CIRCUS: Transplant Rejection Drug Fails to Reduce Infarct Size in Anterior STEMI


LONDON, England—In patients with anterior STEMI, giving the immunosuppressant agent cyclosporine prior to revascularization does not to appear to improve clinical outcomes, according results of a trial presented August 30, 2015, at the European Society of Cardiology (ESC) Congress. 

Implications - CIRCUS: Transplant Rejection Drug Fails to Reduce Infarct Size in Anterior STEMIThe study was simultaneously published online ahead of print in the New England Journal of Medicine.

For the CIRCUS trial, hospitalized ACS patients with anterior STEMI (mean age 60 years; 82% men) who presented within 12 hours of symptom onset were randomized to PCI with (n = 395) or without (n = 396) IV cyclosporine 2.5 mg/kg at 42 centers in Belgium, France, and Spain between April 2011 and February 2014. 

Baseline characteristics, including the size of the area at risk and the proportion of patients with TIMI flow grade 2 or 3, were similar between the 2 groups. However, there were more smokers in the control group and more patients with multivessel disease in the cyclosporine group.

At 1 year, there were no differences between the groups in rates of the primary endpoint (a composite of death, heart failure and LV remodeling), its individual components, or other secondary endpoints (table 1).

Table 1. One-Year Outcomes in Patients With Anterior STEMI
   
Additionally, the similarities extended to the as-treated vs per-protocol analysis and to prespecified subgroups, with the exception of an interaction between Killip class and treatment effect (P = .009).

Early Promise Unfulfilled

In a press conference prior to his presentation, Dr. Ovize explained that the premise for CIRCUS stemmed from a small, proof-of-concept study, published in 2008, which found that giving a 2.5-mg bolus of cyclosporine at time of reperfusion to patients with acute MI reduced infarct size with no adverse effects. Cyclosporine is an inhibitor of cyclophilin D, which regulates the opening of the mitrochodrial permeability transition pore, thereby raising the risk of reperfusion injury.

Despite the negative outcome of the trial, Dr. Ovize maintained that this area of research is worth pursuing—likely with other agents—since nearly 1 in 4 patients in CIRCUS either died or were rehospitalized for heart failure although they were receiving “state-of-the-art medicine.”

Potential explanations Dr. Ovize suggested for the negative findings of CIRCUS compared with the earlier positive study were:

  • Limited use of direct stenting
  • Higher rate of thrombus aspiration
  • Inclusion of only patients with anterior infarcts
  • Higher rate of use of loading doses of P2Y12 inhibitors

Lastly, he said, CIRCUS also used a different formulation of cyclosporine than the earlier study, possibly confounding the results.  

That formulation “contains a lipid emulsion carrier vehicle,” which may explain the findings, add Derek J. Hausenloy, MB, ChB, PhD, and Derek M. Yellon, DSc, both of University College London (London, England) in an editorial accompanying the paper.

While the results are “disappointing,” the editorialists say, the search for effective therapies to prevent myocardial reperfusion injury and improve clinical outcomes should continue. The recently completed CYCLE study used the same formulation of cyclosporine as the earlier, positive study and therefore may shed more light on the issue, they suggest.

In the press conference, Dr. Ovize was asked about the possibility of delivering cyclosporine intraarterially and responded that it “remains an open question.”

Discussant Karin Przyklenk, PhD, of Wayne State University School of Medicine (Detroit, MI), commented after the presentation that cyclosporine “is by no means the first or the only agent that has been evaluated for the treatment of reperfusion injury.” These include oxygen radical scavengers, adenosine, and sodium-hydrogen exchange inhibitors. Despite more than 40 years of investigation, she noted, “the cardioprotection field has failed to deliver a single drug” capable of tackling this task.

In an email communication with TCTMD, Gregg W. Stone, MD, of Columbia University Medical Center (New York, NY), noted that the specifics of how to prevent reperfusion injury remain unclear.

“An intriguing approach would be to give the drug through an infusion catheter as soon as the occlusion is crossed with a guide wire,” he said. “This is the approach that I would take in the future with a promising therapeutic agent.”

  


Sources: 
1. Cung TT, Morel O, Rioufol G, et al. Cyclosporine before PCI in patients with acute myocardial infarction. N Engl J Med. 2015;Epub ahead of print. 
2. Targeting myocardial reperfusion injury—the search continues [editorial]. N Engl J Med. 2015;Epub ahead of print.  

Disclosures:

  • The study was supported by grants from the French Ministry of Health and Research National Program and NeuroVive Pharmaceutical.
  • Drs. Ovize and Przyklenk report no relevant conflicts of interest.  

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