The cardiovascular effects of amodiaquine and structurally related antimalarials: An individual patient data meta-analysis

Abstract

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 at the World Health Organization (WHO)-recommended doses alone or in ACTs are safe for the treatment and prevention of malaria.

Potential policy interventions for slowing the spread of artemisinin-resistantpfkelchR561H mutations in Rwanda

“…Extending the course of treatment with AL has minimal logistical considerations beyond ensuring sufficient quality of doses being distributed and appears to be beneficial compared to the status quo scenario. While there are concerns regarding the cardiotoxicity of antimalarial drugs [27,28], the incidence of adverse cardiac events recorded during clinical trials has been low [29]. Switching to one of several MFT options where future treatment failure rates can be kept close to 10% will ensure there are no concerns with extended artemisinin dosing, and the success of these MFT deployments will depend on operational capability around the supply and distribution of ACTs.…”

Evaluation of Nutritional Substances and Investigation of Antioxidant and Antimicrobial Potentials of Boerhavia diffusa with in Silico Molecular Docking

“…In order to investigate the volatile compounds, present in the extract, GC-MS analysis was applied. Amodiaquine is an alkaloid known for its antimalarial properties [36]. Dipyridamole is an anti-platelet agent found to exert antitumor activity [37].…”

Pharmacokinetic considerations in seasonal malaria chemoprevention

“…One subject from a large SMC study developed an extrapyramidal syndrome, which may have been related to the SMC drug (probably AQ). AQ prolongs the QT interval, and may cause bradycardia in adults but not in children <12 years of age [23]. Unfortunately, readministration of drugs after vomiting is not possible because of the fixed dose SPAQ package.…”