Discussion
critically ill, excessive damage, pulmonary edema, ARDS, extensive endothelial injury, imatinib-responsive, EVLWi
ADVERSE EVENTS, ARDS, CRITICALLY ILL, PULMONARY EDEMA
Administration of IV imatinib in invasively ventilated patients with COVID-19 ARDS had no significant effect on ΔEVLWi between days 1 and 4, indicating that imatinib did not reduce pulmonary edema. Imatinib did not improve clinical outcomes such as oxygenation, duration of invasive ventilation or 28-day mortality. IV imatinib was well-tolerated, with no adverse events attributed to imatinib administration. A posthoc analysis in previously identified subphenotypes suggests that IV imatinib reduced EVLWi in a subgroup of patients characterized by high levels of IL-6, TNFR1 and SP-D.This trial follows up on the CounterCOVID trial, which showed that oral imatinib, in hospitalized COVID-19 patients, resulted in a shorter duration of invasive ventilation and a lower 90-day mortality [Second, a notable difference with the CounterCOVID trial was that in the current trial, virtually all patients received IL-6 receptor inhibitors before starting imatinib treatment. Although attenuation of pulmonary endothelial barrier disruption was the hypothesized working mechanism of imatinib, an immune-modulating effect was previously observed [Third, the timing of treatment may have been too late. Imatinib may not be able to effectively reverse vascular leak and pulmonary edema once the alveolocapillary barrier has suffered excessive damage. The high baseline EVLWi and PVPi levels suggest that the peak in pulmonary edema formation likely occurred before intubation. This could explain the discrepancy with the beneficial clinical effect seen in the CounterCOVID ICU population, in whom imatinib treatment was started within 24 h after hospital admission [Fourth, autopsy studies in COVID-19 patients have revealed extensive endothelial injury [This was the first trial to intravenously administer imatinib and evaluate its safety. While no clear safety concerns were observed, a critical view of the data could indicate a trend towards more (serious) adverse events in the imatinib group. However, these differences were not statistically significant, and none of the AEs could be attributed to the treatment of imatinib. A larger trial is necessary to provide a definitive answer to the question of safety of IV imatinib in critically ill patients.A strength of this trial was that by using EVLWi as a measure of pulmonary edema, we could directly translate the preclinical hypothesis of the effect of imatinib on vascular leak to measurement in the clinical setting. EVLWi is a validated measure of pulmonary edema and an independent prognostic factor in patients with ARDS [Some limitations should be acknowledged. EVLW measurements can be affected by external and patient factors, such as ventilator settings [The study’s findings have several implications. The neutral results of this study question the efficacy of targeting endothelial barrier disruption as a strategy in ARDS. Although preventing or attenuating endothelial barrier disruption may form a suitable strategy to prevent reaching the state of ARDS, the temporal dynamics of vascular leak in ARDS are still insufficiently understood. This precludes the current implementation of imatinib for the general COVID-19 ARDS population or translation to all-cause ARDS. A second implication is that a certain subpopulation may benefit from imatinib. Further clinical and biological characterization of subphenotypes is necessary here. Finally, the trial results underscore the importance of what is taking an increasingly central role in ARDS research: the characterization of biologically distinct subphenotypes for improved predictive enrichment in trials that examine potential treatments.In conclusion, IV imatinib did not reduce EVLWi in invasively ventilated patients with COVID-19 ARDS. The administration of IV imatinib was well-tolerated and did not result in major safety concerns. Possible explanations for the lack of observed benefit include the biological heterogeneity of COVID-19 ARDS, concomitant use of immune-modulating medication and/or timing of imatinib administration. Further characterization of the imatinib-responsive subphenotype in future studies may help identify patients who benefit from vascular barrier-enhancing drugs.