Remdesivir might induce changes in electrocardiogram beyond bradycardia in patients with coronavirus disease 2019—The pilot study

Abstract

We have read the paper by Pallotto et al.1 reporting transient bradycardia in coronavirus-19 disease (COVID-19) patients receiving remdesivir with great interest. At the moment, remdesivir is the only specific antiviral agent approved for the treatment of severe COVID-19. Despite its antiviral activity and shortening of patient recovery time, remdesivir did not show an effect on mortality reduction.2 This may be due, among other things, to the toxicity of the drug in certain, not yet recognized, patient subgroups which cancels out potential benefits of the drug in the overall cohort of patients. Remdesivir is a prodrug and one of its metabolites GS-443902 is an adenosine analog but with a substantially longer elimination half-life than adenosine.3 Adenosine has known antiarrhythmic effects in atrioventricular-nodal re-entry tachycardias but can be proarrhythmic in patients with structural heart disease.4, 5 Several small postmarketing studies and case reports reported cardiovascular side-effects of remdesivir including bradycardia, hypotension, QTc interval prolongation, nonspecific T-wave changes, and cardiac arrest.6-9 Prompted by the study by Palloto et al.1 and reports on potential cardiovascular side-effects of the drug, we prospectively performed the cross-sectional electrocardiographic (ECG) pilot study in 14 consecutive patients with severe COVID-19 treated with remdesivir and dexamethasone in our institution in April 2021. An ECG tracing was recorded before and 2 h after the remdesivir infusion. The ECG analysis included changes in heart rhythm and ventricular rate; changes in PR segment, QT and QTc interval duration; changes in QRS complex duration; P, QRS, and T-wave axis deviation and rV5 and sV5 amplitude (individual and combined). Numerical measurements were summarized as mean ± standard deviation and were compared using the Wilcoxon test for paired samples. MedCalc statistical software ver. 19.8 was used for data analyses. p Values less than 0.05 were considered to be statistically significant. The study was approved by the institutional review board. All patients provided consent for the procedures. There were 9/14 (64%) male and 5/14 (35.7%) female patients, mean age was of 67.6 ± 13.3 years (range: 45–85 years). A total of 12/14 (85.7%) patients were overweight, 4/14 (28.5%) had type II diabetes mellitus, 8/14 (57.1%) had arterial hypertension, 3/14 (21.4%) had a history of myocardial infarction, 2/14 (14.3%) had a history of valve repair, 11/14 (78.6%) had sinus rhythm, and 3/14 (21.4%) had atrial fibrillation, 5/14 (35.7%) patients had no prior comorbidities. Four patients were receiving high flow oxygen therapy. The median day of remdesivir application was 2.5 with six patients receiving the first day of application, one receiving the second day, five receiving the third day, and two receiving the fifth day of the application. A total of four patients died. The dynamics of the ECG measurements are presented in Table 1. A statistically significant effect of remdesivir was observed on the T-wave axis deviation (a total of 10 patients experienced rightward axis deviation, mean 42.2° prior and 69.9° after remdesivir administration; p = 0.047). No significant changes in heart rhythm, ventricular rate, PR segment, QT interval, QTc interval, and QRS complex duration, P wave, QRS complex axis, nor rV5, sV1 amplitudes were observed (p > 0.05) with mostly small changes in the direction of previously reported tendencies. No significant associations of ECG changes with in-hospital mortality could be established. However, the study was underpowered to assess this issue. Several important observations emerge from our study. Our data show that remdesivir application is associated with rightward T-wave axis deviation in patients with severe COVID-19. The T-axis deviation is a strong and independent risk indicator of sudden cardiac death, cardiac death, and nonfatal cardiac events in the elderly.10, 11 Whether this finding and in what extent translates into detrimental clinical outcomes in severe COVID-19 patients treated with remdesivir remains to be elucidated in future studies that are highly needed. No firm conclusions regarding this issue can be drawn from our data at the moment. Elderly patients with a high comorbidity burden that do not fit strict original clinical-trial criteria are often exposed to the drug in the real-life setting. It should be noted that due to the scale of the COVID-19 pandemic, severity of the health hazard imposed on affected individuals and strain put on the healthcare systems, there is a low quality of adverse event reporting in remdesivir clinical trials.12 Adverse effects of the drug might be more common than reported and attributed to the disease course itself. Nevertheless, understanding the true efficacy and safety profile of the drug is the imperative for improving outcomes of patients with severe COVID-19. The authors declare that there are conflict of interests. The study was approved by the Institutional Review Board.

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