Key result
Amodiaquine prolonged the heart rate-corrected QT interval by a mean of 16.9 ms, which was significantly less than chloroquine (21.9 ms) and piperaquine (19.2 ms), but more than lumefantrine and pyronaridine.
Why the study?
Data on the cardiovascular effects of amodiaquine are scarce, although transient effects on cardiac electrophysiology have been observed.
Does amodiaquine cause significant QT prolongation or bradycardia compared to other antimalarials in patients with uncomplicated malaria?
Meta-Analysis (n=2,681)
Randomized
Yes
Does amodiaquine cause significant QT prolongation or bradycardia compared to other antimalarials in patients with uncomplicated malaria?
Amodiaquine causes moderate QT prolongation and increases the risk of sinus bradycardia in adults compared to some other antimalarials, but no serious cardiovascular events were reported, supporting its continued safety for malaria treatment.
Supports amodiaquine safety in uncomplicated malaria despite moderate QT prolongation; confirms its intermediate risk among antimalarials.
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.
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Chan et al. (2021) conducted a meta-analysis in Uncomplicated malaria (n=2,681). Amodiaquine vs. Chloroquine, piperaquine, lumefantrine, pyronaridine was evaluated on QT interval with study-specific heart rate correction (QTcS) prolongation (mean 16.9 ms, 95% CI 15.0 to 18.8, p=0.0069). Amodiaquine prolonged the heart rate-corrected QT interval by a mean of 16.9 ms, which was significantly less than chloroquine (21.9 ms) and piperaquine (19.2 ms), but more than lumefantrine and pyronaridine.
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