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Disclosures

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

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Disclosures

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  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 • 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) • Sunil V. Rao, MD • Research funding: Portola Pharmaceuticals, Cordis Corporation, Ikaria • Consultant: sanofi-aventis, BMS, AstraZeneca, Daiichi Sankyo-Lilly, Terumo USA • This presentation discusses the unapproved and unlabeled use of epoetin alfa in patients with acute myocardial infarction

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

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

  5. Study objectives • 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 • This comparison will comprise two phases: • Dose-escalation safety phase • Efficacy phase using maximal tolerated EPO dose

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

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

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

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

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

  11. Enrollment: Top 10 sites

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

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

  16. Results (3): Procedural characteristics

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

  18. Results (5): Secondary endpoints *P < 0.05 in unadjusted analysis P-values adjusted for age, infarct location, and enrollment phase

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

  20. Results (6): Clinical safety endpoints Values shown are percentages

  21. Summary (1) • 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 • It did not favorably affect measures of LV remodeling at either the early or 12-week time points

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

  23. Conclusions • These data, coupled with the lack of efficacy seen in other STEMI trials involving EPO (REVIVAL-31, HEBE III2), do not support the hypothesis that EPO favorably impacts outcome after reperfusion for STEMI • Whether earlier administration or alternate dosing provides a cardioprotective effect of EPO in humans remains to be determined 1Ott I, et. al. Circ:CVIntv 2010 2Voors AA, et. al. EHJ 2010

  24. REVEAL Trial Organization • Principal investigator – Robert A. Harrington MD • NIA Project Officer – Samer S. Najjar MD PhD • Steering committee – Sunil V. Rao MD, Chiara Melloni MD MHS, Thomas J. Povsic MD PhD, Raymond J. Kim MD • DCRI Project Lead – Laura Melton PhD • Statistics – Kristi Prather MPH, Rakhi Kilaru MS, Vic Hasselblad PhD • NIA – Mark Talan MD PhD, Luigi Ferrucci MD PhD, Dan L. Longo MD, Edward G. Lakatta MD • 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

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