Discussion
One of the most commonly used treatment is HCQ
in COVID-19 patients in all over
the world2. In this study, we evaluated the effect of
HCQ on QTc prolongation in patients with COVID-19. Critical QTc
prolongation was detected in 12% of the population which is similar
with two recent studies(Ramireddy et al., 2020; Saleh et al., 2020).
However, in another one, critical QTc prolongation was reported as
20%(Mercuro et al., 2020).
The HCQ treatment for autoimmune disorders is cited to be safe inin vitro and small non-randomized trials(Tang, Godfrey, Stawell
& Nikpour, 2012). However, the populations of these studies do not
represent the COVID-19 patients because of the differences in clinical
aspects, dynamics and severity of the diseases(Mercuro et al., 2020).
Myocarditis, that has potential to enhance QTc interval, was reported in
4.8% of the cases in the course of COVID-19(Aktoz et al., 2020)
For understanding the adverse events of HCQ, there is not an established
threshold for blood or plasma. During clinical practice, monitoring HCQ
cardiotoxicity by QTc seems practical. As the nature of COVID-19
disease, the concurrent treatments such as AZT, possible underlying
cardiac disorders and electrolyte imbalances have potential to affect
the QTc interval and related TdP and sudden cardiac arrest.
AZT has potential to prolong QTc and is an additional risk factor for
ventricular arrhythmias(Hancox, Hasnain, Vieweg, Crouse & Baranchuk,
2013). The risk of QTc prolongation in patients who use HCQ and AZT
combination was reported to be higher than HCQ mono-theraphy(Mercuro et
al., 2020), however in some other studies there was no significant
increased risk as we detected in our study (Table 1)(Rosenberg et al.,
2020; Saleh et al., 2020).
The patients with DM had significantly higher rates of critical QTc
prolongation in univariate and multivariate analysis (OR:5.8, %95
Cl:1.11-30.32, p=0.037. Table 2) although the baseline QTc levels were
similar (p=0.4). Even the pre-diabetic and newly diagnosed DM patients
are under risk of cardiac autonomic neuropathy (CAN), the diabetic
patients who has poorly controlled blood glucose levels and long-lasting
disease time, are at higher risk(Spallone et al., 2011; Ziegler et al.,
2015). Likewise, tachycardia, orthostatic hypotension, reverse dipping,
and impaired heart rate variability, QTc prolongation is also shown to
be one of the non-invasive methods to display the existence of
(CAN)(Gonin, Kadrofske, Schmaltz, Bastyr & Vinik, 1990; Spallone et
al., 2011; Ziegler et al., 2015). Even if the baseline QTc levels are
normal, medications may easily influence the QTc interval in patients
with DM because of this underlying/hidden autonomic neuropathy. Further
randomized and high-volumed studies are needed to solve this
association.
Oseltamivir which is an antiviral against influenza virus was used in
early dates of the pandemic because of the possibility of influenza
co-infection. In our study, it was used in more than 30% of the
patients (21 out of 66 patients) and in multivariate analysis,
oseltamivir use was found to cause critical QTc prolongation more than 5
times. In a Cochrane systematic review, it was stated that oseltamivir
may cause QTc prolongation(Jefferson et al., 2014). In a two cases
series, QTc prolongation was reported in patients who used oseltamivir
in addition to sotalol which is both an anti-arrhythmic and
pro-arrhythmic drug. However, there is no human study that demonstrates
whether oseltamivir causes QTc prolongation and prospective
well-designed studies are required. Female gender has been accepted as
an underlying risk factor which result in repolarization reserve
reduction(Drici & Clement, 2001; Tisdale et al., 2013), but in our
study the critical QTc prolongation occurred solely in men.