Results of the interim analyses performed after 12 months in the first 111 patients enrolled in phase II Cool AMI trial evaluating safety and effectiveness of systemic therapeutic hypothermia as an adjunctive therapy in anterior STEMI undergoing PCI as compared to PCI only. Analyses showed significant differences among treatment groups, including longer randomisation-to-balloon time and total ischemic time in treatment arm, justifying premature trial discontinuation.
Therapeutic mild systemic hypothermia, when achieved before reperfusion of the infarct related vessel, has shown to limit infarct size in experimental animal models. Despite encouraging initial in vivo results, several prior RCTs reported overall neutral effects. A potential advantage of hypothermia was detected in early presenters with anterior STEMI cooled prior to reperfusion.
Safety of this approach in anterior STEMI patients was initially tested in the COOL AMI EU pilot phase I trial, which results were previously presented at EUROPCR 2017 and published in Eurointervention.
The COOL AMI EU pivotal trial, is an industry initiated, multicenter, prospective, interventional, randomised-controlled phase II trial with a 1:1 randomisation protocol comparing systemic therapeutic hypothermia in patients with recent onset anterior STEMI (< 4.5 h from symptoms onset) cooled before and after primary PCI as compared to primary PCI only. Mild therapeutic hypothermia has been achieved with ZOLL Proteus Intra Vascular Temperature Management system via fast injection of up to 1 litre cold saline through a catheter inserted via the femoral vein into the inferior vena cava reaching a mean body temperature of 33° C during treatment.
Primary efficacy endpoint was set as a relative reduction of 20% in mean anterior myocardial infarct size (as % left ventricular mass) determined by cardiac magnetic resonance imaging at 4-6 days post-infarct in the cooling + PCI arm as compared to the PCI only arm.
The secondary safety endpoint was defined as a composite of cardiac death, myocardial infarction and clinically-indicated target lesion revascularization at 30 day follow-up. According to the statistical analysis plan, 500 patients were expected to be enrolled to detect a relative reduction of 20% in mean infarct size in the treatment group. Interim analyses were pre-specified as per protocol.
During the LBT sessions of the upcoming EUROPCR 2021 congress, results of the interim analyses performed at 12 months after enrolment of 111 patients (58 treatment arm, 52 controls) were presented by Dr. M Noc (Ljubljana, Slovenia). The interim analysis led to premature, sponsor promoted, trial discontinuation.
Trialists observed significant differences among treatment groups, including longer randomisation-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 treatment arm, with comparable onset-to-randomisation delays. Those delays could be associated with potential impact on outcomes. Delays were considered not to be related to cooling manoeuvres.
No significant differences were observed for the primary endpoint (infarct size as a % of LV mass at MRI at 4-6 days 21.3±12.2% in the treatment group vs 20.0±12.2% in the control group, p=0.540). A numerically greater, statistically non-significant increase in the incidence of the secondary endpoint was also observed in the cooling arm (MACE at 30 days n=5 (8.6%) vs n=1 (1,9%), p=0.117). Incidence of two per protocol specified serious adverse events (cardiogenic shock: n=6 (10.3%) vs n=0 (0%), p=0.028 and new onset paroxysmal atrial fibrillation: n=25 (43.1%) vs 2 (3.8%), p<0.001), were also significantly increased in the treatment arm.
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. 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.