Remdesivir induced bradycardia and QT prolongation: A rare side effect of a ubiquitous drug of the COVID -19 era

Design

Case presentation

An 80-year-old patient with diabetes, hypertension, and a history of Coronary Artery Bypass Grafting (CABG) ten years ago was admitted to the COVID ICU due to a three-day history of fever, shortness of breath, and cough. The patient's regular medications included aspirin, ramipril, atorvastatin, sitagliptin, and metformin. There was no prior use of steroids or antibiotics before hospital admission.

The patient had a heart rate of 70-75 beats/min, blood pressure of 140/70 mm Hg, and oxygen saturation (SpO2) of 94% with nasal oxygen at 4 lt/min. The ECG revealed a QT interval of 400 msec and a right bundle branch block. He received intravenous dexamethasone 6 mg and remdesivir 200 mg on day 1, followed by 100 mg for the next 4 days. Following the third dose of remdesivir, the patient experienced asymptomatic bradycardia (heart rate = 48/min) and QT interval prolongation (QTc 486 msec).

Remdesivir was deemed the likely cause of QTc prolongation, leading to its discontinuation. Viral myocarditis was considered in the differential diagnosis, but normal cardiac enzymes and an echocardiogram ruled it out. The underlying cardiac condition might have contributed to the observed phenomenon. Two days post-drug cessation, the QTc interval returned to baseline (QTc 420 msec).

Study Author Conclusions

Bradycardia with remdesivir has been reported, where the authors opined that the safety of remdesivir was dependent on the affinity of its active form for viral RNA polymerase compared to human mitochondrial RNA polymerase (h-mtRNAP). Remdesivir’s affinity for viral polymerases is >500 times than that of h-mtRNAP. Although this affinity for viral RNA polymerase is considerable, possibility of cross-reaction with h-mtRNAP and subsequent mitochondrial dysfunction causing cardiotoxicity is still tenable.

Further, endogenous nucleoside, Adenosine has intrinsic electrophysiological effects on the myocardium, being used in the treatment of supraventricular tachycardias. Since remdesivir is also a nucleoside analog that resembles adenosine triphosphate, its effects on the AV node warrant further investigation.

A case report on the association between QTc prolongation and remdesivir therapy in a critically ill patient

Design

Case presentation

An 80-year-old Saudi woman came to the Emergency Department (ED) experiencing difficulty breathing and cough. She has multiple medical conditions, including obesity, diabetes, dyslipidemia, hypertension, history of ischemic heart disease with a coronary intervention in 2014, chronic kidney disease (CKD), past stroke, asthma, hypothyroidism, and osteoarthritis. On initial assessment, she showed hypoxia, with vital signs: temperature 36.4 °C, heart rate 102 BPM, blood pressure 106/58 mmHg, and respiratory rate 31 breaths/min.

Upon hospitalization, a chest X-ray revealed bilateral peripheral patchy opacities with costo-phrenic angle blunting. The ECG indicated atrial fibrillation with QT/QTc intervals of 352/454 msec. Echocardiogram findings included ejection fraction >55%, moderate tricuspid valve regurgitation, right ventricular systolic pressure >60 mmHg, and moderate atherosclerotic plaque in the aortic arch. A positive SARS-CoV-2 PCR test was confirmed via nasal swab. 

Admitted to the ICU, she received non-invasive ventilation and high-flow nasal oxygen to maintain saturation over 92%. Treatment included anti-hyperkalemic agents, IV furosemide, azithromycin, meropenem, dexamethasone, and tocilizumab. Intravenous heparin was administered for newly diagnosed atrial fibrillation. Due to persistent oxygen needs and worsening chest X-ray findings, remdesivir was given for five days. Palpitations and dizziness occurred two days after starting remdesivir, with QTc prolongation on ECG (504/532 msec). Continuous monitoring showed no worsening, and after the course, QTc decreased to 429 msec. The patient improved and was discharged in good condition.

Study Author Conclusions

We describe a case of QT interval prolongation following the initiation of remdesivir therapy that reversed after finishing the treatment course. Continuous monitoring may be needed especially in high-risk patients. This possible adverse effect needs further evaluation in randomized controlled trials or observational cohort studies.

Torsades de pointes associated with remdesivir treatment for COVID-19 pneumonia

Design

Case presentation

A 55-year-old woman, diagnosed with stage III follicular lymphoma, arrived at a rural emergency department 11 days after a positive SARS-CoV-2 test. She experienced dyspnea and cough. She completed six cycles of bendamustine and rituximab for lymphoma, with quarterly rituximab infusions, the last one administered around 2 months ago. She also takes acyclovir for herpes zoster prophylaxis.

In the emergency department, vital signs showed a heart rate of 87 bpm, blood pressure of 132/74 mmHg, room air oxygen saturation of 80%, and a fever of 40°C. High-flow nasal cannula (HFNC) therapy was initiated for oxygenation support. A positive SARS-CoV-2 PCR test confirmed COVID-19 pneumonia, leading to hospital admission. The next day, the patient began dexamethasone and remdesivir. Empiric ceftriaxone was started for potential bacterial infection. An initial electrocardiogram (ECG) revealed a slightly prolonged QTc interval of 483 ms, with no prior ECGs available for comparison.

On the third day of admission, the patient experienced a sudden episode of non-sustained ventricular tachycardia. Amiodarone infusion was promptly initiated empirically. An immediate 12-lead ECG revealed a markedly prolonged QTc of 609 ms. A repeat ECG four hours later showed the QTc returning to the admission baseline of 480 ms with normal sinus rhythm. The next morning, the patient experienced a witnessed polymorphic ventricular tachycardic cardiac arrest. Return of spontaneous circulation occurred after 4 minutes of standard cardiac arrest management, including intravenous magnesium sulfate (2 g) and calcium gluconate (1 g). The rhythm spontaneously converted before defibrillation, and the cause was attributed to torsades de pointes (TdP). The patient regained consciousness post-cardiac arrest. Telemetry indicated sinus bradycardia with a markedly prolonged QTc of 613 ms. Amiodarone infusion was discontinued due to its association with prolonged QTc. The patient was transferred to the tertiary care center for further management.

Upon arrival, the patient's ECG showed sinus bradycardia with a prolonged QTc of 621 ms. Electrolytes were mostly normal, except for elevated magnesium. A pharmacological profile review identified only amiodarone as a QT-prolonging drug. The patient had two spontaneous TdP episodes, likely linked to a prolonged QT interval from remdesivir and exacerbated by amiodarone. Cardiology initiated isoproterenol infusion, and remdesivir was stopped after three doses.

The patient received a 48-hour isoproterenol infusion, leading to gradual QTc interval normalization. After discontinuation, her intrinsic rhythm stabilized at 70-80 bpm, and the QTc interval returned to baseline. Oxygenation needs for COVID-19 pneumonia decreased, prompting transfer to the medical ward for dexamethasone completion and convalescence. A follow-up ECG after 4 weeks showed a normalized QTc interval of 450 ms.

Study Author Conclusions

There is a risk for cardiac events from QTc prolongation effects of SARS-CoV-2 infection and associated treatment. We recommend pharmacological profile review and cardiac monitoring for patients receiving remdesivir.

Cardiac Adverse Events With Remdesivir in COVID-19 Infection

Design

Case 1

A 26-year-old African American woman presented with a one-week history of cough, chills, nausea, decreased appetite, loose stools, and dry cough. Initial evaluation revealed a temperature of 100.3 °F, heart rate of 83, and blood pressure of 120/68 mmHg. A non-rebreather facemask was used to maintain saturations over 94%. The nasal polymerase chain reaction was positive for SARS-CoV-2. Chest CT showed extensive bilateral consolidative changes. Multimodal therapy included ceftriaxone, azithromycin, methylprednisolone, convalescent plasma, and remdesivir.

At baseline, she had a normal sinus rhythm (80-100 bpm) and a QTc interval of 439 ms, with no EKG abnormalities. After the third dose of remdesivir, she developed sinus bradycardia (40-50 bpm), prolonged QTc (555 ms), and T-wave abnormality. Remdesivir was stopped, and within three days, her heart rate returned to baseline, and the QT interval stabilized at 448 ms.

Case 2

A 77-year-old Caucasian woman presented with weakness, headache, and loose stools for a week. She had a fever (100.1 °F), blood pressure of 115/60 mmHg, and a heart rate of 67 bpm. Chest x-ray revealed atypical infiltrates, and a positive nasal PCR confirmed coronavirus. Treatment included ceftriaxone, azithromycin, methylprednisolone, and remdesivir. On day three of remdesivir, the patient experienced sinus bradycardia (heart rate dropping from 80 bpm to 48 bpm), leading to discontinuation. Subsequently, her heart rate returned to baseline.

Study Author Conclusions

Some SARS-CoV-2 patients on remdesivir develop sinus bradycardia and a prolonged QT interval. Appropriate caution and continuous EKG monitoring should be utilized in all patients participating in ongoing trials for COVID-19 as the safety of remdesivir remains largely uncertain. Even closer surveillance for patients with pre-existing heart disease is warranted when using remdesivir. There remains the need for more high-quality evidence from randomized controlled trials presently underway. Attention to additive cardiovascular adverse effects from other drug classes remains crucial to ensure positive patient outcomes and to minimize the risk of potential fatal arrhythmias or cardiac arrest.