SES AUA 2013: Session Highlights - Management of refractory overactive bladder (OAB)

WILLIAMSBURG, VA USA ( - Dr. Eric Rovner opened his presentation by asking, "what is refractory OAB?” and he went on to state that doing a search on Medline does not give much in the way of results as far as the term “refractory” is concerned.

aua sesHe continued to try to define refractory OAB by asking if it is when the patient fails behavioral modification, or anticholinergic treatment, or is it when the patient fails all non-surgical treatments? And whose definition should be used, the patient’s or the doctor’s? It is obvious that there are many unanswered questions around the term refractory and Dr. Rovner explained that since he was not able to find any information in Medline, he turned to the 2012 AUA Guidelines on OAB and said he was sure he was going to find the definition of refractory in the OAB Guidelines. When he searched the OAB Guidelines, he found the term refractory in two places but it was still not defined. In fact, Dr. Rovner said that the Guidelines are a bit “self-serving” by mentioning the refractory patient, “whoever that is,” and stating that “the refractory patients should be evaluated by an appropriate specialist,” in this case an urologist. Thus after searching both Medline and the OAB Guidelines without finding a definition of refractory, Dr. Rovner went on to define what refractory OAB is not:

  • neurogenic bladder
  • nocturia (isolated)
  • polydipsia/polyuria
  • dysfunctional voiding
  • elevated post-void residual volume (PVR) due to bladder outlet obstruction (BOO), detrusor underactivity, etc.
  • post-sling voiding dysfunction
  • recurrent UTI
  • etc., etc., etc.

He mentioned that he gets many patients referred to him for refractory OAB, and many of them fall into one of the conditions on the list above, i.e., they suffer from something that is not refractory OAB. Dr. Rovner explained that he gives all these patients a bladder diary which many of his referring physicians are not doing, and the diary can explain quite a bit of what is going on with each patient. Going back to the guidelines to look for more information about refractory OAB, Dr. Rovner explained that there are three lines of treatment for OAB defined under “Management of OAB.” First-line treatment consists of behavioral therapies, and second-line treatment is pharmacologic treatment with antimuscarinics or a combination of behavioral and pharmacologic therapies. He mentioned the newly approved β3 agonist – mirabegron (Myrbetriq) and said it is only briefly mentioned in the guidelines as it was approved after the guidelines were finalized.

When he explained what constitutes third-line therapy, Dr. Rovner said he would take the liberty and assume that third-line therapy is the same as treatment of refractory OAB. Included in third-line therapies in the OAB guidelines are:

  1. neuromodulation, which includes peripheral neurostimulation devices like PTNS, and sacral neuromodulation like Interstim,
  2. biological/chemical neuromodulation like OnabotulinumtoxinA, and
  3. urinary reconstruction like augmentation cystoplasty/diversion or tissue engineering.

Dr. Rovner went back to look at available pharmacological therapies and explained that there are many antimuscarinics approved for OAB and there are also numerous ways to apply those medications, i.e. tablets, gel, and patches. Currently available pharmacological therapies for OAB include: oxybutynin, tolterodine, trospium, fesoterodine, darifenacin, solifenacin, and as previously mentioned, the newer β3 agonist mirabegron which was approved in June 2012 and is available in two doses, 25 and 50 mg. In addition to mirabegron, there are other β3 agonists currently in phase III clinical studies, so there will soon be more than one β3 agonist available. The β3 agonist works by relaxing the smooth muscle during the bladder filling and urinary storage phases. The reason there are no β1 or β2 effects from β3 agonist treatment is that the affinity for β3 is much higher than for β1 or β2 and it would require doses that are a lot higher than the available doses for mirabegron to get those unwanted β1 and β2 side effects.

At this time, there is one clinical study published that compares mirabegron to an anticholinergic treatment, in this case tolterodine (Khullar et al., EU 2012), but there is another long-term study going on that will soon be published. The published study by Khullar, et al. looked at 1987 patients who were randomized to either placebo, mirabegron 50 mg (approved dose), mirabegron 100 mg (not approved), or tolterodine ER 4 mg. About 50% of the patients were previously treated with antimuscarinics and about 60% of the patients in the study were incontinent. The primary endpoints in this study were urge incontinence (UI) and frequency. Analysis of these coprimary efficacy endpoints showed a statistically significant decrease from baseline in mean number of micturitions (frequency) with 50 mg and 100 mg of mirabegron and in mean number of incontinence episodes per 24 hours, compared to placebo. Tolterodine also demonstrated improvements in both coprimary endpoints but these did not reach statistical significance.

As far as adverse events, mirabegron did not show any increased rate of hypertension in any of the two doses compared to placebo, and the incidence of dry mouth was similar between placebo and both groups of mirabegron while it was markedly lower than in the tolterodine group. Dr. Rovner summarized the information about mirabegron by saying that there are no antimuscarinics AEs, no glaucoma warning, no evidence of urinary retention, and no voiding dysfunction in males, but there is a warning in the label for obstruction even though there are no data to support this. As for the use of mirabegron, it is approved for OAB but the question, is if it is an add-on in patients with less than optimal response to antimuscarinics, should it be used in antimuscarinic failures, or if it should be the primary treatment for everybody. Dr. Rovner stated that all this is still being played out and it will become more clear as additional studies are published.

After this, Dr. Rovner moved on to discuss some of the third-line treatments for OAB. He started with percutaneous tibial nerve stimulation (PTNS), and explained that this was developed in the 1990s. PTNS treatment is given in 12 sessions, each during 30 minutes. The mechanism of action is still unclear but most likely it has something to do with the afferent pathways. The pivotal clinical trial for PTNS was called the ORBIT trial and it compared PTNS to tolterodine in a double-blind, randomized, controlled clinical study in 100 patients during 12 weeks. The primary endpoints were a two-day diary including OAB symptoms, and patient-reported outcomes (PRO) through a global response assessment. The results showed no difference in the decrease in voids/day; both treatments went from 12 to 10 voids/day but the PRO were much better in the PTNS group so the objective outcomes were about the same, while the subjective outcomes were in favor of the PTNS group. In the PTNS group, about 80% of the patients felt they were cured or improved compared to about 55% in the tolterodine group.

Dr. Rovner highlighted some questions/issues with PTNS and mentioned that we still do not know how it works and why/how the effect is maintained over time when the treatment consists of “only” 30 minutes once a week. This is compared to other types of neurostimulation that requires constant stimulation to be effective. In addition, we do not know who the optimal or sub-optimal patient is yet, and it is not yet clear if PTNS treatment can be combined with other treatments, so there are still a number of unanswered questions about PTNS.

The next form of neuromodulation therapy Dr. Rovner discussed was sacral nerve stimulation (SNS). This was first described over 25 years ago and it was approved by the FDA in 1997 for urinary urgency and frequency, urge incontinence, non-obstructive urinary retention, and fecal incontinence. As with PTNS, the mechanism of action for SNS is still unclear, but it is likely an afferent action.

In a clinical study where half the patients got an implant that was turned on and the other half got an implant that was never turned on, SNS demonstrated good efficacy and 47% of patients were dry and another 29% had more than 50% reduction in number of leaks/day during a 6 month study. Meanwhile, in the placebo group, 74% of patients had no reduction in number of leaks/day. This study showed good data but it was performed in a group of highly selective patients. The most common AE for SNS is pain at the implant site, and the revision rate is fairly high at around 20%. Dr. Rovner pointed out the pros and cons of SNS and mentioned the short operation time, quick recovery time, immediate response, and a reasonable efficacy as advantages of the treatment. The disadvantages he mentioned: we still do not know how it really works, there is very little long-term data, it is very expensive ($25,000-$30,000/patient), patient selection is still unclear -- especially in light of the expensive treatment, the revision rate is fairly high, and the battery life is variable.

Finally, Dr. Rovner discussed biological neuromodulation with onabotulinumtoxinA (Botox). This is the most potent neurotoxin we know and it works by inhibiting acetylcholine release at the pre-synaptic cholinergic junction which leads to muscle relaxation/weakness/paralysis depending on the dose injected. The effect is not immediate, it takes about a week before you see any effect and it is a transient effect but it takes 4-8 months for the effect to wear off after treatment. In the GU tract, Botox is currently FDA approved for neurogenic detrusor overactivity, refractory to anticholinergics, and for idiopathic overactive bladder, refractory to anticholinergics. However, it has been investigated for other conditions like detrusor-external sphincter dyssynergia (DESD), interstitial cystitis (IC) and painful bladder syndrome (PBS), BPH, and different pediatric urological conditions.

The initial clinical trials with Botox were done in patients with neurogenic bladder, and some of the doses were higher than the doses used today in these patients (Schurch, et al., J Urol 2005). The results were good; both doses (200 U and 300 U) of Botox showed significant improvement in UI compared to placebo, and there were no safety issues. For idiopathic OAB, a phase II dose-ranging study has been published and the phase III studies will be published shortly. The phase II study (Dmochowski, et al., J Urol 2010) included only urge urinary incontinence (UUI) patients who were refractory to anticholinergics, and they were randomized to one of five doses of Botox (50, 100, 150, 200 or 300 U), or placebo. The results were dose-dependent and the reduction in UUI from baseline ranged from about 16% for placebo up to almost 60% reduction in the group that received the highest dose (300 U). As far as safety in this phase II study, all treatment groups, except placebo, demonstrated elevated post-void residual volume (PVR), and this peaked at two weeks after injection with a slow drop-off rate. PVR is also dose dependent with the highest PVR in the group with highest Botox concentration and retention (PVR > 200 ml) requiring catheterization (CIC) ranged from about 5% to 21%.

Based on the balance between efficacy and AEs, i.e., retention, the best dose for idiopathic OAB was 100 U and this is now the approved dose. At this dose, the rate of retention requiring CIC was around 11%, and the mean length of CIC was 113 days.

Botox is an intravesical therapy performed in the office for the majority of patients and it is done with local anesthesia, unless it is a neurogenic patient without sensation who therefore does not need anesthesia. For the idiopathic patient, the treatment is given as 20 injections of 0.5 cc each while the neurogenic patient gets 30 injections of 1.0 cc each. As a summary about Botox, Dr. Rovner listed what we do know about Botox: approved for iOAB (100 U) and NDO (200 U), expensive ($565/100 U), reasonable, safe, and effective, risk of CIC is 6-10%, and repeat injections are needed every 4-8 months. He also listed what we do not know yet about Botox: optimal delivery system, optimal delivery template, optimal intravesical location, optimal interval between doses, and long-term effects are still unknown.

To conclude, Dr. Rovner explained his personal opinion on how he approaches treatment for refractory OAB and who gets which therapy. He simply starts with the least invasive, least expensive, and most reversible treatment and progresses from there. However, he stressed that ultimately it is the patient who decides what treatment to get and how to proceed. He explained that he always discusses all options and the pros and cons of each option, the likelihood of success with each therapy, convenience, and cost, and then moves on from there.

To summarize the management of refractory OAB, Dr. Rovner said he still does not know what refractory OAB is, i.e., the definition is unclear. There are lots of treatment options, including a β3 agonist, and PTNS/SNS/Botox/reconstruction are effective treatment options. In the end, the patient makes the decision about treatment choice and how to proceed with the treatment. And more therapies to manage refractory OAB are coming!


Presented by Eric S. Rovner, MD at the 77th Annual Meeting of the Southeastern Section of the AUA - March 14 - 17, 2013 - Colonial Williamsburg Lodge - Williamsburg, VA USA

Medical University of South Carolina, Charleston, SC, USA

Written by Anna Forsberg, medical reporter for

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