The importance of evaluating potential cardiotoxic effects of newly introduced anti-malarial drugs has been highlighted with discovery of the cardiotoxicity of halofantrine after its registration and introduction into clinical practice. Apart from halofantrine, anti-malarials, such as quinine and quinidine, have also been associated with cardiotoxicity, mainly clinically significant delays in ventricular repolarization, which is reflected on the ECG as prolongation of the QT interval. The findings of relatively short pre-treatment QT intervals in this study is consistent with reports from ECG studies in African children with uncomplicated malaria
, and are presumed to result from differences in autonomic state between acute illness and recovery. It is suggested that the increased sympathetic tone, blunted autonomic postural responses, and faster heart rates during acute malaria accelerates cardiac conduction, leading to a shortening of the QT interval. These changes, when reversed during convalescence then result in QT interval prolongation [reviewed in
The observed difference in bradycardia occurrence between the amodiaquine-artesunate and artemether-lumefantrine groups is likely a reflection of a true difference between the treatment regimens. This is because the major differences between childhood and adult ECG (e.g., faster ventricular rate that slows with age, dimunition of right ventricular dominance, leftward shift of QRS axis with age) are related to maturational changes that may not necessarily impact directly on conduction. Furthermore, bradycardia occurred mostly in older children, similar to the previously reported high bradycardia incidence in amodiaquine-treated adults
[4, 20], and also consistent with findings from animal studies that showed that amodiaquine slows cardiac conduction
[21, 22]. Since alterations in cardiac conduction pathways are an important mechanism for pro-arrhythmic events, and bradycardia may by itself, precipitate long QT syndrome
[23, 24], the potential implications of artesunate-amodiaquine associated bradycardia merits further investigation.
The lack of association between plasma DEAQ levels and QTc interval prolongation in the amodiaquine-artesunate group could be due to lack of a consistent effect of amodiaquine on cardiac repolarization. This assertion is supported in part by the finding that baseline QTc intervals were the sole predictor of post-treatment QTc intervals. This lack of dose-related association may also be due to the fact that these effects of amodiaquine-based treatment differ from that of anti-malarials such as halofantrine
[12, 25] or quinine
[26–28] whose cardiotoxic effects have been shown to be clearly dose-dependent.
The mean QTc interval changes from baseline were below the 25% increase beyond which such changes are considered of clinical concern
, and the proportion of children with absolute QTc interval prolongation beyond 60 ms (a threshold that is considered significant for evaluating potential cardiotoxicity of new drugs), was higher in the artesunate-amodiaquine treatment group, though the number of subjects with these changes were low to allow meaningful statistical testing.
The Fridericia’s formula was as sensitive as the Bazett’s formula in identifying prolonged QT intervals in this study population. The utility of the Fridericia’s formula for evaluating potential cardiac effects of anti-malarial drugs in childhood studies could be further evaluated, since this correction formula is less rate-dependent, and other correction methods developed primarily for adults may not be applicable to childhood populations
. However, the weak correlation between the RR and QT intervals, corrected using the various formulae suggests that the different rate correction formulae had the desired effect.
Assessing the effect of antimalarials on an ECG, when used during the treatment of malaria could be problematic. This is because disease-associated changes in malaria confound QT interval measurements, and comparison of ECG changes should be done at the same heart rate, ideally in volunteers without intercurrent illness. The opportunities for such studies however, are limited. Furthermore, any potential disease-drug interactions would be impossible to detect in volunteer populations. The findings from this study are therefore, important not least because: i) there is paucity of published data on the ECG effects of anti-malarials, particularly in children, and ii) the artemether-lumefantrine group provides an exceptionally good reference standard, since this ACT regimen has been extensively evaluated and shown not to have any significant cardiotoxicity
In conclusion, the standard ECG intervals of children with uncomplicated malaria treated with artesunate-amodiaquine or artemether-lumefantrine showed changes that are consistent with those observed in acute malaria. The higher incidence of sinus bradycardia in artesunate-amodiaquine treated subjects may have implications for concomitant use of this ACT with cardiac drugs, or for treatment of patients at increased risk of cardiac dysrhythmiae. The artesunate-amodiaquine regimen appears safe in other patients in this limited study, but further studies in a larger cohort are warranted for conclusive evidence on safety.