CIRCUS: Cyclosporine before PCI fails to improve outcomes after STEMI

LONDON — Intravenous cyclosporine administered before PCI did not improve outcomes or prevent left ventricular remodeling at 1 year compared with placebo in patients with anterior STEMI.

Perspective from W. Douglas Weaver, MD, MACC; Karin Przyklenk, PhD

The phase 3, randomized, double blind CIRCUS trial enrolled 970 patients with acute anterior STEMI and complete occlusion of the culprit coronary artery who were referred for PCI within 12 hours of symptom onset at 42 hospitals Belgium, France and Spain. Patients were randomly assigned to receive a bolus injection of cyclosporine (2.5 mg/kg body weight; CicloMulsion, NeuroVive Pharmaceutical) or placebo before coronary recanalization. Seven patients were lost between randomization and 1 year.

The rate of the primary outcome — a composite of all-cause mortality, worsening HF during initial hospitalization, HF rehospitalization and adverse LV remodeling at 1 year — occurred in 59% of the cyclosporine group vs. 58.1% of the placebo group (OR = 1.04; 95% CI, 0.78-1.39; P = .77), Michel Ovize, MD, PhD, of Louis Pradel Hospital and Claude Bernard University, Lyon, France, reported at the European Society of Cardiology Congress.

Results also demonstrated no differences in the incidence of individual components of the primary outcome at 1 year with cyclosporine vs. placebo:

all-cause mortality, 7.1% vs. 6.6% (OR = 1.09; 95% CI, 0.63-1.9; P = .76);
HF worsening or HF rehospitalization, 22.8% vs. 22.7% (OR = 1.01; 95% CI, 0.72-1.41; P = .97); or
adverse LV remodeling, 42.8% vs. 40.7% (OR = 1.09; 95% CI, 0.82-1.46; P = .53).

“In anterior STEMI, cyclosporine did not reduce the risk of the composite outcome. Nevertheless, it is important to note that nearly [one in four] patients, although optimally treated, died or had severe HF in the first year after MI,” Ovize said during a press conference.

Rates of secondary outcomes including acute renal failure, cardiogenic shock, recurrent MI, stroke and unstable angina were similar in the treatment groups at follow-up.

In other results, patients had comparable values of total creatine kinase, extent of ST-segment elevation, LV ejection fraction, LV end-diastolic volume and end-systolic volume at all time-points studied.

Both cyclosporine and placebo were associated with a similar safety profile.

The treatment groups were well-matched at baseline, with the exception of more smokers in the control group and more multivessel disease in the cyclosporine group. “Hence, the lack of an effect with cyclosporine is unlikely to be related to the influence of … effect modifiers or coexisting conditions,” Ovize and colleagues wrote in The New England Journal of Medicine.

The results of CIRCUS are in contrast to findings of a phase 2 proof-of-concept trial published in NEJM in 2008, in which cyclosporine administered before PCI in patients with STEMI was associated with reduced myocardial infarct size. The difference between that study and CIRCUS may be related to several factors, including limited use of direct stenting in CIRCUS, a higher rate of thrombus aspiration, inclusion of only patients with anterior infarcts and greater use of loading doses of P2Y12 inhibitors, according to the researchers.

In addition, the formulation of cyclosporine investigated in CIRCUS “might not have been effective at preventing myocardial reperfusion injury,” Derek J. Hausenloy, MBChB, PhD, from the University College London, Duke-National University of Singapore, and Derek M. Yellon, DSc, from University College London, wrote in an accompanying editorial in NEJM. “If the benefits of [permeability transition pore] inhibition are to be harnessed, more specific inhibitors will need to be discovered.”

The earlier phase 2 trial evaluated use of Sandimmune (Novartis), a polyoxyethylated castor oil, whereas CicloMulsion is a liquid emulsion.

“Despite the results of CIRCUS, the concept of reperfusion injury is clinically important. The impact on clinical outcome of recent encouraging phase 2 trials remains, however, to be determined,” Ovize said. – by Katie Kalvaitis

References:

Ovize M, et al. Hot Line I: Acute Myocardial Infarction. Presented at: European Society of Cardiology Congress; Aug. 29-Sept. 2, 2015; London.

Cung TT, et al. N Engl J Med. 2015;doi:10.1056/NEJMoa1505489.

Hausenloy DJ, Yellon DM. N Engl J Med. 2015;doi:10.1056/NEJMe1509718.

Disclosure: The study was funded by the French Ministry of Health and NeuroVive Pharmaceutical. Ovize reports consulting for NeuroVive Pharmaceutical. Hausenloy and Yellon report no relevant financial disclosures.

Perspective

W. Douglas Weaver, MD, MACC

This is another study looking at a mechanism to reduce reperfusion injury following angioplasty for heart attack. Experimentally, many different drugs have been [studied] to prevent injury. A 2008 study showed that cyclosporine reduced the amount of injury in a small group of patients, and the results were very provocative. Cyclosporine is an old drug that is easily available. Cyclosporine is believed to block the injury that occurs at the mitochondrial level inside cells. This was, unfortunately, another failed attempt at preventing reperfusion injury.

W. Douglas Weaver, MD, MACC

Past President, American College of Cardiology

Henry Ford Heart and Vascular Institute

Cardiology Today Editorial Board member

Disclosures: Weaver reports no relevant financial disclosures.

Perspective

Karin Przyklenk, PhD

This was a well-conducted trial. In his final slide, Professor Ovize outlined a long-standing, important clinical challenge that we are all facing: the identification of pharmacologic strategies capable of attenuating myocardial ischemia reperfusion injury, reducing infarct size beyond that achieved by reperfusion alone and hopefully improving outcomes post-MI.

Cyclosporine is by no means the first or the only agent that has been evaluated for the treatment of reperfusion injury. Indeed, hundreds, and possibly thousands, of candidates have been investigated in preclinical models and many have gone on to be tested in preclinical trials. … However, despite more than 40 years of investigation, no adjuvant cardioprotective therapy is available for clinical use. In fact, the cardioprotection field has failed to deliver a single drug that effectively reduces ischemia reperfusion injury and myocardial infarct size in patients.

So why look at cyclosporine? There is a very strong and compelling rationale behind CIRCUS. First and foremost, there is very strong molecular evidence for involvement of the mitochondrial permeability transition core to reduce reperfusion injury. … But probably the most important and the most compelling rationale for CIRCUS was the phase 2 study in Piot and colleagues [Piot C, et al. N Engl J Med. 2015;doi:10.1056/NEJMoa071142]. The obvious question is what happened here? Particularly, how can you explain these negative outcomes when compared with the results of the apparently positive phase 2 trial?

There are several differences in the two protocols, including differences in the formulation of cyclosporine, differences in patient populations, changes in standard of care [and so on]. … Given the history of the field of cardioprotection, if I were to play devil’s advocate, I could ask: Can any pharmacologic agent given at reperfusion meet these very stringent criteria and attenuate reperfusion injury? These, I think, are the key discussion points that we need to consider.

Karin Przyklenk, PhD

Professor and Director

Cardiovascular Research Institute

Wayne State University School of Medicine

Disclosures: Przyklenk reports no relevant financial disclosures.