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.

KEYWORDS:

• Antimalarial drugs
• hydroxychloroquine
• azithromycin
• electrocardiogram QT prolonged
• torsade de Pointes
• COVID-19

Author contributions

Conceptualization: Vakaramoko Diaby, Reem D. Almutairi, Ziyan Chen, Richard K. Moussa; Writing – original draft preparation: Vakaramoko Diaby, Reem D. Almutairi, Ziyan Chen, Richard K. Moussa, Abdrahmane Berthe; Writing – review and editing: Vakaramoko Diaby, Reem D. Almutairi, Ziyan Chen, Richard K. Moussa, Abdrahmane Berthe; Supervision: Vakaramoko Diaby. All authors read and approved the final manuscript.

Acknowledgments

The data from the FAERS come from a variety of sources. The likelihood of a causal relationship is not the same in all reports. The information does not represent the opinion of the Food and Drug Administration.

Data availability

The data that support the findings of this study can be accessed upon request to the Food and Drug Administration or through the OpenVigil platform [http://openvigil.sourceforge.net].

Research involving human participants and/or animals: Not applicable

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Informed consent

Not applicable

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewers disclosure

Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Additional information

Funding

This study was not funded.