1. A Randomized, Double-blind, Placebo-controlled Trial of Intravenous Erythropoietin in Patients with ST-Segment Elevation Myocardial Infarction – Primary Results of the REVEAL Trial

2. Disclosures n The REVEAL Trial was funded through a contract with the Intramural Research Program of the National Institute on Aging (HHS-N-260-2005-00010-C) n Sunil V. Rao, MD l Research funding: Portola Pharmaceuticals, Cordis Corporation, Ikaria l Consultant: sanofi-aventis, BMS, AstraZeneca, Daiichi Sankyo-Lilly, Terumo USA n This presentation discusses the unapproved and unlabeled use of epoetin alfa in patients with acute myocardial infarction

3. Background n Despite advances in STEMI management, it remains a significant cause of morbidity, mortality, and disability n Patients who survive STEMI are at risk for infarct expansion, LV remodeling, and heart failure n Given the global burden of heart failure, therapies that limit infarct size and attenuate LV remodeling are needed n Preclinical studies demonstrate that erythropoietin plays a cardioprotective role in models of myocardial ischemia and ischemia-reperfusion

4. Erythropoietin n 165 amino acid glycoprotein n FDA-approved for treatment of anemia n Pleiotropic effects l Receptors on endothelial cells, cardiomyocytes n Prior data + Increased angiogenesis + Recruitment of endothelial progenitor cells + Decreased apoptosis

5. Study objectives n Determine the safety and efficacy of intravenous epoetin alfa (EPO) in reducing infarct size in patients with acute STEMI who have undergone successful primary or rescue PCI l This comparison will comprise two phases: 1. Dose-escalation safety phase 2. Efficacy phase using maximal tolerated EPO dose

6. Inclusion criteria n Age ≥ 21 years n Acute STEMI with TIMI 0 or 1 flow in a major epicardial coronary artery n Revascularization within 8 hours of symptom onset n Successful rescue/primary PCI l ≥ TIMI 2 flow with residual lesion < 50% in IRA Exclusion criteria n Prior heart disease l MI, EF < 50%, CABG, prior PCI in IRA n Need for CABG n Blood pressure l Shock, SBP > 180 mm Hg or DBP > 110 mm Hg at time of drug admin n Thrombotic events l Hypercoagulable disorder, thromboembolic event, venous thrombosis n Hx of stroke/TIA, seizures n Contraindication to MRI or gadolinium contrast (e.g., GFR < 30 cc/min) n Clinical indication or contraindication for EPO n Pregnant or nursing

7. STEMISTEMI Primary or rescue PCI TIMI 0-1 flow in IRA Primary or rescue PCI TIMI 0-1 flow in IRA Successful PCI IV EPO Matching saline placebo placebo 2-6 d infarct size by MRI - Randomize - Study drug within 4 hrs

8. Treatment schema n Randomization stratified by age (< 70 y, ≥ 70 y) and infarct location (anterior vs. non-anterior) n Qualitative safety review by DSMB after each safety cohort Safety cohort 1 Saline Placebo N = 10 15000 u EPO N = 20 Safety cohort 2 Saline Placebo N = 10 30000 u EPO N = 20 Safety cohort 3 Saline Placebo N = 10 60000 u EPO N = 20 Unacceptable STOP TRIAL Efficacy cohort Saline Placebo N = 55 15000 u EPO N = 55 1:1 Unacceptable Efficacy cohort Saline Placebo N = 55 30000 u EPO N = 55 1:1

9. Treatment schema: Efficacy phase n Enrollment continued until at least 110 patients completed the first MRI Efficacy cohort Saline placebo n = 55 60000 u EPO n = 55 1:1

10. Primary and secondary endpoints n Primary endpoint l Infarct size (% of LV) in the territory of the IRA 2-6 days after study drug administration l Measured by contrast-enhanced cardiac magnetic resonance imaging (CMR) n Secondary endpoints l Infarct size at 12 ± 2 weeks l Measures of LV remodeling (LVESVi, LVEDVi, LVMi, LVEF) at early and late timepoints n Safety endpoints l Death, recurrent MI, arterial thrombotic events (stent thrombosis), VTE, stroke/TIA

11. Enrollment: Top 10 sites SitePrincipal Investigator New York Methodist HospitalJohn Heitner, MD The Ohio State University Medical Center Subha Raman, MD Mayo ClinicGreg Barsness, MD Duke University Medical CenterSunil V. Rao, MD Henry Ford Medical CenterAdam Greenbaum, MD Stony Brook University Medical Center Luis Gruberg, MD Geisinger Medical CenterJames Blankenship, MD Washington Hospital CenterRon Waksman, MD Lynchburg General HospitalThomas Nygaard, MD Wake Forest University Baptist Medical Center Sanjay Gandhi, MD

12. Study drug administration & statistical analysis n Study drug administration l EPO or matching saline placebo administered intravenously within 4 hours of successful primary or rescue PCI n Statistical analysis l Sample size: 55 patients/arm provides > 80% power to detect a ≥ 20% difference in infarct size between EPO and placebo l One prespecifed interim analysis performed

13. Data analysis n Efficacy analysis includes patients in efficacy cohort + patients from relevant dose safety cohort n Primary outcome variable compared using log-rank test n Secondary outcomes l ANOVA for unadjusted analyses l ANCOVA for adjusted analyses—adjusted for age, infarct location, enrollment phase l 12-week CMR measures also adjusted for early CMR values n Outcomes further analyzed within prespecified subgroups l Age: < 70 y, ≥ 70 y l Infarct location: anterior vs. non-anterior

14. Results (1) – Patient flow 222 pts, 22 sites 189 with early CMR - 24 pts in 15K cohort - 27 in 30K cohort - 138 in 60K Efficacy cohort 124 (89.9%) of Efficacy cohort With 12 week CMR

15. Results (2): Baseline characteristics TotalEfficacy Cohort EPO n=123 Placebo n=99 EPO n=68 Placebo n=70 Mean age, yrs56.858.855.657.4 % ≥ 70 yrs16.318.216.215.7 % Female18.721.210.320.0 % Diabetes11.425.38.824.3 % HTN47.253.541.248.6 % Current smoker 38.842.440.345.7 % Anterior MI27.627.329.427.1 % Killip class I10094.810095.5

16. Results (3): Procedural characteristics TotalEfficacy Cohort EPO n=123 Placebo n=99 EPO n=68 Placebo n=70 % Primary PCI89.482.894.178.6 % Rescue PCI10.617.25.921.4 Times (min) Symptom onset to reperfusion 207.5208.3210.9201.9 Reperfusion to study drug 176.3183.0172.4175.5 Randomization to study drug 47.539.947.939.6

17. Results (4): Primary endpoint Mean (SE) infarct size at 2-6 days after study drug admin EPO vs. placebo 15.8% vs. 15.0%, P=NS P-value adjusted for age, infarct location, enrollment phase EPOPlacebo Infarct Size (%LV) 0 5 10 15 20 25

18. Results (5): Secondary endpoints 2-6 d CMR12-wk CMR EPO n=68 Placebo n=70 EPO n=61 Placebo n=63 Infarct size, % LV15.815.010.610.4 LVESVi, mL/m 2 34.732.634.132.0 LVEDVi, mL/m 2 65.663.470.066.6 LVMi, g/m 2 *74.269.267.361.8 LVEF, %48.248.952.552.0 *P < 0.05 in unadjusted analysis P-values adjusted for age, infarct location, and enrollment phase

19. Results (7): Prespecified subgroups Mean (SE) infarct size at 2–6 days by age group and MI location

20. Results (6): Clinical safety endpoints EPO n=125 Placebo n=97 P Death0.800.72 Re-MI1.600.35 Stent thrombosis2.400.17 VTE00- Stroke0.800.72 Death/MI/Stroke/ST4.000.04 Death/MI/Stroke3.200.08 Any AE55.241.20.04 Any SAE20.010.30.05 Values shown are percentages

21. Summary (1) n Compared with placebo, a single intravenous bolus of 60,000 u of EPO in STEMI patients who have undergone successful primary or rescue PCI did not reduce infarct size at either the early or 12- week time points n It did not favorably affect measures of LV remodeling at either the early or 12-week time points

22. Summary (2) n EPO as studied in the REVEAL trial may increase infarct size among STEMI patients ≥ 70 years old l Interpret with caution given the small number of patients ≥ 70 years old enrolled n EPO was associated with a greater number of adverse clinical events compared with placebo

23. Conclusions n These data, coupled with the lack of efficacy seen in other STEMI trials involving EPO (REVIVAL-3 1, HEBE III 2 ), do not support the hypothesis that EPO favorably impacts outcome after reperfusion for STEMI n Whether earlier administration or alternate dosing provides a cardioprotective effect of EPO in humans remains to be determined 1 Ott I, et. al. Circ:CV Intv 2010 2 Voors AA, et. al. EHJ 2010

24. REVEAL Trial Organization n Principal investigator – Robert A. Harrington MD n NIA Project Officer – Samer S. Najjar MD PhD n Steering committee – Sunil V. Rao MD, Chiara Melloni MD MHS, Thomas J. Povsic MD PhD, Raymond J. Kim MD n DCRI Project Lead – Laura Melton PhD n Statistics – Kristi Prather MPH, Rakhi Kilaru MS, Vic Hasselblad PhD n NIA – Mark Talan MD PhD, Luigi Ferrucci MD PhD, Dan L. Longo MD, Edward G. Lakatta MD n DSMC – Lawrence J. Appel MD (chair), Victor Ferrari MD, Mark D. Kelemen MD, Jon R. Resar MD, Michael L Terrin MD Thank you to all REVEAL Trial investigators, Study coordinators, and patients