CYCLosporinE A in Reperfused Acute Myocardial Infarction

The possibility of optimizing the results of an early and effective reopening of the occluded artery by reducing/avoiding the impact of the so-called reperfusion injury has been for many years one of the most elusive objectives of pharmacological research, with evolving hypothesis and targets.

A recently published trial has provided support to a line of investigation focused on the role of mitochondrial dysfunction, the so-called permeability transition, as cause of irreversible myocardial injury associated to reperfusion. In fact, a single dose of the widely used immunosuppressant agent, CsA, a potent inhibitor of mitochondrial permeability transition pore opening, was reported to limit ischemia-reperfusion injury in 50 patients with anterior MI who underwent primary PCI.

Since infarct size and left ventricular function are the main determinants of long-term morbidity and mortality, a single measure to limit infarct size is of potential clinical benefit. Therefore the results of the previously mentioned trial should be replicated in a larger sample size, before going on to a trial with clinical endpoints.

• Sample size

Assuming an incidence of the primary endpoint of 55% in the control group, we calculated that 444 patients (222 patients per group) will be required for the study to have 80% power to detect a 25% relative improvement (resulting in an endpoint frequency of 68.7% in the CsA group) with a 5% drop-out rate and a two-sided alpha level of 5%. The size of the trial will allow to investigate treatment benefit for the secondary endpoint hsTnT: assuming a concentration of 2.7 ng/mL on day 4 (common SD=2.1) in the control group, the study will have a 90% power to show a 25% reduction with CsA at a two-sided alpha level of 5%.

• Safety

Adverse events with intravenous CsA (i.e. anaphylactoid reactions/anaphylactic shock, acute renal failure, or hypertensive crisis) are reported to be very rare. In this trial, patients will receive only one iv dose of CsA, therefore we expect a low probability of adverse effects related to repeated administrations, i.e. acute renal failure or hypertensive crisis. Nonetheless a close monitoring of the safety of the single dose of CsA is foreseen with monthly examination of data of safety by the Steering Committee.

Inclusion criteria

• Male and female patients with large STEMI not older than 6 hours, defined as
• angina pectoris or equivalent symptoms of more than 20 minutes duration within last 6 hours, and
• ST elevation in at least 3 leads in anterior MI and/or a deviation in at least 4 leads in inferior MI,
• TIMI flow 0 or 1 in identified culprit artery
• Intended acute primary PCI
• Age ≥ 18 years
• Ability to understand the nature, scope, and possible consequences of the study participation/legal capacity
• Written informed consent

Exclusion criteria

• Left bundle branch block
• TIMI flow > 1 in the identified culprit artery
• Treatment with CsA within last 10 days
• Contraindication to CsA or history of allergic reaction to CsA
• Coronary anatomy not suitable for PCI
• Thrombolytic therapy within 24 h. before randomization
• Previous MI
• Previous CABG
• Severe renal or hepatic insufficiency
• Malignant tumor, not curatively treated
• Women with childbearing potential, esp. pregnant or nursing women
• Participation in another clinical or device trial within the previous 30 days