Dual Antiplatelet Therapy Beyond One Year in Patients Receiving Coronary Stents for Treatment of Acute Coronary Syndromes

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1 Dual Antiplatelet Therapy Beyond One Year in Patients Receiving Coronary Stents for Treatment of Acute Coronary Syndromes Robert W. Yeh, Dean J. Kereiakes, P. Gabriel Steg, Stephan Windecker, Michael J. Rinaldi, Anthony H. Gershlick, Donald E. Cutlip, David J. Cohen, Jean-Francois Tanguay, Alice Jacobs, Stephen D. Wiviott, Joseph M. Massaro, Adrian C. Iancu, and Laura Mauri on behalf of the Dual Antiplatelet Therapy (DAPT) Study Investigators

2 Background In the DAPT Study, 30 months of dual antiplatelet therapy reduced ischemic complications after coronary stenting compared to 12 months. Cumulative Incidence of Stent Thrombosis 10% 8% 6% 4% 2% Thienopyridine Stent Thrombosis HR 0.29 ( ) 0.4% vs. 1.4%, P<0.001 Cumulative Incidence of Death, Myocardial Infarction or Stroke 10% 8% 6% 4% 2% Thienopyridine MACCE HR 0.71 ( ) 4.3% vs. 5.9%, P< % 0% Months After Enrollment Months After Enrollment Moderate or Severe Bleeding was increased 2.5% vs. 1.6%, p = Patients undergoing PCI for acute coronary syndromes (ACS) may derive greater benefit from extended duration dual antiplatelet therapy compared with non-acs patients. Mauri, Kereiakes, Yeh et al. NEJM Dec 4:371:

3 3 Objectives To assess whether the reduction in ischemic events and the increase in bleeding associated with continued thienopyridine beyond 12 months are consistent among patients with versus without ACS in a broadly-inclusive population of patients undergoing PCI with drug-eluting or bare metal stents.

4 Design BMS & DES Primary Analysis Period months Enrollment! Randomiza8on! Study+Drug+ Treatment+Ends+ 121Month+ Observa8onal+Period:+ Open1Label+ Thienopyridine+++ Aspirin+Required++ Thienopyridine+++Aspirin+ +++Aspirin+ 31Month+ Observa8onal+ Period:+Off+ Thienopyridine,+On+ Aspirin Time+in+months+aBer+index+stent+procedure+ Randomized: Alive and free from MI, stroke, repeat revascularizapon, and moderate or severe bleeding, and adherent with thienopyridine. Mauri, Kereiakes et al AHJ 2010; 160(6): ClinicalTrials.gov number NCT

5 Design Multicenter, international, placebo-controlled Operators selected stent and thienopyridine type Single randomized trial incorporating 5 individual component studies for enrollment Randomization stratified by site, DES vs BMS, thienopyridine type, and by presence of risk factors for stent thrombosis (including presentation with ACS) One overall clinical events committee, blinded to treatment Overall data safety monitoring committee Mauri, Kereiakes et al AHJ 2010; 160(6):

6 Study Organization Co-Principal Investigators Laura Mauri, Dean Kereiakes Study Statistician Joseph Massaro Executive Committee Laura Mauri, Dean Kereiakes, Donald Cutlip, Sharon-Lise Normand, P. Gabriel Steg, Robert Yeh, Theodora Cohen, Priscilla Driscoll-Shempp Advisory Committee Eugene Braunwald (Chair), Ralph Brindis, David Cohen, Anthony Gershlick, Paul Gurbel, David Holmes, Alice Jacobs, A. Michael Lincoff, Daniel Simon, Jean-François Tanguay, Douglas Weaver, Stephan Windecker, Steve Wiviott Data Monitoring Committee Robert Bonow (Chair), Charles Davidson, James Neaton, William Wijns, Eric Bates, Clyde Yancy (ex officio) Clinical Events Committee Donald E. Cutlip (Chair) National Coordinating Investigators P. Gabriel Steg (France), Ian Meredith (Australia), John Ormiston (New Zealand), Harold Darius (Germany), Anthony Gershlick (United Kingdom), Wojciech Wrobel (Poland), Laura Mauri & Dean Kereiakes (United States) Public-Private Partnership US Food and Drug Administration (IDE # G080186, 1RO1FD ) 8 Funding Stent and Pharmaceutical Manufacturers: Abbott Vascular, Boston Scientific Corp., Bristol-Myers Squibb Co./ Sanofi Pharmaceuticals Partnership, Cordis Corp., Daiichi Sankyo Co. Limited, Eli Lilly & Co., Medtronic Vascular Harvard Clinical Research Institute (HCRI, Boston, MA) as the study sponsor 6

7 7 Study End Points Efficacy Endpoints Definite or probable stent thrombosis (Academic Research Consortium definition) Major adverse cardiovascular or cerebrovascular events (combined death, MI or stroke) Safety Endpoints Moderate or severe bleeding (GUSTO definition) Bleeding Academic Research Consortium (BARC) 2, 3 or 5 bleeding. Myocardial Infarction (stentrelated and non-stent related) *Primary Endpoints of the DAPT Study are in bold

8 8 Analysis Plan ACS was defined as NSTEMI or STEMI as the indication for the index procedure Site-reported unstable angina without documentation of cardiac biomarker elevation was not classified as ACS Consistency of treatment effect between ACS and non ACS groups assessed using test of treatment interaction in Cox proportional hazards models Within group Kaplan-Meier event rates and log-rank P values are presented comparing 30 vs. 12 months therapy

9 9 Subject Flow ACS Stent- Treated PaBents Enrolled N=7119 with ACS N=18563 without ACS 3576 PaBents With ACS Randomized at 12 Months Randomized Non- ACS 8072 PaBents Without ACS Randomized at 12 Months 5844 Not Eligible for RandomizaPon 8190 Eligible but not Randomized 1805 ConPnued Thienopyridine ConPnued Thienopyridine (94.3%) Clinical Follow- up Available at 30 Months 7708 (95.5%) Clinical Follow- up Available at 30 Months

10 10 Baseline Characteristics ACS N=3576 Non-ACS N=8072 P-value Age (years) 57.8 ± ± 9.8 <0.001 Female 21.8% 26.6% <0.001 Race Non White 8.4% 8.7% 0.69 Diabetes Mellitus 20.9% 32.9% <0.001 Hypertension 58.1% 80.1% <0.001 Cigarette Smoker 41.8% 21.0% <0.001 Prior PCI 15.9% 34.8% <0.001 Prior CABG 4.8% 13.4% <0.001 NSTEMI 53.0% 0.0% <0.001 STEMI 46.9% 0.0% <0.001 All variables equally balanced between randomizabon arms for both ACS and non- ACS groups

11 11 Procedural Characteristics ACS N=3576 Non-ACS N=8072 P-Value Number of Treated Lesions 1.2 ± ± 0.6 <0.001 Drug-Eluting Stent 72.4% 91.3% <0.001 Number of Stents 1.4 ± ± Stent Diameter < 3mm 37.3% 46.0% < Total Stent Length (mm) Bifurcation Lesions 5.9% 6.4% 0.34 Unprotected Left Main 0.3% 0.9% <0.001 Vein Graft Intervention 2.0% 3.1% All variables equally balanced between randomizabon arms for both ACS and non- ACS groups

12 Stent Types At Index Procedure 12 Subjects with ACS, N=3576 SES 6% 208 ZES 8% 303 PES 21% 757 EES 36% 1272 > 1 2% 48 BMS 27% 988 Subjects without ACS, N=8072 SES 11% 910 ZES 12% 961 PES 24% 1909 EES 42% 3431 > 1 2% 162 BMS 9% 699 N = 4703 (47.2%) DES- treated subjects received only EES

13 Thienopyridine Type At Randomization 13 ACS Non- ACS Prasugrel 34% Prasugrel 31% Clopidogrel 66% Clopidogrel 69%

14 Treatment Effect According to ACS Status Primary Endpoints at Months All Randomized Subjects (N=11648) 14 8% 7% Stent Thrombosis ConPnued Thienopyridine MACCE P<0.001 P= % Moderate/Severe Bleeding 6% 5.3% 5% 4% 3% P<0.001 P< % 4.4% P=0.005 P= % 2% 1% 1.9% 0.5% 0.4% 1.1% 1.9% 0.8% 1.7% 0% ACS No ACS ACS No ACS ACS No ACS Interaction P=0.69 Interaction P=0.03 Interaction P=0.21

15 Treatment Effect According to ACS Status Secondary Endpoints at Months All Randomized Subjects (N=11648) 15 8% 7% 6% Death ConPnued Thienopyridine BARC 2, 3, or 5 Bleeding P<0.001 P< % BARC 5 Bleeding (Fatal Bleeding) 5% 4% 3% 2% 1% 0% 4.3% P=0.61 P= % 2.1% 2.1% 1.4% 1.6% 1.1% P=0.97 P= % 0.2% 0.1% 0.1% ACS No ACS ACS No ACS ACS No ACS Interaction P=0.13 Interaction P=0.67 Interaction P=0.55

16 Continued Thienopyridine vs. in Patients With and Without ACS: Stent Thrombosis 1 A. ACS Patients Cumulative Incidence of Stent Thrombosis Thienopyridine 8% 6% 4% 2% 0% Months After Enrollment All DES and BMS randomized pabents Thienopyridine 1.9% 0.5% HR 0.27 ( ) p<0.001 B. Non-ACS Patients Cumulative Incidence of Stent Thrombosis Thienopyridine 8% 6% 4% 2% 0% Thienopyridine Months After Enrollment % 0.4% InteracBon P = 0.69 HR 0.33 ( ) p<0.001

17 Continued Thienopyridine vs. in Patients With and Without ACS: Myocardial Infarction 17 A. ACS Patients Cumulative Incidence of Myocardial Infarction Thienopyridine Cumulative Incidence of Myocardial Infarction 8% 6% 4% 2% 0% % 6% 4% 2% 0% B. Non-ACS Patients Thienopyridine Months After Enrollment Thienopyridine Thienopyridine Months After Enrollment All DES and BMS randomized pabents 5.2% 2.2% 3.5% 2.1% HR 0.42 ( ) p<0.001 InteracBon P = 0.15 HR 0.60 ( ) p<0.001

18 Treatment Effect According to ACS Status Myocardial Infarction Type, M follow-up All Randomized Subjects (N=11648) 18 8% 6% Stent Thrombosis-Related Myocardial Infarction ConPnued Thienopyridine Non-Stent Thrombosis-Related Myocardial Infarction 4% 2% P<0.001 P< % 1.0% 0.5% 0.3% P=0.04 P= % 2.5% 1.8% 1.9% 0% ACS No ACS ACS No ACS Interaction P=0.86 Interaction P=0.24

19 Exploratory Sensitivity Analyses 19 Consistent reductions in ST and MI for ACS and non-acs groups when unstable angina without documented cardiac enzyme elevation was classified as ACS Consistent reductions in ST and MI for ACS and non-acs groups after excluding paclitaxel-eluting stent-treated patients Consistent effects on ST, MI, and bleeding endpoints for ACS and non ACS groups among either prasugrel or clopidogreltreated patients

20 20 Limitations Post-hoc subgroup analyses Interaction testing not powered Multiple hypotheses tested 1 st generation DES included Largest RCT of antiplatelet duration of 2 nd generation DES (> 4500 everolimus-eluting stent patients randomized). Did not assess overall benefit vs. risk of continued thienopyridine accounting for both ischemia and bleeding. Ischemia outcomes may exceed bleeding in terms of impact on patient quality-adjusted life years.* * Garg P, Galper BZ, Cohen DJ, Yeh RW, Mauri L. Balancing the Risks of Bleeding and Stent Thrombosis: A Decision Analytic Model to Compare Duration of Dual Antiplatelet Therapy after Drug-Eluting Stents. Am Heart J 2015 Feb;169(2): e5.

21 21 Conclusions Although they are younger with fewer comorbidities, ACS patients are at higher risk for late ischemic events than non- ACS patients. Compared to treatment with aspirin alone, continuation of thienopyridine plus aspirin beyond one year reduces the risk of ischemic events among both ACS and non-acs patients. Driven by reductions in both stent thrombosis and myocardial infarction not related to stent thrombosis. Absolute risk reductions in ischemic events were greater in ACS patients, but present in both groups.

22 22 Conclusions The benefit of extended thienopyridine treatment was tempered by an increase in bleeding events in both ACS and non-acs patients Among non-acs patients, death occurred more commonly in the continued thienopyridine group. Difference in death mainly not related to bleeding (Mauri NEJM 2014) and not present in meta-analysis of prior randomized studies of thienopyridine duration (Elmariah Lancet 2015) Continuation of dual antiplatelet therapy for 30 months should be strongly considered in both ACS and non- ACS patients who have tolerated 1 year of treatment.

23 23 March 15, 2015 Benefits and Risks of Extended Duration Dual Antiplatelet Therapy After PCI in Patients with and without Myocardial Infarction Robert W. Yeh, Dean J. Kereiakes, Philippe Gabriel Steg, Stephan Windecker, Michael J Rinaldi, Anthony H. Gershlick, Donald E. Cutlip, David J. Cohen, Jean Francois Tanguay, Alice Jacobs, Stephen D. Wiviott, Joseph M. Massaro, Adrian C. Iancu, and Laura Mauri, on behalf of the DAPT Study Investigators