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Background: A central hallmark of ARDS is hypoxemic respiratory failure due to increased pulmonary capillary leakage. The kinase inhibitor imatinib was shown to reverse vascular leak. This study aimed to investigate the effect of intravenous imatinib on pulmonary edema in patients with COVID-19 ARDS. Method(s): This multicentre, randomised, double-blind, placebo-controlled clinical trial (ClinicalTrial.gov identifier NCT04794088) included adult patients admitted to the ICU with moderate or severe COVID-19 ARDS. Patients were randomised 1:1 to receive 200mg intravenous imatinib or placebo twice daily for seven days or until ICU discharge. The change in extravascular lung water index between day 1 and day 4, measured using a PiCCO catheter, was chosen as the primary endpoint. Secondary outcomes included the PaO2/FiO2 ratio, number of ventilator free days, length of ICU admission and 28-day mortality rate. Study drug safety was assessed by daily screening of the patient records for adverse and serious adverse event occurrence and by performing ECGs and targeted clinical laboratory tests to monitor renal, liver and cardiac function. Result(s): Between March 2021 and 2022, 67 predominantly male (58%) patients with a mean age of 63+/-10 years were randomized to receive imatinib or placebo. No adverse events were considered to be related to study drug administration. At the moment of the submission, data cleaning is still ongoing. Conclusion(s): Thus far, intravenous imatinib administration seems safe and feasible in patients with COVID-19 related ARDS.
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Background : Coagulopathy has been reported in severely ill patients with COVID-19, but data are lacking in outpatient settings. In patients treated with vitamin K antagonists (VKAs), whose anticoagulant effect is monitored through international normalized ratios (INRs), such coagulation abnormalities might lead to unstable control of anticoagulation. This could influence their thrombosis and bleeding risk. Aims : To assess stability of VKA therapy in COVID-19 patients through a case-crossover study. Methods : Between February-July 2020, we included patients with a positive COVID-19 test from two anticoagulant clinics in the Netherlands. We collected INRs between 26 weeks prior to diagnosis up to 12 weeks after. Time in Therapeutic Range (TTR), stability between INRs expressed as the Variance Growth Rate (VGR), and proportion of INR ≥ 5.0 were calculated and compared within patients with paired sample t -test (in the 26 weeks before infection, in the first 6 weeks after and between 6 and 12 weeks after diagnosis). Results : 51 COVID-19 patients (mean age 84) were included, of whom 15 (29%) were men. Mean TTR in the 26 weeks prior to COVID-19 infection was 80%(95%CI 75-85) compared to 59%(95%CI 51-68) in the 6 weeks after (Table 1). Mean TTR difference was -23%(95%CI -32 to -14) with a time above therapeutic range of 38% (95%CI 30-47) in the 6 weeks after diagnosis. The TTR rose again to 79% (95%CI 69-89) between 6 and 12 weeks after diagnosis (Figure 2). Also, VGR increased, with a mean increase of 4.8 (95%CI 2.1-7.5) in the first 6 weeks. The risk of INRs ≥ 5.0 was 4.4 (95%CI 2.7-7.3) times higher in the 6 weeks after diagnosis compared with the 26 weeks before. Conclusions : COVID-19 infection was associated with a strong decrease in TTR and INR stability in VKA users compared to their values before infection. Additional monitoring is advised to maintain therapeutic stability, particularly to prevent supratherapeutic INRs.