Which drugs being studied for the treatment of coronavirus disease 2019 (COVID-19) are associated with QT prolongation and an increased risk of cardiac death?

Updated: Jun 25, 2021
  • Author: David J Cennimo, MD, FAAP, FACP, FIDSA, AAHIVS; Chief Editor: Michael Stuart Bronze, MD  more...
  • Print
Answer

Chloroquine, hydroxychloroquine, and azithromycin each carry the warning of QT prolongation and can be associated with an increased risk of cardiac death when used in a broader population. [338] Because of this risk, the American College of Cardiology, American Heart Association, and the Heart Rhythm Society have published a thorough discussion on the arrhythmogenicity of hydroxychloroquine and azithromycin, including a suggested protocol for clinical research QT assessment and monitoring when the two drugs are coadministered. [339, 340]

Giudicessi et al have published guidance for evaluating the torsadogenic potential of chloroquine, hydroxychloroquine, lopinavir/ritonavir, and azithromycin. Chloroquine and hydroxychloroquine block the potassium channel, specifically KCNH2-encoded HERG/Kv11.1. Additional modifiable risk factors (eg, treatment duration, other QT-prolonging drugs, hypocalcemia, hypokalemia, hypomagnesemia) and nonmodifiable risk factors (eg, acute coronary syndrome, renal failure, congenital long QT syndrome, hypoglycemia, female sex, age ≥65 years) for QT prolongation may further increase the risk. Some of the modifiable and nonmodifiable risk factors may be caused by or exacerbated by severe illness. [356]

A cohort study was performed from March 1 through April 7, 2020, at an academic tertiary care center in Boston to characterize the risk and degree of QT prolongation in patients with COVID-19 who received hydroxychloroquine, with or without azithromycin. Among 90 patients given hydroxychloroquine, 53 received concomitant azithromycin. Seven patients (19%) who received hydroxychloroquine monotherapy developed prolonged QTc of 500 milliseconds or more, and 3 patients (3%) had a change in QTc of 60 milliseconds or more. Of those who received concomitant azithromycin, 11 of 53 (21%) had prolonged QTc of 500 milliseconds or more, and 7 of 53 (13 %) had a change in QTc of 60 milliseconds or more. Clinicians should carefully monitor QTc and concomitant medication usage if considering using hydroxychloroquine. [357]

A retrospective study was performed by reviewing 84 consecutive adult patients who were hospitalized at NYU Langone Medical Center with COVID-19 and treated with hydroxychloroquine plus azithromycin. QTc increased by greater than 40 ms in 30% of patients. In 11% of patients, QTc increased to more than 500 ms, which is considered a high risk for arrhythmia. The researcher noted that development of acute renal failure, but not baseline QTc, was a strong predictor of extreme QTc prolongation. [358]

A Brazilian study (n=81) compared chloroquine high-dose (600 mg PO BID for 10 days) and low-dose (450 mg BID for 1 day, then 450 mg/day for 4 days). A positive COVID-19 infection was confirmed by RT-PCR in 40 of 81 patients. In addition, all patients received ceftriaxone and azithromycin. Oseltamivir was also prescribed in 89% of patients. Prolonged QT interval (> 500 msec) was observed in 25% of the high-dose group, along with a trend toward higher lethality (17%) compared with lower dose. The high incidence of QT prolongation prompted the investigators to prematurely halt use of the high-dose treatment arm, noting that azithromycin and oseltamivir can also contribute to prolonged QT interval. The fatality rate was 13.5%. In 14 patients with paired samples, respiratory secretions at day 4 showed negative results in only one patient. [341]

An increased 30-day risk of cardiovascular mortality, chest pain/angina, and heart failure was observed with the addition of azithromycin to hydroxychloroquine. Pooled data from 14 sources of claims data or electronic medical records from Germany, Japan, Netherlands, Spain, United Kingdom, and the United states were analyzed for adverse effects of hydroxychloroquine, sulfasalazine, or the combinations of hydroxychloroquine plus azithromycin or amoxicillin. Overall, 956,374 and 310,350 users of hydroxychloroquine and sulfasalazine, respectively, and 323,122 and 351,956 users of hydroxychloroquine-azithromycin and hydroxychloroquine-amoxicillin, respectively, were included in the analysis. [342]


Did this answer your question?
Additional feedback? (Optional)
Thank you for your feedback!