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Ruchika Talwar: Hi, everyone. Welcome back to UroToday's Health Policy Center of Excellence. As always, my name is Ruchika Talwar, and I'm really excited to be joined today by Dr. Avery Braun, who is a urologic oncology fellow at UCSF. Thanks so much for being here with us today, Dr. Braun.

Avery Braun: Thank you. I am pleased to be here. I'm really excited about the opportunity to talk about our work.

Ruchika Talwar: So she'll be discussing work that was recently published in the Gold Journal surrounding the use of anticholinergic medications in prostate cancer patients.

Avery Braun: Thank you, Dr. Talwar, for the very kind introduction. I'm really excited about the opportunity to present some work I've done at UCSF looking at common urologic medications and the onset of dementia in men with prostate cancer, who are managed throughout the spectrum of different primary treatment modalities. So this work really builds on multiple things, but a growing understanding of how different medications may impact the risk of dementia. And specifically, looking at in the prostate cancer world, there have been great advancements in the diagnosis and treatment of prostate cancer. And there's a growing portion of men that are living decades after primary management. These men may often be prescribed PDE5 inhibitors or anticholinergics to manage treatment-related erectile dysfunction or overactive bladder. It is important to note that these men also, as they age, carry an innate risk of development of dementia because these diseases disproportionately affect older patients.

The literature to date has conflicting reports on if and how PDE5 inhibitors or anticholinergic exposure may impact the risk of dementia onset. Understanding if there is a unique relationship between these medications and the risk of dementia in this context is a priority. Therefore, we sought to assess the association between PDE5 inhibitors and anticholinergic usage with dementia onset in men with prostate cancer, comparing between users and non-users who underwent different primary treatment modalities. Using the CaPSURE national database, the cohort comprised men at least 50 years of age at the time of diagnosis for prostate cancer, who underwent primary management with either radical prostatectomy, radiation therapy which included external beam radiation or brachytherapy, primary androgen deprivation, or active surveillance/watchful waiting. Here, we had at least five years of post-treatment follow-up and we excluded men with a preexisting history of dementia. Our primary outcome was the onset of dementia at least 12 months after primary treatment.

We performed univariable competing risk regression models to assess which characteristics at diagnosis were associated with the risk of dementia onset, with all-cause mortality treated as a competing risk. Then we performed competing risk regression modeling for patients matched on medication-specific propensity score, to determine the association between each medication exposure and the risk of dementia onset. Now going into some of the key findings from our paper. From the CaPSURE cohort that included over 15,000 patients, 5,937 were included in our final cohort. The group was notably predominantly white, at 90%, with a younger median age of 66 years. The cohort comprised an overall healthy cohort that was non-smokers with few comorbidities as listed on the page. Primary treatment modalities are also listed. Interestingly, 53% of men were exposed to PDE5 inhibitors while only 14% received anticholinergics. Those that were PDE5 users compared to non-PDE5 users were younger and healthier, with less cardiovascular disease, history of stroke, diabetes, and also were more likely to be treated at an academic center with a radical prostatectomy.

In comparison, anticholinergic users, compared to non-anticholinergic users, were older and had a higher incidence of those comorbidities and were more likely to undergo radiation. On unadjusted analysis, 248 men were diagnosed with dementia with a cumulative incidence of 6.5% at 15 years. The median onset for dementia was 145 months. On initial univariable competing risk modeling, only age per 10 years was associated with the risk of dementia. On multivariable competing risk modeling for patients matched on propensity score for medication use, PDE5 use, as well as anticholinergic use, were not associated with dementia risk. When propensity-matched models were stratified by treatment-specific modality, again, neither PDE5 use nor anticholinergic use was associated with dementia onset in this group. In conclusion, the use of PDE5 and anticholinergic medications did not appear to be independently associated with the risk, either increased or decreased, of dementia onset in this cohort of prostate cancer patients treated across treatment modalities. However, dedicated prospective investigations are still warranted. Thank you.

Ruchika Talwar: Thanks, Avery. That was a really great deep dive into what I consider to be a very important topic for a few reasons. So first of all, there's been an increased interest in looking at the effect of anticholinergics, specifically on dementia risk. And there are a couple of interesting findings I wanted to highlight and pick your brain on a bit more. So first, I think it makes a lot of sense that you have younger, healthier patients on the PDE5s while you have older patients, and those patients who may have been more likely to undergo radiation, on the anticholinergic medications.

However, if you think about the risk of dementia, that often correlates with the patients who you would want to put on anticholinergics, to improve their quality of life. Now, the reason your study caught my eye is that there's been a lot of discussion on the dementia risk associated with the medication. So I really wanted to highlight this literature to reassure our population of urologists that there may not be as high of a dementia risk as is advertised. And certainly, we shouldn't be deprioritizing quality of life without an extensive discussion. Now, the caveat is obviously, as you mentioned, this is not a prospective study. It's limited. But it does start to shed a little bit of light on this question from a different perspective. So tell me your thoughts on that. What are your main takeaways?

Avery Braun: Yeah, I think first and foremost, I think it's really important to get literature published even with null results. I think just like you said, it can provide a degree of reassurance for providers. I think we initially went into this work more from the PDE5 inhibitor angle. There's been a lot of interesting work recently regarding the ill-defined and unknown underlying mechanism for dementia, and the idea that the phosphodiesterase inhibitor pathway may actually be helpful. So initially, the work was to try to look at whether these men are already on this medication. Is it protective in any way? And then it spun off exactly like what you said. We're getting more and more cautious with an AUA white paper, really encouraging judicious and careful use of anticholinergics. We wanted to look into whether there was any association of higher risk for these men that might be on anticholinergics.

I think the largest takeaway, like you said, is that we need to be very careful in how we extrapolate the results from this. It is very limited. But I think we measured everybody, or to be included, they had to be on the medications for at least three months. And due to how CaPSURE is structured, we struggled a little bit with full duration, and a lot of the studies have been on total usage based on days or months, and how we're structured is limited in capturing that. So I think largely, we want to provide reassurance that for short-term use, there doesn't seem to be an increased risk. And exactly like you said, we should be providing quality care. And so I think for those patients that are having symptoms longer, getting them plugged in with the right people to manage that sooner instead of continuing medication. But I think the largest takeaway is that perhaps there is a safe window. Further work needs to be done to define what that window may be, but that we need to balance everything.

Ruchika Talwar: Yeah, that's a key point there, that especially for patients who are having acute lower urinary tract symptoms, perhaps during the time period of radiation, anticholinergics may be a good way to go, especially because some of those anticholinergics that have been associated with dementia are actually cheaper. They're generics. Certainly, they can get patients through that acute window, and perhaps as patients are able to explore other ways to improve the financial toxicity associated with some of those newer novel medications that help with LUTS, it's a good alternative. So I think that's a great point. I think we do have to be cautious, as you said, in how we interpret this kind of data overall. But you're right. Publishing these sorts of null studies is really important, and we certainly don't do it enough both in the retrospective observational space and in the clinical trial space as well. So thank you for presenting your work, and thank you for making sure that it does get published, despite the fact that oftentimes these studies are abandoned by investigators because they think that there's not a positive result here, no one would be interested in the findings.

Avery Braun: Absolutely. No, thank you for the opportunity to highlight it. Like we've mentioned, I think it is important and it can help guide providers through some of the care for our patients.

Ruchika Talwar: Great. And to our UroToday audience, thanks so much for joining us. We hope to see you next time.