Conclusions
There have been more than 200 clinical trials registered for
hydroxychloroquine and/or chloroquine each considering different dosing
regimes and different combinations with drugs including azithromycin
(www.clinicaltrials.gov). Although these drugs are generally well
tolerated when used for their approved indications, there is ample
evidence that both can cause QT prolongation and carry a risk of
drug-induced arrhythmia (7). Preliminary data from observational studies
points to QT prolonging effects being more pronounced in COVID-19
patients than heathy individuals (5). Furthermore, patient comorbidities
such as renal failure may add to the proarrhythmic risk in COVID-19
patients (35) . In the current absence of gold-standard randomized
clinical trial data that is sufficiently powered to assess cardiac
safety, coupled with the urgent need to identify potential therapies for
COVID-19, there is a critical need for a comprehensive preclinical
assessment of the cardiac safety profile of these drugs, in relation to
COVID-19 patients. Our data indicate a significant proarrhythmic risk
for hydroxychloroquine and chloroquine at doses being proposed to treat
COVID-19 that can be increased by electrolyte imbalances reported in
these patients (Graphical Abstract). Thus, it would be prudent to
implement long term QT interval monitoring in these patients,
particularly those with electrolyte imbalances. More broadly, our study
demonstrates how the proarrhythmic risk associated with drugs that
prolong cardiac repolarisation can be modified by disease related
metabolic changes that occur in patients and acts as a blueprint for how
high-throughput in vitro screening, combined with in
silico simulations can integrate these effects into preclinical
screening for proarrhythmic risk.