Accepted on 04 Jun 2021
Submitted on 18 May 2021
Remdesivir is a nucleoside analog used against several RNA-dependent RNA polymerase viruses, affecting their replication and resulting in the early termination of the viral cycle, and it has shown a positive impact in clinical improvement of patients with COVID-19 [1, 2]. There is clear evidence of the broad-spectrum antiviral activity of remdesivir via mediation of RNA synthesis inhibition in coronaviruses [3]. However, this medication has been associated with cardiac arrhythmias and events after its administration [4, 5].
The mechanism of the adverse cardiac effects of this drug is not clearly understood, but there is a hypothesis positing that the cumulative dose effects could lead to toxicity, conduction defects, ECG abnormalities (prolongation of QTc, ventricular arrhythmia, cardiac arrest), and cardiomyopathy [6].
Remdesivir is a potential therapeutic measure in present and future viral infections. Recently, we faced one of the worst pandemics in history, and possible recurrent waves could be expected, which is why we performed this retrospective study to establish the relationship of remdesivir with cardiac arrhythmias.
To establish the relationship of remdesivir with cardiac arrhythmias in COVID-19, as well as to determine its relationship with cardiac arrest in COVID-19.
This is a descriptive retrospective study establishing the relationship of remdesivir with cardiac arrhythmias and also determining the relationship between remdesivir and cardiac arrest. The data were collected retrospectively for patients in the period from May to November 2020. The process of the collection was based on a questionnaire inspired by our variables. The literature review was based on the analysis of 20 original studies published in prominent medical journals regarding remdesivir side effects and remdesivir treatment options for COVID-19 infection.
The variables studied and evaluated in this study are age (18–44, 45–65, >65), sex (male, female), days of remdesivir infusion (1–2, 3–5, >5 days), BMI (<29.9, >30), cardiovascular (CV) and metabolic factors (hypertension (HTN), dyslipidemia (DLP), cardiovascular accident (CVA), peripheral vascular disease, congestive heart failure, endocarditis, diabetes mellitus (DM), thyroid pathology, previous CV procedures), history of arrhythmia (atrial, ventricular, none), familial CV history (prolonged QTc, sudden death, congenital cardiomyopathy, arrhythmia, Brugada, myocardial infarction (MI), congestive heart failure, coronary artery disease (CAD)), ECG findings on admission (atrial fibrillation (Afib), block grade 1, block grade 2, block grade 3, evidence of MI (previous), evidence of acute MI (AMI), complete right bundle branch block (CRBBB), complete left bundle branch block (CLBBB), ventricular fibrillation or ventricular tachycardia, torsade, Afib or atrial flutter (Aflut), fascicular block, pericarditis, left ventricular hypertrophy (LVH), electrocardiogram (ECG) events during hospitalization (Afib (uncontrolled), multifocal atrial tachycardia (MAT), supraventricular tachycardia, ventricular fibrillation, ventricular tachycardia, other), cardiac events (cardiac arrest, respiratory arrest, none), and death during admission (yes, no).
During the questionnaire analysis, the supervisors of the study reviewed each questionnaire and compared it with our electronic medical record system, verifying the correct collection of the data. A total of 43 records were reviewed. Our analysis was verified by chi2, p = 0.04.
Adult patients who received remdesivir for COVID-19 in the established period.
A total of 43 patients (pts) were studied, of whom we excluded six because they did not complete the first dose of the medication studied. Our analysis of 37 pts was composed of 19 males and 18 females, and the predominant age group was 65 years old (yo) or older, with 56.76% (21 pts), followed by 45–65 yo, with 29.73% (11), and then 18–45 yo, representing 13.51% (5) (Table 1). The Hispanic population was the biggest, with 91.9% (34 pts), followed by the African American (AA) population, with 2.7% (1), and then others, with 5.40% (2).
Table 1
Age Groups.
| AGE | PATIENTS |
|---|---|
| > 65 | 21 |
| 45–65 | 11 |
| 18–45 | 5 |
The most common CV factor present in our patients was HTN, with 72.97% (27 pts), followed by DM, with 48.65% (18); obesity, with 40.54% (15); DLP, with 32.43% (12); and others (Table 2).
Table 2
Cardiovascular Risk Factors.
| CV RISK | PATIENTS (N = 37) |
|---|---|
| HTN | 27 |
| DM | 18 |
| Obesity | 15 |
| DLP | 12 |
| CKD ≥ 3 | 11 |
| CAD | 2 |
| Other | 2 |
| H. failure | 1 |
| CKD ≤ 2 | 0 |
| ESRD | 0 |
CKD, chronic kidney disease; ESRD, end-stage renal disease.
Electrocardiographic events during hospitalization were not documented in our patients, but a total of 43.24% (16 pts) presented bradycardia after remdesivir administration, and no significant difference between sexes was observed (8 males vs 7 females). Regarding the duration of the infusion in these patients, we observed that patients with 3 days or more, or 75% (12 out of 16 pts), versus less than 3 days, or 25% (4), presented bradycardia (Table 3). Four of the 16 pts with at least 3 days of treatment were noted to have QTc > 450 ms during their admission. A total of 2 pts in this group died, and one required re-hospitalization.
Table 3
Bradycardia After Remdesivir Infusion.
| PATIENTS | BRADYCARDIA | |
|---|---|---|
| >5 days | 6 | 2 |
| 3–5 days | 27 | 10 |
| 1–2 days | 4 | 3 |
| <1 day* | 6 | 0 |
| Total |
|
15 |
* Excluded.
Only 1 pt who presented bradycardia was receiving a beta-blocker, and only 1 pt was receiving sedatives.
Patients without bradycardia had a longer hospitalization (20.5 vs 15.5 days) and higher mortality (5 vs 2 pts). Overall, 18.92% (7 pts) died, and prolonged hospitalization (10–50 days) was noted for 100% of them (10–50 days). All had DM and HTN, 3 pts had thyroid disease, 4 were obese, and 4 had QTc > 450 ms. Only 4 pts were noted to require re-hospitalization (within 90 days) at our center.
Remdesivir’s mechanism is based on the inhibition of viral replication via an adenosine analog that becomes incorporated into the virus and inhibits viral replication by early termination of its cycle [7].
The efficacy of this medical agent is related to its affinity for viral RNA polymerase compared with human mitochondrial RNA polymerase (h-mtRNAP). Based on a literature review of papers on the Ebola pandemic, remdesivir’s affinity for viral polymerases is >500 times that for h-mtRNAP [8]. However, there is an association between its mechanism of action and cardiotoxicity via an increase in mitochondrial oxidative/nitrative stress [9]. Mouse models also showed a reduction in viral load and lung infection after remdesivir was administered [10].
Although the SOLIDARITY trial did not show a difference in mortality with remdesivir, lopinavir or ritonavir hydroxychloroquine, and interferon [11], the administration of remdesivir 200 mg as a loading dose followed by 100 mg daily for the next 10 days showed a clinical improvement in SARS-CoV-2 [12, 13]. The most common side effects of remdesivir that have been identified are increased hepatic enzymes, diarrhea, anemia, rash, renal impairment, and hypotension [14, 15, 16, 17].
Another side effect, which could be missed, is electrocardiographic changes [18], including cardiac arrhythmias, but based on the literature, bradycardia and hypotension are more common than QT prolongation [19, 20, 21, 22]. Marked sinus bradycardia after the initiation of remdesivir and its resolution after stopping the drug have been evident [23] and suggest attention to the CV adverse effects from this and other drug classes to avoid potentially fatal side effects and improve the outcome of our patients [24]. A randomized controlled trial that included 233 patients showed cardiac arrest during remdesivir therapy, which was not noted in the placebo group [25].
Our review exposed the potential cardiac adverse side effects and events that could be a consequence of remdesivir administration, and our analysis showed a tendency toward bradycardia related to the duration of the treatment and not necessarily related to the history of prolonged QTc or the severity of the disease in our patients. However, we have observed the substantial benefit of this therapy in the current pandemic that we are facing from the infectious, pulmonary, and critical care points of view. The benefit versus risk always has to be discussed, and the best benefit to our patients has to be prioritized.
The systemic inflammatory response and the acute state in severe COVID-19 could also predispose patients to cardiac injury, including conduction disease, but in our analysis, bradycardia was evident in the patients who received remdesivir infusion at our medical center despite the severity of their condition.
In conclusion, our results have shown clear evidence of bradycardia after remdesivir infusion. Prospective, double-blinded, and randomized studies with alarger sample size with various ethnicities and races are highly needed earlier rather than later to confirm these important findings.
The additional file for this article can be found as follows:
Supplementary fileSociodemographic Questionnaire for Remdesivir Project. DOI: https://doi.org/10.29024/ijsm.64.s1
The authors have no competing interests to declare.
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