Sertraline Dose and the Risk of Serious Adverse Events in Older Adults With Low Kidney Function: A Population-Based Cohort Study Research Protocol

Background: Many older adults experience mental health disorders, such as depression and anxiety, alongside having low kidney function. Sertraline is a selective serotonin reuptake inhibitor. It is commonly prescribed to older adults for depression and anxiety treatment. However, aging and low kidney function can lead to increased plasma levels and a higher risk of adverse events. In prescribing references, product monographs, and other standard sources, inconsistent starting dose adjustments for patients with low kidney function have been noted. This inconsistency may contribute to the variable dosing observed in routine practice. Many older adults with low kidney function are initiated on sertraline at a dose of 50 mg per day. Compared to the lower dose of 25 mg per day, the higher dose may be associated with a higher rate of falls, fractures, gastrointestinal bleeding, arrhythmias, hospitalization, and mortality. Despite these concerns, there is a lack of real-world evaluation. The investigators used a novel high-throughput approach with Ontario healthcare databases. They identified an increased risk of adverse outcomes in patients with advanced CKD (estimated glomerular filtration rate (eGFR) <45 mL/min/1.73 m² without a history of dialysis or a kidney transplant) who were newly prescribed sertraline compared to a similar cohort of non-users. To build upon and validate these early findings, the investigators plan to conduct a population-based retrospective cohort study among older adults in Ontario, Canada. The study will use data to investigate the 30-day risk of serious adverse events after starting high versus low doses of sertraline in older adults with low kidney function. The aim is to enhance safer prescribing practices.

Methods: This population-based retrospective cohort study will include older adults (aged 66 years or older) with an estimated glomerular filtration rate (eGFR) less than 45 mL/min/1.73 m2, who are not receiving dialysis and have no history of kidney transplantation. Eligible participants will be identified from Ontario, and potentially Alberta, if they have been dispensed a new outpatient prescription for oral sertraline (25 or 50 mg/day) with a supply of at least seven days. In Ontario, participant accrual will occur from January 1, 2008, to January 1, 2025. Participants will be categorized into two groups based on the prescribed daily dose: low-dose (25 mg/day) and high-dose (50 mg/day). Propensity score weighting will be applied to achieve balance between groups across a comprehensive set of measured baseline characteristics. The primary outcome will be a 30-day composite of all-cause hospitalization, emergency department visit, or mortality.

Objectives: The study will assess whether initiation of a high dose (50 mg/day) compared to a low dose (25 mg/day) of sertraline is associated with a higher 30-day risk of a composite outcome (all-cause hospitalization, emergency department visit, or mortality) among older adults with low kidney function (eGFR <45 mL/min/1.73 m2, not on dialysis, no history of transplantation) in the outpatient setting. Additionally, the study will evaluate whether baseline eGFR category modifies the risk of the 30-day composite outcome among patients initiating higher versus lower doses of sertraline as outpatients. The cohort will be expanded to include all baseline eGFR levels, categorized as ≥60, 45-59, and <45 mL/min/1.73 m2.

Study Design and Setting: Data Sources: This study will employ a population-based retrospective cohort design using linked administrative health data from Ontario, Canada. If the Ontario cohort is insufficient to generate reliable estimates, the sample size will be augmented by conducting the same analysis using Alberta health administrative data. Ontario data will be obtained from ICES (ices.on.ca), which provides secure, encrypted individual-level data for Ontario residents, all of whom have universal access to hospital and physician services under a government-funded, single-payer healthcare system. Data use in this study is authorized under section 45 of Ontario's Personal Health Information Protection Act, which does not require review by a research ethics board. The study will utilize Ontario's comprehensive health databases, including the Ontario Drug Benefit (ODB) for prescription data, the Registered Persons Database (RPDB) for demographics and vital status, the Canadian Institute for Health Information Discharge Abstract Database (CIHI-DAD) and National Ambulatory Care Reporting System (NACRS) for hospitalizations and emergency visits, the Ontario Health Insurance Plan (OHIP) Database for physician billing claims, and the Ontario Laboratories Information System (OLIS) for laboratory data, including serum creatinine, to estimate kidney function. If the study is conducted in Alberta, data will be accessed through the Alberta Kidney Disease Network (AKDN), with the dataset available through approximately 2021. The study protocol, including the study description, design, and statistical analysis plan, will be publicly registered prior to conducting outcome analyses. Study results will be reported in accordance with RECORD reporting guidelines.

Study Population: The study will include all adults aged 66 years or older with an estimated glomerular filtration rate (eGFR) less than 45 mL/min per 1.73 m2. Individuals receiving dialysis or with a history of kidney transplantation will be excluded. Eligible participants must have received a new outpatient prescription for oral sertraline at an initial dose of 25 or 50 mg per day, with a supply of at least 7 days, between 2008 and 2024. The dispensing date of the prescription will define the index date. To ensure unique cohort entry, only the first eligible prescription per individual will be considered, and each person will be included in the cohort only once. Patients will be categorized as either high-dose or low-dose sertraline users.