Imatinib as a Tool Against COVID-19: A Balancing Act Between Effectiveness and Cardiac Safety

Heat not a furnace for your foe so hot that it do singe yourself

–William Shakespeare

Despite tremendous ongoing efforts at prevention, diagnosis, risk-stratification, management, and rehabilitation, COVID-19 still represents a crucial threat for public health, and it continue to cause an enormous burden of death, hospitalization, and disability. This holds true despite almost universal vaccine and booster coverage and the availability of several new treatments approved or under investigation for COVID-19 infection, aimed at preventing severe symptoms and hospital admission, including imatinib.1 Indeed, imatinib is a tyrosine kinase inhibitor, largely used for the treatment of hematological tumors and gastrointestinal stromal tumors (GISTs), at the moment being tested for clinical use in severe COVID-19 because of its action on endothelial dysfunction, which is an important pathway involved in COVID-19 infection.2,3

However, cardiac toxicity is one of the most frequent and disabling drawbacks related to imatinib, and it may lead to congestive heart failure, acute coronary syndrome, corrected QT interval (QTc) prolongation, and arrhythmias.4 In addition, COVID-19 itself may affect the cardiovascular system, causing short- or long-term cardiac injury through several mechanisms, such as interleukin (IL)-6 storming, viral cardiomyocyte invasion, or unopposed angiotensin II effects.5,6 Because of the potential interplay between imatinib toxicity and COVID-19 cardiovascular complications, it is worth to gauge in detail the precise safety profile of imatinib use in the clinical setting of severe COVID-19 infection.

Focusing explicitly on patients hospitalized for COVID-19, several treatments have been tested and currently are under examination, but at the moment, the gold standard treatment is represented by the use of dexamethasone and heparin (Fig. 1).7 Dexamethasone is used in all patients requiring oxygen therapy. In contrast, low-molecular-weight heparin is used at therapeutic dosage for patients with thrombotic complications and at prophylactic dosage in patients with respiratory distress and poor mobility. In addition, remdesivir is recommended in the first 10 days of infection in patients requiring low-flow oxygen. Baricitinib and imatinib have been studied mainly in hospitalized patients requiring early oxygen treatment and with increased inflammatory burden. Similarly, tocilizumab and sarilumab have been studied in patients with rapidly progressing conditions and high inflammatory indices.7 Anakinra, an anti-IL-1 medication, has been tested for patients with moderate-to-severe COVID-19 infection and with increased levels of soluble urokinase-type plasminogen activator receptor.7 To date, imatinib has been tested with controversial results in hospitalized patients for COVID-19, especially in the clinical setting of high inflammatory burden.8 Indeed, recent findings suggest that imatinib does not reduce time to discontinuation of oxygen and ventilatory support but can reduce mortality rate and enhance a shorter duration of invasive ventilation.2,9

In the current issue of the Journal, Duijvelaar et al10 expand the evidence base on imatinib, focusing on its potential cardiotoxicity. This is evidently relevant because imatinib is typically administered in patients hospitalized for COVID-19 for approximately 10 days, whereas the duration of treatment is longer for GIST and hematological tumors, so that side effects on cardiovascular system have been described only for long-duration treatment.4 Specifically, Duijvelaar et al leverage the CounterCOVID study data, in which patients received 400 mg of imatinib, after a loading dose of 800 mg, were 18 years of age or more, and required supplemental oxygen to maintain a peripheral oxygen saturation over 94%. Overall, 385 hospitalized patients were enrolled and followed for 28 days or until death, with exclusion criteria being QTc interval >500 milliseconds, left ventricular ejection fraction <40%, or drugs interacting with imatinib. Three endpoints were considered relevant for cardiac safety appraisal: cardiac adverse events, electrocardiogram parameters, and cardiac biomarkers (troponin T and N-terminal prohormone of brain natriuretic peptide [NT-proBNP]). As many as 197 patients were randomly assigned to imatinib and 188 to placebo.

F1FIGURE 1.:

Main tools for hospital management of Covid-19 infection. LMWH, low-molecular-weight heparin; suPAR, soluble urokinase-type plasminogen activator receptor.

Notably, no statistically significant differences were found regarding the QTc interval, an essential drawback of imatinib treatment previously described for tyrosine kinase inhibitors. Furthermore, there was a similar incidence in cardiac adverse events in both groups and no relevant differences in biomarkers.10 These findings were also confirmed in multivariate models.

In conclusion, although COVID-19 and imatinib both may both affect the cardiovascular system, imatinib is a promising tool for the treatment of hospitalized patients with COVID-19 requiring oxygen and seems safe for cardiovascular outcomes. However, given the study limitations, including lack of inclusion of patients with systolic dysfunction or prolonged QTc at baseline, further data are required before routinely considering this drug in severe COVID-19. In particular, we recommend a baseline electrocardiogram and transthoracic echocardiogram and a thorough cardiological evaluation of COVID-19 patients before imatinib administration to maximize the efficacy and the cardiac safety of this agent.

1. Amani B, Zareei S, Amani B, et al. Artesunate, imatinib, and infliximab in COVID-19: a rapid review and meta-analysis of current evidence. Immun Inflamm Dis. 2022;10:e628. 2. Aman J, Duijvelaar E, Botros L, et al. Imatinib in patients with severe COVID-19: a randomised, double-blind, placebo-controlled, clinical trial. Lancet Respir Med. 2021;9:957–968. 3. Huertas A, Montani D, Savale L, et al. Endothelial cell dysfunction: a major player in SARS-CoV-2 infection (COVID-19)? Eur Respir J. 2020;56:2001634. 4. Binzaid AA, Baqal OJ, Soheib M, et al. Cardiovascular toxicity associated with tyrosine kinase inhibitor therapy in chronic myeloid leukemia. Gulf J Oncolog. 2021;1:79–84. 5. Mohammad M, Emin M, Bhutta A, et al. Cardiac arrhythmias associated with COVID-19 infection: state of the art review. Expert Rev Cardiovasc Ther. 2021;19:881–889. 6. Imazio M, Abbate A. The inflammasome as a therapeutic target for myopericardial diseases. Minerva Cardiol Angiol. 2022;70:238–247. 7. AIFA—Agenzia Italiana del Farmaco. Farmaci utilizzabili per il trattamento della malattia COVID-19. 2022. Available at: https://www.aifa.gov.it/web/guest/aggiornamento-sui-farmaci-utilizzabili-per-il-trattamento-della-malattia-covid19. Accessed July 26, 2022. 8. Bernal-Bello D, Morales-Ortega A, Isabel Farfan-Sedano A, et al. Imatinib in COVID-19: hope and caution. Lancet Respir Med. 2021;9:938–939. 9. Duijvelaar E, Schippers JR, Smeele PJ, et al. Long-term clinical outcomes of COVID-19 patients treated with imatinib. Lancet Respir Med. 2022;10:e34–e35. 10. Duijvelaar E, Vanhove A, Schippers JR, et al.; CounterCOVID Collaborative Group. Cardiac safety of imatinib for the treatment of COVID-19: a secondary analysis of a randomised, double blind, placebo-controlled trial. J Cardiovasc Pharmacol. 2022. doi: 10.1097/FJC.0000000000001344. Online ahead of print.

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