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.