Antidepressants and the Risk of Stroke Recurrence
Antidepressants and the Risk of Stroke Recurrence
This cohort study used the Longitudinal Health Insurance Database (LHID), a sub-dataset of National Health Insurance (NHI) Research Database containing healthcare claims between 1996 and 2010 for a cohort of one million people randomly sampled from beneficiaries of NHI. The NHI provides coverage to 99 % or more of Taiwanese population. LHID consists of many data files, including inpatient records, ambulatory care records, contracted pharmacies records, and registries for beneficiaries and contracted medical facilities.
Included in this study were patients had a first hospitalization with diagnosis of stroke during 2000 and 2009. The date of the first hospitalization for stroke was identified as the index date. Stroke was identified by principal diagnosis with ICD-9-CM code (International Classification of Diseases, 9th revision, Clinical Modification codes) 430 to 432 for hemorrhagic stroke and 433 to 437 for ischemic stroke. Those who had any diagnosis of stroke from 1996 to 1999 were excluded to reduce the possibility of including prevalent stroke cases. We further excluded patients who were aged <20 years (N = 91), who had inappropriate data with index date after the date of withdrawing from insurance (N = 293), and patients with recurrent stroke or died within 30 days after index date (N = 2232). Patients who had use of combinations of antidepressants and psycholeptics (amitriptyline-psycholeptics or melitracen-psycholeptics) (N = 1553) or too high dose (>3 DDDs, defined daily doses) (N = 69) during the follow-up period were also excluded. Therefore, the study included 16770 patients with stroke (Fig. 1). This study was approved by the institutional ethics review board at the National Taiwan University Hospital.
(Enlarge Image)
Figure 1.
Patients Inclusion Chart
For each patient, the records (detail information of drug code by Bureau of National Health Insurance, total dosage and days of use for each prescription) of prescriptions of antidepressants were obtained during the follow-up. The types of antidepressants were categorized by Anatomical Therapeutic Chemical (ATC) classification system: non-selective monoamine reuptake inhibitors (tricyclic antidepressants, TCAs), selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs), and other antidepressants. The average dosage for the each prescription of antidepressants per day was calculated. We classified average dose by defined daily doses (DDDs), as defined by the World Health Organization, into <0.5, 0.5–1, and > =1 DDDs.
Other covariates included sex, age, related-disease and prescriptions of other drugs within one year before the index date such as antipsychotics (ATC code: N05A), antithrombotic agents included anticoagulant (ATC code: B01AA03) and antiplatelet (ATC code: B01AC06, B01AC04, B01AC05, B01AC23, B01AC07), anti-inflammatory (ATC code: M01A), antidepressants use before stroke (ATC code: N06A), depression (ICD-9-CM code: 296.2, 296.3, 300.4, 311), other mood disorders or (ICD-9-CM code: 296.0, 296.1, 296.4–296.9) anxiety (ICD-9-CM code: 300.0), atrial fibrillation (ICD-9-CM code: 427.3), coronary heart disease (ICD-9-CM code: 410–414), congestive heart failure (ICD-9-CM code: 428), chronic obstructive pulmonary disease (ICD-9-CM code: 490,491,492,493,494,495,496), cancer (ICD-9-CM code: 140–208), diabetes mellitus or medicine treatment (ICD-9-CM code: 250; ATC code: A10), hypertension or medicine treatment (ICD-9-CM code: 401–405; ATC code: C02, C03, C07, C08, C09), and hyperlipidemia or medicine treatment (ICD-9-CM code: 272; ATC code: C10). These variables were all possible confounders between antidepressants and stroke recurrence. The presence of depression during the follow-up was also obtained.
The main outcome was a re-hospitalization with hemorrhagic stroke or ischemic stroke during the follow-up period. The follow-up started from the index date, which was between 2000 and 2009, and ended on the date of stroke recurrence, the date of withdrawing from insurance, or date of termination of this study, December 31, 2010; whichever came first.
Demographic and clinical characteristics between use of antidepressants group (at least one prescription of antidepressants during follow-up) and non-use were compared by the chi-square test. We also divided the type of antidepressants into TCAs, SSRIs, MAOIs, others, or multiple types, as well as dose groups into >0.5, 0.5–1, and > =1 DDDs to perform the descriptive analyses. Because of the time-varying nature of drug use, we defined the duration of antidepressants exposure as days of use for each prescription from database at ambulatory care, and contracted pharmacies, but not at inpatient records because data on days supplied for each prescription were not obtained. We classified the exposure status into "use" during the duration of antidepressants and "non-use" during the days of no prescriptions. We computed their incidence rate (per 1000 person-year) by dividing number of events of recurrent stroke with person-years of exposure to each antidepressant. We used the Simon and Makuchmethod to graphically represent survival curves for time to use of antidepressants by Stata to compute 'Kaplan-Meier' estimates for time-dependent covariates.
We used univariable and multivariable models to estimate the hazard ratios (HR) and 95 % confidence interval (C.I.) by the Cox proportional hazards model with time-varying antidepressants use to assess the association between each antidepressants use category and recurrent stroke with "non-use" as the reference group and adjusted the models for demographic and clinical characteristics. Moreover, subgroup analyses were performed including antidepressants use before stroke or not (prevalent users, or new users), depression status (no-diagnosed depression, prevalent depression, or post-stroke depression with newly-diagnosed depression), other drugs use, and other disease. Finally, we performed two sensitivity analyses. First, the duration of antidepressants exposure was redefined by adding seven days to the end of days supply for each prescription in order to take into account for the potential carry over effect and gaps in therapies. Second, we added the prescriptions of antidepressants in the inpatient settings. Because the inpatients claims do not contain information on the days supply for medications, we defined the duration of antidepressants exposure using the length of hospital stay. All analyses were carried out with SAS 9.2 and Stata 10. A two-sided p value < 0.05 was considered statistically significant.
Methods
Data Source and Study Subjects
This cohort study used the Longitudinal Health Insurance Database (LHID), a sub-dataset of National Health Insurance (NHI) Research Database containing healthcare claims between 1996 and 2010 for a cohort of one million people randomly sampled from beneficiaries of NHI. The NHI provides coverage to 99 % or more of Taiwanese population. LHID consists of many data files, including inpatient records, ambulatory care records, contracted pharmacies records, and registries for beneficiaries and contracted medical facilities.
Included in this study were patients had a first hospitalization with diagnosis of stroke during 2000 and 2009. The date of the first hospitalization for stroke was identified as the index date. Stroke was identified by principal diagnosis with ICD-9-CM code (International Classification of Diseases, 9th revision, Clinical Modification codes) 430 to 432 for hemorrhagic stroke and 433 to 437 for ischemic stroke. Those who had any diagnosis of stroke from 1996 to 1999 were excluded to reduce the possibility of including prevalent stroke cases. We further excluded patients who were aged <20 years (N = 91), who had inappropriate data with index date after the date of withdrawing from insurance (N = 293), and patients with recurrent stroke or died within 30 days after index date (N = 2232). Patients who had use of combinations of antidepressants and psycholeptics (amitriptyline-psycholeptics or melitracen-psycholeptics) (N = 1553) or too high dose (>3 DDDs, defined daily doses) (N = 69) during the follow-up period were also excluded. Therefore, the study included 16770 patients with stroke (Fig. 1). This study was approved by the institutional ethics review board at the National Taiwan University Hospital.
(Enlarge Image)
Figure 1.
Patients Inclusion Chart
Exposure to Antidepressants and Covariates
For each patient, the records (detail information of drug code by Bureau of National Health Insurance, total dosage and days of use for each prescription) of prescriptions of antidepressants were obtained during the follow-up. The types of antidepressants were categorized by Anatomical Therapeutic Chemical (ATC) classification system: non-selective monoamine reuptake inhibitors (tricyclic antidepressants, TCAs), selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs), and other antidepressants. The average dosage for the each prescription of antidepressants per day was calculated. We classified average dose by defined daily doses (DDDs), as defined by the World Health Organization, into <0.5, 0.5–1, and > =1 DDDs.
Other covariates included sex, age, related-disease and prescriptions of other drugs within one year before the index date such as antipsychotics (ATC code: N05A), antithrombotic agents included anticoagulant (ATC code: B01AA03) and antiplatelet (ATC code: B01AC06, B01AC04, B01AC05, B01AC23, B01AC07), anti-inflammatory (ATC code: M01A), antidepressants use before stroke (ATC code: N06A), depression (ICD-9-CM code: 296.2, 296.3, 300.4, 311), other mood disorders or (ICD-9-CM code: 296.0, 296.1, 296.4–296.9) anxiety (ICD-9-CM code: 300.0), atrial fibrillation (ICD-9-CM code: 427.3), coronary heart disease (ICD-9-CM code: 410–414), congestive heart failure (ICD-9-CM code: 428), chronic obstructive pulmonary disease (ICD-9-CM code: 490,491,492,493,494,495,496), cancer (ICD-9-CM code: 140–208), diabetes mellitus or medicine treatment (ICD-9-CM code: 250; ATC code: A10), hypertension or medicine treatment (ICD-9-CM code: 401–405; ATC code: C02, C03, C07, C08, C09), and hyperlipidemia or medicine treatment (ICD-9-CM code: 272; ATC code: C10). These variables were all possible confounders between antidepressants and stroke recurrence. The presence of depression during the follow-up was also obtained.
Main Outcome
The main outcome was a re-hospitalization with hemorrhagic stroke or ischemic stroke during the follow-up period. The follow-up started from the index date, which was between 2000 and 2009, and ended on the date of stroke recurrence, the date of withdrawing from insurance, or date of termination of this study, December 31, 2010; whichever came first.
Statistical Analyses
Demographic and clinical characteristics between use of antidepressants group (at least one prescription of antidepressants during follow-up) and non-use were compared by the chi-square test. We also divided the type of antidepressants into TCAs, SSRIs, MAOIs, others, or multiple types, as well as dose groups into >0.5, 0.5–1, and > =1 DDDs to perform the descriptive analyses. Because of the time-varying nature of drug use, we defined the duration of antidepressants exposure as days of use for each prescription from database at ambulatory care, and contracted pharmacies, but not at inpatient records because data on days supplied for each prescription were not obtained. We classified the exposure status into "use" during the duration of antidepressants and "non-use" during the days of no prescriptions. We computed their incidence rate (per 1000 person-year) by dividing number of events of recurrent stroke with person-years of exposure to each antidepressant. We used the Simon and Makuchmethod to graphically represent survival curves for time to use of antidepressants by Stata to compute 'Kaplan-Meier' estimates for time-dependent covariates.
We used univariable and multivariable models to estimate the hazard ratios (HR) and 95 % confidence interval (C.I.) by the Cox proportional hazards model with time-varying antidepressants use to assess the association between each antidepressants use category and recurrent stroke with "non-use" as the reference group and adjusted the models for demographic and clinical characteristics. Moreover, subgroup analyses were performed including antidepressants use before stroke or not (prevalent users, or new users), depression status (no-diagnosed depression, prevalent depression, or post-stroke depression with newly-diagnosed depression), other drugs use, and other disease. Finally, we performed two sensitivity analyses. First, the duration of antidepressants exposure was redefined by adding seven days to the end of days supply for each prescription in order to take into account for the potential carry over effect and gaps in therapies. Second, we added the prescriptions of antidepressants in the inpatient settings. Because the inpatients claims do not contain information on the days supply for medications, we defined the duration of antidepressants exposure using the length of hospital stay. All analyses were carried out with SAS 9.2 and Stata 10. A two-sided p value < 0.05 was considered statistically significant.
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