Bradycardia associated with remdesivir therapy for COVID-19 in a 59-year-old man

Discussion

Remdesivir was approved through an emergency use authorization by the United States Federal Drug Administration (FDA) for the treatment of patients with COVID-19 requiring admission to hospital.2 Health Canada approved remdesivir for patients in hospital with severe COVID-19 with pneumonia requiring supplemental oxygen.3

The 2 largest randomized controlled trials (RCTs) evaluating the efficacy and safety of remdesivir are the Adaptive COVID-19 Treatment Trial (ACTT-1) and the World Health Organization Solidarity Trial.1^,4 ACTT-1 showed that patients randomized to remdesivir (n = 541) recovered faster than patients randomized to placebo (i.e., 15 d v. 10 d, p < 0.001).4 Solidarity demonstrated that patients randomized to remdesivir (n = 2750) had a mortality rate similar to those randomized to standard of care.1 Despite no evidence of a reduction in mortality in the Solidarity trial, remdesivir is one of the most commonly prescribed medications for people admitted to hospital with COVID-19. It is estimated that more than 2 million doses of remdesivir have been administered worldwide during the COVID-19 pandemic.6

Remdesivir is an intravenous prodrug of an adenosine analogue originally developed in research programs in hepatitis C and respiratory syncytial virus and later refined for the treatment of Ebola. It inhibits viral ribonucleic acid (RNA) polymerase and is active against a broad range of viruses, including the Middle East respiratory syndrome coronavirus, SARS and SARS-CoV-2.4 It is generally well tolerated although transaminitis, which primarily manifests as an elevated ALT, is a common adverse effect seen in both patients and healthy volunteers receiving remdesivir.2

Recent case reports suggest that remdesivir may also cause bradycardia. 5^,7^,8 Our patient had both an elevated ALT and sinus bradycardia. Although there were no adverse clinical sequelae of the latter, if remdesivir does cause bradycardia, it will be particularly relevant for patients who are admitted to hospital with COVID-19 and have other risk factors for bradycardia (e.g., older age, concomitant β-blocker use). Our discussion will focus primarily on the potential association between remdesivir and bradycardia and briefly summarize the efficacy and safety data for remdesivir.

Common adverse events for remdesivir (1%–10% incidence) include rash, headache, nausea, diarrhea, and moderate to severely elevated transaminases.2^,4 Rarely, hypersensitivity reactions (infusion related and anaphylaxis), hypotension and renal impairment may also occur (< 0.1% incidence). In ACTT-1, arrhythmias (other than ventricular fibrillation and tachycardia, supraventricular tachycardias and atrial fibrillation) affected 0.2% of patients receiving remdesivir, compared with no reported events in the placebo group. Data specifically on bradycardia were not reported.

Other potential cardiac complications described with remdesivir include supraventricular tachycardia, which was reported in 0.6% of patients in the ACTT-1 experimental group (compared with 0.4% in the control group) and serious atrial fibrillation in 0.9% of patients in the experimental group (compared with 0.2% in the control group). There was also 1 case of cardiac arrest during remdesivir therapy in 0.6% of patients in 1 RCT of remdesivir versus placebo (compared with no events in the control group).7 ACTT-1 reported cardiac arrests in 1.9% of patients receiving remdesivir compared with 1.4% receiving placebo. Additionally, in the initial clinical trial evaluating remdesivir for the treatment of Ebola, 1 patient out of 175 had hypotension leading to cardiac arrest after remdesivir, which was deemed potentially related to the drug.7

Although neither ACTT-1 nor Solidarity identified bradycardia as a potential adverse effect, clinical trials are generally underpowered to detect uncommon adverse events.9 Recent case reports have described 4 cases of sinus bradycardia in patients with COVID-19 who received remdesivir (Table 1).5^,7^,8 Gubitosa and colleagues described a case of a 54-year-old woman with a baseline left bundle branch block of unknown cause, who developed marked sinus bradycardia to 38 beats/min within 24 hours after her first dose of remdesivir for COVID-19, along with mild widening of the QRS and lengthening of her QT interval (QTc 496 ms from 440 ms). Her bradycardia worsened to a nadir of 34 beats/min after her third dose and she required atropine temporarily for angina and hypotension.7 Sanchez-Codez and colleagues described a case of severe sinus bradycardia (heart rate 40 beats/min) in an otherwise healthy 13-year-old boy after he received his third dose of remdesivir.5 The bradycardia resolved within 24 hours of discontinuing remdesivir. Transient sinus bradycardia associated with QT prolongation (QTc 439 ms to 555 ms) was also reported in a 26-year-old woman with a past medical history of obesity, who was receiving remdesivir for treatment of COVID-19. A 77-year-old woman had similar transient bradycardia after administration of remdesivir.8 Additionally, the FDA reported 9 cases of bradycardia with remdesivir use for COVID-19 between January and June 2020, which were not in the context of an infusion reaction.10

There are several possible mechanisms for cardiac adverse effects with remdesivir. First, an active metabolite of remdesivir is similar to adenosine triphosphate, which has been shown to reduce sinus node automaticity through vagal stimulation, which could cause sinus bradycardia.11 Although remdesivir has a markedly high binding affinity for viral polymerases, any cross-reactivity with human mitochondrial RNA polymerase could lead to mitochondrial dysfunction, which is an established mechanism for drug-induced cardiotoxicity.5^,8 Drug-induced cardiac myocyte cytotoxicity has been shown in in-vitro studies of cardiomyocytes derived from human stem cells treated with remdesivir.12 Choi and colleagues showed that the cytotoxic effects of remdesivir on cardiomyocytes increased over time, such that a longer duration of treatment (48 v. 24 h) was associated with reduced cell viability.12 Additionally, as an adenosine analogue, remdesivir could affect atrioventricular nodal conduction, which could explain the QRS prolongation seen in previous cases.5^,7^,8 Further studies to evaluate these mechanisms and their effect specifically on sinoatrial node activity are needed.

In our patient, the bradycardia occurred soon after starting the medication (Figure 3) and improved within 48 hours of discontinuing it. He was on no other medications that would otherwise account for the bradyarrhythmia seen and there were no clinical features suggestive of heightened vagal tone. Although case reports cannot establish causality, this time course raises suspicion that remdesivir was a causative factor. Additionally, although bradycardia has been reported among patients with severe COVID-19, our patient did not present with bradycardia, and the bradycardia occurred after starting remdesivir when he was improving clinically.7^,10 Furthermore, our patient had a score of 6 on the Naranjo Adverse Drug Reaction Probability Scale, a score that suggests a probable causative association between remdesivir and the bradycardia.13 We did not re-trial the medication because the patient was well enough to be discharged home.