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CME / ABIM MOC

Challenges and Opportunities in Overactive Bladder Care: A Framework to Optimize Outcomes

  • Authors: Alan J. Wein, MD, PhD (Hon), FACS; Benjamin M. Brucker, MD; Nitya Abraham, MD; Craig V. Comiter, MD
  • CME / ABIM MOC Released: 9/29/2022
  • Valid for credit through: 9/29/2023
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  • Credits Available

    Physicians - maximum of 0.75 AMA PRA Category 1 Credit(s)™

    ABIM Diplomates - maximum of 0.75 ABIM MOC points

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Target Audience and Goal Statement

This activity is intended for urologists, primary care physicians, and obstetricians/gynecologists.

The goal of this activity is that learners will be better able to remain current on key evidence when making clinical decisions regarding the use of pharmacotherapy in the management of OAB.

Upon completion of this activity, participants will:

  • Have increased knowledge regarding the
    • Burden of adverse effects associated with anticholinergic therapy in patients with OAB
    • Role of beta-3 adrenergic receptor agonists in the management of OAB
    • Unmet needs surrounding the pharmacoeconomics of medications used to treat OAB
  • Demonstrate greater confidence in their ability to
    • Appropriately manage patients with OAB


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All relevant financial relationships for anyone with the ability to control the content of this educational activity are listed below and have been mitigated. Others involved in the planning of this activity have no relevant financial relationships.


Faculty

  • Alan J. Wein, MD, PhD (Hon), FACS

    Professor of Surgery (Urology)
    Emeritus Chief of Urology
    Associate Director, Residency Program in Urology
    University of Pennsylvania
    Philadelphia, Pennsylvania

    Disclosures

    Alan J. Wein, MD, PhD (Hon), FACS , has the following relevant financial relationships:
    Consultant or advisor for: Urovant
    Speaker or member of speakers bureau for: Urovant

  • Benjamin M. Brucker, MD

    Associate Professor
    Director of Urogynecology and Neurourology
    NYU Langone Health
    New York, New York

    Disclosures

    Benjamin M. Brucker, MD, has the following relevant financial relationships:
    Consultant or advisor for: AbbVie; Anteres; Watkins-Conti
    Speaker or member of speakers bureau for: Allergan; Anteres; Urovant
    Research funding from: AbbVie; Boston Scientific

  • Nitya Abraham, MD

    Associate Professor of Urology
    Co-Director, Pelvic Floor Center
    Montefiore Medical Center
    Bronx, New York

    Disclosures

    Nitya Abraham, MD, has the following relevant financial relationships:
    Speaker or member of speakers bureau for: Urovant (former)

  • Craig V. Comiter, MD

    Professor of Urology
    Professor of Obstetrics and Gynecology
    Stanford University School of Medicine
    Stanford, California

    Disclosures

    Craig V. Comiter, MD, has no relevant financial relationships.

Editor

  • Lisa Cockrell, PhD

    Medical Education Director, Medscape, LLC 

    Disclosures

    Lisa Cockrell, PhD, has no relevant financial relationships. 

Compliance Reviewer

  • Susan L. Smith, MN, PhD

    Associate Director, Accreditation and Compliance, Medscape, LLC

    Disclosures

    Susan L. Smith, MN, PhD, has no relevant financial relationships.

Peer Reviewer

This activity has been peer reviewed and the reviewer has no relevant financial relationships.


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    Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to 0.75 MOC points in the American Board of Internal Medicine's (ABIM) Maintenance of Certification (MOC) program. Participants will earn MOC points equivalent to the amount of CME credits claimed for the activity. It is the CME activity provider's responsibility to submit participant completion information to ACCME for the purpose of granting ABIM MOC credit. Aggregate participant data will be shared with commercial supporters of this activity.

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CME / ABIM MOC

Challenges and Opportunities in Overactive Bladder Care: A Framework to Optimize Outcomes

Authors: Alan J. Wein, MD, PhD (Hon), FACS; Benjamin M. Brucker, MD; Nitya Abraham, MD; Craig V. Comiter, MDFaculty and Disclosures

CME / ABIM MOC Released: 9/29/2022

Valid for credit through: 9/29/2023

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Activity Transcript

Alan J. Wein, MD, PhD (Hon), FACS: Hello, I'm Dr Alan Wein from the University of Pennsylvania. Welcome to this program titled "Challenges and Opportunities in Overactive Bladder Care: A Framework to Optimize Outcomes." In this program, you'll hear from several faculty who will discuss specific aspects of treating overactive bladder (OAB).

First, I'll spend some time providing some insight into the symptom syndrome of OAB, and the burdens associated with its inadequate control. It is not technically a disease. It is a symptom syndrome, the definition of which is urgency—that is the primary symptom—with or without urgency incontinence. How many people with OAB have incontinence, or wet OAB? Approximately one-third, and the remaining two-thirds have so-called dry OAB. This occurs usually with frequency (normal frequency is probably 7 or 8 times per day) and nocturia.

If urgency is really the primary definer of OAB, then what is urgency? The current definition from 2002 from the International Continence Society is a sudden, compelling desire to pass urine that is difficult to defer. Now, the previous definition included fear of urgency or pain. Pain we took out, because that really makes it more of an interstitial cystitis bladder pain syndrome than OAB. I am a little sorry that we took fear of leakage out because that is basically the way that I think of it. Does urgency always end in a void or a leak? No, it can be suppressed. In fact learning how to suppress it is part of the behavioral modification regimen to treat OAB.

This is the first epidemiologic study of OAB that was done in the United States, the NOBLE study. The age and sex prevalence of OAB is maybe not what you would expect in a population over 18 years of age. The prevalence was similar in men and women. There was a difference in OAB wet and OAB dry gender-wise. OAB wet with urgency urinary incontinence was more common in women in this study. OAB dry was more common in men, probably because the sphincter mechanism in men, which is a part of the behavioral modification regimen to try to suppress the symptoms of OAB, is stronger in men. Also the prostate adds to outlet resistance.

Quality of life is impaired in OAB, and the wetter you get, the worse the quality of life.

These are some other epidemiologic studies that show the prevalence of OAB. The EPIC study, which was also over the age of 18, men and women. The study from Finland, the same. And the EPILUTS study, which looked at people over the age of 40, the prevalence was higher. In that particular population, it was more prominent in women than in men.

There is no question about the fact that OAB impairs the quality of life. Everyone that has looked into this issue has come to the same conclusion. This is a slide that Diane Newman and I put together to show the various spheres of quality of life that are impacted. Starting at 12 o’clock and going clockwise, physical, psychological, social, domestic, even occupational, and of course, sexual.

These are the AUA treatment guidelines that Ben Brucker will go through with you in more detail. I just want to say that, personally, I use behavioral modification and oral pharmacologic therapy together. Now there have been studies by Kathy Burgio that show both in women and in men, the use of the 2 together (behavioral modification and oral pharmacologic therapy) is more efficacious than the use of either by itself.

We have not been terribly successful in managing OAB. Here is one of the reasons. The predominant therapy when this slide was produced, and actually also now I think as far as oral pharmacologics are concerned, is antimuscarinic therapy. You can see from this graph that regardless of the preparation, the compliance rate—the number of people who are still on the drug at the end of a year—is poor. It is around 20% and maximum 30%.

Why is that? Well, lack of efficacy, plus, the incidence of adverse events and probably a lack of follow up on our part. I think these people have to be followed frequently and encouraged in order to have the best results. But I think that you will agree that this is a pretty poor compliance rate.

Thanks so much for participating in this activity. Please continue on to the next section, where Ben Brucker will discuss some of the goals in the management of patients with OAB.

Benjamin M. Brucker, MD: Hello, I'm Benjamin Brucker. I'm an associate professor of urology and urogynecology at NYU Langone Health in New York City. I treat patients with OAB, both men and women. I'm excited to talk with you today. In this chapter, we will be considering some of the strategies and goals for the management of OAB.

I think any discussion about OAB probably deserves mentioning the American Urologic Association (AUA) treatment guidelines, which does provide recommendations for how we are supposed to diagnose and ultimately treat and follow our patients with OAB. The AUA guidelines lay out the treatment strategies into first-, second-, third-, and fourth-line therapies.

The first-line therapies revolve around behavioral therapies, bladder training, bladder control, things like pelvic floor muscle exercises, and then the ever important fluid management. Second-line therapies include pharmacotherapy. Pharmacotherapy traditionally had been done with anticholinergic medications, but newer renditions of the guideline do include beta-3 agonists, such as mirabegron and now vibegron. Third-line therapies include intradetrusor onabotulinumtoxinA, and nerve stimulation, both peripheral or sacral. Thankfully fourth-line therapies are really not all that commonly carried out today, but do include augmentation cystoplasty and even urinary diversion.

As we look at the amendments and start to dive into the guidelines with a little bit more of a fine-tooth comb, we start to realize that it is okay to combine first- and second-line therapies. There is a statement that says it is fine to combine them. I think all too often, if we use the step therapy in a very rigid way, we are a little hesitant to move on to pharmacotherapy, which ultimately may be needed for patients to get to their goals. Then we are stuck on the behavioral therapies. But it is okay to combine. As I mention second-line therapies, sometimes guidelines do lag behind a little bit and some of the new agents that come on board may not be in earlier renditions or earlier versions. We do have pharmacotherapy with both anticholinergic and beta-3 adrenergic receptor agonists. There is not really a statement that designates which one we should begin with.

If we consider the guidelines, one of the other things that I think is a bit sort of unique is the amendment in 2019 does call out the idea that these therapies are really in different tiers due to their invasiveness. It does not necessarily mean as clinicians we are stuck by having to go through first-line therapies and fail, then having to go through second-line therapies and fail before going to third and fourth. The invasiveness may be something that patients and clinicians and healthcare systems care about, but from a patient-doctor relationship, I think it is okay to individualize the care. It may even be the case that sometimes starting with later therapies or in certain cases, moving to a later therapy might be appropriate. With that said, we do know a lot of the data we have for how well drugs work or other therapies work, often we are beginning with some of the conservative therapies, such as fluid modification, behavioral modification, pelvic floor exercises.

One of the things that has come about in the last few years, and this goes back many years but the noise in the medical community has gotten a little bit louder, is the idea of trying to limit the cumulative burden of treatment and more specifically long-term anticholinergic burden. We know that anticholinergics can cause dry mouth and constipation, which obviously is annoying for patients. Anticholinergic medications are associated with falls and fractures, but the sort of concerning features that we are starting to see in the literature more and more revolve around the idea that there are neurologic issues such as delirium or impaired cognitive function, confusion, and even dementia that can come with chronic anticholinergic use.

These are anticholinergics in general and they do not necessarily specify bladder anticholinergics. The American Geriatric Society, Beers criteria includes recommendations for older adults, especially those with dementia and cognitive impairment or delirium to avoid drugs with strong anticholinergic properties. Many of the bladder medications that we have do show up in the growing body of literature that suggest that these drugs perhaps should be avoided in patients. The American Urologic Gynecologic Society statement in 2020 came out and really told providers to avoid anticholinergic medications in patients over the age of 70. There may be differences in the anticholinergic drugs. There definitely is probably a little bit more of a concern with drugs like oxybutynin, which have been studied a little bit more and are definitely more prevalent in terms of use. It turns out about 85% of prescriptions that are filled for OAB probably end up being oxybutynin.

While there are some anticholinergics which may have different properties, potentially being somewhat more protective or at least not as well studied, I think the reality of it is in terms of treating patients today, there are going to be a lot of patients that we are making a choice about trying to avoid anticholinergic burden and trying to treat their symptoms.

There has been a lot published now about anticholinergics and dementia. I would like to mention a study that got a lot of traction, probably because of its quality, that was published in JAMA Internal Medicine. What the study is showing is really the cumulative effect of anticholinergic medication, and looking at this dose effect where the anticholinergic burden does start to align and correlate with the burden, showing an increase in impact and the hazard ratio as well.

What is also somewhat concerning is there are going to be some patients that do not necessarily need a very long-term or large burden of treatment, and instead show effects right away. There was a study, and I see a lot of multiple sclerosis patients in my practice, where patients were asked to do a cognitive test, then given anticholinergics bladder medication, then do the cognitive test. And really in the short-term they started to have worse scores. This brings up the point that there may be some patients you are treating that are at higher risk of potentially the anticholinergic burden and these at-risk patients include those with neurologic conditions, cognitive issues, certainly my patients with a family history of cognitive disease, definitely those that are already suffering from dementia and Parkinson's disease, history of stroke, or transient ischemic attack, may be something that is important to realize.

Unfortunately, a lot of these patient populations do have a predisposition to develop OAB so we are often grabbing for these medications, even though there is a potential increased burden. The other patient population that is worth mentioning, which is a huge part of the patients that we are treating with incontinence from OAB, are those patients that are in long-term nursing facilities, such as nursing homes. Here too, we see that certainly there are going to be patients, as they get older, that may be more predisposed. As the burden does increase, so does the potential impact.

There are definitely barriers beyond the fear of cognitive issues that will keep patients from long-term OAB therapy. Anticholinergic medications in general are frequently associated with very poor rates of persistence and adherence. It is very common for patients to fall off of their medication, sometimes as soon as the first month, but certainly as you get to 6 months and 12 months. We do know, however, that adherence is a strong predictor of decreased healthcare costs in patients with OAB. I would actually argue that as we are being constantly rated and evaluated by our peers and by our patients, if a patient comes to see me for incontinence or an OAB, and I give a medication they are not taking and then you look at my outcome, supposedly as an expert in this, if my patient is not taking the medication, I do not think they are any better and I am not sure that I am going to perform any better in terms of getting them satisfied. And that's really a little bit of a conundrum for those treating physicians that are seeing a large volume of patients with OAB.

Mike Chancellor has published extensively on the idea of long-term anticholinergic persistence. I would highlight that the treatment failures in his study, and about 50% of patients by 3 months were considered treatment failures. This was the proportion of patients who discontinued therapy or switched anticholinergic medication. The treatment failures at 2 years went up to 90%. A large proportion of patients actually discontinue these medications permanently. And in this study from 2013, by 2 years, about 51% of patients have permanently discontinued medication.

We often talk about different anticholinergics and perhaps there are differences in properties, maybe some drugs are better tolerated and more efficacious. But the truth of the matter is most of the anticholinergic drugs we are using can have side effects that cause people to consider stopping their medications. In addition to side effects, there may be cost issues that drive patients not to necessarily want to stay on a medication, and then also lack of efficacy. Remember, these are drugs that should be helping patients by keeping them dry. We do see lack of persistence across all medications. So while even for blood pressure medications, there is a big drop-off, really anticholinergics and specifically the bladder anticholinergics have a tremendous drop off. Only about half of the patients show adherence of 80% or greater. High rates, upwards of 90%, of treatment failure are seen across all anticholinergic agents. There are some dermal or gel oxybutynin formulations that you would think, "Well, they may have fewer side effects; they may have less risk," but when you look at the overall persistence, those numbers really do not necessarily tease out the way you think that they would.

One of the barriers that I mentioned was side effects of medication. We do have a new class of medication, the beta-3 agonists, that seem to have a better side effect profile. This may be an opportunity if we are trying to optimize our outcomes in OAB patients and improve outcomes of using agents such as these.

There is a systematic review that exists and certainly I can then also share with you my personal experience, but the suggestion is that patients do fall off of beta-3 agonists. The systematic review does include mirabegron, and vibegron was not out at the time. Comparing it to some of the anticholinergic agents, overall persistence does drop off and adherence does drop off with all of the agents. But there is I think still a meaningful clinical improvement in mirabegron compared to some of the other drugs. The notable drugs that actually were associated in the anticholinergic group with maybe a higher persistence rate were solifenacin and fesoterodine. But we do know that over time this reduces. Adherence at one year was significantly higher in patients that were receiving mirabegron, which was the first-in-class beta-3 agonist, when compared to antimuscarinics.

Again, managed care and some of the issues that as clinicians we run into is even if we know this medication, the question is, can we plead our case? I love the fact that many of you are joining this webcast and this series and trying to understand the impact and hopefully can advocate for our patients so that we can get better coverage to medications that are more effective, potentially not only from the efficacy standpoint, but actually from the adherence standpoint, which is going to get patients drier and hopefully happier.

So when it comes to the goals of management of OAB, the guideline that I mentioned at the start of this talk is incredibly clear that we have to have really clear expectations. If a patient is not at their goal, then it is important that we continue to work toward the goal. It may be possible for patients to say, "Hey, I want to be cured of this," knowing that there may not be an actual cure, but it does not mean we should not be pushing to try to get things better. So what does that mean in terms of optimizing our outcomes? If a patient starts with first line therapies or an agent, it is okay to add another therapy, add another agent, or in some cases, progress to other therapies or combination therapy. It is one of those things where if we are not going back to patients and checking in to say, "Hey, are we at our goal?", then are we really being successful?

I will leave you with the algorithm from the AUA/SUFU guideline. Obviously we are getting to the point where we are using pharmacotherapy and you can see an arrow directly to treatment goals met. If treatment goals are not met, then I would urge you to say, "Okay, well, what can we be doing differently?" If you find out that your patient is not following up to get to the treatment goal or they are on a medication that is persistently causing side effects like dry mouth or constipation, then it may be worth using a different agent combination or even considering moving on to an advanced therapy.

With that, our time comes to a close. There is never enough time to talk about OAB, a topic that I am very excited about and I hope many of you are. I would like to thank you for taking the time participating in this activity. Please continue to the next section where Dr Nitya Abraham will discuss the use of beta-3 agonists, which I had alluded to a little bit in this talk, for treating OAB. I would like to thank you and I hope you enjoyed.

Nitya Abraham, MD: Hello. My name is Nitya Abraham. I'm an associate professor of urology at Montefiore Medical Center in the Bronx, New York. In this chapter, we will review some of the data regarding the beta-3 agonists, the newest class of agents in the management of OAB.

First, let's talk about bladder physiology. Bladder storage is mediated through the sympathetic nervous system. Norepinephrine is released from the hypogastric nerve and stimulates the beta-3 adrenergic receptors, ultimately resulting in relaxation of the bladder smooth muscle. When the bladder volume reaches a certain threshold, and it is a socially appropriate time to void, the pontine micturition center initiates voiding. Through parasympathetic innervation via the pelvic nerve, acetylcholine is released, stimulating the muscarinic receptors in the bladder, specifically the M2 and M3 receptors, ultimately resulting in contraction of the bladder smooth muscle.

In OAB, there are involuntary contractions during the storage phase. A therapeutic target are the beta-3 adrenergic receptors, since stimulating these receptors can cause bladder smooth muscle relaxation, and ultimately, increased capacity. Ninety-seven percent of the beta-adrenergic receptor subtypes in the bladder are the beta-3 subtype. You may be wondering, where are the beta-1 and beta-2? Beta-1 receptors are found in the heart and kidney, and beta-2 receptors are found in vascular smooth muscle and skeletal muscle.

There are 2 beta-3 agonists that are FDA-approved for the management of OAB. Mirabegron was approved in 2012, and vibegron was approved in 2020. Both are approved for the treatment of OAB in adults, with symptoms of urinary incontinence, urgency, and urinary frequency. They work by acting on the beta-3 receptors in the bladder. The dosage for mirabegron is 25 milligrams once a day, and can be titrated up to 50 milligrams. For vibegron, the dosage is 75 milligrams a day, no titration needed. You do need to make dose adjustments for renal or hepatic impairment with mirabegron; no adjustment needed for vibegron.

There are 3 main phase 3 trials to be aware of with regard to mirabegron: the SCORPIO, ARIES, and CAPRICORN trials. All 3 of these were pretty similar, in that they compared mirabegron to placebo, but used varying doses in some of the trials. In the SCORPIO trial, mirabegron was also compared to tolterodine. The co-primary endpoints were the same in all the trials, the reduction in the number of voids per day, and the number of incontinence episodes for 24 hours, by the 12th week of treatment. They also looked at adverse events.

The main takeaway of these phase 3 trials was that mirabegron decreased the number of voids for 24 hours and the number of leakage episodes for 24 hours, in comparison to placebo, almost 2 fewer voids and 2 fewer incontinence episodes.

What about safety or side effects? A common reason that people stop antimuscarinics is because of side effects, especially dry mouth and constipation. There was a systematic review that was done that compared many of the antimuscarinics that are available to mirabegron. When looking at dry mouth, they found that all the antimuscarinics had a higher odds ratio for dry mouth, compared to mirabegron. The only exclusion was placebo. When looking at constipation, similarly, they found that there were certain agents that had a much higher odds ratio of causing constipation compared to mirabegron. Whereas, some agents, they had similar odds ratios of constipation. Another concern in using mirabegron is in patients with poorly controlled hypertension, as there is worry about increases in blood pressure.

The key trial looking at the efficacy of vibegron was the EMPOWUR trial, which was a phase 3 international, randomized, double-blind trial. This included adult patients with OAB, who had at least eight or more voids per day. What was really interesting about this trial is that they had up to 25% of patients who had OAB dry, with no leakage episodes. It was almost 1,500 patients randomized to either vibegron, placebo, or tolterodine. The main outcomes that they looked at were changes from baseline in the number of micturitions or voids per day, and changes in the number of leakage episodes per day.

They found that there was a statistically significant decrease in the number of voids and leakage episodes for vibegron compared to placebo. This was seen as early as at 2 weeks of treatment, and continued up through the twelfth week of treatment. Other endpoints that they looked at were decreases in the number of urgency episodes per day, increase in the average volume voided, and the proportion of those with OAB wet who had at least a 75% or more reduction from baseline in urge incontinence episodes per day. For all 3 of these endpoints, they found that vibegron had statistically significant improvement, compared to placebo, through the twelfth week of treatment.

What about adverse events? This is a reason why many patients stop taking medications. Well, in the EMPOWUR trial, they found that compared to placebo and tolterodine, the overall rate of adverse events was quite low.

Patient reported outcomes are key. Do patients feel like this treatment works? The EMPOWUR trial did look at several parameters, such as coping, concern, sleep, social interaction, and health-related quality of life. They found that vibegron improved all of these parameters compared to placebo. On a Patient Global Impression of Improvement questionnaire, at week 12 they found a statistically significant improvement for vibegron compared to placebo. Patients do feel that it works and improves their quality of life.

The EMPOWUR trial also looked at the elderly population, and these are our patients who are especially burdened by OAB. They looked at patients who were over the age of 65, and even over the age of 75. When it came to efficacy and adverse events, they found similar results, compared to the overall population. So the treatment is efficacious and safe in the elderly.

Finally, are there any differences between mirabegron and vibegron? There have not been any head-to-head comparisons, but there are certain differences. For example, vibegron is selective for the beta-3 receptor, while mirabegron can stimulate the beta-1 receptor at high doses. As far as drug-drug interactions, there is no clinically significant difference with vibegron and other drugs, but there may be some differences in drug-drug interactions with mirabegron and other drugs.

Overall, this is an important therapeutic option for patients with OAB, given its efficacy and side effect profile. Thank you for participating in this activity, and please continue on to the next section.

Craig V. Comiter, MD: Hello, my name is Dr Craig Comiter, and I am a professor of urology and a professor of obstetrics and gynecology at Stanford University Medical School. Today, I am going to talk about some strategies to improve collaboration between payers and providers in the management of overactive bladder.

Second-line therapy is really the first point in the treatment algorithm where medication with its potential side effects is introduced, but there is an increasing amount of evidence that highlights the association between anticholinergic use and negative cognitive side effects, including dementia. The beta-3 adrenoceptor agonists have fewer cognitive side effects compared with anticholinergics, which leaves providers in a potentially awkward position and patients facing the unenviable decision of, is it worth the monetary cost, or should I go with a higher risk, but less expensive medication? This is an untenable situation. In addition, many insurance payers require multiple trials of second-line therapy, including those which risk the development of permanent cognitive dysfunction, thereby delaying progression to third line therapy despite the AUA/SUFU Guidelines, which specifically recommend third line therapy after pharmacologic failure.

Several studies show that the patient compliance and adherence is typically better for the beta-3 agonists compared with anticholinergics, and this difference in adherence rates is related to a couple of factors. Firstly, there is a different side effect profile. Each medication has its own rates of adverse events. Dry eyes, constipation, and dry mouth are experienced 10-times more frequently with anticholinergic medications compared to beta-3 agonists, 24% versus 2%. New onset or worsening hypertension is a unique side effect of mirabegron occurring at about 2%. However, and most notably, the beta-3 agonists do not demonstrate the same risk of dementia when compared with the anticholinergics.

Therefore, most female pelvic medicine and reconstructive surgery providers recommend that it is preferable to start oral overactive bladder treatments with a beta-3 agonist and monitor for hypertension. This is a rare, benign, and completely and immediately reversible side effect, unlike the cognitive dysfunction that can occur with anticholinergics. The quaternary amine trospium has shown limited passage across the blood-brain barrier. Although short-term data shows no change in cognitive function compared with placebo after taking trospium for four weeks, long-term data are insufficient to confirm long-term safety.

Thus, prescribing these central nervous system-sparing anticholinergic formulations in an attempt to decrease the risk of dementia in patients is not well supported by current data. However, current prescribing patterns do not reflect these differences in medication side effect and safety profiles. An analysis of insurance claims databases suggests that anticholinergics were the most commonly dispensed medications for overactive bladder at 88% versus only 12% who were prescribed beta-3 agonists.

A recent study of overactive bladder prescribing patterns showed that before advancing to third-line therapy, 96% of women tried anticholinergics compared to only 30% of women who tried beta-3 agonists. It seems obvious that these adverse prescribing practices are at least in part attributable to the high cost of beta-3 agonists within our US healthcare system. The out of pocket price for a 30-day supply of mirabegron 25 mg was $407.93 compared to a 30-day supply of oxybutynin extended-release 10 mg at only $16.70.

In a registry of patients receiving treatment for overactive bladder, patients either without insurance or who have government assisted insurance, they were more often prescribed anticholinergics than mirabegron compared to patients who have private insurance. The kindness that the prescribers are trying to demonstrate in considering out-of-pocket cost to the patients leads paradoxically to favoring a treatment that carries a burden of higher risk and a lower chance for adherence for this most vulnerable population. Most healthcare professionals in the United States are indeed aware of the inequities in our healthcare system.

Not only do we navigate the challenges with the uninsured, but even among those who carry insurance, there are significant variations in formulary structure and utilization management policies that result in these cost variations for overactive bladder medications. These formulary structures are not random. And even when medications are covered, there is different out-of-pocket expenses. These more expensive copays or out-of-pocket costs prohibit a subset of patients from access to the medications that may ultimately be safer for them. Thus, the prescriber and the patient who already have to balance the risks and the benefits of pharmacotherapy are now forced to weigh that third variable cost.

In a disease state such as overactive bladder where progression to third-line therapy is less than 10%, the addition of high treatment cost creates yet another hurdle. After all, despite the high efficacy and the high safety profile of third-line therapy, patients may be denied coverage for third-line therapy until they have failed multiple second-line medications. Each of these medications may have the risk of cognitive dysfunction and they may be prohibited from trying beta-3 agonists due to cost constraints.

Thus, we have created a barrier where patients may find second-line therapy either unacceptable due to the medication risk profile or inaccessible due to the expense of the therapy. Access and cost can supersede the shared decision-making between the patient and the physician, but understanding these clinical and these systemic barriers in treating overactive bladder can grant us as health professionals insight to an equitable solution. What could this solution be? To repair the overactive bladder treatment algorithm, there needs to be collaboration among the key stakeholders. Who are these stakeholders?

There is the individual healthcare professional. The prescribers should discuss beta-3 agonists as an equally effective option with fewer side effects than anticholinergics. When we see the patient, we must give them the data that anticholinergics and beta-3 agonists work equally well, but they differ by side effects and risks. Obtaining prior authorization or fulfilling pretreatment requirements, as dictated by the insurance payers, can be burdensome to the physician and her or his office. Establishing a workflow for prior authorizations and designating individuals to directly work with patients to obtain beta-3 agonists at the lowest cost are two management strategies.

Healthcare professionals can create toolkits of pre-templated prior authorization requests, premade templates for appeals letters, and a document containing key points to emphasize in peer-to-peer evaluations that demonstrate the associated cognitive risks with anticholinergic medications. In circumstances where insurance coverage is still denied, the provider should consider going straight to third-line therapy. Remember, third-line therapy is indicated if patients fail or are unable to tolerate pharmacotherapy.

Professional societies are another stakeholder. These societies can appropriately modify existing guideline statements to include this new and the evolving evidence. For example, the 2019 Joint American Urological Association and Society of Urodynamics, Female Pelvic Medicine and Urogenital Reconstruction OAB guidelines update stated that either anticholinergics or beta-3 agonists or a combination of both may be used in the second-line pharmacologic treatment of overactive bladder.

The American Urogynecologic Society, AUGS, took this even one step further. And in 2020, they published a document that actually recommended against the use of anticholinergics in those older than 70, and they favor beta-3 agonists for this vulnerable population and third-line therapies for these older folks. Establishing consensus among professional societies should and will help to clarify these best, which means safest and most preferred, practices. These are best practices that healthcare professionals should follow, and it is logical that coverage by payers would follow.

Should not the compelling data that questions the safety of anticholinergic medications warrant a true reevaluation and restructuring of overactive bladder medication formularies? Why is this not happening? At present, patients are frequently required by insurance payers to trial one or even two or three anticholinergic medications before qualifying for third-line therapy, or even before qualifying for alternative second-line treatments, such as beta-3 agonists.

These necessary changes could be cost neutral for insurance companies. They do not have to hurt that major stakeholder. This is supported by a 2016 analysis that estimated the beta-3 agonist mirabegron was a cost effective treatment for overactive bladder when you took into consideration the commercial health and Medicare Advantage plans. This was largely due to decreased healthcare utilization associated with lower anticholinergic burden. Of note, this model did not even include that anticholinergic burden is related to cognitive dysfunction. If it had included the new data on cognitive dysfunction, it would be even more cost effective.

The potential downstream decreased costs of beta-3 agonists as a result of the decrease anticholinergic burden and cognitive side effects must be incorporated into the overall formulary structure and the pricing of beta-3 agonists. Thank you.

This transcript has been edited for style and clarity.

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