Effect of ciclosporin on safety, lymphocyte kinetics and left ventricular remodelling in acute myocardial infarction

Suzanne Cormack, Ashfaq Mohammed, Pedram Panahi, Rajiv Das, Alison J Steel, Thomas Chadwick, Andrew Bryant, Mohaned Egred, Konstantinos Stellos, Ioakim Spyridopoulos, CAPRI investigators, Suzanne Cormack, Ashfaq Mohammed, Pedram Panahi, Rajiv Das, Alison J Steel, Thomas Chadwick, Andrew Bryant, Mohaned Egred, Konstantinos Stellos, Ioakim Spyridopoulos, CAPRI investigators

Abstract

Aims: Following a favourable pilot trial using a single bolus of ciclosporin, it has been unclear why 2 large studies (CYCLE and CIRCUS) failed to prevent reperfusion injury and reduce infarct size in STEMI (ST elevation myocardial infarction). The purpose of this study was to assess the effect of ciclosporin on myocardial injury, left ventricular remodelling and lymphocyte kinetics in patients with acute STEMI undergoing primary percutaneous coronary intervention.

Methods: In this double-blind, single centre trial, we randomly assigned 52 acute STEMI patients with an onset of pain of <6 hours and blocked culprit artery to a single bolus of ciclosporin (n = 26) or placebo (n = 26, control group) prior to reperfusion by stent percutaneous coronary intervention. The primary endpoint was infarct size at 12 weeks.

Results: Mean infarct size at 12 weeks was identical in both groups (9.1% [standard deviation= 7.0] vs 9.1% [standard deviation = 7.0], P = .99; 95% confidence interval for difference: -4.0 to 4.1). CD3 T-lymphocytes dropped to similar levels at 90 minutes (867 vs 852 cells/μL, control vs ciclosporin) and increased to 1454 vs 1650 cells/μL at 24 hours.

Conclusion: In our pilot trial, a single ciclosporin bolus did not affect infarct size or left ventricular remodelling, matching the results from CYCLE and CIRCUS. Our study suggests that ciclosporin does either not reach ischaemic cardiomyocytes, or requires earlier application during first medical contact. Finally, 1 bolus of ciclosporin is not sufficient to inhibit CD4 T-lymphocyte proliferation during remodelling. We therefore believe that further studies are warranted. (Evaluating the effectiveness of intravenous Ciclosporin on reducing reperfusion injury in pAtients undergoing PRImary percutaneous coronary intervention [CAPRI]; NCT02390674).

Keywords: T-lymphocytes; acute myocardial infarction; cardiac MRI; ciclosporin; left ventricular function; reperfusion injury.

Conflict of interest statement

There are no competing interests to declare.

© 2020 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.

Figures

Figure 1
Figure 1
CONSORT diagram with participant flow for each group, losses and exclusions after randomisation
Figure 2
Figure 2
Ciclosporin does not affect cardiac remodelling post infarction. (A) Ciclosporin serum level kinetics for n = 8 randomly selected patients from ciclosporin group (displayed as mean ± standard error of the mean per time point). (B) Infarct size after 3 days and 12 weeks. (C, D) correlation of changes in left ventricular ejection fraction (LVEF), end‐diastolic volume (EDV) and end‐systolic volume (ESV) in 48 patients with both magnetic resonance images (Spearman r)

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