A pharmacovigilance study to quantify the strength of association between the combination of antimalarial drugs and azithromycin and cardiac arrhythmias: implications for the treatment of COVID-19.

Abstract

Background : Hydroxychloroquine, an antimalarial drug, combined with azithromycin has been considered a potential treatment for COVID-19. However, these drugs may cause electrocardiogram QT prolongation (QTp) and torsade de Pointes (TdP). We examined potential safety signals for these cardiac arrhythmias. Methods : Using the OpenVigil 2.1 MedDRA platform, we mined data from the U.S. Food and Drug Administration’s Adverse Event Reporting System (FAERS) from December 2019 to June 2020. We extracted individual case safety reports based on exposures of seven antimalarial drugs, azithromycin, and combinations. All other drugs in FAERS served as controls. Events of interest included QTp and TdP, with associations between drug exposures and events expressed as adjusted Reporting-Odds-Ratios (aRORs) and confidence intervals. The lower end of aROR 95% confidence interval >1 was used as the statistically significant signal detection threshold. Results : QTp safety signals were found for hydroxychloroquine[aROR:11.70 (10.40–13.16)], chloroquine[aROR:18.97 (11.30–31.87)], quinine[aROR:16.66 (10.18–27.25)], atovaquone[aROR:6.91 (4.14–11.56)], azithromycin alone [aROR:28.02 (22.87–34.32)] and hydroxychloroquine + azithromycin [aROR:75.23 (51.15–110.66)]. TdP safety signals were found for hydroxychloroquine [aROR: 5.62 (4.94–6.38)], chloroquine[aROR:49.37 (30.63–79.58)], and hydroxychloroquine + azithromycin[aROR:33.09 (21.22–51.61)]. Conclusion : Hydroxychloroquine/chloroquine and/or azithromycin was associated with QTp/TdP safety signals and their use should be monitored carefully.

Serious Cardiovascular Adverse Events Associated with Hydroxychloroquine/Chloroquine Alone or with Azithromycin in Patients with COVID-19: A Pharmacovigilance Analysis of the FDA Adverse Event Reporting System (FAERS)

“…Our findings regarding HCQ/CQ monotherapy and HCQ/CQ + azithromycin combination therapy are consistent with both the most recent analysis [ 32 ] of the World Health Organization’s pharmacovigilance database and previous studies [ 9 , 21 , 33 , 34 ] suggesting that HCQ/CQ monotherapy is associated with an increased risk of QTc prolongation and cardiovascular events and that concurrent use may increase this risk. A case series report of 84 patients with COVID-19 treated with 5 days of HCQ + azithromycin found that QTc increased significantly from a mean ± standard deviation of 435 ± 24 ms to a maximum of 463 ± 32 ms ( P < 0.001) on day 3.6 ± 1.6 of therapy [ 10 ].…”

“…In this study, case reports of HCQ-induced SCAEs before and during COVID-19 were found to be significantly different because of the changes in patient characteristics, comorbid conditions, effects of drug interactions, and possible modifications to drug pharmacokinetics in patients with COVID-19 [ 19 , 20 ]. Another disproportionality analysis, conducted by Diaby et al [ 21 ], evaluated QTc prolongation and TdP with HCQ/CQ monotherapy or HCQ/CO + azithromycin for COVID-19 from December 2019 to the second quarter of 2020 [ 21 ]; however, the sample size of patients with COVID-19 was relatively limited. Considering the increased use of HCQ, CQ, and azithromycin, even after revocation of the HCQ EUA and after the reporting of new safety profiles for these agents in patients with COVID-19, reevaluation of SCAE risk is needed.…”

An observational, retrospective, comprehensive pharmacovigilance analysis of hydroxychloroquine-associated cardiovascular adverse events in patients with and without COVID-19

“…We found a significant increase in azithromycin use among COVID-19 patients who reported AEs. The drug combinations could lead to potential drug-drug interactions and the outbreak of reports about the unsafe use of HCQ [ 14 , 24 , 30 , 31 ]. Interestingly, we found that the proportion of CVAEs developed after combining azithromycin and HCQ in the COVID group was lower than in the non-COVID group (OR 0.34, P = 0.001).…”