Patients using anticholinergic medications for the management of overactive bladder (OAB) are at increased risk of new-onset dementia compared with individuals treated with the beta-3 agonist mirabegron (Myrbetriq), according to findings of a new population-based, retrospective study 

The research, which was conducted by Blayne Welk, MD, MSc, and Eric McArthur, MSc, both of Western University in London, Ontario, Canada, compared matched cohorts of patients who were newly prescribed an anticholinergic agent or mirabegron for OAB. By Cox proportional hazards modeling, the investigators found a statistically significant, 1.23-fold increased risk of new-onset dementia in the anticholinergic-treated group. The difference in the event rate between the two groups was 1 case per 137 person-years.

Welk, an associate professor of surgery (urology) at Western University, told 

, “The increase in the absolute risk of dementia associated with the anticholinergic agents appears small. Nevertheless, it may be a consideration when selecting medications for treating OAB, particularly in patients concerned about cognitive changes.”

Welk observed that previous studies have raised concern about an association between anticholinergic medication use and dementia. Protopathic bias, however, may be a limitation of those studies because their methods do not rule out that patients were using anticholinergic agents to manage urinary symptoms that were prodromal of dementia.

“Our study is unique because it specifically looks at anticholinergic medications that are commonly used by urologists to treat OAB, and we believe it is the first to study the risk of dementia with anticholinergic medications by using a comparator group treated with a nonanticholinergic medication, mirabegron, for the same condition,” Welk said.

Patients included in the study were identified via linked administrative databases that were searched for new users of an anticholinergic agent or mirabegron to treat OAB. A propensity score was created to match the anticholinergic and mirabegron users, taking into account 75 baseline characteristics, which included demographic features, medical comorbidities, other medications, and prior health care utilization.

A total of 47,324 patients prescribed oxybutynin (Ditropan), tolterodine (Detrol), solifenacin (VESIcare), darifenacin (Enablex), fesoterodine (Toviaz), or trospium (Sanctura) for OAB were matched to 23,662 new users of mirabegron. The patients in each group had a mean age of 73 years and included a slight predominance of women (55.5%). The median prescription duration was twice as long for the anticholinergics compared with mirabegron, 30 vs 60 days.

New-onset dementia, which was identified using a validated administrative data definition, occurred among 3.3% of anticholinergic users during 38,069 patient-years of follow-up and 2.6% of mirabegron users during 17,755 patient-years of follow-up. The new-onset dementia event rate was 41.3/1000 person-years in the anticholinergic group and 34.0/1000 person-years among the mirabegron users.

Dementia risk similar among anticholinergics

Tolterodine, including both immediate-release and long-acting formulations, was the most commonly used anticholinergic agent (40%) followed by oxybutynin (29%) and solifenacin (26%). In an exploratory analysis, the risk of dementia did not vary between the different anticholinergics.

“Some previous studies suggest that oxybutynin in particular causes cognitive impairment, but we did not find that association,” Welk said.

Additional analyses compared rates of new-onset dementia between anticholinergic and mirabegron users with patients categorized into subgroups according to various demographic and clinical characteristics. The results showed that the risk of dementia development with anticholinergic treatment was highest among men and in patients aged 75 years or younger.

“These findings of significant effect modification are novel and should be investigated further in the OAB population,” Welk said.

Articles

Patients using anticholinergic medications for the management of overactive bladder (OAB) are at increased risk of new-onset dementia compared with individuals treated with the beta-3 agonist mirabegron (Myrbetriq), according to findings of a new population-based, retrospective study published online March 13, 2020, in BJU International.

Study adds to evidence linking anticholinergics, dementia

In a study presented at the 2020 Genitourinary Cancers Symposium, researchers examined real-world outcomes for patients with metastatic castration-resistant prostate cancer treated with radium-223 (Xofigo). Study author 

, assistant professor of medicine at UC San Diego Health, discusses this study and its significance in the castration-resistant prostate cancer landscape.

 Please discuss the rationale for this study.

Radium-223 is a liquid radiopharmaceutical that has been shown to improve survival in patients with advanced prostate cancer. It’s specifically used for patients who have bone metastases, may have symptomatic bone pain, and don’t have visceral metastases. Results from the ALSYMPCA trial demonstrated the improvement of overall survival with this agent.

However, there’s not really been a lot of real-world data documenting how this agent is used in the changing landscape for metastatic castration-resistant prostate cancer. Since the ALSYMPCA trial, we’ve seen approvals of several androgen receptor (AR)-targeting agents and potentially PARP inhibition in the future, so placing radium-223 in the context of real-world practice has not really been established. The rationale for this study was to characterize the utilization of radium-223 within the real world.

 What did the results of the study show about the timing of initiating radium-223?

In the study, we included a total of 220 patients who had received radium between 2013 and 2017. We wanted to look at the characteristics of those patients who had received radium pre chemotherapy versus post chemotherapy. About half of our patients had received radium pre and half post chemotherapy on average.

We showed that when radium-223 was given prior to chemotherapy, it did not influence the amount of chemotherapy that any individual patient could receive. There have been some data suggesting that if you give radium pre chemo, their counts may not be sustained or they may have reasons for them to not actually receive all cycles of chemotherapy. In our data, we demonstrated that the median number of chemotherapy cycles given when radium was given either pre or post chemotherapy was 9 for both groups, and it did not seem that radium affected how much chemotherapy any one patient was able to receive.

The other thing we showed was that if radium was given pre chemotherapy as opposed to post chemotherapy, it was more likely that any individual patient would be able to complete all 6 cycles of radium-223. It’s given intravenously every 4 weeks for up to 6 doses, and it was more likely for a patient to complete all 6 cycles if radium had been given first and chemotherapy given second.

 What were some of the lessons learned from this study?

The biggest lesson learned was about placement of radium. This trial was not meant to examine what is the proper sequence of treatment but instead suggests that there is no increased toxicity or increased decline in the amount of chemotherapy that somebody may receive when they’ve received radium first.

The other thing that we did was characterize how radium is used. How many people are getting radium as a monotherapy; how many patients are getting radium in combination with another agent? Looking at real-world practice patterns, about 40% of patients are getting radium-223 in combination with an AR-targeting agent, the majority of which is enzalutamide (Xtandi). That’s not necessarily on-label use of radium, but in real-world practice there is this use of the concurrent AR-targeting agents. Also, with the ERA data, it’s important to stress the importance of using a bisphosphonate or bone-strengthening agent when radium is used and just the risk of fragility fractures. That’s why the two are used together.

It was a good study to paint the landscape of how we utilize radium in the real world and provide some instruction to clinicians regarding placement of radium for patients with metastatic CRPC. 

 Are there any other kinds of real-world analyses that you would like to see conducted with radium-223?

That is a good segue to the project that we’re doing. There has been a lot of excitement around the DNA repair pathway in prostate cancer. Given that radium is an alpha particle that induces DNA damage in cells within the bone niche, we began thinking about synergy in the context of those who have homologous recombination deficiency (HRD). For our next project, we’re working from this data set to look at outcomes in HRD-mutated versus -nonmutated patients. 

 Were there any other takeaways from this study for clinicians?

When we think about CRPC and we look at the data that’s out there, I think real-world data are important. What we are understanding is that CRPC is probably an undertreated disease. A lot of patients may see first-line therapy for CRPC, but there are a lot of patients who never see second- and third-line treatments. These agents have been shown to improve overall survival; radium-223 demonstrated an OS benefit in a large phase III study. I think the first step for any practicing clinician is to actually treat CRPC patients. There may be reasons to not treat somebody, but these drugs are life-prolonging agents, and with a lot of drugs moving into the castration-sensitive space, the treatment options for CRPC are decreasing. Radium-223 is a good agent to use for those patients who have bone metastases and have castration-resistant disease.

Disclosures: Bayer provided funding for the

Medivation, Bristol-Myers Squibb, Dendreon, Exelixis, Janssen, Novartis, Pfizer, and Tempus. For full disclosures, see 

In a recent study, researchers examined real-world outcomes for patients with metastatic castration-resistant prostate cancer treated with radium-223 (Xofigo). Study author Rana R. McKay, MD, of UC San Diego Health, discusses this study and its significance in the castration-resistant prostate cancer landscape.

Pre-chemo radium-223 does not affect chemo regimens

The CARES Act has many features designed to provide relief during the coronavirus disease 2019 (COVID-19) pandemic. What are the most important features I should know?

On March 27, President Trump signed into law the Coronavirus Aid, Relief, and Economic Security (CARES) Act in an effort to support US businesses and families. The bill was extensive and wide reaching.

The following details are the most important for individuals to know:

• Payments of $1200 (single/head of household) and $2400 (joint filers) will be sent to taxpayers within certain income limits. An additional $500 payment is available for each qualifying child. These payments will be determined based on your most recently filed tax return or Social Security benefit statement, if no return was filed. The amount of the payment is reduced by 5% of the amount by which income exceeds $75,000 (single), $112,500 (head of household), or $150,000 (joint filers).

• Required minimum distribution (RMD) rules are waived for 2020 distributions from IRAs, including inherited IRAs, and 2019 distributions taken in 2020, which had a required beginning date of April 1, 2020. RMDs are also waived for 2020 distributions from certain defined contribution plans including 401(k), 403(b), 457(b), and IRA-based plans.

• Distributions from IRAs and qualified retirement plans of up to $100,000 received during 2020 for COVID-19–related purposes are allowed without a 10% penalty for individuals aged below 59.5 years. They are taxable evenly over 3 years beginning with the year of distribution and may be recontributed within 3 years. Related purposes include a COVID-19 diagnosis for you, your spouse, or dependent, and financial hardship as a result of business closures, reduced work hours, layoff, furlough, or lack of childcare.

• Loans of up to $100,000 or 100% of the account value, whichever is less, are allowed from qualified retirement plans.

• Student loan payments and accrual of interest under certain federal loan programs are suspended through September 30, 2020.

• A charitable deduction of up to $300 is allowed for those who do not itemize their deductions. The adjusted gross income limitation is waived, allowing you to offset more of your taxable income. These two items apply only to cash contributions and are not available for contributions to donor advised funds or other supporting organizations.

COVID-19 and market fluctuation: What you should do

Provisions that may impact physicians in particular include the following:

• Small businesses, including medical practices, with no more than 500 employees are eligible to apply for the Small Business Administration (SBA) Payroll Protection Program. This allows a small business to apply to an SBA-approved lender for a loan of up to 250% of its average monthly payroll costs to cover 8 weeks of payroll, as well as help with other expenses like rent, mortgage payments, and utilities. The maximum loan amount is $10 million. Sole proprietors, independent contractors, and other self-employed individuals are eligible. A loan can be forgiven based on the business maintaining employee and salary levels. For any portion of the loan that is not forgiven, the terms include a maximum duration of 10 years and a maximum interest rate of 4%.

• Employers and self-employed individuals may defer payment of the employer share of applicable Social Security taxes beginning on the date of enactment through the remainder of 2020. The deferred amount may be paid over 2 years, half in 2021 and half in 2022. These taxes are being deferred, not forgiven, so businesses should be mindful about planning to pay these tax liabilities when they are eventually due.

• $100 billion has been made available through the Public Health and Social Service Emergency Fund to provide immediate financial relief by covering nonreimbursable expenses attributable to COVID-19. Health care entities, including physician practices, that provide health care, diagnoses, or testing are eligible. Nonreimbursable expenses attributable to COVID-19 qualify for funding. Examples include increased staffing or training, personal protective equipment, and lost revenue. 

• Physicians who provide volunteer medical services during the public health emergency related to COVID-19 have liability protections. These new protections are in addition to those provided by the Volunteer Protection Act of 1997.

The information in this column is designed to be authoritative. The publisher is not engaged in rendering legal, investment, or tax advice.

The bill provides coverage of nonreimbursable expenses attributed to COVID-19, writes Jeff Witz, CFP.

Vol 48 No 5

Study adds to evidence linking anticholinergics, dementia

Pre-chemo radium-223 does not affect chemo regimens

CARES Act: Here’s what physicians should know