Frequency of Long QT in Patients with SARS-CoV-2 Infection Treated with Hydroxychloroquine: A Meta-analysis.

Introduction Hydroxychloroquine (HCQ) has been proposed as a SARS-CoV-2 treatment but the frequency of long QT (LQT) during use is unknown. Objective To conduct a meta-analysis of the frequency of LQT in patients with SARS-CoV-2 infection treated with HCQ. Data Sources PubMed, EMBASE, Google Scholar, the Cochrane Database of Systematic Reviews and preprint servers (medRxiv, Research Square) were searched for studies published between December 2019 and June 30, 2020. Methods Effect statistics were pooled using random effects. The quality of observational studies and randomized controlled trials was appraised with STROBE and the Cochrane Risk of Bias Assessment tools, respectively. Outcomes Critical LQT was defined as: (1) maximum QT corrected (QTc)≥500 ms (if QRS<120 ms) or QTc≥550 ms (if QRS≥120 ms), and (2) QTc increase ≥60 ms. Results In the 28 studies included (n=9124), the frequency of LQT during HCQ treatment was 6.7% (95% confidence interval [CI]: 3.7-10.2). In 20 studies (n=7825), patients were also taking other QT-prolonging drugs. The frequency of LQT in the other 8 studies (n=1299) was 1.7% (95% CI: 0.3-3.9). Twenty studies (n=6869) reported HCQ discontinuation due to LQT, with a frequency of 3.7% (95% CI: 1.5-6.6). The frequency of ventricular arrhythmias during HCQ treatment was 1.68% (127/7539) and that of arrhythmogenic death was 0.69% (39/5648). Torsades de Pointes occurred in 0.06% (3/5066). Patients aged >60 years were at highest risk of HCQ-associated LQT (P<0.001). Conclusions HCQ-associated cardiotoxicity in SARS-CoV-2 patients is uncommon but requires ECG monitoring, particularly in those aged >60 years and/or taking other QT-prolonging drugs.

Effect of hydroxychloroquine on the cardiac ventricular repolarization: A randomized clinical trial.

AIMS: Hydroxychloroquine has been suggested as possible treatment for severe acute respiratory syndrome-coronavirus-2. Studies reported an increased risk of QTcF-prolongation after treatment with hydroxychloroquine. The aim of this study was to analyse the concentration-dependent effects of hydroxychloroquine on the ventricular repolarization, including QTcF-duration and T-wave morphology. METHODS: Twenty young (≤30 y) and 20 elderly (65-75 y) healthy male subjects were included. Subjects were randomized to receive either a total dose of 2400 mg hydroxychloroquine over 5 days, or placebo (ratio 1:1). Follow-up duration was 28 days. Electrocardiograms (ECGs) were recorded as triplicate at baseline and 4 postdose single recordings, followed by hydroxychloroquine concentration measurements. ECG intervals (RR, QRS, PR, QTcF, J-Tpc, Tp-Te) and T-wave morphology, measured with the morphology combination score, were analysed with a prespecified linear mixed effects concentration-effect model. RESULTS: There were no significant associations between hydroxychloroquine concentrations and ECG characteristics, including RR-, QRS- and QTcF-interval (P = .09, .34, .25). Mean ΔΔQTcF-interval prolongation did not exceed 5 ms and the upper limit of the 90% confidence interval did not exceed 10 ms at the highest measured concentrations (200 ng/mL). There were no associations between hydroxychloroquine concentration and the T-wave morphology (P = .34 for morphology combination score). There was no significant effect of age group on ECG characteristics. CONCLUSION: In this study, hydroxychloroquine did not affect ventricular repolarization, including the QTcF-interval and T-wave morphology, at plasma concentrations up to 200 ng/mL. Based on this analysis, hydroxychloroquine does not appear to increase the risk of QTcF-induced arrhythmias.