The Effect of Chloroquine, Hydroxychloroquine and Azithromycin on the Corrected QT Interval in Patients with SARS-CoV-2 Infection
MD Moussa Saleh, MD James Gabriels, MD David Chang, ; Beom, MD Soo Kim, MD Amtul Mansoor, MD Eitezaz Mahmood, MD Parth Makker, MD Haisam Ismail, MD Bruce Goldner, MD Jonathan Willner, MD Stuart Beldner, MD Raman Mitra, MBBS Roy John, MD Jason Chinitz, MD Nicholas Skipitaris, MD Stavros Mountantonakis, MD Laurence M Epstein
Background -The novel SARs-CoV-2 coronavirus is responsible for the global COVID-19 pandemic. Small studies have shown a potential benefit of chloroquine/hydroxychloroquine ± azithromycin for the treatment of COVID-19. Use of these medications alone, or in combination, can lead to a prolongation of the QT interval, possibly increasing the risk of Torsade de pointes (TdP) and sudden cardiac death. Methods -Hospitalized patients treated with chloroquine/hydroxychloroquine ± azithromycin from March 1st through the 23rd at three hospitals within the Northwell Health system were included in this prospective, observational study. Serial assessments of the QT interval were performed. The primary outcome was QT prolongation resulting in TdP. Secondary outcomes included QT prolongation, the need to prematurely discontinue any of the medications due to QT prolongation and arrhythmogenic death. Results -Two hundred one patients were treated for COVID-19 with chloroquine/hydroxychloroquine. Ten patients (5.0%) received chloroquine, 191 (95.0%) received hydroxychloroquine and 119 (59.2%) also received azithromycin. The primary outcome of TdP was not observed in the entire population. Baseline QTc intervals did not differ between patients treated with chloroquine/hydroxychloroquine (monotherapy group) vs. those treated with combination group (chloroquine/hydroxychloroquine and azithromycin) (440.6 ± 24.9 ms vs. 439.9 ± 24.7 ms, p =0.834). The maximum QTc during treatment was significantly longer in the combination group vs the monotherapy group (470.4 ± 45.0 ms vs. 453.3 ± 37.0 ms, p = 0.004). Seven patients (3.5%) required discontinuation of these medications due to QTc prolongation. No arrhythmogenic deaths were reported. Conclusions -In the largest reported cohort of COVID-19 patients to date treated with chloroquine/hydroxychloroquine ± azithromycin, no instances of TdP or arrhythmogenic death were reported. Although use of these medications resulted in QT prolongation, clinicians seldomly needed to discontinue therapy. Further study of the need for QT interval monitoring is needed before final recommendations can be made.
*These patients were monitored with MCOTs. The remainder were monitored with 12-lead electrocardiograms. †The cause of death for these patients was multi-system organ failure. ‡F: female, M: male, HCQ: hydroxychloroquine, AZM: azithromycin, CAD: coronary artery disease, HF: heart failure, EF: ejection fraction, HS: high sensitivity, Trop: troponin, K: potassium, Mg: magnesium, Ca 2+ : calcium, ICU: intensive care unit *This was the only patient that monitored with an MCOT. The remainder were monitored with 12-lead electrocardiograms. †A transthoracic echocardiogram performed during the admission showed apical and mid left ventricular hypokinesis with sparing of the basal segments. ‡The cause of death was hypoxic respiratory failure and sepsis for both patients. F: female, M: male, §HCQ: hydroxychloroquine, AZM: azithromycin, CAD: coronary artery disease, HF: heart failure, EF: ejection fraction, HS: high sensitivity, Trop: troponin, K: potassium, Mg: magnesium, Ca 2+ : calcium, ICU: intensive care unit QTc of 40-60 ms and >60 ms. QTc = Corrected QT; HCQ = Hydroxychloroquine; AZM = Azithromycin. What is Known: • The antimalaria drugs chloroquine and hydroxychloroquine and the commonly used macrolide antibiotic azithromycin are all known to increase the corrected QT interval (QTc). • A QTc greater than 500 ms increases the risk of torsade de pointes by two to three-fold. Other risk factors include drug interactions affecting drug serum levels, concomitant use of QT..
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doi:10.1093/cid/ciaa237DOI record:
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"abstract": "<jats:sec>\n <jats:title>Background:</jats:title>\n <jats:p>The novel SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) is responsible for the global coronavirus disease 2019 pandemic. Small studies have shown a potential benefit of chloroquine/hydroxychloroquine±azithromycin for the treatment of coronavirus disease 2019. Use of these medications alone, or in combination, can lead to a prolongation of the QT interval, possibly increasing the risk of Torsade de pointes and sudden cardiac death.</jats:p>\n </jats:sec>\n <jats:sec>\n <jats:title>Methods:</jats:title>\n <jats:p>Hospitalized patients treated with chloroquine/hydroxychloroquine±azithromycin from March 1 to the 23 at 3 hospitals within the Northwell Health system were included in this prospective, observational study. Serial assessments of the QT interval were performed. The primary outcome was QT prolongation resulting in Torsade de pointes. Secondary outcomes included QT prolongation, the need to prematurely discontinue any of the medications due to QT prolongation, and arrhythmogenic death.</jats:p>\n </jats:sec>\n <jats:sec>\n <jats:title>Results:</jats:title>\n <jats:p>\n Two hundred one patients were treated for coronavirus disease 2019 with chloroquine/hydroxychloroquine. Ten patients (5.0%) received chloroquine, 191 (95.0%) received hydroxychloroquine, and 119 (59.2%) also received azithromycin. The primary outcome of torsade de pointes was not observed in the entire population. Baseline corrected QT interval intervals did not differ between patients treated with chloroquine/hydroxychloroquine (monotherapy group) versus those treated with combination group (chloroquine/hydroxychloroquine and azithromycin; 440.6±24.9 versus 439.9±24.7 ms,\n <jats:italic>P</jats:italic>\n =0.834). The maximum corrected QT interval during treatment was significantly longer in the combination group versus the monotherapy group (470.4±45.0 ms versus 453.3±37.0 ms,\n <jats:italic>P</jats:italic>\n =0.004). Seven patients (3.5%) required discontinuation of these medications due to corrected QT interval prolongation. No arrhythmogenic deaths were reported.\n </jats:p>\n </jats:sec>\n <jats:sec>\n <jats:title>Conclusions:</jats:title>\n <jats:p>In the largest reported cohort of coronavirus disease 2019 patients to date treated with chloroquine/hydroxychloroquine±azithromycin, no instances of Torsade de pointes, or arrhythmogenic death were reported. Although use of these medications resulted in QT prolongation, clinicians seldomly needed to discontinue therapy. Further study of the need for QT interval monitoring is needed before final recommendations can be made.</jats:p>\n </jats:sec>",
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