BACKGROUND Amodiaquine is a 4-aminoquinoline antimalarial similar to chloroquine that is used extensively for the treatment and prevention of malaria. Data on the cardiovascular effects of amodiaquine are scarce, although transient effects on cardiac electrophysiology (electrocardiographic QT interval prolongation and sinus bradycardia) have been observed. We conducted an individual patient data meta-analysis to characterise the cardiovascular effects of amodiaquine and thereby support development of risk minimisation measures to improve the safety of this important antimalarial. METHODS AND FINDINGS Studies of amodiaquine for the treatment or prevention of malaria were identified from a systematic review. Heart rates and QT intervals with study-specific heart rate correction (QTcS) were compared within studies and individual patient data pooled for multivariable linear mixed effects regression. The meta-analysis included 2,681 patients from 4 randomised controlled trials evaluating artemisinin-based combination therapies (ACTs) containing amodiaquine (n = 725), lumefantrine (n = 499), piperaquine (n = 716), and pyronaridine (n = 566), as well as monotherapy with chloroquine (n = 175) for uncomplicated malaria. Amodiaquine prolonged QTcS (mean = 16.9 ms, 95% CI: 15.0 to 18.8) less than chloroquine (21.9 ms, 18.3 to 25.6, p = 0.0069) and piperaquine (19.2 ms, 15.8 to 20.5, p = 0.0495), but more than lumefantrine (5.6 ms, 2.9 to 8.2, p < 0.001) and pyronaridine (-1.2 ms, -3.6 to +1.3, p < 0.001). In individuals aged ≥12 years, amodiaquine reduced heart rate (mean reduction = 15.2 beats per minute [bpm], 95% CI: 13.4 to 17.0) more than piperaquine (10.5 bpm, 7.7 to 13.3, p = 0.0013), lumefantrine (9.3 bpm, 6.4 to 12.2, p < 0.001), pyronaridine (6.6 bpm, 4.0 to 9.3, p < 0.001), and chloroquine (5.9 bpm, 3.2 to 8.5, p < 0.001) and was associated with a higher risk of potentially symptomatic sinus bradycardia (≤50 bpm) than lumefantrine (risk difference: 14.8%, 95% CI: 5.4 to 24.3, p = 0.0021) and chloroquine (risk difference: 8.0%, 95% CI: 4.0 to 12.0, p < 0.001). The effect of amodiaquine on the heart rate of children aged <12 years compared with other antimalarials was not clinically significant. Study limitations include the unavailability of individual patient-level adverse event data for most included participants, but no serious complications were documented. CONCLUSIONS While caution is advised in the use of amodiaquine in patients aged ≥12 years with concomitant use of heart rate-reducing medications, serious cardiac conduction disorders, or risk factors for torsade de pointes, there have been no serious cardiovascular events reported after amodiaquine in widespread use over 7 decades. Amodiaquine and structurally related antimalarials in the World Health Organization (WHO)-recommended dose regimens alone or in ACTs are safe for the treatment and prevention of malaria.

中文翻译：

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阿莫地喹和结构相关抗疟药的心血管作用：个体患者数据荟萃分析。


背景阿莫地喹是一种类似于氯喹的4-氨基喹啉抗疟药，广泛用于治疗和预防疟疾。尽管观察到阿莫地喹对心脏电生理学的短暂影响（心电图 QT 间期延长和窦性心动过缓），但有关阿莫地喹对心血管影响的数据很少。我们进行了个体患者数据荟萃分析，以描述阿莫地喹对心血管的影响，从而支持制定风险最小化措施，以提高这种重要抗疟药的安全性。方法和结果 阿莫地喹治疗或预防疟疾的研究是通过系统评价确定的。在研究中比较心率和 QT 间期与研究特定心率校正 (QTcS)，并汇总个体患者数据以进行多变量线性混合效应回归。该荟萃分析纳入了来自 4 项随机对照试验的 2,681 名患者，这些试验评估了基于青蒿素的联合疗法 (ACT)，其中包括阿莫地喹 (n = 725)、本芴醇 (n = 499)、哌喹 (n = 716) 和咯萘啶 (n = 566) ，以及氯喹单一疗法（n = 175）治疗无并发症的疟疾。阿莫地喹延长 QTcS（平均值 = 16.9 ms，95% CI：15.0 至 18.8）低于氯喹（21.9 ms，18.3 至 25.6，p = 0.0069）和哌喹（19.2 ms，15.8 至 20.5，p = 0.0495），但大于苯芴醇（5.6 ms，2.9 至 8.2，p < 0.001）和咯萘啶（-1.2 ms，-3.6 至 +1.3，p < 0.001）。在年龄 ≥ 12 岁的个体中，阿莫地喹降低心率的效果（平均降低 = 15.2 次/分钟 [bpm]，95% CI：13.4 至 17.0）比哌喹（10.5 bpm，7.7 至 13.3，p = 0.0013）、本芴醇（9.3 bpm，6.4 至 12.2，p < 0.001)，咯萘啶（6.6 bpm，4.0 至 9。3, p < 0.001) 和氯喹 (5.9 bpm, 3.2 至 8.5, p < 0.001) 与苯芴醇相比，潜在症状性窦性心动过缓 (≤50 bpm) 的风险更高（风险差异：14.8%, 95） % CI：5.4 至 24.3，p = 0.0021）和氯喹（风险差异：8.0%，95% CI：4.0 至 12.0，p < 0.001）。与其他抗疟药相比，阿莫地喹对 <12 岁儿童心率的影响不具有临床显着性。研究的局限性包括大多数参与者无法获得个体患者水平的不良事件数据，但没有记录严重并发症。结论 虽然建议 12 岁以上、同时使用减心率药物、严重心脏传导障碍或尖端扭转型室性心动过速危险因素的患者使用阿莫地喹时要谨慎，但目前尚未有报告称阿莫地喹导致严重心血管事件。 7 年来广泛使用。世界卫生组织 (WHO) 推荐的阿莫地喹和结构相关抗疟药单独或联合治疗方案对于治疗和预防疟疾是安全的。