1. How Should We Study Duration of Antiplatelet Therapy to Prevent Stent Thrombosis Update from ongoing trials
Laura Mauri, MD, MSc
Brigham and Women’s Hospital
Harvard Clinical Research Institute
Harvard Medical School

2. Laura Mauri, MD DISCLOSURES
Laura Mauri has consulted for Cordis Corporation and Medtronic Vascular
Research support for the DAPT Study is being provided to Harvard Clinical Research Institute from:
Abbott, Boston Scientific Corporation, Cordis Corporation, Medtronic, Inc., Bristol-Myers Squibb/Sanofi-Aventis Pharmaceuticals Partnership, Eli Lilly and Company and Daiichi Sankyo Company Limited
With additional funding from the U.S. Department of Health and Human Services and National Institutes of Health

3. ARC Stent Thrombosis in DES vs BMS at 4 years
Definite and probable stent thrombosis
1.7%
1.5%
1.8%
1.4%
Mauri, L. N Engl J Med 2007;356: 4

4. Non Target Lesion Events outnumber stent specific outcomes in long term follow up HCRI database N=6186 with complete 5y follow up
Cutlip et al. Circulation 2004; 110: 1226–1230.

5. Overall Clinical Outcomes 4 year cumulative incidence
SES
BMS
PES
Death
57 (6.7%)
45 (5.3%)
86 (6.1%)
92 (6.6%)
ST Death
4 (0.5%)
5 (0.6%)
7 (0.5%)
5 (0.4%)
STdeath/
total death 7%
11% 8%
6 %
Overall, stent thrombosis accounts for <10% of total mortality at 4y.
Therefore, looking at ST as an endpoint is the most sensitive way to compare rates of this rare event.
Mauri, L. N Engl J Med 2007;356:

6. Risk of Very Late Stent Thrombosis in DES Decision Analysis
Data favor 1st gen DES over BMS
Favors DES
Difference in QALY (DES-BMS)
Favors BMS
Incremental VLST Risk in DES (% per year, Years 2-4)
Garg, P, Cohen, D, Gaziano, T, Mauri, L. JACC May 2008.

7. DES Safety: Lessons Learned
1 year data not sufficient to evaluate DES
Divergence with BMS appeared at 2 years
BMS assumption of no very late ST was incorrect
RCT in simple subjects may not be sufficient to evaluate safety
Sample sizes of subjects not sufficient to detect small relative differences
Importance of both clinical and stent related outcomes

8. Safety of Long-Term Clopidogrel 3 Placebo Controlled Trials

9. How should we study duration of antiplatelet therapy after stenting?
Design
Registry vs randomized
Population and treatments
On label vs all comer
Endpoint(s)
Clinical vs stent thrombosis
Benefit vs risk
Power and sample size

10. ACC/AHA PCI Scientific Advisory 2007
For DES, recommend 12 months of dual antiplatelet therapy in patients without excess risk of bleeding
Educate patients and provide mechanisms for antiplatelet therapy compliance
Grines, C. JACC Feb 13; 49(6):734-9

11. Effect of Clopidogrel on 24-Month Events in Patients Event-Free at 12 Months*
With Clopidogrel
Without Clopidogrel
Difference (95% CI)
P Value
Drug-Eluting Stent (DES)
Patients (n)
252
276
Death
0.0%
3.5%
-3.5% (-5.9% to -1.1%)
0.004
Death or MI
4.5%
-4.5% (-7.1% to -1.9%)
<0.001
Bare-Metal Stent (BMS)
346
1644
3.3%
2.7%
0.6% (-1.5% to 2.8%)
0.57
4.7%
3.6%
1.0% (-1.6% to 3.6%)
0.44
In a large consecutive cohort of contemporary patients receiving PCI, the long-term risk for death and major cardiac events was significantly increased among patients in the DES group who had discontinued clopidogrel therapy at 6 or 12 months. Extended-duration clopidogrel therapy, however, led to significantly improved prognosis compared with similar patients not receiving long-term clopidogrel. However, the appropriate duration for clopidogrel administration remains unclear and will require a large-scale randomized trial.
Reference: Eisenstein EL, Anstrom KJ, Kong DF, et al. Clopidogrel use and long-term clinical outcomes after drug-eluting stent implantation. JAMA 2007;297:
Eisenstein EL et al. JAMA. 2007;297: 12

12. Study Background
Uncertainty regarding optimal duration of DAPT after DES has led to wide variation in clinical practice 13 13

13. DAPT and DES Is it better to continue >1y?
Balance of safety and efficacy
Is benefit mediated by prevention of stent thrombosis, or global cardiovascular risk reduction?
If benefit exists, is it specific to DES? 14 14

14. 50% of patients continue on Dual Antiplatelet Therapy
Study Design
Laura Mauri, PI
Dean Kereiakes, co-PI
12 mos.
18 mos.
3 mos.
DES n = 15,245
BMS n = 5,400
50% of patients continue on
Dual Antiplatelet Therapy
All patients on
aspirin +open-label
thienopyridine
therapy for
12 months
50% of patients receive
aspirin + placebo
Please make the following revisions to this slide:
Instead of stating “1:1 randomization at month 12” in the dark blue area, can we have a vertical arrow between the “12 mos’ and ’18 mos” blocks that is accompanied with the words “1:1 randomization”?
Add a vertical line at the end of the “18 mos” block that says ‘End of Randomized Treatment’”
Add an arrow that says “3 mos” on top of the last light blue section to the right/ (similar to how we have ’12 mos” and “18 mos’ at the top of the first 2 light blue sections
1:1 Randomization
at month 12
End of Randomized
Treatment
Total 33 month patient evaluation including additional 3-month follow-up
– NCT 15

15. Randomized trial 12 months vs 30 months of dual antiplatelet therapy
Key Design Features
Randomized trial 12 months vs 30 months of dual antiplatelet therapy
Operator selection of stent and thienopyridine from FDA-approved stents (including BMS) and drugs (clopidogrel or prasugrel)
2 co-primary endpoints
Stent thrombosis
MACCE
Powered safety endpoint
Major bleeding 16 16

16. Broad Enrollment Criteria
Inclusion Criteria at Index PCI
Age > 18y
PCI with any FDA approved stent
No known contraindication to dual antiplatelet therapy
Inclusion Criteria at 12m Randomization
Free from death, MI, stroke, repeat revasc, major bleeding and compliant with dual antiplatelet therapy 17 17

17. Rationale for Co-Primary Endpoints
Two potential mechanisms of benefit of extending dual antiplatelet therapy beyond 12 months
Device oriented (reduction in ST)
Patient oriented (disease progression/non-target lesion events)
Significance on either endpoint would be clinically relevant

18. BMS Non-inferiority comparison to DES
If DES 12 vs 30m study is positive, it will be important to distinguish whether this effect is DES specific.
Main study will allow operator selection of stent type
Comparison of BMS vs DES is powered to determine non-inferiority of DES after propensity score adjustment for characteristics and treatments (including duration of DAPT) 19 19

19. Collected periprocedure and at one year
Platelet Function, Genetics, & Protein Biomarkers
BLUE TOP
(Plt Fxn, DNA)
RED & PURPLE TOPS
(Biomarkers)
Platelet Reactivity
Genetic Variants
Protein Biomarkers
Collected periprocedure and at one year
Funded by National Institutes of Health. Marc Sabatine, Ancillary Study PI
Mega et al. NEJM ; 20 20

20. Study Personnel
Principal Investigators: Laura Mauri (PI), Dean Kereiakes (co-PI)
Statistician: Joe Massaro
Executive Committee: Don Cutlip, Sharon-Lise Normand, P. Gabriel Steg
Advisory Committee: Eugene Braunwald (chair), Ralph Brindis, David Cohen, Tony Gershlick, Paul Gurbel, David Holmes, Alice Jacobs, Michael Lincoff, Daniel Simon, Jean-Francois Tanguay, Douglas Weaver, Stephan Windecker, Stephen Wiviott
Data Safety Monitoring Board: Robert Bonow (chair), Charles Davidson, Jim Neaton, William Wijns, Clyde Yancy
Study Funding: Abbott, Boston Scientific Corporation, Cordis Corporation, Medtronic, Inc., Bristol-Myers Squibb/Sanofi-Aventis Pharmaceuticals Partnership, Eli Lilly and Company and Daiichi Sankyo Company Limited. With additional supplementary funding from NIH (Sabatine platelet function and genetics substudy), and U.S. FDA/HHS.
>900 patients enrolled in the US to date 21 21

21. Ongoing Randomized Trials comparing Duration of Antiplatelet Therapy after DES
Study
Target
Enrollment
Eligibility
Requirements
Durations
Endpoint(s)
DAPT
20,645
12 m event free
Operator selection of any DES or BMS, clopidogrel or prasugrel
12 m vs. 30 m
1. 33 m composite of death, MI, stroke
2. ARC definite/probable stent thrombosi
3. major bleed
ISAR-SAFE
6,000
6 m event free
6 m vs. 12 m
15 m composite of death, MI, stroke, TIMI major bleed
GRAVITAS
2,783
No STEMI
Standard vs. placebo loading;
75 mg vs. 150 mg for 6 m
6 m composite of cardiac death, MI, ARC definite/probable stent thrombosis
REAL-LATE
2,000
12 m vs. 24 m
2 y composite of cardiac death, MI
ZEST-LATE
2 y composite of death, MI
OPTIDUAL
1,966
12 m vs. 36 m
36 m composite of death, MI, stroke, severe bleeding

22. ISAR-SAFE Study Design
Drug- Eluting Stenting
8th to -5th
Continuous Clopidogrel therapy for 5 to 8 months
Randomization
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
Byrne et al., Am Heart J 2009;157:

23. GRAVITAS Trial Design
Price et al., Am Heart J 2009;157:

24. Conclusions
Definitive answers are needed regarding duration of dual antiplatelet therapy after stents and will be provided by ongoing studies
The DAPT Study is designed to answer whether patients should continue dual antiplatelet therapy for more than 12m after DES.
Randomized, sufficiently powered for separate MACCE, ST and bleeding, endpoints, inclusive and broad patient and treatment characteristics
Additional randomized studies are underway
ISAR SAFE: 6 vs 12m
GRAVITAS: impact of platelet function testing on clopidogrel dose