1. Dual Antiplatelet Therapy (DAPT) Duration
Dilemma: Recent Trials And Guidelines For
Clinical Practice
Dean J. Kereiakes, MD FACC FSCAI
Medical Director, The Christ Hospital Heart & Vascular Center and the Lindner Research Center at The Christ Hospital, Cincinnati, Ohio
Professor of Clinical Medicine, Ohio State University

2. Dean J. Kereiakes, MD – Disclosure Information
Consulting fees:
Modest: Medpace, HCRI, Ablative Solutions, Inc.
Significant: Boston Scientific, Abbott Vascular, REVA Medical Inc.

3. 2011 ACC/AHA/SCAI Guideline for PCI
DURATION
The duration of P2Y12 inhibitor therapy
should generally be as follows: I
IIa
IIb
III B
In patients receiving a stent (BMS or DES)
during PCI for ACS, P2Y12 inhibitor therapy should be given for at least 12 months. Options include clopidogrel 75 mg daily,prasugrel 10 mg daily or ticagrelor 90mg twice daily
b. In patients receiving DES for non-ACS indication, clopidogrel should be given for at least 12 months if patients are not at high risk for bleeding.
c. In patients receiving BMS for a non-ACS indication, clopidogrel should be given for a minimum of 1 month and ideally up to 12 months (unless patient is at increased risk for bleeding;then it should be given for a minimum of 2 weeks) I
IIa
IIb
III B I
IIa
IIb
III B
Circulation 2011;124:e 3 3 3

4. Randomized Trials of DAPT Duration
Patients
Test
Randomization
1° EP
Prolonged DAPT Studies
REAL/ZEST Late
2701
DES
1 vs. 2 yrs
A vs. A+C
Superiority
D/MI
2 yrs after rand
DAPT
N=20,645
(15,245 DES)
(5,400 BMS)
1 vs. 2.5 yrs*
A+P vs. DAPT (clop or pras)
NI and Sup
D/MI/CVA
ST, Bleeding
PRODIGY
N=1,800
DES, BMS
6 mos vs. 2 yrs
Abbreviated DAPT Studies
EXCELLENT
N=1,443
SES and EES
6 vs. 12 mos
Noninferiority
D/MI/TVR
ISAR-SAFE**
N=6,000
6 vs. 12 mos*
A+P vs. A+C
D/MI/CVA/
ST/TIMI MB
ITALIC
N=3,700
EES
Urg Revasc/MB
OPTIMIZE
N=3,120
ZES
3 vs. 12 mos
D/MI/CVA/MB
RESET‡
N=2,148
E-ZES vs RZES, SES, EES
A+C vs. A+C
CVD/MI/ST/
ID-TVR, Bleed
‡Strategy not DAPT duration **
*Plus a 3 month washout period

5. Correlation of Clopidogrel Therapy Discontinuation in REAL-world Patients Treated with Drug-Eluting Stent Implantation and Late Coronary Arterial Thrombotic Events:
REAL-LATE Trial
Patients on current dual antiplatelet therapy without MACCE or major bleeding
for at least the first 12 months after DES implantation (Total N~2,700)
1:1 randomization Stratified by (1) centers
(2) Initial DES types
Aspirin + clopidogrel
Dual-therapy
(N=1,000)
Aspirin Mono-therapy
(N=1,000)
Sample Size: <25% of patients (600 DES) reached 2 year follow-up (incomplete follow-up)
Regular Clinical assessment after randomization
Primary end points: The composite of cardiac death or MI 5

6. PRODIGY Study: 6 vs 24m DAPT after DES or BMS, randomized at 30 days
2,013 randomly allocated to recieve one of the four study stent types
499 randomized to and received EES
498 randomized to and received PES
500 randomized to and received ZES
502 randomized to and received BMS
(1497 DES)
1,970 DES and BMS randomized at 30 days
694 Excluded, 353 Not Meeting Inclusion Criteria
232 Refused to Participate, 109 Operator’s choice
Sample Size: <1500 DES patient reached 2 year follow-up (1/4 of patient in the primary analysis received BMS)
Allowed those randomized to 6m to actually take 30 days if BMS, accentuating difference in bleeding
983
6 Months DAPT
Not blinded
987
24 Months DAPT
BMS 30d treatment
allowed and counted as 6m Ff f
984
2 year follow-up
Primary EP
Death,MI,CVA Ff f
979
2 year follow-up
Valgimigli, M., et al., Circulation, 2012. 6

7. EXCELLENT Trial Design
Prospective, open label, two-arm, randomized multi-center trial
1372 Patients Matching Enrollment Criteria
19 centers in Korea
Everolimus-Eluting Stent N=1029
Randomization
3:1
Sirolimus-Eluting Stent N=343
DAT 6 mo N=515
DAT 12 mo N=514
2x2 factorial design
DAT 6 mo N=171
DAT 12 mo N=172
Percutaneous Coronary Intervention
Sample Size: 1442
Endpoints: no difference in TVF, no difference in bleeding 
1mo
3mo
9mo
12mo
Clinical
Angiographic
3yr
2yr
4yr
5yr
clinical endpoint evaluation
Primary endpoint:
In-segment LL
TVF*
Am Heart J 2009 May;157: e1.
Gwon et al. Circ. 2012;125:
*CD,MI,IDTVR 7 7

8. OPTIMIZE STUDY 3,120 minimally selected* patients undergoing PCI
with E-ZES in 33 sites in Brazil
Randomization ** (1:1)
DAPT for 3 months DAPT for 12 months
N = 1, N= 1,560
Clinical FU at 1, 3, 6, 12 and 18 months and yearly up to 3 yrs
Primary endpoint: Net Clinical Benefit † at 12-month FU
Feres et al. AHJ 2012:164:810 e3
Feres et al. TCT 2013 LBCT
* Exclude ACS with + biomarker; prior DES Rx;SVG target
** Stratified by DM and Institution; not blinded
† composite endpoint of all-cause death, MI, CVA and major bleeding

9. Ischemic Endpoints By DAPT Duration In Randomized Trials
EXCELLENT t PRODIGY tt REAL-LATE/ OPTIMIZE tttt
ZEST-LATE ttt
6 mos (n=957) mos (n=1546) mos (n=1344) mos (n=1563)
12 mos (n=970) mos (n=1500) mos (n=1357) mos (n=1556)
Adapted from t Gwon et al. ACC 2011
tt Valgimigli et al. ESC 2011
ttt Park et al. NEJM 2010;362:1374
tttt Feres et al. TCT 2013 LBCT
*Cardiac death / MI / TVR
**Death / MI, CVA, Revasc
***Death/MI/Revasc

10. Major Bleeding (TIMI or GUSTO/REPLACE 2
Major Bleeding (TIMI or GUSTO/REPLACE 2* ) By DAPT Duration In Randomized Trials
EXCELLENT t PRODIGY tt REAL-LATE/ OPTIMIZE tttt*
ZEST-LATE ttt
6 mos mos mos mos
12 mos mos mos mos
P=0.42
P=0.04
P=0.35
P=0.66
Adapted from t Gwon et al. ACC 2011
tt Valgimigli et al. ESC 2011
ttt Park et al. NEJM 2010;362:1374
tttt Feres et al. TCT 2013 LBCT

11. Type II, III or V BARC Bleeding: PRODIGY
CEC adjudicated P=
7.4
3.5
Hazard ratio: 0.46 ( )
No. at Risk
24-month clopidogrel
987
925
884
6-month clopidogrel
983
919
881
Valgimigli et al. Circulation 2012; 125:

12. PRODIGY BARC Bleeding Categories
*BARC 2 “Any overt, actionable sign of hemorrhage that…meets at least one of the following criteria: (1) requiring nonsurgical, medical intervention by a healthcare professional, (2) leading to hospitalization or increased level of care, or (3) prompting evaluation…no change in hemoglobin, blood transfusion or hemodynamic sequelae are required”
Mehran et al. Circ 2011;123:

13. Time After Initial Procedure (Months)
OPTIMIZE : NACCE at 1 Year (All-Cause Death, MI, Stroke, Major Bleeding)
Cumulative Incidence
of NACCE (%)
Time After Initial Procedure (Months) 12 10 15 5 3 6 9
3M DAPT
12M DAPT
Log-Rank P = 0.838
6.0
5.8
No. at risk
3M DAPT
1563
1520
1504
1468
1384
12M DAPT
1556
1514
1497
1466
1381
Feres et al. TCT 2013 LBCT

14. Zone of non-inferiority Pre-specified margin = 2.7%
Primary Endpoint: NACCE at 1 Year (All-Cause Death, MI, Stroke, Major Bleeding)
3M DAPT
(N = 1563)
6.1%
12M DAPT
(N = 1556)
5.9%
Difference : 0.2%
Upper 1-sided 95% CI : 2.0%
Non-inferior
Upper one-sided 95% CI
Non-inferiority
P value =
0.002
Zone of non-inferiority
Pre-specified margin = 2.7%
-1.0
-0.5
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0 %
Primary Non-Inferiority Endpoint Met

15. OPTIMIZE :Other Clinical Events at 1 Year*
Ischemic / Efficacy
Bleeding
/ Safety
12%
12%
9.4%
Events (%)
14%
12.5%
*All P=NS
Feres et al. TCT 2013 LBCT

16. OPTIMIZE: Stent Thrombosis* vs. Major Bleeding
ARC Def./Prob. Stent Thrombosis
3M DAPT
12M DAPT
Time After Initial Procedure (months)
0.26
0.07
P = 0.18
HR 3.97
( ) 12 10 5 3 6 9
P = 0.64
HR 0.81
( )
Cumulative Incidence (%)
Major Bleeding
0.4
0.2
Cumulative Incidence (%)
P = 0.31
HR 0.50
( )
Time After Initial Procedure (months) 12 10 5 3 6 9
P = 0.79
HR 0.87
( )
12M DAPT
3M DAPT
~4x 2x
0.7
0.6
*0.2% absolute difference
Feres et al. TCT 2013 LBCT

17. RESET Primary Endpoint: 2,148 patients enrolled and randomized
Divided into 4 subsets and 1:1 randomization was performed
31 patients excluded
- 16 withdrawal of consent
- 15 Met exclusion criteria
E-ZES with 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=301)
(N=300)
E-ZES (N=341)
SES
(N=340)
(N=271)
EES
(N=272)
E-ZES with 3-month DAPT
Standard Therapy
Other DES with 12-month DAPT
Primary Endpoint:
CV death, MI, ST, ID-TVR, Bleed (TIMI major & minor)
Kim et al. JACC 2012;60:

18. RESET: Clinical Events Through 1 Year
Adapted from Kim et al. JACC 2012 Sep 5 (e-Pub ahead of print)
% Patients
*Primary Endpoint: (Assumed 10% with N.I. margin 4% for absolute difference in risk)
**SORT OUT III / ENDEAVOR IV / PROTECT / KAMIR

19. ISAR-SAFE Study Flowchart
Drug- Eluting Stenting
8th to -5th
Continuous Clopidogrel therapy for 5 to 8 months
Randomization
Primary Analysis 2015
Placebo
for 6 months
Clopidogrel 75 mg/d
for 6 months
1st FU: 1 month after randomization
2nd FU: 6 months after randomization (at least one day after study drug cessation)
3rd FU: 9 months after randomization (at least 3 months after study drug cessation)
Follow Up
1st
6th
9th
PEP = death,MI,stent thrombosis,stroke,TIMI major bleed

20. Primary Analysis 2014 DAPT: Study Design
Eligible for Enrollment after PCI
Any PCI with DES or BMS
>18 years of age
No contradictions to dual antiplatelet therapy
Able and willing to provide written informed consent
Not Eligible for Randomization at 12 m
Death
MI or repeat PCI at > 6 weeks
CABG
Stroke
Major Bleed
Primary Analysis 2014
Eligible for Randomization at 12 m
Stratified by DES v BMS, drug type, and complexity (ACS or lesion-based)
Total 33 month follow-up
Primary analysis of DES
Secondary analysis of matched BMS.
Primary analysis DES treated subjects, 12-30m
Secondary analysis propensity matched BMS to DES subjects 0-30m
2 co-primary endpoints: stent thrombosis and MACCE (death, myocardial infarction or stroke)
Powered safety endpoint: major bleeding (GUSTO) 18
mos
12 m DAPT Arm
Aspirin + blinded placebo
30 m DAPT Arm
Aspirin + blinded thienopyridine
Study treatment period m
Study observation period 30-33m
Total 33 month follow-up
Mauri, Kereiakes et al AHJ 2010;160: 20 20 20

21. Thienopyridine Type: DAPT Study
All Randomized Subjects; N = 11,649

22. All Randomized Subjects
Stent Type: DAPT Study
All Randomized Subjects
N = 11,649
DES Type*
N = 9,961
Cypher (n=1,196)
12.0%
Endeavor (n=1,310)
13.1%
TAXUS (n=2,786)
28.0%
Xience/PROMUS (n=4,874)
48.9%
*Some patients received more than one DES type

23. Complexity Amongst Randomized Subjects: DAPT
*clinical =ACS, renal insufficiency LVEF <30%
**anatomic=UPLM; >3 vessels; >2 lesions/vessel; LL ≥30mm; bifurcation; DES ISR; SVG; thrombus; VBT

24. Cumulative incidence rate (%) Months after initial procedure
EXCELLENT Trial:
Target Vessel Failure
6-mo DAT
12-mo DAT
P=0.507
HR = 1.17 (95% CI )
4.7%
Cumulative incidence rate (%)
4.4%
The primary endpoint of 12-month TVF (a composite of cardiovascular death, myocardial infarction [MI], and clinically driven target vessel revascularization) was met by 4.7% of 716 patients in the 6-month DAT group versus 4.4% of 727 patients in the 12-month DAT group, a nonsignificant difference (hazard ratio [HR]=1.17).
Months after initial procedure
Patient Number at Risks
6-month
722
707
701
697
681
12-month
721
710
699
698
680
Am Heart J 2009 May;157: e1. 24

25. TVF According To Diabetes And DAPT Duration: EXCELLENT
Non-diabetics
Diabetics
6-mo DAT
12-mo DAT
p=0.022
HR = 0.42 (95% CI )
p=0.005
HR = 3.15 (95% CI )
8.8%
5.2%
2.9%
2.2%
Patient Number at Risk
6-mo
450
446
445
443
437
12-mo
435
432
429
416
Patient Number at Risk
272
261
259
255
245
278
275
271
270
265
Gwon et al,ACC 2011 LBCT

26. 6 vs. 12 months DAPT After DES: EXCELLENT
Total
6 mo
DAPT
n (%)
12 mo DAPT n (%)
HR (95% CI)
P value
Interaction
P-value
Age <65
767
19 (5.1)
12 (3.2)
1.61 ( )
0.20
0.19
≥65
676
15 (4.5)
18 (5.5)
0.83 ( )
0.59
ACS No
699
21 (6.03)
13 (3.82)
1.61 ( )
0.18
0.15
Yes
744
13 (3.65)
17 (4.69)
0.78 ( )
0.50
Diabetes No
893
10 (2.27)
22 (5.08)
0.44 ( )
0.03
<0.001
550
24 (9.09)
8 (2.96)
3.16 ( )
0.005
LVEF ≥50%
1097
26 (4.91)
24 (4.42)
1.12 ( )
0.69
0.27
<50%
124
2 (3.08)
4 (7.41)
0.41 ( )
0.30
Stent type
EES
1079
25 (4.72)
26 (4.94)
0.96 ( )
0.89
SES
364
9 (5.14)
4 (2.27)
2.31 ( )
0.16
Favors 6 mo DAPT Favors 12 mo DAPT
Gwon et al. Circulation 2012;125:505-13

27. Cumulative Incidence (%)
Clopidogrel Duration after PCI in Diabetics*: Death and Non-Fatal Myocardial Infarction
< 6 months months > 9 months
Composite of death & MI Death
p < p < 0.001
Cumulative Incidence (%)
Time (days) Time (days)
# at risk
< 6 mos
6- 9 mos
> 9 mos
*749 consecutive diabetic patients/Kaiser L.A.
Brar et al. JACC 2008;51:2220

28. landmark-left censored landmark-left censored
Stent Type and Clopidogrel Duration After PCI in Diabetics: Death and Non-Fatal Myocardial Infarction
w/ clopidogrel w/ clopidogrel
w/o clopidogrel w/o clopidogrel
BMS
landmark-left censored
P=0.01
DES
landmark-left censored
P=0.07
Cumulative Incidence (%)
Time (days) Time (days)
# at risk # at risk
BMS with clop DES with clop
BMS w/o clop DES w/o clop
Brar et al. JACC 2008;51:2220

29. Multivariate Analysis Predictors of BARC Bleeding Events on DAPT*
OR (95% CI) P
Female
2.7 ( )
<0.001
Non-diabetic
1.9 ( )
0.005
VLTPR (VASP≤10%)
4.7 ( )
*1,542 patients (clopidogrel 1155; prasugrel 387)
Adapted from Cuissett et al. JACC Card Int 2013;6:

30. Stent Thrombosis Stratified by Clinical Syndrome
and Stent Type
BMS: SA vs. ACS logrank p=0.01
DES: SA vs. ACS logrank p=0.0007
SA: BMS vs. DES logrank p=0.2
ACS: BMS vs. DES logrank p=0.06
Definite Stent Thrombosis (%)
ACS vs SA logrank p<0.0001
ACS SA
DES, ACS
BMS, ACS
DES, SA
BMS, SA
Time (months) Time (months)
N=5,816
Kukreja et al. JACC Intv 2009;2:534

31. Analysis of DAPT Duration Beyond 1 Year Following PCI for AMI
Analysis of DAPT Duration Beyond 1 Year Following PCI for AMI*: COREA-AMI Registry
*2293 consecutive patients MACCE + major bleed free at 1 year post-MI
Koh et al. JACC 2013;61:A40 (abstract E161; presentation 1255M-178)

32. Mortality Following PCI for ACS by Clopidogrel Use: Veterans Administration 2003-2004*
Cumulative mortality rate
Off clopidogrel
On clopidogrel
Follow-up time, days
*n=1455 (66% BMS, 34% DES)
HR BMS 2.65; DES 2.0
Ho et al. Am Heart J 2007;154:846

33. Target And Non-target Lesion MACE* After Stenting
In 1,057 Patients (Sirius Trial) %
Target Vessel Non-target Vessel %
74.3%
74.2%
72.3%
57.1%
Freedom from Cardiac Death, M I and Revasc
SES
BMS
Log-Rank p<0.001
SES
BMS
Log-Rank p=0.096
Time after Initial Procedure (days) Time after Initial Procedure (days)
*CV Death, M I, Revasc Chacko, Cutlip et al. JACC Intv 2009;2:498

34. CHARISMA: Dual Therapy Vs. ASA Monotherapy In Symptomatic* Patients
CD / MI / Stroke
*Prior MI, CVA or symptomatic PAD
Bhatt et al. JACC 2007;49:

35. Death / MI Events Following Clopidogrel Discontinuation After SVG PCI
Failure rate
Failure rate
Sachdeva et al. JACC 2012; Oct 25 [Epub ahead of print]

36. Stenting for ISR: PRODIGY Substudy
short DAPT regimen (n=114)
long DAPT regimen (n=110)
0.85
0.90
0.95
1.00
Cumulative incidence of D / MI / CVA (%)
P=0.034
Time (days)
Campo et al. JACC 2013 prepub

37. Definite Stent Thrombosis Through 3 Years In 18,334 Patients (28,739 Lesions) By Stent Type
3-Year Incidence of Stent Thrombosis Year Landmark Analysis
BMS
1G-DES
2G-DES
BMS
1G-DES
2G-DES
Stent Thrombosis (%)
Stent thrombosis (%)
Tada, Kastrati et al. JACC INTV 2013; 6:

38. Clinical Outcomes By Statistical Model, Duration of DAPT And Follow-Up: Meta Analysis of 13 RCCT Involving 17,097 Patients
Stent Thrombosis
TVR MI
Statistical Model
Random (13)
Fixed (13)
Clopidogrel Duration
6 months (5)
12 months (7)
Follow-up Duration
≤ 1 year (12)
> 1 year (7)
EES Non-EES EES Non-EES EES Non-EES
Favors
Baber et al. JACC 2011;58:569-77

39. Long-term Risk Of Def/Prob Stent Thrombosis: Network Meta-Analysis Of 76 RCCT*
Control
Treatment
Odds Ratio
95%
CrI
BMS (Ref)
Sirolimus
0.80
0.61
1.10
Paclitaxel
1.11
0.85
1.49
Everolimus
0.46
0.31
0.70
Zotarolimus
0.69
0.39
1.28
Zotarolimus-R
0.62
0.29
1.44
Sirolimus (Ref)
1.38
1.02
1.84
0.57
0.84
0.87
0.48
1.50
0.78
0.35
1.73
Paclitaxel (Ref)
0.41
0.60
0.56
0.26
1.25
Everolimus (Ref)
1.52
0.77
2.83
1.36
0.68
2.71
Zotarolimus (Ref)
0.91
0.36
2.40
* >86% probability that EES has lowest rate of “any” stent thrombosis
Bangalore et al. Circ 2012;125:

40. Network Meta-Analysis of 49 Trials Involving 50,844 Patients
Late definite or probable thrombosis
ds rtio (95% CI)
CoCr-EES vs BMS
0.42 ( )
CoCr-EES vs PES
0.33 ( )
CoCr-EES vs R-ZES
0.24 ( )
CoCr-EES vs E-ZES
0.19 ( )
SES vs PES
0.41 ( )
PC-ZES vs SES
4.31 ( )
Favors stent Favors stent 2
Palmerini et al. Lancet 2012;379:

41. DAPT Duration: Conclusions
“One size shoe” approach for DAPT duration is unlikely to fit all patients
ACS
Diabetes
CABG-SVG / ISR
We treat symptomatic patients and non-target lesions with objective to reduce events (D/MI/CVA) which may not be stent (target lesion) related
Stent platforms differ with respect to risk for early , late and/or very late stent thrombosis events (“All DES not created equal”)
Conclusions regarding “optimal” DAPT duration should be based on adequately powered RCCT

42. 11,219 / 13,259 (84.6%) pts complete DAPT data to 2 years
Stent Thrombosis and DAPT Interruption Through 2 Years: Pooled Analysis of SPIRIT II-V; WOMEN; XV USA/India
Analysis population
11,219 / 13,259 (84.6%) pts complete DAPT data to 2 years
85 events in 83 pts (0.74%) through 2 years
45 ST events occurred in 44 pts with no DAPT interruption from day 1 through 2 yrs
40 ST events occurred in 39 pts with some DAPT interruption from day 1 though 2 yrs
45 events occurred “On” DAPT*
23 events occurred “On” DAPT
One patient did not have loading dose, and had ST on day 0 and therefore was off DAPT at ST. The patient started DAPT on day 1 and did not interrupt from day
Interruption is defined as not on DAPT for any 1 day between 1 and 730 days. On/off DAPT is only for the day of ST.
There were 18 total events off DAPT. 17 were in the interruption group, 1 is in the no interruption group. Patients on loading dose with ST on day 0 were considered on DAPT at time of ST.
17 events occurred “Off” DAPT
►68/85 ST events (80.0%) occurred “On” DAPT
*One patient did not receive loading lose and was off DAPT at ST event (day 0) but started day 1 and never interrupted through 730 days.
Stone et al. JACC 2011;58(Suppl B):78