Comparative Mortality Risk of Antipsychotic Medications in Elderly Patients with Stroke: Adjusting for Unmeasured Confounders with Stroke Registry Database

  • 蘇 建州

Student thesis: Doctoral Thesis


Background: Elderly patients are at risk for developing psychosis after stroke including delusions hallucinations agitation and disorganized behavior According to previous guidelines antipsychotics are the first-line pharmacological intervention for psychosis but elderly patients who are treated with antipsychotics might have an increased risk of mortality based on US FDA safety communications However there are limited studies examining mortality risk associated with antipsychotic use in elderly patients who have had a stroke The major limitations of these studies include selection bias immortal time bias and unmeasured confounders which can lead to bias related to the relative risks of antipsychotic treatment and result in controversial findings Objectives: To evaluate prescription patterns and comparative mortality risk of antipsychotic use in elderly patients after a stroke by using an active comparator and new user design with an external adjustment method Methods design and setting: We conducted a retrospective cohort study to identify patients aged above 65 years old admitted for stroke in the National Health Insurance Database (NHID) from 2002 to 2014 These patients were not prescribed antipsychotics before their discharge date and were followed until they started to receive antipsychotic treatment The date of antipsychotic use was set as the index date The covariates were retrieved from claims during the one-year look-back period prior to the index date We then linked to multi-center stroke registry databases to retrieve additional variables including smoking history body mass index National Institute of Health Stroke Scale (NHISS) the Barthel index and the modified Rankin Scale (mRS) Exposure: Antipsychotics covered by the NHI program Main outcome: One-year all-cause mortality Secondary outcome: One-year cause-specific mortality Statistical analysis: Descriptive statistics were used to characterize the baseline demographics and antipsychotic prescription patterns To compare antipsychotics with respect to risk of all-cause and cause-specific mortality we performed Cox proportional hazard models using the propensity score calibration (PSC) method to adjust for unmeasured confounders in order to estimate the relative risk among antipsychotics in elderly stroke patients In addition in order to avoid the surrogacy assumption due to the use of the PSC method the two-stage calibration (TSC) method (without the surrogacy assumption) was used to adjust unmeasured confounders and to compare the differences between the PSC and TSC methods Results: There were 72 441 elderly stroke patients who initiated treatment with antipsychotics during the study period The proportion of incident use of antipsychotics was 26 2% (2002-2015) The majority of the elderly stroke patients had received only a single antipsychotic treatment (99%) and the most commonly used antipsychotic was quetiapine (39 9%) We selected the antipsychotics including quetiapine haloperidol and risperidone which were prescribed for post-stroke psychosis treatment in previous literature on this topic and compared the mortality risk among these antipsychotics In the PSC-adjusted intent to treat analyses haloperidol [adjusted hazard ratio (aHR)=1 22; 95% confidence interval (CI) 1 18-1 27] and risperidone (aHR=1 31; 95% CI 1 24-1 38) users had a higher mortality risk as compared to quetiapine users Haloperidol and risperidone exhibited a dose-response related to mortality risk after controlling for confounders The sensitivity analyses assessing the influence of the study population showed similar patterns In the cause-specific mortality analyses risperidone (aHR=1 25; 95% CI 1 14-1 38) users had higher cause-specific mortality from cerebro-cardiovascular disease compared to quetiapine users but there were no significant differences found in the haloperidol (aHR=1 04 95% CI 0 97-1 12) and quetiapine (reference) users In addition we found that the surrogacy assumption was not violated PSC and TSC methods exhibited similar results in terms of mortality risk related to the use of antipsychotics Conclusions: The significant variations in the differences in mortality risk among antipsychotic agents suggests that antipsychotic selection and dosing may affect survival in elderly stroke patients In addition we also found the surrogacy assumption should be tested to determine whether the assumption is violated when the PSC method is performed to adjust for unmeasured confounders If this assumption is violated PSC is far less useful and may even increase bias When the PSC assumption is violated the TSC method can provide more precise treatment effects than PSC
Date of Award2019
Original languageEnglish
SupervisorYea-Huei Kao (Supervisor)

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