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)

Abstract

IMPORTANCE Administration of hydroxychloroquine with or without azithromycin for the treatment of coronavirus disease 2019 (COVID-19)-associated pneumonia carries increased risk of corrected QT (QTc) prolongation and cardiac arrhythmias.OBJECTIVE To characterize the risk and degree of QT prolongation in patients with COVID-19 in association with their use of hydroxychloroquine with or without concomitant azithromycin. DESIGN, SETTING, AND PARTICIPANTSThis was a cohort study performed at an academic tertiary care center in Boston, Massachusetts, of patients hospitalized with at least 1 positive COVID-19 nasopharyngeal polymerase chain reaction test result and clinical findings consistent with pneumonia who received at least 1 day of hydroxychloroquine from March 1, 2020, through April 7, 2020. MAIN OUTCOMES AND MEASURESChange in QT interval after receiving hydroxychloroquine with or without azithromycin; occurrence of other potential adverse drug events. RESULTS Among 90 patients given hydroxychloroquine, 53 received concomitant azithromycin; 44 (48.9%) were female, and the mean (SD) body mass index was 31.5 (6.6). Hypertension (in 48 patients [53.3%]) and diabetes mellitus (in 26 patients [28.9%]) were the most common comorbid conditions. The overall median (interquartile range) baseline QTc was 455 (430-474) milliseconds (hydroxychloroquine, 473 [454-487] milliseconds vs hydroxychloroquine and azithromycin, 442 [427-461] milliseconds; P < .001). Those receiving concomitant azithromycin had a greater median (interquartile range) change in QT interval (23 [10-40] milliseconds) compared with those receiving hydroxychloroquine alone (5.5 [−15.5 to 34.25] milliseconds; P = .03). Seven patients (19%) who received hydroxychloroquine monotherapy developed prolonged QTc of 500 milliseconds or more, and 3 patients (8%) 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. The likelihood of prolonged QTc was greater in those who received concomitant loop diuretics (adjusted odds ratio, 3.38 [95% CI, 1.03-11.08]) or had a baseline QTc of 450 milliseconds or more (adjusted odds ratio, 7.11 [95% CI,). Ten patients had hydroxychloroquine discontinued early because of potential adverse drug events, including intractable nausea, hypoglycemia, and 1 case of torsades de pointes. CONCLUSIONS AND RELEVANCEIn this cohort study, patients who received hydroxychloroquine for the treatment of pneumonia associated with COVID-19 were at high risk of QTc prolongation, and concurrent treatment with azithromycin was associated with greater changes in QTc. Clinicians should carefully weigh risks and benefits if considering hydroxychloroquine and azithromycin, with close monitoring of QTc and concomitant medication usage.

Towardin vivo-relevant hERG safety assessment and mitigation strategies based on relationships between non-equilibrium blocker binding, three-dimensional channel-blocker interactions, dynamic occupancy, dynamic exposure, and cellular arrhythmia

“…anti-viral therapies [42]. The anti-viral efficacy of these drugs is unconfirmed (and is under considerable scrutiny [43]), whereas both drugs are known to exhibit pro-arrhythmic and arrhythmic levels of hERG blockade in the clinical setting (based on data from the Federal Adverse Event Reporting System summarized in [44], a recent COVID-19 patient cohort [45], and reports of QT prolongation above 500 ms in COVID-19 patients [46]). Furthermore, hERG is likely blocked as well by the principal metabolites of HCQ, which consist of desethylchloroquine, desethylhydroxychloroquine, and bisdesethylchloroquine [47].…”

The Cardiovascular Effects of Treatment with Hydroxychloroquine and Azithromycin

“…1 However, there is no evidence from randomized controlled trials that this therapeutic regimen is effective for COVID-19. Observational data showed mixed or conflicting signals, [1][2][3][4][5] making it difficult to determine efficacy. Given the absence of clear therapeutic benefit, many experts have cautioned against the use of these drugs given their potential side effects, especially adverse cardiovascular (CV) reactions.…”

Mitigating Arrhythmia Risk in Hydroxychloroquine and Azithromycin Treated COVID-19 Patients using Arrhythmia Risk Management Plan

“…For example, 89.6% of patients were taking Oseltamivir for suspected in uenza infection, which may have contributed to QT prolongation (9). In a retrospective HCQ and AZI treatment cohort of 90 patients with COVID-19, 11 of 53 (21%) subjects developed QTc≥500 ms and 7 of 53 (13 %) had ΔQTc≥60 ms (10). One case of torsades de pointes (TdP) which happened three days after discontinuation of treatment may indicate delayed risk possibly due to long half-life of HCQ (11).…”