Lorazepam and the Risk of Serious Adverse Events

NCT07179978 | Completed

• 2 other identifiers: 2025 0906 609 0001ICES # 2025 0906 609 001
• Study Type: observational
• Target: 12,308
• Locations: 1 country
• Sites: 1

Brief Summary

This is a population-based cohort study assessing whether initiating a new outpatient prescription of a higher dose of lorazepam (\>1-4 mg/day) compared to a lower dose (0.5-1 mg/day) in older adults with low kidney function (an eGFR \<45 mL/min per 1.73 m2 but not receiving dialysis or having a history of kidney transplantation) is associated with an increased 30-day risk of a composite outcome, including all-cause hospitalization, all-cause emergency visit, or all-cause mortality.

Conditions

Chronic Kidney Disease (CKD)

Keywords

chronic kidney disease; older adults; benzodiazepines; adverse events; cohort study; drug safety; lorazepam; sleeping pills; gediatrics

Outcome Measures

Primary Outcomes (1)

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

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

  Older adults exposed to high-dose (>1-4 mg/day) vs low-dose (0.5-1 mg/day) lorazepam will enter the cohort and will be followed until study outcome (first event), death, or 30 days from the cohort entry date.

Secondary Outcomes (3)

• Number of participants with all-cause hospitalization.

  Older adults exposed to high-dose (>1-4 mg/day) vs low-dose (0.5-1 mg/day) lorazepam will enter the cohort and will be followed until 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 (>1-4 mg/day) vs low-dose (0.5-1 mg/day) lorazepam will enter the cohort and will be followed until 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 (>1-4 mg/d) vs low-dose (0.5-1 mg/d) lorazepam will enter the cohort and will be followed until study outcome (first event), death, or 30 days from the cohort entry date.

Other Outcomes (2)

• 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 (>1-4 mg/day) vs low-dose (0.5-1 mg/day) lorazepam will enter the cohort and will be followed until 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 (>1-4 mg/day) vs low-dose (0.5-1 mg/day) lorazepam will enter the cohort and will be followed until study outcome (first event), death, or 30 days from the cohort entry date.

Study Arms (2)

High dose of lorazepam (>1-4 mg/day)

Residents of Alberta and Ontario, aged 66 years or older with low kidney function (an 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 lorazepam (high-dose \>1-4 mg/day) at an outpatient pharmacy under the Ontario Drug Benefit (ODB) program from January 01, 2008, to September 1, 2024, with a day supply of ≥5 days. The date when the prescription was filled will serve as the patient's entry or index date for the cohort, and each patient will enter the cohort only once. The accrual period for Alberta will be determined.

Drug: Lorazepam

Low-dose of lorazepam (0.5-1 mg/day)

Residents of Ontario and Alberta, aged 66 years or older with low kidney function (an 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 lorazepam (low-dose 0.5-1 mg/day) at an outpatient pharmacy under the Ontario Drug Benefit (ODB) program from January 01, 2008, to September 1, 2024, with a day supply of ≥5 days. The date when the prescription was filled will serve as the patient's entry or index date for the cohort, and each patient will enter the cohort only once. The accrual period for Alberta will be determined.

Drug: Lorazepam

Interventions

Lorazepam DRUG

The primary exposure of interest will be oral lorazepam at a dose range of \>1-4 mg/day.

High dose of lorazepam (>1-4 mg/day); Low-dose of lorazepam (0.5-1 mg/day)

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 lorazepam with a dose range of 0.5-4 mg/day and a day supply of ≥5 days between 2008 and 2024 in Ontario. The study accrual period for Alberta will be determined based on data availability.

You may qualify if:

• The cohort will include older adults aged 66 years or greater with low kidney function (an 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 lorazepam at an outpatient pharmacy with a dose range of 0.5-4 mg/day and a day supply of ≥5 days from January 1, 2008, to September 1, 2024 for Ontario; dates in Alberta to be finalized based on data availability.

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 other benzodiazepine and benzodiazepine-related drugs (alprazolam, bromazepam, chlordiazepoxide, clobazam, clonazepam, clorazepate, diazepam, ketazolam, midazolam, estazolam, flurazepam, nitrazepam, oxazepam, temazepam, triazolam, eszopiclone, zopiclone, and zolpidem) prescription in the previous 180 days before the index date or on the index date.
• 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 other related drugs (melatonin, trazodone, doxepin, and suvorexant) and non-oral formulations of the study drugs in the previous 180 days, including the index date.
• 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 (2)

• 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

• 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 RESULT

MeSH Terms

Conditions

Renal Insufficiency, Chronic

Interventions

Lorazepam

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)

Benzodiazepinones; Benzodiazepines; Benzazepines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Design

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

Study Record Dates

• First Submitted: September 5, 2025
• First Posted: September 18, 2025
• Study Start: January 1, 2008
• Primary Completion: September 1, 2024
• Study Completion: October 1, 2024
• Last Updated: September 24, 2025

Record last verified: 2025-09

Data Sharing

• IPD Sharing: Will not share

Locations

CA (1)