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 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:
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 Obón, 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).
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 -