1. PARIS Registry Patterns of Non-Adherence to Anti-Platelet Regimens In Stented Patients: An Observational Single Arm Study Roxana Mehran, MD on behalf of PARIS Investigators PARIS Registry

2. Background and Rationale Anti-platelet agents are the cornerstone of therapy in pts with ACS and in those undergoing PCI. Current ACC/AHA guidelines 1 recommend 30 days DAPT following placement of a BMS and 1 year following placement of a DES. (In patients with ACS 12 months of DAPT is recommended regardless of stent type.) Premature discontinuation of DAPT (within the first 6 months after DES) has been associated with an increased risk of stent thrombosis, but the optimal duration of DAPT has not yet been precisely determined, especially with regard to second generation DES. 1. Wright et al. JACC 10 May 2011

3. Background and Rationale The mode and circumstances around non- adherence to DAPT has not been previously studied. Whether or not discontinuation of DAPT secondary to bleeding or other events (ie: non- cardiac surgery) may lead to subsequent ischemic events has not been systematically studied. Previous studies have only addressed patients “on” or “off” DAPT at specific follow-up points or at the time of events.

4. Study Design Multicenter, multinational, observational study 5033 subjects to be followed for approximately 24 months post stent implantation Includes bare metal and drug eluting stents PARIS Registry

5. Modes of Non-adherence Discontinuation: subjects have discontinued use of DAPT as per recommendation of their physician who felt subject no longer needed therapy. Interruption: subjects have interrupted DAPT use on a voluntary basis and under guidance and recommendation of their physician due to need for surgery. DAPT will be reinstituted within 14 days. Disruption: subjects have disrupted DAPT use due to bleeding or non-compliance. Includes use of DAPT at lower dose levels than prescribed. PARIS Registry

6. Eligibility for Enrollment (1) Inclusion Criteria Successful stent placement in one or more lesions in native coronary arteries using an approved coronary stent, and intent to discharge on DAPT Diagnosis of Acute Coronary Syndrome, Stable Angina, or Documented Silent Ischemia Subject is over 18 years old, provides consent, and agrees to follow-up PARIS Registry

7. Eligibility for Enrollment (2) Exclusion Criteria Evidence of stent thrombosis during baseline procedure Subject is participating in an investigational device or drug study PARIS Registry

8. Objectives Primary Objectives To examine the modes of non-adherence to dual anti-platelet therapy (DAPT) following stenting To evaluate subsequent clinical outcomes and the relation to non-adherence to DAPT Secondary Objectives To examine factors associated with non- adherence To examine the relationship of major & minor bleeding to stent thrombosis & MACE PARIS Registry

9. Study Organization Principal Investigators:Roxana Mehran, MD Principal Investigators:Roxana Mehran, MD Antonio Colombo, MD Steering Committee:Roxana Mehran, MD (Chair); Antonio Colombo, MD (Co-Chair); Alaide Chieffo, MD; David J. Cohen, MD, MSc; C. Michael Gibson, MD; Mitchell W. Krucoff, MD; David J. Moliterno, MD; Ph. Gabriel Steg, MD; Giora Weisz, MD; Bernhard Witzenbichler, MD Steering Committee:Roxana Mehran, MD (Chair); Antonio Colombo, MD (Co-Chair); Alaide Chieffo, MD; David J. Cohen, MD, MSc; C. Michael Gibson, MD; Mitchell W. Krucoff, MD; David J. Moliterno, MD; Ph. Gabriel Steg, MD; Giora Weisz, MD; Bernhard Witzenbichler, MD PARIS Registry

10. Study Organization Sponsor:Mount Sinai School of Medicine Sponsor:Mount Sinai School of Medicine :Sanofi-Aventis and Bristol-Myers Squibb Grant Support:Sanofi-Aventis and Bristol-Myers Squibb Data Coordinating Center:Mount Sinai School of Medicine Data Coordinating Center:Mount Sinai School of Medicine Clinical Event Committee:Dr. Steven Marx (Chair) Clinical Event Committee:Dr. Steven Marx (Chair) Site and Data Monitoring:Medical Devices Consultancy Ltd Site and Data Monitoring:Medical Devices Consultancy Ltd EDC:Study Manager EDC:Study Manager PARIS Registry

11. Investigators and Site Name PI Name Site name 1 James Hermiller, MD Heart Center of Indiana, IN 2 Annapoorna Kini, MD Mount Sinai Medical Center, NY 3 Fayaz Shawl, MD Washington Adventist Hospital, MD 4 Giora Weisz, MD Columbia University Medical Center, NY 5 Bernhard Witzenbichler, MD Charité, Germany 6 Antonio Colombo, MD Alaide Chieffo, MD San Raffaele Hospital, Italy 7 David J. Cohen, MD, MSc Saint Luke's Mid-America Heart Institute, MO 8 David J. Moliterno, MD University of Kentucky, KY

12. PARIS Registry Investigators and Site Name (cont.) PI Name Site name 9David Antoniucci, MDCareggi Hospital, Italy 10Ph. Gabriel Steg, MDHopital Bichat, France 11Peter B. Berger, MDGeisinger Medical Center, PA 12Thomas Stuckey, MDLeBauer Cardiovascular Research Foundation, NC 13Ron Waksman, MDWashington Hospital Center, DC 14Timothy D. Henry, MDMinneapolis Heart Institute Foundation, MN 15Ioannis Iakovou, MD, PhDOnassis Cardiac Surgery Center, Greece

13. PARIS Registry Paris Enrollment - Patients 5,033 pts enrolled at 15 centers in 5 countries USA [10] n=3,666, 72,9% July 1 st, 2009 and October 29 th, 2010 Columbia University Medical Center (n=927, 18,5%)Columbia University Medical Center (n=927, 18,5%) Minneapolis Heart Institute Foundation (n=704, 14%)Minneapolis Heart Institute Foundation (n=704, 14%) Mount Sinai Medical Center (n=555, 11%)Mount Sinai Medical Center (n=555, 11%) LeBauer Cardiovascular Research Foundation/ Moses Cone Heart and Vascular Center (n=344, 6,8%)LeBauer Cardiovascular Research Foundation/ Moses Cone Heart and Vascular Center (n=344, 6,8%) St. Luke's Hospital/ Mid-America Heart Institute (n=318, 6,3%)St. Luke's Hospital/ Mid-America Heart Institute (n=318, 6,3%) Geisinger Medical Center (n=276, 5,5%)Geisinger Medical Center (n=276, 5,5%) Washington Adventist Hospital (n=199, 4%)Washington Adventist Hospital (n=199, 4%) University of Kentucky (n=143, 2,8%)University of Kentucky (n=143, 2,8%) Heart Center of Indiana/ St. Vincent's/ The Care Group (n= 125, 2,5% )Heart Center of Indiana/ St. Vincent's/ The Care Group (n= 125, 2,5% ) Washington Hospital Center (n=75, 1,5%)Washington Hospital Center (n=75, 1,5%)

14. PARIS Registry Paris Enrollment - Patients 5,033 pts enrolled at 15 centers in 5 countries July 1 st, 2009 and October 29 th, 2010 Germany [1] n=720, 14,3% Italy [2] n=307, 6% France [1] n=160, 3,2% Greece [1] n=180, 3,6% EUROPE [5] n=1,367, 27,1% Charité Hospital, Germany (n=720, 14,3%)Charité Hospital, Germany (n=720, 14,3%) San Raffaele Hospital, Italy (n=221, 4,4%)San Raffaele Hospital, Italy (n=221, 4,4%) Onassis Cardiac Surgery Center, Greece (n= 180, 3,5%)Onassis Cardiac Surgery Center, Greece (n= 180, 3,5%) Hospital Bichat, France (n=160, 3,2%)Hospital Bichat, France (n=160, 3,2%) Careggi Hospital, Italy (n=86, 1,7%)Careggi Hospital, Italy (n=86, 1,7%)

15. Enrollment Over Time PARIS Registry

16. Baseline Characteristics VariablePatients (n=5033) Age, years63.96 ± 11.32 Body mass index, kg/m 2 29.26 ± 5.63 Male, n (%)3750 (74.5) Acute coronary syndrome, n (%)2047 (40.9) Current smoker, n (%)984 (19.6) Diabetes Mellitus, n (%)1663 (33.0) Insulin-requiring DM, n (%)547 (10.9) Dyslipidemia, n (%)3810 (75.7) Hypertension, n (%)4020 (79.9) Peripheral Vascular Disease, n (%)396 (7.9) Prior coronary artery disease, n (%)1613 (32.1) Prior MI, n (%)1220 (24.2) Prior PCI with stenting, n (%)1853 (36.8) Prior CABG, n (%)691 (13.7) Prior stroke, n (%)174 (3.5) PARIS Registry Enrolled: n= 5033 Complete 30 Day Follow-Up Available: 5023 (99.3%)

17. Medication Usage PARIS Registry 3582 (71.1%)2014 (40.0%)991 (19.7%)1894 (37.6%)47 (0.9%) 5012 (99.6%)5031 (100%)1177 (23.4%)5012 (99.6%)311 (6.2%)

18. Procedural Information PARIS Registry

19. Stents by Type Total # of stents used: 8434 (1.68 stents/pt) PARIS Registry

20. Thienopyridine at Discharge PARIS Registry

21. Rates of Non-Adherence (Patient-level) PARIS Registry

22. Any Non-Adherence VariablePatientsEpisodes Any Non-adherence104 (2.1)147 Disruption, n (%)72 (69)102 (70) Interruption, n (%)20 (19)27 (18) Discontinuation, n (%)12 (12)18 (12) Incidence of Non-Adherence

23. Non Adherence to Thienopyridine: VariablePatientsEpisodes Any Non-adherence, n (%)66 (1.3)69 Disruption, n (%)43 (65)46 (67) Interruption, n (%)12 (18)12 (17) Discontinuation, n (%)11 (17)11 (16) Incidence of Non-Adherence (Cont.) PARIS Registry

24. Non Adherence to Aspirin: VariablePatientsEpisodes Any Non-adherence, n (%)70 (1.4)78 Disruption, n (%)51 (73)56 (72) Interruption, n (%)12 (17)15 (19) Discontinuation, n (%)7 (10)7 (9) Incidence of Non-Adherence (Cont.) PARIS Registry

25. BleedingNon-ComplianceOther ASA18344 Thienopyridine14302 Reasons for Disruption PARIS Registry

26. Surgery Other Medical Procedure (epidural, catheter removal, GI Scope) GI UpsetAllergyCoumadin ASA52332 Thienopyridine53040 Reasons for Interruption PARIS Registry

27. Non-Adherence guided by healthcare professionals PARIS Registry Total episodes of “Recommended” DAPT non-adherence: 82

28. PARIS Registry Baseline Characteristics Variable Adherent n=4929 Non-adherent n=104 p-value Age, years63.94 [11.33]64.83 [11.31]0.42 Male, n (%)3676 (74.6)74 (71.2)0.43 Acute coronary syndrome, n (%)1987 (40.5)60 (58.3)<0.0001 Diabetes Mellitus, n (%)1627 (33.0)36 (34.6)0.73 Dyslipidemia, n (%)3744 (76.0)66 (63.5)0.003 Hypertension, n (%)3944 (80.0)76 (73.1)0.08 Peripheral Vascular Disease, n (%)387 (7.9)9 (8.7)0.76 Prior coronary artery disease, n (%)1987 (40.5)60 (58.3)<0.0001 Prior MI, n (%)1201 (24.4)19 (18.3)0.15

29. Rates of 30-Day non-adherence in Similar Registries StudyTimeframePopulationN DAPT Discontinuation at 30 days (%) Airoldi et al 1 2002 – 2004PCI with DES30212.4% PREMIER Registry 2 2003 – 2004DES for MI50013.6% MATRIX Registry 3 2004-2006PCI with SES15045.8% E-Five Registry 4 2005-2007PCI with ZES79882.1% E-SELECT Registry 5 2006-2008PCI with SES14,3652% 1.Airoldi F et al. Circulation. 2007 Aug 14;116(7):745-54. 2.Spertus J et al. Circulation 2006 June 20; 113(24):2803-9. 3.Claessen B et al. Am J Cardiol 2011;107:528-534. 4.Lotan C et al. J Am Coll Cardiol Interv 2009; 2(12), 1227-1235. 5.Urban P et al J Am Coll Cardiol 2011;57:1445-54. PARIS Registry

30. Adverse Event Rates TotalAdherent(n=4929)Non-adherent(n=104) Ischemic MACE, n (%)78 (1.5)67 (1.4)11 (10.6) Death, all-cause, n(%)17 (0.3)15 (0.3)2 (1.9) Cardiac Death, n (%)15 (0.3)14 (0.3)1 (1.0) Myocardial Infarction, n (%)54 (1.1)46 (0.9)8 (7.7) Stent Thrombosis, n (%)26 (0.5)23 (0.5)3 (2.9) TVR, n (%)30 (0.6)25 (0.5)5 (4.8) TLR, n (%)23 (0.5)19 (0.4)4 (3.8) Bleeding TIMI major, n (%)9 (0.2)6 (0.1)3 (2.9) ACUITY Major, n (%)35 (0.7)23 (0.5)12 (11.5) BARC ≥ 3, n (%)30 (0.6)18 (0.4)12 (11.5)

31. BARC Bleeding Scale 1 BARC ClassificationN (% of total population) Type 1 (not actionable)26 (0.5) Type 2 (requiring medical attention)37 (0.7) Type 330 (0.6) 3a15 (0.3) 3b15 (0.3) 3c0 Type 4 (CABG related)0 BARC Type 5 (Fatal)0 1. Mehran et al. Circulation 2011 Jun 14;123(23):2736-47.

32. Stent Thrombosis PARIS Registry Stent Thrombosis (n=26) Probable (n=9) Definite (n=17) Adherent (n=14) Non-adherent (n=3) Disrupted ASA (n=2) Disrupted Clopidogrel (n=1) Odds Ratio (95% CI) for stent thrombosis associated with non-adherence: 6.3 (1.9-21.4)

33. PARIS Registry Relative Risk of Non-Adherence on 30 Day Stent Thrombosis in Contemporary Registries AdherentNon-AdherentRR PARIS Registry0.5%2.9%5.8 Airoldi et al 1 0.9%4.2%4.7 eSELECT Registry 2 0.5%4.6%9.2 1.Airoldi F et al. Circulation. 2007 Aug 14;116(7):745-54. 2.Urban P et al. J Am Coll Cardiol 2011;57:1445-54.

34. Educational Status Non-adherent Adherent Non-Adherent Less than Secondary School57323 Secondary School245240 University132128 Advanced Degree47312 TOTALS4819103 p = 0.006