Electrocardiographic safety evaluation of extended artemether-lumefantrine treatment in patients with uncomplicated Plasmodium falciparum malaria in Bagamoyo District, Tanzania

Lwidiko E Mhamilawa, Sven Wikström, Bruno P Mmbando, Billy Ngasala, Andreas Mårtensson, Lwidiko E Mhamilawa, Sven Wikström, Bruno P Mmbando, Billy Ngasala, Andreas Mårtensson

Abstract

Background: Extended artemisinin-based combination therapy (ACT) for treatment of uncomplicated Plasmodium falciparum malaria with already existing drug regimens, such as artemether-lumefantrine, might be effective in tackling the emerging ACT resistance. However, given the history of cardiotoxicity among anti-malarial drugs structurally similar to lumefantrine, the potential effect of extended artemether-lumefantrine treatment on the electrocardiographic (ECG) QTc interval is of high concern.

Methods: Male and non-pregnant females aged 1-65 years, diagnosed with uncomplicated P. falciparum malaria in Bagamoyo district, Tanzania, were randomized into two arms. The intervention arm received an extended, i.e. 6-day, course of artemether-lumefantrine and an additional single low-dose primaquine (0.25 mg/kg) administered together with the last artemether-lumefantrine dose. The control arm received the standard weight-based 3-day course. ECGs were performed at day 0 and 4-5 h after the last dose at day 5. QT intervals were read manually using the tangent method and automatically. Bazett's (QTcB) and Fridericia's (QTcF) formulae were used for correction for heart rate. Descriptive statistics were used to calculate baseline characteristics and the number of supra-thresholds QTc intervals (QTc prolongation > 500, change in QTc interval (ΔQTc) > 60 ms). The mean change in QTc interval in and between the two arms was compared using the paired t-test and independent samples t-test, respectively.

Results: A total of 195 patients were enrolled, 103 and 92 in the intervention and control arm, respectively. No patient experienced QTc intervals > 500 ms on day 5 by both formulae. Patients with ΔQTc > 60 ms, for QTcF were 6/103 (5.8%) vs 2/92 (2.2%) and for QTcB 2/103 (1.9%) vs 1/92 (1.1%) in the intervention and control arms, respectively. The mean difference in ΔQTc interval was statistically significant between the two arms with both correction formulae, 11.4 ms (95% CI 2.7-20.0, p = 0.010) and 13.4 ms (95% CI 5.3-21.5, p = 0.001), for QTcB and QTcF, respectively.

Conclusion: The extended 6-day course of artemether-lumefantrine did not reveal clinically relevant QTc prolonging effects. However, significant QTcF prolongation and presence of patients with supra-threshold QTc values observed in the intervention arm underscore the importance of further monitoring of QTc parameters in extended artemether-lumefantrine treatment. Trial registration ClinicalTrials.gov, NCT03241901. Registered July 27, 2017. https://ichgcp.net/clinical-trials-registry/NCT03241901.

Keywords: Artemether–lumefantrine; Artemisinin resistance; Cardiotoxicity; ECG; Malaria; Plasmodium falciparum; Prolonged treatment; Tanzania.

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Flow chart of study participants
Fig. 2
Fig. 2
a QTcB/RR plot, b QTcF/RR plot, c QTc-age/RR plot superimposed with line of best fit from linear regression

References

    1. WHO . World Malaria Report 2019. Geneva: World Health Organization; 2019.
    1. Verlinden BK, Louw A, Birkholtz L-M. Resisting resistance: is there a solution for malaria? Expert Opin Drug Discov. 2016;11:395–406. doi: 10.1517/17460441.2016.1154037.
    1. Dini S, Zaloumis S, Cao P, Price RN, Fowkes FJI, van der Pluijm RW, et al. Investigating the efficacy of triple artemisinin-based combination therapies for treating Plasmodium falciparum malaria patients using mathematical model. Antimicrob Agents Chemother. 2018;62:e01068–e01118. doi: 10.1128/AAC.01068-18.
    1. Tun KM, Jeeyapant A, Myint AH, Kyaw ZT, Dhorda M, Mukaka M, et al. Effectiveness and safety of 3 and 5 day courses of artemether-lumefantrine for the treatment of uncomplicated falciparum malaria in an area of emerging artemisinin resistance in Myanmar. Malar J. 2018;17:258. doi: 10.1186/s12936-018-2404-4.
    1. Kloprogge F, Workman L, Borrmann S, Tekete M, Lefevre G, Hamed K, et al. Artemether-lumefantrine dosing for malaria treatment in young children and pregnant women: a pharmacokinetic-pharmacodynamic meta-analysis. PLoS Med. 2018;15:e1002579. doi: 10.1371/journal.pmed.1002579.
    1. Onyamboko MA, Hoglund RM, Lee SJ, Kabedi C, Kayembe D, Badjanga BB, et al. A randomized controlled trial of three versus five days artemether-lumefantrine regimen for uncomplicated Plasmodium falciparum treatment in pregnancy in Africa. Antimicrob Agents Chemother. 2020;64:e01140–e01219.
    1. Postema PG, Wilde AAM. The measurement of the QT interval. Curr Cardiol Rev. 2014;10:287–294. doi: 10.2174/1573403X10666140514103612.
    1. Luo S, Michler K, Johnston P, Macfarlane PW. A comparison of commonly used QT correction formulae: the effect of heart rate on the QTc of normal ECGs. J Electrocardiol. 2004;37(Suppl):81–90. doi: 10.1016/j.jelectrocard.2004.08.030.
    1. Sagie A, Larson MG, Goldberg RJ, Bengtson JR, Levy D. An improved method for adjusting the QT interval for heart rate (the Framingham Heart Study) Am J Cardiol. 1992;70:797–801. doi: 10.1016/0002-9149(92)90562-D.
    1. White NJ. Cardiotoxicity of antimalarial drugs. Lancet Infect Dis. 2007;7:549–558. doi: 10.1016/S1473-3099(07)70187-1.
    1. Bindschedler M, Lefevre G, Degen P, Sioufi A. Comparison of the cardiac effects of the antimalarial co-artemether and halofantrine in healthy participants. Am J Trop Med Hyg. 2002;66:293–298. doi: 10.4269/ajtmh.2002.66.293.
    1. Malvy D, Receveur MC, Ozon P, Djossou F, Le Metayer P, Touze JE, et al. Fatal cardiac incident after use of halofantrine. J Travel Med. 2000;7:215–216. doi: 10.2310/7060.2000.00065.
    1. Bouchaud O, Imbert P, Touze JE, Dodoo ANO, Danis M, Legros F. Fatal cardiotoxicity related to halofantrine: a review based on a worldwide safety data base. Malar J. 2009;8:289. doi: 10.1186/1475-2875-8-289.
    1. Haeusler IL, Chan XHS, Guerin PJ, White NJ. The arrhythmogenic cardiotoxicity of the quinoline and structurally related antimalarial drugs: a systematic review. BMC Med. 2018;16:200. doi: 10.1186/s12916-018-1188-2.
    1. Chan XHS, Win YN, Mawer LJ, Tan JY, Brugada J, White NJ. Risk of sudden unexplained death after use of dihydroartemisinin 2013; piperaquine for malaria: a systematic review and Bayesian meta-analysis. Lancet Infect Dis. 2018;18:913–923. doi: 10.1016/S1473-3099(18)30297-4.
    1. van Vugt M, Ezzet F, Nosten F, Gathmann I, Wilairatana P, Looareesuwan S, et al. No evidence of cardiotoxicity during antimalarial treatment with artemether-lumefantrine. Am J Trop Med Hyg. 1999;61:964–967. doi: 10.4269/ajtmh.1999.61.964.
    1. Makanga M, Premji Z, Falade C, Karbwang J, Mueller EA, Andriano K, et al. Efficacy and safety of the six-dose regimen of artemether-lumefantrine in pediatrics with uncomplicated Plasmodium falciparum malaria: a pooled analysis of individual patient data. Am J Trop Med Hyg. 2006;74:991–998. doi: 10.4269/ajtmh.2006.74.991.
    1. van Agtmael M, Bouchaud O, Malvy D, Delmont J, Danis M, Barette S, et al. The comparative efficacy and tolerability of CGP 56697 (artemether + lumefantrine) versus halofantrine in the treatment of uncomplicated falciparum malaria in travellers returning from the Tropics to The Netherlands and France. Int J Antimicrob Agents. 1999;12:159–169. doi: 10.1016/S0924-8579(99)00070-9.
    1. Novartis Pharmaceutical Coorporation. NDA 22-268 for Coartem Clinical Pharmacology and Biopharmaceutics reviews. 2008;39.
    1. International Conference on Harmonization. E14 Implementation Working Group ICH E14 Guideline: The Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs Questions & Answers (R3). Internet. 2015;3:1–18.
    1. Wernicke JF, Faries D, Breitung R, Girod D. QT correction methods in children and adolescents. J Cardiovasc Electrophysiol. 2005;16:76–81. doi: 10.1046/j.1540-8167.2005.03520.x.
    1. Benatar A, Feenstra A. QT correction methods in infants and children: effects of age and gender. Ann Noninvasive Electrocardiol. 2015;20:119–125. doi: 10.1111/anec.12200.
    1. Funck-Brentano C, Ouologuem N, Duparc S, Felices M, Sirima SB, Sagara I, et al. Evaluation of the effects on the QT-interval of 4 artemisinin-based combination therapies with a correction-free and heart rate-free method. Sci Rep. 2019;9:883. doi: 10.1038/s41598-018-37113-5.
    1. Lawpoolsri S, Klein EY, Singhasivanon P, Yimsamran S, Thanyavanich N, Maneeboonyang W, et al. Optimally timing primaquine treatment to reduce Plasmodium falciparum transmission in low endemicity Thai-Myanmar border populations. Malar J. 2009;8:159. doi: 10.1186/1475-2875-8-159.
    1. Bazett HC. An analysis of the time-relations of electrocardiograms. Ann Noninvasive Electrocardiol. 1997;2:177–194. doi: 10.1111/j.1542-474X.1997.tb00325.x.
    1. Fridericia LS. Die Systolendauer im Elektrokardiogramm bei normalen Menschen und bei Herzkranken. Acta Med Scand. 1920;53:469–486. doi: 10.1111/j.0954-6820.1920.tb18266.x.
    1. ICH. E14 clinical evaluation of QT/QTc interval prolongation and proarrhythmic potential for non-antiarrhythmic drugs. 2005.
    1. Trinkley KE, Page RL, 2nd, Lien H, Yamanouye K, Tisdale JE. QT interval prolongation and the risk of Torsades de pointes: essentials for clinicians. Curr Med Res Opin. 2013;29:1719–1726. doi: 10.1185/03007995.2013.840568.
    1. Buchanan AM, Fiorillo SP, Omondi MW, Cunningham CK, Crump JA. Establishment of biochemistry reference values for healthy Tanzanian infants, children and adolescents in Kilimanjaro Region. Trop Med Int Health. 2015;20:1569–1577. doi: 10.1111/tmi.12580.
    1. WHO Evidence Review Group. The cardiotoxicity of antimalarial. Geneva, World Health Organization, 2016. .
    1. Wu W, Liang Y, Wu G, Su Y, Zhang H, Zhang Z, et al. Effect of artemisinin-piperaquine treatment on the electrocardiogram of malaria patients. Rev Soc Bras Med Trop. 2019;52:e20180453. doi: 10.1590/0037-8682-0453-2018.
    1. Bethell DB, Phuong PT, Phuong CX, Nosten F, Waller D, Davis TM, et al. Electrocardiographic monitoring in severe falciparum malaria. Trans R Soc Trop Med Hyg. 1996;90:266–269. doi: 10.1016/S0035-9203(96)90241-2.
    1. Adjei GO, Oduro-Boatey C, Rodrigues OP, Hoegberg LC, Alifrangis M, Kurtzhals JA, et al. Electrocardiographic study in Ghanaian children with uncomplicated malaria, treated with artesunate-amodiaquine or artemether-lumefantrine. Malar J. 2012;11:420. doi: 10.1186/1475-2875-11-420.
    1. Chan XHS, Win YN, Haeusler IL, Tan JY, Loganathan S, Saralamba S, et al. Factors affecting the electrocardiographic QT interval in malaria: a systematic review and meta-analysis of individual patient data. PLoS Med. 2020;17:e1003040. doi: 10.1371/journal.pmed.1003040.
    1. Vandenberk B, Vandael E, Robyns T, Vandenberghe J, Garweg C, Foulon V, et al. Which QT correction formulae to use for QT monitoring? J Am Heart Assoc. 2016;5:e003264. doi: 10.1161/JAHA.116.003264.
    1. Viskin S, Rosovski U, Sands AJ, Chen E, Kistler PM, Kalman JM, et al. Inaccurate electrocardiographic interpretation of long QT: the majority of physicians cannot recognize a long QT when they see one. Hear Rhythm. 2005;2:569–574. doi: 10.1016/j.hrthm.2005.02.011.
    1. Postema PG, De Jong JSSG, Van der Bilt IAC, Wilde AAM. Accurate electrocardiographic assessment of the QT interval: teach the tangent. Hear Rhythm. 2008;5:1015–1018. doi: 10.1016/j.hrthm.2008.03.037.
    1. Bexton RS, Vallin HO, Camm AJ. Diurnal variation of the QT interval–influence of the autonomic nervous system. Br Heart J. 1986;55:253–258. doi: 10.1136/hrt.55.3.253.

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