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].