Conclusion and implications:
Combined HCQ+AZM treatment exerts pro-arrhythmic ventricular events by
synergetically inhibiting IKr, IKs with
resulting effects on cellular Ca2+ signalling, and
action potential propagation and duration. These findings provide an
electrophysiological basis for recent FDA cardiac safety guidelines
cautioning against combining HCQ/AZM when treating Covid-19.
Key words: Cardiac safety; Ion channels,
Hydroxychloroquine; Azithromycin, CiPA, COVID-19
Introduction
The severe acute respiratory( syndrome coronavirus 2 (SARS-CoV-2)
pandemic has now infected >6.34 million individuals causing
380 810 deaths as of 3-June-2020 (www.ecdc.eurpoe.eu). Although there
are no approved drugs to prevent or treat SARS-CoV-2 infection, recent
use of the anti-malarial 4-aminoquinolines chloroquine (CQ) or
hydroxychloroquine (HCQ) alone, or combined with the antibiotic
azithromycin (AZM) in Covid-19 therapy has attracted global attention
and extensive early clinical use and trials(NIH, 2020; Pharmafield,
2020). An initial nonrandomized open label clinical trial of 20 cases,
had associated HCQ treatment with viral load reduction or disappearance
in COVID-19 patients, effects reinforced by AZM(Gautret et al., 2020).
This subsequently prompted the US Food and Drugs Administration (FDA)
authorization of emergency use of CQ or HCQ, alone or in combination
with AZM in Covid-19 therapy(Hinton, 2020; Lenzer, 2020). Currently,
large number of trials of these combinations, with or without the
addition of further drugs, are registered worldwide (NIH, 2020;
Pharmafield, 2020).
However, several recent studies have flagged cardiac safety concerns for
the CQ/HCQ and AZM regime in Covid-19 therapy. Particular concern has
arisen regarding potential synergistic effects of HCQ and AZM on QT
duration and cardiovascular mortality (Borba et al., 2020; Chorin et
al., 2020; Lane et al., 2020; Magagnoli et al., 2020; Mercuro et al.,
2020). Higher mortalities and incidences of prolonged corrected QT (QTc)
intervals were reported in patients at a Brazilian hospital receiving
the high dose (12 g total dose over 10 days, ~1.2 g/day,
giving plasma levels of ~10 µM) than the lower dose of
CQ, typified by its use in other conditions such as rheumatoid arthritis
and systemic lupus erythematosus (SLE). This phase 2b randomized
Covid-19 trial was terminated after enrolment of only 81 out of the
target of 440 patients owing to occurrences of adverse events (Borba et
al., 2020). A retrospective data analysis from United States Veterans
Health Administration medical centers suggested increased overall
mortality even in patients treated with HCQ alone (Magagnoli et al.,
2020). The largest available analysis from an international consortium
on HCQ safety covering over 950,000 patients from six countries declared
HCQ safe for short-term use at doses currently used for conditions such
as rheumatoid arthritis. However, it urged caution in its use when
combined with AZM in view of potential risks of cardiovascular mortality
related to QTc prolongation (Lane et al., 2020). Two recent reports of
90 and 201 patients hospitalized with COVID-19 treated with HCQ, with or
without AZM, associated these drugs with QTc prolongation, especially
when used in combination (Mercuro et al., 2020; Saleh et al.). Although
these studies are small, only one case of torsades de pointes was
documented and the therapy was seldom discontinued. They suggested that
more QT interval monitoring studies should be undertaken before final
recommendations can be made(Saleh et al.). Based on these findings, the
FDA issued a cautions warning against use of HCQ or CQ for COVID-19
outside of the hospital setting or a clinical trial, due to risks of
heart rhythm problems(Hinton, 2020). This does not affect FDA-approved
uses in malaria, systemic lupus erythematosus (SLE), and rheumatoid
arthritis where they have been used many years. Both HCQ and AZM have
been in clinical use alone or in combination in other disease conditions
for many years with cardiac safety then not considered a major concern.
Currently, there is very limited data evaluating cardiac safety
particularly concerning use of HCQ in combination with AZM, although
multiple randomized trials are currently in progress evaluating the
efficacy of this combination for Covid-19. We therefore explored the
cardiac safety of HCQ alone or in combination with AZM using the FDA
recommended Comprehensive in Vitro Proarrhythmia Assay (CiPA) protocols
to understand arrhythmic mechanisms (Strauss et al., 2018). Furthermore,
we expanded the CiPA protocol by introducing assessments of effects on
membrane and Ca2+ clocks, their interaction and
cardiac conduction recently suggested as crucial indicators for
ventricular arrhythmogenesis (Lei & Huang, 2019; Lei, Wu, Terrar &
Huang, 2018).