What literature is available describing the occurrence of bradycardia with remdesivir?
Introduction
Remdesivir is a broad-spectrum antiviral with activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that has caused the worldwide pandemic of COVID-19.1 An Emergency Use Authorization (EUA) for remdesivir use to treat severe COVID-19 in hospitalized adult and pediatric patients was granted by the Food and Drug Administration (FDA) in May 2020.2 Subsequently, the drug received FDA approval for use in hospitalized adults and pediatric patients 12 years of age and older in October 2020. Remdesivir use in hospitalized patients weighing 3.5 kg to < 40 kg and for patients under 12 years of age weighing at least 3.5 kg is admissible under the EUA.
Common (≥ 5%) adverse drug reactions (ADRs) of remdesivir observed in phase 3 clinical trials include nausea and elevation in transaminases.1 Serious reactions or those that led to discontinuation included transaminase elevations, kidney injury, infusion site reactions, rash, and decreased heart rate (<1%). As the use of remdesivir has increased, data on its safety has also accumulated. An increasing number of case reports, retrospective, and prospective studies have been published reporting the occurrence of bradycardia with remdesivir use.3-21 The purpose of this review is to summarize the current published literature available describing the effect of remdesivir on heart rate (HR).
Literature Review
As summarized in Table 1, a number of case reports have described the onset of bradycardia, its sequelae, and management in patients who received remdesivir as a component of treatment for COVID-19.3-13 With respect to patient characteristics, there is no consistency in the age or past medical history of the patients affected. The onset of bradycardia was also inconsistent with signs occurring as early as within 6 hours of the first dose and as late as after the fourth dose. Severity of bradycardia varied but most patients remained asymptomatic. Bradycardia resolved either spontaneously or with remdesivir discontinuation and additional treatment was not required in most cases. Patients who required treatment received atropine as needed and/or a dopamine infusion of 3 or 5 mcg/kg/min.
Summaries of ADRs of COVID-19 treatments submitted to the adverse reporting databases of the World Health Organization (WHO), Vigibase, and the FDA’s adverse event reporting system (FAERS) have been published.14,15 According to global adverse reaction reporting between January 1, 2020 to December 31, 2020 on COVID-19 treatments to VigiBase, approximately 35% (5299/14,574) of the reports were related to remdesivir treatment.14 Of these, frequency of effects on HR were: 4.6% bradycardia, 1.1% HR decreased, 0.7% sinus bradycardia, 0.3% QT prolongation, and 0.4% dizziness. The authors concluded that these cardiac effects are not outlined in the labeling of remdesivir, were unexpected, and deserve attention. In FAERS reporting from January 1, 2020 to May 28, 2021, remdesivir was considered a possible cause of approximately 51% of ADRs reported for COVID-19 treatments.15 Bradycardia associated with remdesivir (5.37%) was significantly higher compared with other treatments. Occurrence of bradycardia was not found to be more common based on age or sex.
Prospective and retrospective studies (see Table 2) in larger populations have attempted to determine incidence and/or association of remdesivir with bradycardia.16-21 Incidence of bradycardia ranged from 21% to 46.8%.17-20 One prospective study demonstrated a reduction in HR from baseline but no cases of bradycardia.16 No significant sequelae or major intervention was required in any of these larger studies.
| Table 1. Case reports of bradycardia after initiation of remdesivir.3-13 | |||
|---|---|---|---|
| Citation | Patient characteristics | Description | Intervention and outcome |
| Ching et al 20213 | 37-year-old male HTN Baseline HR = 102 bpm Remdesivir dose not specified | HR: 40 to 44 bpm after second dose | Remdesivir discontinued on day 2 Day 6: HR increased to 56 to 58 bpm Day 8 (2 days post-discharge): 60 to 70 bpm No sequelae at 2-month follow-up |
| Eleftheriou et al 20214 | Patient 1: 13.5-year-old female Baseline HR = 80 bpm Patient 2: 10-year-old female Baseline HR = 80 bpm Patient 3: 3-month-old Baseline HR = 130 bpm Remdesivir doses not specified | Patient 1: HR: 50 bpm after fourth dose Patient 2: HR: 60 bpm after third dose Patient 3: HR: 80 bpm after third dose | HR normalized within 24 h in all patients with either discontinuation or completion of remdesivir treatment |
| Jacinto et al 20215 | 78-year-old female HTN Prediabetes Dyslipidemia former tobacco user Baseline HR range: 65 to 75 bpm Baseline systolic BP range: 120 to 180 mm Hg Baseline ECG: Left bundle branch block Received remdesivir 200 mg on day 1 and 100 mg daily for 4 days | HR: 38 bpm 20 h after first dose Symptomatic bradycardia with BP 73/50 mm Hg ECG: sinus bradycardia with left bundle branch block | Refractory to atropine so dopamine 5 mcg/min was maintained for course of remdesivir therapy and HR maintained between 65 to 75 bpm Dopamine titrated down and discontinued 18 h after last remdesivir dose; HR and ECG remained normal Naranjo score=7 probable side effect |
| Selvaraj et al 20216 | 72-year-old male Lung cancer COPD Atrial fibrillation (no specific treatment) Baseline HR range: 68 to 86 bpm Baseline ECG: atrial fibrillation; right bundle branch block Received remdesivir 200 mg on day 1 and 100 mg daily for 4 days | HR range: 30 to 40 bpm within 24 h of first dose and continued for duration of remdesivir treatment Complete AV block on day 5 of treatment | AV block spontaneously resolved within 48 h of completion of remdesivir treatment HR range on day 10: 52 to 58 bpm |
| Chow et al 20217 | 16-year-old male Obesity (BMI 43.9 kg/m2) Baseline HR range: > 90 bpm Received remdesivir 200 mg on day 1 | HR range: 46 and 65 bpm over 12 h after first dose; reduction in HR started within 6 h after the first dose Patient reported no symptoms specific to low HR | Remdesivir discontinued HR range: 40 to 60 bpm for 2 days after discontinuation HR at 14 days after discharge: 107 bpm |
| Sanchez-Cortez et al 20218 | 13-year-old male Asthma Baseline HR range: 80 to 90 bpm Received remdesivir 200 mg on day 1, then 100 mg daily | HR: 40 bpm after 3rd dose Asymptomatic, ECG-confirmed sinus bradycardia | Remdesivir discontinued upon bradycardia HR normalized to 80 to 100 bpm within 24 h Naranjo score 6=probable side effect |
| Day et al 20219 | 59-year-old male No significant PMH Baseline HR range: 79 to 89 bpm Baseline ECG: Normal sinus rhythm Received remdesivir 200 mg on day 1, then 100 mg daily | HR: 50 bpm after third dose ECG-confirmed sinus bradycardia Fatigue, generalized weakness, and headache but no lightheadedness | Remdesivir discontinued upon bradycardia HR normalized to 62 bpm 3 days after remdesivir was discontinued |
| Barkas et al 202110 | 36-year-old male No significant PMH Baseline HR: 92 bpm Baseline ECG: Normal sinus rhythm Received remdesivir 200 mg on day 1, then 100 mg daily | HR: 39 bpm after third dose Asymptomatic; ECG-confirmed sinus bradycardia; other cardiac abnormalities ruled out | Remdesivir discontinued HR normalized to 58 bpm measured on day 9 after remdesivir discontinuation |
| Abdelmajid et al 202111 | Patient 1: 55-year-old male Dyslipidemia Active smoker Baseline HR: 61 bpm Baseline ECG: Normal sinus rhythm Patient 2: 54-year-old female No significant PMH Baseline HR: 70 bpm Baseline ECG: Normal sinus rhythm Both patients received remdesivir 200 mg on day 1, then 100 mg daily | Patient 1: HR: 31 bpm after fourth dose ECG-confirmed sinus bradycardia Thyroid and cardiac markers were normal Patient 2: HR range: 37 to 42 bpm after second dose ECG: QT prolongation, then atrial fibrillation Cardiac enzymes were normal Symptomatic bradycardia with dizziness and fatigue | Patient 1: Remdesivir discontinued on day 5 of treatment HR increased to 54 bpm 2 days after remdesivir discontinuation and to 74 bpm before discharge Patient 2: Remdesivir discontinued before third dose with HR Patient required ICU admission and received atropine as needed (if HR < 35 bpm) and dopamine 3 mcg/kg/min HR normalized to above 60 bpm and ECG was normal within unspecified time frame after remdesivir discontinuation |
| Gubitosa et al 202012 | 54-year-old female HTN Left bundle branch block B-cell lymphoma Baseline HR range: 60 to 70 bpm Received remdesivir 200 mg on day 1, then 100 mg daily | HR: 38 bpm within 24 h of first dose and to 34 bpm on day 4 of treatment Cardiac enzymes normal; other potential causes ruled out ECG: sinus bradycardia and widened QRS complex Symptomatic with dizziness, chest pressure and shortness of breath | Remdesivir discontinued after continued bradycardia Atropine administered HR normalized to 60 to 70 bpm with resolution of chest pain and dizziness within unspecified time frame after remdesivir discontinuation |
| Gupta et al 202013 | Patient 1: 26-year-old female Obesity Baseline HR range: 80 to 100 bpm Baseline ECG: normal sinus rhythm Patient 2: 77-year-old female Baseline HR: 67 bpm Baseline ECG: Normal sinus rhythm Both patients received remdesivir 200 mg on day 1, then 100 mg daily | Patient 1: HR: 40 to 50 bpm after third dose ECG: sinus bradycardia; prolonged QT interval and T wave abnormality Patient 2: HR: 48 bpm after third dose ECG: sinus bradycardia | Patient 1: Remdesivir discontinued upon bradycardia HR returned to baseline and QT interval shortened 3 days after remdesivir discontinuation. Patient 2: Remdesivir discontinued upon bradycardia HR returned to baseline 2 days after remdesivir discontinuation |
| Abbreviations: AV, atrioventricular, BMI, body mass index; BP, blood pressure; bpm, beats per minute; COPD, chronic obstructive pulmonary disease; ECG, electrocardiogram; HR, heart rate; HTN, hypertension; ICU, intensive care unit; PMH, past medical history. |
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| Table 2. Studies evaluating incidence and risk of bradycardia with remdesivir treatment.16-21 |
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|---|---|---|---|
| Study type | Definition of bradycardia | Results | Conclusions |
| Brunetti et al16 Prospective cohort of COVID-19 patients treated with remdesivir (N=52) At baseline: 56% male 76% > 50 years 53% at least 1 CV comorbidity 57% HTN | Bradycardia (HR < 60 bpm) Symptomatic bradycardia (bradycardia + clinical symptoms*) | HR reduction was significantly reduced from a baseline of 85 bpm to 70 bpm (p<0.05) Reduction observed in the first days of treatment The extent of HR reduction was proportional to the baseline HR (p<0.001) No episodes of bradycardia, symptomatic bradycardia or QTc prolongation. No patients discontinued remdesivir | HR reduction is observed with remdesivir; however, extent of reduction was not significant to cause bradycardia or symptoms Perhaps, the improvement in symptoms of COVID-19 is causing HR reduction as patients may be presenting with higher baseline HR |
| Kumar et al+, 17, 18 Multicenter, retrospective analysis COVID-19 positive patients admitted between March and August 2020 (N=1053) | Absolute bradycardia (HR < 60 bpm) Profound bradycardia (HR < 50 bpm) Episodes occurring on 2 separate measures at least 4 h apart during hospitalization | 28.7% of those receiving remdesivir developed absolute bradycardia Incidence of profound bradycardia in patients receiving remdesivir was not reported | Bradycardia resolved with remdesivir discontinuation in some cases (full analysis is pending) |
| Pallotto et al19 Single-center, retrospective analysis COVID-19 positive patients admitted between September and December 2020 Cases (n=62): full course of remdesivir with no prior history of bradycardia Controls (n=79): did not receive remdesivir | Transient bradycardia: HR < 60 bpm for 2 consecutive measures or < 50 bpm on 1 measure | Transient bradycardia: 46.8% cases vs 27.8% controls; p=0.023 (OR, 2.15, 95% CI 1.05 to 4.4, p=0.036) No symptomatic bradycardia or ECG changes were observed | All patients had received full course of remdesivir treatment No adverse sequelae reported from transient bradycardia |
| Attena et al20 Single-center, prospective, observational study COVID-19 positive patients hospitalized between September and December 2020 Remdesivir treatment (n=100) No remdesivir treatmennt-control group (n=66) | ECG-detected sinus bradycardia Extreme sinus bradycardia: HR < 50 bpm | ECG-detected sinus bradycardia on day 5: 21/100 (21%) remdesivir group vs 2/66 (3%) control group (p=0.001) Extreme sinus bradycardia: 4/21 (19%) of patients with bradycardia who received remdesivir Female sex, low resting HR, and high baseline D-dimer were associated with incident sinus bradycardia | Sinus bradycardia was reversed upon remdesivir discontinuation in all cases No interventions were required for bradycardia, specifically |
| Touafchia et al21 Retrospective comparative study using Vigibase reports of patients with COVID-19 up to September 23, 2020 Remdesivir ADR reports (n=2603) Hydroxychloroquine, lopinavir/ritonavir, tocilizumab, or glucocorticoids ADR reports (n=3971) | Cases: reports containing terms ‘bradycardia’ or ‘sinus bradycardia’ found in MedDRA dictionary Non-cases: any other adverse events | Cases/non-cases: 94/2509 (3.7%) remdesivir vs. 88/3883 (2.3%) other treatments; ROR 1.65 (1.23 to 2.22) ** Of the 94 cases, 75 (80%) were serious and 16 (17%) were fatal Median onset of bradycardia: 2.4 days (range 1 to 6) | Specific interventions for bradycardia not described |
| *clinical symptoms= syncope or presyncope, transient dizziness or light-headedness, heart failure, or confusion; **ROR=exposure odds among reported cases of bradycardia over the exposure odds among reported non-cases; + original analysis18 evaluated occurrence of bradycardia in all COVID-19 patients and results presented here were in response to a comment to the authors on remdesivir.17 Abbreviations: ADR, adverse drug reaction; bpm, beats per minute; CI, confidence interval; CV, cardiovascular; ECG, electrocardiogram; HR, heart rate; HTN, hypertension; OR, odds ratio; ROR, reporting odds ratio. |
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COVID-19 and Cardiac Effects
Cardiac effects, including viral myocarditis, heart failure, cardiomyopathy, myocardial infarction, thromboembolism, and arrhythmias (including bradycardia), as a complication of COVID-19 have been described.18, 22-26 Entry of SARS-CoV-2 into cardiomyocytes and inflammation causing a prothrombotic state are some proposed mechanisms leading to these cardiac effects.22,24 In a meta-analysis on cardiac manifestations in COVID-19 illness, the incidence of acute cardiac injury was found to be 15%.22 In other observational studies, 8% to 17% of patients had arrhythmia-related events including atrial fibrillation (21%), sinus bradycardia (8%), and heart block (8%).18 In pediatric patients, cardiac manifestations have included cardiogenic shock, electrocardiogram (ECG) changes, and myocardial infarction.23
Kumar and colleagues studied the incidence of bradycardia in 1053 patients hospitalized for COVID-19 between March and August of 2020.18 Absolute bradycardia (HR < 60 bpm) and profound bradycardia (HR < 50 bpm) with episodes occurring on 2 separate measures at least 4 hours apart during hospitalization were the primary outcomes. Approximately 25% (n=262 patients) had absolute bradycardia and 13% (n=137) had profound bradycardia. Mortality rate was significantly higher in patients who had profound vs. absolute bradycardia (25.5% vs. 17.7%, p<0.01). Patients with HR 60 bpm.
A report by Bhasin and colleagues describes a case of complete heart block in a patient with myocarditis due to COVID-19.25 The patient received treatment for COVID-19 with remdesivir with no worsening of cardiac consequences.
Conclusion
Remdesivir’s active metabolite, a nucleoside triphosphate, is an inhibitor of the SARS-CoV-2 polymerase involved in viral replication.1,5 One suggested mechanism for its effect on HR is the metabolite’s resemblance to adenosine 5′ triphosphate (ATP) which suppresses the sinoatrial and atrioventricular node activity and increases vagal tone.5,16 Another postulation is the reduction in HR observed with treatment of COVID-19 may be an indicator of response to therapy.16
Current literature describing the occurrence of bradycardia with remdesivir treatment includes published case reports, ADR database reporting, small prospective, observational, and retrospective studies. Based on the data currently available, the association between bradycardia and remdesivir remains inconclusive as some cases have reported transient bradycardia and resolution with continuation of remdesivir treatment as well as successful use of remdesivir in a patient with heart block. Clinicians should obtain baseline HR and an ECG in patients with COVID-19.27 If remdesivir treatment is initiated, close attention should be given to daily HR measures during the course of treatment. Management of bradycardia, should it occur, depends on patient symptoms and comorbid conditions. Remdesivir should be considered a potential cause and, if suspected, management (based on available literature) can include continued monitoring, discontinuation of remdesivir, and treatment for persistent/symptomatic bradycardia with dopamine and atropine (as needed). Given the cardiac effects of COVID-19, cardiac monitoring with or without remdesivir treatment may be warranted.22,27
References
- Veklury [package insert]. Gilead Sciences, Inc.; 2021.
- Frequently asked questions for Veklury (remdesivir). US Food and Drug Administration. Updated February 4, 2021. Accessed September 29, 2021. https://www.fda.gov/media/137574/download.
- Ching PR, Lee C. Remdesivir-associated bradycardia. BMJ Case Rep. 2021;14(9):e245289. doi: 10.1136/bcr-2021-245289
- 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
- Jacinto JP, Patel M, Goh J, Yamamura K. Remdesivir-induced symptomatic bradycardia in the treatment of COVID-19 disease. HeartRhythm Case Rep. 2021;7(8):514-517. doi: 10.1016/j.hrcr.2021.05.004.
- Selvaraj V, Bavishi C, Patel S, Dapaah-Afriyie K. Complete heart block associated with remdesivir in COVID-19: a case report. Eur Heart J Case Rep. 2021 Jul 1;5(7):ytab200. doi: 10.1093/ehjcr/ytab200
- 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 Jun 26:piab029. doi: 10.1093/jpids/piab029.
- 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
- Day LB, Abdel-Qadir H, Fralick M. Bradycardia associated with remdesivir therapy for COVID-19 in a 59-year-old man. CMAJ. 2021;193(17):E612-E615. doi: 10.1503/cmaj.210300.
- Barkas F, Styla CP, Bechlioulis A, Milionis H, Liberopoulos E. Sinus Bradycardia Associated with Remdesivir Treatment in COVID-19: A Case Report and Literature Review. J Cardiovasc Dev Dis. 2021;8(2):18. doi: 10.3390/jcdd8020018.
- Abdelmajid A, Osman W, Musa H, et al. Remdesivir therapy causing bradycardia in COVID-19 patients: Two case reports. IDCases. 2021;26:e01254. doi: 10.1016/j.idcr.2021.e01254.
- Gubitosa JC, Kakar P, Gerula C, et al. Marked Sinus Bradycardia Associated With Remdesivir in COVID-19: A Case and Literature Review. JACC Case Rep. 2020;2(14):2260-2264. doi: 10.1016/j.jaccas.2020.08.02
- Gupta AK, Parker BM, Priyadarshi V, Parker J. Cardiac Adverse Events With Remdesivir in COVID-19 Infection. Cureus. 2020;12(10):e11132. doi: 10.7759/cureus.11132.
- Rocca E, Gauffin O, Savage R, Vidlin SH, Grundmark B. Remdesivir in the COVID-19 Pandemic: An Analysis of Spontaneous Reports in VigiBase During 2020. Drug Saf. 2021;44(9):987-998. doi: 10.1007/s40264-021-01091-x
- Singh A, Kamath A. Assessment of adverse events associated with remdesivir use for coronavirus disease 2019 using real-world data. Expert Opin Drug Saf. 2021:1-6. doi: 10.1080/14740338.2021.1962846
- Brunetti ND, Poliseno M, Bottalico IF, et al. Safety and heart rate changes in Covid-19 patients treated with remdesivir. Int J Infect Dis. 2021:S1201-9712(21)00741-4. doi: 10.1016/j.ijid.2021.09.036
- Kumar S, Arcuri C, Chaudhuri S, et al. Remdesivir therapy associated with bradycardia in SARS-CoV2. Clin Cardiol. 2021;44(9):1190-1191. doi: 10.1002/clc.23700
- Kumar S, Arcuri C, Chaudhuri S, et al. A novel study on SARS‐COV‐2 virus associated bradycardia as a predictor of mortality‐retrospective multicenter analysis. Clin Cardiol. 2021;44(6):857‐862. 10.1002/clc.23622
- Pallotto C, Blanc P, Esperti S, et al. Remdesivir treatment and transient bradycardia in patients with coronavirus diseases 2019 (COVID-19). J Infect. 2021;83(2):237-279. doi: 10.1016/j.jinf.2021.05.025.
- Attena E, Albani S, Maraolo AE, et al. Remdesivir-Induced Bradycardia in COVID-19: A Single Center Prospective Study. Circ Arrhythm Electrophysiol. 2021;14(7):e009811. doi: 10.1161/CIRCEP.121.009811.
- Touafchia A, Bagheri H, Carrié D, et al. Serious bradycardia and remdesivir for coronavirus 2019 (COVID-19): a new safety concerns. Clin Microbiol Infect. 2021;27(5):791.e5-8. doi: 10.1016/j.cmi.2021.02.013.
- Azevedo RB, Botelho BG, Hollanda JVG, et al. Covid-19 and the cardiovascular system: a comprehensive review. J Hum Hypertens. 2021;35(1):4-11. doi: 10.1038/s41371-020-0387-4
- Vakhshoori M, Heidarpour M, Shafie D, Taheri M, Rezaei N, Sarrafzadegan N. Acute Cardiac Injury in COVID-19: A Systematic Review and Meta-analysis. Arch Iran Med. 2020;23(11):801-812. doi: 10.34172/aim.2020.107
- Rodriguez-Gonzalez M, Castellano-Martinez A, Cascales-Poyatos HM, Perez-Reviriego AA. Cardiovascular impact of COVID-19 with a focus on children: A systematic review. World J Clin Cases. 2020;8(21):5250-5283. doi: 10.12998/wjcc.v8.i21.5250
- 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 May;180(5):1629-1630. doi: 10.1007/s00431-021-03952-0
- Bhasin V, Carrillo M, Ghosh B, Moin D, Maglione TJ, Kassotis J. Reversible complete heart block in a patient with coronavirus disease 2019. Pacing Clin Electrophysiol. 2021 Jul 21:10.1111/pace.14321. doi: 10.1111/pace.14321
- Prutkin JM, Knight BP, Parikh N. COVID-19: arrhythmias and conduction system disease. In: Post TW, ed. UpToDate. UpToDate; 2021. Accessed September 30, 2021. https://www-uptodate-com.proxy.cc.uic.edu/contents/covid-19-arrhythmias-and-conduction-system-disease?search=covid%2019%20bradycardia&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1
Prepared by:
Rita Soni, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy
October 2021
The information presented is current as of September 22, 2021. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.