Note: The following study has been retracted by the journal. Read more here: Retraction—Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis

The QT Interval in Patients with SARS-CoV-2 Infection Treated with Hydroxychloroquine/Azithromycin

Ehud Chorin, Matthew Dai, Eric Shulman, Lailt Wadhwani, Roi Bar Cohen, Chirag Barbhaiya, Anthony Aizer, Douglas Holmes, Scott Bernstein, Michael Soinelli, David S Park, Larry Chinitz, Lior Jankelosn doi: https://doi.org/10.1101/2020.04.02.20047050

Abstract:

We report the change in the QT interval in 84 adult patients with SARS-CoV-2 infection treated with Hydroxychloroquine/Azithromycin combination. QTc prolonged maximally from baseline between days 3 and 4. In 30% of patients QTc increased by greater than 40ms. In 11% of patients QTc increased to >500 ms, representing high risk group for arrhythmia. The development of acute renal failure but not baseline QTc was a strong predictor of extreme QTc prolongation.

Clinical Pharmacology Perspectives on the Antiviral Activity of Azithromycin and Use in COVID-19

Damle, B., Vourvahis, M., Wang, E., Leaney, J. and Corrigan, B. (2020), Clinical Pharmacology Perspectives on the Antiviral Activity of Azithromycin and Use in COVID‐19. Clin. Pharmacol. Ther.. Accepted Author Manuscript. doi:10.1002/cpt.1857

Excerpts:

Azithromycin (AZ) is a broad-spectrum macrolide antibiotic with a long half-life and a large volume of distribution. It is primarily used for the treatment of respiratory, enteric, and genitourinary bacterial infections. AZ is not approved for the treatment of viral infections, and there is no well-controlled, prospective, randomized clinical evidence to support AZ therapy in COVID-19 (Coronavirus Infectious Disease-2019). Nevertheless, there are anecdotal reports that some hospitals have begun to include AZ in combination with hydroxychloroquine (HCQ) or chloroquine (CQ) for treatment of COVID-19.

Dose adjustment is not considered to be required for geriatric patients with normal renal and hepatic function, however it should be noted that elderly patients may be more susceptible to the development of Torsades de Pointes. In subjects with severe renal impairment, the mean AUC and Cmax increased 35% and 61%, respectively, compared to subjects with normal renal function, thus caution should be exercised when dosing AZ in this population.

Prolonged cardiac repolarization and QT interval, which may impart a risk of Torsade de Pointes, has been seen in treatment with macrolides including AZ; CQ is also known to prolong the QT interval. In the studies presented in this document (Table 4), in a total of >2000 subjects exposed to 3-day regimens of AZ and CQ combinations, no relevant cardiovascular SAEs of concern were reported. Available data on the concomitant use of AZ and CQ in these studies indicated no increased risk of QT prolongation above that observed with CQ alone.

Azithromycin, cardiovascular risks, QT interval prolongation, torsade de pointes, and regulatory issues

Hancox, J. C., Hasnain, M., Vieweg, W. V., Crouse, E. L., & Baranchuk, A. (2013). Azithromycin, cardiovascular risks, QTc interval prolongation, torsade de pointes, and regulatory issues: A narrative review based on the study of case reports. Therapeutic advances in infectious disease, 1(5), 155–165. https://doi.org/10.1177/2049936113501816

Excerpt:

Azithromycin has recently come under regulatory scrutiny because of its purported link to life-threatening cardiac tachyarrhythmias and cardiac death. This appears to be less of an issue for younger and healthier patients. Both epidemiologic studies and individual reports suggest this link derives from aspects of the drug itself.