Chloroquine, but not hydroxychlorquine, prolongs the QT interval in a primary care population
MSc Jonas L Isaksen, MD, PhD b , Anders G Holst, MD d Adrian Pietersen, MD, PhD Jonas B Nielsen, MSc, PhD Claus Graff, MD Jørgen K Kanters
doi:10.1101/2020.06.19.20135475
Background-Chloroquine (CQ) and Hydroxychloroquine (HCQ) have recently been suggested as treatment for the current Corona Virus Disease 2019 (COVID-19) pandemic. However, despite their long-term use and only few case reports on adverse effects, CQ and HCQ are listed as a known risk of the lethal ventricular arrhythmia Torsade de Pointes and their cardiac safety profile is being questioned. Thus, we aimed to investigate the electrocardiographic and mortality effects of CQ and HCQ in a primary care population. Methods-We used Danish health care registers and electrocardiograms (ECGs) from primary care to define three studies. 1) A paired study of subjects with ECGs before and during use of CQ/HCQ, 2) a matched ECG study of subjects taking CQ/HCQ compared to controls, and 3) a mortality study on people taking HCQ matched to control. In both matched studies, we adjusted for connective tissue diseases, use of QT-prolonging drugs, and cardiac disease. We used the QTc interval as the marker for electrocardiographic safety. In the mortality study, cases were followed from first claimed prescription until 300 days after estimated completion of the last prescription. 95% confidence intervals follow estimates in parenthesis. Results-Use of CQ was associated with a 5.5 (0.7;10) ms increase in QTc in the paired study (n=10). In the matched study (n=28, controls=280), QTc was insignificantly increased in subjects taking CQ by 4.7 (-3.4;13) ms. With a ΔQTc of 1.0 (-5.6;7.5), use of HCQ was not associated with an increased QTc in the paired study (n=32). In the matched study (n=172, controls=1,720), QTc also was not different between groups (p=0.5). In the mortality study (n=3,368), use of HCQ was associated with a hazard ratio of 0.67 (0.43;1.05). Conclusions-In subjects free of COVID-19, we found a small increase in QTc associated with use of chloroquine, but not hydroxychloroquine. We found no increased mortality associated with use of hydroxychloroquine. is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
References
Bessière, Roccia, Delinière, Charrière, Chevalier 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
Capel, Herring, Kalla, Yavari, Mirams et al., Hydroxychloroquine reduces heart rate by modulating the hyperpolarization-activated current If: Novel electrophysiological insights and therapeutic potential, Heart Rhythm
Chen, Wang, Lin, Chronic hydroxychloroquine use associated with QT prolongation and refractory ventricular arrhythmia, Clin Toxicol (Phila)
Gautret, Lagier, Parola, Hoang, Meddeb et al., Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial, Int J Antimicrob Agents
Ghouse, Isaksen, Skov, Lind, Svendsen et al., Effect of diabetes duration on the relationship between glycaemic control and risk of death in older adults with type 2 diabetes, Diabetes Obes Metab
Kapoor, Kapoor, Role of Chloroquine and Hydroxychloroquine in the Treatment of COVID-19
Mcchesney, Animal toxicity and pharmacokinetics of hydroxychloroquine sulfate, Am J Med
Mercuro, Yen, Shim, Maher, Mccoy 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, JAMA Cardiol
Morgan, Patel, Dvorkina, Suspected hydroxychloroquine-associated QT-interval prolongation in a patient with systemic lupus erythematosus, J Clin Rheumatol
Mzayek, Deng, Mather, Wasilevich, Liu et al., Randomized dose-ranging controlled trial of AQ-13, a candidate antimalarial, and chloroquine in healthy volunteers, PLoS Clin Trials
O'laughlin, Mehta, Wong, Life Threatening Severe QTc Prolongation in Patient with Systemic Lupus Erythematosus due to Hydroxychloroquine, Case Rep Cardiol
Saleh, Gabriels, Chang, Kim, Mansoor et al., The Effect of Chloroquine, Hydroxychloroquine and Azithromycin on the Corrected QT Interval in Patients with SARS-CoV-2 Infection, Circ Arrhythm Electrophysiol
Shi, Qin, Shen, Cai, Liu et al., Association of Cardiac Injury With Mortality in Hospitalized Patients With COVID-19 in Wuhan, China, JAMA Cardiol
Sinha, Balayla, Hydroxychloroquine and covid-19, Postgrad Med J
Vicente, Johannesen, Mason, Crumb, Pueyo et al., Comprehensive T wave morphology assessment in a randomized clinical study of dofetilide, quinidine, ranolazine, and verapamil, J Am Heart Assoc
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DOI record:
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"abstract": "<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>Chloroquine (CQ) and Hydroxychloroquine (HCQ) have recently been suggested as treatment for the current Corona Virus Disease 2019 (COVID-19) pandemic. However, despite their long-term use and only few case reports on adverse effects, CQ and HCQ are listed as a known risk of the lethal ventricular arrhythmia Torsade de Pointes and their cardiac safety profile is being questioned. Thus, we aimed to investigate the electrocardiographic and mortality effects of CQ and HCQ in a primary care population.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>We used Danish health care registers and electrocardiograms (ECGs) from primary care to define three studies. 1) A paired study of subjects with ECGs before and during use of CQ/HCQ, 2) a matched ECG study of subjects taking CQ/HCQ compared to controls, and 3) a mortality study on people taking HCQ matched to control. In both matched studies, we adjusted for connective tissue diseases, use of QT-prolonging drugs, and cardiac disease. We used the QTc interval as the marker for electrocardiographic safety. In the mortality study, cases were followed from first claimed prescription until 300 days after estimated completion of the last prescription. 95% confidence intervals follow estimates in parenthesis.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Use of CQ was associated with a 5.5 (0.7;10) ms increase in QTc in the paired study (n=10). In the matched study (n=28, controls=280), QTc was insignificantly increased in subjects taking CQ by 4.7 (−3.4;13) ms. With a ΔQTc of 1.0 (−5.6;7.5), use of HCQ was not associated with an increased QTc in the paired study (n=32). In the matched study (n=172, controls=1,720), QTc also was not different between groups (p=0.5). In the mortality study (n=3,368), use of HCQ was associated with a hazard ratio of 0.67 (0.43;1.05).</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>In subjects free of COVID-19, we found a small increase in QTc associated with use of chloroquine, but not hydroxychloroquine. We found no increased mortality associated with use of hydroxychloroquine.</jats:p></jats:sec>",
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