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Cyclosporine before PCI fails to fulfil reperfusion injury promise

ESC Congress News 2015 - London

Cyclosporine delivered intravenously before primary PCI does not improve clinical outcomes in patients with anterior STEMI, according to the CIRCUS (Does Cyclosporine Improve Clinical Outcome in ST-elevation myocardial infarction patient?) study presented as a Hot Line yesterday.

Cardiovascular Pharmacotherapy
Coronary Artery Disease, Acute Coronary Syndromes, Acute Cardiac Care

Michel Ovize, ‘surprised and disappointed’ by results of CIRCUS study.Principal investigator Michel Ovize from Louis Pradel Hospital and Claude Bernard University, Lyon, France, said he was ‘very surprised and disappointed’ by the findings which were reported simultaneously in the New England Journal of Medicine.

A pharmacologic inhibitor of cyclophilin, cyclosporine had been shown in a small phase II study to reduce post-AMI infarct size and reperfusion injury, a severe complication for which there is currently no specific treatment.

Now advanced to a phase III trial, the CIRCUS study thus aimed to show whether cyclosporine would improve clinical outcomes and prevent adverse left ventricular remodelling at one year in patients with anterior STEMI.

The study recruited 970 patients with acute STEMI and complete occlusion of the culprit artery at 42 centres in Belgium, Spain and France. They were randomised within 12 hours of symptom onset to placebo or a bolus injection of cyclosporine given intravenously at 2.5 mg per kilogram body weight before coronary recanalisation.

The primary endpoint was a combined incidence within one year of all-cause mortality, worsening heart failure during initial hospitalisation (or re-hospitalisation for heart failure, and left ventricular remodelling. Adverse LV remodelling was defined as an increase of 15% or more in left ventricular end-diastolic volume.

A total of 395 patients in the cyclosporine group and 396 in the placebo group had sufficient data for evaluation at one year. Results showed a primary outcome rate of 59% in the cyclosporine group and 58% in the control group (OR 1.04; 95% CI 0.78-1.39), and further showed that cyclosporine did not reduce the incidence of the separate clinical components or other events, including recurrent infarction, unstable angina and stroke.

The study findings, Ovize concluded, showed that cyclosporine did not result in better clinical outcomes compared with placebo and did not prevent adverse left ventricular modelling at one year. Indeed, one out of four patients died or was hospitalised for heart failure despite receiving state-of-the-art medical care.

However, despite the results of CIRCUS, Ovize insisted that ‘the concept remains that reperfusion injury is clinically important’. He added that damage to the heart occurs in the very first minute, which may explain the trial’s neutral outcome. ‘The window for reaching the target is very narrow but we hope in future we can tackle reperfusion injury,’ he said.