Associate Professor, Obstetrics and Gynecology, Division of Female Pelvic Medicine and Reconstructive Surgery, Washington University School of Medicine, St. Louis, MO
SYNOPSIS: There is a significant increase in dementia risk associated with the use of anticholinergic medications for three months or longer.
SOURCE: Dmochowski RR, Thai S, Iglay K, et al. Increased risk of incident dementia following use of anticholinergic agents: A systematic literature review and meta-analysis. Neurourol Urodyn 2021;40:28-37.
The main objective of this study was to determine the effect of three or more months of anticholinergic use and, specifically, medications used to treat overactive bladder (OAB) on the risk of dementia, mild cognitive impairment, and change in cognitive function. This was a systematic literature review and meta-analysis performed according to PRISMA guidelines and registered in the PROSPERO database. PubMed, Embase, and Cochrane Library databases were searched for English-language articles published before August 2019. Studies eligible for this review included full-text articles of primary publications of randomized controlled trials (RCTs), and cohort and case-control studies. Studies were reviewed by two reviewers and eligible if studies examined the effect of anticholinergic drug use for
≥ 3 months on dementia or cognitive function in adult patients and contained an adequate description of the methods used. Studies were excluded if they assessed only serum anticholinergic activity, used a combined scale of drug burden that did not specify the risk for exposure to anticholinergic agents only, or examined acute outcomes, such as delirium or acute cognitive dysfunction. Studies assessing anticholinergics used to treat OAB were considered for a separate meta-analysis.
Of the initial 2,092 articles identified on search, 1,990 were screened based on title and abstract. Of these, 316 were assessed by full text and 21 met inclusion criteria and underwent qualitative analysis. An increased cognitive impairment risk was reported in the studies evaluated using a variety of endpoints (incident dementia, Alzheimer’s disease, mild cognitive impairment, and change in cognitive function). Only the incident dementia category had sufficient studies (six of nine studies) to perform a meta-analysis. These comprised three case-control and three cohort studies and collectively included data from 645,865 patients. The six studies used varying anticholinergic exposure and dementia definitions. The authors reported an average relative risk for incident dementia using these six studies of 1.46 (95% confidence interval, 1.17-1.81; 95% prediction interval, 0.70-3.04) and ranged from 1.05 to 2.63. Clinically, this translates into an average increased risk of dementia of 46% with use of anticholinergics compared to nonuse. Three of these studies reported anticholinergic dosing data; using these studies, any anticholinergic exposure was associated with increased incident dementia when compared to no anticholinergic exposure. Two studies specifically examined the role OAB medications had on dementia. In these two studies, the risk of dementia from OAB medications appeared higher than the overall risk across all anticholinergic agents for most levels of exposure (adjusted odds ratios ranged from 1.21 to 1.65).
COMMENTARY
Urinary incontinence is defined as the involuntary loss of urine and it affects more than 50% of women.1,2 Despite this being a very common condition that affects women, urinary incontinence remains frequently undertreated. Urgency incontinence, or OAB, is associated with a strong urge to void that is difficult to defer.1 Although the evaluation of urinary incontinence is similar for all types, treatment options vary by diagnosis.
Guidelines for the evaluation of urinary incontinence consistently recommend characterization of symptoms, history, physical exam, and testing for urinary tract infection as well as an assessment of post-void residual, but guidelines vary in specific details and in testing recommendations.1 Treatment for urge incontinence should begin with behavioral and lifestyle modification, and often simple, conservative measures can improve symptoms dramatically. Behavioral and lifestyle modifications include fluid management; limiting bladder irritant consumption (diet beverages, in particular), carbonated beverages, and caffeine; addressing and managing constipation, smoking cessation, and weight loss; and treating vaginal atrophy. In addition, pelvic floor physical therapy and pelvic floor exercises have been shown to be effective strategies in the treatment of urge incontinence.3 Pharmacotherapy can be used concomitantly with these measures or used as the next step in women in whom conservative options have not fully resolved symptoms. Other treatments for urge incontinence include intradetrusor botulinum toxin injections, percutaneous tibial nerve stimulation, and sacral neuromodulation. It should be noted that some insurance plans require a trial of pharmacotherapy prior to authorizing some of these additional procedural treatments.
Antimuscarinics are the most commonly prescribed medications to treat urge urinary incontinence. These include darifenacin, fesoterodine, oxybutynin, solifenacin, tolterodine, and trospium. Modest improvements have been seen in pharmacotherapy when compared to placebo.4 Combined therapy with behavior modification has been shown to be more successful than medication alone.5 Antimuscarinic agents are contraindicated in patients with untreated narrow angle glaucoma and supraventricular tachycardia. Nearly 50% of patients taking these medications have side effects; most commonly, these medications have peripheral anticholinergic effects, including dry mouth and constipation. As a result of these side effects, discontinuation is common. It is important to keep in mind that these medications have additive side effects with other medications, and patients often are on other medications with significant anticholinergic properties.
Importantly, the study by Dmochowski et al further adds to the growing literature linking anticholinergic drug use with the risk of dementia. Cognitive impairment is a significant public health issue. One in nine U.S. adults experience symptomatic cognitive decline.6 There are an estimated 6 million people living with dementia in the United States today, and this number is projected to increase to 14 million by 2060.7 Worldwide, more than 50 million people have dementia and 10 million new cases are added annually.8 One of the studies included in the systematic review noted earlier is a nested case control study from the United Kingdom by Coupland et al.9 This study included 58,769 patients with a diagnosis of dementia and 225,574 matched controls. The authors found a significant dementia risk in patients with exposure to several types of strong anticholinergic drugs, including antimuscarinics. They found 50% increased odds of dementia with an exposure equivalent to three years of daily use of a sole strong anticholinergic medication and estimated that 10% of dementias could be attributable to this exposure.
As obstetrician gynecologists and as urogynecologists, we must strongly consider these associations prior to prescribing antimuscarinics. Although we may be most familiar with antimuscarinic bladder medications, frequently our patients come to us taking other anticholinergic medications, such as antiarrhythmic medications, antihistamines, antidepressants, antiepileptics, antiemetics, antiparkinson agents, and antipsychotics. Alongside becoming more familiar with the broader class of anticholinergic medications, screening women for signs of cognitive changes and assessing their family history of dementia prior to prescribing antimuscarinics may aid us in better understanding the risks and benefits of pharmacologic therapy for our patients. We should strive to maximize nonpharmacologic management of urge incontinence with behavioral and lifestyle modification and then refer for nonpharmacologic treatment with intradetrusor botulinum toxin injections or neuromodulation. As women’s health providers, we are in the unique position to affect the long-term well-being of women and can help educate patients and colleagues as we work toward deprescribing antimuscarinic medications for the management of urge incontinence.
REFERENCES
- Abrams P, Andersson KE, Birder L, et al. Fourth International Consultation on Incontinence recommendations of the International Scientific Committee: Evaluation and treatment of urinary incontinence, pelvic organ prolapse, and fecal incontinence. Neurourol Urodyn 2010;29:213-240.
- Minassian VA, Stewart WF, Wood GC. Urinary incontinence in women: Variation in prevalence estimates and risk factors. Obstet Gynecol 2008;111:324-331.
- Lukacz ES, Santiago-Lastra Y, Albo ME, Brubaker L. Urinary incontinence in women: A review. JAMA 2017;318:1592-1604.
- Shamliyan T, Wyman JF, Ramakrishnan R, et al. Benefits and harms of pharmacologic treatment for urinary incontinence in women: A systematic review. Ann Intern Med 2012;156:861-874.
- Burgio KL, Kraus SR, Menefee S, et al. Behavioral therapy to enable women with urge incontinence to discontinue drug treatment: A randomized trial. Ann Intern Med 2008;149:161-169.
- Centers for Disease Control and Prevention. Subjective cognitive decline – A public health issue. Alzheimer’s Disease and Healthy Aging. Last reviewed Feb. 27, 2019. https://www.cdc.gov/aging/data/subjective-cognitive-decline-brief.html#:~:text=Subjective%20Cognitive%20Decline%20(SCD)%20is,Alzheimer's%20disease%20and%20related%20dementias
- Centers for Disease Control and Prevention. Minorities and women are at greater risk for Alzheimer’s disease. Alzheimer’s Disease and Healthy Aging. Last reviewed Aug. 20, 2019. https://www.cdc.gov/aging/publications/features/Alz-Greater-Risk.html#:~:text=Current%20estimates%20are%20that%20about,65%20with%20younger%2Donset%20Alzheimer's
- World Health Organization. Dementia. Sept. 21, 2020. https://www.who.int/news-room/fact-sheets/detail/dementia#:~:text=Worldwide%2C%20around%2050%20million%20people,dependency%20among%20older%20people%20worldwide
- Coupland CA, Hill T, Dening T, et al. Anticholinergic drug exposure and the risk of dementia: A nested case-control study. JAMA Intern Med 2019;179:1084-1093.
There is a significant increase in dementia risk associated with the use of anticholinergic medications for three months or longer.
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