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Arrhythmogenic potential of drugs (ARITMO)

Keyword:
aritmo (look for word fragments)

Description

The ability of some drug compounds to prolong the QT interval of the electrocardiogram and to precipitate Torsade de Pointes, a potentially fatal arrhythmia, has caused several regulatory interventions: a number of drugs were withdrawn from the market, whereas others were restricted in use. Specific guidelines were implemented to detect QT liability of new compounds as early as possible. However there is increasing evidence showing that an increase in the QT interval does not necessarily lead to Torsade de Pointes which further increased the regulatory and clinical difficulties, intrinsically due to the fact that Torsade de Pointes is a serious, albeit rare event.
The ARITMO project (“Arrhythmogenic Potential of Drugs”) was funded by 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. In ARITMO, the arrhythmic potential of 588 individual compunds of the following classes: antipsychotics, anti-infectives (antibacterials, antimycotics and antivirals) and H1-antihistamines was assessed globally and in specific subgroups (defined by age, co-morbidity, genetic composition).
This was done for each drug by systematically investigating pharmacokinetics and dynamics (hERG affinity, the most important mechanism of drug-induced Torsade de Pointes) from literature, experimental and in silico data, and by estimating the effect of the drug on the QT interval (literature), risk of Torsade de Pointes (pharmacovigilance, field studies), QT prolongation (pharmacovigilance and field studies), as well as ventricular arrhythmia or sudden cardiac death (database studies & pharmacovigilance). Patient-related factors that may influence arrhythmogenicity were investigated by an attempt to find new ECG parameters that would predict Torsade de Pointes, and genetic analyses. All new ARITMO drug-related evidence was aggregated in an overall score presenting the level of evidence of arrhythmogenic risk based on a Dempster Shafer model. This was compared to the knowledge we have on hERG affinity, QT prolongation and VA/SCD risk from published studies.
BIPS has been involved primarily with three aspects of the ARITMO project:
• Analysis of national and international pharmacovigilance databases
• Integration of field studies into a common analysis
• Conduct of multi-database, nested case-control studies in cohorts of users of the respective drug classes to assess the risk of ventricular arrhythmia and sudden cardiac death

Funding period

Begin:   January 2010
End:   June 2013

Sponsor

  • BIPS funding
  • European Commission (7th Framework Programme)

Contact

Dr. rer. medic. Tania Schink

Project management (international)

Prof. Dr. Miriam Sturkenboom, Erasmus Universiteit Medisch Centrum Rotterdam, Niederlande

Cooperation

  • Aarhus University Hospital/Aarhus Sygehus, Dänemark
  • Academic Medical Center, Amsterdam, Niederlande
  • Alma Mater Studiorum-Universita di Bologna, Italien
  • AOK Bremen/Bremerhaven
  • AstraZeneca, Sweden
  • Charite-Universitätsmedizin Berlin, Deutschland
  • Deutsche Angestellten-Krankenkasse (DAK)
  • Drug Safety Research Trust, Großbritannien
  • Erasmus Universiteit Medisch Centrum, Rotterdam/Niederlande
  • Fondatione Scientifica SIMG-ONLUS, Italien
  • Fundacio IMIM, Spanien
  • Handelskrankenkasse (HKK)
  • IRCCS Fondazione Salvatore Maugeri, Pavia, Italien
  • London School of Hygiene and Tropical Medicine, Großbritannien
  • PHARMO Coöperatie U.A, Niederlande
  • St. Georges Hospital Medical School, Großbritannien
  • Techniker Krankenkasse (TK)
  • Universita degli Studi di Verona, Italien
  • Universite Victor-Segalen Bordeaux2, Frankreich
  • University of Newcastle upon Tyne, Großbritannien

Link

http://www.aritmo-project.org/

Selected project-related publications

    Articles with peer-review

  • Trifirò G, de Ridder M, Sultana J, Oteri A, Rijnbeek P, Pecchioli S, Mazzaglia G, Bezemer I, Garbe E, Schink T, Poluzzi E, Frøslev T, Molokhia M, Diemberger I, Sturkenboom MCJM. Use of azithromycin and risk of ventricular arrhythmia. Canadian Medical Association Journal. 2017;189(15):E560-E568.
    https://doi.org/10.1503/cmaj.160355
  • Oteri A, Mazzaglia G, Pecchioli S, Molokhia M, Ulrichsen SP, Pedersen L, Poluzzi E, De Ponti F, Garbe E, Schink T, Herings R, Bezemer I, Sturkenboom MCJM, Trifirò G. Prescribing pattern of antipsychotic drugs during the years 1996-2010: A population-based database study in Europe with a focus on torsadogenic drugs. British Journal of Clinical Pharmacology. 2016;82(2):487-497.
    https://doi.org/10.1111/bcp.12955
  • Raschi E, Poluzzi E, Salvo F, Koci A, Suling M, Perina L, Hazell L, Moretti U, Sturkenboom MCJM, Garbe E, Pariente A, De Ponti F. The contribution of national spontaneous reporting systems to detect signals of torsadogenicity: Issues emerging from the ARITMO project. Drug Safety. 2016;39(1):59-68.
    https://doi.org/10.1007/s40264-015-0353-1
  • Holstiege J, Enders D, Schink T, Innocenti F, Oteri A, Bezemer I, Lapi F, Kaguelidou F, Poluzzi E, Puccini A, Ulrichsen SP, Sturkenboom MCJM, Trifirò G, Garbe E. Trends in paediatric macrolide use in five European countries - A population-based study. European Journal of Clinical Pharmacology. 2015;71(8):991-999.
    https://doi.org/10.1007/s00228-015-1870-7
  • Mor A, Frøslev T, Thomsen RW, Oteri A, Rijnbeek P, Schink T, Garbe E, Pecchioli S, Innocenti F, Bezemer I, Poluzzi E, Sturkenboom MCJM, Trifirò G, Søgaard M. Antibiotic use varies substantially among adults: A cross-national study from five European countries in the ARITMO project. Infection. 2015;43(4):453-472.
    https://doi.org/10.1007/s15010-015-0768-8
  • Holstiege J, Schink T, Molokhia M, Mazzaglia G, Innocenti F, Oteri A, Bezemer I, Poluzzi E, Puccini A, Ulrichsen SP, Sturkenboom MCJM, Trifirò G, Garbe E. Systemic antibiotic prescribing to paediatric outpatients in 5 European countries: A population-based cohort study. BMC Pediatrics. 2014;14:174.
    https://doi.org/10.1186/1471-2431-14-174
  • Letters

  • Mor A, Thomsen RW, Frøslev T, Garbe E, Poluzzi E, Sturkenboom MCJM, Trifirò G, Søgaard M. Response to comment on: "Antibiotic use varies substantially among adults - A cross-national study from five European Countries in the ARITMO project". Infection. 2016;44(1):135-141.
    https://doi.org/10.1007/s15010-015-0829-z
  • Presentations at scientific meetings/conferences

  • Oteri A, Mazzaglia G, Innocenti F, Herings R, Bezemer I, Garbe E, Holstiege J, Schink T, Poluzzi E, Puccini A, Ulrichsen SP, Pedersen L, Sturkenboom MCJM, Trifirò G. Was the use of antipsychotic drugs with arrythmogenic potential changed in the last years? A population-based database study in 5 European countries. 28th International Conference on Pharmacoepidemiology & Therapeutic Risk Management (ICPE), 23-26 August 2012, Barcelona, Spain. (Abstract published in: Pharmacoepidemiology & Drug Safety. 2012;21(Suppl.3):331)
  • Posters at scientific meetings/conferences

  • Oteri A, de Ridder M, Pecchioli S, Bezemer I, Garbe E, Schink T, Clò M, Frøslev T, Sturkenboom MCJM, Trifirò G. Use of antibiotics and risk of ventricular arrhythmia: A nested case-control multi-database study in 5 European countries. 13th Annual Meeting of the International Society of Pharmacovigilance (ISoP), 1-4 October 2013, Pisa, Italy.
  • Oteri A, de Ridder M, Pecchioli S, Bezemer I, Garbe E, Schink T, Puccini A, Ulrichsen SP, Sturkenboom MCJM, Trifirò G. Use of antipsychotics and risk of ventricular arrhythmia: A nested case-control multi-database study in 5 European countries. 13th Annual Meeting of the International Society of Pharmacovigilance (ISoP), 1-4 October 2013, Pisa, Italy.
  • Holstiege J, Schink T, Mazzaglia G, Trifirò G, Innocenti F, Oteri A, Herings R, Bezemer I, Poluzzi E, Puccini A, Ulrichsen SP, Pedersen L, Sturkenboom MCJM, Garbe E. Antibiotic prescription rates in paediatric populations of 5 European countries: A drug utilization study from the ARITMO project. 28th International Conference on Pharmacoepidemiology & Therapeutic Risk Management (ICPE), 23-26 August 2012, Barcelona, Spain. (Abstract published in: Pharmacoepidemiology & Drug Safety. 2012;21(Suppl.3):131)
  • Holstiege J, Schink T, Mazzaglia G, Trifirò G, Innocenti F, Oteri A, Herings R, Bezemer I, Poluzzi E, Puccini A, Ulrichsen SP, Pedersen L, Sturkenboom MCJM, Garbe E. Antiviral prescription rates in paediatric populations of 5 European countries: A drug utilization study from the ARITMO project. 28th International Conference on Pharmacoepidemiology & Therapeutic Risk Management (ICPE), 23-26 August 2012, Barcelona, Spain. (Abstract published in: Pharmacoepidemiology & Drug Safety. 2012;21(Suppl.3):131)
  • Mazzaglia G, Innocenti F, Oteri A, Herings R, Bezemer I, Holstiege J, Poluzzi E, Puccini A, Ulrichsen SP, Pedersen L, Schink T, Garbe E, Molokhia M, Sturkenboom MCJM, Trifirò G. Antibiotic use across five European countries: A drug utilization study from the ARITMO project. 28th International Conference on Pharmacoepidemiology & Therapeutic Risk Management (ICPE), 23-26 August 2012, Barcelona, Spain. (Abstract published in: Pharmacoepidemiology & Drug Safety. 2012;21(Suppl.3):100)
  • Poluzzi E, Puccini A, Mazzaglia G, Innocenti F, Oteri A, Herings R, Bezemer I, Holstiege J, Ulrichsen SP, Pedersen L, Garbe E, Schink T, De Ponti F, Sturkenboom MCJM, Trifirò G. Antimycotic use across Europe: A drug utilization study from the ARITMO project. 28th International Conference on Pharmacoepidemiology & Therapeutic Risk Management (ICPE), 23-26 August 2012, Barcelona, Spain. (Abstract published in: Pharmacoepidemiology & Drug Safety. 2012;21(Suppl.3):101)