Abstract
Introduction: It has not yet been possible to demonstrate the well-established increased bleeding risk related to antidepressants (ADs) with methods of pharmacovigilance as disproportionality analysis. As bleeding events related to ADs often occur under comedication with antithrombotics, ADs might not be considered causative of, but merely “linked” with the bleeding event. Therefore, we hypothesized that causality assessment of bleeding events related to ADs and the competitive impact of antithrombotics are factors contributing to the mentioned previous non-findings.Methods: We performed a case/non-case study based on data from VigiBase™ and calculated reporting odds ratios (RORs) for 25 ADs. We used individual case safety reports (ICSRs) that were differently categorized in the database regarding the type of association between drug and event. Furthermore, we investigated the competitive impact of antithrombotics by comparing RORs calculated with and without ICSRs related to antithrombotics.Results: Analysis of ICSRs that were categorized as causally associated with ADs resulted in detection of only 2 signals (citalopram and escitalopram; upper gastrointestinal bleeding). Analysis of ICSRs irrespective of the type of association resulted in detection of 8 signals (regarding bleeding in general, gastrointestinal bleeding and upper gastrointestinal bleeding). In our analysis, consideration of ICSRs associated with antithrombotics as competitive substances did not have significant impact on signal detection.Conclusion: Categorization of the type of association between drug and event may affect quantitative signal detection toward reduced sensitivity. Causality assessment seems to significantly impact signal detection, probably particularly in rare, unknown, or clinically unremarkable adverse drug reactions. ADs appear to increase the bleeding risk considerably, even independent of antithrombotic comedication.
Highlights
Until now, methods of pharmacovigilance as disproportionality analysis were not capable of proving the otherwise well-established increased bleeding risk related to antidepressants (ADs)
In the analysis of individual case safety reports (ICSRs) categorized as “suspected/interacting” concerning the standardized MedDRA Queries (SMQs) “haemorrhage” (ICSRs related to antithrombotics included; no consideration of the competition bias), no signal was found; using ICSRs categorized as “suspected/interacting/concomitant,” eight signals were detected: amitriptyline [reporting odds ratios (RORs): 1.09], citalopram [ROR: 1.41 (1.38–1.45)], escitalopram (ROR: 1.35 (1.32–1.39), fluoxetine [ROR: 1.03 (1.01–1.05)], hypericum perforatum [ROR: 1.26 (1.10–1.45)], paroxetine [ROR: 1.05 (1.02–1.07)], sertraline [ROR: 1.22 (1.20–1.25)], and trazodone [ROR: 1.28 (1.25–1.32)]
In the analysis of ICSRs categorized as “suspected/interacting” regarding the preferred term (PT) “Upper gastrointestinal haemorrhage” (ICSRs related to antithrombotics included; no consideration of the competition bias) two signals were found: citalopram [ROR: 1.61 (1.15–2.25)] and escitalopram [ROR: 1.56 (1.06–2.29)]
Summary
Methods of pharmacovigilance as disproportionality analysis were not capable of proving the otherwise well-established increased bleeding risk related to antidepressants (ADs). The impact of the categorization as “concomitant” or “suspected/interacting” on the results of disproportionality analysis regarding the bleeding risk of ADs has not yet been studied This consideration might be of particular importance as disproportionality analysis has not yet been able to demonstrate the bleeding risk related to ADs. in the present paper, we (i) evaluated the impact of the categorization of drug/event (ADs/haemorrhages) reports as causally linked (category: “suspected/interacting”) versus all types of association/irrespective of the type of association (category: “suspected/interacting/concomitant”) on signal detection, (ii) evaluated the risk of different types of bleeding events (haemorrhages, in general, gastrointestinal bleeding and upper gastrointestinal bleeding) related to antidepressants, and (iii) analyzed the impact of the competition bias by evaluating the role of antithrombotics as competitive substances
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