This is a population-based cohort study assessing whether initiation of a higher dose of pramipexole (0.25 or 0.375 mg/day), compared with a lower dose (0.125 mg/day), in older adults with advanced chronic kidney disease (CKD) (an estimated glomerular filtration rate [eGFR] <45 mL/min/1.73 m² but not receiving dialysis or having a history of kidney transplantation) is associated with a higher 30-day risk of a composite outcome of all-cause hospitalization or all-cause emergency visits, or all-cause mortality.

*Summary*

Background: Pramipexole, a dopamine agonist used to treat Parkinson's disease and restless legs syndrome, is predominantly eliminated by the kidneys. Despite this, there is currently no direct evidence evaluating its safety or efficacy in patients with chronic kidney disease (CKD). In 2012, the U.S. Food and Drug Administration (FDA) issued a safety announcement regarding a potential increased risk of heart failure with pramipexole, based on two epidemiological studies. Although product monographs recommend dose reductions in CKD, the absence of robust clinical data creates a significant gap in understanding the risks and benefits of pramipexole in this population. Using a novel high-throughput computing approach, the investigators identified pramipexole as a potential safety concern among older adults with advanced CKD (eGFR <45 mL/min/1.73 m²). Initiation of pramipexole in the outpatient setting was associated with a higher 30-day risk of adverse outcomes compared with a similar cohort of non-users. These outcomes included a composite of hospital admissions for any reason or emergency department visits or all-cause mortality.

To validate these findings, the investigators plan to conduct a population-based cohort study among older adults in Ontario, Canada, comparing the risk of serious adverse events among those initiating a higher dose versus a lower dose of pramipexole in the outpatient setting.

Methods: The study will include older adults (≥66 years of age) 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 pramipexole. In Ontario, the sample will be accrued from January 1, 2008, through December 01, 2024. The prescription date will be the index date (start of cohort follow-up). Older adults with advanced CKD initiating treatment with pramipexole will be divided into two groups based on their dosage: high dose (0.25 or 0.375 mg/day) and low dose (0.125 mg/day). The investigators will use propensity score weighting to ensure groups are well-balanced on a comprehensive set of measured baseline characteristics.

The Patient outcome will be a 30-day composite of all-cause hospitalization, emergency department visits, or mortality.

*Literature Review*

Pramipexole, a dopamine agonist, is widely prescribed for the treatment of Parkinson's disease and restless legs syndrome (RLS) due to its efficacy in managing motor and sensory symptoms. However, its pharmacokinetic profile-characterized by predominant renal elimination, with approximately 90% primarily excreted unchanged by the kidneys-poses significant challenges for patients with CKD, who may experience drug accumulation and heightened adverse effects. In adults with impaired kidney function, pramipexole clearance is reduced by approximately 75% in severe renal impairment (creatinine clearance [CrCl] ~20 mL/min) and by about 60% in moderate impairment (CrCl ~40 mL/min). Additionally, in older adults (≥65 years), the elimination half-life increases by approximately 40% and drug clearance decreases by about 30%, largely attributable to age-related declines in renal function. Although product monographs recommend dose adjustments in CKD, there is limited clinical evidence to inform the safety of pramipexole in patients with advanced CKD (eGFR <45 mL/min/1.73m²).

Concerns about pramipexole's cardiovascular safety further complicate its use in this population. In 2012, the U.S. FDA issued a safety communication citing epidemiological studies that suggested a potential increased risk of heart failure, although causality was not firmly established. Whether this risk extends to CKD patients-who often have heightened susceptibility to fluid retention, arrhythmias, and hemodynamic instability-is unknown. These concerns are particularly salient in older adults, who are disproportionately affected by adverse drug reactions and are often underrepresented in clinical trials despite high rates of polypharmacy and age-related declines in kidney function. Many medications, including pramipexole, are eliminated via the kidneys and therefore may require dose adjustments or even avoidance in patients with reduced kidney function. However, prescribing guidelines and product monographs often lack clear recommendations for this population.

Using a high-throughput drug-safety computing approach, investigators previously identified a potential 30-day increased risk of emergency visits, hospitalizations, and mortality after initiating pramipexole. Understanding the risks of initiating higher versus lower doses of pramipexole in older adults with advanced CKD can be used to guide safe prescribing and better outcomes in this population.

*Objectives*

Is there a higher 30-day risk of a composite outcome of all-cause hospitalization or all-cause emergency visits, or all-cause mortality among older adults with advanced CKD (an eGFR <45 mL/min per 1.73 m² but not receiving dialysis or having a history of kidney transplantation) who initiate a higher dose (0.25 or 0.375 mg/day) vs lower dose (0.125 mg/day) of pramipexole in the outpatient setting?

*Study Design and Setting*

The investigators propose a population-based retrospective cohort study using linked administrative health data from Ontario, Canada. If the Ontario cohort is 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 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 for analyzing the primary outcomes is available across specific databases within the ICES system: data on all-cause hospitalizations are available in the Canadian Institute for Health Information Discharge Abstract Database, emergency visits in the National Ambulatory Care Reporting System, and mortality in the Registered Persons Database.

If the investigators proceed with also conducting the study in Alberta and combining the findings with Ontario, the Alberta data will be accessed through the Alberta Kidney Disease Network (AKDN). This dataset ends in ~ 2021.

The investigators are publicly registering our 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 RECORD reporting guidelines.

*Study Population*

The investigators 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 pramipexole at an outpatient pharmacy under the Ontario Drug Benefit (ODB) program from January 1, 2008, to December 01, 2024. The dispensing date of the prescription will serve as the index date, and only the first eligible prescription will be included to ensure unique cohort entry, and each individual can enter the cohort only once.

*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), 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*

Software:

All statistical analyses will be conducted using SAS software version 9.4 (SAS Institute, Cary, NC).

Descriptive Statistics:

Categorical variables will be reported as frequencies and proportions, while continuous variables will be presented as means with standard deviations (SD) or medians with interquartile ranges (IQR), as appropriate. Differences in baseline characteristics between the high-dose (0.25 or 0.375 mg/day) and low-dose groups (0.125 mg/day) groups will be examined using standardized differences, with differences ≥10% considered meaningful.

Balancing comparator group:

The investigators will use the inverse probability of treatment weighting on the propensity score to balance baseline characteristics between the high-dose and low-dose groups based on their baseline characteristics, including known indicators for pramipexole use.

The investigators will conduct multivariable logistic regression analyses to generate propensity scores using all baseline characteristics. Average treatment effect in the treated (ATT) weights will be used, where patients in the low dose group will be assigned weights calculated as (propensity score / [1 - propensity score]). In contrast, patients in the high dose group will receive a weight of 1. This method will produce a weighted pseudo sample of patients in the referent group (i.e. low-dose: pramipexole 0.125 mg/day) with a similar distribution of measured characteristics as the high-dose (pramipexole 0.25 or 0.375 mg/day) group. Baseline characteristics between groups will be compared using standardized differences in unweighted and weighted samples, with differences exceeding 10% considered meaningful.

Regression analysis:

To evaluate the primary outcome composite measure of all-cause hospitalization or all-cause emergency department visits or all-cause mortality- the investigators will apply a modified Poisson regression analysis to estimate the risk ratio (RR) with 95% confidence intervals (CIs) and a binomial regression to estimate the risk difference (RD) with 95% CIs using the weighted cohort, with low-dose pramipexole (0.125 mg/day) group as the referent.

Secondary analysis:

The investigators will conduct independent testing for all secondary and mechanistic outcomes without adjusting for multiple comparisons. Each test will be performed and reported independently. In line with the best practices, the investigators will present the P-value for the primary outcome and report all secondary and mechanistic outcomes using point estimates with 95% confidence intervals, acknowledging them as exploratory analyses.

Additional analysis:

The investigators will conduct four additional analyses.

1. Effect measure modification (EMM):

   For EMM, the investigators will expand our 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 high-dose (0.25 or 0.375 mg/day) and low-dose (0.125 mg/day) pramipexole groups will be assessed using standardized differences for all renal function categories combined and then within each of three eGFR categories (≥60, 45-<60, and <45 mL/min/1.73 m²).

   To further balance baseline characteristics between high-dose and low-dose pramipexole groups, the investigators will apply the IPTW method (described above), based on propensity scores for all the eGFR categories combined and within each of the three 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 low-dose and high-dose pramipexole groups and eGFR strata.
   • For multiplicative interaction, the investigators will use modified Poisson regression analysis to estimate risk ratios, including an interaction term between low-dose and high-dose pramipexole groups and eGFR strata.

2. The investigators will conduct a pre-specified subgroup analysis of the primary outcome stratified by pre-2020 (which overlaps with high-throughput computing) (January 1, 2008, to March 01, 2020) and post-2020 (which does not overlap with high-throughput computing) (March 02, 2020, to December 01, 2024). The investigators will examine whether the association between higher-dose vs. lower-dose pramipexole and the primary outcome is different (modified) in 2 period categories (the period prior to the end date of the high-throughput computing, and the period after the end-date of the high-throughput computing).

3. In a cohort of new users of pramipexole, the investigators will compare the risk of toxicity between those who initiate a higher dose (0.25 or 0.375 mg/day) and those on a lower dose (0.125 mg/day) of pramipexole in the outpatient setting, versus non-users, specifically in older adult patients with advanced CKD (eGFR <45 mL/min per 1.73 m²). The investigators will apply the primary study outcomes, utilize the same baseline characteristics, and employ the statistical analysis methods used in the primary analysis.

4. 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.

*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 methods:

The investigators plan to use a privacy-preserving Cox-based approach for estimating risk ratios for multisite studies where individual-level data cannot be shared due to privacy constraints described by Shu et al. (2025). 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 for confounding mitigation strategies such as propensity score matching or weighting to be done individually in each province. Each province will independently calculate these summary tables using their 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 where they will be used to estimate the combined risk ratios and 95% confidence intervals. This will enable a robust and consistent analysis while maintaining data privacy and adhering to regulatory compliance. To comply with privacy regulations for minimizing the chance of identification of any individual, in all manuscripts, numbers of individuals are suppressed in the case of 5 or fewer participants (reported as ≤5). All team members will sign any required data confidentiality and data use agreements.

Inclusion Criteria:

The cohort will include older adults aged 66 years or older with advanced CKD (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 pramipexole at an outpatient pharmacy under the Ontario Drug Benefit (ODB) program from January 1, 2008, to December 01, 2024. 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:

1. Data cleaning exclusions (e.g., individuals with missing or invalid age or sex or administrative database number, OHIP ineligible on index date, death on or before the index date, non-Ontario residents). The investigators anticipate that very few records will be excluded due to data cleaning.
2. To ensure that patients are new pramipexole users, the investigators will exclude those with any evidence of pramipexole use in the 180 days before the index date.
3. Patients with more than one study drug prescription on the index date will be excluded, as this complicates the ability to ascertain the prescribed dose accurately.
4. The investigators will exclude patients with a prescription of dopamine agonists and non-oral study drugs in the previous 180 days, including the index date.
5. Individuals with end-stage renal disease, chronic dialysis, or a kidney transplant prior to the index date.
6. 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.
7. Patients with no outpatient serum creatinine measurement 0- 365 days before the index date will be excluded.
8. Patients with unstable baseline kidney function (If the most recent serum creatinine test before 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) (If the most recent prior serum creatinine test before 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 before differs by an eGFR 10 mL/min/1.73 m2 or more from the value on ) will be excluded. In Ontario, it has been shown that outpatient serum creatinine measurements in the province, conducted on a single occasion, indicate stable values.
9. The investigators will exclude patients receiving pramipexole doses other than 0.125, 0.25, or 0.375 mg/day.
10. If more than one eligible prescription is available, restrict it to the first. The date of this prescription will be the index date.

Older adults aged 66 years or older with advanced CKD (eGFR <45 mL/min per 1.73 m² but not receiving dialysis or having a history of kidney transplantation) who have filled at least one outpatient prescription for oral pramipexole between 2008 and 2024 in Ontario.

The dataset from this study is held securely in coded form at ICES. While legal data sharing agreements between ICES and data providers (e.g., healthcare organizations and government) prohibit ICES from making the dataset publicly available, access may be granted to those who meet pre-specified criteria for confidential access, available at www.ices.on.ca/DAS (email: das@ices.on.ca). The full dataset creation plan and underlying analytic code are available from the authors upon request, understanding that the computer programs may rely upon coding templates or macros that are unique to ICES and are therefore either inaccessible or may require modification.