TY - JOUR
T1 - Risk of Acute Liver Injury in Agomelatine and Other Antidepressant Users in Four European Countries
T2 - A Cohort and Nested Case–Control Study Using Automated Health Data Sources
AU - Pladevall-Vila, Manel
AU - Pottegård, Anton
AU - Schink, Tania
AU - Reutfors, Johan
AU - Morros, Rosa
AU - Poblador-Plou, Beatriz
AU - Timmer, Antje
AU - Forns, Joan
AU - Hellfritzsch, Maja
AU - Reinders, Tammo
AU - Hägg, David
AU - Giner-Soriano, Maria
AU - Prados-Torres, Alexandra
AU - Cainzos-Achirica, Miguel
AU - Hallas, Jesper
AU - Brandt, Lena
AU - Cortés, Jordi
AU - Aguado, Jaume
AU - Perlemuter, Gabriel
AU - Falissard, Bruno
AU - Castellsagué, Jordi
AU - Jacquot, Emmanuelle
AU - Deltour, Nicolas
AU - Perez-Gutthann, Susana
N1 - Funding Information:
The authors would like to acknowledge the following people: Estel Plana, MSc (Epidemiology, RTI Health Solutions, Barcelona, Spain),?for her support and expertise during the analysis; Carla Franzoni, BSc (Epidemiology, RTI Health Solutions, Barcelona, Spain), for her administrative support;?Dr. Niklas Schmedt (InGef - Institute for Applied Health Research, Berlin, Germany), for his involvement in planning the analysis at the beginning of the study;?Marieke Niemeyer, MSc (Leibniz Institute for Prevention Research and Epidemiology ? BIPS, Bremen, Germany) and?Sandra Ulrich, MSc (Leibniz Institute for Prevention Research and Epidemiology ? BIPS, Bremen, Germany),?for their contribution to the programming of the analysis datasets; Morten Olesen (Clinical Pharmacology and Pharmacy, Department of Public Health, University of Southern Denmark, Odense, Denmark) and?Martin Thomsen Ernst (Clinical Pharmacology and Pharmacy, Department of Public Health, University of Southern Denmark, Odense, Denmark; OPEN, Odense Patient data Explorative Network, Odense University Hospital, Odense Denmark),?for their help with data management; Javier Marta, MD [EpiChron Research Group, IACS, IIS Aragon; REDISSEC ISCIII, Miguel Servet University Hospital, Zaragoza, Spain] and?Blanca Ob?n, MD [EpiChron Research Group, IACS, IIS Aragon; REDISSEC ISCIII, Lozano Blesa?University Clinic?Hospital, Zaragoza, Spain],?for their assistance with the clinical validation activities. The authors would also like to thank the German statutory health insurance providers that provided data for the study in GePaRD, namely the AOK Bremen/Bremerhaven, the DAK-Gesundheit, and Die Techniker (TK).
Funding Information:
The estimates of risk associated with agomelatine use in this study are consistent with those from a recent cohort study funded by the French National Agency for Medicines and Health Products Safety and conducted using the French health insurance database. This study did not find an increased risk of severe liver injury associated with the use of agomelatine compared with use of selective serotonin reuptake inhibitors (adjusted hazard ratio 1.07; 95% CI 0.51–2.23) [39].
Funding Information:
Funding This study was funded by Servier under a contract granting independent publication rights to the research team. Servier co-authors of this manuscript, Emmanuelle Jacquot and Nicolas Deltour, provided feedback and contributed to the design of the study. The sponsor had the opportunity to review the report and contribute to the dissemination of the results. The open access fee was paid by RTI-HS with general funds from the study account, which was funded by Servier.
Funding Information:
Achirica, Jaume Aguado, Jordi Castellsagué, and Susana Perez-Gut-thann are employees of RTI Health Solutions, a unit of RTI International, a nonprofit organisation that conducts work for government, public, and private organisations, including pharmaceutical companies like Servier. Alexandra Prados-Torres and Beatriz Poblador-Plou are members of the EpiChron Research Group on Chronic Diseases of the Aragon Health Sciences Institute (IACS), ascribed to IIS Aragón, and do not have any conflict of interest with this project. Maria Gin-er-Soriano, Rosa Morros, and Jordi Cortés worked on other projects funded by pharmaceutical companies in their institution that were not related to this study and without personal profit. Tania Schink and Tammo Reinders, as employees of the Leibniz Institute for Prevention Research and Epidemiology – BIPS, worked on projects funded by pharmaceutical companies unrelated to this study and without personal profit. Anton Pottegård reports participation in research projects funded by Alcon, Almirall, Astellas, Astra-Zeneca, Novo Nordisk, LEO Pharma, and Servier, all with funds paid to the institution where he was employed (no personal fees) and with no relation to the work reported in this paper. Jesper Hallas has participated in research projects funded by Novartis, Pfizer, Menarini, MSD, Nycomed, LEO Pharma, Almi-rall, Servier, Astellas, and Alkabello, with grants paid to the institution where he was employed. He has personally received fees for teaching or consulting from the Danish Association of Pharmaceutical Manufacturers and from Pfizer and Menarini. Maja Hellfritzsch has received speaker honorarium fees from Bristol-Myers Squibb and Pfizer and a travel grant from LEO Pharma. Johan Reutfors, David Hägg, and Lena Brandt are employees of the Centre for Pharmacoepidemiology, which receives grants from several entities (pharmaceutical companies, regulatory authorities, and contract research organisations) for the performance of drug safety and drug utilisation studies. Gabriel Perlemuter reports participation in research projects funded by Biocodex, Servier, Physiogenex, Gilead, and Pileje as an external expert consultant. He received royalties from Elsevier-Masson, Solar, and John-Libbey and reports travel and participation in meetings funded by Gilead, Abbvie, and Servier. Bruno Falissard has been consultant for E. Lilly, BMS, Servier, Sanofi, GSK, HRA, Roche, Boeringer Ingelheim, Bayer, Almirall, Allergan, Stallergene, Genzyme, Pierre Fabre, AstraZeneca, Novartis, Janssen, Astellas, Biotronik, Daiichi-Sankyo, Gilead, MSD, Lundbeck, Stallergene, Actelion, UCB, Otsuka, Grunenthal, and ViiV. Prof. Antje Timmer participates in a project funded by a consortium of pharmaceutical companies not related to this study and without personal benefit. Nicolas Deltour and Emmanuelle Jacquot are employees of Servier. The statistical analysis was performed by the different research partners in each data source. In EpiChron, the main contributor to the analysis was BP; in SIDIAP, it was JC; in Denmark, it was AP; in GePaRD, the main contributors were TS and TR; and in Sweden, the main contributors were DH and LB. The study protocol is publicly available at the European Union Electronic Register of Post-Authorisation Studies [EU PAS Register # EUPAS10446] [18].
Publisher Copyright:
© 2019, The Author(s).
PY - 2019/4/5
Y1 - 2019/4/5
N2 - Background: Agomelatine is a melatonin receptor agonist and serotonin 5-HT 2C receptor antagonist indicated for depression in adults. Hepatotoxic reactions like acute liver injury (ALI) are an identified risk in the European risk management plan for agomelatine. Hepatotoxic reactions have been reported for other antidepressants, but population studies quantifying these risks are scarce. Antidepressants are widely prescribed, and users often have risk factors for ALI (e.g. metabolic syndrome). Objective: The goal was to estimate the risk of ALI associated with agomelatine and other antidepressants (fluoxetine, paroxetine, sertraline, escitalopram, mirtazapine, venlafaxine, duloxetine, and amitriptyline) when compared with citalopram in routine clinical practice. Method: A nested case–control study was conducted using data sources in Denmark, Germany, Spain, and Sweden (study period 2009–2014). Three ALI endpoints were defined using International Classification of Diseases (ICD) codes: primary (specific codes) and secondary (all codes) endpoints used only hospital discharge codes; the tertiary endpoint included both inpatient and outpatient settings (all codes). Validation of endpoints was implemented. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for current use were estimated for each data source and combined. Results: We evaluated 3,238,495 new antidepressant and 74,440 agomelatine users. For the primary endpoint, the OR for agomelatine versus citalopram was 0.48 (CI 0.13–1.71). Results were also < 1 when no exclusion criteria were applied (OR 0.37; CI 0.19–0.74), when all exclusion criteria except alcohol and drug abuse were applied (OR 0.47; CI 0.20–1.07), and for the secondary (OR 0.40; CI 0.05–3.11) and tertiary (OR 0.79; CI 0.50–1.25) endpoints. Regarding other antidepressants versus citalopram, most OR point estimates were also below one, although with varying widths of the 95% CIs. The result of the tertiary endpoint and the sensitivity analyses of the primary endpoint were the most precise. Conclusion: In this study, using citalopram as a comparator, agomelatine was not associated with an increased risk of ALI hospitalisation. The results for agomelatine should be interpreted in the context of the European risk minimisation measures in place. Those measures may have induced selective prescribing and could explain the lower risk of ALI for agomelatine when compared with citalopram. Most other antidepressants evaluated had ORs suggesting a lower risk than citalopram, but additional studies are required to confirm or refute these results.
AB - Background: Agomelatine is a melatonin receptor agonist and serotonin 5-HT 2C receptor antagonist indicated for depression in adults. Hepatotoxic reactions like acute liver injury (ALI) are an identified risk in the European risk management plan for agomelatine. Hepatotoxic reactions have been reported for other antidepressants, but population studies quantifying these risks are scarce. Antidepressants are widely prescribed, and users often have risk factors for ALI (e.g. metabolic syndrome). Objective: The goal was to estimate the risk of ALI associated with agomelatine and other antidepressants (fluoxetine, paroxetine, sertraline, escitalopram, mirtazapine, venlafaxine, duloxetine, and amitriptyline) when compared with citalopram in routine clinical practice. Method: A nested case–control study was conducted using data sources in Denmark, Germany, Spain, and Sweden (study period 2009–2014). Three ALI endpoints were defined using International Classification of Diseases (ICD) codes: primary (specific codes) and secondary (all codes) endpoints used only hospital discharge codes; the tertiary endpoint included both inpatient and outpatient settings (all codes). Validation of endpoints was implemented. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for current use were estimated for each data source and combined. Results: We evaluated 3,238,495 new antidepressant and 74,440 agomelatine users. For the primary endpoint, the OR for agomelatine versus citalopram was 0.48 (CI 0.13–1.71). Results were also < 1 when no exclusion criteria were applied (OR 0.37; CI 0.19–0.74), when all exclusion criteria except alcohol and drug abuse were applied (OR 0.47; CI 0.20–1.07), and for the secondary (OR 0.40; CI 0.05–3.11) and tertiary (OR 0.79; CI 0.50–1.25) endpoints. Regarding other antidepressants versus citalopram, most OR point estimates were also below one, although with varying widths of the 95% CIs. The result of the tertiary endpoint and the sensitivity analyses of the primary endpoint were the most precise. Conclusion: In this study, using citalopram as a comparator, agomelatine was not associated with an increased risk of ALI hospitalisation. The results for agomelatine should be interpreted in the context of the European risk minimisation measures in place. Those measures may have induced selective prescribing and could explain the lower risk of ALI for agomelatine when compared with citalopram. Most other antidepressants evaluated had ORs suggesting a lower risk than citalopram, but additional studies are required to confirm or refute these results.
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U2 - 10.1007/s40263-019-00611-9
DO - 10.1007/s40263-019-00611-9
M3 - Article
C2 - 30830574
AN - SCOPUS:85062789282
VL - 33
SP - 383
EP - 395
JO - CNS Drugs
JF - CNS Drugs
SN - 1172-7047
IS - 4
ER -