Depression is considered an important public health issue. Nowadays, about 300 million people are affected by depressive disorders and a quarter of them just in Europe. Antidepressant (AD) treatment like tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs) or newer atypical antidepressants (NAAs) seems to be the most appropriate therapy in order to treat depressive symptoms. In the first study, a synthesis of the available scientific literature was performed on the possible association between use of AD and cardiovascular diseases (CVD). A search of published observational studies was carried out using terms directly related with cardiovascular and antidepressive field. In addition, the quality of the included studies, the heterogeneity among them as well as the presence of publication bias was evaluated. The second part of the thesis regards the studies conducted within the Italian Medicines Agency (Agenzia Italiana del Farmaco, AIFA) project, where data from different regional healthcare utilization databases involved in the Italian Group for Appropriate Drug Prescription in the Elderly (I-GrADE) was used. The project is focused on the evaluation of inappropriate prescribing in a population of elderly hospitalized with a diagnosis of CVD. In the second study, nested-case control studies were applied for the evaluation of the role of AD respect to the occurrence of CVD, among the elderly population. Sensitivity analyses were performed, like a Monte Carlo Sensitivity Analysis (MCSA), which quantified the potential bias introduced by a particular confounder (smoking factor) and by changing the length of AD exposure’s window. In the third study, the acute effect of AD treatment was evaluated respect to the onset of arrhythmia. The cohort selection was restricted to the new AD users who did not developed a previous event of arrhythmia. Nested case-control and case-crossover studies were applied and estimates were adjusted for drug prescriptions and hospitalizations. Sensitivity analyses were performed by using different criteria to define the outcome of interest or by changing length of AD exposure’s window. In the fourth study, we focused on the role of AD medication respect to mortality. The possible link between adherence to AD and increased or decreased risk of mortality was tested among the elderly cohort. The selection was restricted to elderly who were all AD users and started AD therapy since cohort recruitment. A Cox model was applied and the combined levels of adherence to AD and co-treatments were evaluated during observation time. Estimates were adjusted for several variables such as the polypharmacy. Then, sensitivity analyses were performed on the basis of AD coverage’s definition. The results of the meta-analysis showed a significant increased risk of cerebrovascular disease and acute heart failure respectively for SSRIs and TCA users. Then, these results were confirmed by the observational studies performed within the AIFA Project. A positive relation was found between AD exposure and CVD in a cohort of elderly patients already affected by a CVD, in particular a proarrhythmic effect of AD exposure was revealed by our estimates. Finally, adherence to AD treatment was associated with a decreased risk of death by considering different levels of adherence to co-treatments assumed during the observation time. In conclusion, these studies showed that the use of AD could increase the risk of several CV disease, therefore, physicians need to carefully monitor their patients to ensure a correct assumption of the drugs and concurrently try to prevent the onset of CV outcomes. Since any potential increased risk may result in a considerable impact, the risk effect estimates provided by these studies may support both clinical practices and regulatory activities.

La sindrome depressiva è considerata una importante questione nel campo della sanità pubblica. Oggigiorno, circa 300 milioni di persone sono colpiti da disturbi depressivi e un quarto di questi solo in Europa. La terapia con antidepressivi AD come i farmaci triciclici TCA, inibitori selettivi della ricaptazione della serotonina SSRI e nuovi AD atipici, sembra essere il trattamento più appropriato per la cura dei sintomi depressivi. Diversi studi sono realizzati per valutare l’associazione tra trattamento con farmaci AD e insorgenza di patologie cardiovascolari CV. Nel primo studio, è stata eseguita una sintesi della letteratura scientifica riguardante la possibile associazione tra l’utilizzo di AD e patologie CV. È stata eseguita una ricerca di studi osservazionali utilizzando termini collegati alle patologie CV e al trattamento con AD. In più, è stata valutata la qualità degli studi inclusi, l’eterogeneità tra questi e la presenza di publication bias. La seconda parte della tesi riguarda studi condotti entro il progetto AIFA Agenzia Italiana del Farmaco, dove sono stati utilizzati dati da diversi database sanitari regionali partecipanti a I-GrADE Gruppo Italiano per l’Appropriata Prescrizione Farmacologica nei soggetti Anziani. Il progetto si focalizza sull’inappropriatezza delle prescrizioni in una popolazione anziana con diagnosi CV. Nel secondo studio, disegni caso-controllo innestati sono stati applicati per valutare la terapia AD rispetto all’insorgenza di patologie CV. Analisi di sensibilità sono state effettuate come una Monte Carlo Sensitivity Analysis, che ha valutato il potenziale bias introdotto dal confondente fumo e modificando l’ampiezza della finestra di esposizione. Nel terzo studio, l’effetto acuto del trattamento con AD è stato valutato rispetto all’insorgenza di aritmia. La selezione della coorte è stata ristretta ai nuovi utilizzatori di AD senza precedente aritmia. Disegni caso-controllo innestato e case-crossover sono stati applicati e le stime sono state aggiustate per le prescrizioni di farmaci e i ricoveri. Analisi di sensibilità sono state effettuate utilizzando diversi criteri per definire l’outcome e modificando la finestra di esposizione. Nel quarto studio, è stato valutato il link tra aderenza al trattamento con AD rispetto alla mortalità. La selezione è stata ristretta agli utilizzatori di AD trattati dal reclutamento in coorte. Un modello di Cox è stato applicato ed è stata valutata la combinazione tra diversi livelli di aderenza ad AD a co-trattamenti durante il periodo di osservazione. Le stime sono state aggiustate per diverse variabili, come la politerapia. Infine, analisi di sensibilità sono state effettuate applicando una diversa definizione per la copertura con AD. I risultati della meta-analisi hanno mostrato un incremento di rischio di patologie cerebrovascolari e di cardiopatie acute rispettivamente per utilizzatori di SSRI e TCA. Questi risultati sono confermati dagli studi osservazionali effettuati nell'ambito del Progetto AIFA. Una relazione positiva è stata trovata tra esposizione con AD e malattie CV, in particolare un effetto proaritmico dell'esposizione AD è stato rivelato in una coorte di pazienti anziani già affetti da una malattia CV. Infine, l'aderenza al trattamento AD è stata associata ad un ridotto rischio di morte, considerando diversi livelli di aderenza di co-trattamenti assunti durante il periodo di osservazione. In conclusione, gli studi condotti hanno mostrato che l’uso di AD sembra incrementare il rischio di patologie CV, perciò i medici devono attentamente monitorare il trattamento con AD per assicurarne la corretta assunzione e provare a prevenire l’insorgenza di patologie CV. Poiché il potenziale aumento del rischio può comportare un impatto considerevole, le stime fornite da questi studi possono supportare sia le pratiche cliniche che normative.

(2018). Antidepressants and the risk of cardiovascular diseases. (Tesi di dottorato, Università degli Studi di Milano-Bicocca, 2018).

Antidepressants and the risk of cardiovascular diseases

BIFFI, ANNALISA
2018

Abstract

Depression is considered an important public health issue. Nowadays, about 300 million people are affected by depressive disorders and a quarter of them just in Europe. Antidepressant (AD) treatment like tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs) or newer atypical antidepressants (NAAs) seems to be the most appropriate therapy in order to treat depressive symptoms. In the first study, a synthesis of the available scientific literature was performed on the possible association between use of AD and cardiovascular diseases (CVD). A search of published observational studies was carried out using terms directly related with cardiovascular and antidepressive field. In addition, the quality of the included studies, the heterogeneity among them as well as the presence of publication bias was evaluated. The second part of the thesis regards the studies conducted within the Italian Medicines Agency (Agenzia Italiana del Farmaco, AIFA) project, where data from different regional healthcare utilization databases involved in the Italian Group for Appropriate Drug Prescription in the Elderly (I-GrADE) was used. The project is focused on the evaluation of inappropriate prescribing in a population of elderly hospitalized with a diagnosis of CVD. In the second study, nested-case control studies were applied for the evaluation of the role of AD respect to the occurrence of CVD, among the elderly population. Sensitivity analyses were performed, like a Monte Carlo Sensitivity Analysis (MCSA), which quantified the potential bias introduced by a particular confounder (smoking factor) and by changing the length of AD exposure’s window. In the third study, the acute effect of AD treatment was evaluated respect to the onset of arrhythmia. The cohort selection was restricted to the new AD users who did not developed a previous event of arrhythmia. Nested case-control and case-crossover studies were applied and estimates were adjusted for drug prescriptions and hospitalizations. Sensitivity analyses were performed by using different criteria to define the outcome of interest or by changing length of AD exposure’s window. In the fourth study, we focused on the role of AD medication respect to mortality. The possible link between adherence to AD and increased or decreased risk of mortality was tested among the elderly cohort. The selection was restricted to elderly who were all AD users and started AD therapy since cohort recruitment. A Cox model was applied and the combined levels of adherence to AD and co-treatments were evaluated during observation time. Estimates were adjusted for several variables such as the polypharmacy. Then, sensitivity analyses were performed on the basis of AD coverage’s definition. The results of the meta-analysis showed a significant increased risk of cerebrovascular disease and acute heart failure respectively for SSRIs and TCA users. Then, these results were confirmed by the observational studies performed within the AIFA Project. A positive relation was found between AD exposure and CVD in a cohort of elderly patients already affected by a CVD, in particular a proarrhythmic effect of AD exposure was revealed by our estimates. Finally, adherence to AD treatment was associated with a decreased risk of death by considering different levels of adherence to co-treatments assumed during the observation time. In conclusion, these studies showed that the use of AD could increase the risk of several CV disease, therefore, physicians need to carefully monitor their patients to ensure a correct assumption of the drugs and concurrently try to prevent the onset of CV outcomes. Since any potential increased risk may result in a considerable impact, the risk effect estimates provided by these studies may support both clinical practices and regulatory activities.
CORRAO, GIOVANNI
Cardiovascular; Diseases,; Antidepressants,; Meta-Analysis,; Database
Cardiovascular; Diseases,; Antidepressants,; Meta-Analysis,; Database
MED/01 - STATISTICA MEDICA
English
7-mar-2018
SANITA' PUBBLICA - 78R
30
2016/2017
open
(2018). Antidepressants and the risk of cardiovascular diseases. (Tesi di dottorato, Università degli Studi di Milano-Bicocca, 2018).
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10281/199081
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