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 Unpublished studies were identified by the World Health Organization (WHO) Evidence Review Group (ERG) on the Cardiotoxicity of Antimalarials.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.

Abstract

Xin Hui Chan and co-workers report an individual patient data meta-analysis on disease-specific heart rhythm alterations in malaria.

Author summary

Why was this study done?

• Prolongation of the electrocardiographic (ECG) QT interval is a widely used marker of the risk of developing abnormal heart rhythms, which can cause sudden death.

• Several antimalarial drugs are associated with QT interval prolongation, motivating systematic ECG safety monitoring in many malaria clinical studies.

• Malaria illness itself may also affect the heart and QT interval, but these disease effects are not well-understood.

• Interpretation of ECG changes after antimalarial treatment is complicated by the coincidence of peak antimalarial drug concentrations with malaria recovery.

What did the researchers do and find?

• We performed a systematic review and meta-analysis of individual patient data to investigate the effect of malaria disease factors on the ECG QT interval.

• We included pretreatment data from 10,452 individuals (9,778 malaria patients and 674 healthy participants) from 43 studies in 20 countries.

• Malaria was associated with QT interval shortening and increased sensitivity of the QT interval to heart rate changes, and these effects increased with malaria severity.

• Body temperature increase (fever) was associated independently with clinically significant QT shortening.

What do these findings mean?

• To improve cardiac safety assessments of antimalarial medicines, adjustment for malaria recovery- and defervescence-related QT interval prolongation is needed to avoid misattributing QT changes solely to drugs.

• These findings are relevant to drug developers, healthcare providers, clinical trialists, and policymakers who use QT interval safety data to decide which antimalarials to develop and use and at what dose.

• Further study of the QT interval in other infections and inflammatory disorders that cause fever and are treated with QT-prolonging medicines is recommended in order to understand the role of disease factors in QT interval changes.