• Jovan Bozidar Jovanovic Clinic for Cardiology, Clinical Center “Kragujevac”
  • Slobodan M. Jankovic
  • Natasa Zdravkovic
  • Goran Davidovic
  • Mirjana Veselinovic
  • Petar Canovic
  • Milan Zaric
  • Maja Sazdanovic
  • Predrag Sazdanovic
  • Katarina Pantic
  • Ivan Cekerevac
  • Marko M. Folic
  • Dejana Ruzic Zecevic
  • Dejan Baskic
  • Natasa Djordjevic
  • Dragan Milovanovic


Background: After the beginning of the COVID-19 pandemic caused by the SARS-CoV -2 virus, enormous pressure fell on the entire health system. Since there is no adequate cure for this disease, "off-label" use of several drugs (azithromycin, chloroquine, hydroxychloroquine, etc.) was resorted to. The aim of this study was to analyse QTc interval dynamics and its relationship with other factors which could influence outcome in patients with COVID-19.

Methods: Study has observational, case-control design with retrospective data collection from medical files of adult patients, with RT-PCR confirmed COVID-19. The cases (n=30) were subjects with fatal outcome and the controls (n=169) were the survivors. The QTc interval was calculated on admission, during and after initial drug treatments with presumed activity against SARS-CoV-2, mostly antimalarials. Primary independent and outcome variables were QTc interval prolongation and all-cause mortality, respectively.

Results: Study population included 120 males (60.3%), the mean patients’ agewas 57.3±15.8 years (±SD). The most common comorbid illnesses were hypertension (98 patients), pre-existing arrhythmias (32) and diabetes mellitus (29). The most frequently prescribed QTc prolonging drugs were azithromycin (69.8% of patients), chloroquine (50.3%) and hydroxychloroquine (42.7%). Total of 131 patients (65.8%) had QTc interval increase >60 ms from baseline, of whom 5 had QTc prolongation >500 ms (2.5%). De novo ventricular tachyarrhythmias were registered at 14 patients (7%) and 13 (92.8%) of them died. Pre-existing arrhythmias (odds ratio 9.30, 95% confidence interval 2.91-29.73, p<0.001) and furosemide (8.94, 3.27-24.41, p<0.001) were independently associated with mortality but QTc prolongation (>480 ms) did not (1.02, 0.22-4.67, p=0.974). Case fatality rate was 15.1%, as 30 patients died during hospitalization.

Conclusion: Clinical importance of drug-induced QTc interval prolongation of hospitalized patients with COVID-19 should be considered primarily within the context of other risks, particularly older age, pre-existing cardiovascular disorders and major electrolyte disturbances.


1. Brankovich Bolevich S, Frantzevich Litvitsky P, Vitalievich Grachev S, Ivanovich Vorobyev S, Sergeevna Orlova A, Anatolievna Fokina M, et al. Fundamental basis of COVID-19 pathogenesis. Ser J Exp Clin Res. 2020; 21: 93-111.
2. Aćimović J, Jandrić L, Đakovic-Dević J, Bojanić J, Subotić B, Radojčić T, et al. Epidemiological characteristics of COVID-19 infection in the Republic of Srpska: a hundred days survey. Scripta Medica. 2020; 51: 74-80.
3. Poduri R, Joshi G, Jagadeesh G. Drugs targeting various stages of the SARS-CoV-2 life cycle: Exploring promising drugs for the treatment of Covid-19. Cell Signal. 2020; 74: 109721.
4. Jankovic S. Antiviral therapy of COVID-19. Scr Med. 2020; 51: 131-133.
5. Bimonte S, Crispo A, Amore A, Celentano E, Cuomo A, Cascella M. Potential antiviral drugs for SARS-Cov-2 treatment: preclinical findings and ongoing clinical research. In Vivo. 2020; 34: 1597-1602.
6. RECOVERY Collaborative Group, Horby P, Lim WS, Emberson JR, Mafham M, Bell JL, et al. Dexamethasone in hospitalized patients with Covid-19 - preliminary report. N Engl J Med. 2020; NEJMoa2021436. doi: 10.1056/NEJMoa2021436. Online ahead of print.
7. Milovanović DR, Janković SM, Ružić Zečević D, Folić M, Rosić N, Jovanović D, et al. Treatment of coronavirus disease (COVID-19). Med Čas. 2020; 54: 23-43. (in Serbian).
8. Chinese Centre for Disease Control and Prevention. Diagnosis and treatment. COVID-19 Prevention and control. Bejing: Chinese Centre for Disease Control and Prevention, 2020. Available at: http://www.chinacdc.cn/en/COVID19/202002/P020200310326343385431.pdf , date accessed: 07/23/2021.
9. Mercuro NJ, Yen CF, Shim DJ, Maher TR, McCoy CM, Zimetbaum PJ, 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 2019 (COVID-19). JAMA Cardiol. 2020; 5: 1036-1041.
10. 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: 1472-1479.
11. Saleh M, Gabriels J, Chang D, Kim BS, 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.
12. Ramireddy A, Chugh H, Reinier K, Ebinger J, Park E, Thompson M, et al. Experience with hydroxychloroquine and azithromycin in the coronavirus disease 2019 pandemic: implications for QT interval monitoring. J Am Heart Assoc. 2020; 9: e017144.
13. Savić N, Gojković-Bukarica L. Long QT syndrome: genetic implications and drug influence. Vojnosanit Pregl. 2008; 65: 308-312.
14. Wang M, Cao R, Zhang L, Yang X, Liu J, Xu M, et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res. 2020; 30: 269-71.
15. Devaux CA, Rolain JM, Colson P, Raoult D. New insights on the antiviral effects of chloroquine against coronavirus: what to expect for COVID-19?. Int J Antimicrob Agents. 2020; 55: 105938.
16. Gautret P, Lagier JC, Parola P, Hoang VT, Meddeb L, Mailhe M, et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Int J Antimicrob Agents. 2020; 56: 105949.
17. Bleyzac N, Goutelle S, Bourguignon L, Tod M. Azithromycin for COVID-19: more than just an antimicrobial? Clin Drug Investig. 2020; 40: 683-686.
18. World Health Organization. Clinical management of COVID-19: interim guidance, 27 May 2020. Geneva: World Health Organization, 2020. Available at: https://apps.who.int/iris/handle/10665/332196 , date accesed 07/23/2021.
19. COVID-19 Treatment Guidelines Panel. Coronavirus disease 2019 (COVID-19) treatment guidelines. Bethesda: National Institutes of Health, 2020. Available at https://www.covid19treatmentguidelines.nih.gov/ , date accesed: 07/23/2021.
20. Arshad S, Kilgore P, Chaudhry ZS, Jacobsen G, Wang DD, Huitsing K, et al. Treatment with hydroxychloroquine, azithromycin, and combination inpatients hospitalized with COVID-19. Int J Infect Dis. 2020; 97: 396-403.
21. 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.
22. Molina JM, Delaugerre C, Le Goff J, Mela-Lima B, Ponscarme D, Goldwirt L, et al. No evidence of rapid antiviral clearance or clinical benefit with the combination of hydroxychloroquine and azithromycin in patients with severe COVID-19 infection. Med Mal Infect. 2020; 50: 384.
23. Cavalcanti AB, Zampieri FG, Rosa RG, Azevedo LCP, Veiga VC, Avezum A, et al. Hydroxychloroquine with or without azithromycin in mild-to-moderate Covid-19. N Engl J Med. 2020; NEJMoa2019014. doi: 10.1056/NEJMoa2019014. Online ahead of print.
24. Bessiere F, Roccia H, Delinière A, Charrière R, Chevalier P, Argaud L, 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. 2020; 5: 1067-1069.
25. Mehra MR, Desai SS, Ruschitzka F, Patel AN. RETRACTED: Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis. Lancet. 2020; S0140-6736(20)31180-6.
26. Ayad RF, Assar MD, Simpson L, Garner JB, Schussler JM. Causes and management of drug-induced long QT syndrome. Proc (Bayl Univ Med Cent). 2010; 23: 250-255.
27. Fernandes FM, Silva EP, Martins RR, Oliveira AG. QTc interval prolongation in critically ill patients: prevalence, risk factors and associated medications. PLoS One. 2018; 13: e0199028.
28. Vandael E, Vandenberk B, Vandenberghe J, Willems R, Foulon V. Risk factors for QTc-prolongation: systematic review of the evidence. Int J Clin Pharm. 2017; 39: 16-25.
29. Lu QB, Jiang WL, Zhang X, Li HJ, Zhang XA, Zeng HL, et al. Comorbidities for fatal outcome among the COVID-19 patients: A hospital-based case-control study. J Infect. 2020; S0163-4453(20)30507-7.
30. 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: aretrospective cohort study. Lancet. 2020; 395: 1054-1062.
31. Global COVID-19 Clinical Platform. Rapid core case report form (CRF) Geneva: World Health Organization, 2020. WHO/2019-nCoV/Clinical_CRF/2020.4
32. Reeves G. C-reactive protein. Aust Prescr. 2007; 30: 74-76.
33. Bazett H.C. An analysis of the time-relations of the electrocardiograms. Heart. 1920; 7: 353–370.
34. 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. Circ Cardiovasc Qual Outcomes. 2013; 6: 479-487.
35. Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, et al. Prevention of torsade de pointes in hospital settings: a scientific statement from the American Heart Association and the American College of Cardiology Foundation. J Am Coll Cardiol. 2010; 55: 934-947.
36. Note for guidance on the clinical evaluation of QT/QTc interval prolongation and proarrhythmic potential for nonantiarrhythmic drugs. CHMP/ICH/2/04. London: European Medicines Agency, 2005.
37. 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 Netw Open. 2020; 3: e208857.
38. Sinkeler FS, Berger FA, Muntinga HJ, Jansen MMPM. The risk of QTc-intervalprolongation in COVID-19 patients treated with chloroquine. Neth Heart J. 2020; 28: 418-423.
39. Li X, Xu S, Yu M, Wang K, Tao Y, Zhou Y, et al. Risk factors for severity and mortality in adult COVID-19 inpatients in Wuhan. J Allergy ClinImmunol. 2020; 146: 110-118.
40. Mikami T, Miyashita H, Yamada T, Harrington M, Steinberg D, Dunn A, et al. Risk Factors for Mortality in Patients with COVID-19 in New York City. J Gen Intern Med. 2020. (Online ahead of print).
41. Das RR, Jaiswal N, Dev N, Jaiswal N, Naik SS, Sankar J. Efficacy and safety of anti-malarial drugs (chloroquine and hydroxy-chloroquine) in treatment of COVID-19 infection: a systematic review and meta-analysis. Front Med (Lausanne). 2020; 7: 482.
42. Browning DJ. Pharmacology of chloroquine and hydroxychloroquine. In: Hydroxychloroquine and chloroquine retinopathy. New York: Springer, 2014: 35-36.
43. Perinel S, Launay M, Botelho-Nevers E, Diconne E, Louf-Durier A, Lachand R, et al. Towards optimization of hydroxychloroquine dosing in intensive care unit COVID-19 patients. Clin Infect Dis. 2020; ciaa394.
44. Tugwell P, Haynes B. Assessing claims of causation. In: Haynes RB, Sackett DL, Guyatt GH, Tugwell P, eds. Clinical Epidemiology - how to do clinical practice research. 3rd ed. Philadelphia: Lippincot Williams & Wilkins, 2006: 356-387.


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