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.