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

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

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;356:1020-9. 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.

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;356:1020-9.

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.

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 1-2000 subjects not sufficient to detect small relative differences Importance of both clinical and stent related outcomes

Safety of Long-Term Clopidogrel 3 Placebo Controlled Trials

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

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. 2007 Feb 13; 49(6):734-9

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;297:159-68. Eisenstein EL et al. JAMA. 2007;297:159-68. 12

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

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 www.daptstudy.org www.clinicaltrials.gov – NCT00977938 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

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

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

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

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 2009.4;354-62. 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

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

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;157:620-624

GRAVITAS Trial Design Price et al., Am Heart J 2009;157:818-824

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