Nortriptyline and the Risk of Serious Adverse Events

NCT07527481 | Completed

• 1 other identifier: 2026 0906 635 002
• Study Type: observational
• Target: 5,000
• Locations: 0 countries
• Sites: N/A

Brief Summary

This is a population-based retrospective, new-user, active comparator cohort study assessing whether initiating a new outpatient prescription of high-dose nortriptyline (\>10-150 mg/day), compared with low dose (10 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.

Conditions

Chronic Kidney Disease

Keywords

Nortriptyline; Tricyclic antidepressants; Older adults; Serious adverse events; Chronic kidney disease; Cohort study; Glomerular filteration rate

Outcome Measures

Primary Outcomes (1)

• Number of participants with a 30-day composite outcome of all-cause emergency department visit, all-cause hospitalization, or all-cause mortality.

  30-day all-cause emergency department visit, all-cause hospitalization, 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 (>10-150 mg/day) vs low-dose (10 mg/day) oral nortriptyline will enter the cohort and will be followed until study outcome (first event), death, or 30 days from the cohort entry date.

Secondary Outcomes (7)

• Number of participants with 30-day all-cause emergency department visit.

  Older adults exposed to high-dose (>10-150 mg/day) vs low-dose (10 mg/day) oral nortriptyline 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 30-day all-cause hospitalization.

  Older adults exposed to high-dose (>10-150 mg/day) vs low-dose (10 mg/day) oral nortriptyline 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 30-day all-cause mortality

  Older adults exposed to high-dose (>10-150 mg/day) vs low-dose (10 mg/day) oral nortriptyline 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 (>10-150 mg/day) vs low-dose (10 mg/day) oral nortriptyline will enter the cohort and will be followed until study outcome (first event), death, or 30 days from the cohort entry date.

• 30-day hospital encounter composite of atrial fibrillation/flutter, ventricular arrhythmia/sudden cardiac death, and other arrhythmia.

  Older adults exposed to high-dose (>10-150 mg/day) vs low-dose (10 mg/day) oral nortriptyline 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)

Low dose nortriptyline (10 mg/day)

Residents of 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 nortriptyline (low dose 10 mg/day) at an outpatient pharmacy under the Ontario Drug Benefit program from January 01, 2008, to December 01, 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: Nortriptyline Hydrochloride

High dose nortriptyline (>10-150 mg/day)

Residents of 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 nortriptyline (high dose \>10-150 mg/day) at an outpatient pharmacy under the Ontario Drug Benefit program from January 01, 2008, to December 01, 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: Nortriptyline Hydrochloride

Interventions

Nortriptyline Hydrochloride DRUG

The primary exposure of interest will be oral nortriptyline at a dose of \>10-150 mg/day. For the primary comparison, oral nortriptyline at 10 mg/day will serve as the referent group to reduce confounding by indication.

Also known as: Nortriptyline, Aventyl, Pamelor, Tricyclic antidepressant

High dose nortriptyline (>10-150 mg/day); Low dose nortriptyline (10 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 of oral nortriptyline between 2008 and 2025 in Ontario.

You may qualify if:

• 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 nortriptyline 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.

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.
• Evidence of clinically non-meaningful nortriptyline doses (doses that are either too low or too high). The recommended nortriptyline dose range is 10 to 150 mg per day.
• Evidence of other tricyclic antidepressants in the previous 180 days (including 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.
• 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).

Sponsors & Collaborators

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

Related Publications (3)

• Koiso K, Akaza H, Kikuchi K, Aoyagi K, Ohba S, Miyazaki M, Ito M, Sueyoshi T, Matsushima H, Kamimura H, Watanabe T, Higuchi S. Pharmacokinetics of tamsulosin hydrochloride in patients with renal impairment: effects of alpha 1-acid glycoprotein. J Clin Pharmacol. 1996 Nov;36(11):1029-38. doi: 10.1177/009127009603601107.

  PMID: 8973992 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

• 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

MeSH Terms

Conditions

Renal Insufficiency, Chronic

Interventions

Nortriptyline; Antidepressive Agents, Tricyclic

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)

Dibenzocycloheptenes; Benzocycloheptenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Polycyclic Compounds; Antidepressive Agents; Psychotropic Drugs; Central Nervous System Agents; Therapeutic Uses; Pharmacologic Actions; Chemical Actions and Uses

Study Design

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

Study Record Dates

• First Submitted: April 7, 2026
• First Posted: April 14, 2026
• Study Start: January 1, 2008
• Primary Completion: December 1, 2025
• Study Completion: December 31, 2025
• Last Updated: April 14, 2026

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will not share