Factors affecting the electrocardiographic QT interval in malaria: A systematic review and meta-analysis of individual patient data

Abstract

Background: Electrocardiographic QT interval prolongation is the most widely used risk marker for ventricular arrhythmia potential and thus an important component of drug cardiotoxicity assessments. Several antimalarial medicines are associated with QT interval prolongation. However, interpretation of electrocardiographic changes is confounded by the coincidence of peak antimalarial drug concentrations with recovery from malaria. We therefore reviewed all available data to characterise the effects of malaria disease and demographic factors on the QT interval in order to improve assessment of electrocardiographic changes in the treatment and prevention of malaria.

Methods and findings: We conducted a systematic review and meta-analysis of individual patient data. We searched clinical bibliographic databases (last on August 21, 2017) for studies of the quinoline and structurally related antimalarials for malaria-related indications in human participants in which electrocardiograms were systematically recorded. Unpublished studies were identified by the World Health Organization (WHO) Evidence Review Group (ERG) on the Cardiotoxicity of Antimalarials. Risk of bias was assessed using the Pharmacoepidemiological Research on Outcomes of Therapeutics by a European Consortium (PROTECT) checklist for adverse drug events. Bayesian hierarchical multivariable regression with generalised additive models was used to investigate the effects of malaria and demographic factors on the pretreatment QT interval. The meta-analysis included 10,452 individuals (9,778 malaria patients, including 343 with severe disease, and 674 healthy participants) from 43 studies. 7,170 (68.6%) had fever (body temperature ≥ 37.5°C), and none developed ventricular arrhythmia after antimalarial treatment. Compared to healthy participants, patients with uncomplicated falciparum malaria had shorter QT intervals (-61.77 milliseconds; 95% credible interval [CI]: -80.71 to -42.83) and increased sensitivity of the QT interval to heart rate changes. These effects were greater in severe malaria (-110.89 milliseconds; 95% CI: -140.38 to -81.25). Body temperature was associated independently with clinically significant QT shortening of 2.80 milliseconds (95% CI: -3.17 to -2.42) per 1°C increase. Study limitations include that it was not possible to assess the effect of other factors that may affect the QT interval but are not consistently collected in malaria clinical trials.

Conclusions: Adjustment for malaria and fever-recovery-related QT lengthening is necessary to avoid misattributing malaria-disease-related QT changes to antimalarial drug effects. This would improve risk assessments of antimalarial-related cardiotoxicity in clinical research and practice. Similar adjustments may be indicated for other febrile illnesses for which QT-interval-prolonging medications are important therapeutic options.

Fig 1. Study selection flow chart.

ECG, electrocardiogram.

Fig 2. Body temperature and the QT interval in malaria.

Independent effect of body temperature on the QT interval from hierarchical generalised additive model adjusting for heart rate/RR interval (as $\sqrt{RR}$), age, sex, malaria type, and individual study. Shaded area represents 95% CIs, and circles represent original data points without adjustment. CI, credible interval.

Fig 3. Malaria type, RR interval, and the QT interval.

Interaction between malaria type and the RR interval (on the square root scale) and conditional effect on the QT interval (on the linear scale) from a hierarchical generalised additive model adjusting for age, sex, body temperature, and individual study. Shaded areas represent 95% CIs, and circles represent original data points without adjustment. CI, credible interval.

Fig 4. Age, sex, and the QT interval in malaria.

Interaction between age and sex, and conditional effect on the QT interval, from a hierarchical generalised additive model adjusting for heart rate/RR interval (as $\sqrt{RR}$), malaria type, body temperature, and individual study. Shaded areas represent 95% CIs, and rug marks represent age distribution of original data points. CI, credible interval.