CIRCUS: Cyclosporine Fails to Reduce Clinical Events in PCI-Treated STEMI Patients

August 30, 2015

LONDON, UK ( updated ) — A bolus injection of cyclosporine administered before PCI in patients with anterior ST-segment-elevation MI (STEMI)—the intent being to reduce myocardial infarct size resulting from reperfusion injury and to prevent downstream events—did not result in better clinical outcomes when compared with patients who did not receive the intravenous injection, a new study has shown[1].

The primary outcome of the trial, a composite end point including all-cause mortality, worsening heart failure during the initial hospitalization, rehospitalization for heart failure, and adverse left ventricular remodeling at 1 year, occurred in 59.0% of the 395 patients randomized to cyclosporine and 58.1% of the 396 individuals randomized to placebo. The difference was not statistically significant.

There was no benefit with cyclosporine on any of the individual components of the primary end point. Of note, cyclosporine had no effect on the peak release of creatine kinase, an estimate of myocardial infarct size.

The results of the study, known as the Cyclosporine and Prognosis in Acute Myocardial Infarction Patients (CIRCUS) trial, were presented today here at the European Society of Cardiology 2015 Congress by Dr Michel Ovize (Clinical Investigation Center, Lyon, France) and published simultaneously in the New England Journal of Medicine.

Dr Michel Ovize

Despite the negative results, Ovize, along with first author Dr Thien Tri Cung (Centre Hospitalier Universitaire, Montpellier, France), state the data do not undercut the idea that reperfusion injury is "clinically important" and there is a need for additional therapies among these high-risk patients undergoing PCI.

"It is important to note that nearly 25% of patients, although optimally treated, still died or had severe heart failure during the first year after myocardial infarction," said Ovize. "This study does not challenge the concept of reperfusion injury."

Speaking with the media during the ESC press conference, Ovize said patients with STEMI experience a "double injury" resulting from the infarction, the first being the damage to the heart during ischemia and the second assault occurring when the artery is reopened. For reperfusion injury, there currently is no treatment, although numerous therapies have been tested. The list of failed therapies includes everything from a sodium-nitrite infusion to peptides targeting the inner mitochondrial membrane.

"The mechanism [of reperfusion injury] is likely related to a dysfunction within the cells at the level of the mitochondria," said Ovize. "There is a channel called the permeability transition pore [PTP] that causes death when the artery is reopened."

With cardiomyocyte death thought to be mediated by the mitochondrial PTP opening in the first few minutes after reperfusion, cyclosporine had been hypothesized as a means to limit this opening and subsequently reduce myocardial infarct size. In a small 2008 pilot study, as reported by heartwire from Medscape, Ovize and colleagues showed that cyclosporine did in fact reduce myocardial infarct size.

Was the Formulation to Blame?

In an editorial[2], Drs Derek Hausenloy and Derek Yellon (University College London, UK) state that timely reperfusion with PCI limits myocardial infarct size in STEMI patients, and even though mortality rates in these patients have been declining, heart-failure rates are on the rise. For this reason, new treatments are needed to reduce myocardial infarct size and to preserve left ventricular function (and prevent the onset of heart failure).

As to why cyclosporine did not yield a clinical benefit in CIRCUS, the editorialists question one of the end points used—that being left ventricular end-diastolic volume as a marker for left ventricular remodeling—and noted data were missing in 17% of the patients. They also noted the CIRCUS investigators used a different formulation of cyclosporine (CicloMulsion, NeuroVive Pharmaceuticals) rather than a formulation used in previous studies (Sandimmune, Novartis), and this might have contributed to the neutral results.

"The finding that CicloMulsion did not reduce enzymatic myocardial infarct size is problematic and might suggest that this formulation of cyclosporine was ineffective at preventing myocardial reperfusion injury, thereby explaining why it had no effect on clinical outcomes," write Hausenloy and Yellon.

To heartwire , Ovize conceded that the drug used in CIRCUS was slightly different from the one in the pilot study and that the question raised is fair. He does not believe the formulation was responsible for the negative clinical results, however. He noted the new formulation did reduce myocardial infarct size in experimental studies, which suggests the formulation is effective.

Dr Gregg Stone (Columbia University Medical Center, New York) said there is a very strong correlation between infarct size, myocardial salvage, heart failure, and mortality. That said, Stone is not overly optimistic about studies looking at compounds to reduce reperfusion injury and preventing downstream clinical events. He noted there are even some individuals who have questioned whether myocardial reperfusion injury is real.

"It certainly exists in animal models," he told heartwire , "and there have been a hundred different compounds that have been able to affect it in animals, especially in mice. However, whenever this is translated to human beings, the results have been negative nearly every single time."

Dr Kim Williams (Rush University Medical Center, Chicago, IL) told heartwire the results of CIRCUS are disappointing, especially since the pilot study was positive, but the bottom line is a continued emphasis on "preventing the first myocardial infarction rather than treating them."

The study was sponsored by grants from the French Ministry of Health and Research national program and NeuroVive Pharmaceuticals. Ovize reports grants and nonfinancial support from and consulting for NeuroVive Pharmaceuticals. Cung has no relevant financial relationships; disclosures for the coauthors are listed in the article. Hausenloy and Yellon have no relevant financial relationships.


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