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 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
Recombinant epoetin alfa is FDA-approved for treatment of anemia
May have 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) at reducing infarct size in patients with acute STEMI who have undergone successful primary or rescue PCI
This comparison was composed of two phases:
Dose-escalation safety phase
Efficacy phase using maximal tolerated EPO dose

6. Inclusion criteria Exclusion criteria Age ≥ 21 years
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. Primary and Secondary endpoints
STEMI
Primary or rescue PCI
TIMI 0-1 flow in IRA
Successful PCI
IV EPO
Matching saline
placebo
Primary and Secondary endpoints
- Randomize
- Study drug within 4 hrs

8. 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

9. Sample size
Sample size for Efficacy cohort
55 patients/arm provides > 80% power to detect a ≥ 20% difference in infarct size between EPO and placebo

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

11. Treatment schema: Efficacy phase
Efficacy cohort
Saline placebo
n = 55
60000 u EPO
1:1
Enrollment continued until at least 110 patients completed the first MRI
Two prespecified subgroups analyzed: Age (< 70 yrs, ≥ 70 yrs), Infarct location (anterior, non-anterior)

12. Principal Investigator
Enrollment: Top 10 sites
Site
Principal Investigator
New York Methodist Hospital
John Heitner, MD
The Ohio State University Medical Center
Subha Raman, MD
Mayo Clinic
Greg Barsness, MD
Duke University Medical Center
Sunil V. Rao, MD
Henry Ford Medical Center
Adam Greenbaum, MD
Stony Brook University Medical Center
Luis Gruberg, MD
Geisinger Medical Center
James Blankenship, MD
Washington Hospital Center
Ron Waksman, MD
Lynchburg General Hospital
Thomas Nygaard, MD
Wake Forest University Baptist Medical Center
Sanjay Gandhi, MD

13. 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

14. Results (2): Baseline characteristics
Total
Efficacy Cohort
EPO
n=123
Placebo
n=99
n=68
n=70
Mean age, yrs
56.8
58.8
55.6
57.4
% ≥ 70 yrs
16.3
18.2
16.2
15.7
% Female
18.7
21.2
10.3
20.0
% Diabetes
11.4
25.3
8.8
24.3
% HTN
47.2
53.5
41.2
48.6
% Current smoker
38.8
42.4
40.3
45.7
% Anterior MI
27.6
27.3
29.4
27.1
% Killip class I
100
94.8
95.5

15. Results (3): Procedural characteristics
Total
Efficacy Cohort
EPO
n=123
Placebo
n=99
n=68
n=70
% Primary PCI
89.4
82.8
94.1
78.6
% Rescue PCI
10.6
17.2
5.9
21.4
Times (min)
Symptom onset to reperfusion
207.5
208.3
210.9
201.9
Reperfusion to study drug
176.3
183.0
172.4
175.5
Randomization to study drug
47.5
39.9
47.9
39.6

16. Results (4): Primary endpoint Mean (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

17. Results (5): Secondary endpoints
2-6 d CMR
12-wk CMR
EPO
n=68
Placebo
n=70
n=61
n=63
Infarct size, % LV
15.8
15.0
10.6
10.4
LVESVi, mL/m2
34.7
32.6
34.1
32.0
LVEDVi, mL/m2
65.6
63.4
70.0
66.6
LVMi, g/m2*
74.2
69.2
67.3
61.8
LVEF, %
48.2
48.9
52.5
52.0
*P < 0.05 in unadjusted analysis
P-values adjusted for age, infarct location, and enrollment phase

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

19. Results (6): Clinical safety endpoints
EPO
n=125
Placebo
n=97 P
Death
0.8
0.72
Re-MI
1.6
0.35
Stent thrombosis
2.4
0.17
VTE -
Stroke
Death/MI/Stroke/ST
4.0
0.04
Death/MI/Stroke
3.2
0.08
Any AE
55.2
41.2
Any SAE
20.0
10.3
0.05
Values shown are percentages

20. 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

21. 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

22. 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:CV Intv 2010
2Voors AA, et. al. EHJ 2010

23. REVEAL Trial Organization
Principal investigator – Robert A. Harrington MD
NIA Project Officer – Samer S. Najjar MD PhD
Subinvestigators – 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, E. Pete Miller MD
Thank you to all REVEAL Trial investigators,
Study coordinators, and patients