Analyses of the COOL-AMI pivotal trial for a therapeutic hypothermia device, the ZOLL Proteus Intra Vascular Temperature Management System, reveal longer randomization-to-balloon time and longer total ischemic time for the trial device arm, as well as high rates of new-onset paroxysmal atrial fibrillation.
The delays were not considered to be related to the cooling maneuvers but could be associated with potential outcomes impact, according to a press statement released Tuesday morning at the EuroPCR conference.
Animal data suggest that therapeutic indication of mild systemic hypothermia prior to reperfusion of the infarct-related vessel in a perioperative percutaneous coronary intervention (PCI) setting could limit infarct size.
The cooling device’s manufacturer, ZOLL Circulation, launched the pivotal phase II Cool-AMI trial after further promising results in 50 patients in phase I. Although the earlier study was not powered to test efficacy in reducing infarct size, focused instead on the safety of “more rapid and profound cooling” with the ZOLL Proteus Intravascular Temperature Management System, it demonstrated a numerical reduction in infarct size.
In phase II, COOL-AMI pitted the ZOLL device – administering a fast injection of up to 1 liter of cold saline through a catheter inserted via the femoral vein into the inferior vena cava reaching a mean body temperature of 33° C before and after PCI – against PCI only.
However, following interim analyses of the first 111 patients (58 treatment arm, 52 control) in the pivotal study after 12 months, ZOLL made the decision to end the trial early. The plan had been to recruit 500 patients to detect a relative reduction of 20% in mean infarct size for the treatment group.
During a EuroPCR press conference, principal investigator Marko Noc, MD, PhD, of University Medical Center in Slovenia, noted significant differences between the treatment groups, including 25 new-onset paroxysmal atrial fibrillation cases for the treatment group (43.1%) versus 2 (3.8%) in control (p < 0.001).
The researchers saw longer randomization-to-balloon time (61 ± 21 vs. 32 ± 18 minutes, p<0.001) and total ischemic time (232 ± 63 vs. 188 ± 64 minutes, p<0.001) in the trial device arm, with comparable onset-to-randomization delays.
No significant differences were observed for the primary efficacy endpoint – a relative reduction of 20% in mean anterior myocardial infarct size (as a percentage of left ventricular mass) determined by cardiac magnetic resonance imaging (MRI) at 4 to 6 days post-infarct. Infarct size at 4 to 6 days in the trial device group was 21.3% ± 12.2%, compared to 20.0% ± 12.2% in the control group (p=0.540).
A numerically greater but not statistically different increase in the secondary endpoint was also observed for the secondary safety endpoint, defined as a composite of cardiac death, myocardial infarction and clinically indicated target lesion revascularization at 30-day follow-up. The endpoint occurred in 5 (8.6%) in the trial device arm compared to 1 (1.9%) in control (p = 0.117).
The treatment arm also had significantly increased other serious adverse events, including cardiogenic shock for 6 patients (10.3%) versus none in the control group (p = 0.028).
“Early interruption of the trial clearly limits the statistical power of the trial not allowing to definitely assess its safety and efficacy in anterior STEMI patients,” according to the accompanying press statement.
“While the experience acquired with COOL AMI EU pivotal trial will be of help in designing future trials assessing the effects of systemic hypothermia, additional evidence will be required to support its adoption.”