Laxative Use in Patients With Advanced Chronic Kidney Disease Transitioning to Dialysis

Keiichi Sumida; Ankur A. Dashputre; Praveen K. Potukuchi; Fridtjof Thomas; Yoshitsugu Obi; Miklos Z. Molnar; Justin D. Gatwood; Elani Streja; Kamyar Kalantar-Zadeh; Csaba P. Kovesdy

Disclosures

Nephrol Dial Transplant. 2021;36(11):2018-2026. 

In This Article

Materials and Methods

Study Population

We analyzed longitudinal data from the US Renal Data System (USRDS) Transition of Care in CKD study, a nationally representative retrospective cohort study of US veterans who transitioned to ESRD.[23–25] In this study, a total of 102 477 US veterans who transitioned to ESRD from 1 October 2007 through 31 March 2015 were identified from the USRDS as a source population. In order to describe the trend in laxative use during the transition period (as detailed in the next subsection), we first identified 20 127 patients who had at least one prescription record for any medication within each 6-month time period over 36-months pre- and post-transition to ESRD. Prescribed medications were ascertained using both inpatient and outpatient prescriptions sourced from Centers for Medicare and Medicaid Services (CMS) Medicare Part D and Veterans Affairs (VA) pharmacy dispensation records.[26]

For identifying factors associated with pre-ESRD laxative use, we separately identified 70 128 patients with at least one prescription for any medication during the last 1-year prior to dialysis initiation. In order to stringently define the laxative users and non-laxative users for this aim, we selected 11 667 out of 70 128 patients who had at least two laxative prescriptions 30 days apart during the 1-year pre-ESRD period (i.e. laxative users). Among the remaining 58 461 patients, we additionally identified 34 965 patients who did not have any laxative prescription during the entire pre-ESRD period and defined these as comparators (i.e. non-laxative users), resulting in the final analytical population of 46 632 patients (Supplementary data, Figure S1). Compared with patients in the final analytical population, those who were excluded from the analysis (i.e. n = 23 496) were younger, less likely to be married and more likely to be African American and use medications (Supplementary data, Table S1).

Laxative use Prevalence and Patterns

Laxative use during the transition period was described as the proportion of patients who used any type of laxative, which was defined as the ratio of the number of patients who filled at least one prescription of any laxative (i.e. numerator) to the 20 127 patients identified to have at least one prescription medication (i.e. denominator) within each 6-month period over the 36-month pre- and post-ESRD transition periods. Laxative agents were ascertained according to prescription information for the following six types of laxatives: stool softeners, hyperosmotics, stimulants, bulk formers, chloride channel activator and lubricants (Supplementary data, Table S2). Among patients with at least one laxative prescription, the proportion of each or combination of these types of laxatives was assessed for each 6-month period over the 72-month evaluation period. All proportions were reported as percentages. The relationship between the number of different types of laxatives and the number of prescribed drugs was additionally examined among patients with at least one prescription medication in the last 6-month pre-ESRD period.

Covariates

Patient demographic characteristics, including age, sex, and self-identified race and ethnicity, were ascertained from the following three national databases: the USRDS, VA and CMS. Data on marital status, smoking status and service connectivity (a measure indicating whether one or more of a patient's comorbidities were caused by their military service, resulting in certain privileges, such as preferential access to care and lower copayments) were obtained from VA records only.[27,28] Preexisting comorbidities were identified from the VA Inpatient and Outpatient Medical SAS Datasets, using the International Classification of Diseases, Ninth Revision, Clinical Modification diagnostic and procedure codes and Current Procedural Terminology codes, as well as from VA/CMS data.[29] The Charlson comorbidity index (CCI) score was calculated using the Deyo modification for administrative datasets, without including kidney disease.[30] Cardiovascular disease was defined as the presence of diagnostic codes for coronary artery disease, angina, myocardial infarction or cerebrovascular disease.[31] Bowel disorders were defined as the presence of diagnostic codes for inflammatory bowel disease, irritable bowel syndrome or diarrhea. Laboratory data were obtained from the VA research databases as previously described,[32,33] and their baseline values were defined as the average of each laboratory test during the 2-year baseline period (vide infra). Similarly, patients with at least one prescription over the 2-year baseline period were recorded as having been treated with the medication. Estimated glomerular filtration rate (eGFR) was calculated with the CKD Epidemiology Collaboration creatinine equation using outpatient serum creatinine and demographic data.[34] Intraindividual slope of eGFR was calculated using a linear mixed-effects model using all outpatient eGFR values available in the 2-year baseline period and, given the potential non-linear association of eGFR slope with laxative use, stratified into four a priori categories (i.e. less than −10, −10 to less than −5, −5 to <0 and ≥0 mL/min/1.73 m2/year) for the analysis.[25]

Statistical Analysis

Baseline patient characteristics were summarized by laxative users (n = 11 667) and non-laxative users (n = 34 965) and presented as number (percentages) for categorical variables and mean [standard deviation (SD)] for continuous variables with a normal distribution or median [interquartile range (IQR)] for those with a skewed distribution. In order to account for the temporality of the association between baseline clinical characteristics and laxative use status and not to miss the potential short-term effects of factors that might affect subsequent use of laxatives, the baseline was defined based on the 2-year time period immediately prior to the first date of laxative prescription during the last 1-year pre-ESRD period among laxative users. Among non-laxative users, the 2-year baseline period was anchored by an index date of 296 days prior to dialysis initiation, which corresponded to the median time interval from the first date of laxative prescription to dialysis initiation in laxative users.

We performed multivariable logistic regression to identify factors independently associated with laxative use during the last 1-year pre-ESRD period. Based on theoretical consideration and the availability in this study, the following variables were included in the main adjusted model: demographics [age, sex, race and marital status), smoking status, service connectivity, comorbidities (diabetes, hyperlipidemia, cardiovascular disease, congestive heart failure, cerebrovascular disease, lung disease, connective tissue disease, peptic ulcer disease, liver disease, human deficiency virus/acquired immunodeficiency syndrome (HIV/AIDS), malignancy, anemia, atrial fibrillation, depression and bowel disorders], CCI, medications [renin–angiotensin system inhibitors, β-blockers, calcium channel blockers, diuretics, phosphate binders (calcium acetate, sevelamer or lanthanum), sodium polystyrene sulfonate, antidepressants, non-opioid analgesics, opioids, antihistamines, anticholinergics, antiarrhythmics, anticoagulants, antipsychotics, anti-Parkinson drugs, antacids, anticonvulsants and oral iron supplements] and cumulative length of hospitalizations over the 2-year baseline period. Of the variables included in the multivariable model, data points were missing for race (0.01%), marital status (5.4%), service connectivity (1.9%), comorbidities (0.8%) and medications (7.6%). Of the 46 632 patients in the analytical cohort, 39 578 (88.7%) had complete data available for the multivariable model.

Due to the relatively high proportion of missing information for body mass index (BMI; 33.3%), systolic blood pressure (30.4%), last eGFR and eGFR slope during the 2-year baseline period (37.7%), these variables were additionally included in the main model as a sensitivity analysis, which resulted in 57.8% of the population in the analytical cohort. A two-sided P < 0.05 was used as a threshold of statistical significance for all analyses. Due to the large sample size, the significance of differences in baseline characteristics by laxative use status was established based on considerations of biologically or clinically meaningful differences. All analyses were conducted in SAS Enterprise guide version 7.1 (SAS Institute, Cary, NC, USA) and STATA/MP version 15 (STATA Corporation, College Station, TX, USA). The study was approved by the Institutional Review Boards of the Memphis and Long Beach VA Medical centers, with exemption from informed consent.

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