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NCT07531173

Serotonin Norepinephrine Reuptake Inhibitors and the Risk of Serious Adverse Events

Sponsor: London Health Sciences Centre Research Institute OR Lawson Research Institute of St. Joseph's

View on ClinicalTrials.gov

Summary

This is a population-based retrospective, new-user design, active comparator cohort study assessing whether initiating a new outpatient prescription of high-dose serotonin norepinephrine reuptake inhibitors (SNRIs)-venlafaxine (\>37.5-150 mg/day) or duloxetine (\>30-120 mg/day), compared with low-dose SNRIs- venlafaxine (37.5 mg/day) or duloxetine (30 mg/day), is associated with an increased 30-day risk of serious adverse events among older adults with low kidney function (estimated glomerular filtration rate \[eGFR\] \<45 ml/min/1.73m2) who are not receiving dialysis and have no history of kidney transplantation. The primary outcome is a 30-day composite of all-cause emergency department visit, all-cause hospitalization, or all-cause mortality.

Official title: Risk of Serious Adverse Events Associated With Serotonin Norepinephrine Reuptake Inhibitors Use in Older Adults, With a Focus on Chronic Kidney Disease.

Key Details

Gender

All

Age Range

66 Years - Any

Study Type

OBSERVATIONAL

Enrollment

8688

Start Date

2008-09-01

Completion Date

2025-12-31

Last Updated

2026-04-15

Healthy Volunteers

Not specified

Conditions

Chronic Kidney Disease

Interventions

DRUG

Venlafaxine or duloxetine

The primary exposure of interest will be oral serotonin norepinephrine reuptake inhibitors-venlafaxine at a dose of \>37.5-150 mg/day or duloxetine (30-120 mg/day). For the primary comparison, low-dose serotonin norepinephrine reuptake inhibitors- venlafaxine (37.5 mg/day) or duloxetine (30 mg/day) will serve as the referent group to reduce confounding by indication.

Inclusion Criteria: * The cohort will include all older adults (≥66 years) with an eGFR \<45 mL/min per 1.73 m2 (not receiving dialysis or having a history of kidney transplantation) who received a new outpatient prescription for oral venlafaxine or duloxetine between January 1, 2008, and December 1, 2025. The age criterion is set to guarantee that individuals in this population have had at least one year of prior prescription drug coverage. The date when the prescription was filled will serve as the patient's entry or index date for the cohort, with each patient entering the cohort only once. Exclusion Criteria: * Individuals with missing administrative database number, missing or invalid age (\<0 or \>105 years), missing or invalid sex, death on or before the index date, non-Ontario resident (for Ontario data), or non-Alberta residents (for Alberta data). * Individuals less than 66 years of age on the index date. * Those with evidence of any study drug prescription 180 days before the index date (to restrict to new users only). * Individuals with more than one study drug prescription on the index date, as this complicates the ability to ascertain the prescribed dose accurately. * Evidence of clinically non-meaningful venlafaxine or duloxetine doses (doses that are either too low or too high). The recommended dose range for venlafaxine is 37.5 to 150 mg per day, and for duloxetine is 30 to 120 mg per day. * Individuals with end-stage renal disease, chronic dialysis, or a kidney transplant prior to the index date. * Evidence with hospital discharge or emergency department visit in the two days prior to or on the index date to ensure a new outpatient prescription. Individuals with no serum creatinine lab value in the 0-365 days prior to the index date. * Individuals with unstable baseline kidney function: If the most recent serum creatinine test prior to the index date was an inpatient test \[ER or hospitalization\], and there is not at least one 'outpatient' serum creatinine in the year before test date 1, OR If the most recent prior serum creatinine test prior to the index date was an inpatient test \[ER or hospitalization\], and while there is at least 'outpatient' serum creatinine test in the year before, the most recent outpatient test prior to differs by an eGFR 10 mL/min/1.73 m2 or more from the value on \<test date 1\>. In Ontario, it has been shown that outpatient serum creatinine measurements in the province, conducted on a single occasion, indicate stable values. * The investigators restrict to the first prescription in individuals with more than one eligible prescription. The date of this prescription will be the index date (the date from which outcomes start being assessed).