title: The Contribution of National Spontaneous Reporting Systems to Detect Signals of Torsadogenicity: Issues Emerging from the ARITMO Project.
abstract: BACKGROUND
  Spontaneous reporting systems (SRSs) are pivotal for signal detection, especially for rare events with a high drug-attributable component, such as torsade de pointes (TdP). Use of different national SRSs is rarely attempted because of inherent difficulties, but should be considered on the assumption that rare events are diluted in international databases.
  
  
  OBJECTIVE
  The aim was to describe TdP-related events associated with antipsychotics, H1-antihistamines and anti-infectives in three national SRSs (in Italy, Germany and France) and highlight potential signals of torsadogenicity through a combined literature evaluation.
  
  
  METHODS
  A common search strategy was applied to extract TdP-related events: (1) TdP, (2) QT interval abnormalities, (3) ventricular fibrillation/tachycardia, and (4) sudden cardiac death. Signals of disproportionate reporting (SDRs) were calculated for TdP + QT interval abnormalities and defined by a lower limit of the 95 % confidence interval of the reporting odds ratio (ROR) >1. Among SDRs with at least three cases without concomitant pro-arrhythmic drugs, we defined potential new signal of torsadogenicity as drugs with no published evidence from (a) the crediblemeds(®) website ( http://www.crediblemeds.com , as of November 1st, 2014); (b) studies on the FDA Adverse Event Reporting System (FAERS); and (c) safety trials or pharmaco-epidemiological studies (as of December 16th, 2014).
  
  
  RESULTS
  Overall, 3505 cases were retrieved (1372, 1468, and 801 for France, Germany and Italy, respectively). Antipsychotics were mainly recorded in Germany (792 cases), whereas antibiotics peaked at 515 and 491 (France and Italy, respectively). Forty-one drugs met criteria for SDRs in at least one single source, of which 31 were detected only from one single SRS: 18, ten and three (French, German and Italian SRS, respectively). By contrast, only five SDRs were detected in all national data sources (amisulpride, aripiprazole, haloperidol, olanzapine, risperidone). Overall, five potential new signals of torsadogenicity were identified: flupentixol, ganciclovir, levocetirizine, oxatomide and tiapride.
  
  
  CONCLUSIONS
  We found differences across and within national SRSs in the reporting of drug-induced TdP, which finally resulted in five potential new signals of torsadogenicity. These findings warrant targeted pharmacovigilance studies to formally assess the existence of actual drug-event associations.
authors.affiliation: Department of Medical and Surgical Sciences, Alma Mater Studiorum-University of Bologna, Via Irnerio, 48, 40126, Bologna, BO, Italy.
authors.forename: Emanuel
authors.initials: E
authors.lastname: Raschi
authors.affiliation: Department of Medical and Surgical Sciences, Alma Mater Studiorum-University of Bologna, Via Irnerio, 48, 40126, Bologna, BO, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Poluzzi
authors.affiliation: Univ. Bordeaux, U657, 33000, Bordeaux, France.|INSERM U657, 33000, Bordeaux, France.|CIC Bordeaux CIC1401, 33000, Bordeaux, France.
authors.forename: Francesco
authors.initials: F
authors.lastname: Salvo
authors.affiliation: Department of Medical and Surgical Sciences, Alma Mater Studiorum-University of Bologna, Via Irnerio, 48, 40126, Bologna, BO, Italy.
authors.forename: Ariola
authors.initials: A
authors.lastname: Koci
authors.affiliation: Leibniz Institute for Prevention Research and Epidemiology-BIPS, Bremen, Germany.|Techniker Krankenkasse, Hamburg, Germany.
authors.forename: Marc
authors.initials: M
authors.lastname: Suling
authors.affiliation: Univ. Bordeaux, U657, 33000, Bordeaux, France.|Unit of Clinical Pharmacology, Department of Biomedical and Clinical Sciences, University Hospital "Luigi Sacco", Università di Milano, 20157, Milan, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Antoniazzi
authors.affiliation: Department of Medical and Surgical Sciences, Alma Mater Studiorum-University of Bologna, Via Irnerio, 48, 40126, Bologna, BO, Italy.
authors.forename: Luisella
authors.initials: L
authors.lastname: Perina
authors.affiliation: Drug Safety Research Unit, Southampton, UK.
authors.forename: Lorna
authors.initials: L
authors.lastname: Hazell
authors.affiliation: Department of Public Health and Community Medicine, University of Verona, Verona, Italy.
authors.forename: Ugo
authors.initials: U
authors.lastname: Moretti
authors.affiliation: Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Miriam
authors.initials: M
authors.lastname: Sturkenboom
authors.affiliation: Leibniz Institute for Prevention Research and Epidemiology-BIPS, Bremen, Germany.
authors.forename: Edeltraut
authors.initials: E
authors.lastname: Garbe
authors.affiliation: Univ. Bordeaux, U657, 33000, Bordeaux, France.|INSERM U657, 33000, Bordeaux, France.|CIC Bordeaux CIC1401, 33000, Bordeaux, France.
authors.forename: Antoine
authors.initials: A
authors.lastname: Pariente
authors.affiliation: Department of Medical and Surgical Sciences, Alma Mater Studiorum-University of Bologna, Via Irnerio, 48, 40126, Bologna, BO, Italy. fabrizio.deponti@unibo.it.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: De Ponti
mesh_terms: D016907:Adverse Drug Reaction Reporting Systems / Q000706:statistics & numerical data*; D000890:Anti-Infective Agents / Q000009:adverse effects; D014150:Antipsychotic Agents / Q000009:adverse effects; D016208:Databases, Factual / Q000706:statistics & numerical data; D064420:Drug-Related Side Effects and Adverse Reactions / Q000453:epidemiology*; D005602:France / Q000453:epidemiology; D005858:Germany / Q000453:epidemiology; D006634:Histamine H1 Antagonists / Q000009:adverse effects; D006801:Humans; D007558:Italy / Q000453:epidemiology; D060735:Pharmacovigilance; D016171:Torsades de Pointes / Q000139:chemically induced* / Q000453:epidemiology
chemical_list: D000890:Anti-Infective Agents; D014150:Antipsychotic Agents; D006634:Histamine H1 Antagonists