Safety monitoring of chloroquine and hydroxychloroquine in COVID-19 patients in Indonesia on QT prolongation: hospital based monitoring study
Chloroquine (CQ) and Hydroxychloroquine (HCQ) are the challenging drugs used for COVID-19. Several studies show its beneficial, however, both medications can prolong the QTc interval and increase the risk of patients for torsades de pointes and death. The Tisdale score is identified to have successfully predicted the at-risk population of side effects of these drugs. This study aim to evaluate the QT prolongation caused by the administration of chloroquine and hydroxychloroquine in COVID-19 patients and the association with the treatment outcomes based on their Tisdale score. We conducted an observational study on 213 hospitalized patients with confirmed or suspect COVID-19 in 6 referral hospitals in Indonesia. All baseline demographic such as age and gender, RT-PCR test result, severity of disease, history of cardiovascular disease (myocardial infarction, heart failure, hypertension), serum kalium level at baseline, and the use of medication associated with risk QTc interval prolongation were collected. The Tisdale risk score was used for predicting high-risk patients for QT corrected (QTc) interval prolongation. Out of 213 patients who were treated with CQ/HCQ, there were 60 (28.2%) patients had QTc interval prolongation, included 43 patients (20.2%) who had normal QTc interval at baseline and at the end of treatment had prolong interval; or 17 patients (8.0%) who had QTc interval more than 470 msec at baseline and QTc interval prolongation was worsen at the end of treatment. Several factors, including age more than 50 years, COVID-19 confirm PCR, and had comorbidity heart failure, were statistically significant associated with QTc interval prolongation. The high-risk score of Tisdale score have increased risk significantly on QTc interval prolongation (RR: 2.15, 95%CI 1.07-4.32) and associated with risk of death (RR: 3.50, 95%CI 1.34-9.13) compared to low-risk score. Our findings showed that the treatment of CQ/HCQ in COVID-19 patients is associated with QTc prolongation. The Tisdale score can be used as a valuable tool to predict the COVID-19 patients’ outcome after treatment of these QTc-prolonging drugs.
2. World Health Organization. Coronavirus disease (COVID-19), 05 March 2023. 2023.
3. Kupferschmidt K, Cohen J. WHO launches global megatrial of the four most promising coronavirus treatments. Science. 2020;22(3).
4. Yao X, Ye F, Zhang M, Cui C, Huang B, Niu P, et al. In vitro antiviral activity and projection of optimized dosing design of hydroxychloroquine for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Clinical infectious diseases. 2020;71(15):732-9.
5. Gao J, Tian Z, Yang X. Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies. Bioscience trends. 2020;14(1):72-3.
6. Savarino A, Boelaert JR, Cassone A, Majori G, Cauda R. Effects of chloroquine on viral infections: an old drug against today's diseases. The Lancet infectious diseases. 2003;3(11):722-7.
7. Chatre C, Roubille F, Vernhet H, Jorgensen C, Pers Y-M. Cardiac Complications Attributed to Chloroquine and Hydroxychloroquine: A Systematic Review of the Literature. Drug Safety. 2018;41(10):919-31.
8. Tisdale JE, Jaynes HA, Kingery JR, Mourad NA, Trujillo TN, Overholser BR, et al. Development and validation of a risk score to predict QT interval prolongation in hospitalized patients. Circulation: Cardiovascular Quality and Outcomes. 2013;6(4):479-87.
9. Hu TY, Frieman M, Wolfram J. Insights from nanomedicine into chloroquine efficacy against COVID-19. Nature Nanotechnology. 2020;15(4):247-9.
10. Mitra RL, Greenstein SA, Epstein LM. An algorithm for managing QT prolongation in coronavirus disease 2019 (COVID-19) patients treated with either chloroquine or hydroxychloroquine in conjunction with azithromycin: Possible benefits of intravenous lidocaine. HeartRhythm case reports. 2020;6(5):244-8.
11. Chorin E, Dai M, Shulman E, Wadhwani L, Bar-Cohen R, Barbhaiya C, et al. The QT interval in patients with COVID-19 treated with hydroxychloroquine and azithromycin. Nature medicine. 2020;26(6):808-9.
12. Borba MGS, Val FFA, Sampaio VS, Alexandre MAA, Melo GC, Brito M, et al. Effect of high vs low doses of chloroquine diphosphate as adjunctive therapy for patients hospitalized with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection: a randomized clinical trial. JAMA network open. 2020;3(4):e208857-e.
13. Lane JC, Weaver J, Kostka K, Duarte-Salles T, Abrahao MTF, Alghoul H, et al. Safety of hydroxychloroquine, alone and in combination with azithromycin, in light of rapid wide-spread use for COVID-19: a multinational, network cohort and self-controlled case series study. MedRxiv. 2020.
14. Cao B, Wang Y, Wen D, Liu W, Wang J, Fan G, et al. A trial of lopinavir–ritonavir in adults hospitalized with severe Covid-19. New England journal of medicine. 2020.
15. Roden DM. Drug-induced prolongation of the QT interval. New England Journal of Medicine. 2004;350(10):1013-22.
16. Nachimuthu S, Assar MD, Schussler JM. Drug-induced QT interval prolongation: mechanisms and clinical management. Therapeutic advances in drug safety. 2012;3(5):241-53.
17. Zequn Z, Yujia W, Dingding Q, Jiangfang L. Off-label use of chloroquine, hydroxychloroquine, azithromycin and lopinavir/ritonavir in COVID-19 risks prolonging the QT interval by targeting the hERG channel. European Journal of Pharmacology. 2021;893:173813.
18. Ponte ML, Keller GA, Girolamo GD. Mechanisms of drug induced QT interval prolongation. Current drug safety. 2010;5(1):44-53.
19. Ma Q, Li Z, Guo X, Guo L, Yu S, Yang H, et al. Prevalence and risk factors of prolonged corrected QT interval in general Chinese population. BMC cardiovascular disorders. 2019;19:1-10.
20. O’Connell TF, Bradley CJ, Abbas AE, Williamson BD, Rusia A, Tawney AM, et al. Hydroxychloroquine/azithromycin therapy and QT prolongation in hospitalized patients with COVID-19. Clinical Electrophysiology. 2021;7(1):16-25.
21. Pornwattanakavee SP, Priksri W, Leelakanok N. QTc prolongation in patients with COVID-19: a retrospective chart review. Translational and clinical pharmacology. 2021;29(4):197-205.
22. Mangoni AA, Kinirons MT, Swift CG, Jackson SH. Impact of age on QT interval and QT dispersion in healthy subjects: a regression analysis. Age and ageing. 2003;32(3):326-31.
23. Wu C-I, Postema PG, Arbelo E, Behr ER, Bezzina CR, Napolitano C, et al. SARS-CoV-2, COVID-19, and inherited arrhythmia syndromes. Heart rhythm. 2020;17(9):1456-62.
24. White NJ. Cardiotoxicity of antimalarial drugs. The Lancet infectious diseases. 2007;7(8):549-58.
25. Burhan E, Susanto A, Nasution S, Ginanjar E, Pitoyo C, Susilo A. Protokol Tatalaksana COVID-19, edisi 1 April 2020. Perhimpunan Dokter Paru Indonesia (PDPI) Perhimpunan Dokter Spesialis Kardiovaskular Indonesia (PERKI) Perhimpunan Dokter Spesialis Penyakit Dalam Indonesia (PAPDI) Perhimpunan Dokter Anestesiologi dan Terapi Intensif Indonesia (PERDATIN) Ikatan Dokter Anak Indonesia (IDAI) Jakarta, Indonesia. 2020.
26. Hartopo AB, Trisnawati I, Budiono E, Jhundy BW, Anggraeni VY. The use of Tisdale risk score during hydroxychloroquine/chloroquine treatments on COVID-19 patients. ACI (Acta Cardiologia Indonesiana). 2021;7(1):19-23.
27. Naderi Z, Tajmirriahi M, Dolatshahi K, Hashemi H, Sadeghi S, Mansouri V, et al. Tisdale score successfully predict outcomes of QT-prolonging treatment in COVID-19 patients. Immunopathologia Persa. 2022.