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CIRCUS: Cyclosporine before PCI fails to improve outcomes after STEMI
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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.
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.