Effect of Cyclosporine on Reperfusion Injury in Acute Myocardial Infarction - Effect of Cyclosporine on Reperfusion Injury in AMI

Jul 30, 2008
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Author/Summarized by Author:
Anthony A. Bavry, MD, MPH, FACC
Summary Reviewer:
Deepak L. Bhatt, MD, MPH, MBA, FACC
Trial Sponsor:
Programme Hospitalier de Recherche Clinique 2004 grant
Date Published:
01/01/2008
Date Updated:
07/30/2008
Original Posted Date:
07/30/2008
References

Description:

The goal of the trial was to evaluate treatment with cyclosporine compared with saline in ST-elevation myocardial infarction patients undergoing percutaneous coronary intervention (PCI).

Hypothesis:

Cyclosporine will be more effective at decreasing the size of myocardial infarction.

Study Design

  • Placebo Controlled
  • Randomized

Patients Screened: 148
Patients Enrolled: 58
Mean Follow Up: 3 months
Mean Patient Age: 58 years
Female: 21
Mean Ejection Fraction: 50%

Patient Populations:

  • ST-elevation myocardial infarction within 12 hours of symptom onset
  • At least 18 years of age
  • Primary or rescue PCI
  • Occluded culprit vessel with no flow

Exclusions:

  • Cardiac arrest or cardiogenic shock
  • Ventricular fibrillation
  • Stent thrombosis
  • Previous myocardial infarction or angina in the last 48 hours
  • Left main or circumflex artery occlusion
  • Collaterals to the region at risk
  • Hypersensitivity to cyclosporine
  • Renal insufficiency
  • Liver failure
  • Uncontrolled hypertension
  • Pregnancy or women of childbearing age not on contraception
  • Any disorder resulting in immunologic dysfunction such as cancer or human immunodeficiency virus

Primary Endpoints:

Size of infarct assessed by area under the curve from cardiac biomarkers

Secondary Endpoints:

  • Size of infarct assessed by delayed hyperenhancement on cardiac magnetic resonance imaging
  • Concentration of cyclosporine at 1 and 20 minutes and at 3 and 12 hours after injection
  • Blood pressure
  • Creatinine, potassium, bilirubin, gamma-glutamyltransferase, and alkaline phosphatase levels
  • Major adverse events within 48 hours and 3 months

Drug/Procedures Used:

After coronary angiography, but before stent implantation, patients were randomized to cyclosporine (2.5 mg/kg; n = 30) or control (saline; n = 28).

Concomitant Medications:

In the cyclosporine group, at the time of PCI, the use of aspirin or clopidogrel was 29%, heparin was 30%, and glycoprotein IIb/IIIa inhibitor was 11%. There was no difference in medication use between treatment groups.

Principal Findings:

Ischemic time was 4.9 hours in the cyclosporine group and 5.0 hours in the control group. Rescue PCI was employed in 5% versus 8%, respectively.

The area under the curve for creatine kinase was 138,053 arbitrary units for cyclosporine versus 247,930 for control (p = 0.04), and the area under the curve for troponin I was 112,312 versus 129,320 (p = 0.15), respectively. The absolute mass of infarcted tissue (i.e., the area of hyperenhancement by magnetic resonance imaging on day 5) was 37 g versus 46 g (p = 0.04), respectively.

In the first 48 hours, there were three adverse events in the cyclosporine group versus seven in the control group (p = 0.11). At 3 months, one patient in the cyclosporine group versus three in the control group were rehospitalized for heart failure (p = 0.28).

There were no clinical symptoms related to the administration of cyclosporine. Specifically, there was no change in blood pressure, creatinine, potassium, or white blood cell count.

Interpretation:

This proof-of-concept experiment showed that cyclosporine prior to PCI is beneficial in reducing the area under the curve for creatine kinase. There was a nonsignificant reduction in the area under the curve for troponin I. Cyclosporine also decreased the infarct size, as detected by magnetic resonance imaging. There were no serious adverse events detected in the cyclosporine group.

Despite the benefits of reperfusion, there is also the possibility of deleterious effects from reperfusion injury. One explanation is that ischemia may cause mitochondrial dysfunction by opening mitochondrial permeability-transition pores. Experimentally, cyclosporine inhibits this process.

This small randomized trial will need to be followed by larger studies examining clinical endpoints. Cyclosporine is known to cause renal insufficiency and hypertension. These side effects will need to be carefully studied in the ST-elevation myocardial infarction patient population since these patients are already at risk of contrast nephropathy.

References:

Piot C, Croisille P, Staat P, et al. Effect of cyclosporine on reperfusion injury in acute myocardial infarction. N Engl J Med 2008;359:473-81.

Keywords: Myocardial Infarction, Creatine Kinase, Leukocyte Count, Blood Pressure, Creatinine, Magnetic Resonance Imaging, Angioplasty, Balloon, Coronary, Cyclosporins, Stents, Renal Insufficiency, Potassium, Reperfusion Injury, Coronary Angiography, Troponin I, Heart Failure, Hypertension


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