Since December 2019, a novel coronavirus -SARS-CoV-2 -has caused a global pandemic of respiratory illness termed Covid-19. This virus has rapidly shown to be highly contagious and to cause a high number of severe complications. The scientific community has begun a rush to look for possible treatments, given the absence of known therapeutic agents for the disease. Many drugs are being tested, including antivirals (lopinavir/ritonavir, darunavir/cobicistat, remdesevir), chloroquine, hydroxychloroquine (HCQ), antibiotics (azithromycin), immune system modulators (steroids, tocilizumab, colchicine and others) and anticoagulants 1 3, 4 . Many large RCTs are ongoing worldwide and hopefully will soon clarify if HCQ alone or in combination with azithromycin is safe and useful.
Finally, antivirals have shown promising pre-clinical data with mixed results in recent papers 5, 6 .
Due to the lack of effective treatment, even in the absence of convincing evidences all the drugs cited above, are/have been widely used alone or in combination, even outside clinical trials. Limited data on safety are available and concerns about cardiac safety have been raised, mainly regarding the possible risk of Torsade de Pointes (TdP) due to corrected QT interval (QTc) prolongation. Some cardiology societies have therefore published practical guidelines on the argument in order to diminish the potential risk of fatal arrhythmias, despite the paucity of clinical data, mainly recommending intensive ECG monitoring and some safety thresholds of QTc prolongation mandating treatment interruption 7, 8 . However, since these drugs in the majority of cases have been used for many years (e.g. chloroquine was discovered in 1934) and their side effects are well known, why bother? Many think that in COVID-19 a perfect storm could occur: the use of many QTc-prolonging drugs together, the presence of hypokalemia due to diarrhea and sweating, and possibly the presence of fever and cytokines storm.
However, to date few small studies have investigated the risk of QTc prolongation during COVID-19 outbreak and the attributable risk of ventricular arrhythmias and sudden deaths mainly focusing on HCQ and azithromycin [9] [10] [11] . The purpose of our study is to investigate the incidence of QTc prolongation in hospital patients admitted for COVID-19 infections evaluating the potential correlation between the medication used, the QTc and their outcome with particular attention to arrhythmic events.
We performed a multicentre retrospective observational study to analyse the issue of QTc prolongation in patients with COVID-19. All the data were collected in a digital database of the coordinating centre, San Luigi Gonzaga University Hospital, and previously deidentified. The study was performed according to the Institution Review Board guidance of each participating centres and conducted in accordance with the Declaration of Helsinki and its later amendments. For each patient, all the variables potentially involved in QTc prolongation were collected from paper or electronic medical records, including: (i)demographic variables;
(II)patient history (esp. regarding heart disease); (iii)serial ECGs; (iv)previous medications and medications used during hospitalization; (v)blood tests including high sensitivity troponin I (HsTnI -Abbot Architect TM ) and serial measurements of electrolytes, coagulation, inflammation, kidney and liver function; (vi)Any complications occurred during hospitalizations and status of the patient at discharge.
Inclusion criteria of this study were: (i)> 18 years of age; (ii)COVID-19 confirmed by RT-PCR on nasopharyngeal swab or COVID-19 highly suspected based on history, clinical and imaging findings even in the absence of positive nasopharyngeal swab;
(iii)Completeness of the data about the kind of therapy and its duration, at least two ECG examinations (one at baseline and at least one during the treatment), at least two electrolyte determinations during the treatment, performed within 48 hours from each ECG recordings, and complete data about the status of the patient at the end of therapy and complications.
Patients hospitalized in the intensive care units (ICUs) were excluded from the study because they were not able to swallow HCQ. All the formulations of HCQ available in Europe are film-coated and cannot be divided so, in order to avoid potential bias in the study, we excluded all the patients not able to assume the medications properly.
All ECGs coming from Sant'Andrea Hospital, Vercelli, and San Carlos University Hospital, Madrid were centralized to the San Luigi Gonzaga University Hospital and all the QTc were manually calculated by two expert cardiologists (PD and AL) blinded about the ongoing treatments of the patients. In case of conflicts, a third cardiologist (AP) measured QTc and the final value was established by majority.
The "Tangent" method on 12 leads ECGs was used to calculate the QT interval in lead II or in V5-V6 if T waves could not be easily measured. The RR interval and QT were used to calculate the QTc with the Bazett's formula. In the presence of bundle branch block the Bogossian formula or the fixed QRS replacement method were used 12, 13 ; in patients with paced rhythm the Bogossian formula or spline formula were used.
ECG signs of ischemia were defined as new/dynamic ST segment changes > 0.5 mm in two contiguous leads, T wave flattening or inversion in leads with predominant R wave All patients admitted in the sub-intensive care units, but not those in low-intensity wards, were monitored with telemetry.
The two Italian centres involved in the study adopted the Italian society of cardiology given similar recommendations, suggesting to identify and correct any modifiable risk factor for QTc prolongation before starting the treatment, to perform a baseline ECG and an ECG once on treatment, and to consider reduction or suspension of the treatment in case of QTc≥500 ms or QTc prolongation≥60 ms. However, no strict rules were imposed to the involved centres and physicians were left free to decide when to start and stop medications based on their clinical judgment.
HCQ was used with a loading dose of 400 mg/twice daily the first day followed by 200 mg/twice daily. Azithromycin was given at the dosage of 500 mg/daily. The length of the therapies was left to the decision of the treating physician.
The primary clinical outcome of the study was to analyse the QTc prolongation in Mortality rate and adverse events resulted to be numerically higher in patients with QTc≥500 ms ( 
The results of our analysis on an unbiased population of confirmed or highly suspected COVID-19 patients treated in a non-ICU setting, give us various insights on the aspect of QTc monitoring and arrhythmia risk in this special population. First of all, in our cohort the number of patients with a warning QTc≥500 ms was lower than reported in other papers 9, 11 Another important result of our analysis is the absence of suspected deaths due to fatal arrhythmias associated with QTc prolongation. This is the most important finding of our study because it represents the main concern when using these drugs.
Uncertainty remains to what extent it is to be attributed to a low proarrhythmic effect of the drugs or the result of the clinician's interventions in order to carefully manage these patients (e.g. with ECG and electrolyte monitoring). Concerning the risk of turning QTc prolongation in life-threatening arrhythmias, it has to be considered that, for the same degree of QTc prolongation, different drugs could generate various clinical risk; it is the case, for example, of Sotalol and Amiodarone, both potential QTcprolonging antiarrhythmic drugs, whose proarrhythmic risk differs for their diverse effect on the dispersion of repolarization, a phenomenon which is not visible on surface ECG and for the potent calcium channel block effect of amiodarone. Accordingly, with drugs used to treat COVID-19, we do not exactly know what is the potential proarrhythmic effect beyond the measured QTc.
Moreover, the Tisdale score, a tool developed to predict the drug induced QTc prolongation was able to predict the QTc ≥ 500 msec in our population. This observation could be of clinical relevance and the calculation of Tisdale score could be adopted to identify patients at major risk of developing a QTc prolongation even among those treated for COVID-19 infection. In our opinion, all the studies which specifically evaluated the impact of QT on the safety of COVID-19 experimental drugs showed a limited number of adverse events and this should be taken into account in order to avoid further premature interruption of clinical trials potentially capable to find a disease modifying therapy.
In our population of 196 COVID-19 confirmed or highly suspected patients treated in a non-ICU setting with combinations of HCQ, azithromycin and/or antivirals, a QTc prolongation over 500 ms was observed in 10.2% of patients, and no fatal arrhythmias due to QTc prolongation has been observed. Tisdale score can help in predicting QTc prolongation. Our study, despite retrospective, suggests that current experimental therapies on COVID-19 have an acceptable cardiovascular profile. The numerous ongoing RCTs will give us a definitive answer on the safety and efficacy of COVID-19 experimental drugs.
The authors report no relationships that could be construed as a conflict of interest. 