Safety doubts unwarranted, important anti-malarial drug DHA-PPQ is safe to use, study finds

8 June Bangkok (Thailand) – One of the world’s most widely used anti-malarial drugs is safe to use, say researchers, after a thorough review and analysis of nearly 200,000 malaria patients who’d taken the drug dihydroartemisinin-piperaquine (DHA-PPQ).

There is such a low risk of sudden unexpected death from DHA-PPQ, one of the world’s most effective medicines to treat malaria, that there is no need to limit its current use, the researchers say in a study published today in The Lancet Infectious Diseases.

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Patients being screened for malaria in a Kinshasa clinic. A recent MORU-led study showed that DHA-piperaquine, one of the most effective and commonly used antimalarial drugs in Africa and Asia is safe to use. © MORU 2018

"There had been some concerns that DHA-PPQ could be toxic for the heart. This very large study provides reassurance about the safety of one of our most important antimalarial drugs," said study co-author University of Oxford Prof Sir Nick White.

Used to treat P. falciparum and P. vivax malaria in Africa and Asia and in large-scale pilot programmes to eliminate malaria, DHA-PPQ is a highly efficacious and well-tolerated oral artemisinin combination treatment (ACT) medication that is on the WHO’s List of Essential Medicines. Although DHA-PPQ has been used to treat more than 5.4 million people since its use was approved in Europe in 2011, there were concerns its use could lead to potentially lethal heart arrhythmias and sudden cardiac death.

After carefully examining 96 studies, totalling 197,867 people who’d taken DHA-PPQ, researchers found one potentially drug-related sudden death. They concluded that the risk of sudden unexplained death after DHA-PPQ was no higher than the baseline rate for sudden cardiac death in the general population – and therefore  that there was no reason to limit the use of DHA-PPQ.

“This analysis of almost 200,000 malaria patients treated with DHA-PPQ provides the definite answer and reassuring message that the cardiac effects of piperaquine are not related to life threatening cardiac events and that DHA-PPQ is very safe to use," said University of Oxford Prof Arjen Dondorp, Deputy Director of the Bangkok-based Mahidol Oxford Tropical Medicine Research Unit (MORU).

“This study is important: It clearly shows no evidence of increased cardiac mortality associated with DHA-PPQ therapy in large population studies. It certifies the safety of using DHA-piperaquine as a preventive strategy. The next step should be prospective studies to confirm these very reassuring results," said cardiologist and study co-author Prof Josep Brugada of the University of Barcelona.

The study results were hailed by people active in the global fight against malaria, a parasitic disease transmitted by mosquitoes that killed 445,000 people in 2016, most of them children in Africa.

Michael Chew, from Wellcome's Infection and Immunobiology team, said: "DHA-PPQ is one of the most effective and widely used anti-malarial drugs we have today, and concerns it could lead to heart attacks risked limiting its use and impact. This important study confirms that this drug is safe to use, as the risk of sudden cardiac death in patients is the same as in the general population."

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Reference

Risk of Sudden Unexplained Death after Dihydroartemisinin-Piperaquine:  A Systematic Review and Bayesian Meta-analysis. Chan XHS, Win YN, Mawer LJ, Tan JY, Brugada J, White NJ. The Lancet Infectious Diseases, The Lancet Infectious Diseases, S1473-3099(18)30297-4, https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(18)30297-4/fulltext

Commentary

Reappraising the cardiosafety of dihydroartemisinin-piperaquine. Millat-Martinez P, Bassat Q. The Lancet Infectious Diseases, Published 7 June 2018, DOI: https://doi.org/10.1016/S1473-3099(18)30360-8

Notes for editors

Mahidol Oxford Tropical Medicine Research Unit (MORU), www.tropmedres.ac, is a research collaboration between Mahidol University (Thailand) and University of Oxford and Wellcome (UK).

Funders

This research was funded with support from Wellcome, the Medical Research Council (United Kingdom), World Health Organization, Bill & Melinda Gates Foundation, and University of Oxford.

Authors

Dr Xin Hui S. Chan1,2,3, MRCP; Dr Yan Naung Win1,4, MPH; Dr Laura J. Mawer1,5, MBBChir; Mr Jireh Y. Tan1, MS; Prof Josep Brugada6, PhD; Prof Nicholas J. White1,2,3, FRS.

1Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand

2­Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, United Kingdom

3Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom

4Defence Services Medical Research Centre & Health and Disease Control Unit, Naypyidaw, Myanmar

5Royal Free London NHS Foundation Trust, United Kingdom

6Arrhythmia Section, Cardiology Department, Hospital Clinic, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), University of Barcelona, Spain