key: cord-0804427-gcpllzzd authors: Schiavone, Marco; Gasperetti, Alessio; Gherbesi, Elisa; Bergamaschi, Luca; Arosio, Roberto; Mitacchione, Gianfranco; Viecca, Maurizio; Forleo, Giovanni B. title: Arrhythmogenic Risk and Mechanisms of QT Prolonging Drugs to Treat COVID-19 date: 2021-10-30 journal: Card Electrophysiol Clin DOI: 10.1016/j.ccep.2021.10.009 sha: f519026f308b35e2878ae42fa9a69292ad4508f1 doc_id: 804427 cord_uid: gcpllzzd While looking for a “magic bullet” to treat COVID-19, the massive off-label use of several of drugs in COVID-19, including repurposed antimalarial drugs, immunosuppressive agents, anti-virals and antibacterial agents, have generated concerns in the early phase of the pandemic due a possible arrhythmogenic effects in relation to QTc interval prolongation. Indeed, some of these drugs have been historically associated to QT prolongation and Torsade de Point, a potentially lethal ventricular arrhythmia, and their first-time use on a very large scale has raised several concerns in the scientific community. The aim of this work is to summarize the underlying arrhythmogenic mechanisms related to the use of potentially QT prolonging drugs used during the pandemic to treat COVID-19. -COVID-19 patients might experience an increased arrhythmic risk due to QT 30 prolongation, as for their clinical status or for the massive off-label use of potentially 31 QT-prolonging drugs. 32 -In such patients, a complete baseline QT assessment at a 12-lead ECG should be 33 performed, as well as with Tisdale score calculation and ECG monitoring during drug 34 administration. in different studies, acute coronary syndromes (ACS) and cardiac arrhythmias have been 50 reported as potential complications in hospitalized patients, often impairing COVID-19 patients 51 prognosis [11] [12] [13] [14] [15] [16] [17] [18] . Besides a disease-related cardiac involvement, the massive off-label use of 52 several of drugs 19,20 , including immunosuppressive agents (e.g. anakinra or tocilizumab), 53 different anti-virals (e.g. oseltamivir, remdesevir or the lopinavir/ritonavir combination), and 54 antimalarial drugs such as chloroquine (CQ) and hydroxychloroquine (HCQ) with or without 55 azithromycin (AM) have generated concerns in the early phase of the pandemic due to their 56 possible arrhythmogenic effects, in relation to QT interval prolongation. Indeed, some of these 57 drugs have never been used on a large scale and little is known about their possible 58 arrhythmogenic effects in elderly, critically-ill patients, often showing multiple co-morbidities, 59 being treated with multiple drugs. Most of these drugs may prolong the QT interval both with 60 direct (channel blocking activity) or indirect effects (e.g. liver and/or kidney toxicity, 61 cytochrome interactions, electrolyte imbalance), potentially increasing the arrhythmic (e.g. 62 Torsade de Pointes [TdP] ) and non-arrhythmic mortality. The aim of this work is to summarize 63 The QT interval is the interval from the beginning of ventricular depolarization to the 67 completion of the repolarization of the entire ventricular mass. Ideally, the QT interval should 68 be measured at a paper rate of 25 mm/s from the beginning of the QRS until the return to 69 baseline of the T wave. The QT interval should be calculated in a total of six leads, with three 70 leads taken from peripheral leads (avoiding DIII and aVR due to frequent low voltages and 71 inverted polarity, respectively) and three precordial leads (preferably V2, V4 and V6 in QTc of >50 msec are often used as safety endpoints when evaluating drug effects and may 88 justify a treatment interruption. A proposed algorithm to identify patients at risk of developing 89 COVID-19 pandemic is reported in Figure 1 . 91 J o u r n a l P r e -p r o o f QT prolongation is associated with an increase in both arrhythmic and non-arrhythmic 93 mortality, and it is often used as a metric of drug safety 26 . Indeed, QT prolongation is related to 94 a mix of modifiable and unmodifiable risk factors that may determine why at same drugs Table 1 . prolongation. Among those, hypokalemia has a particular arrhythmogenic effect, not only 144 prolonging the QT interval, but also being a major risk factor for drug-induced LQTS as it 145 increases the tendency of Kv11.1 channels to remain inactivated and decreases repolarizing 146 currents. Hypocalcemia and hypomagnesemia as well may show a QT-prolonging effect. 147 Kidney and liver failure have both been associated with the risk of QT prolongation, due to 148 their role in metabolite/toxin clearance; finally, bradycardia is a relevant additional risk factor. 149 Patients accessing intensive care such as COVID-19 severe infections should therefore 150 be strictly monitored because of their potential exposure to these risk factors. Lastly, to estimate 151 the risk of drug-induced QT prolongation, all the patients treated with a potential QT-152 prolonging drug should be evaluated with a Tisdale score at baseline (Table 2) 38 . Indeed, the 153 Tisdale risk classes are respectively associated with 15%, 37% and 73% risk of QT 154 prolongation, and can be extremely useful for a quick but reliable baseline risk assessment. 155 While waiting for the massive vaccination campaign to be completed to reach the herd 157 immunity, several drugs proposed as potential treatment are still used worldwide to treat 158 COVID-19. However, most of these drugs are not specific and targeted against SARS-CoV-2, 159 so that using pre-existing drugs have represented a fast and very useful strategy with known 160 safety, characteristics, and dosage used during the early and even late phase of the pandemic 19 . 161 If some of these drugs have been investigated for their efficacy and safety in treating COVID-162 19, some others are still undergoing clinical trials to test their profile. One of the main concerns 163 regarding the use of some of these reproposed drugs is the potential impact on the QT interval 164 and their arrhythmogenic effects, which is particularly noteworthy due to the common co-165 prescription of several drugs that may show combined effects on the QT interval, as well as 166 several clinical characteristics that may eventually lead to arrhythmic manifestations 39 . The 167 knowledge on these potential adverse events is mostly derived from the historical data collected prolongation, that was attributed to the short duration of HCQ treatment in COVID-19, since 219 HCQ reaches the steady state after 180 days of HCQ therapy 46 . Therefore, caution should be 220 adopted when extending these safety results to patients treated for several years for other 221 indications, that could experience a more severe QTc prolongation and related arrhythmic 222 effects. The authors recommend to always perform a baseline ECG before starting HCQ, 223 followed by a subsequent recording "on therapy" for patients with a normal baseline QTc, with 224 an advisable daily monitoring for patients with baseline QTc >480 msec. 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