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.