Association of Hydroxychloroquine With QTc Interval in Patients With COVID-19
Authors: Andrea Mazzanti, Martina Briani, Deni Kukavica, Francesca Bulian, Stefano Marelli, Alessandro Trancuccio, Nicola Monteforte, Tommaso Manciulli, Massimo Morini, Annalisa Carlucci, Giacomo Viggiani, Francesco Cannata, Sara Negri, Raffaella Bloise, Mirella Memmi, Patrick Gambelli, Andrea Carbone, Martina Molteni, Raffaella Bianchini, Rita Salgarello, Silvia Sozzi, Pasquale De Cata, Francesco Fanfulla, Piero Ceriana, Carlo Locatelli, Carlo Napolitano, Luca Chiovato, Luca Tomasi, Giulio G. Stefanini, Gianluigi Condorelli, Silvia G. Priori
Journal: Circulation (2020)

arrhythmia ◼ COVID-19 ◼ hydroxychloroquine ◼ long QT syndrome H ydroxychloroquine is currently prescribed in many countries as a treatment for patients with coronavirus disease 2019 (COVID-19).The notion that hydroxychloroquine blocks the hERG (human ether-a-go-go-related gene) potassium channel, potentially leading to QT interval prolongation and arrhythmias, mitigates the enthusiasm for the compound.Recent studies conducted on cohorts of COVID-19 patients treated with hydroxychloroquine reported different signals, ranging from serious concern related to 20% of patients with major corrected QT (QTc) interval prolongation, 1 to more reassuring data. 2 The potential benefit of hydroxychloroquine underscores the need to evaluate the QTc prolongation during the short-term treatment with hydroxychloroquine used in COVID-19.In particular, the effect of combining hydroxychloroquine with other hERG-blocking drugs such as azithromycin, or lopinavir/ ritonavir should be assessed.An ongoing, observational, prospective study was established to determine whether the short-term use of hydroxychloroquine alone, or in combination with at least 1 other hERG-blocking COVID-19 drug, is associated with an excessive QT prolongation, defined as QTc interval ≥500 ms.The study protocol was approved by the ethics committees of the participating centers, and patients provided informed consent.Between March 7, 2020, and April 30, 2020, we enrolled 150 consecutive inpatients (63% men; median age 69 years, interquartile range [IQR] 57-81 years; 46% with hypertension and 19% with diabetes mellitus) with a diagnosis of COVID-19 confirmed by polymerase chain reaction, who were admitted to our hospitals and were treated with hydroxychloroquine for a median of 9 days (IQR 5-11 days), at a daily dosage of 400 mg (97%), or 600 mg (3%).In 67% of cases, hydroxychloroquine was associated with azithromycin (26%), lopinavir/ritonavir (35%), or azithromycin+lopinavir/ritonavir (6%).A 12-lead ECG was recorded after a median of 5 days (IQR 3-7 days) of treatment.The QT interval was corrected using the Bazett formula.In patients with atrial fibrillation (7%), the QTc interval was calculated as an averaged value over 3 consecutive cycles.In patients with significant intraventricular conduction delays (ie, QRS >120 ms), which were observed in 14% of cases, we applied the formula for QT adjustment proposed by Rautaharju. 3 The median QTc interval on treatment with hydroxychloroquine was 433 ms (IQR 414-447 ms), without differences between hydroxychloroquine monotherapy and combination therapies with azithromycin, lopinavir/ritonavir, or azithromycin+lopinavir/ritonavir (P=0.742;Kruskal-Wallis test).Overall, the proportion of patients with mild (460-479 ms), intermediate (480-499 ms), and severe (≥500 ms) QTc prolongation was 9%, 4%, and 2%, respectively.Since some patients had an ECG recorded before the termination of therapy, we cannot