Risk of sudden unexplained death after use of dihydroartemisinin–piperaquine for malaria: a systematic review and Bayesian meta-analysis

Abstract

SummaryBackgroundDihydroartemisinin–piperaquine is an effective and well tolerated artemisinin-based combination therapy that has been assessed extensively for the prevention and treatment of malaria. Piperaquine, similar to several structurally related antimalarials currently used, can prolong cardiac ventricular repolarisation duration and the electrocardiographic QT interval, leading to concerns about its proarrhythmic potential. We aimed to assess the risk of potentially lethal iatrogenic ventricular arrhythmias in individuals receiving dihydroartemisinin–piperaquine.MethodsWe did a systematic review and Bayesian meta-analysis. We searched clinical bibliographic databases (last on May 24, 2017) for studies of dihydroartemisinin–piperaquine in human beings. Further unpublished studies were identified with the WHO Evidence Review Group on the Cardiotoxicity of Antimalarials. We searched for articles containing “dihydroartemisinin-piperaquine” as title, abstract, or subject heading keywords, with synonyms and variant spellings as additional search terms. We excluded animal studies, but did not apply limits on language or publication date. Eligible studies were prospective, randomised, controlled trials or cohort studies in which individuals received at least one 3-day treatment course of dihydroartemisinin–piperaquine for mass drug administration, preventive therapy, or case management of uncomplicated malaria, with follow-up over at least 3 days. At least two independent reviewers screened titles, abstracts, and full texts, agreed study eligibility, and extracted information about study and participant characteristics, adverse event surveillance methodology, dihydroartemisinin–piperaquine exposures, loss-to-follow up, and any deaths after dihydroartemisinin–piperaquine treatment into a standardised database. The risk of sudden unexplained death after dihydroartemisinin–piperaquine with 95% credible intervals (CI) generated by Bayesian meta-analysis was compared with the baseline rate of sudden cardiac death.FindingsOur search identified 94 eligible primary studies including data for 197 867 individuals who had received dihydroartemisinin–piperaquine: 154 505 in mass drug administration programmes; 15 188 in 14 studies of repeated courses in preventive therapies and case management of uncomplicated malaria; and 28 174 as single-course treatments of uncomplicated malaria in 76 case-management studies. There was one potentially drug-related sudden unexplained death: 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 (no autopsy or ECG was done). 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). This risk estimate was not higher than the baseline rate of sudden cardiac death (0·7–11·9 per 100 000 person-years or 1 in 1 714 280 to 1 in 100 835 over a 30-day risk period). The risk...

The arrhythmogenic cardiotoxicity of the quinoline and structurally related antimalarial drugs: a systematic review

“…In these 24 studies, there were no reports of sudden death suggestive of a fatal arrhythmia nor of any other major cardiovascular adverse outcomes following piperaquine use. A systematic review and meta-analysis was recently published (after the period of this review) of nearly 200,000 DP-treated individuals, including over 150,000 individuals in unpublished studies of mass drug administration in which exclusion of TdP risk factors was not possible [ 45 ]. The review reported one case of sudden death following DP use in MDA of a previously healthy 16-year-old female in Mozambique who developed palpitations after her second dose of DP, then collapsed, and died on the way to hospital (no ECG or autopsy was performed).…”

“…This case of sudden unexplained death was considered possibly drug-related by cardiology and pharmacology experts at the WHO Evidence Review Group on the Cardiotoxicity of Antimalarials (there are also non-drug-related and non-cardiogenic causes of sudden unexplained death) [ 44 ]. The subsequent meta-analysis found that the risk of sudden unexplained death within 30 days of taking DP was no higher than the baseline risk of sudden cardiac death over the same period [ 45 ]. In addition, despite millions of doses having been distributed, there have been no cases of TdP after DP reported to global pharmacovigilance databases [ 44 ].…”

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

“…QT interval prolongation has been the most common reason for drug withdrawal and relabelling [4]. As part of ongoing safety assessments of population-based use of ACTs and other quinoline-or structurally related compound-containing combinations for malaria control and elimination in both acutely unwell patients and healthy people at risk of symptomatic disease, there has been renewed interest in the evaluation of antimalarial effects on the ECG to guide antimalarial selection and dosage [5][6][7].…”

COVID-19 prevention and treatment: A critical analysis of chloroquine and hydroxychloroquine clinical pharmacology

“…Sudden, unexplained death has not been associated with chloroquine previously, despite administration of billions of prophylaxis and treatment courses and wide variation in dosing [72,73]. Recent prospective studies providing data from 200,000 patients treated with the related bisquinoline antimalarial compound piperaquine (which has similar hERG channel blocking properties) found no increased risk of TdP after standard treatment [81]. Thus, overall, the concerns that chloroquine or hydroxychloroquine given alone in currently recommended doses are likely to provoke TdP, which have seriously hindered studies in COVID-19, are largely unfounded.…”