Regenerate Vital Myocardium by Vigorous Activation of Bone Marrow Stem Cells - REVIVAL-3

Description:

Ex vivo studies have demonstrated a protective effect of human recombinant erythropoietin on ischemia and reperfusion. The REVIVAL-3 study sought to study the safety and efficacy of erythropoietin in reducing infarct size in patients with ST-segment elevation myocardial infarction (STEMI).

Hypothesis:

Erythropoietin will be associated with a significant reduction in infarct size compared with placebo in patients undergoing primary percutaneous coronary intervention (PCI) for STEMI.

Study Design

  • Blinded
  • Parallel
  • Placebo Controlled
  • Randomized

Patient Populations:

  • Primary PCI for first STEMI within 24 hours of symptom onset
  • Successful reperfusion with PCI
  • Angiographic LVEF <50%
  • Age >18 years

    Number of enrollees: 138
    Duration of follow-up: 6 months
    Mean patient age: 60.6 years
    Percentage female: 22%
    Ejection fraction: 46%

Exclusions:

  • Congestive heart failure defined as Killip class >2
  • Previous MI
  • Malignancies or other comorbid conditions with life expectancy <1 year
  • Thrombolysis for the index infarction
  • Uncontrolled hypertension unresponsive to therapy
  • Epilepsy
  • Hematologic disorders and relevant hematologic deviations
  • Renal insufficiency (glomerular filtration rate <30 ml/min)
  • Chronic liver disease
  • Pericarditis
  • Any contraindication to MRI
  • Known allergy to erythropoietin
  • Known or suspected pregnancy

Primary Endpoints:

  • LVEF at 6 months

Secondary Endpoints:

  • Changes in LVEF between 5 days and 6 months, measured by MRI
  • Changes in infarct size between 5 days and 6 months, measured by MRI
  • LV volumes on MRI
  • Infarct size on MRI
  • Number of hypokinetic chords on angiography
  • MACCE at 30 days and 6 months

Drug/Procedures Used:

The study drug was given at three distinct time points: immediately after successful PCI in the catheterization laboratory and at 24 hours and 48 hours after random assignment. Each time, patients received either 3.33 x 104 IU of recombinant human epoetin-β (NeoRecormon; F. Hoffmann-La Roche, Basel, Switzerland) or a matching placebo intravenously for 30 minutes.

Concomitant Medications:

All patients received 600 mg of clopidogrel orally, 500 mg aspirin, and unfractionated heparin with or without abciximab intravenously. Heparin was given as a bolus of 140 IU or 70 IU in case of additional abciximab (0.25 mg/kg body weight bolus, followed by an infusion of 0.125 mcg/kg/min for 12 hours). Postinterventional antithrombotic therapy consisted of clopidogrel 75 mg twice a day for 3 days followed by 75 mg/d for at least 6 months. Aspirin 100 mg twice a day was recommended indefinitely.

Principal Findings:

A total of 138 patients were randomized, 68 to erythropoietin, and 70 to placebo. Baseline characteristics were fairly similar between the two arms. About 15% had diabetes mellitus, and 63% had hypertension. Median door-to-balloon time was 81 minutes. Multivessel disease was noted in about 66% of the patients; the left anterior descending was the culprit vessel in 47% of the patients, and the right coronary artery in 45%. Thrombolysis in Myocardial Infarction (TIMI) 0/1 grade was noted in 70% of the patients at baseline, with 8% needing an intra-aortic balloon pump. The majority of patients underwent PCI with drug-eluting stent (94%), and final angiographic flow was TIMI 3 grade in about 92% of the patients. Most patients had mild left ventricular (LV) dysfunction on angiographic evaluation (mean LV ejection fraction [LVEF] 46%).

Erythropoietin induced an elevated maximal increase in circulating reticulocytes 5 days after administration, as compared with placebo (34.2 x 104 vs. 16.8 x 104/microL, p < 0.001). There was also an elevation in platelet count (265 x 109 vs. 232 x 109/L, p = 0.011), but no difference in maximal hemoglobin levels (14.8 vs. 15.0 mg/dl, p = 0.59). The primary endpoint of LVEF on magnetic resonance imaging (MRI) 6 months after primary PCI was similar between the two arms (52.0% vs. 51.8%, p = 0.92). Secondary endpoints at 6 months such as change in LVEF (2.6% vs. 1.0%, p = 0.19), final infarct size (17.3 vs. 20.9, p = 0.27), LV end-systolic volume index (40.0 vs. 40.1%, p = 0.97), and LV end-diastolic volume index (80.7 vs. 81.9, p = 0.76) were also similar between the two arms.

Clinical events at 6 months were infrequent, but numerically higher in the erythropoietin arm compared with placebo, including stent thrombosis (4.4% vs. 2.9%), MI (4.4% vs. 1.4%), death (2.9% vs. 4.3%), stroke (1.5% vs. 0%), infarct artery revascularization (10.3% vs. 2.9%), and death, MI, revascularization or stroke (13.2% vs. 5.7%).

Interpretation:

The results of the REVIVAL-3 trial indicate that erythropoietin is not associated with a clinical benefit compared with placebo in reducing infarct size or improving LVEF, and may paradoxically be associated with a higher risk of major adverse cardiac and cerebrovascular events (MACCE) at 6 months.

It is possible that increased platelet activation/margination with erythropoietin may contribute to some of the adverse ischemic results noted. These results are interesting because they mirror other reports of increased adverse outcomes with erythropoietin and erythropoietin stimulating agents in a number of clinical scenarios, especially in nonanemic patients.

References:

Ott I, Schulz S, Mehilli J, et al., on behalf of the REVIVAL-3 Study Investigators. Erythropoietin in patients with acute ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention: a randomized, double-blind trial. Circ Cardiovasc Interv 2010;Aug 24:[Epub ahead of print].

Clinical Topics: Invasive Cardiovascular Angiography and Intervention, Noninvasive Imaging, Prevention, Atherosclerotic Disease (CAD/PAD), Interventions and Coronary Artery Disease, Interventions and Imaging, Magnetic Resonance Imaging, Hypertension

Keywords: Coronary Artery Disease, Stroke, Myocardial Infarction, Platelet Count, Drug-Eluting Stents, Reticulocytes, Magnetic Resonance Imaging, Percutaneous Coronary Intervention, Stents, Erythropoietin, Hemoglobins, Thrombosis, Catheterization, Platelet Activation, Hypertension, Diabetes Mellitus


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