Hydroxychloroquine With or Without Azythromycin for COVID-19 Treatment Associated With Increased Risk for QTc Prolongation

Patients treated with hydroxychloroquine alone or in combination with azithromycin for pneumonia associated with COVID-19 were found to be at increased risk for corrected QT interval prolongation.

Patients treated with hydroxychloroquine alone or in combination with azithromycin for pneumonia associated with novel coronavirus disease 2019 (COVID-19) were found to be at increased risk for corrected QT interval (QTc) prolongation, according to study results published in JAMA Cardiology.1

Treatment with hydroxychloroquine or azithromycin has been associated with a risk for prolonged QTc and cardiac dysrhythmias.

In this single-center, retrospective, observational cohort study, f 90 patients with COVID-19-associated pneumonia (mean age, 60.1±16.7 years; 48.9% women; mean body mass index, 31.5±6.6 kg/m2) who were hospitalized at an academic medical center in Boston, Massachusetts between March 1 and April 7, 2020. Patients in this cohort were treated with hydroxychloroquine for ≥1 day, with or without azithromycin and had ≥1 positive COVID-19 polymerase chain reaction test result using nasopharyngeal swabbing.

The study’s outcomes included changes in QT interval after hydroxychloroquine administration, with or without azithromycin, and incidence of any adverse events related to the medication(s).

In this cohort, 37 individuals (41.1%) received hydroxychloroquine alone, and 53 patients (58.9%) were treated hydroxychloroquine plus azithromycin. The most frequent comorbidities were diabetes mellitus (n=26; 28.9%) and hypertension (n=48; 53.3%).

At baseline, the median QTc was: 455 ms in the cohort (interquartile range [IQR], 430-474), 473 ms in patients administered hydroxychloroquine alone (IQR, 454-487), and 442 ms (IQR, 427-461) in patients given hydroxychloroquine plus azithromycin (P <.001).

The combination therapy group receiving hydroxychloroquine with concomitant azithromycin experienced a bigger The median QT interval change was greater in patients administered hydroxychloroquine plus azithromycin vs alone  (23 ms; IQR, 10-40 vs 5.5 ms; IQR, -15.5 to 34.25, respectively; P =.03).  

In the hydroxychloroquine-only treatment group, there were 7 and 3 patients (18.9% and 8.1%, respectively) who developed a QTc prolongation ≥500 ms and ≥60 ms, respectively. A total of 11 and 7 patients (20.8% and 13.2%, respectively) treated with the combination therapy had QTc prolongations prolongation ≥500 ms and ≥60 ms, respectively.

A baseline QTc ≥450 ms (adjusted odds ratio [OR], 7.11; 95% confidence interval [CI], 1.75-28.87) and concomitant administration of a loop diuretic (OR, 3.38; 95% CI, 1.03-11.08) were found to be associated with an increased risk for QTc prolongation in multivariable-adjusted analyses.

In this cohort, 10 patients (11.1%) had to discontinue hydroxychloroquine early due to possible drug-related adverse events, which included hypoglycemia, intractable nausea, and a single case of torsades de pointes.

Study limitations include the lack of a control group, the possibility that stress associated with myocarditis or stress cardiomyopathy may have contributed to adverse events, a possible underestimation of the QTc prolongation, a short follow-up duration, and a potential underrepresentation of high-risk patient groups.

“Clinicians should carefully weigh risks and benefits if considering hydroxychloroquine and azithromycin, with close monitoring of QTc and concomitant medication usage,” noted the authors.

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In a related research letter published in JAMA Cardiology, a separate team of intensivists discussed their experience managing patients with COVID-19-related pneumonia in a case series.2 In this study, 40 patients (median age, 68 years; 80% men) were treated with hydroxychloroquine alone or combination with azithromycin. QTc prolongation was also observed in >90% of these patients. “This study raises safety concerns about the use of hydroxychloroquine with or without azithromycin for patients with COVID-19, particularly when both drugs are administered together. There were no baseline clinical factors associated with subsequent QT prolongation,” they noted.  


  1. Mercuro NJ, Yen CF, Shim DJ, et al. Risk of QT interval prolongation associated with use of hydroxychloroquine with or without concomitant azithromycin among hospitalized patients testing positive for coronavirus disease 2019 (COVID-19). JAMA Cardiol. May 2020:E1-E6. doi:10.1001/jamacardio.2020.1834
  2. Bessière F, Roccia H, Delinière A, et al. Assessment of QT intervals in a case series of patients with coronavirus disease 2019 (COVID-19) infection treated with hydroxychloroquine alone or in combination with azithromycin in an intensive care unit. JAMA Cardiol. May 2020:E1-E3. doi:10.1001/jamacardio.2020.1787