Project investigates the arrhythmia-risks of antipsychotics and other medicines

Drug-induced cardiac arrhythmias, such as those deriving from prolongation of the electrocardiographic QT interval, are a major pharmacological safety concern as they are difficult to predict. Torsades de Pointes (TdP) and sudden cardiac death are serious side effects of drugs that induce QT prolongation but these occur very rarely and do not occur with all QT prolonging drugs. As a result of the difficulties in predicting which drugs may result in serious arrhythmic side effects, a number of antipsychotic, antihistaminic and anti-infective drugs have been withdrawn from the market in recent years and others were restricted in use.

In order to better understand which drugs prolong the QT interval and result in serious consequences (and which circumstances may affect this risk), the ARITMO project was initiated. This was requested by the Pharmacovigilance Working Party of the European Medicines Agency through a public call in the 7^th Framework Programme of the European Commission. The project, involving researchers from the London School of Hygiene and Tropical Medicine in the UK, will use health care and surveillance systems to assess the arrhythmic potential of three specific classes of drugs: antipsychotics, anti-infectives, and antihistaminics (totalling more than 250 compounds). The Consortium is an international network for the conduct of common protocol database and surveillance studies in the field. Analysis of the databases and surveillance systems allows healthcare workers to study one of the largest collections of data available. They also have the potential to examine risks arising from differences in patterns of prescribing between Northern and Southern Europe.

Mariam Molokhia, Senior Lecturer in Genetic Epidemiology at the London School of Hygiene & Tropical Medicine, says, “LSHTM is Britain’s national school of public health. It is an internationally recognized centre of excellence in epidemiology and biostatistics, and one of the highest-rated research institutions in the UK.

The research group has considerable experience in pharmaco-epidemiology, computational methods for analysing large, complex datasets, genetic epidemiology, experience with genome wide association studies and evidence synthesis, ideally suited to projects of this nature.”

A multidisciplinary approach will be followed to achieve the ARITMO objectives including:

• Critically reviewing the literature on preclinical and clinical evidence
• Conducting in silico modelling to predict the arrhythmic potential through target profiling and docking molecules in existing models and predicting the effects on hERG K⁺, Na⁺, Ca⁺⁺ channels
• Analysing the information in national and international pharmacovigilance databases of spontaneous reports of arrhythmias
• Conducting prospective case control surveillance on symptomatic QT prolongation
• Conducting cohort studies in patients receiving antipsychotics or anti-infectives
• Analysing information on the association between drug use and adverse effects from health care databases on more than 27 million persons
• Analysing information from ongoing clinical studies to assess the association between drug use and various arrhythmia outcomes
• Collecting blood samples from cases and drug-matched controls to investigate potential effect modification by candidate genes and a hypothesis generating approach including more than 2000 genes

Knowledge integration from the above mentioned actions will provide assistance for the risk/benefit ranking of drugs for treatment and regulatory decision making. The comprehensive knowledge database generated will include a score that will be assigned by weighing both the quality and strength of information, and a risk chart for clinicians, which will allow for more informed treatment and decision making in prescribing drugs.

Notes

The ARITMO project (full title: “Arrhythmogenic Potential of Drugs”) is funded with a 2.7 million Euro grant from the European Commission in the 7th Framework Programme, coordinated by Professor Dr. Miriam Sturkenboom of Erasmus Universitair Medisch Centrum (Netherlands), and carried out by a consortium of 17 leading research institutions.

Additional Information

The ARITMO project started on 1^st January 2010, with a total duration of 36 months.

Project website: www.aritmo-project.org

Participating institutions:

• Erasmus Universitair Medisch Centrum Rotterdam, Netherlands
• Fundació IMIM, Spain
• London School for Hygiene and Tropical Medicine, United Kingdom
• Alma Mater Studiorum-Università di Bologna, Italy
• Universitaet Bremen, Germany
• University of Newcastle, United Kingdom
• Université Victor-Segalen Bordeaux 2, France
• Fondazione Salvatore Maugeri Clinica del Lavoro e Della Riabilitazione – IRCCS, Pavia, Italy
• Charite – Universitaetsmedizin Berlin, Germany
• Università Degli Studi di Verona, Italy
• St. Gerorge’s Hospital Medical School, United Kingdom
• AstraZeneca, Sweden
• PHARMO Institute, Netherlands
• Fondazione Scientifica SIMG-ONLUS, Italy
• Aarhus Universitetshospital, Aarhus Sygehus, Denmark
• Academisch Medisch Centrum bij de Universiteit van Amsterdam, Netherlands
• Drug Safety Research Trust, United Kingdom