Risk of Acute Liver Injury in Agomelatine and Other Antidepressant Users in Four European Countries: A Cohort and Nested Case-Control Study Using Automated Health Data Sources

Manel Pladevall-Vila, Anton Pottegård, Tania Schink, Johan Reutfors, Rosa Morros, Beatriz Poblador-Plou, Antje Timmer, Joan Forns, Maja Hellfritzsch, Tammo Reinders, David Hägg, Maria Giner-Soriano, Alexandra Prados-Torres, Miguel Cainzos-Achirica, Jesper Hallas, Lena Brandt, Jordi Cortés, Jaume Aguado, Gabriel Perlemuter, Bruno FalissardJordi Castellsagué, Emmanuelle Jacquot, Nicolas Deltour, Susana Perez-Gutthann

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Resumé

BACKGROUND: Agomelatine is a melatonin receptor agonist and serotonin 5-HT2C 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.

OriginalsprogEngelsk
TidsskriftCNS Drugs
Vol/bind33
Udgave nummer4
Sider (fra-til)383-395
ISSN1172-7047
DOI
StatusUdgivet - 5. apr. 2019

Fingeraftryk

S 20098
Information Storage and Retrieval
Citalopram
Case-Control Studies
Odds Ratio
Confidence Intervals
Liver
Health
Wounds and Injuries
Melatonin Receptors
Receptor, Serotonin, 5-HT2C
Sertraline
Paroxetine
Amitriptyline
Fluoxetine
International Classification of Diseases
Denmark
Alcoholism
Germany
Inpatients

Citer dette

Pladevall-Vila, Manel ; Pottegård, Anton ; Schink, Tania ; Reutfors, Johan ; Morros, Rosa ; Poblador-Plou, Beatriz ; Timmer, Antje ; Forns, Joan ; Hellfritzsch, Maja ; Reinders, Tammo ; Hägg, David ; Giner-Soriano, Maria ; Prados-Torres, Alexandra ; Cainzos-Achirica, Miguel ; Hallas, Jesper ; Brandt, Lena ; Cortés, Jordi ; Aguado, Jaume ; Perlemuter, Gabriel ; Falissard, Bruno ; Castellsagué, Jordi ; Jacquot, Emmanuelle ; Deltour, Nicolas ; Perez-Gutthann, Susana. / Risk of Acute Liver Injury in Agomelatine and Other Antidepressant Users in Four European Countries : A Cohort and Nested Case-Control Study Using Automated Health Data Sources. I: CNS Drugs. 2019 ; Bind 33, Nr. 4. s. 383-395.
@article{6b941f41be874f1c9b1a277db7d5bb6e,
title = "Risk of Acute Liver Injury in Agomelatine and Other Antidepressant Users in Four European Countries: A Cohort and Nested Case-Control Study Using Automated Health Data Sources",
abstract = "BACKGROUND: Agomelatine is a melatonin receptor agonist and serotonin 5-HT2C 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.",
author = "Manel Pladevall-Vila and Anton Potteg{\aa}rd and Tania Schink and Johan Reutfors and Rosa Morros and Beatriz Poblador-Plou and Antje Timmer and Joan Forns and Maja Hellfritzsch and Tammo Reinders and David H{\"a}gg and Maria Giner-Soriano and Alexandra Prados-Torres and Miguel Cainzos-Achirica and Jesper Hallas and Lena Brandt and Jordi Cort{\'e}s and Jaume Aguado and Gabriel Perlemuter and Bruno Falissard and Jordi Castellsagu{\'e} and Emmanuelle Jacquot and Nicolas Deltour and Susana Perez-Gutthann",
year = "2019",
month = "4",
day = "5",
doi = "10.1007/s40263-019-00611-9",
language = "English",
volume = "33",
pages = "383--395",
journal = "CNS Drugs",
issn = "1172-7047",
publisher = "Adis International Ltd.",
number = "4",

}

Pladevall-Vila, M, Pottegård, A, Schink, T, Reutfors, J, Morros, R, Poblador-Plou, B, Timmer, A, Forns, J, Hellfritzsch, M, Reinders, T, Hägg, D, Giner-Soriano, M, Prados-Torres, A, Cainzos-Achirica, M, Hallas, J, Brandt, L, Cortés, J, Aguado, J, Perlemuter, G, Falissard, B, Castellsagué, J, Jacquot, E, Deltour, N & Perez-Gutthann, S 2019, 'Risk of Acute Liver Injury in Agomelatine and Other Antidepressant Users in Four European Countries: A Cohort and Nested Case-Control Study Using Automated Health Data Sources', CNS Drugs, bind 33, nr. 4, s. 383-395. https://doi.org/10.1007/s40263-019-00611-9

Risk of Acute Liver Injury in Agomelatine and Other Antidepressant Users in Four European Countries : A Cohort and Nested Case-Control Study Using Automated Health Data Sources. / Pladevall-Vila, Manel; Pottegård, Anton; Schink, Tania; Reutfors, Johan; Morros, Rosa; Poblador-Plou, Beatriz; Timmer, Antje; Forns, Joan; Hellfritzsch, Maja; Reinders, Tammo; Hägg, David; Giner-Soriano, Maria; Prados-Torres, Alexandra; Cainzos-Achirica, Miguel; Hallas, Jesper; Brandt, Lena; Cortés, Jordi; Aguado, Jaume; Perlemuter, Gabriel; Falissard, Bruno; Castellsagué, Jordi; Jacquot, Emmanuelle; Deltour, Nicolas; Perez-Gutthann, Susana.

I: CNS Drugs, Bind 33, Nr. 4, 05.04.2019, s. 383-395.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

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

PY - 2019/4/5

Y1 - 2019/4/5

N2 - BACKGROUND: Agomelatine is a melatonin receptor agonist and serotonin 5-HT2C 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-HT2C 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.

U2 - 10.1007/s40263-019-00611-9

DO - 10.1007/s40263-019-00611-9

M3 - Journal article

C2 - 30830574

VL - 33

SP - 383

EP - 395

JO - CNS Drugs

JF - CNS Drugs

SN - 1172-7047

IS - 4

ER -