By Chiara Ghetti, MD

Associate Professor, Obstetrics and Gynecology, Division of Female Pelvic Medicine and Reconstructive Surgery, Washington University School of Medicine, St. Louis

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 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 2,092 articles identified on search, 1,990 were screened based on title and abstract. Of these, 316 were assessed by full text; 21 met inclusion criteria and underwent qualitative analysis. A higher 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 included sufficient studies (six of nine) 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% CI, 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% for anticholinergics vs. nonuse. Three studies reported anticholinergic dosing data; using these studies, any anticholinergic exposure was associated with increased incident dementia vs. no anticholinergic exposure. Two studies specifically examined the role OAB medications played in 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. It affects more than 50% of women.1,2 Still, 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. 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 shown efficacy.3 Pharmacotherapy can be used concomitantly with these measures or used as the next step in women for 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. Some insurance plans require a trial of pharmacotherapy before 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 vs. placebo.4 Combined therapy with behavior modification has shown more efficacy 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 report side effects; most commonly, these medications produce peripheral anticholinergic effects, including dry mouth and constipation. Thus, discontinuation is common. It is important to keep in mind these medications produce 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.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. They estimated 10% of dementias could be attributable to this exposure. Clinicians must strongly consider these associations before prescribing antimuscarinics. Although we may be most familiar with antimuscarinic bladder medications, patients often are 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 before prescribing antimuscarinics may aid 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. Clinicians can affect the long-term well-being of women and help educate patients and colleagues as we work toward deprescribing antimuscarinic medications for the management of urge incontinence.

REFERENCES

  1. 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.
  2. Minassian VA, Stewart WF, Wood GC. Urinary incontinence in women: Variation in prevalence estimates and risk factors. Obstet Gynecol 2008;111:324-331.
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  6. Centers for Disease Control and Prevention. Subjective cognitive decline – A public health issue. Alzheimer’s Disease and Healthy Aging. Last reviewed Feb. 27, 2019.
  7. 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.
  8. World Health Organization. Dementia. Sept. 21, 2020. https://bit.ly/3xhWPY1
  9. 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.