Trazodone and the Risk of Serious Adverse Events

NCT07381101 | Completed

• 2 other identifiers: 2026 0906 635 001ICES #2026 0906 635 001
• Study Type: observational
• Target: 31,459
• Locations: 1 country
• Sites: 1

Brief Summary

This is a population-based retrospective, new-user, active comparator cohort study assessing whether initiating a new outpatient prescription of trazodone (\>75-150 mg/day), compared to a lower dose (25-75 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/1.73 m², who are not receiving dialysis and have no history of kidney transplantation. The primary outcome is a 30-day composite of all-cause hospitalization, all-cause emergency department visit, or all-cause mortality.

Conditions

Chronic Kidney Disease (CKD); Older Adults (65 Years and Older)

Keywords

Chronic Kidney Disease (CKD); Trazodone; Adverse events; Safety; Cohort study; Pharmacoepidemiology

Outcome Measures

Primary Outcomes (1)

• Number of participants with a composite outcome of all-cause hospitalization or all-cause emergency department visit, or all-cause mortality.

  All-cause hospitalization, all-cause emergency visits, and all-cause mortality will be combined into a composite measure. Only the first hospitalization or first emergency department visit occurring within 30 days after the cohort entry date will be considered.

  Older adults exposed to high-dose (>75-150 mg/day) versus low-dose (25-75 mg/day) trazodone will enter the cohort and be followed until the study outcome (first event), death, or 30 days from the cohort entry date.

Secondary Outcomes (6)

• Number of participants with all-cause hospitalization.

  Older adults exposed to high-dose (>75-150 mg/day) versus low-dose (25-75 mg/day) trazodone will enter the cohort and be followed until the study outcome (first event), death, or 30 days from the cohort entry date.

• Number of participants with all-cause emergency department visit.

  Older adults exposed to high-dose (>75-150 mg/day) versus low-dose (25-75 mg/day) trazodone will enter the cohort and be followed until the study outcome (first event), death, or 30 days from the cohort entry date.

• Number of participants with all-cause mortality

  Older adults exposed to high-dose (>75-150 mg/day) versus low-dose (25-75 mg/day) trazodone will enter the cohort and be followed until the study outcome (first event), death, or 30 days from the cohort entry date.

• 30-day composite outcome of a hospital encounter with fragility fracture, falls, hypotension, or syncope.

  Older adults exposed to high-dose (>75-150 mg/day) versus low-dose (25-75 mg/day) trazodone will enter the cohort and be followed until the study outcome (first event), death, or 30 days from the cohort entry date.

• 30-day composite outcome of a hospital encounter with delirium, encephalopathy, or hospital admission with receipt of an urgent computed tomography scan of the head

  Older adults exposed to high-dose (>75-150 mg/day) versus low-dose (25-75 mg/day) trazodone will enter the cohort and be followed until the study outcome (first event), death, or 30 days from the cohort entry date.

Study Arms (2)

Low dose (25-75 mg/day) Trazodone

Residents of Ontario, aged 66 years or older with low kidney function (estimated glomerular filtration rate (eGFR) \<45 mL/min per 1.73 m² but not receiving dialysis or having a history of kidney transplantation) who have filled a new oral prescription for trazodone (low dose 25-75 mg/day) with a day supply ≥ 5 days at an outpatient pharmacy under Ontario Drug Benefit (ODB) program from January 1, 2008, to March 1, 2025. 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. If the investigators conduct the study in Alberta, the accrual period for Alberta will be determined.

Drug: Trazodone HCl

High dose (>75-150 mg/day) Trazodone

Residents of Ontario, aged 66 years or older with low kidney funciton (estimated glomerular filtration rate (eGFR) \<45 mL/min per 1.73 m² but not receiving dialysis or having a history of kidney transplantation) who have filled a new oral prescription for trazodone (high dose \>75-150 mg/day) at an outpatient pharmacy with a day supply ≥ 5 days under Ontario Drug Benefit (ODB) program from January 1, 2008, to March 31, 2025. 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. If the investigators conduct the study in Alberta, the accrual period for Alberta will be determined.

Drug: Trazodone HCl

Interventions

Trazodone HCl DRUG

The primary exposure of interest will be oral trazodone at a dose \>75-150 mg/day.

High dose (>75-150 mg/day) Trazodone; Low dose (25-75 mg/day) Trazodone

Eligibility Criteria

• Age: 66 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

Adults aged 66 years or older with low kidney function (eGFR \<45 mL/min per 1.73 m2 but not receiving dialysis or having a history of kidney transplantation) who have filled a new outpatient prescription for trazodone with a dose range of 25-150 mg/day and a day supply of ≥5 days between 2008 and 2025 in Ontario.

You may qualify if:

• The cohort will 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 trazodone with an initial dose between 25 and 150 mg/day and a day supply of ≥5 days between January 1, 2008 to March 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.

You may not qualify if:

• 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.
• 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 \[ER or hospitalization\] \<refer to this as test date 1\>, 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 \[ER or hospitalization\] \<refer to this as test date 1\>, and while there is at least 'outpatient' serum creatinine test in the year before \<test date 1\>, the most recent outpatient test prior to \<test date 1\> 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.
• Individuals receiving palliative care in the 0-365 days prior to the index date, in this setting, dosing is less relevant; rather, the focus is comfort care.
• The investigators restrict to the first prescription in individuals with more than one eligible prescription. Date of this prescription will be the index date (the Date from which the outcomes start being assessed).

Sponsors & Collaborators

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

Study Sites (1)

London Health Sciences Centre Research Institute

London, Ontario, Canada

Location

Related Publications (4)

• Shu D, Zou G, Hou L, Petrone AB, Maro JC, Fireman BH, Toh S, Connolly JG. A simple Cox approach to estimating risk ratios without sharing individual-level data in multisite studies. Am J Epidemiol. 2025 Jan 8;194(1):226-232. doi: 10.1093/aje/kwae188.

  PMID: 38973755 BACKGROUND

• Bathini L, Jeyakumar N, Sontrop J, McArthur E, Kang Y, Luo B, Bello A, Collister D, Ahmed S, Kaul P, Youngson E, Braam B, Melamed N, Hladunewich M, Garg AX. Impact of Baseline Kidney Function on the Rate of Progressive Kidney Disease After Pregnancy: A Population-Based Cohort Study Research Protocol. Can J Kidney Health Dis. 2025 Feb 28;12:20543581251318836. doi: 10.1177/20543581251318836. eCollection 2025.

  PMID: 40027936 BACKGROUND

• Abdullah SS, Rostamzadeh N, Muanda FT, McArthur E, Weir MA, Sontrop JM, Kim RB, Kamran S, Garg AX. High-Throughput Computing to Automate Population-Based Studies to Detect the 30-Day Risk of Adverse Outcomes After New Outpatient Medication Use in Older Adults with Chronic Kidney Disease: A Clinical Research Protocol. Can J Kidney Health Dis. 2024 Jan 6;11:20543581231221891. doi: 10.1177/20543581231221891. eCollection 2024.

  PMID: 38186562 BACKGROUND

• Zou G. A modified poisson regression approach to prospective studies with binary data. Am J Epidemiol. 2004 Apr 1;159(7):702-6. doi: 10.1093/aje/kwh090.

  PMID: 15033648 BACKGROUND

MeSH Terms

Conditions

Renal Insufficiency, Chronic

Interventions

Trazodone

Condition Hierarchy (Ancestors)

Renal Insufficiency; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Piperazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Pyridones; Pyridines

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: RETROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 23, 2026
• First Posted: February 2, 2026
• Study Start: January 1, 2008
• Primary Completion: March 1, 2025
• Study Completion: March 31, 2025
• Last Updated: March 5, 2026

Record last verified: 2026-01

Data Sharing

• IPD Sharing: Will not share

Locations

CA (1)