1. DAPT in Contemporary PCI Risk, Benefit and Much to Still Learn
38 RCTs
18,000 pts
DAPT in Contemporary PCI Risk, Benefit and Much to Still Learn
David E. Kandzari, MD Director, Interventional Cardiology Research Scripps Clinic La Jolla, California

2. David E. Kandzari, MD DISCLOSURES Consulting Fees
Abbott Vascular, Cordis, a Johnson & Johnson company, Edwards Lifesciences LLC , Medtronic CardioVascular, Inc., Micell Technologies
Grants/Contracted Research
Abbott Vascular, Cordis, a Johnson & Johnson company, Medtronic CardioVascular, Inc.
I intend to reference unlabeled/unapproved uses of drugs or devices in my presentation.
I intend to reference drug eluting stents for off-label indications.

3. Antiplatelet Therapy and DES Revascularization Timeline Perspective
Stent thrombosis, irrespective of timing or stent type, is associated with considerable morbidity and mortality
January 2006, December ACC/AHA/SCAI guidelines consensus-opinion based recommendations of 12 months DAPT following DES for pts without apparent contraindications
December FDA Panel concern over annualized ST rates motivate FDA to mandate DES labeling incorporate 12 month DAPT recommendation
December Inter-society Scientific Advisory reiterates 12 month guidelines
1. The principal driver for extended term DAPT is to reduce the risk of ST
2. We need evidence to support long-term DAPT in reducing the ST risk
3. This evidence does not exist, and in fact, multiple studies now report data to the contrary, that long-term DAPT does not reduce the occurrence of late and very late ST and may also in selected populations yield conflicting results regarding D/MI benefit

4. ‘Optimal’ DAPT Duration and DES Revascularization A Less than ‘Optimal’ Evidence Basis
RCT and RCT substudies (CREDO, PCI-CURE)
Pharma trials evaluating pretreatment and dosing strategies
Follow-up limited to ≤12 months
Majority of treatment effect within initial days
Observational studies consistently demonstrate ‘premature’ thienopyridine discontinuation with increased risk of ST
Single-center, observational surveys demonstrating reductions in death and MI, but not ST
Duke Cardiovascular Database, Eisenstein et al. JAMA 2007
Kaiser Permanente, Brar et al. J Am Coll Cardiol 2008
No estimate of bleeding risk
CHARISMA Severe bleeding: 1.7% over ~2 year follow-up
‘Clopidogrel survivor’ theory reflects selection bias
Consensus opinion: Emotive, intuitive perception that extended DAPT could reduce ST events
No prospective, (randomized) data associating long-term DAPT with reductions in ST
There is a time for the art of medicine in the absence of well-founded science, and thus an emotive, seemingly intuitive perception that extended DAPT could reduce ST events

5. 58 cases of ST through 540 Days (1.9%)
Rate of ST in Patients On DualAnti-platelet Therapy and in Patients Who Discontinued Thienopyridine Therapy
0.16
0.14
Patients who discontinued thienopyridine therapy
0.12
0.10
58 cases of ST through 540 Days (1.9%)
0.08
Event Rates
0.06
0.04
Patients who on thienopyridine therapy
0.02
0.00 60
120
180
240
300
360
420
480
540
No. of Patients
Discontinued Thienopyridine
258
422
560
1,128
1,180
1,680
2,044
2,138
2,251
On Thienopyridine
2,750
2,576
2,411
1,829
1,771
1,245
865
756
634
* Aalen-Nelson estimate of cumulative hazard function
Airoldi F, Colombo A, et al., Circulation 2007;116:745-54

6. Relationship Between Thienopyridine Discontinuation and ST
VLST 360 – 540 days (0.2%)
LST 180 – 360 days (0.3%)
LST 30 – 180 days (0.4%)
58 Patients with Stent Thrombosis
SAT (0.9%) 60
120
180
240
300
360
420
480
540
Days post-PCI
Median time from clopidogrel discontinuation and ST: - ST within first 6 months: 13.5 days (IQR range, 5.2 to 25.7) - ST after the first 6 months: 90 days (IQR, 30 to 365 days)
Airoldi F, Colombo A, et al., Circulation 2007;116:745-54

7. Temporal Trends in DAPT Compliance and Incidence of ST while On or Off Thienopyridine Therapy Is Thienopyridine Discontinuation a Cause or Epiphenomenon?
Thienopyridine Adherence Over Time
A common statistical error is to associate 2 parallel occurring events with each other or as causative, but the observation that thienopyridine discontinuation beyond a certain time point does not result in an uptick in events suggests against a strong association or that DAPT is somehow suppressive of late ST events. In fact, in this analysis, beyond 6 months, ST is if anything more common among patients with continued thienopyridine therapy
Airoldi F, Colombo A, et al., Circulation 2007;116:745-54

8. Japan Cypher 2-Year Relationship Between ST Events and APT, N=10,778
Kimura, T. et al. Circulation 2009;119:

9. Japan Cypher 6-Month Landmark Analysis Based on Thienopyridine Use
OFF Thienopyridine,
N=2,628
P value
Death
3.4
0.90
Myocardial Infarction
0.6
0.8
0.42
Death/ Myocardial Infarction
4.1
0.99
Death, MI or Stroke
4.0
0.79
Kimura, T. et al. Circulation 2009;119:

10. Korean Stent Thrombosis Registry Multicenter Observational Cohort Study
7,221 PCI patients (48.3% DES)
DES associated with significantly higher risk of ST beyond 1 year
Adjusted risks of D, D/MI and TLR significantly lower with DES
Despite increased risk of VLST with DES, thienopyridine continuation beyond 1 year not associated with reduced risk of D, D/MI or ST
Park DW, et al. J Am Coll Cardiol Interv 2008

11. Korean Stent Thrombosis Registry Multicenter Observational Cohort Study
Aalen-Nelson Estimate Curves of Cumulative Hazard Function for Definite ST
Park DW, et al. J Am Coll Cardiol Interv 2008

12. ISAR Relationship Between DAPT and ST over 4 year Follow-up, N=6,8162 3 4
Cumulative incidence of stent thrombosis
(%) 5 10 15
Years after procedure
5,181
1,074
398
116
6,816
1,277
3,934
2,539
1,373
No. of patients
Discont. clopidogrel
On clopidogrel
Patients who discontinued clopidogrel therapy
Patients on clopidogrel therapy
6 months
Schulz S, Kastrati A, et al. Eur Heart J 2009

13. ISAR Relationship Between DAPT and ST over 4 year Follow-up, N=6,816
Schulz S, Kastrati A, et al. Eur Heart J 2009

14. van Werkum, J. W. et al. J Am Coll Cardiol 2009;53:1399-1409
Dutch Stent Thrombosis Registry Independent Risk Factors for ST, N=21,009
van Werkum, J. W. et al. J Am Coll Cardiol 2009;53:

15. ENDEAVOR IV Very Late Stent Thrombosis to 3-Years
ARC Definite/Probable ST
12–36 Months (VLST) 2
Endeavor DES
Taxus DES
1.5%
Definite/Probable Thrombosis (%)
Cumulative Incidence of 1
93% RRR
p = 0.004
(1–3 years)
0.1%
360
450
540
630
720
810
900
990
1080
Time After Initial Procedure (days)
Endeavor
732
719
716
710
699
688
684
680
Taxus
734
721
718
714
701
690
681
674

16. ENDEAVOR IV Timing of ARC Def/Prob VLST
413
495
619
645
689
697
835
838
878
949
1024
Taxus VLST ( n=11)
5/11 On ASA or Plavix
4/11 on ASA
2/11 No DAPT
9/11 Result in MI
Taxus
369
Endeavor VLST ( n=1)
1/1 No DAPT
1/1 Result in MI
Endeavor
360
480
600
720
840
960
1080
Days

17. SYNTAX Trial Graft Occlusion and Stent Thrombosis Medication Status at Time of ST/GO Per Patient
Patients
Patients
Aspirin
DAPT
Single
Thienopyridine
Neither/
Unknown
Aspirin
DAPT
Single
Thienopyridine
Neither/
Unknown
CABG Arm (n=27)
PCI Arm (n=28)
Presented by Dr. Ted Feldman, EuroPCR, 2009
See Glossary for prescribing information outside the US

18. What is the ‘Optimal’ Trial for the ‘Optimal’ DAPT Duration
What is the ‘Optimal’ Trial for the ‘Optimal’ DAPT Duration? DAPT durations, inclusion of BMS, landmarking and ‘event-free’ patients
Inclusion Group, N
DAPT Duration
DES Type
1° Endpoint
2° Endpoint(s)
DAPT
20, month event free
12 vs 30 months
All DES, BMS
D/MI/Stroke at 33 mos
Def/prob ST at 33 mos
GUSTO Bleeding
ISAR-SAFE
6, month event free
6 vs 12 months
All DES
D/MI/Stroke/TIMI major bleed at 15 mos
Individual component endpoints
REAL-LATE
2, month event free
12 vs 24 months
2-yr Cardiac D/MI
ARC ST, Bleeding
ZEST-LATE
SES, PES, ZES
2-yr D/MI
DATE
823 non-ACS
3 months
ZES
1y cardiac D/MI/ST
Individual component endpoints, TLR
OPTIMIZE
3, non-STEMI
3 vs. 12 months
1-yr D/MI/Stroke/TIMI major bleed
ARC ST
SEASIDE
900 non-ACS
6 months
1-yr D/MI/Stroke
CYP2C19
Kandzari et al. JACC Int 2009;

19. Unplanned DAPT Interruption Following ZES Revascularization SENS Trial Outcomes within 30 days of Non-cardiac Surgery and DAPT Discontinuation
Characteristics
N=3,099 (%)
Patients with brief interruption of DAP
194 (6.2)
Age (yrs)/Male
63.5/54.9
Comorbid illness
Diabetes illness
88 (46.4)
Hypertension
123 (64/1)
Hyperlipidemia
56 (29.1)
Smoking
49 (25.6)
EF (%)
60.1 ± 11.1
ACS at stenting
122 (63.5)
Type of procedure(s)
Orthopedic/Head and neck
34 (18)
Abdominal
27 (14)
Gynecological/Uro
15 (8)
Vascular
7 (3)
Dental
44 (23)
Ophthalmic
13 (7)
Endoscopy, GI/Broncho
54 (28), 43/11, (23/5)
Kim JW, et al. ACC 2009

20. Aortic-femoral bypass
Unplanned DAPT Interruption Following ZES Revascularization SENS Trial Outcomes within 30 days of Non-cardiac Surgery and DAPT Discontinuation
Early Surgery
Late Surgery
Op Name
Tracheostomy
Wound debridement
Aortic-femoral bypass
HNR
Days from stenting to events 28 86 13
334
DAP withdrawal days 7 14 5 3
MACE
Death
MI (LCX)
MI (LCX Os)
Procedural Characteristics
Stented vessel
LAD
RCA
LAD, LCX
Main to LAD
Stent
diameter (mm)
2.75
4.0, 3.5
2.75, 2.5
3.5, 3.3
Stent number 1 2
Stent length (mm)
24 mm
48 mm
35 mm
Post-events management
POBA
Medication
Kim JW, et al. ACC 2009
Kim JW, et al. ACC 2009

21. Antiplatelet Therapy and DES 2010 What We Still Don’t Know
What is the ‘optimal’ duration of DAPT? What is ‘premature’ discontinuation?
Is the ‘optimal’ duration same for all DES?
What are the consequences of brief DAPT interruption?
Is there a rebound phenomenon with thienopyridine discontinuation?
Will there be differences between different APT agents in real world practice?
Is there a role for platelet and/or genomic testing to individualize therapy?

22. TRITON TIMI 38 Stent Thrombosis (ARC Definite + Probable)
Any Stent at Index PCI N= 12,844
2.4 (142)
Clopidogrel 2
Endpoint (%)
>30 days: 0.49 vs 0.82, P=0.03
DM: 3.6 vs 2.0, P=0.007
No DM: 0.9 vs. 2.0, P<0.001
1.1 (68) 1
Among the 12,844 patients receiving a stent at the index PCI,
PRASUGREL REDUCED the rate of stent thrombosis from 2.4% in the clopidogrel group to 1.1% .
The prevention of 74 stent thromboses with prasugrel represented a highly significant 52% reduction in the HR.
Although not shown on the slide, there was a significant reduction of about 50% in stent thrombosis in both BMS and DES-treated patients.
Prasugrel
HR 0.48 P <0.0001
NNT= 77 30 60 90
180
270
360
450
Wiviott et al. NEJM 2007
Days 22

23. Influence of Trial Conduct and Definitions What is Meaningful to a Doctor May Differ to a Trial Committee
Definite Stent Thrombosis
Prasugrel
Clopidogrel RR
P Value
CEC adjudicated 52
122
0.42
<0.001
Site reported
139
204
0.68
2.7x 
1.7x 

24. DAPT in Contemporary PCI Summary
Given that ST is uniformly associated with MI and 30% mortality, any measure that may reduce events is clinically meaningful but must be proven and without excessive risk!
Role of DAPT in reducing early ST is firmly established
Issue is not that thienopyridine should be discontinued for all pts at a predetermined timepoint but whether it is safe to discontinue (ST risk) and if there is acceptable benefit to maintain (D, MI, stroke)
While extended DAPT may decrease late death or MI proportionate to risk, the benefit is most likely associated with reduction of events independent of stent territory
Available evidence predominantly demonstrates that in all-comer, broad PCI populations, extended DAPT (eg, >6-12 months) likely does not reduce ST risk

25. DAPT in Contemporary PCI Summary
Whether patient variable responsiveness may be overcome by increased clopidogrel dose vs prasugrel is issue of ongoing study
Role of APT responsiveness point of care assays
Evolution of genomic assays
Studies are underway to identify the ‘optimal’ DAPT duration, but must consider:
Variability in DAPT durations studied
Potential differences in DES, thienopyridine therapy, individual patients
Bleeding risk
Intention to treat vs as treated, “clear” patients vs. those with events