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Intravenous administration of cyclosporine just before percutaneous coronary intervention was not associated with a reduced risk of adverse outcomes at 1 year in a study of patients who underwent the procedure after experiencing an acute anterior ST-segment elevation myocardial infarction.
Findings from the multicenter, randomized study, known as the Does Cyclosporine Improve Clinical Outcome in ST Elevation Myocardial Infarction Patients (CIRCUS) trial, were presented at the annual congress of the European Society of Cardiology and published simultaneously in the New England Journal of Medicine (doi: 10.1056/NEJMoa1505489).
For the phase 3 trial, Dr. Michel Ovize and associates investigated whether a single intravenous dose of cyclosporine, administered just before PCI, would improve clinical outcomes and prevent left adverse left ventricular modeling at 1 year in patients with anterior STEMI.
“Growing evidence from experimental studies and small-size proof-of-concept clinical trials shows that reperfusion injury contributes greatly to the final infarct size,” the researchers wrote. “Preclinical studies indicate that the opening of the mitochondrial permeability transition pore (PTP) in the inner mitochondrial membrane plays a major role in reperfusion injury. Either genetic or pharmacologic inhibition of cyclophilin D, a major component of the PTP, reduces the severity of myocardial reperfusion injury.”
Dr. Ovize of the Clinical Investigation Center of Lyon, France, and his associates chose to test cyclosporine, a pharmacologic inhibitor of cyclophilin D, after a phase 2 trial conducted by the same researchers found that administration of cyclosporine immediately before PCI reduced the myocardial infarct size in patients with STEMI. In CIRCUS, which was conducted from April 2011 through February 2014 at 42 hospitals in three countries, 475 patients with an acute anterior STEMI who were undergoing PCI within 12 hours of symptom onset received IV cyclosporine at a dose of 2.5 mg/kg of body weight, while 495 patients received placebo. The primary outcome was a composite of death from any cause, worsening of heart failure during initial hospitalization, rehospitalization for heart failure, or adverse left ventricular remodeling at 1 year.
At baseline, the mean age of patients was 60 years, 82% were men, and their mean body mass index was 27 kg/m2. One year of follow-up data was available for 395 patients in the cyclosporine group and 396 in the placebo group. The researchers found no significant differences between the two groups in the proportion who experienced a primary outcome event (59% in the cyclosporine group vs. 58% in the control group) or in the rate of all-cause mortality (7.1% vs. 6.6%).
There were also no differences between groups in the rate of initial worsening of heart failure or rehospitalization for heart failure at 1 year (22.8% vs. 22.7%). In addition, a similar proportion of patients in both groups experienced adverse left ventricular remodeling (42.8% vs. 40.7%).
“One important limitation of this trial is that we included in the primary outcome the nonclinical outcome of adverse left ventricular remodeling, which accounted for a substantial proportion of the primary outcome rate,” the researchers wrote. “Left ventricular remodeling is a surrogate outcome – one that was not successfully measured in 17.4% of the trial participants. However, in secondary analyses, no beneficial effect of cyclosporine was detected on any of the hard clinical outcomes.”
They went on to note that nearly one of four patients in CIRCUS died or was hospitalized for heart failure, “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. Recent phase 2 trials that have used either ischemic or pharmacologic postconditioning suggest that interventions applied at the time of reperfusion can limit infarct size and improve functional recovery. Their effect on clinical outcome remains to be determined in phase 3 studies.”
The study was supported by grants from the French Ministry of Health and Research National Program and NeuroVive Pharmaceutical. Dr. Ovize disclosed that he is a consultant for NueroVive Pharmaceutical.
Why, despite the promising experimental and clinical data, did cyclosporine have no effect on clinical outcomes? Several factors may be considered. First, although the experimental data supporting the cardioprotective effect of cyclosporine are extensive, not all the studies have been positive. The clinical evidence in favor of a cardioprotective effect is limited to one study in this patient group. Another study involving patients with STEMI who were treated with thrombolysis showed no effect with cyclosporine.
Second, the use of an increase in left ventricular end-diastolic volume as one of the primary outcomes has to be queried. This outcome, for which data were missing in 17% of patients, is not a clinical one but a surrogate marker of adverse left ventricular modeling.
Finally, the use of CicloMulsion (NeuroVive Pharmaceutical), a new formulation of cyclosporine that was used in this study, instead of Sandimmune (Novartis), which was used in the original study by Piot et al., may have contributed to the neutral results.
CicloMulsion contains a lipid emulsion carrier vehicle, thereby avoiding the risk of anaphylaxis that has been associated with Sandimmune, which uses an ethanol and polyoxyethylated castor oil (Cremophor EL) carrier vehicle.
Although the results of the CIRCUS study are disappointing, 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. If the benefits of PTP inhibition are to be harnessed, more specific inhibitors will need to be discovered. Therefore, the search to find an effective therapy for preventing myocardial reperfusion injury and improving clinical outcomes in patients with reperfused STEMI should continue.
Dr. Derek J. Hausenloy and Derek M. Yellon, D.Sc., are with the Hatter Cardiovascular Institute, University College London, and the National Institute of Health Research University College London Hospitals Biomedical Research Centre. Both reported having no financial disclosures. This text was extracted from an editorial that appeared online Aug. 30, 2015 in the New England Journal of Medicine (doi: 10.1056/NEJMe1509718).
Why, despite the promising experimental and clinical data, did cyclosporine have no effect on clinical outcomes? Several factors may be considered. First, although the experimental data supporting the cardioprotective effect of cyclosporine are extensive, not all the studies have been positive. The clinical evidence in favor of a cardioprotective effect is limited to one study in this patient group. Another study involving patients with STEMI who were treated with thrombolysis showed no effect with cyclosporine.
Second, the use of an increase in left ventricular end-diastolic volume as one of the primary outcomes has to be queried. This outcome, for which data were missing in 17% of patients, is not a clinical one but a surrogate marker of adverse left ventricular modeling.
Finally, the use of CicloMulsion (NeuroVive Pharmaceutical), a new formulation of cyclosporine that was used in this study, instead of Sandimmune (Novartis), which was used in the original study by Piot et al., may have contributed to the neutral results.
CicloMulsion contains a lipid emulsion carrier vehicle, thereby avoiding the risk of anaphylaxis that has been associated with Sandimmune, which uses an ethanol and polyoxyethylated castor oil (Cremophor EL) carrier vehicle.
Although the results of the CIRCUS study are disappointing, 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. If the benefits of PTP inhibition are to be harnessed, more specific inhibitors will need to be discovered. Therefore, the search to find an effective therapy for preventing myocardial reperfusion injury and improving clinical outcomes in patients with reperfused STEMI should continue.
Dr. Derek J. Hausenloy and Derek M. Yellon, D.Sc., are with the Hatter Cardiovascular Institute, University College London, and the National Institute of Health Research University College London Hospitals Biomedical Research Centre. Both reported having no financial disclosures. This text was extracted from an editorial that appeared online Aug. 30, 2015 in the New England Journal of Medicine (doi: 10.1056/NEJMe1509718).
Why, despite the promising experimental and clinical data, did cyclosporine have no effect on clinical outcomes? Several factors may be considered. First, although the experimental data supporting the cardioprotective effect of cyclosporine are extensive, not all the studies have been positive. The clinical evidence in favor of a cardioprotective effect is limited to one study in this patient group. Another study involving patients with STEMI who were treated with thrombolysis showed no effect with cyclosporine.
Second, the use of an increase in left ventricular end-diastolic volume as one of the primary outcomes has to be queried. This outcome, for which data were missing in 17% of patients, is not a clinical one but a surrogate marker of adverse left ventricular modeling.
Finally, the use of CicloMulsion (NeuroVive Pharmaceutical), a new formulation of cyclosporine that was used in this study, instead of Sandimmune (Novartis), which was used in the original study by Piot et al., may have contributed to the neutral results.
CicloMulsion contains a lipid emulsion carrier vehicle, thereby avoiding the risk of anaphylaxis that has been associated with Sandimmune, which uses an ethanol and polyoxyethylated castor oil (Cremophor EL) carrier vehicle.
Although the results of the CIRCUS study are disappointing, 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. If the benefits of PTP inhibition are to be harnessed, more specific inhibitors will need to be discovered. Therefore, the search to find an effective therapy for preventing myocardial reperfusion injury and improving clinical outcomes in patients with reperfused STEMI should continue.
Dr. Derek J. Hausenloy and Derek M. Yellon, D.Sc., are with the Hatter Cardiovascular Institute, University College London, and the National Institute of Health Research University College London Hospitals Biomedical Research Centre. Both reported having no financial disclosures. This text was extracted from an editorial that appeared online Aug. 30, 2015 in the New England Journal of Medicine (doi: 10.1056/NEJMe1509718).
Intravenous administration of cyclosporine just before percutaneous coronary intervention was not associated with a reduced risk of adverse outcomes at 1 year in a study of patients who underwent the procedure after experiencing an acute anterior ST-segment elevation myocardial infarction.
Findings from the multicenter, randomized study, known as the Does Cyclosporine Improve Clinical Outcome in ST Elevation Myocardial Infarction Patients (CIRCUS) trial, were presented at the annual congress of the European Society of Cardiology and published simultaneously in the New England Journal of Medicine (doi: 10.1056/NEJMoa1505489).
For the phase 3 trial, Dr. Michel Ovize and associates investigated whether a single intravenous dose of cyclosporine, administered just before PCI, would improve clinical outcomes and prevent left adverse left ventricular modeling at 1 year in patients with anterior STEMI.
“Growing evidence from experimental studies and small-size proof-of-concept clinical trials shows that reperfusion injury contributes greatly to the final infarct size,” the researchers wrote. “Preclinical studies indicate that the opening of the mitochondrial permeability transition pore (PTP) in the inner mitochondrial membrane plays a major role in reperfusion injury. Either genetic or pharmacologic inhibition of cyclophilin D, a major component of the PTP, reduces the severity of myocardial reperfusion injury.”
Dr. Ovize of the Clinical Investigation Center of Lyon, France, and his associates chose to test cyclosporine, a pharmacologic inhibitor of cyclophilin D, after a phase 2 trial conducted by the same researchers found that administration of cyclosporine immediately before PCI reduced the myocardial infarct size in patients with STEMI. In CIRCUS, which was conducted from April 2011 through February 2014 at 42 hospitals in three countries, 475 patients with an acute anterior STEMI who were undergoing PCI within 12 hours of symptom onset received IV cyclosporine at a dose of 2.5 mg/kg of body weight, while 495 patients received placebo. The primary outcome was a composite of death from any cause, worsening of heart failure during initial hospitalization, rehospitalization for heart failure, or adverse left ventricular remodeling at 1 year.
At baseline, the mean age of patients was 60 years, 82% were men, and their mean body mass index was 27 kg/m2. One year of follow-up data was available for 395 patients in the cyclosporine group and 396 in the placebo group. The researchers found no significant differences between the two groups in the proportion who experienced a primary outcome event (59% in the cyclosporine group vs. 58% in the control group) or in the rate of all-cause mortality (7.1% vs. 6.6%).
There were also no differences between groups in the rate of initial worsening of heart failure or rehospitalization for heart failure at 1 year (22.8% vs. 22.7%). In addition, a similar proportion of patients in both groups experienced adverse left ventricular remodeling (42.8% vs. 40.7%).
“One important limitation of this trial is that we included in the primary outcome the nonclinical outcome of adverse left ventricular remodeling, which accounted for a substantial proportion of the primary outcome rate,” the researchers wrote. “Left ventricular remodeling is a surrogate outcome – one that was not successfully measured in 17.4% of the trial participants. However, in secondary analyses, no beneficial effect of cyclosporine was detected on any of the hard clinical outcomes.”
They went on to note that nearly one of four patients in CIRCUS died or was hospitalized for heart failure, “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. Recent phase 2 trials that have used either ischemic or pharmacologic postconditioning suggest that interventions applied at the time of reperfusion can limit infarct size and improve functional recovery. Their effect on clinical outcome remains to be determined in phase 3 studies.”
The study was supported by grants from the French Ministry of Health and Research National Program and NeuroVive Pharmaceutical. Dr. Ovize disclosed that he is a consultant for NueroVive Pharmaceutical.
Intravenous administration of cyclosporine just before percutaneous coronary intervention was not associated with a reduced risk of adverse outcomes at 1 year in a study of patients who underwent the procedure after experiencing an acute anterior ST-segment elevation myocardial infarction.
Findings from the multicenter, randomized study, known as the Does Cyclosporine Improve Clinical Outcome in ST Elevation Myocardial Infarction Patients (CIRCUS) trial, were presented at the annual congress of the European Society of Cardiology and published simultaneously in the New England Journal of Medicine (doi: 10.1056/NEJMoa1505489).
For the phase 3 trial, Dr. Michel Ovize and associates investigated whether a single intravenous dose of cyclosporine, administered just before PCI, would improve clinical outcomes and prevent left adverse left ventricular modeling at 1 year in patients with anterior STEMI.
“Growing evidence from experimental studies and small-size proof-of-concept clinical trials shows that reperfusion injury contributes greatly to the final infarct size,” the researchers wrote. “Preclinical studies indicate that the opening of the mitochondrial permeability transition pore (PTP) in the inner mitochondrial membrane plays a major role in reperfusion injury. Either genetic or pharmacologic inhibition of cyclophilin D, a major component of the PTP, reduces the severity of myocardial reperfusion injury.”
Dr. Ovize of the Clinical Investigation Center of Lyon, France, and his associates chose to test cyclosporine, a pharmacologic inhibitor of cyclophilin D, after a phase 2 trial conducted by the same researchers found that administration of cyclosporine immediately before PCI reduced the myocardial infarct size in patients with STEMI. In CIRCUS, which was conducted from April 2011 through February 2014 at 42 hospitals in three countries, 475 patients with an acute anterior STEMI who were undergoing PCI within 12 hours of symptom onset received IV cyclosporine at a dose of 2.5 mg/kg of body weight, while 495 patients received placebo. The primary outcome was a composite of death from any cause, worsening of heart failure during initial hospitalization, rehospitalization for heart failure, or adverse left ventricular remodeling at 1 year.
At baseline, the mean age of patients was 60 years, 82% were men, and their mean body mass index was 27 kg/m2. One year of follow-up data was available for 395 patients in the cyclosporine group and 396 in the placebo group. The researchers found no significant differences between the two groups in the proportion who experienced a primary outcome event (59% in the cyclosporine group vs. 58% in the control group) or in the rate of all-cause mortality (7.1% vs. 6.6%).
There were also no differences between groups in the rate of initial worsening of heart failure or rehospitalization for heart failure at 1 year (22.8% vs. 22.7%). In addition, a similar proportion of patients in both groups experienced adverse left ventricular remodeling (42.8% vs. 40.7%).
“One important limitation of this trial is that we included in the primary outcome the nonclinical outcome of adverse left ventricular remodeling, which accounted for a substantial proportion of the primary outcome rate,” the researchers wrote. “Left ventricular remodeling is a surrogate outcome – one that was not successfully measured in 17.4% of the trial participants. However, in secondary analyses, no beneficial effect of cyclosporine was detected on any of the hard clinical outcomes.”
They went on to note that nearly one of four patients in CIRCUS died or was hospitalized for heart failure, “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. Recent phase 2 trials that have used either ischemic or pharmacologic postconditioning suggest that interventions applied at the time of reperfusion can limit infarct size and improve functional recovery. Their effect on clinical outcome remains to be determined in phase 3 studies.”
The study was supported by grants from the French Ministry of Health and Research National Program and NeuroVive Pharmaceutical. Dr. Ovize disclosed that he is a consultant for NueroVive Pharmaceutical.
FROM THE ESC CONGRESS 2015
Key clinical point: Cyclosporine administration prior to PCI did not benefit STEMI patients.
Major finding: There were no significant differences between intervention and control groups in the proportion who experienced a primary outcome event (59% in the cyclosporine group vs. 58% in the control group).
Data source: A randomized, placebo-controlled trial of 970 patients with an acute anterior ST-segment elevation myocardial infarction who were undergoing percutaneous coronary intervention within 12 hours after symptom onset.
Disclosures: The study was supported by grants from the French Ministry of Health and Research National Program and NeuroVive Pharmaceutical. Dr. Ovize disclosed that he is a consultant for NueroVive Pharmaceutical.