5.2- Safety data
In the context of COVID-19, the potential cardiotoxicity of azithromycin
has been a concern. Hydroxychloroquine is known to prolong the QTc
interval, and the combination of these drugs has been associated with an
increased risk of adverse events[78].
Several reports have shown the higher risk of QTc prolongation with the
use of hydroxychloroquine alone or in combination with
macrolides[28,76,81–85]. Furthermore, these treatments have been
related to a higher risk of developing cardiac arrest or ventricular
arrythmia. An incidence of 0.4 % in the development of TdP was
described with the use of combination therapy[85]. This abnormal
findings appear to be developed at day 3-4 of the
treatment[28,75,82]. The main data concerning the cardiovascular
risk of the treatment with azithromycin (alone or in combination) were
detailed in Table 3.
In patients with mild disease, overall azithromycin and its combination
with hydroxychloroquine were well tolerated. Million et al .
reported a 2.4 % incidence of adverse events, mainly gastrointestinal
with a very low rate of QTc interval prolongation[73]. None of the
reasons for treatment discontinuation in 3 (0.28 %) patients were
cardiovascular. Guerin et al . reported no cardiovascular
events[79]. In the study of Barbosa et al. the main adverse
effect was diarrhea, but 12.9 % of patients presented diarrhea before
the onset of the treatment.[80] No cardiovascular adverse effects
were recorded.
Rosenberg et al. reported a higher risk of cardiac arrest and
arrhythmia with the use of hydroxychloroquine alone or in
combination[78]. Patients treated with hydroxychloroquine alone
presented a higher risk of cardiac arrest (aOR 2.97 [95% CI
1.56-5.64]) than those treated with azithromycin. This difference
among the two treatments was maintained even in patients without
mechanical ventilation (aOR 3.01 [95% CI 1.07-8.51]), excluding
other factors for adverse events as severity. Azithromycin alone did not
increase the risk of cardiovascular adverse events compared to standard
of care group. This was also shown in another study where the addition
of azithromycin to hydroxychloroquine increased the risk of 30-day
cardiovascular mortality[86]. In this study, however, in the other
analyzed outcomes no differences were found and, in addition, when
accounting by the standard Bonferroni correction of multiple comparison,
only chest pain/angina remained statistically significant[87].
Other factors may also play a role in the development of these adverse
events. The use of loop diuretic drugs, baseline QTc ≥ 450 ms, more than
2 systemic inflammatory response syndrome criteria and intensive care
status at time of test were associated with a higher risk of developing
QTc ≥ 500 ms[81]. The use of other medications that prolong the QTc,
electrolyte disturbances, female gender, older age, personal or family
history of QT interval prolongation and other diagnoses as chronic renal
failure, cardiac heart failure, structural heart disease, genetic
polymorphisms and congenital long QT syndrome are other potential risk
factors[28,88].
Some algorithms have been proposed to try to minimize the associated
risks[88]. A careful revision of the history of the patient to
detect any diseases with an increased risk of QTc prolongation, together
with the assessment of potential electrolyte disturbances and the
presence of other QTc prolonging medications and their interactions is
advised before initiating the treatment[88]. An electrocardiogram
and electrolyte monitoring are recommended during the first days of
therapy to detect any potential alterations[88].