PARIS Registry Incidence and Impact of Dual Antiplatelet Therapy (DAPT) Cessation on Adverse Events following Percutaneous Coronary Intervention (PCI): Results from the Real-World PARIS Registry Roxana Mehran, MD Professor of Medicine (Cardiology) and Health Evidence Policy Director of Interventional Cardiovascular Research and Clinical Trials The Icahn School of Medicine at Mount Sinai, New York, NY on behalf of PARIS Investigators 1

Conflict of Interest: Institutional Grant/Research Support: Bristol-Myers Squibb/ Sanofi Lilly/ DSI The Medicines Company BG Medicine Consulting Fees/Honoraria Sanofi Abbott Vascular Astra Zeneca Merck Regado Biosciences Janssen (J+J) BSC Covidien CSL Behring

Background and Rationale PARIS Registry Antiplatelet agents are the cornerstone of therapy in patients with ACS and in those undergoing PCI Current ACC/AHA guidelines1 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 1. Wright et al. JACC. 10 May.2011.

DAPT Cessation and PCI: Existing Evidence PARIS Registry Premature cessation of DAPT, within the first 6 months after PCI, has been associated with an increased risk of stent thrombosis.1 Sustained DAPT (one year or longer) has been associated with lower risk for adverse events in observational studies.2,3 Most studies involved select cohorts and limited by pre-specified or standard criteria to define DAPT status 1Schulz et al., EHJ 2009; 2Ho et al., AHJ 2007; 3Park et al., AJC 2006

DAPT Cessation and PCI: Unresolved Questions PARIS Registry Does risk after DAPT cessation depend on the underlying context or clinical circumstances in which antiplatelet therapy is stopped (surgery vs. bleeding vs. physician-guidance)? How long does risk persist after antiplatelet therapy is withdrawn? What is the overall contribution of DAPT cessation on adverse events in the contemporary PCI era?

PARIS – Objectives PARIS Registry Determine the incidence of different modes of DAPT cessation after PCI. Evaluate the associations between DAPT cessation and adverse events following PCI by the underlying clinical context in which antiplatelet therapy was withdrawn.

Study Design Multicenter, multinational, observational study PARIS Registry Study Design Multicenter, multinational, observational study 5,031 subjects were followed for approximately 24 months post stent implantation Included bare metal and drug-eluting stents All events, including all occurrences of DAPT cessation, were adjudicated by a blinded external clinical events committee

Enrollment Eligibility (1) PARIS Registry Inclusion Criteria Successful stent placement in one or more lesions in native coronary arteries using an approved coronary stent, and discharged on DAPT Diagnosis of acute coronary syndrome, stable angina, or documented silent ischemia Patient was over 18 years old, provided consent, and agreed to follow-up

Eligibility for Enrollment (2) PARIS Registry Exclusion Criteria Evidence of stent thrombosis during baseline procedure Patient was already participating in an investigational device or drug study

Modes of DAPT Cessation PARIS Registry Discontinuation patients had discontinued DAPT as per recommendation of their physician who felt the patient no longer needed therapy Interruption patients had interrupted DAPT use on a voluntary basis and as guided by a physician due to (e.g. surgery) DAPT was then reinstituted within 14 days Disruption patients had disrupted DAPT use due to bleeding or non-compliance.

Paris Enrollment - Patients PARIS Registry 5,031 patients enrolled at 15 centers in 5 countries USA [10] n=3,666, 72,9% Columbia University Medical Center (n=927, 18,5%) Minneapolis Heart Institute Foundation (n=704, 14%) Mount Sinai Medical Center (n=555, 11%) 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%) Geisinger Medical Center (n=276, 5,5%) Washington Adventist Hospital (n=199, 4%) University of Kentucky (n=143, 2,8%) Heart Center of Indiana/ St. Vincent's/ The Care Group (n= 125, 2,5% ) Washington Hospital Center (n=75, 1,5%) July 1st, 2009 to Dec 2nd, 2010

Paris Enrollment - Patients PARIS Registry 5,031 patients enrolled at 15 centers in 5 countries Germany [1] n=720, 14,3% EUROPE [5] n=1,367, 27,1% Greece [1] n=180, 3,6% France [1] n=160, 3,2% Italy [2] n=307, 6% Remove animation Charité Hospital, Germany (n=720, 14,3%) San Raffaele Hospital, Italy (n=221 , 4,4%) Onassis Cardiac Surgery Center, Greece (n= 180, 3,5%) Hospital Bichat, France (n=160, 3,2%) Careggi Hospital, Italy (n=86, 1,7%) July 1st, 2009 to Dec 2nd, 2010

Participating Sites, Principal Investigators and Patients Enrolled Total # Enrolled Columbia University, USA Dr. Giora Weisz 927 Charité, Germany Dr. Bernhard Witzenbichler 720 Minneapolis Heart, USA Dr. Tim Henry 704 Mount Sinai, USA Dr. Annapoorna Kini 553 LeBauer/Moses Cone, USA Dr. Thomas Stuckey/Dr. Bruce Brodie 344 St. Luke's /Mid-America Heart, USA Dr. David Cohen 318 Geisinger Medical, USA Dr. Peter Berger 276 San Raffaele, Italy Dr. Antonio Colombo 221 Washington Adventist, USA Dr. Fayaz Shawl 199 Onassis, Greece Dr. George Dangas/Dr. Ioannis Iakovou 180 Hospital Bichat, France Dr. Gabriel Steg 160 University of Kentucky, USA Dr. David Moliterno 143 Heart Center of Indiana/St. Vincent's, USA Dr. James Hermiller 125 Careggi, Italy Dr. David Antonucci 86 Washington Hospital Center, USA Dr. Ron Waksman 75

PARIS: Study Organization PARIS Registry PARIS: Study Organization Data Management and Monitoring Medical Devices Consultancy, Ltd. New Zealand Statistical Analysis London School of Tropical Health and Hygiene: Stuart Pocock, Cono Ariti Mount Sinai School of Medicine: Usman Baber, Samantha Sartori Project Management/Clinical Coordinating Center Mount Sinai School of Medicine: Kristin Falciglia, Maria Alu Funding (Investigator-Initiated) Bristol Myers Squib/Sanofi-Aventis

Executive Committee and CEC Executive Committee Members *Dr. Roxana Mehran, USA and **Dr. Antonio Colombo, Italy Dr. Alaide Chieffo, Italy Dr. David Cohen, USA Dr. David Moliterno, USA Dr. Gabriel Steg, France Dr. Michael Gibson, USA Dr. Mitch Krucoff, USA Dr. Bernhard Witzenbichler, USA Dr. Giora Weisz, USA Clinical Events Committee *Dr. Steven Marx, Columbia University, NY Dr. Jason C. Kovacic, Mount Sinai, NY Dr. Mun Hong, St. Luke’s Roosevelt Hospital, NY Dr. S. Chiu Wong, NYP Cornell, NY Dr. Bruce Darrow, Mount Sinai, NY * Chair, ** Co-chair

Sequence of Results PARIS Registry Baseline characteristics compared between subjects by presence or absence of any DAPT cessation over 2 years. Incidence of major ischemic and bleeding adverse events calculated in overall population. Association between modes of DAPT cessation on adverse events examined using Cox proportional hazards regression with DAPT cessation entered as time updated covariate. Time updated covariates were generated using hierarchy of ‘worst’ DAPT status defined as Recommended Discontinuation -> Interruption -> Disruption

5,031 Patients with successful PCI with stenting enrolled at 15 sites in the US and Europe Final Study Population – 5018 Patients 13 Patients excluded from analysis (1 died prior to discharge and 12 not discharged on DAPT) Within 30 days Available Follow-up: 4972/5018 (99.1%) Lost to follow-up (n=46) Lost to follow-up (n=133) Within 365 days Available Follow-up: 4885/5018 (97.3%) Lost to follow-up (n=340) Within 2 years Available Follow-up: 4678/5018 (93.2%)

2-Year Kaplan-Meier Plot of Any DAPT Cessation Two Years (57.3%) 60 50 40 Cumulative Incidence, % 30 One Year (23.3%) 20 30 Days (2.9%) 10 6 12 18 24 Time From PCI, Months Incidence rates calculated over entire study population. Patients censored at last known contact, death or study end.

2-Year Kaplan-Meier Plots of Any Discontinuation, Interruption and Disruption 60 Discontinuation Disruption Interruption 50 40.8% 40 Cumulative Incidence, % 30 20 14.4% 10.5% 10 6 12 18 24 Time From PCI, Months Incidence rates calculated over entire study population. Patients censored at last known contact, death or study end.

Baseline Characteristics by Any DAPT Cessation Over 2 Years No DAPT Cessation (n= 2304) Recommended Discontinuation (n = 1611) Interruption (n = 412) Disruption (n = 691) Age (years) 62.9 ± 11.4 64.7 ± 10.85 65.3 ± 10.74 64.8 ± 12.26 Female Gender, n (%) 559 (24.3) 404 (25.1) 103 (25) 213 (30.8) BMI (kg/m2) 29.5 ± 5.7 28.7 ± 5.3 30.0 ± 5.5 29.3 ± 6.2 Hypertension, n (%) 1860 (80.7) 1258 (78.1) 355 (86.2) 536 (77.6) Previous MI, n (%) 637 (27.6) 329 (20.4) 109 (26.5) 139 (20.1) Previous CABG, n (%) 374 (16.2) 169 (10.5) 67 (16.3) 75 (10.9) Stroke, n (%) 79 (3.4) 52 (3.2) 17 (4.1) 25 (3.6) PVD, n (%) 188 (8.2) 120 (7.4) 33 (8) 51 (7.4) Current smoker, n (%) 445 (34.7) 315 (41.1) 62 (27.7) 159 (40.3) Diabetes, n (%) 829 (36) 456 (28.3) 150 (36.4) 219 (31.7) Acute Coronary Syndrome, n (%) 938 (40.7) 640 (39.7) 140 (34) 338 (48.9) BMS, n (%) 255 (11.1) 325 (20.2) 68 (16.5) 163 (23.6) 1st generation DES, n (%) 347 (15.1) 194 (12.0) 58 (14.1) 2nd generation DES, n (%) 1702 (73.9) 1092 (67.8) 286 (69.4) 453 (65.6) *SD = standard deviation; PVD = peripheral vascular disease; MI = myocardial infarction; CABG = coronary artery bypass graft; DAPT=dual antiplatelet therapy. BMI= body mass index. P-value is for each DAPT status versus the No DAPT cessation category.

Procedure Characteristics by DAPT Cessation Over 2 Years No DAPT Cessation (n= 2304) Recommended Discontinuation (n = 1611) Interruption (n = 412) Disruption (n = 691) PCI vessel Left Main, n (%) 77 (3.3) 44 (2.7) 11 (2.7) 26 (3.8) LAD, n (%) 1066 (46.3) 766 (47.5) 183 (44.4) 309 (44.7) Proximal LAD, n (%) 498 (21.6) 407 (25.3) 85 (20.6) 127 (18.4) LCx, n (%) 747 (32.4) 468 (29.1) 130 (31.6) 205 (29.7) RCA, n (%) 806 (35.0) 549 (34.1) 150 (36.4) 255 (36.9) Number of vessels treated 1 vessel, n (%) 1941 (84.2) 1406 (87.3) 355 (86.2) 590 (85.4) 2 vessels, n (%) 334 (14.5) 194 (12.0) 52 (12.6) 98 (14.2) 3 vessels, n (%) 29 (1.3) 11 (0.7) 5 (1.2) 3 (0.4) Bifurcation lesion, n (%) 255 (11.1) 211 (13.1) 36 (8.7) 93 (13.5) Chronic total occlusion, n (%) 86 (3.7) 66 (4.1) 16 (3.9) 24 (3.5) Thrombotic lesion, n (%) 156 (6.8) 178 (11.0) 25 (6.1) 56 (8.1) Stent type BMS, n (%) 325 (20.2) 68 (16.5) 163 (23.6) 1st generation DES, n (%) 347 (15.1) 58 (14.1) 75 (10.9) 2nd generation DES, n (%) 1702 (73.9) 1092 (67.8) 286 (69.4) 453 (65.6) Number of stents implanted 1 stent, n (%) 1250 (54.3) 892 (55.4) 247 (60.0) 393 (56.9) 2 stents, n (%) 664 (28.8) 460 (28.6) 94 (22.8) 197 (28.5) 3+ stents, n (%) 390 (16.9) 259 (16.1) 71 (17.2) 101 (14.6) *SD = standard deviation; PVD = peripheral vascular disease; MI = myocardial infarction; CABG = coronary artery bypass graft; DAPT=dual antiplatelet therapy. BMI= body mass index.

Overall Event Rates Over 2 Years Cumulative Incidence, % Incidence calculated as cumulative incidence from a Kaplan-Meier estimate of the time to the first occurrence of the adverse event.

Major Bleeding Rates Over 2 Years Cumulative Incidence, % Incidence calculated as cumulative incidence from a Kaplan-Meier estimate of the time to the first occurrence of the adverse event.

Impact of DAPT Cessation on Adverse Events

DAPT Cessation and MACE* HR (95% CI) P Events (n) On-DAPT 1.00 (Ref) 413 Discontinuation 0.63 (0.46, 0.86) 0.004 52 Interruption 1.41 (0.94, 2.12) 0.101 26 Disruption 1.50 (1.14, 1.97) 0.004 67 7.04 (3.31, 14.95) 2.17 (0.97, 4.88) 1.30 (0.97, 1.76) 0-7 Days 8-30 days 31+ days <0.001 0.06 0.083 7 6 54 0.25 0.5 1 2 4 8 16 Hazard Ratio *Cardiac Death, Def/Prob ST, Spontaneous MI, Clinically Driven TLR. All Cox Models adjusted for age, gender, region, ACS presentation, type of stent, number of stents implanted.

DAPT Cessation and Cardiac Death, Def/Prob ST, Spontaneous MI HR (95% CI) P Events (n) On-DAPT 1.00 (Ref) 218 Discontinuation 0.76 (0.50, 1.14) 0.181 31 Interruption 1.05 (0.58, 1.92) 0.864 12 Disruption 2.06 (1.49, 2.83) <0.001 54 9.82 (4.57, 21.12) 2.96 (1.21, 7.24) 1.71 (1.20, 2.44) 0-7 Days 8-30 days 31+ days <0.001 0.017 0.003 7 5 42 0.25 0.5 1 2 4 8 16 32 Hazard Ratio All Cox Models adjusted for age, gender, region, ACS presentation, type of stent, number of stents implanted.

DAPT Cessation and Spontaneous MI HR (95% CI) P Events (n) On-DAPT 1.00 (Ref) 116 Discontinuation 0.92 (0.53, 1.58) 0.748 18 Interruption 1.20 (0.55, 2.63) 0.647 7 Disruption 2.95 (1.99, 4.38) <0.001 39 0-7 Days 8-30 days 31+ days 18.25 (8.34, 39.95) 4.69 (1.71, 12.83) 2.22 (1.42, 3.46) <0.001 0.003 7 4 28 0.25 0.5 1 2 4 8 16 32 64 Hazard Ratio All Cox Models adjusted for age, gender, region, ACS presentation, type of stent, number of stents implanted.

DAPT Cessation and Def/Prob Stent Thrombosis Events (n) HR (95% CI) P 1.00 (Ref) 57 On-DAPT 0.39 (0.11, 1.35) 0.137 3 Discontinuation 0.64 (0.09, 4.82) 0.664 1 Interruption 2.58 (1.22, 5.46) 0.013 10 Disruption 0-7 Days 8-30 days 31+ days 15.94 (5.57, 45.58) 2.68 (0.36, 19.68) 1.35 (0.50, 3.64) <0.001 0.334 0.551 4 1 5 0.25 0.5 1 2 4 8 16 32 64 Hazard Ratio All Cox Models adjusted for age, gender, region, ACS presentation, type of stent, number of stents implanted.

DAPT Cessation and Cardiac Death HR (95% CI) P Events (n) On-DAPT 1.00 (Ref) 100 Discontinuation 0.64 (0.36, 1.16) 0.141 15 Interruption 1.06 (0.48, 2.34) 0.885 7 Disruption 1.68 (1.05, 2.67) 0.029 26 5.73 (1.39, 23.62) 3.44 (1.08, 10.98) 1.44 (0.87, 2.38) 0-7 Days 8-30 days 31+ days 0.016 0.037 0.161 2 3 21 0.25 0.5 1 2 4 8 16 32 Hazard Ratio All Cox Models adjusted for age, gender, region, ACS presentation, type of stent, number of stents implanted.

Overall Contribution of DAPT Cessation on Adverse Events

Number (%) of Spontaneous MI events by DAPT Status* Number of Events *Out of 180 spontaneous MI events at 2 years, 116 (64.4%) occurred while patients were ON DAPT. Spontaneous MI defined according to Universal Definition.

Number (%) of Def/Prob ST events by DAPT Status* Number of Events *Out of 71 ST events at 2 years, 57 (80.3%) occurred while patients were ON DAPT. ST defined by the Academic Research Consortium (ARC) Critera.

Number (%) of Cardiac Death events by DAPT Status* Number of Events *Out of 148 Cardiac Death events at 2 years, 100 (67.6%) occurred while patients were ON DAPT. Cardiac Death defined using ARC criteria.

Number (%) of Major (BARC ≥ 3) Bleeding Events by DAPT Status* Number of Events *Out of 196 Bleeding events at 2 years, 131 (66.8%) occurred while patients were ON DAPT. Major Bleeding defined as BARC ≥ 3).

Proportion of Ischemic Adverse Events Attributable to DAPT Disruption or Interruption Attributable Risk, %

Limitations Observational design precludes causal inferences Follow-up phone calls to ascertain DAPT status can introduce recall bias Small number of events (n=7) occurring early (days 1-7) after disruption led to imprecise risk estimates with wide CI. Findings merit confirmation in larger studies.

Conclusions The impact of DAPT cessation on cardiac risk after PCI is not uniform but varies substantially by underlying mode, a novel finding with important implications for future study design and clinical practice. Relative risk for MACE due to disruption is substantial, albeit short-lived, compared to those on DAPT. The overall impact of DAPT cessation on adverse events is modest and may have been mitigated with the introduction of safer stent platforms. Findings highlight the need for uniform approaches in classifying DAPT cessation, analogous to those currently used for bleeding and MI.