Benign prostate hyperplasia (BPH) is a prevalent condition, especially in older men, and is usually associated with lower urinary tract symptoms (LUTS) that impact quality of life. Bothersome LUTS may require pharmacological and/or surgical treatment. Alpha-adrenergic antagonists are recommended as the first line pharmacological treatment of LUTS from BPH. These medications have been widely prescribed over the last decades and result in good symptom control and tolerability due to limited side effects. In 2018, a study reported an increased risk of dementia in patients with BPH using alpha-adrenergic antagonists compared to patients not using this class of medication [1]. Conversely, another large cohort study failed to demonstrate an association between dementia and the use of alpha-adrenergic antagonists [2] and a small retrospective study did not show an association between alpha-adrenergic antagonists and cognitive decline in patients with possible Alzheimer disease [3]. Our objective is to use the National Alzheimer’s Center (NACC) dataset to investigate if there is an increased risk of cognitive decline among patients with normal cognition, Mild Cognitive Impairment (MCI), or dementia who are first time users of alpha-adrenergic antagonists compared to patients who are not using these medications. Our hypothesis is that alpha-adrenergic antagonist use is not associated with dementia.

We conducted a retrospective, propensity-score matched-cohort study using prospectively collected data from the National Alzheimer’s Coordinating Center (NACC). The NACC started collecting their uniform data set through Alzheimer's Disease Research Centers in the United States in 2005 and all participants provided written consent at the time of enrollment. 

We identified all participants enrolled between September 1, 2005 and January 1, 2020. We excluded patients who did not have a follow-up visit within 4-years of the initial visit, those whose medication list was not available for all visits, people that were using alpha-adrenergic antagonists at the time of enrollment, patients with a cognitive condition other than mild cognitive impairment or dementia, and those with an unknown APOE e4 carrier status. 

Our primary exposure was the new use of a prostate specific alpha-adrenergic antagonist (tamsulosin, alfuzosin, or silodosin) at any one of the follow-up visits. Patients who started alpha-adrenergic antagonist medication were matched 1:1 to people not using this class of medication based on cognitive status at the initial visit, total number of NACC visits, and propensity for exposure. The propensity score was created using 38 covariates including age, sex, years of education, marital status, living situation, degree of independence, vision impairment, and hearing impairment.

Our primary outcome was cognitive decline measured with the CDR Dementia Staging Instrument (CDR, 0=no dementia, 4=severe cognitive impairment) and the mini-mental state examination (MMSE, which measures orientation, attention, memory, language and visual-spatial skills and is scored from 0-30, with lower scores associated with cognitive impairment). We considered a ≥1 point increase on the CDR, or a ≥3 point decrease on the MMSE to be a significant change. Secondary outcomes include the Boston naming test, Wechsler Adult Intelligence Scale-revised (WAIS-R), and the trail making test part B.  

We calculated the score difference for each outcome measure between the visit after initial exposure (or the matched visit number for the unexposed) and the immediately preceding visit. Changes in outcome measure scores were compared between groups using t-tests. A conditional logistic regression model was used to evaluate if alpha-adrenergic antagonist medication exposure predicted a clinically important cognitive decline after adjusting for APOE e4 carrier status. Statistical analysis was carried out using SAS EG 8.3, and a two-sided p<0.05 was considered significant.

The initial cohort included 44,713 patients. We excluded 25,930 patients, leaving 18,783 patients. We identified 926 patients who newly started an alpha-adrenergic antagonist, and we were able to match 916 of these patients to the same number of patients who did not start an alpha-adrenergic antagonist. Baseline characteristics between the matched groups were similar and a selection of them are shown on Table 1. The most common alpha-adrenergic antagonist medication used by patients was tamsulosin (91.1%), followed by alfuzosin (6.7%), and silodosin (2.3%). There was no statistically significant difference in the primary and secondary outcomes when comparing patients who were exposed to alpha-adrenergic antagonists to those not exposed to alpha-adrenergic antagonists (Table 2). Eighty-nine (9.72%) patients exposed to alpha-adrenergic antagonists had a clinically relevant decline in the cognitive function in the CDR compared to 75 (8.19%) patients who were not exposed to the medication. A decrease of ≥3 points in the MMSE was noted in 136 (18.04%) of the patients exposed to alpha-adrenergic antagonists compared to 146 (19.21%) of the patients who were not exposed. The use of alpha-adrenergic antagonists was not predictive of a significant change in the CDR or the MMSE (OR 1.34, 95% CI 0.91 – 1.97, p = 0.14 and OR 0.98, 95% CI 0.71 – 1.36, p = 0.92, respectively). Subgroup analysis stratified by baseline cognitive status (normal, MCI, or dementia) did not show any statistically significant association between exposure to alpha-adrenergic antagonists and a clinically relevant change in the CDR or MMSE.

Alpha-adrenergic antagonists are frequently prescribed in elderly men with LUTS due to BPH; therefore, an increased risk in cognitive decline could lead to a change in disease management. While this topic has been extensively studied in relation to anticholinergic medications, the current literature on alpha-adrenergic antagonists has conflicting results. Our study is unique in that it uses established, detailed measures of cognition as outcomes, and includes patients with different cognitive states. We did not demonstrate association between alpha-adrenergic antagonists and cognitive decline as measured by two global measures of cognitive function (and three specific cognitive tests) and there was no association between cognitive decline with alpha-adrenergic antagonists exposure in patients with different baseline cognitive status.

This study provides reassurance that alpha-adrenergic antagonists are a safe medication and are not associated with cognitive decline. A strength of our study is the use of matched groups created using a propensity score to decrease confounding factors between exposed and non-exposed patients and the use of valid and sensitive measures of cognitive function to assess for clinically relevant cognitive decline. Limitations of our research include the lack of data on the duration of use of the alpha-adrenergic antagonists, and the fact that patients who used this class of medication between visits but were not using at the time of the visits may have been misclassified.

We did not find a significant association between the use of alpha-adrenergic antagonist medications and cognitive decline in patient with normal, mild cognitive impairment, or dementia when comparing matched cohorts of patients who were or were not exposed to this class of medication.

Duan Y, J. Grady J, C. Albertsen P, Helen Wu Z. Tamsulosin and the risk of dementia in older men with benign prostatic hyperplasia. doi:10.1002/pds.4361
Sik Tae B, Jo Jeon B, Choi H, Cheon J, Young Park J, Hyun Bae J. a-Blocker and Risk of Dementia in Patients with Benign Prostatic Hyperplasia: A Nationwide Population Based Study Using the National Health Insurance Service Database. doi:10.1097/ju.0000000000000209
Sohn J-H, Lee S-H, Kwon Y-S, Kim J-H, Kim Y, Jun Lee J. The impact of tamsulosin on cognition in Alzheimer disease with benign prostate hyperplasia: A study using the Hallym Smart Clinical Data Warehouse. doi:10.1097/md.0000000000020240

Continence 7S1 (2023) 100835
DOI: 10.1016/j.cont.2023.100835