Department of Women's and Children's Health, International Maternal and Child Health (IMCH), Uppsala University, Uppsala, Sweden.
Department of Parasitology and Medical Entomology, Muhimbili University of Health and Allied Sciences, Dar es Salaam, Tanzania.
Malar J. 2020 Jul 14;19(1):250. doi: 10.1186/s12936-020-03309-2.
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.
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.
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.
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://clinicaltrials.gov/show/NCT03241901.
针对已经存在的药物方案（如青蒿琥酯-咯萘啶），延长青蒿素类复方疗法（ACT）治疗无并发症恶性疟原虫疟疾可能有效，以应对新兴的 ACT 耐药性。然而，鉴于与咯萘啶结构相似的抗疟药物存在心脏毒性，延长青蒿琥酯-咯萘啶治疗对心电图（ECG）QTc 间期的潜在影响是一个非常关注的问题。
在坦桑尼亚巴加莫约区，年龄在 1-65 岁之间、被诊断患有无并发症恶性疟原虫疟疾的男性和非孕妇女性被随机分为两组。干预组接受延长疗程，即 6 天的青蒿琥酯-咯萘啶治疗，并在最后一剂青蒿琥酯-咯萘啶时加用单剂低剂量伯氨喹（0.25mg/kg）。对照组接受标准的基于体重的 3 天疗程。在第 0 天和第 5 天的最后一剂药后 4-5 小时进行心电图检查。手动使用切线法和自动法读取 QT 间期。Bazett 公式（QTcB）和 Fridericia 公式（QTcF）用于校正心率。使用描述性统计来计算基线特征和超过阈值的 QT 间期数量（QTc 延长>500ms，QTc 间期变化（ΔQTc）>60ms）。使用配对 t 检验和独立样本 t 检验分别比较两组之间的 QTc 间期的平均变化。
共纳入 195 名患者，干预组和对照组各 103 名和 92 名。根据两种公式，第 5 天没有患者的 QTc 间期>500ms。QTcF 为 6/103（5.8%）和 2/92（2.2%），QTcB 为 2/103（1.9%）和 1/92（1.1%）的患者存在ΔQTc>60ms。与两种校正公式相比，两组之间的ΔQTc 差异均具有统计学意义，分别为 11.4ms（95%CI 2.7-20.0，p=0.010）和 13.4ms（95%CI 5.3-21.5，p=0.001）。
延长 6 天的青蒿琥酯-咯萘啶疗程并未显示出临床相关的 QTc 延长作用。然而，干预组中观察到 QTcF 显著延长和存在超过阈值的 QTc 值的患者突显了在延长青蒿琥酯-咯萘啶治疗中进一步监测 QTc 参数的重要性。
ClinicalTrials.gov，NCT03241901。于 2017 年 7 月 27 日注册。https://clinicaltrials.gov/show/NCT03241901。
