES
(n=271)
EES
(n=272)
R-ZES = Resolute zotarolimus-eluting stent ; SES = sirolimus-eluting stent; EES = everolimus-eluting stents
Baseline clinical characteristics
Variables
Age (year)
Male sex, n (%)
Body mass index, kg/m2
Hypertension, n (%)
Diabetes mellitus, n (%)
Dyslipidemia, n (%)
Current smoker, n (%)
Congestive heart failure, n (%)
Ejection fraction, %
Prior myocardial infarction, n (%)
Prior percutaneous coronary intervention, n (%)
Prior coronary bypass surgery, n (%)
Clinical presentation, n (%)
Stable angina
Unstable angina
Acute myocardial infarction
Medications at discharge
Statins, no. (%)
Beta blockers, no. (%)
ACE inhibitors, no. (%)
Angiotensin receptor blockers, no. (%)
E-ZES+3-month DAPT
(n=1,059)
Standard therapy
(n=1,058)
62.4±9.4
682 (64.4)
25.0±3.2
660 (62.3)
316 (29.8)
611 (57.7)
267 (25.2)
120 (11.3)
64.2±9.4
19 (1.8)
37 (3.5)
2 (0.2)
62.4±9.8
665 (62.9)
24.9±3.1
650 (61.4)
305 (28.8)
634 (59.9)
241 (22.8)
125 (11.8)
63.9±9.4
17 (1.6)
32 (3.0)
6 (0.6)
471 (44.5)
432 (40.8)
156 (14.7)
490 (46.3)
422 (39.9)
146 (13.8)
923 (87.2)
712 (67.2)
331 (31.3)
323 (30.5)
914 (86.4)
730 (69.0)
349 (33.0)
301 (28.4)
P
0.94
0.47
0.50
0.69
0.63
0.31
0.20
0.74
0.45
0.87
0.63
0.18
0.66
0.61
0.40
0.40
0.32
Baseline angiographic characteristics
Variables
No. of lesions
Treated vessel, LAD, n (%)
ACC/AHA class B2/C C, n (%)
Lesion length, mm
Type of drug-eluting stent, n (%)
Endeavor zotarolimus-eluting stents
Cypher sirolimus-eluting stents
Xience everolimus-eluting stents
Resolute zotarolimus-eluting stents
Multi-vessel intervention / patients, n (%)
Number of lesions per patient
Stent diameter, mm
Stent length per lesion, mm
Adjuvant post-dilation, n (%)
Maximum stent pressure, atm
Use of GP IIb/IIIa inhibitors/patient, n (%)
Procedure success, no. (%)
E-ZES+3-month DAPT Standard therapy
(n=1,059)
(n=1,058)
P
1341
707 (52.7)
910 (67.9)
19.6±10.1
1346
722 (53.6)
932 (69.2)
20.1±10.8
0.54
0.46
0.21
1341 (100.0)
233 (22.0)
1.27±0.53
3.18±0.42
22.7±10.1
539 (40.2)
16.2±3.7
20 (1.9)
1339 (99.9)
383 (28.5)
404 (30.0)
559 (41.5)
248 (23.4)
1.27±0.68
3.17 ± 0.83
22.9±10.7
540 (40.1)
16.5±3.6
21 (2.0)
1345 (99.9)
0.44
0.88
0.63
0.35
0.97
0.35
0.89
0.63
Quantitative Angiographic analysis
Variables
No. of lesions
E-ZES+3-month DAPT Standard therapy
(n=1,059)
(n=1,058)
P
1341
1346
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
65.0±14.1
65.5±13.8
0.36
In-stent
2.7±0.4
2.7±0.4
0.28
In-segment
2.2±0.5
2.1±0.5
0.58
In-stent
11.2±7.8
11.1±8.1
0.65
In-segment
30.7±11.7
30.7±11.7
0.83
Pre-intervention
Percent diameter stenosis, %
Post-intervention
Minimum luminal diameter, mm
Percent diameter stenosis, %
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
0.08
* Primary end-point; A composite of death from CV cause, MI, stent thrombosis, TVR or bleeding at 1 year
0.06
0.07
Standard therapy
E-ZES + 3-month DAPT
Difference = 0.0%
95% CI, -2.5 to 2.5; p = 0.84
0.05
6
0.04
p-value for non-inferiority < 0.01
0.02
0.03
4
4.7%
4.7%
2
0.00
0.01
rate (%)
event (%)
Cumulative
Cumulative incidence
8
0
No. at Risk
00
66
12
12
E-ZES +3-month
DAPT
1059
1049 Months after
1037
1027
the index procedure
945
Standard therapy
1058
1046
920
1032
1024
Months
Death from any cause, myocardial infarction, or stent thrombosis
0.08
Any death, MI, or stent thrombosis
8
0.06
p-value by log-rank test = 0.48
0.04
0.05
6
0.02
0.03
4
2
0.01
1.3%
0.8%
0.00
Cumulative
incidencerate
(%) (%)
event
Cumulative
0.07
Standard therapy
E-ZES + 3-month DAPT
0
00
No. at Risk
E-ZES+ 3-month
DAPT
Standard therapy
66
12 Months
12
1059
Months after the index procedure
1051
1045
1041
966
1058
1051
937
1042
1037
Individual component of primary endpoint (ITT)
E-ZES+3-month
DAPT (n=1,059)
Standard therapy
(n=1,058)
Difference
(95% CI)
p
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
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
6 (0.6)
6 (0.7)
0.1% (-0.1 – 1.0)
0.96
Variables
Death, n (%)
Bleeding, n (%)
CVA, n (%)
Subgroup analysis
Subgroup
3Mo-DAPT
12Mo-DAPT
Difference
95% CI
p-value p-for-interaction
Age
< 65 (n=1153)
≥ 65 (n=964)
20/582 (4.4%)
20/477 (5.1%)
18/571 (4.5%)
23/487 (4.8%)
-0.2%
0.4%
(-3.8%~3.3%)
(-2.8%~3.6%)
0.805
0.636
Gender
Male (n=1347)
Female (n=770)
29/682 (5.8%)
11/377 (3.0%)
26/665 (5.1%)
15/393 (3.8%)
0.6%
-0.9%
(-3.0%~4.2%)
(-3.4%~1.7%)
0.786
0.483
Diabetes mellitus
Yes (n=621)
No (n=1496)
11/316 (3.8%)
29/743 (5.1%)
14/305 (4.7%)
27/753 (4.6%)
-0.9%
0.5%
(-4.1%~2.4%)
(-2.7%~3.6%)
0.426
0.769
Congestive heart failure
Yes (n=245)
No (n=1872)
4/120 (3.4%)
36/939 (4.8%)
5/125 (4.0%)
36/933 (4.8%)
-0.6%
0.0%
(-5.4%~4.1%)
(-2.7%~2.8%)
0.783
0.897
Multivessel disease
Yes (n=910)
No (n=1207)
18/456 (4.2%)
22/603 (5.3%)
19/454 (4.3%)
22/604 (5.1%)
-0.1%
0.1%
(-2.8%~2.6%)
(-3.9%~4.2%)
0.829
0.934
Reference diameter
≤ 3.0mm (n=669)
> 3.0mm (n=1448)
8/322 (2.5%)
32/737 (5.7%)
16/347 (6.6%)
25/711 (3.5%)
-4.1%
2.2%
(-8.6%~0.4%)
(-0.7%~5.0%)
0.166
0.370
Lesion length
< 20mm (n=1301)
≥ 20mm (n=816)
20/653 (3.9%)
20/406 (6.0%)
15/648 (3.4%)
26/410 (6.4%)
0.5%
-0.4%
(-2.7%~3.8%)
(-4.3%~3.5%)
0.330
0.400
Subsets
Acute coronary syndrome (n=601)
Diabetes mellitus (n=292)
Long (n=543)
Short (n=681)
12/301 (6.4%)
4/146 (2.8%)
15/271 (7.2%)
9/341 (2.7%)
6/300 (2.0%)
5/146 (3.4%)
22/272 (8.4%)
8/340 (4.1%)
4.4%
-0.6%
-1.2%
-1.5%
(-1.4%~10.2%)
(-4.6%~3.3%)
(-6.6%~4.3%)
(-5.3%~2.4%)
0.158
0.735
0.219
0.855
Overall (n=2117)
40/1059 (4.7%)
41/1058 (4.7%)
0.0%
(-2.5%~2.5%)
0.843
0.599
0.424
0.416
0.840
0.902
0.105
0.203
0.344
-5
-2.5
Favor E-ZES +
3mo DAPT
0
Difference (%)
2.5
5
Favor Standard
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
Difference
(95% CI)
E-ZES+3-month
DAPT (n=997)
Standard therapy
(n=1,058)
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 (%)
Each components
Death, n (%)
From any cause
From cardiovascular cause
MI, n (%)
TVR, n (%)
Non-TVR, n (%)
Stent thrombosis, n (%)
< 1months
1-3 months
3-12 months
Bleeding, n (%)
Major or minor
Major
CVA, n (%)
4 (0.4)
7 (0.7)
-0.3% (-0.9–0.4) 0.42
3 (0.3)
2 (0.2)
2 (0.2)
27 (3.7)
14 (1.5)
2 (0.2)
2
0
0
8 (1.0)
4 (0.4)
4 (0.4)
27 (3.7)
11 (1.5)
3 (0.3)
0
0
3
-0.7% (-1.5–0.2)
-0.2% (-0.6–0.3)
-0.2% (-0.7–0.3)
0.0% (-2.5–2.4)
0.0% (-1.4–1.4)
-0.1% (-0.5–0.3)
5 (0.5)
2 (0.2)
5 (0.5)
10 (1.0)
6 (0.6)
6 (0.7)
-0.5% (-1.2–0.3) 0.24
-0.4% (-0.9–0.2) 0.18
-0.2% (-0.9–0.6) 0.80
Characteristics
* Analysis after exclusion of the patients with interrupting 3-month DAPT
p
0.15
0.46
0.46
0.94
0.55
0.70
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