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

Fig 1. Study selection flowchart.

Fig 2. Corrected QT interval and RR interval relationships by correction method and individual study.

QT intervals adjusted with study-specific ($QTcS=\frac{QT}{{RR}^{{\beta }_{age}}}$, where β_age decreased with increasing age), Fridericia ($QTcF=\frac{QT}{\sqrt[3]{RR}}$), and Bazett heart rate corrections ($QTcB=\frac{QT}{\sqrt{RR}}$) and their relationship with RR intervals in the pooled dataset (top panels) and by individual study (bottom panels) with means (blue line) and 95% CIs (shaded area) from linear regression. A slight positive relationship is expected even with ideal correction because of confounding by body temperature changes, i.e., fever and defervescence, in malaria.

Fig 3. Change in corrected QT interval after antimalarial treatment for uncomplicated malaria.

Change in QT interval adjusted with study-specific heart rate correction (QTcS) after treatment with the antimalarials artesunate-amodiaquine (ASAQ), chloroquine (CQ), dihydroartemisinin-piperaquine (DP), artemether-lumefantrine (AL), and pyronaridine-artesunate (PyAS) from a multivariable linear mixed effects regression model adjusting for age group, sex, body temperature, and individual study/site/person effects. Lines indicate means with colour representing antimalarial treatment arm, shaded areas denote 95% confidence intervals, and dots are partial residuals.

Fig 4. Differences in corrected QT interval by age group and sex.

Mean differences in QT interval adjusted with study-specific heart rate correction (QTcS) by age group and sex compared with the mean value for children aged <5 years from a multivariable linear mixed effects regression model adjusting for treatment day, antimalarial treatment arm, body temperature, and individual study/site/person effects. Lines indicate means with colour representing sex, shaded areas denote 95% confidence intervals, and dots are partial residuals.

Fig 5. Change in heart rate after antimalarial treatment for uncomplicated malaria in adolescents and adults (age ≥12 years).

Change in heart rate after treatment with the antimalarials artesunate-amodiaquine (ASAQ), chloroquine (CQ), dihydroartemisinin-piperaquine (DP), artemether-lumefantrine (AL), and pyronaridine-artesunate (PyAS) in adolescents and adults aged ≥12 years from a multivariable linear mixed effects regression model adjusting for sex, body temperature, and individual study/site/person effects. Lines indicate means with colour representing antimalarial treatment arm, shaded areas denote 95% confidence intervals, and dots are partial residuals.

Fig 6. Change in heart rate after antimalarial treatment for uncomplicated malaria in children (age <12 years).

Change in heart rate after treatment with the antimalarials artesunate-amodiaquine (ASAQ), dihydroartemisinin-piperaquine (DP), artemether-lumefantrine (AL), and pyronaridine-artesunate (PyAS) in children aged <12 years from a multivariable linear mixed effects regression model adjusting for age, body temperature, and individual study/site/person effects. Lines indicate means with colour representing antimalarial treatment arm, shaded areas denote 95% confidence intervals, and dots are partial residuals.