Patients with an acute anterior ST-segment elevation MI (STEMI) who were injected with cyclosporine immediately before undergoing PCI did not have better clinical outcomes compared with a group receiving placebo, according to a randomized, double-blind trial.
One year after surgery, 59 percent of patients in the cyclosporine group and 58.1 percent of patients in the placebo group had the primary outcome of death from any cause, worsening of heart failure during the initial hospitalization, rehospitalization for heart failure or adverse left ventricular remodeling.
Lead researcher Thien-Tri Cung, MD, of Centre Hospitalier Universitaire in France, and colleagues published their results online in the New England Journal of Medicine on Aug. 30. The French Ministry of Health helped fund the study through a grant, and NeuroVive Pharmaceuticals provided cyclosporine at no charge and provided funding to include sites in Belgium and Spain.
The findings were also presented at the European Society of Cardiology Congress in London.
“Almost one of four patients in the current trial died or was hospitalized for heart failure despite receiving state-of-the-art medical care,” the researchers wrote. “This finding is a reminder of the substantial residual risk in this population and the persistent room for improvement in the medical treatment of high-risk patients with STEMI. The results of this trial do not challenge the concept that reperfusion injury is clinically important.”
In a previous phase 2 trial, the researchers found administering cyclosporine in patients with STEMI before PCI reduced the myocardial infarct size.
This study included 970 patients at 42 hospitals in three countries who underwent PCI within 12 hours of symptom onset and had complete occlusion of the culprit coronary artery. From April 2011 through February 2014, they were randomized to receive a bolus injection of cyclosporine administered intravenously or placebo before coronary recanalization. The dose of cyclosporine was 2.5 mg per kilogram of body weight.
At baseline, the groups were well balanced. The mean age was approximately 60, and more than 80 percent of patients were males.
After one year, 7.1 percent of patients in the cyclosporine group and 6.6 percent of patients in the placebo group had died, while the rates of initial worsening of heart failure or hospitalization for heart failure were 22.8 percent and 22.7 percent, respectively. Further, adverse left ventricular remodeling occurred in 42.8 percent and 40.7 percent of the patients, respectively.
The researchers defined adverse left ventricular remodeling an increase of 15 percent or more in the left ventricular end-diastolic volume, which they said was a non-clinical, surrogate outcome.
Derek J. Hausenloy, MB, ChB., PhD and Derek M. Yellon, DSc, of University College London, wrote in an accompanying editorial that the high incidence of adverse left ventricular remodeling made it difficult to detect a significant difference in the rate of death from any cause, worsening of heart failure after the initial hospitalization or rehospitalization for heart failure.
They also mentioned that using a new formulation of cyclosporine known as CicloMulsion instead of Sandimmune (Novartis) may have contributed to the 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,” they wrote. “Although CicloMulsion has been shown to be similar to Sandimmune in terms of bioefficacy, there appear to be no published experimental or clinical data showing that it can reduce myocardial infarct size.”
Hausenlov and Yellon wrote that the results were “disappointing,” but they added that “they do not disprove the existence or clinical significance of myocardial reperfusion injury, because it appears that the formulation of cyclosporine used in the study might not have been effective at preventing myocardial reperfusion injury.”