Reappraising the cardiosafety of dihydroartemisinin-piperaquine
Authors: Pere Millat-Martínez, Quique Bassat
Journal: The Lancet Infectious Diseases (2018)

The arsenal of efficacious drugs for the treatment of malaria remains small and is clearly insufficient to tackle the global burden of malaria, with more than 216 million clinical episodes and nearly half a million deaths annually.1WHOWorld malaria report 2017. World Health Organization, Geneva2017Google Scholar Among the new antimalarials that have been developed in the past decade, the artemisinin-based combination dihydroartemisinin–piperaquine is one of the most promising, on account of its good efficacy and tolerability, simplified dose schedule (ie, once daily for 3 days), and long post-treatment prophylactic effect.2Zani B Gathu M Donegan S Olliaro PL Sinclair D Dihydroartemisinin-piperaquine for treating uncomplicated Plasmodium falciparum malaria.Cochrane Database Syst Rev. 2014; 1 (CD010927.)Google Scholar The only brand of dihydroartemisinin–piperaquine that has been registered under stringent regulatory authority is Eurartesim (licensed by the European Medicines Agency [EMA] in 2011), although at least three other brands exist: Duo-cotecxin (also prequalified by WHO), D-ARTEPP, and Arterakine. Dihydroartemisinin–piperaquine is not only used as a treatment of uncomplicated malaria but also has been proposed as an alternative to sulphadoxine–pyrimethamine for intermittent preventive treatment of malaria during pregnancy,3Gutman J Kovacs S Dorsey G Stergachis A ter Kuile FO Safety, tolerability, and efficacy of repeated doses of dihydroartemisinin-piperaquine for prevention and treatment of malaria: a systematic review and meta-analysis.Lancet Infect Dis. 2017; 17: 184-193Summary Full Text Full Text PDF PubMed Scopus (67) Google Scholar or as a suitable drug for the mass treatment of entire populations as part of malaria-elimination endeavours.4Eisele TP Bennett A Silumbe K et al.Short-term impact of mass drug administration with dihydroartemisinin plus piperaquine on malaria in southern province Zambia: a cluster-randomized controlled trial.J Infect Dis. 2016; 214: 1831-1839Crossref PubMed Scopus (76) Google Scholar However, because piperaquine can cause a dose-dependent effect on cardiac repolarisation, which can manifest as a prolonged QT interval in surface electrocardiograms (ECG), concerns have been raised regarding the cardiosafety of dihydroartemisinin–piperaquine, which have limited its much wider deployment and use. Indeed, such potentially pro-arrhythmogenic characteristics, which theoretically could be linked to an increased risk of ventricular fibrillation and sudden death, led the EMA to recommend that an ECG should be done before the drug's administration, that the drug should be administered under strict fasting conditions (because food increases piperaquine's plasma concentration), and that repeated doses should be limited in number and frequency.5European Agency of MedicinesEurartesim: Summary of product characteristics.http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/001199/WC500118113.pdfDate accessed: May 18, 2018Google Scholar These recommendations reduced the potential use of the drug in most areas of the world where malaria remains highly endemic. Dihydroartemisinin–piperaquine has since become one of the most studied drugs in relation to its associated repolarisation-related cardiotoxicity, conditions that were not applied to other antimalarial drugs with similar potential (quinine, amodiaquine, or chloroquine) when they were licensed, more than half a century ago. Although the occurrence of clinically relevant adverse cardiovascular effects associated with dihydroartemisinin–piperaquine or piperaquine on its own after several years of extensive use seems rare, the drug's association with life-threatening cardiac events remains unchallenged. In this issue of Lancet Infectious Diseases, Xin Hui S Chan and colleagues6Chan XHS Win YN Mawer LJ Tan JY Brugada J White NJ Risk of sudden unexplained death after use of dihydroartemisinin–piperaquine for malaria: a systematic review and Bayesian meta-analysis.Lancet Infect Dis. 2018; (published online June 7.)http://dx.doi.org/10.1016/S1473-3099(18)30297-4Summary Full Text Full Text PDF Scopus (33) Google Scholar present the results of a systematic review and meta-analysis of 94 studies including nearly 200 000 pooled individuals given dihydroartemisinin–piperaquine for several indications, including treatment of uncomplicated malaria, intermittent preventive treatment, and mass drug administration. The investigators compared the risk of sudden unexplained death after dihydro-artemisinin–piperaquine with the baseline rate of sudden cardiac death in a reference population aged younger than 35 years, chosen to reflect the typical age of antimalarial users in malaria-endemic areas. The median pooled risk estimate of sudden unexplained death after dihydroartemisinin–piperaquine was 1 in 757 950 (95% CI 1 in 2 854 490 to 1 in 209 114), a finding deemed to be similar (and not higher) than the baseline rate of sudden cardiac death in the reference population after standardisation to 30-day risks (0·7–11·9 per 100 000 person-years or 1 in 1 714 280 to 1 in 100 835). The investigators also examined the 61 deaths of individuals in the studies who received the drug, 31 of which occurred during the 3-day treatment period, and a further 30 that occurred during one terminal elimination half-life of piperaquine (around 30 days). Members of a WHO Expert Review Group, specifically convened to review the cardiosafety of antimalarial drugs,7WHOWHO Evidence Review Group on the Cardiotoxicity of Antimalarial Medicines. World Health Organization, Geneva2017Google Scholar concluded that only one of these deaths (of a healthy woman aged 16 in Mozambique who developed heart palpitations several hours after the second dose of dihydroartemisinin–piperaquine and collapsed and died on the way to hospital) was consistent with sudden cardiac death and possibly causally related to drug exposure. Although under-reporting is likely, that only one death among nearly 200 000 studied individuals could be linked to the drug strongly supports the idea that sudden deaths potentially attributable to repolarisation-related tachyarrhythmia after treatment with dihydroartemisinin–piperaquine are infrequent. These reassuring data further corroborate the conclusions of the aforementioned WHO expert panel,7WHOWHO Evidence Review Group on the Cardiotoxicity of Antimalarial Medicines. World Health Organization, Geneva2017Google Scholar of findings from a previous smaller systematic review and meta-analysis on this subject,3Gutman J Kovacs S Dorsey G Stergachis A ter Kuile FO Safety, tolerability, and efficacy of repeated doses of dihydroartemisinin-piperaquine for prevention and treatment of malaria: a systematic review and meta-analysis.Lancet Infect Dis. 2017; 17: 184-193Summary Full Text Full Text PDF PubMed Scopus (67) Google Scholar and of various surveillance efforts undertaken by many independent research groups to study the safety of dihydroartemisinin–piperaquine.2Zani B Gathu M Donegan S Olliaro PL Sinclair D Dihydroartemisinin-piperaquine for treating uncomplicated Plasmodium falciparum malaria.Cochrane Database Syst Rev. 2014; 1 (CD010927.)Google Scholar, 8West African Network for Clinical Trials of Antimalarial DrugsPyronaridine-artesunate or dihydroartemisinin-piperaquine versus current first-line therapies for repeated treatment of uncomplicated malaria: a randomised, multicentre, open-label, longitudinal, controlled, phase 3b/4 trial.Lancet. 2018; 391: 1378-1390Summary Full Text Full Text PDF PubMed Scopus (84) Google Scholar, 9Kabanywanyi AM Baiden R Ali AM et al.Multi-country evaluation of safety of dihydroartemisinin/piperaquine post-licensure in African public hospitals with electrocardiograms.PLoS ONE. 2016; 11: e0164851Crossref PubMed Scopus (12) Google Scholar, 10Coldiron ME Lasry E Bouhenia M et al.Intermittent preventive treatment for malaria among children in a refugee camp in northern Uganda: lessons learned.Malar J. 2017; 16: 218Crossref PubMed Scopus (4) Google Scholar Additionally, a multicentre clinical trial in five sub-Saharan African countries of a new dispersible paediatric formulation of dihydroartemisinin–piperaquine in infants aged 6–12 months did not note any clinical cardiosafety concerns.11Gargano N Madrid L Valentini G et al.Efficacy and tolerability outcomes of a phase II, randomized, open-label, multicenter study of a new water-dispersible pediatric formulation of dihydroartemisinin-piperaquine for the treatment of uncomplicated plasmodium falciparum malaria in African infants.Antimicrob Agents Chemother. 2018; 62: e00596-e00617PubMed Google Scholar Further studies (NCT02605720) assessing the safety in healthy individuals (including detailed ECG assessment) of cumulative repeated monthly treatment with dihydroartemisinin–piperaquine, mimicking regimen used in mass-drug administration are underway. Reappraising the value of the few available effective antimalarials is more important now than ever. The global effort against malaria is at a crossroads;12Alonso P Noor AM The global fight against malaria is at crossroads.Lancet. 2017; 390: 2532-2534Summary Full Text Full Text PDF PubMed Scopus (69) Google Scholar malaria incidence seems to be rising again after many years of decreases. Dihydroartemisinin–piperaquine should be shed of its cardiotoxic reputation, so that malaria-endemic areas can benefit from its full potential and to decrease the toll that malaria still imposes globally. We declare no competing interests. QB is a member of the WHO Malaria Treatment Guidelines Group, which produces global guidance on the treatment of malaria including decisions about dihydroartemisinin–piperaquine. The views expressed by the authors are personal opinions and do not represent the recommendations of WHO. Risk of sudden unexplained death after use of dihydroartemisinin–piperaquine for malaria: a systematic review and Bayesian meta-analysisDihydroartemisinin–piperaquine was associated with a low risk of sudden unexplained death that was not higher than the baseline rate of sudden cardiac death. Concerns about repolarisation-related cardiotoxicity need not limit its current use for the prevention and treatment of malaria. Full-Text PDF Open Access