What is the incidence of bradycardia with remdesivir in pediatric patients?

Comment by InpharmD Researcher

The data regarding the incidence of remdesivir-associated bradycardia in pediatric patients appear to be limited to case reports. While an interim analysis of an ongoing clinical trial in pediatric patients (CARAVAN study) has not yet reported the incidence of bradycardia, continuous cardiac monitoring as well as therapeutic drug monitoring in pediatric patients, especially those with pre-existing cardiac conditions is warranted.
Background

An interim analysis of an ongoing phase 2/3 single-arm, open-label clinical trial (CARAVAN study; N= 53) on safety, tolerability, pharmacokinetics, and efficacy of remdesivir in patients aged <18 years with coronavirus disease 2019 (COVID-19) was presented in the 29th Conference on Retroviruses and Opportunistic Infections (February 12-16, 2022). Pediatric patients were placed into 5 cohorts (cohorts 1, 2, 3, 4, and 8) based on age and weight. Cohorts 1 and 8 included children weighing ≤ 40 kg who received 200 mg on Day 1 followed by 100 mg daily whereas cohorts 2-4 included children weighing <40 kg who received weight-based dosing of 5mg/kg on Day 1 followed by 2.5 mg/kg daily. The interim results demonstrated that remdesivir was generally well tolerated in the pediatric population hospitalized with COVID-19. The most common reported adverse event was constipation (17%), followed by acute kidney injury (11%), hyperglycemia (9%), pyrexia (9%), and increased alanine transaminase (8%). There were no reports of bradycardia presented in this interim analysis. The estimated completion date of the study is February 2023. [1]

A 2021 letter to editor described the observation of sinus bradycardia in children treated with remdesivir for COVID-19 in several pediatric case reports. An 11-year-old male with advanced neuronal ceroid lipofuscinoses type 2 experienced COVID-19 pneumonia and developed episodes of sinus bradycardia (heart rate dropped to 59 beats per minutes [bpm] from 90 to 100 bpm at baseline) on day 3 and day 4 of receiving remdesivir. Another 13-year-old male with primordial dwarfism also had symptoms of pneumonia and was in demand of oxygen. On day 5 of receiving remdesivir, his heart rate dropped from > 100 bpm at baseline to 56 bpm. Both patients survived, although suffered from further residual lung damage aggravating their chronic disease. A third 7-year-old female with dystrophy, mild microcephaly, and hypothyroidism developed critical COVID-19 disease for which remdesivir was initiated. The patient experienced severe sinus bradycardia (38 bpm) on day 5 of remdesivir treatment despite having confirmation of remdesivir and its metabolite being within target levels. However, she also had severe myocarditis leading to extracorporeal life support, hemofiltration, catecholamine use, and multiple other drugs that could be responsible for bradycardia. She succumbed to fulminant COVID-19. Another letter to the editor also reported that 3 out 4 children who were treated with remdesivir in a single-center hospital with normal cardiologic evaluation developed asymptomatic sinus bradycardia. Remedivir was only discontinued in an infant whereas the other two older children completed the 5-day therapy period. Having an uncomplicated course, all three patients were discharged after a median of 5 days (range 4-7). The authors emphasized the importance of continuous cardiac monitoring as well as therapeutic drug monitoring in pediatric patients, especially those with pre-existing cardiac conditions. [2-3]

A 2021 article described while the available literature regarding the incidence of arrhythmia in children with COVID-19 is limited to case reports, some small case series reported up to 16% arrhythmia in children who were treated with remdesivir; however, the arrhythmia was reported to be mild or less harmful in nature compared to ones reported in adult cases. Given the limited data on the association of bradycardia and remdesivir utilized in children with COVID-19, performing electrocardiographic monitoring in all children with COVID-19, especially those with a cardiac underlying condition is warranted. [4,5]

A 2019 case report and review of literature described a post-marketing study that found that patients who received remdesivir had a 1.7-fold increased odds of developing bradycardia than those treated with other COVID-19 therapies. Several pediatric cases reported remdesivir-induced bradycardia (see Tables 1-2). Several adult case reports also exist confirming the potential for remdesivir-induced bradycardia. As the safety and effectiveness of remdesivir treatment in pediatric patients <12 years had not been assessed in depth at the time of the review, the authors noted that pediatricians should be aware of this potential cardiovascular effect of remdesivir administration. [6]

References:

[1] Gilead Sciences. Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Efficacy of Remdesivir (GS-5734™) in Participants From Birth to <18 Years of Age With Coronavirus Disease 2019 (COVID-19) (CARAVAN). ClinicalTrials.gov Identifier: NCT04431453. Updated June 23, 2022. Accessed June 27, 2022. https://www.clinicaltrials.gov/ct2/show/NCT04431453
[2] Eleftheriou I, Liaska M, Krepis P, et al. Sinus Bradycardia in Children Treated With Remdesivir for COVID-19. Pediatr Infect Dis J. 2021;40(9):e356. doi:10.1097/INF.0000000000003214
[3] Rau C, Apostolidou S, Singer D, Avataneo V, Kobbe R. Remdesivir, Sinus Bradycardia and Therapeutic Drug Monitoring in Children With Severe COVID-19. Pediatr Infect Dis J. 2021;40(12):e528-e529. doi:10.1097/INF.0000000000003309
[4] Méndez-Echevarría A, Pérez-Martínez A, Gonzalez Del Valle L, et al. Compassionate use of remdesivir in children with COVID-19. Eur J Pediatr. 2021;180(4):1317-1322. doi:10.1007/s00431-020-03876-1
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7814184/
[5] Mendez-Echevarria A, Sándor-Bajusz KA, Calvo C. Severe sinus bradycardia associated with remdesivir in a child with severe SARS-COV-2 infection-reply. Eur J Pediatr. 2021;180(5):1629-1630. doi:10.1007/s00431-021-03952-0
[6] Chow EJ, Maust B, Kazmier KM, Stokes C. Sinus Bradycardia in a Pediatric Patient Treated With Remdesivir for Acute Coronavirus Disease 2019: A Case Report and a Review of the Literature. J Pediatric Infect Dis Soc. 2021;10(9):926-929. doi:10.1093/jpids/piab029

Literature Review

A search of the published medical literature revealed 2 studies investigating the researchable question:

What is the incidence of bradycardia with remdesivir in pediatric patients?

Please see Tables 1-2 for your response.


 

Severe sinus bradycardia associated with Remdesivir in a child with severe SARS-CoV-2 infection

Design

Case report

Case presentation

A 13-year-old male with a history of episodic asthma who was diagnosed with severe bilateral pneumonia with hypoxemia due to SARS-CoV-2 infection presented and started on oxygen therapy, dexamethasone, ceftriaxone, and remdesivir (loading dose of 200 mg/day, followed by 100 mg/day). Electrocardiogram (ECG) revealed non-hemodynamically significant sinus bradycardia (40 beats per minute from the previous heart rate of 80–90 beats per minute) following the third dose of remdesivir. Remdesivir was discontinued and his heart rate normalized (80-100 beats per minute) in the following 24 hours. He was discharged after 5 days without complications.

Study Author Conclusions

In this case, the Naranjo scale value of 6 points suggested that bradycardia was a probable side effect of remdesivir. This indicates a need for continuous cardiac rhythm monitoring in children under treatment with remdesivir, especially in those with underlying heart diseases, a population at risk for worse clinical outcomes in COVID-19 and therefore more likely to receive this treatment.

References:

Sanchez-Codez MI, Rodriguez-Gonzalez M, Gutierrez-Rosa I. Severe sinus bradycardia associated with Remdesivir in a child with severe SARS-CoV-2 infection. Eur J Pediatr. 2021;180(5):1627. doi:10.1007/s00431-021-03940-4

 

Sinus Bradycardia in a Pediatric Patient Treated With Remdesivir for Acute Coronavirus Disease 2019: A Case Report and a Review of the Literature

Design

Case report

Case presentation

A 16-year-old obese male (body-mass index of 43.9 kg/m2) and no other past medical history presented with fatigue and progressed to include headache, dry cough with shortness of breath, and subjective fevers starting 6 days before admission. Polymerase chain reaction nasopharyngeal swab was positive for SARS-CoV-2. After 8 hours, given his mild symptoms, he was discharged. However, over the next 2 days, he developed a worsening cough and difficulty breathing, ultimately returning to the emergency room for further assessment. While being afebrile, he was tachypneic at 32 breaths per minute and his oxygen saturations were 93% to 95% in room air. His WBC increased to 11.2 K/mm3. Following a negative SARS-CoV-2 IgG, a chest x-ray revealed multi-focal patchy airspace opacities. While receiving supplemental oxygen, he received intravenous remdesivir with a plan for 5 days of therapy on the second day of admission. After he received his first dose of remdesivir 200 mg over 1 hour, his heart rate trended downward over the next 6 hours with the lowest recorded rate at 46 bpm and a 15 lead electrocardiogram (EKG) was notable only for sinus bradycardia. Although no further doses of remdesivir were initiated, his heart rate remained in the range of 40–60 bpm. He had normal status during the week after discharge and his follow-up EKG 14 days after discharge revealed normal sinus rhythm at a heart rate of 107 bpm. 

Study Author Conclusions

This pediatric patient’s case highlights reversible sinus bradycardia as a potential side effect of remdesivir. While severe COVID- 19 is less common in pediatric patients, the continued spread of SARS-CoV-2 will lead to increased pediatric cases and will likely increase the use of remdesivir. 

References:

Chow EJ, Maust B, Kazmier KM, Stokes C. Sinus Bradycardia in a Pediatric Patient Treated With Remdesivir for Acute Coronavirus Disease 2019: A Case Report and a Review of the Literature. J Pediatric Infect Dis Soc. 2021;10(9):926-929. doi:10.1093/jpids/piab029