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

Drug Saf (2016) 39:59–68 DOI 10.1007/s40264-015-0353-1 ORIGINAL RESEARCH ARTICLE The Contribution of National Spontaneous Reporting Systems to Detect Signals of Torsadogenicity: Issues Emerging from the ARITMO Project Emanuel Raschi1 • Elisabetta Poluzzi1 • Francesco Salvo2,3,4 • Ariola Koci1 • Marc Suling5,9 • Stefania Antoniazzi2,10 • Luisella Perina1 • Lorna Hazell6 • Ugo Moretti7 • Miriam Sturkenboom8 • Edeltraut Garbe5 • Antoine Pariente2,3,4 • Fabrizio De Ponti1 Published online: 8 October 2015 Ó The Author(s) 2015. This article is published with open access at Springerlink.com 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 antiinfectives 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 E. Raschi and E. Poluzzi equally contributed to the present work. Electronic supplementary material The online version of this article (doi:10.1007/s40264-015-0353-1) contains supplementary material, which is available to authorized users. & Fabrizio De Ponti 1 Department of Medical and Surgical Sciences, Alma Mater Studiorum-University of Bologna, Via Irnerio, 48, 40126 Bologna, BO, Italy 2 Univ. Bordeaux, U657, 33000 Bordeaux, France 3 INSERM U657, 33000 Bordeaux, France 4 CIC Bordeaux CIC1401, 33000 Bordeaux, France 5 Leibniz Institute for Prevention Research and EpidemiologyBIPS, Bremen, Germany Key points Diversity across and within national spontaneous reporting systems is likely to be multifactorial but informative of the local reporting pattern of druginduced arrhythmia. Five potential signals, undetected by recent studies in the FDA Adverse Event Reporting System, warrant validation through additional post-marketing sources, namely analytical pharmacoepidemiological approaches. In the era of large international spontaneous reporting systems, we provide preliminary evidence on the role of national databases in detecting rare adverse drug reactions, at least for drugs with wellestablished use. 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, 6 Drug Safety Research Unit, Southampton, UK 7 Department of Public Health and Community Medicine, University of Verona, Verona, Italy 8 Erasmus Medical Center, Rotterdam, The Netherlands 9 Present Address: Techniker Krankenkasse, Hamburg, Germany 10 Present Address: Unit of Clinical Pharmacology, Department of Biomedical and Clinical Sciences, University Hospital ‘‘Luigi Sacco’’, Università di Milano, 20157 Milan, Italy 60 we defined potential new signal of torsadogenicity as drugs with no published evidence from (a) the crediblemedsÒ 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. E. Raschi et al. events, especially as compared with the large catchment area of international databases, such as the FDA Adverse Event Reporting System (FAERS). Nonetheless, national databases have the advantage of providing the actual local picture of the risk (which depends on the real drug use) and offer access to the patient’s medical history (the so-called ‘‘narratives’’), thus potentially enhancing the performance of signal detection. In particular, multiple database analysis can be used to compare results across databases, while maintaining the diversity of reporting pattern within each single source, and avoid the theoretical dilution phenomenon that may occur when analyzing international SRSs [3]. On these grounds, we analyzed three European national SRSs (i.e., French, German and Italian databases), with the following aims: (1) to describe the distribution of TdPrelated events associated with antipsychotics, H1-antihistamines and anti-infectives among the different databases; and (2) to identify novel signals of torsadogenicity, by comparing published literature data, especially from international SRSs, namely FAERS. 2 Methods 2.1 Data Sources: Accessibility and Technical Issues 1 Introduction Torsade de pointes (TdP) is a rare but potentially fatal arrhythmia characterized by a marked drug-attributable component; its suboptimal prediction and detection in pre-marketing phases of drug development caused a number of regulatory interventions worldwide, including drug withdrawals, restrictions and warnings, thus making spontaneous reporting systems (SRSs) pivotal in signal detection. The post-marketing epidemic caused by non-cardiac drugs with TdP liability has triggered a global response from drug regulators, drug developers and academia, which resulted in the stabilization of the reporting rate of TdP [1]. Within the ARITMO project (http://www.aritmo-project. org), both international and national SRSs have been exploited to comprehensively collect and analyze the torsadogenic liability of antipsychotics, H1-antihistamines and anti-infectives for systemic use, with the ultimate goal of capturing potential signals of torsadogenicity requiring population-based studies and possible regulatory consideration. National databases have (...truncated)