1. STENT THROMBISIS Insights on Outcomes and Impact of DUAL ANTIPLATELET THERAPY Permanent Discontinuation SPIRIT II, SPIRIT III, SPIRIT IV and COMPARE
Elvin Kedhi
Gregg. W. Stone, Dean J. Kereiakes, Patrick W. Serruys,
Helen Parise, Martin Fahy, Charles A. Simonton,
Krishnankutty Sudhir, Poornima Sood, Pieter C. Smits.

2. Background
Recent studies have suggested that EES may reduce ST compared to PES, but no individual trial has been adequately powered for this endpoint
The on-going propensity of the first generation DES for ST has lead towards longer DAPT regimens in current practice (Current guidelines: 1 year or more), despite the associated risks of such treatment and despite the lack of evidence that such an approach improves clinical outcomes post PCI
Whether DAPT duration with newer generation DES can be shortened is unknown

3. Objective To investigate
ST incidence with second generation EES as compared to first generation PES
relation between the 2 year ST rates and permanent discontinuation of DAPT in EES and PES treated patients
from a patient level pooled analysis
SPIRIT II, SPIRIT III, SPIRIT IV and COMPARE trials

4. Design Summary of the four (EES vs PES) Trials Pooled for the Analysis (n=6789)
Study
Population
Geography
Study Design
Device usage
SPIRIT II
300 (3:1)
Europe
India
New Zealand
Multi-center
randomized
blinded
active-control
On-label
SPIRIT III
1002 (2:1)
USA
SPIRIT IV
3687(2:1)
COMPARE
1800(1:1)
Netherlands
Single-center
Randomised
All-comer
EES : Xience V Abbott Vascular, Santa Clara (CA) USA
PES : Taxus Boston Scientific, Natick (MA) USA

5. Methods
Baseline clinical, angiographic and procedural data of the four trials were pooled to allow for a patient-level analysis
Events as adjudicated in each trial were utilized
To adjust for slight differences in the baseline characteristics of the study population, a propensity score matching analysis was performed
The ST analyses were performed using time-to-event data and were compared with the log-rank test before and after PS adjustment

6. RESULTS Baseline patient demographic characteristics
EES
PES p
Age (years)
63.09 ± (4247)
63.36 ± 10,68 (2541)
0.30
Gender: Male
68.5% (2911/4247)
69.5% (1766/2541)
0.42
Diabetes mellitus
28.0% (1188/4244)
26.9% (681/2536)
0.31
- Insulin-treated
7.3% (310/4244)
7.3% (184/2536)
0.96
Smoking During Past Year
25.0% (1042/4176)
25.0% (624/2493)
0.95
Hypertension
70.1% (2976/4243)
66.1% (1677/2537)
<0.001
Hyperlipidemia
70.5% (2949/4184)
65.8% (1658/2518)
<0.0001

7. RESULTS Baseline patient demographic characteristics
EES
PES p
Prior CABG
7.2% (306/4244)
6.0% (153/2541)
0.06
Prior myocardial infarction
20.4% (847/4157)
19.0% (476/2508)
0.17
Prior PCI
14.5% (610/4194)
13.9% (350/2516)
0.49
Stable angina
53.8% (2254/4193)
49.8% (1248/2506)
0.002
Unstable angina
22.9% (959/4193)
22.3% (559/2506)
0.61
Stable ischemic heart disease
67.2% (2854/4247)
61.1% (1551/2539)
<0.0001
Acute coronary syndrome
32.8% (1393/4247)
38.9% (988/2539)

8. RESULTS Baseline procedural characteristics
EES
PES p
Vessel Location--RCA
34.2% (1865/5460)
33.8% (1132/3353)
0.71
Vessel Location--LAD
40.5% (2209/5460)
39.6% (1329/3353)
0.45
Vessel Location--LCX
25.0% (1364/5460)
25.9% (870/3353)
0.31
Vessel Location--LM
0.4% (22/5460)
0.7% (22/3353)
0.12
Vessel Location--SVG
0.5% (27/5460)
0.7% (24/3353)
0.19
Modified ACC/AHA Lesion Class A
9.0% (487/5417)
9.3% (309/3334)
0.67
Modified ACC/AHA Lesion Class B1
33.6% (1820/5417)
31.8% (1060/3334)
0.08
Modified ACC/AHA Lesion Class B2
31.7% (1716/5417)
31.0% (1034/3334)
0.52
Modified ACC/AHA Lesion Class C
25.7% (1394/5417)
27.9% (931/3334)
0.02

9. RESULTS Baseline procedural characteristics
ESS
PES p
Number treated lesions
1.29 ± 0.53 (4246)
1.32 ± 0.57 (2540)
0.02
Number treated vessels
1.20 ± 0.43 (4246)
1.22 ± 0.44 (2541)
0.04
Pre-procedure LL (mm)
15.96 ± 9.50 (4963)
16.78 ± (2867)
0.001
Pre-procedure RVD (mm)
2.68 ± 0.51 (5077)
2.68 ± 0.54 (2958)
0.88
Pre-procedure MLD (mm)
0.80 ± 0.42 (5103)
0.83 ± 0.44 (2986)
0.01
Pre-procedure %DS
70.3 ± 14.7 (5147)
69.5 ± 15.5 (3007)
0.03
Total stent length (mm)
32.2 ± 21.6 (4227)
34.0 ± 25.8 (2530)
0.004
Total number stents
1.7 ± 1.0 (4238)
1.7 ± 1.1 (2538)
0.05

10. DAPT compliance during 2y FU
EES
PES p
Discharge
Aspirin
97.3% (4123/4238)
96.9% (2454/2533)
0.33
Any thienopyridine
99.3% (4208/4238)
99.4% (2517/2533)
0.76
Aspirin + any thienopyridine
96.9% (4106/4238)
96.7% (2449/2533)
0.67
6-Months
95.9% (4047/4220)
94.5% (2379/2517)
0.01
Any Thienopyridine
96.8% (4085/4220)
96.9% (2439/2517)
0.89
93.6% (3964/4233)
92.5% (2338/2528)
0.07
1-Year
93.7% (3929/4194)
92.7% (2318/2501)
0.12
81.7% (3428/4194)
81.3% (2033/2501)
0.65
78.3% (3310/4230)
77.0% (1941/2522)
0.23
2-Year
91.0% (3772/4144)
91.1% (2243/2461)
53.3% (2209/4144)
47.8% (1177/2461)
<0.0001
50.0% (2107/4215)
44.5% (1117/2508)

11. Unadjusted def/prob (ARC) ST at 2y
<0.0001
2·3%
EES
PES
HR 0·30 [95% CI: 0·19 to 0·47]
p = <0·0001
Unadjusted ARC Definite/Probable (%)
Unadjustzd ARC Definite/Probable (%) 1 2 3
Time in Months
4247
4177
4082
3998
3479
2542
2463
2408
2350
2110
Number at risk
p= <.001
HR: 0.30 [95% CI: 0.19, 0.47]
0.7%
2.3% 6 9 12 15 18 21 24
HR: %CI:[0.10,0.46] p<0.0001

12. Unadjusted and PS adjusted definite/probable ST (ARC)
<0.0001
2·3%
EES
PES
HR 0·30 [95% CI: 0·19 to 0·47]
p = <0·0001
Unadjusted ARC Definite/Probable (%)
Unadjustzd ARC Definite/Probable (%) 1 2 3
Time in Months
4247
4177
4082
3998
3479
2542
2463
2408
2350
2110
Number at risk
p= <.001
HR: 0.30 [95% CI: 0.19, 0.47]
0.7%
2.3% 6 9 12 15 18 21 24
2.2%
0.9%
EES
PES
HR 0·37 [95% CI: 0·22 to 0·63]
p = <0·001
Adjusted ARC Definite/Probable (%)
Adjusted ARC Definite/Probable (%) 1 2 3
Time in Months
2348
2310
2263
2218
1959
2283
2236
2186
1968
Number at risk
p= <.001
HR: 0.37 [95% CI: 0.22, 0.63] 6 9 12 15 18 21 24

13. Unadjusted definite ST (ARC) at 2y
1·6%
0·5%
HR 0·30 [95% CI: 0·18 to 0·52]
p = <0·001
Unadjusted ARC Definite (%)
Unadjusted ARC Definite (%) 1 2 3
Time in Months
4247
4178
4084
4001
3483
2542
2466
2413
2358
2121
Number at risk
EES
PES
p= <.001
HR: 0.30 [95% CI: 0.18, 0.52]
0.5%
1.6% 6 9 12 15 18 21 24

14. Unadjusted and PS adjusted definite ST at 2 years (ARC)
EES
EES
PES 3
PES
EES
PES 3
HR 0·30 [95% CI: 0·18 to 0·52]
p = <0·001
HR: 0.30 [95% CI: 0.18, 0.52]
HR: 0.37 [95% CI: 0.19, 0.70]
HR 0·37 [95% CI: 0·19 to 0·70]
p = 0·001
p= <.001
p= 0.001 2 2
Unadjusted ARC Definite (%)
Adjusted ARC Definite (%)
Unadjusted ARC Definite (%)
1·6%
1.5%
1.5%
1.6%
Adjusted ARC Definite/Probable (%) 1 1
0·5%
0.5%
0.6%
0.6% 3 6 9 12 15 18 21 24 3 6 9 12 15 18 21 24
Time in Months
Time in Months
Number at risk
Number at risk
EES
4247
4178
4084
4001
3483
EES
2348
2311
2265
2221
1962
PES
2542
2466
2413
2358
2121
PES
2348
2286
2240
2193
1978

15. ST Incidence Rate 1 year EES PES HR [95% C.I.] p Early ST (0-30 Days)
EES
PES
HR [95% C.I.] p
Early ST (0-30 Days)
ARC Definite
0.2% (9)
0.8% (19)
0.28 [0.13,0.63]
0.0009
ARC Definite/Probable
1.0% (25)
0.21 [0.10,0.46]
<0.0001
Late ST ( Days)
0.1% (5)
0.4% (10)
0.30 [0.10,0.87]
0.02
0.6% (14)
0.38 [0.17,0.88]
ST (0-365 Days)
0.3% (14)
1.2% (29)
0.29 [0.15,0.54]
0.4% (18)
1.5% (38)
0.28 [0.16,0.49]
Cardiac Death or MI
(0-30 Days)
1.6% (68)
2.8% (70)
0.58 [0.41,0.81]
0.001
(0-365 Days)
2.7% (113)
4.5% (114)
0.59 [0.45,0.76]

16. ST (ARC) Incidence Rate at 2 years
EES
PES
HR [95% C.I.] p
Very Late ST ( Days)
ARC Definite
0.2% (6)
0.5% (11)
0.32 [0.12,0.87]
0.02
ARC Definite/Probable
0.3% (10)
0.8% (19)
0.31 [0.14,0.67]
0.001
ST (0-730 Days)
0.5% (20)
1.6% (39)
0.30 [0.18,0.52]
<0.0001
0.7% (28)
2.3% (56)
0.30 [0.19,0.47]
Cardiac Death or MI
(0-730 Days)
4.0% (166)
6.6% (163)
0.60 [0.48,0.74]
Does EES improved safety profile
have an impact on DAPT duration?

17. DAPT permanent discontinuation analysis (either aspirin and/or a thienopyridine)
DAPT status at 0,1,6, 12 and 24 months as well as at event time was known in all studies
1-6 m
NO DAPT
ST 2y
DAPT
6-12 m
NO DAPT
DAPT
12-24m
PCI
1 month
6 months
12 months
24 months
DAPT
Patients in whom a ST occurred while not on DAPT were included in the respective DAPT
interruption group based on their DAPT status at the time of the event, regardless of DAPT
usage afterwards

18. ST at 2 years according DAPT discontinuation timing
DAPT interruption
1-6 m
6-12m
12-24m
No DAPT interruption
>24m p
EES
75.0% (75/100)
92.3% (562/609)
97.8% (1168/1194)
97.5% (1969/2019)
<0.0001
ARC Definite
1.1% (1)
0.2% (1)
0.3% (4)
0.6% (11)
0.43
ARC Probable
0.0% (0)
0.3% (2)
0.2% (2)
0.2% (4)
0.86
ARC Def/Prob
0.5% (3)
0.5% (6)
0.8% (15)
0.75
PES
74.3% (55/74)
94.6% (336/355)
98.2% (808/823)
97.1% (1023/1054)
6.2% (4)
1.1% (4)
1.4% (11)
1.3% (14)
0.01
1.2% (4)
1.0% (8)
0.3% (3)
0.16
2.3% (8)
2.3% (19)
1.5% (16)
0.05

19. Two-year Cumulative Def/Prob ST (ARC) according to DAPT Permanent Discontinuation
p for trend= 0.75
p for trend = 0.05
discontinuation at 24 m
No DAPT
DAPT discontinuation
1-6 m
DAPT discontinuation
6-12 m
DAPT discontinuation
12-24 m

20. DAPT permanent discontinuation LANDMARK ANALYSIS 6m
ST 2y
DAPT
Events of first 6m excluded
Group 1
6-12m
NO DAPT
DAPT
Group 1
12-24 m
NO DAPT
DAPT
Group 3
>24m
1 month
6 months
12 months
24 months
PCI
DAPT permanent discontinuation

21. Two-year Cumulative Definite/Probable Stent Thrombosis (ARC)
Landmark Analysis Beyond 6 Months
2.5
EES
PES
p for trend = 0·97
p for trend = 0·04 2
1·7
1.5
p = 0·82
p = 0·51
1·2
Stent Thrombosis Definite/Probable ARC (%)
p = 0·86
p = 0·17 1
p = 0·89
p = 0·01
0·5
1.5
0·4
0·4
0·3
discontinuation at 24 m
No DAPT
DAPT discontinuation
6-12 m
DAPT discontinuation
12-24 m
discontinuation at 24 m
No DAPT
DAPT discontinuation
6-12 m
DAPT discontinuation
12-24 m

22. Conclusions
Second generation EES (Xience V) was associated with a significant reduction in definite and definite/probable ST at 2 years as compared to first generation PES (Taxus)
This reduction was already present in early phase and increased in magnitude during the first and second year of FU
The reduction in ST rates with EES was paralleled by a significant reduction in the rate of the composite safety endpoint of Death and Myocardial Infarction

23. Conclusions
Permanent DAPT discontinuation at any time beyond one month did not impact ST rates at 2 years in EES (Xience V) treated patients, while DAPT treatments longer that 2 years may be safer for PES (Taxus) treated patients
The hypothesis that DAPT could be safely permanently discontinued starting from 6 months after EES implantation is supported from findings of the landmark analysis
These results should be regarded as hypothesis generating and need to be confirmed by larger dedicated randomised studies