Final Data Presented From Discontinued COOL AMI EU Evaluating Hypothermia as Adjunct Therapy to PCI

May 18, 2021—Final results of the COOL AMI EU pivotal trial evaluating systemic mild hypothermia as an adjunctive therapy to primary percutaneous coronary intervention (PCI) in patients with anterior ST-segment elevated myocardial infarction (STEMI) were presented by Marko Noc, MD, as part of a late-breaking trial session at the virtual EuroPCR conference held May 18-20. The data were simultaneously published online in EuroIntervention.

In the presentation announcement by PCR, it was explained that COOL AMI EU was discontinued following an ad interim analysis of the first 111 patients at 12 months that showed significant differences among treatment groups, including longer randomization-to-balloon time and total ischemic time in the treatment arm.

The trial used a 1:1 randomization protocol comparing systemic therapeutic hypothermia in patients with recent-onset anterior STEMI (< 4.5 hours from symptoms onset) cooled before and after primary PCI as compared to primary PCI only.

As noted in the PCR press release, therapeutic mild systemic hypothermia, when achieved before reperfusion of the infarct-related vessel, has been shown to limit infarct size in experimental animal models. Despite encouraging initial in vivo results, several previous randomized controlled trials reported overall neutral effects. A potential advantage of hypothermia was detected in early presenters with anterior STEMI cooled before reperfusion.

The 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 (2017;13:e531-e539).

Mild therapeutic hypothermia has been achieved with the Proteus IVTM intravascular temperature management system (Zoll Medical Corporation, an Asahi Kasei company) via fast injection of up to 1-liter 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. Zoll is the trial's sponsor.

Within the COOL AMI EU study, the primary efficacy endpoint was set as a relative reduction of 20% in mean anterior myocardial infarct size (as percentage left ventricular [LV] mass) determined by cardiac MRI at 4 to 6 days postinfarct 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 prespecified as per protocol.

At EuroPCR 2021, Coprincipal investigator Dr. Noc presented the results of the interim analyses performed at 12 months after enrollment of 111 patients (58 treatment arm, 52 controls) that led to premature, sponsor-promoted, trial discontinuation.

As summarized in the PCR press release, the investigators observed significant differences among treatment groups, including longer randomization-to-balloon time (61 ± 21 vs 32 ± 18 minutes; P < .001) and total ischemic time (232 ± 63 vs 188 ± 64 minutes; P < .001) in the treatment arm versus the PCI-only arm, with comparable onset-to-randomization delays. Those delays could be associated with a potential impact on outcomes. Delays were considered not to be related to cooling maneuvers.

No significant differences were observed for the primary endpoint (infarct size as a percentage of LV mass at MRI at 4-6 days) in the treatment group (21.3 ± 12.2%) versus the control group (20.0 ± 12.2%; P = .54). An increase in the incidence of the secondary endpoint (MACE at 30 days) was observed in the cooling arm (five [8.6%] vs one [1.9%]; P = .117).

Incidence of two per protocol-specified serious adverse events were also significantly increased in the treatment arm

• Cardiogenic shock, six and none (10.3% vs 0%; P = .028)
• New-onset paroxysmal atrial fibrillation, 25 and two (43.1% vs 3.8%; P < .001)

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, noted the PCR announcement.