Discussion
In this retrospective cohort study, the researchers compared the arrhythmogenic adverse effects of favipiravir and HQ in COVID-19 patients. The key findings of this cohort were (1) the favipiravir group’s arrhythmic events were numerically superior to the HQ group; however, there was no statistically significant difference between them, (2) favipiravir revealed arrhythmic events, the majority of which were sinus bradycardia, (3) both favipiravir and HQ groups had an increase in the QTc interval; nevertheless, no significant difference occurred among the groups.
The arrhythmogenic adverse effects of HQ have been reported in several previous studies [19–22]. These studies remarkably emphasize QT prolongation and its consequence, TdP. Chorin et al. documented that QTc interval prolonged >500 ms in 23% of patients treated with HQ [21]. Furthermore, previous studies recommended that QT-prolonging agents not be used in individuals with a QTc >500 ms due to increased risk for TdP [23,24]. Four of 93 (4.3%) HQs’ patients had a QT prolongation >500 ms in this cohort. Jankelson et al. reviewed that HQ lengthened QTc up to 35 ms on day 3, and the combination of azithromycin and HQ prolonged the QTc by an average of 5 ms in addition to HQ alone [22]. This study calculated a median of 12 ms of QTc prolongation between the terminal and initial ECG in the HQ group on day 7±3 (p<0.001). A previous case reported a prolonged QT interval, resulting in TdP in lupus erythematosus patient treated with HQ [25]. Likewise, another research of 90 COVID-19 inpatients revealed that the QT prolongation incidence was 20%, besides a case of TdP was recorded in a patient treated with HQ and azithromycin [7]. Other published rare arrhythmic events of HQ were as following: nonsustained and sustained monomorphic ventricular tachycardia, atrial fibrillation, sinus bradycardia, first degree AV block, left bundle branch block, widened QRS complex, and sudden death [9,19,22]. The present study found that 9 of 93 (9.7%) patients treated with the HQ prolonged the QTc interval on day 4.2±1.7 of therapy. None of those induced TdP. The QTc prolongation was the most frequent arrhythmogenic adverse effect of the HQ in this study, consistent with previous studies. We also discovered sinus bradycardia (n=3), first-degree AV block (n=1), third-degree AV block (n=1) and nonsustained monomorphic ventricular tachycardia (n=2) in the HQ group.
Contrary to the findings of previously published research of favipiravir [14,26], we found a high rate of arrhythmic events in the subjects treated with favipiravir. Twenty patients (19.8%) prescribed with favipiravir had an arrhythmogenic adverse effect. Arrhythmic events included thirteen patients (65%) with sinus bradycardia, four patients (20%) with complete AV block, three patients (15%) with prolonged QTc, and one patient (5%) with first-degree AV block in the favipiravir group. A recent study computed that favipiravir yielded high-risk parameters regarding QT prolongation [27]. Chinello et al. reported that an Ebola virus-infected patients’ QT interval had prolonged 98 ms on day seven of favipiravir therapy [28]. In this cohort, among the favipiravir-treated patients, 3 of 101(3%) patients had a QT prolongation. Additionally, the QTc interval of patients treated with favipiravir increased by a median of 11 ms (p<0.001) on day 6. Since the patients’ QTc interval treated with favipiravir did not exceed 500 ms, the treatment protocol continued.
A review conducted with 93 favipiravir patients reported that sinus tachycardia (9%), QT prolongation (5%), and bradycardia (3%) were the most frequent arrhythmic events. Naksuk et al. reviewed that favipiravir was associated with QT prolongation but was safe for conduction disturbances. In this study, the researchers documented that sinus bradycardia was the most observed arrhythmogenic adverse effect in the favipiravir group. We found a median of 12 and 5 bpm (p<0.001) decreases in post-treatment HR in the favipiravir and HQ groups. Five of the favipiravir patients with sinus bradycardia were symptomatic. An improvement in the heart rate was observed two or three days after the favipiravir withdrawal in these subjects.
Another notable finding indicated that a complete AV block was developed in the four patients using favipiravir. The entirety of these patients had required a temporary pacemaker; consequently, a permanent pacemaker was implanted in one of these. We also found that the favipiravir group’s PR interval extended more than the HQ group’s, although it was not statistically significant (p=0.08). However, they did not develop PR prolongation to the degree that led to drug withdrawal.
According to these findings, the inquiry arises about whether the arrhythmic events are only due to favipiravir and HQ. Tsikouris et al. reported that a 7-day levofloxacin course did not prolonged QT interval [29]. In a controlled clinical trial, moxifloxacin patients had a significant QT prolongation than levofloxacin patients (17.8 vs. 3.5, p<0.001, respectively) [30]. Therefore, the role of levofloxacin in QT prolongation is weak or uncertain. A prospective study manifested a mild but not significant QT interval prolongation on day 7 of azithromycin therapy (406 ms to 412 ms) [31]. A case documented that a QT prolongation leading to TdP developed on day 7 of azithromycin treatment [32]. A retrospective study on 89 cystic fibrosis patients revealed no significant difference in the QT prolongation between patients receiving and not receiving azithromycin [33]. Given these confusing findings, it should keep in mind that azithromycin may extend the QT interval.
The difference in troponin and D-dimer levels between the groups might affect developing arrhythmic events, even though they were under the upper reference limit. Also, fever, inflammation, hypoxia, myocarditis, myocardial ischemia, electrolyte imbalance, and usage of other drugs can trigger arrhythmic events in COVID-19 patients. However, the two groups’ clinical conditions were similar, and critically ill patients were not included in the study. Eventually, after existing drug withdrawal in both groups, the improvement in arrhythmic events suggested that favipiravir and HQ should be the primary culprit.
This study has several limitations. The researchers evaluated the participants’ baseline and final ECGs; however, arrhythmic events could have been followed more closely by daily ECG recordings. Second, as a retrospective study, valuable information such as echocardiography and Holter monitoring were not presented in the study, as data were lacking due to limited conditions associated with isolation. Third, the arrhythmic events may involve multiple causes, and it is not easy to discriminate the favipiravir or HQ as the direct trigger. Further works with a larger group of patients are needed to confirm these study findings.
In conclusion, this research fortifies previous studies regarding the arrhythmic events of HQ. Although the proportion of patients with QT prolongation in the HQ group was significantly higher than that of the favipiravir group, there was no significant difference in ΔQTc. In addition, conduction disorders such as sinus bradycardia and complete AV block, most of which improved with favipiravir withdrawal, were identified. Therefore, patients using favipiravir should be pursued with attention in arrhythmic events, such as HQ.