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ClinicalTrials.gov Identifier NCT00390832
Prospective, Randomized, Double-Blind,
Placebo-controlled Trial of Erythropoietin in
Patients With ST-Segment Elevation Myocardial
Infarction Undergoing Percutaneous Coronary
Intervention (REVIVAL-3) Ilka Ott, Stefanie
Schulz, Julinda Mehilli, Stephanie Fichtner,
Martin Hadamitzky, Tarek Ibrahim, Janina Hackl,
Katharina Hoppe, Stefan Martinoff, Josef
Dirschinger, Adnan Kastrati, Albert
Schömig Deutsches Herzzentrum und 1.
Medizinische Klinik der Technischen Universität
München No conflict of interest to disclose
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REVIVAL-3 Background
Although primary percutaneous coronary
interventions (PCI) improve survival of patients
with acute myocardial infarction (AMI), ischemia/
reperfusion injury is still a major unresolved
problem. Experimental studies have shown a
protective role of erythropoietin (Epo) during
ischemia and reperfusion in the heart with a
reduction in infarct size.
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REVIVAL-3 Erythropoietin (Epo) Experimental
Studies
control
Epo
control
Epo
Epo reduces infarct size and improves myocardial
function. This was associated with a decrease in
apoptotic cells, an increase in EPC recruitment
and neovascularization.
Parsa et al. 2003 Westenbrink et al. 2007
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REVIVAL-3 Erythropoietin (EPO) Clinical
Studies
In patients with ischemic stroke high-dose
Epoetin beta improved clinical outcome and
reduced infarct size by trend (n40) Ehrenreich
et al. 2002 Mol Med In patients with AMI
high-dose Darbopoietin was safe and well
tolerated (n22) Lipsic et al. 2006
Cardiovascular Drugs and Therapy
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REVIVAL-3
Objective...
... was to assess the effect of high-dose
erythropoietin in patients with acute
ST-elevation myocardial infarction treated with
primary PCI
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Inclusion Criteria
REVIVAL-3
Patients with acute ST-elevation myocardial
infarction with primary PCI

• chest pain lasting more than 20 min
• 0.1 mV of ST-segment elevation in 2 limb leads
  or 0.2 mV in 2 contiguous precordial leads
  or new left bundle branch block on surface ECG

Angiographically left ventricular ejection
fraction lt50
Written, informed consent
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Key Exclusion Criteria
REVIVAL-3

• Age gt 80 or lt 18 years
• Cardiogenic shock or prolonged cardiopulmonary
  resuscitation
• Previous MI
• Severe uncontrolled hypertension (gt180mmHg,
  unresponsive to therapy)
• Hematological disorders such as essential
  thrombocytosis, megakaryoblastic leukemia,
  polycythemia vera
• Relevant hematologic deviations (hemoglobin lt
  10.0g/L or gt 15.5 g/L, platelet count lt 100 x
  109/L or gt 600 x 109/L)
• Coronary intervention within the last 30 days
• Any contraindication to magnetic resonance
  imaging
• Known allergy to study medication, pregnancy,
  prior inclusion in the study

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Study Therapy
REVIVAL-3
1. balloon inflation
24 hrs
48 hrs
3.3 x 104 U Epoetin beta
3.3 x 104 U Epoetin beta
3.3 x 104 U Epoetin beta
n68
138 patients with STEMI
Cath Lab Randomization
n70
Placebo
Placebo
Placebo
1. balloon inflation
24 hrs
48 hrs
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REVIVAL-3 Primary Endpoint
EF (EDV-ESV)/EDV100
EDV
ESV
Primary end point Left ventricular-EF at
6-month follow-up in MRI
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REVIVAL-3 Key Secondary Endpoints
Key Secondary end points Change in LV-ejection
fraction and infarct size over 6 months after
randomization Death, recurrent myocardial
infarction, infarct related artery
revascularization and stroke at 30 days and 6
months
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REVIVAL-3 Sample Size Calculation

• Assumptions
• LV-EF in placebo group 45 9
• Increase in EF with Epo by 5
• ?-level 0.05 (two-sided) power 80
• Sample size
• 52 patients per group with MR study
• to accommodate for possible missing MR studies
  60 patients per group planned

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REVIVAL-3 Patient Characteristics
Epo (n68)
Placebo (n70)
Age, yrs
5913
6212
Women,
18
26
Hypercholesterolemia,
35
36
Arterial hypertension,
63
63
Diabetes mellitus,
16
14
Current smoker,
43
43
Body mass index, kg/m2
284
274

MeanSD,
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REVIVAL-3 Infarct Characteristics
Epo (n68)
Placebo (n70)
Infarct localization,
anterior
49
43
posterior
43
50
lateral
8
7
Killip Class,
I
75
72
II
22
27
III
3
1
Symptom to admission minutes
175 108361
168 109315
Admission to PCI minutes
84 6698
78 5796
, Median 25th, 75th percentiles
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REVIVAL-3 Infarct Characteristics
Epo (n68)
Placebo (n70)
LV- ejection fraction,
468
468
Area at risk (SESTA-MIBI),
2922
3020
Multivessel disease,
62
71
Infarct related coronary artery,
50
44
LAD
LCx
6
9
RCA
44
46
LMCA
0
1
Reperfusion strategy
93
95
DES
BMS
4
4
PTCA
1
3
MeanSD
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REVIVAL-3 Infarct Related TIMI Flow Rates
After PCI
Prior to PCI
100
100


60
60
20
20
Epo
Placebo
Epo
Placebo
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REVIVAL-3 Blood Count
Reticulocytes
Hemoglobin
18
45

Epo


16
40
Epo

14
35
12
30
Placebo

hemoglobin mg/dl
10
25
reticulocytes
Placebo
8
20
6
15
4
10
2
5
0
0
0
1
2
3
4
5
6
7
0
1
2
3
4
5
6
7
days after randomization
days after randomization
MeanSD
p lt 0.05
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REVIVAL-3 Primary End Point
EF in MRI
P .91

Epo
Placebo
n52
n55
6-month follow-up
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REVIVAL-3 MRI Results
Left Ventricular Endsystolic Volume Index
Left Ventricular Enddiastolic Volume Index
P .68
P .92
ml/m2
ml/m2
Epo
Epo
Placebo
Placebo
6-month follow-up
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REVIVAL-3 MRI Results
Decrease in infarct size over 6 months
Infarct Size
P .80
P .38

Delta
Epo
Placebo
Epo
Placebo
6-month follow-up
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REVIVAL-3 Angiographic Results
Increase in EF over 6 months
P .38
Delta
Epo
Placebo
6-month follow-up
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REVIVAL-3 Subgroup Analysis
Difference in 6-month EF
All
Age
lt 62 yrs
gt 62 yrs
Renal function
GFR75 ml/min
GFRgt75 ml/min
LV-EF
47.8
gt47.8
Early reperfusion from symptom onset
3h
gt3h
-8
-6
-4
-2
0
2
4
6
8
Placebo better
Epo better
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REVIVAL-3 Clinical Adverse Events 30 days
6

P .99
P .74
P .98
P .98
P .74
4
2.9
2.9
2.9
2.9
2.9
2.9
2
1.5
1.5
1.4
0
0
Death
MI
Stroke
Stent
IRA Revasc.
thrombosis
Epo (n68)
Placebo (n70)
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REVIVAL-3 Survival Free of MACCE at 6 Months
100
Placebo

95
90
Epo
Survival free of recurrent MI, IRA revasc. and
stroke
85
80
P0.14 RR 2.35 (0.75-7.37)
75
70
0
1
2
3
4
5
6
Months after randomization
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REVIVAL-3 Conclusion
High dose epoetin beta does not improve left
ventricular function or reduce infarct size in
patients with ST-elevation myocardial infarction
treated with primary PCI. The trend towards a
higher risk of adverse clinical events should be
taken into account before planing future
investigations with this drug in patients with
AMI.