Incidence and determinants of QT interval prolongation in COVID‐19 patients treated with hydroxychloroquine and azithromycin

Maraj, Ilir; Hummel, James P.; Taoutel, Roy; Chamoun, Romy; Workman, Virginia; Li, Cindy; Tran, Lydia; Delvecchio, Alexander; Howes, Christopher; Akar, Joseph G.

doi:10.1111/jce.14594

Cited by 33 publications

(34 citation statements)

References 7 publications

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“…Azithromycin was cited as part of the COVID-19 treatment in these studies but not hydroxychloroquine. There have been several studies, both observational studies and randomized control trials, demonstrating the risk of QT prolongation with hydroxychloroquine, chloroquine, and/or azithromycin (49,50,51,52). On April 24, 2020, the US Food & Drug Administration published a drug safety communication warning health care professionals and patients of the known risk of QT prolongation associated with hydroxychloroquine or chloroquine in combination with azithromycin, especially their increased use through the outpatient prescriptions for treating or preventing COVID-19 (53).…”

Section: Discussionmentioning

confidence: 99%

Assessing the Elevation of Cardiac Biomarkers and the Severity of COVID-19 Infection: A Meta-analysis

Walker

Deb²,

Ling³

et al. 2020

J Pharm Pharm Sci

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- Purpose: Since December 2019, coronavirus disease 2019 infection has become a global pandemic. The cases of Coronavirus Disease 2019 (COVID-19)-related acute cardiac injury with unknown pathophysiologic mechanism has become increasingly prevalent. However, it is not yet understood how the extent of cardiac injury differs with the intensity of viral infection. In the current study, we aimed to assess the association between elevated cardiac biomarkers and the severity of COVID-19 infection. Methods: A systematic literature search was performed across PubMed and Embase databases from December 1, 2019 to July 10, 2020, to identify studies that reported cardiac biomarkers of troponin (TnI) and creatine kinase-myocardial band (CK-MB) in patients with COVID-19. These studies compared non-severe patients with severe patients, or survivors with non-survivors or medical patients with critically ill patients. The data were extracted for TnI, CK-MB, N-terminal-brain natriuretic peptide (NT-BNP), D-dimer, and lactate dehydrogenase (LDH), C-reactive protein (CRP), and interleukin 6 (IL-6). Wherever possible, the data were pooled for meta-analysis (Review Manager, RevMan. version 5.3) with standard or weighted mean or median difference and corresponding 95% confidence intervals (95% CI). Results: A total of 25 studies involving 5,626 patients were included in the present analysis. More severe COVID-19 infection was found to be associated with higher mean values of TnI (-0.54 [-0.72, -0.36]) (ng/mL), CK-MB (-1.55 [-2.23, -0.88]) (ng/mL) and (-4.75 [-13.31, 3.82]) (units/L), NT-BNP (-815.7 [-1073.97, -557.42]) (pg/mL), D-dimer (-1.4 [-2.04, -0.77]) (mcg/mL), and LDH (-176.59 [-224.11, -129.06]) (units/L), as well as CRP (-64.03 [-68.88, -59.19]) (mg/L) and IL-6 (-22.59 [-29.39, -15.79]) (pg/mL). Conclusions: There is significant association between elevated cardiac biomarkers and the severity of COVID-19, which underlines the increased risk of acute cardiac injury with more severe viral infection. This highlights the need to understand the cardiac history among the COVID-19 patients during initial assessment and for monitoring.

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Section: Discussionmentioning

confidence: 99%

Assessing the Elevation of Cardiac Biomarkers and the Severity of COVID-19 Infection: A Meta-analysis

Walker

Deb²,

Ling³

et al. 2020

J Pharm Pharm Sci

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“…Maraj et al retrospectively studied 91 patients admitted consecutively to a single centre for COVID-19 and treated with HCQ + azithromycin (dose not described) [25]. All patients underwent a baseline ECG and continuous telemetry monitoring.…”

Section: Studies Addressing Cardiac Adverse Eventsmentioning

confidence: 99%

Update I. A systematic review on the efficacy and safety of chloroquine/hydroxychloroquine for COVID-19

Cortegiani

Ippolito

Ingoglia

et al. 2020

Journal of Critical Care

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Purpose: To assess efficacy and safety of chloroquine (CQ)/hydroxychloroquine (HCQ) for treatment or prophylaxis of COVID-19 in adult humans. Materials and methods: MEDLINE, PubMed, EMBASE and two pre-print repositories (bioRxiv, medRxiv) were searched from inception to 8th June 2020 for RCTs and nonrandomized studies (retrospective and prospective, including single-arm, studies) addressing the use of CQ/HCQ in any dose or combination for COVID-19. Results: Thirty-two studies were included (6 RCTs, 26 nonrandomized, 29,192 participants). Two RCTs had high risk, two 'some concerns' and two low risk of bias (Rob2). Among nonrandomized studies with comparators, nine had high risk and five moderate risk of bias (ROBINS-I). Data synthesis was not possible. Low and moderate risk of bias studies suggest that treatment of hospitalized COVID-19 with CQ/HCQ may not reduce risk of death, compared to standard care. High dose regimens or combination with macrolides may be associated with harm. Postexposure prophylaxis may not reduce the rate of infection but the quality of the evidence is low. Conclusions: Patients with COVID-19 should be treated with CQ/HCQ only if monitored and within the context of high quality RCTs. High quality data about efficacy/safety are urgently needed.

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“…The likelihood of prolonged QTc was reportedly greater in patients receiving concomitant loop diuretics or had a baseline QTc ≥ 450 ms 73 . In the study by Maraj et al, 74 one patient developed polymorphic ventricular tachycardia which degenerated into ventricular fibrillation and another developed self‐terminating TdP. Collectively, these five studies suggest that although a significant proportion of patients develop marked prolongation of QTc interval at the doses studied, the risk of a proarrhythmia is very small.…”

Section: Current Efforts At Repurposing Cq and Hcq For Covid‐19 Infecmentioning

confidence: 92%

“…QT‐related findings from five studies, investigating the QT liability of HCQ, are summarized in Table 3. The dose of HCQ used was 800 mg on day 1 followed by 400 mg daily for 4 days in three studies 70,71,73 and 400 mg for 10 days in one 72 ; the dosing scheme was not specified in the other 74 . Concomitant AZM (250‐500 mg for 5 days) was variously administered in all the five studies.…”

Section: Current Efforts At Repurposing Cq and Hcq For Covid‐19 Infecmentioning

confidence: 99%

Chloroquine and hydroxychloroquine for COVID‐19: Perspectives on their failure in repurposing

Shah

2020

J Clin Pharm Ther

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What is known and Objective Non‐clinical studies suggest that chloroquine (CQ) and hydroxychloroquine (HCQ) have antiviral activities. Early clinical reports of successful HCQ‐associated reduction in viral load from small studies in COVID‐19 patients spurred a large number of national and international clinical trials to test their therapeutic potential. The objective of this review is to summarize the current evidence on the safety and efficacy of these two agents and to provide a perspective on why their repurposing has hitherto failed. Methods Published studies and rapidly emerging data were reviewed to gather evidence on safety and efficacy of CQ and HCQ in patients with COVID‐19 infection or as prophylaxis. The focus is on clinically relevant efficacy endpoints and their adverse effects on QT interval. Results and Discussion At the doses used, the two agents, given alone or with azithromycin (AZM), are not effective in COVID‐19 infection. The choice of (typically subtherapeutic) dosing regimens, influenced partly by "QT‐phobia," varied widely and seems anecdotal without any pharmacologically reliable supporting clinical evidence. A substantial proportion of patients receiving CQ/HCQ/AZM regimen developed QTc interval prolongation, many with absolute QTc interval exceeding the potential proarrhythmic threshold, but very few developed proarrhythmia. What is new and Conclusion The strategy to repurpose CQ/HCQ to combat COVID‐19 infection is overshadowed by concerns about their QT liability, resulting in choice of potentially subtherapeutic doses. Although the risk of QT‐related proarrhythmia is real, it is low and manageable by careful monitoring. Recent discontinuation of HCQ from at least four large studies effectively marks the end of efforts at repurposing of CQ or HCQ for COVID‐19 infection. This episode leaves behind important questions on dose selection and risk/benefit balance in repurposing drugs generally.

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Incidence and determinants of QT interval prolongation in COVID‐19 patients treated with hydroxychloroquine and azithromycin

Cited by 33 publications

References 7 publications

Assessing the Elevation of Cardiac Biomarkers and the Severity of COVID-19 Infection: A Meta-analysis

Assessing the Elevation of Cardiac Biomarkers and the Severity of COVID-19 Infection: A Meta-analysis

Update I. A systematic review on the efficacy and safety of chloroquine/hydroxychloroquine for COVID-19

Chloroquine and hydroxychloroquine for COVID‐19: Perspectives on their failure in repurposing

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