Clinical Assessment of Patients with Acute Coronary Syndrome Managed - PowerPoint PPT Presentation

Clinical Assessment of Patients with Acute Coronary Syndrome Managed with Percutaneous Coronary Intervention and Treated with Prasugrel or Clopidogrel using Academic Center Databases - The PROMETHEUS Study-

Study Organization Data Coordination/Analysis Study Leadership Roxana Mehran (PI) – Mount Sinai Usman Baber Samantha Sartori Steering Committee Melissa Aquino Timothy Henry – Cedars Sinai Sonny Sayseng Sunil Rao – Duke University William Weintraub – Christiana Icahn School of Medicine at Mount Sinai Study Sponsor Mark B. Effron Stuart Keller Statistical Consultation Douglas Faries Cliff Molife Prof. Stuart Pocock Brian A. Baker Elizabeth Marrett London School of Hygiene Eli Lilly and Daiichi Sankyo

Study Rationale • Randomized studies have shown that compared to clopidogrel, prasugrel significantly reduces thrombotic events, albeit with an excess risk of bleeding, in ACS patients undergoing PCI with stent implantation • Data examining the safety and efficacy profile of prasugrel in non-randomized patients presenting across the entire clinical spectrum of ACS remains limited • The overall frequency and determinants of prasugrel use remains poorly characterized

Study Design • Cohort study evaluating ACS (UA, NSTEMI or STEMI) patients undergoing PCI with stent implantation in academic centers in the United States between 1/1/2010 – 6/30/2013 • Each center maintains an institutional database with baseline clinical, procedural and outcome data on patients undergoing PCI • Center feasibility to extract and provide relevant data (baseline and outcomes) was assessed and confirmed with a site selection questionnaire • The study sponsor had no access to patient level data

Definitions • Major Adverse Cardiovascular Events (MACE) ¡ Composite occurrence of all-cause death, myocardial infarction, unplanned revascularization or stroke • Bleeding ¡ Clinically overt hemorrhage requiring hospitalization • Primary Efficacy Endpoint ¡ MACE at 90 days from index PCI • Primary Safety Endpoint ¡ Bleeding requiring hospitalization

Study Schema Index ¡PCI ¡ ¡

Data Extraction and Analysis Data Extraction • Data Elements • Data pre-specified Coordinating Aggregation by Steering Center Committee • Local Sites Analysis Extraction Validation/ Sheet Quality Check

Statistical Methods • Sample Size Assumptions ¡ MACE rate ~ 8.0% at 90 days ¡ Relative reduction with prasugrel ~ 20% ¡ Minimum of 4,300 prasugrel patients required to achieve 80% power • Propensity score adjustment ¡ Stratification (Primary) ¡ Inverse Probability weighting ¡ Matching ¡ Covariate adjustment

Propensity Score Histogram Predicted Probability to Receive Prasugrel

PROMETHEUS Sites 19,914 patients over 8 US Sites from 01 Jan 2010 to 30 June 2013 Aurora Healthcare Anthony DeFranco Mount Sinai Medical, Minneapolis Annapoorna Kini Heart Institute, UPMC, Craig Strauss Catalin Toma Cleveland Clinic, Samir Kapadia Christiana Care, Intermountain Heart Institute, Sandra Weiss Brent Muhlestein Duke University, Sunil Rao

Prasugrel and Clopidogrel Use in Overall Cohort 20% n = 4058 Prasugrel 80% n = 15856 Clopidogrel

CAD Presentation in Overall Cohort STEMI (n=3285) 17% NSTEMI 56% 27% (n=5412) Unstable angina (n=11,216) CAD Presentation by Therapy 100% 15.8% 19.1% STEMI 80% (n=3,285) 26.8% 28.6% 60% NSTEMI (n=5,412) 40% Unstable 57.3% 52.3% Angina 20% (n=11,216) 0% Prasugrel Clopidogrel

Baseline Characteristics * Prasugrel Clopidogrel (n = 4,058) (n = 15,856) Age, years 58.7 ± 10.3 65.8 ± 12.3 Female sex 989 (24.4%) 5315 (33.5%) African-American 253 (6.2%) 1,872 (11.8%) Weight <60 kg 124 (3.1%) 1145 (7.2%) Diabetes 1382 (34.1%) 6198 (39.1%) Diabetes on insulin 394 (9.7%) 2140 (13.5%) Hypertension 2915 (71.8%) 13466 (84.9%) Dyslipidemia 3220 (79.3%) 13469 (84.9%) Smoking 1175 (29.0%) 3832 (24.2%) Prior MI 833 (20.5%) 5130 (32.4%) Prior PCI 788 (19.4%) 4250 (26.8%) Prior CABG 359 (8.8%) 3074 (19.4%) Prior cerebrovascular disease 188 (4.6%) 2197 (13.9%) CKD 619 (15.3%) 4995 (31.6%) Anemia 339 (8.4%) 2553 (16.1%) *p <0.0001 for all

Procedural Characteristics* Prasugrel Clopidogrel (n = 4,058) (n = 15,856) Multivessel disease 1672 (41.2%) 6723 (42.4%) PCI vessel Left Main 84 (2.1%) 583 (3.9%) LAD 1972 (48.6%) 6926 (43.7%) Circumflex 1100 (27.1%) 4795 (30.2%) RCA 1430 (35.2%) 5368 (33.9%) At least one B2/C type lesion 2848 (71.7%) 10763 (75.3%) At least one lesion with moderate/severe 468 (12.0%) 2694 (19.3%) calcification Total stent length 31.4 ± 20.2 30.50 ± 20.9 Minimum stent diameter 3.01 ± 0.49 2.96 ± 0.50 At least one 1 st gen DES 297 (7.3%) 2496 (15.7%) At least one 2 nd gen DES 3297 (81.2%) 10525 (66.4%) At least one BMS 569 (14.0%) 3927 (24.8%) Procedural anticoagulation Bivalirudin 2743 (67.6%) 11730 (74.0%) GP2b3a inhibitor 1178 (29.0%) 3391 (21.4%) *p <0.05 for all except multivessel disease (p=0.17) and RCA (0=0.096)

Overall MACE 40% p-value<0.001 p-value<0.001 p-value<0.001 p-value<0.001 30% MACE % 20.7 [20.0-21.3] 20% 14.3 [13.7-14.9] 9.6 [9.1-10.1] 6.2 [5.8-6.6] 12.1 [11.0-13.2] 10% 8.3 [7.4-9.2] 5.7 [5.0-6.5] 3.5 [2.9-4.1] 0% 0 30 90 180 365 Days After PCI Number at risk Clop 15856 13612 12413 11322 9438 Pras 4058 3605 3376 3169 2636 *MACE is defined as all cause death, myocardial infarction, stroke, or unplanned revascularization. Clopidogrel Prasugrel

Hazard Ratios for Overall MACE HR [95% CI] p-value 30 Days 0.56 <0.001 Unadjusted 0.84 0.09 Adjusted (PS) 90 Days 0.58 <0.001 Unadjusted 0.89 0.17 Adjusted (PS) 180 Days 0.56 <0.001 Unadjusted 0.90 0.12 Adjusted (PS) 365 Days 0.56 <0.001 Unadjusted 0.86 0.01 Adjusted (PS) 0.1 1 10 Prasugrel Better Clopidogrel Better PS – Propensity stratified

Hazard Ratios for Myocardial Infarction HR [95% CI] p-value 30 Days 0.53 <0.001 Unadjusted 0.81 0.15 Adjusted (PS) 90 Days 0.51 <0.001 Unadjusted 0.84 0.18 Adjusted (PS) 180 Days 0.49 <0.001 Unadjusted 0.85 0.15 Adjusted (PS) 365 Days 0.54 <0.001 Unadjusted 0.90 0.30 Adjusted (PS) 0.1 1 10 Prasugrel Better Clopidogrel Better PS – Propensity stratified

Hazard Ratios for All-Cause Death HR [95% CI] p-value 30 Days 0.15 <0.001 Unadjusted 0.47 0.04 Adjusted (PS) 90 Days 0.21 <0.001 Unadjusted 0.62 0.04 Adjusted (PS) 180 Days 0.25 <0.001 Unadjusted 0.69 0.04 Adjusted (PS) 365 Days 0.26 <0.001 Unadjusted 0.69 0.01 Adjusted (PS) 0.01 0.1 1 10 100 Prasugrel Better Clopidogrel Better PS – Propensity stratified

Hazard Ratios for Bleeding HR [95% CI] p-value 30 Days 0.61 <0.001 Unadjusted 0.98 0.89 Adjusted (PS) 90 Days 0.65 <0.001 Unadjusted 1.03 0.79 Adjusted (PS) 180 Days 0.61 <0.001 Unadjusted 0.97 0.82 Adjusted (PS) 365 Days 0.64 <0.001 Unadjusted 0.97 0.83 Adjusted (PS) Prasugrel Better Clopidogrel Better 0.1 1 10 PS – Propensity stratified

Limitations • Observational design precludes causal inferences • Outpatient medication adherence not available • Potential for residual/unmeasured confounding on point estimates despite extensive statistical adjustment • Lack of standardized definition for bleeding endpoint • Potential for therapeutic cross-over may result in biasing point estimates to the null

Conclusions • The clinical profile of ACS patients treated with clopidogrel as compared to prasugrel differs substantially across US academic medical centers ¡ The overall burden of risk factors for both ischemic and hemorrhagic events are much lower in patients treated with prasugrel • Although in this study prasugrel use was associated with lower rates of ischemic adverse events, the magnitude of benefit attenuated and was no longer statistically significant after adjusting for baseline differences • Analogously, lack of adjusted bleeding difference with prasugrel may reflect selection of patients at very low risk for hemorrhagic complications • Recalibrating ‘real-world’ use of prasugrel to better approximate a patient’s ischemic risk may yield a more appreciable therapeutic benefit, a hypothesis that warrants prospective evaluation

Acknowledgements Minneapolis Heart Institute Ross Garberich Aurora Medical Center Sandra Hubatch Cleveland Clinic Kanhaiya Poddar Intermountain Heart Institute Stacey Knight Duke University Medical Center Amanda McBroom Brooks Christiana Care Health Services Angela Herman University of Pittsburgh Medical Center Floyd Thoma Jaya Chandrasekhar Ioannis Mastoris Icahn School of Medicine at Mount Sinai Swathi Roy Amreen Rahman