The cardiovascular effects of amodiaquine and structurally related antimalarials: An individual patient data meta-analysis.
The cardiovascular effects of amodiaquine and structurally related antimalarials: An individual patient data meta-analysis.
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阿莫地喹和结构相关抗疟药的心血管作用：一项个体患者数据荟萃分析
DOI：
10.1371/journal.pmed.1003766
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发表时间：
2021-09
期刊：
影响因子：
15.8
通讯作者：
White NJ
中科院分区：
文献类型：
--
作者：
Chan XHS;Haeusler IL;Win YN;Pike J;Hanboonkunupakarn B;Hanafiah M;Lee SJ;Djimdé A;Fanello CI;Kiechel JR;Lacerda MV;Ogutu B;Onyamboko MA;Siqueira AM;Ashley EA;Taylor WR;White NJ
阿莫地喹是一种4-氨基喹啉抗疟药，类似于氯喹，广泛用于治疗和预防疟疾。尽管已观察到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），但有关阿莫地喹心血管影响的数据很少。我们进行了一项个体患者数据荟萃分析，以验证阿莫地喹的心血管效应，从而支持制定风险最小化措施，以提高这一重要抗疟药物的安全性。阿莫地喹用于治疗或预防疟疾的研究是从系统评价中确定的。在研究内比较了心率和QT间期以及研究特异性心率校正（QTcS），并汇总了个体患者数据，以进行多变量线性混合效应回归。荟萃分析包括来自4项随机对照试验的2，681名患者，这些试验评估了以青蒿素为基础的联合治疗（ACT），包括阿莫地喹（n = 725），苯芴醇（n = 499），哌喹（n = 716）和咯萘啶（n = 566），以及氯喹单药治疗（n = 175）。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），但高于本芴醇（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（平均减少= 15.2次/分钟[bpm]，95% CI：13.4至17.0），高于哌喹（10.5 bpm，7.7 - 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），与本芴醇相比，（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）。阿莫地喹对<12岁儿童心率的影响与其他抗疟药相比无临床意义。研究的局限性包括无法获得大多数入选受试者的个体患者水平的不良事件数据，但没有记录严重并发症。虽然建议在合并使用降低心率药物、严重心脏传导障碍或尖端扭转型室性心动过速风险因素的≥12岁患者中谨慎使用阿莫地喹，但阿莫地喹广泛使用70多年后未报告严重心血管事件。世界卫生组织（世卫组织）推荐的剂量方案中的阿莫地喹和结构相关抗疟药单独使用或与青蒿素综合疗法合用，对于治疗和预防疟疾是安全的。在这项荟萃分析中，Xin Hui Supanee Chan及其同事使用来自试验的个体患者数据研究了阿莫地喹和结构相关抗疟药的心血管作用。阿莫地喹是一种广泛用于治疗和预防疟疾的抗疟药。青蒿素类复方疗法-青蒿琥酯-阿莫地喹是20多个疟疾流行国家中治疗无并发症疟疾的一线疗法。阿莫地喹也是阿莫地喹+磺胺嘧啶-乙胺嘧啶的主要药物，这是唯一推荐用于季节性疟疾化学预防的药物方案，每年向非洲萨赫勒地区数百万3至59个月的儿童提供。与其他结构相关的抗疟药一样，阿莫地喹给药后观察到心电图QT间期短暂延长和窦性心动过缓，但这些心血管效应尚不清楚。我们进行了二次分析，包括多变量线性混合效应回归模型的荟萃分析，个体患者数据来自阿莫地喹治疗疟疾的研究，这些研究是从系统评价中确定的。我们纳入了来自4项随机对照试验的2，681例患者的数据，这些试验评估了含阿莫地喹（n = 725）、苯芴醇（n = 499）、哌喹（n = 716）和咯萘啶（n = 566）的ACT，以及氯喹单药治疗（n = 175）治疗无并发症疟疾。阿莫地喹延长QT间期的研究特定的心率校正（QTcS）评估小于氯喹和哌喹，但大于苯芴群和咯萘啶。与其他一线抗疟药相比，阿莫地喹在成人和≥12岁的青少年中也与潜在症状性窦性心动过缓的风险更高相关，但在<12岁的儿童中不相关。虽然建议在年龄≥12岁的患者中使用阿莫地喹时要谨慎，这些患者正在服用其他降低心率的药物或患有严重心脏疾病，心率降低是不可取的，但在广泛使用阿莫地喹70多年后，没有报告严重心血管事件。我们的分析支持阿莫地喹和结构相关的抗疟药在世界卫生组织（WHO）推荐的剂量方案中单独使用或在青蒿素综合疗法中用于治疗和预防疟疾的心血管安全性。
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. 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. 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. In this meta-analysis, Xin Hui Supanee Chan and colleagues investigate the cardiovascular effects of amodiaquine and structurally-related antimalarials using individual patient data from trials. Amodiaquine is a widely used antimalarial for the treatment and prevention of malaria. The artemisinin-based combination therapy (ACT) artesunate–amodiaquine (ASAQ) is a first-line treatment for uncomplicated malaria in >20 malaria endemic countries. Amodiaquine is also the backbone of amodiaquine + sulfadoxine–pyrimethamine, the only drug regimen recommended for seasonal malaria chemoprevention (SMC) given annually to millions of children aged 3 to 59 months across the African Sahel. As with other structurally related antimalarials, transient prolongation of the electrocardiographic QT interval and sinus bradycardia has been observed after amodiaquine, but these cardiovascular effects are not well understood. We conducted secondary analyses, including meta-analyses with multivariable linear mixed effects regression models, of individual patient data from studies of amodiaquine for malaria identified from a systematic review. We included data from 2,681 patients from 4 randomised controlled trials evaluating 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 the QT interval assessed with study-specific heart rate correction (QTcS) less than chloroquine and piperaquine, but more than lumefantrine and pyronaridine. Amodiaquine was also associated with a higher risk of potentially symptomatic sinus bradycardia compared with other front-line antimalarials in adults and adolescents aged ≥12 years but not in children aged <12 years. While caution is advised when using amodiaquine in patients aged ≥12 years who are taking other drugs that reduce heart rate or have serious heart conditions for which heart rate reduction would be undesirable, there have been no serious cardiovascular events reported after extensive use of amodiaquine over 7 decades. Our analysis supports the cardiovascular safety of amodiaquine and structurally related antimalarials in the World Health Organization (WHO)-recommended dose regimens alone or in ACTs for the treatment and prevention of malaria.
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影响因子：
5.5
作者：
Capel RA;Herring N;Kalla M;Yavari A;Mirams GR;Douglas G;Bub G;Channon K;Paterson DJ;Terrar DA;Burton RA
通讯作者：
Burton RA
影响因子：
4.9
作者：
Borsini, Franco;Crumb, William;Funck-Brentano, Christian
通讯作者：
Funck-Brentano, Christian
影响因子：
3
作者：
Adjei, George O.;Oduro-Boatey, Collins;Goka, Bamenla Q.
通讯作者：
Goka, Bamenla Q.
影响因子：
168.9
作者：
Fleming, Susannah;Thompson, Matthew;Stevens, Richard;Heneghan, Carl;Plueddemann, Annette;Maconochie, Ian;Tarassenko, Lionel;Mant, David
通讯作者：
Mant, David
DOI：
10.1016/s1473-3099(18)30297-4
发表时间：
2018-08
期刊：
The Lancet. Infectious diseases
影响因子：
--
作者：
Chan XHS;Win YN;Mawer LJ;Tan JY;Brugada J;White NJ
通讯作者：
White NJ