Nortriptyline and the Risk of Serious Adverse Events

Nortriptyline is a tricyclic antidepressant commonly prescribed in older adults for the treatment of depression and neuropathic pain. Primarily, it is metabolized by the hepatic cytochrome P450 (CYP) 2D6 enzyme and undergoes minimal renal excretion as an unchanged drug. However, some of its metabolites are excreted through the kidneys. Altered nortriptyline pharmacokinetics, along with reduced protein binding in patients with low kidney function, can lead to increased systemic exposure. Altogether, this may increase the risk of developing nortriptyline-related adverse events in patients with low kidney function.

The most common measure to assess kidney function in routine clinical care is the estimated glomerular filtration rate (eGFR), expressed in lab reports as mL/min/1.73 m2. A normal eGFR is >90 mL/min/1.73 m2, and a value <45 mL/min/1.73 m2 is considered to be low.

Product monographs advise caution when using nortriptyline in patients with reduced kidney function, but do not provide specific dosing recommendations for these patients. Nortriptyline has not been well studied in patients with low kidney function (eGFR <45 mL/min/1.73 m2).

The investigators aim to conduct a population-based cohort study among older adults with low kidney function, comparing the risk of serious adverse events among those initiating high-dose (>10-150 mg/day) versus low-dose (10 mg/day) nortriptyline in the outpatient setting.

Methods:

In this population-based retrospective cohort study, eligible participants will include older adults (≥66 years) with eGFR <45 mL/min/1.73 m² (not receiving dialysis or having a history of kidney transplantation) who were dispensed a new outpatient prescription for oral nortriptyline. In Ontario, accrual will occur between January 1, 2008, and December 1, 2025.

Based on the prescribed daily dose at treatment initiation, individuals initiating nortriptyline will be categorized into two groups: high-dose (>10-150 mg/day) and low-dose (10 mg/day) nortriptyline.

Propensity score weighting will be used to ensure both groups are well-balanced on a comprehensive set of measured baseline characteristics. The primary outcome will be a 30-day composite of emergency department visit, all-cause hospitalization, or all-cause mortality.

*Background* Nortriptyline is a tricyclic antidepressant commonly used in older adults with low kidney function for the management of major depressive disorder and neuropathic pain, across a range of daily doses. Serious adverse events associated with nortriptyline reported in the literature include cardiac arrhythmias, hypotension, falls, anticholinergic effects, and central nervous system-related adverse events such as delirium.

Overall, safety data on nortriptyline dosing in patients with low kidney function are limited, highlighting the need for a population-based study to assess its real-world safety profile and inform better care.

Understanding the dose-specific risks of initiating high-dose (>10-150 mg/day) and low-dose nortriptyline (10 mg/day) in older adults with low kidney function may help inform safer prescribing and improve clinical outcomes in this population.

*Objective* Is there a higher 30-day risk of a composite outcome of all-cause emergency department visit, all-cause hospitalization, or all-cause mortality among 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) who initiate high-dose (>10-150 mg/day) versus low-dose (10 mg/day) nortriptyline in the outpatient setting?

*Study design and setting* The investigators propose a population-based retrospective cohort study using linked administrative health data from Ontario. If the Ontario cohort is too small to generate reliable estimates, the investigators will augment the study by performing an analysis using Alberta health administrative data.

Ontario data will be sourced from the Institute for Clinical Evaluative Sciences (ICES; ices.on.ca). It offers secure, encrypted individual-level data for Ontario residents, all with universal access to hospital and physician services under a government-funded, single-payer healthcare system. The use of data 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 information needed to analyze the primary outcomes is available across specific databases within the ICES system: data on all-cause hospitalizations in the Canadian Institute for Health Information Discharge Abstract Database, emergency department visits in the National Ambulatory Care Reporting System, and mortality in the Registered Persons Database.

If the investigators proceed with conducting the study in Alberta and combining the findings with Ontario, the Alberta data will be accessed through the Alberta Kidney Disease Network; this dataset ends in ~ 2021.

The investigators are publicly registering the study protocol and documenting the study description, design, and statistical analysis prior to conducting outcome analyses. The results of this study will be reported adhering to the REporting of studies Conducted using Observational Routinely-collected health Data (RECORD) reporting guidelines.

*Baseline Characteristics* Health records, census files, hospital discharge records, laboratory data, and physician claims will provide baseline variables, including demographic characteristics (such as age, sex, rurality, neighborhood income quintile, etc.), comorbidities, and medication use. Baseline comorbidities and healthcare utilization will be assessed using 5-year and 1-year look-back periods from the index date. Baseline medication use will be assessed within 120 days prior to the index date.

*Statistical analysis plan* Categorical variables will be summarized as frequencies and proportions, while continuous variables will be summarized as means with standard deviations (SDs) or medians with interquartile ranges (IQRs), as appropriate.

Baseline characteristics will be compared between exposure groups using standardized mean differences (SMDs), with an absolute SMD greater than 10% considered indicative of a meaningful imbalance. This approach will be used for the primary comparison between high-dose (>10-150 mg/day) and low-dose (10 mg/day) nortriptyline.

Balancing comparator group: The investigators will use inverse probability of treatment weighting (IPTW) on the propensity score to balance baseline characteristics between the exposure groups, including predictors of nortriptyline use.

Propensity scores will be generated using a multivariable logistic regression model with all baseline characteristics.

Average treatment effect in the treated (ATT) weights will be used, where patients in the low-dose nortriptyline group will be assigned weights calculated as (propensity score / [1 - propensity score]) and patients in the high-dose nortriptyline group will receive a weight of 1. This method will produce a weighted pseudo-population in which the distribution of measured baseline characteristics in the low-dose nortriptyline group is balanced to that of the high-dose nortriptyline group. Baseline characteristics will be compared between groups using standardized differences in both unweighted and weighted samples.

Participant observation time will be censored at the time of the first occurrence of the outcome of interest, death (if not the outcome of interest), or 30 days after the index date, whichever comes first.

Regression analysis: To evaluate the primary outcome composite measure of all-cause emergency department visit, all-cause hospitalization, or all-cause mortality, the investigators will apply a modified Poisson regression analysis to estimate the risk ratio (95% confidence intervals) and binomial regression to estimate the risk difference (95% confidence intervals) using the weighted cohort, with the low-dose nortriptyline group as the referent.

Secondary analyses:

The investigators will conduct independent testing for all secondary outcomes without adjusting for multiple comparisons. Each outcome will be analyzed and reported independently. In line with best practices, the primary outcome will be presented with its P-value, and the investigators will report all secondary outcomes using point estimates with 95% confidence intervals.

Additional analyses: The investigators plan to conduct six additional analyses.

1. Effect measure modification (EMM): To evaluate EMM, the investigators will expand the cohort to all the eGFR levels and categorize them into three groups: eGFR ≥60, 45-<60, and <45 mL/min/1.73 m2. Baseline characteristics between the high-dose (>10 mg/day) and low-dose (10 mg/day) nortriptyline will be assessed using standardized differences for all renal function categories combined, and within each of the three eGFR categories (≥60, 45-<60, and <45 mL/min/1.73 m²). To further balance baseline characteristics between the high-dose (>10 mg/day) and low-dose (10 mg/day) nortriptyline groups, the investigators will apply the IPTW method (described above), based on propensity scores for all eGFR categories combined and within each of the three eGFR categories. EMM on the absolute scale for the primary composite outcome (30-day composite outcome of all-cause emergency department visit, all-cause hospitalization, or all-cause mortality) will be examined across three baseline eGFR categories. EMM will be assessed on both the additive and multiplicative scales. For additive interaction, the investigators will use binomial regression with an identity link to estimate risk differences, including an interaction term between high-dose (>10-150 mg/day) and low-dose nortriptyline (10 mg/day) and eGFR strata. For multiplicative interaction, the investigators will use modified Poisson regression analysis to estimate risk ratio, including an interaction term between high-dose (>10-150 mg/day) and low-dose nortriptyline (10 mg/day) and eGFR strata.
2. The investigators' interest in examining the safety of nortriptyline in older adults with low kidney function is derived from high-throughput computing analysis in which the investigators executed 700+ population-based, new-user cohort studies, each comparing 74 acute (30-day) outcomes across strata of kidney function. In this analysis, nortriptyline was compared against non-users, separately; the investigators found signs of harm, which motivated the current study. High-throughput analysis was run using Ontario data from January 1, 2008, to March 1, 2020. To confirm results, when there is no overlap, the investigators will perform the analysis restricting the cohort after March 1, 2020. Examine whether the association between high-dose (>10-150 mg/day) and low-dose nortriptyline (10 mg/day) and the primary outcome is different (modified) in 2 period categories (the period before the end date of the high-throughput computing, and the period after the end date of the high-throughput computing). The investigators will perform analysis restricted to the non-overlap period, i.e., after March 1, 2020.
3. Compute the hazard ratio for all outcomes within 30 days, illustrating the effect of the intervention on each outcome over time. The investigators expect hazard ratio results similar to risk ratio. Although the difference between hazard ratio and risk ratio may be minimal over a short follow-up period, the hazard ratio offers additional insight by accounting for time-to-event analysis.
4. Compare high-dose (>10-150 mg/day) and low-dose nortriptyline (10 mg/day) with non-users of nortriptyline, separately, to contextualize the magnitude and direction of risk observed in the dose-comparison analysis. This analysis will follow a new-user design and apply propensity score weighting to balance baseline characteristics between nortriptyline users and non-users.
5. The investigators will perform E-value analyses to determine the minimum association strength an unmeasured confounder would need with both the prescription drug and the outcome of interest (while adjusting for measured covariates) to eliminate the observed association.
6. Among patients with low kidney function (eGFR <45 mL/min/1.73 m²), the investigators will conduct prespecified subgroup analyses to examine whether the association between high-dose (>10-150 mg/day) versus low-dose nortriptyline (10 mg/day) users and the 30-day primary composite outcome differs across baseline eGFR categories (30-<45 and <30 mL/min/1.73 m²). Effect measure modification will be assessed on both the additive and multiplicative scales using interaction terms in weighted regression models.

• Combining Outcome Results from Ontario and Alberta* This approach will only be used if the investigators proceed with conducting the analysis in Alberta. Privacy-preserving method: The investigators plan to use a privacy-preserving Cox-based approach to estimate risk ratio in multisite studies where individual-level data cannot be shared due to privacy constraints. The proposed method requires only a single transfer of summary-level outputs from each province to the research team. It produces results identical to those from a corresponding log-binomial regression with combined individual-level data. The method was developed by adapting the risk-set table approach for survival outcomes, assuming stratified, province-specific baseline risks, and allowing confounding mitigation strategies, such as propensity score matching or weighting, to be applied individually in each province. Each province will independently calculate these summary tables using its individual-level data. The summary-level risk-set tables generated in Alberta will be shared in a single data transfer to the coordinating site's analyst, who will use them to estimate the combined risk ratio and 95% confidence intervals. This will enable robust, consistent analysis while maintaining data privacy and ensuring regulatory compliance. To comply with privacy regulations and minimize the risk of identifying any individual, in the manuscript, the number of participants will be suppressed for 5 or fewer participants (reported as ≤5). All team members will sign any required data confidentiality and data use agreements.