Clinical update of medications associated with QT prolongation among COVID-19 patients

Abstract

In the struggle against COVID-19 pandemic, chloroquine (CQ) (a 4-aminoquinoline) and its derivative hydroxychloroquine (HCQ) have both been used as a potential form of treatment among infected patients. Originally known as an antimalarial quinolone, many countries have adopted their use as an option to treat COVID-19 patients. In humans, dose-dependent chloroquine induces QT interval prolongation. It also blocks the human ether-a-go-go-related gene (hERG), which encodes the rapidly activating delayed rectifier K+ channel. The action potential duration is then prolonged, as the eventual QTc interval of the electrocardiogram (ECG), resulting in torsade de pointes and cardiac arrhythmias that could lead to sudden death. It is yet unknown whether COVID-19 itself has any effect on the QTc interval. The current review established what is new and different from other studies involving the use of chloroquine and hydroxychloroquine among COVID-19 patients plus the corresponding QT interval prolongation in affected individuals.

Keywords

• Long QT prolongation
• hERG
• ionic channels
• drug repurposing
• mobile devices
• SARS-CoV-2

References

1. 1. Worldometer. Reported cases and deaths by country, territory, or conveyance Globally: Worldometer; 2020 [July 5, 2020]. Available from: https://www.worldometers.info/.
2. 2. Bavel JJV, Baicker K, Boggio PS, Capraro V, Cichocka A, Cikara M, et al. Using social and behavioural science to support COVID-19 pandemic response. Nat Hum Behav 2020;4:460-71.
3. 3. Sanders JM, Monogue ML, Jodlowski TZ, Cutrell JB. Pharmacologic treatments for coronavirus disease 2019 (COVID-19): a review. JAMA 2020;323:1824-36.
4. 4. 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. Nat Med 2020;26:808-9.
5. 5. Michaud V, Dow P, Al Rihani SB, Deodhar M, Arwood M, Cicali B, et al. Risk assessment of drug-induced long QT syndrome for some COVID-19 repurposed drugs. Clin Transl Sci 2021;14:20-8.
6. 6. Zhou Y, Wang F, Tang J, Nussinov R, Cheng F. Artificial intelligence in COVID-19 drug repurposing. Lancet Digit Health 2020;2:e667-76.
7. 7. Jankelson L, Karam G, Becker ML, Chinitz LA, Tsai MC. QT prolongation, torsades de pointes, and sudden death with short courses of chloroquine or hydroxychloroquine as used in COVID-19: a systematic review. Heart Rhythm 2020;17:1472-9.
8. 8. Manolis AS, Manolis AA, Manolis TA, Apostolopoulos EJ, Papatheou D, Melita H. COVID-19 infection and cardiac arrhythmias. Trends Cardiovasc Med 2020;30:451-60.

9. 9. Wang Y, Wang Z, Tse G, Zhang L, Wan EY, Guo Y, et al. Cardiac arrhythmias in patients with COVID-19. J Arrhythm 2020;36:827-36.
10. 10. Babapoor-Farrokhran S, Rasekhi RT, Gill D, Babapoor S, Amanullah A. Arrhythmia in COVID-19. SN Compr Clin Med 2020;2:1430-5.
11. 11. Kochav SM, Coromilas E, Nalbandian A, Ranard LS, Gupta A, Chung MK, et al. Cardiac arrhythmias in COVID-19 infection. Circ Arrhythm Electrophysiol 2020;13:e008719.
12. 12. Lakkireddy DR, Chung MK, Gopinathannair R, Patton KK, Gluckman TJ, Turagam M, et al. Guidance for cardiac electrophysiology during the COVID-19 pandemic from the Heart Rhythm Society COVID-19 Task Force; Electrophysiology Section of the American College of Cardiology; and the Electrocardiography and Arrhythmias Committee of the Council on Clinical Cardiology, American Heart Association. Heart Rhythm 2020;17:e233-41.
13. 13. Makkar RR, Fromm BS, Steinman RT, Meissner MD, Lehmann MH. Female gender as a risk factor for torsades de pointes associated with cardiovascular drugs. JAMA 1993;270:2590-7.
14. 14. Bednar MM, Harrigan EP, Ruskin JN. Torsades de pointes associated with nonantiarrhythmic drugs and observations on gender and QTc. Am J Cardiol 2002;89:1316-9.
15. 15. Lehmann MH, Hardy S, Archibald D, quart B, MacNeil DJ. Sex difference in risk of torsade de pointes with d,l-sotalol. Circulation 1996;94:2535-41.
16. 16. Darpo B, Karnad DR, Badilini F, Florian J, Garnett CE, Kothari S, et al. Are women more susceptible than men to drug-induced QT prolongation? Concentration-QTc modelling in a phase 1 study with oral rac-sotalol. Br J Clin Pharmacol 2014;77:522-31.
17. 17. Rosenberg ES, Dufort EM, Udo T, Wilberschied LA, Kumar J, Tesoriero J, et al. Association of treatment with hydroxychloroquine or azithromycin with in-hospital mortality in patients with COVID-19 in New York State. JAMA 2020;323:2493-502.
18. 18. Tristani-Firouzi M, Chen J, Mitcheson JS, Sanguinetti MC. Molecular biology of K(+) channels and their role in cardiac arrhythmias. Am J Med 2001;110:50-9.
19. 19. Li G, Cheng G, Wu J, Zhou X, Liu P, Sun C. Drug-induced long QT syndrome in women. Adv Ther 2013;30:793-802.
20. 20. Molokhia M, Pathak A, Lapeyre-Mestre M, Caturla L, Montastruc JL, L'Association Francaise des Centres Regionaux de P, et al. Case ascertainment and estimated incidence of drug-induced long-QT syndrome: study in Southwest France. Br J Clin Pharmacol 2008;66:386-95.
21. 21. Shah RR. Chloroquine and hydroxychloroquine for COVID-19: Perspectives on their failure in repurposing. J Clin Pharm Ther 2021;46:17-27.
22. 22. Saleh M, Gabriels J, Chang D, Soo Kim B, Mansoor A, Mahmood E, et al. Effect of chloroquine, hydroxychloroquine, and azithromycin on the corrected QT interval in patients with SARS-CoV-2 infection. Circ Arrhythm Electrophysiol 2020;13:e008662.
23. 23. Shah RR. Drug-induced QT interval prolongation: does ethnicity of the thorough QT study population matter? Br J Clin Pharmacol 2013;75:347-58.
24. 24. 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). Clin Infect Dis 2020;71:732-9.
25. 25. Pastick KA, Okafor EC, Wang F, Lofgren SM, Skipper CP, Nicol MR, et al. Review: hydroxychloroquine and chloroquine for treatment of SARS-CoV-2 (COVID-19). Open Forum Infect Dis 2020;7:ofaa130.
26. 26. Giudicessi JR, Noseworthy PA, Friedman PA, Ackerman MJ. Urgent guidance for navigating and circumventing the QTc-prolonging and torsadogenic potential of possible pharmacotherapies for coronavirus disease 19 (COVID-19). Mayo Clin Proc 2020;95:1213-21.
27. 27. Gupta A, Malviya A. Chloroquine and hydroxychloroquine for COVID-19: time to close the chapter. Postgraduate Med J 2021;97:676-7.
28. 28. Varma N, Marrouche NF, Aguinaga L, Albert CM, Arbelo E, Choi JI, et al. HRS/EHRA/APHRS/LAHRS/ACC/AHA Worldwide Practice Update for telehealth and arrhythmia monitoring during and after a pandemic. Circ Arrhythm Electrophysiol 2020;13:e009007.
29. 29. Nair TRG. Advances in Electrocardiogram Information Management. In: Khosrow-Pour M, editor. Encyclopedia of Information Science and Technology. 3rd ed. Pennsylvania: IGI Global, 2015: pp. 3296-304.
30. 30. Roden DM, Harrington RA, Poppas A, Russo AM. Considerations for drug interactions on QTc in exploratory COVID-19 treatment. Circulation 2020;141:e906-7.
31. 31. O'Hare M, Maldonado Y, Munro J, Ackerman MJ, Ramakrishna H, Sorajja D. Perioperative management of patients with congenital or acquired disorders of the QT interval. Br J Anaesth 2018;120:629-44.
32. 32. Guo T, Fan Y, Chen M, Wu X, Zhang L, He T, et al. Cardiovascular implications of fatal outcomes of patients with coronavirus disease 2019 (COVID-19). JAMA Cardiol 2020;5:811-8.
33. 33. Minhas AS, Scheel P, Garibaldi B, Liu G, Horton M, Jennings M, et al. Takotsubo syndrome in the setting of COVID-19. JACC Case Rep 2020;2:1321-5.
34. 34. Lazzerini PE, Laghi-Pasini F, Acampa M, Boutjdir M, Leopoldo Capecchi P. IL-6 (interleukin 6) blockade and heart rate corrected QT interval prolongation in COVID-19. Circ Arrhythm Electrophysiol 2020;13:e008791.
35. 35. De Clercq E. Remdesivir: Quo vadis? Biochem Pharmacol 2021;193:114800.
36. 36. Cave JA, Phizackerley D. Molnupiravir: evidence by press release. Drug Ther Bull 2022;60:2.
37. 37. Heskin J, Pallett SJC, Mughal N, Davies GW, Moore LSP, Rayment M, et al. Caution required with use of ritonavir-boosted PF-07321332 in COVID-19 management. Lancet 2022;399:21-2.
38. 38. Montgomery H, Hobbs FDR, Padilla F, Arbetter D, Templeton A, Seegobin S, et al. Efficacy and safety of intramuscular administration of tixagevimab-cilgavimab for early outpatient treatment of COVID-19 (TACKLE): a phase 3, randomised, double-blind, placebo-controlled trial. Lancet Respir Med 2022. doi: 10.1016/S2213-2600(22)00180-1
39. 39. Self WH, Semler MW, Leither LM, Casey JD, Angus DC, Brower RG, et al. Effect of hydroxychloroquine on clinical status at 14 days in hospitalized patients with COVID-19: a randomized clinical trial. JAMA 2020;324:2165-76.
40. 40. White NJ, Watson JA, Hoglund RM, Chan XHS, Cheah PY, Tarning J. COVID-19 prevention and treatment: A critical analysis of chloroquine and hydroxychloroquine clinical pharmacology. PLoS Med 2020;17:e1003252.
41. 41. Tleyjeh IM, Kashour Z, AlDosary O, Riaz M, Tlayjeh H, Garbati MA, et al. Cardiac toxicity of chloroquine or hydroxychloroquine in patients with COVID-19: a systematic review and meta-regression analysis. Mayo Clin Proc Innov Qual Outcomes. 2021;5:137-50.
42. 42. Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet 2020;395:1054-62.
43. 43. Funck-Brentano C, Salem JE, Nguyen LS, Drici MD, Roden DM. Response to the editorial "COVID-19 in patients with cardiovascular diseases": Covid-19 treatment with hydroxychloroquine or chloroquine and azithromycin: A potential risk of Torsades de Pointes. Arch Cardiovasc Dis 2020;113:367-8.
44. 44. Fiolet T, Guihur A, Rebeaud ME, Mulot M, Peiffer-Smadja N, Mahamat-Saleh Y. Effect of hydroxychloroquine with or without azithromycin on the mortality of coronavirus disease 2019 (COVID-19) patients: a systematic review and meta-analysis. Clin Microbiol Infect 2021;27:19-27.
45. 45. Chalmers JD, Crichton ML, Goeminne PC, Cao B, Humbert M, Shteinberg M, et al. Management of hospitalised adults with coronavirus disease 2019 (COVID-19): a European Respiratory Society living guideline. Eur Respir J 2021;57:2100048.
46. 46. WHO Solidarity Trial Consortium; Pan H, Peto R, Henao-Restrepo AM, Preziosi MP, Sathiyamoorthy V, Karim QA, et al. Repurposed antiviral drugs for Covid-19 - interim WHO solidarity trial results. N Eng J Med 2021;384:497-511.
47. 47. Levett JY, Raparelli V, Mardigyan V, Eisenberg MJ. Cardiovascular pathophysiology, epidemiology, and treatment considerations of coronavirus disease 2019 (COVID-19): a review. CJC Open 2021;3:28-40.