The Contribution of National Spontaneous Reporting Systems to Detect Signals of Torsadogenicity: Issues Emerging from the ARITMO Project

Emanuel Raschi, Elisabetta Poluzzi, Francesco Salvo, Ariola Koci, Marc Suling, Stefania Antoniazzi, Luisella Perina, Lorna Hazell, Ugo Moretti, Miriam Sturkenboom, Edeltraut Garbe, Antoine Pariente and Fabrizio Ponti ()
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Emanuel Raschi: Alma Mater Studiorum-University of Bologna
Elisabetta Poluzzi: Alma Mater Studiorum-University of Bologna
Francesco Salvo: Univ. Bordeaux, U657
Ariola Koci: Alma Mater Studiorum-University of Bologna
Marc Suling: Leibniz Institute for Prevention Research and Epidemiology-BIPS
Stefania Antoniazzi: Univ. Bordeaux, U657
Luisella Perina: Alma Mater Studiorum-University of Bologna
Lorna Hazell: Drug Safety Research Unit
Ugo Moretti: University of Verona
Miriam Sturkenboom: Erasmus Medical Center
Edeltraut Garbe: Leibniz Institute for Prevention Research and Epidemiology-BIPS
Antoine Pariente: Univ. Bordeaux, U657
Fabrizio Ponti: Alma Mater Studiorum-University of Bologna

Drug Safety, 2016, vol. 39, issue 1, No 6, 59-68

Abstract: Abstract Introduction 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.

Date: 2016
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DOI: 10.1007/s40264-015-0353-1

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