Cardiac Conduction Delay Associated With Remdesivir in COVID-19

A 22-year-old male presented to the emergency department for evaluation of progressive shortness of breath and decreased appetite. His medical history included obesity (body mass index 39) and a diagnosis of COVID-19 pneumonia seven days prior to admission using nasopharyngeal PCR. He was hemodynamically stable, breathing at 21–36 breaths per minute and oxygen saturation was 86% on room air.

Laboratory workup on admission was significant for elevated hemoglobin (17.4 g/dL), D-Dimer (782 ng/mL), sodium (133 mmol/L), alanine aminotransferase (89 U/L) and Ferritin (447 mcg/L). CT scan of the chest demonstrated bilateral patchy ground glass opacities throughout both lungs consistent with COVID-19 infection. An electrocardiogram (ECG) performed on admission showed normal sinus rhythm with a ventricular rate of 98 beats per minute and a PR interval of 172 milliseconds (Figure 1).

Remdesivir was initiated with a loading dose of 200 mg followed by infusions of 100 mg/day for five days. Additionally, oral dexamethasone was started at a dose of 6 mg daily. Other medications administered during hospitalization included acetaminophen 1,000 mg, IV ketorolac, and subcutaneous enoxaparin for deep vein thrombosis prophylaxis. His dyspnea improved over the first two days of hospitalization and supplemental oxygen was titrated down to room air.

On hospital day four, he developed asymptomatic bradycardia to as low as 38 beats per minute within five minutes of completing his fourth dose of remdesivir. This bradycardia persisted for 11.5 hours before resolving and during this time, an ECG (Figure 2) was performed. The ECG performed 2.5 hours after onset of bradycardia demonstrated sinus bradycardia with first-degree atrioventricular (AV) block and a PR interval of 212 milliseconds. A subsequent ECG performed at 1,000 the next morning showed interval resolution of previously noted bradycardia and first-degree AV block.

The differentials for transient AV block were drug effect, electrolyte abnormalities, subclinical, undiagnosed sleep apnea, COVID-19 myocarditis and nocturnal parasympathetic response. Serum electrolytes including potassium and magnesium levels were within normal range. The conduction abnormality’s transient nature and temporal association with remdesivir infusion argued against myocarditis. Nocturnal parasympathetic response is less likely because the effects began well before sleep and did not resolve when awoken for ECG. He was subsequently discharged to home on the next day without receiving his originally scheduled fifth dose of remdesivir. Subsequently, a follow-up ECG was performed one month after discharge that showed normal sinus rhythm, PR interval 188 milliseconds.

Remdesivir is a prodrug of GS-441524, a nucleoside metabolite with an intermediate metabolite GS-704277. GS-441524 undergoes intracellular conversion into the pharmacologically active triphosphate form, GS-443902 which inhibits viral RNA polymerases.^4,5  The most common side effects of this medication are nausea and transaminase elevation. Cardiac events noted in randomized controlled trials involving remdesivir use in Ebola and COVID-19 have included hypotension, atrial fibrillation and rarely cardiac arrest.^6,7  The median serum t1/2 of GS-441524 is 24–27 hours, while remdesivir median t1/2 is one hour and GS-704277 t1/2 is 1.5–1.8 hours.⁸ 

We hypothesize that bioaccumulation of the metabolite GS-441524, which is similar in chemical structure to adenosine results in transient cardiac conduction delays in patients being treated for COVID-19.^5,9  It is likely that the cardiac conduction delay noted in our patient was related to the bioaccumulation of the GS-441524 metabolite, which is under-recognized partially as a result of attribution to COVID-19 myocarditis. The Naranjo scale was used to assess the probability of remdesivir being the causative agent, scoring 7/13 (Figure 3) which indicates probable association.¹¹ 

In this case, transient AV block did not have significant clinical effect, however other recent case reports have described cardiac conduction abnormalities with significant clinical effects including complete AV block, QT prolongation > 550 ms, and symptomatic bradycardia requiring atropine.^10,12,13  This case report demonstrates the spectrum of potential side effects that can affect patients without predisposing factors such as renal dysfunction or baseline cardiovascular disease. We propose clinicians consider either telemetry monitoring or daily ECGs among patients being administered remdesivir.