I'd like to invite all of our debate panel to come up to the stage because we have an exciting one for you. This is a very hot topic. The next debate is about how best to treat refractory overactive bladder, and I think we couldn't have brought together a better panel of experts. Dr. Sydney Munson is going to be our moderator for this. Dr. Tony Visco is going to be speaking on behalf of onobotulatum toxin, and Dr. Karen Noblitt is going to be speaking on behalf of sacral neuromodulation. Thank you all, and good luck. Can you bring up my slides? I do not see my slides brought up. Amundsen? Sorry, this will be Amundsen. Well, we can get started. Welcome, everybody, to the debate. I agree, I think it's going to be a very exciting debate comparing intracem versus Botox for the treatment of overactive bladder symptoms. It is well known that overactive bladder symptoms, and particularly urgency urinary incontinence, is very prevalent, and the prevalence increases with age. Seventeen percent of women over 45 and 27 percent of women over the age of 75 have bothersome urgency urinary incontinence symptoms. The problem affects tremendously the women's well-being and quality of life, and the economic burden is significant, with projected spending to be over $82 billion by 2020. Women try first- and second-line therapies, but because they have limited efficacy, first- and third-line therapies are then sought, and these include InterStim and Botox. One aspect of the increased economic burden has been the increase in utilization of both Botox and InterStim. There's actually been a 10 percent increase in the number of InterStim implants per year since FDA approval in 1997. And over the last 10 years, there's been even a higher increase of 20 percent per year increase in InterStim implants. This totals that 225,000 InterStim implants have been performed over the last 19 years. This increase in utilization is also mirrored by botulinum toxin. Since 2013, each year they have seen a 35 to 40 percent increase in the number of Botox injections. And over the last three years, 160,000 Botox injections have been performed. So now let me introduce the debaters. We have in the red corner, wearing the striped tie and representing Botox, is Dr. Visco. And in the green corner, wearing the gray suit, is Dr. Noblitt, representing InterStim. I'll discuss the rules. Dr. Visco will have eight minutes to present his side on Botox. Dr. Noblitt will follow with eight minutes presenting InterStim. And they will have each a two-minute rebuttal. Let us begin the debate. Okay. I don't know how they got that video or that song. So I actually think the winner is Dr. Amundsen, who basically just on the fly gave a great introduction without slides. Can I have my slides, please? Well, I'm really excited to be here today to share with you the many benefits of Botox and why it's superior to InterStim for the treatment of urgency urinary incontinence. Now, full disclosure, I don't perform InterStim. We made a decision a long time ago to limit this procedure to a few attendings, but I assure you I'm quite capable of evaluating the medical literature, in particular studies comparing these two modalities. Why should you believe me? Well, I led a multi-centered randomized trial comparing Botox to anticholinergics and was very involved in the design and implementation of Rosetta, the only randomized trial that directly compared Botox to InterStim. We'll get to that in a little bit. Well, I'm going to show you today why Botox is frankly better. It's better for you. It's better for your patients. And I'm going to prove that to you by showing you clear evidence showing that it's superior. My very capable opponent, Dr. Novelet, was going to somehow try to dissuade you, but I am confident that at the end you'll come to the same conclusion that I did, that Botox is the clear winner. So I contend several things. Number one, Botox is superior at reducing urgency urinary incontinence episodes per day. That's been proven. It's more likely to achieve complete continence. It's more likely to improve quality of life, and it's cost-effective. Is it perfect? No, nothing's perfect. There's higher rates of UTIs that are easily treated, and there's a lot of work to try to prevent those in the future, and also intermittent self-cath is rare and temporary. Plus there's a ton of practical benefits. Botox can easily be done in the office. There's no radiation exposure. It's less expensive. There's no MRI limitations, a diagnostic modality that is increasingly being used. And frankly, you know, the converse, InterSim has to be done in the OR. This concept that Botox needs to be repeated but InterSim doesn't is frankly false. There's lead migration. There's surgical infections. There's reprogramming and battery changes. And I'm going to focus today on three main trials, the ABC, which was Botox versus anticholinergics, the Rosetta that was Botox versus InterSim, and Insight that was InterSim versus anticholinergics. And there's a few important distinctions. Number one, ABC and Rosetta were fully funded by NIH, the Public Floor Disorders Network, and Insight was completely funded by industry, by Medtronics, the manufacturer of InterSim. There were PI conflicts reported in Insight, certainly, but not for ABC or Rosetta. And then when you look at the strength of the evidence, ABC and Rosetta had more than four times as many patients as the Insight trial. And then we get to another important thing, urge urinary incontinence. Actually, 100% of the patients in ABC actually leaked urine. Right? That's an important thing. In Insight, only 72% leaked urine. The rest had just sort of OAB urgency frequency. And then when we look at the severity of incontinence, in ABC and Rosetta, on average, they had five incontinent episodes per day versus 2.4% per day in Insight, that is, in those that actually leaked urine. So if you might recall, for ABC, Botox versus anticholinergics, both groups, and this was with 100 units, had a significant reduction in urge incontinent episodes per day. The important thing is we did everything to maximize the anticholinergic arm. We had a very standardized regimen. We allowed for dose escalation. And we even allowed for a drug change to a different medication with a different mechanism of action. ABC also found that there was a two-fold higher likelihood of achieving complete continence, 27% with 100 units. And this will be important later. It also had a good duration of effect. 52% still had adequate symptom control, and this continued even beyond nine months. Now, Insight, in contrast, if you read the paper, it describes interstim versus standard medical therapy, whatever that means. I don't know what standard means, but it certainly was not standardized. They had mild OAB symptoms, and 28% didn't even leak urine. The severity was half as much as I mentioned compared to ABC or Rosetta. When you look at the study, there was 38 sites recruiting over three years to enroll 70 participants in the interstim arm. Of those 70 on the right that were randomized to interstim, only 59 went on to stage one. And of those, 51 went on to stage two lead placement. It's very important to read the fine print. When you look at the Insight trial, in women who leaked urine and had urgency-frequency, the primary outcome was a composite of one of these three. So if you had urinary incontinence and urgency-frequency, look at the last bullet. On your diary, if you had return of less than eight voids per day, you would be considered a success, even if you had just as much urinary incontinence as when you walked in the door. That's not my definition of success. And in the subset of patients that actually had urinary incontinence, Insight, 39% had complete resolution. Keep in mind they had milder disease to begin with. Now before we get on to Rosetta, it's important to talk about off-label use of medications. This is when you use a drug at a different dose or for a different indication that it was FDA approved. It's commonplace. We do things like magnesium for preterm labor, that sort of thing. Dose adjustments in pediatrics. We adjust dosages for antibiotics perioperatively. We're up now up to three grams for ANSEF. That's not FDA approved. In fact, FDA takes the stance that it's part of good medical decision-making. If you're going to do that, however, you need to be careful to monitor safety and efficacy. And in Rosetta, we did both. So Rosetta trial was 200 units of Botox versus InterStim. And Botox had a greater reduction in urge urinary incontinence episodes than InterStim. They had a five-fold likelihood of achieving complete continence for Botox compared to InterStim and had improvement in symptom bother. Now when we're looking at cost-benefit analysis, it's important that something might actually cost more, but if it works better, it's actually still cost-effective. So in 2009, our group did a cost-effectiveness study looking at 200 units of Botox versus InterStim. Now at that point, we didn't have Rosetta, so we assumed that InterStim was going to work better but cost more. Now we actually have Rosetta. Botox now is cheaper and it works better. It's frankly a no-brainer. So in conclusion, I strongly contend that Botox is superior to InterStim at reducing urge urinary incontinence episodes per day. That has been proven in a randomized trial. It's five times more likely to achieve complete continence than InterStim given the same population and, again, in a randomized trial. It's frankly cost-effective and it's easy to administer without all the other issues related to two trips to the OR and radiation exposure. Is it perfect? No. Voiding is rare and temporary and can be easily managed. UTI can be reduced. And the need for surgical revisions is really obviated. Thanks very much. Very nice presentation. Based on Dr. Visco's slides, I would like version 3B of my slides, please. Perfect. Thank you. Thank you very much. Yes. That's the right one. Thanks that we got that. At least you had slides. Yeah, I did have slides. Thank you. So full disclosure, I have been on the advisory board and research support from both Medtronic and Allergan, and I actually do use both in my practice quite frequently. So I offer Botox and I offer sacral neuromodulation to all of my patients with going on to third-line therapy. So I just want to start out with a very, very fundamental question, very, very basic. So you're sitting down with your patient. You're counseling her about options for therapy, and you're talking about how these therapies might work. And one of the therapies restores function, and one of it is actually destructive. What do you think the patient's going to pick? So we know that sacral neuromodulation actually restores function by activating the somatic afferents, which then activate the inhibitory reflexes down to the bladder, restoring function, versus botulinum toxin, and it is called toxin for a reason, that it actually inhibits release of a neurotransmitter, which causes a denervation injury to the bladder and destroys bladder function. So let's just talk about some global things we might consider when we're thinking about why we would choose neuromodulation over a neurotoxin. We already talked about it. Neuromodulation restores function while the neurotoxin actually takes it away. Neuromodulation actually can treat urinary retention where the neurotoxin causes it, and I know that Dr. Visco said that the intermittent catheterization is rare. A 4% to 10% rate of intermittent self-catheterization may be rare in his book, but I don't think it would feel rare to the patient who's having to catheterize themselves. It actually can improve fecal incontinence and treat fecal incontinence. There's absolutely no potential for the neurotoxin to actually treat that. We have a trial period with sacral neuromodulation, something very unique to this therapy where the patient can try it out and decide whether or not it's beneficial and then go on to have the implant, whereas when you get the Botox, you're committing to six to nine months, whether or not it's working or whether or not you have an adverse event. If you go through a trial of sacral neuromodulation, it doesn't work for the patient, the patient chooses not to have that, they can go right into a treatment arm with Botox, whereas it's recommended to wait six to nine months after Botox injection before you would go on to sacral neuromodulation. We know that overactive bladder is a chronic condition. We don't just treat this for one year, six months, two years. It's a chronic condition over a long period of time. We know that sacral neuromodulation has long-term benefit where the neurotoxin actually only provides temporary benefit. There is infrequent re-operation, although there are re-operation rates, and that's definitely out there in the literature. However, it's very predictable that there's going to be a high number of frequent re-treatments in the neurotoxin group. If you're having an adverse event, something's going on with your sacral simulation, you can actually just turn the device off. If you're having an adverse event with the neurotoxin, you've got to wait that six to nine months before that adverse event wears off. Let's just look at the things that both can treat. Both can treat overactive bladder. It can treat urgency frequency, urgency incontinence, with a caveat only of Botox being able to treat urgency incontinence in patients that have a normal post-void residual. What do we have with Botox that doesn't have an indication of sacral neuromodulation? They are approved for neurogenic detrusor overactivity, so we'll give that to Botox. What about sacral neuromodulation? It can treat urgency incontinence with an elevated post-void residual. It can treat fecal incontinence. It can treat urinary retention. It can treat dual incontinence. We know many of our patients that are presenting with overactive bladder symptoms, up to 20% are going to have concomitant bowel dysfunction. Now, not approved here in the United States, but approved in Europe and currently being used. Sacral neuromodulation is being used for painful bladder syndrome, for pelvic pain, and for chronic constipation. Just recall, the Europeans were using sacral neuromodulation for fecal incontinence many years before we had it approved here in the United States. These are future indications that we may be able to offer to our patients. Let's look at the ABC trial versus the Insight trial. Dr. Visco reviewed some of this. The standard medical therapy, in our definition, was just an anticholinergic. He said they optimized in the ABC trial. It was optimized in the Insight trial as well. The physicians were allowed their discretion to choose whatever anticholinergic and dose escalate or not. This is a short trial, six months. The patients were pretty refractory in the Insight trial. They tended to have failed the medication, where the ABC trial, 40%, were treatment naive. We look at the primary endpoint, which is reduction of incontinence episodes. The medication was actually the same benefit in the ABC trial, so there was no superiority from the Botox over medication and no significant improvement in quality of life. When we compare that to the Insight trial, in all our objective outcomes, primary and secondary, significant reduction in incontinence episodes as well as superior improvements in quality of life. We can see this here on the left side of the screen in the Insight trial, showing significant improvement in quality of life. We did not see that when you compare that if you looked at that same graph in the ABC trial. On the right side, showing the reduction in incontinence episodes, and you saw this slide earlier from Dr. Visco, there was no difference in the reduction in incontinence episodes compared to medication. And again, look at this slide, very similar to a slide we might see a little bit later. But I think the one important thing is we know this condition is a chronic condition. Look at the follow-up. Patients do not continue on Botox therapy. In fact, most of the studies actually show that 60% to 70% of patients will actually discontinue Botox therapy after only one to two injections. That is a very similar number to what we see, the drop-off, in patients that stop anticholinergic medications based on lack of efficacy or side effects. So you can see here, less than 35 patients actually then completed or had more than two injections at a five-year follow-up. And in the Mohi study, about two-thirds of patients actually quit Botox within three years. Whereas sacral nerve modulation has sustained benefit, in the Insight trial we actually now have our four-year data. We're presenting at this meeting where we see sustained response. You can see in 86% of patients. And that quality-of-life graph has been consistent throughout in every single domain. And quality-of-life has been persistent out to that. We have the quality-of-life at three years and the improvement in four years. So we've also had continued advancements in sacral nerve modulation. We now have the Verify, which is a wireless. We have the Curve Stilette, which helps us to get a better implant, all four electrodes at low voltages. We have new protocols to reduce infection, which is one of the complications that we've seen. We have cycling recommendations that improve programming. We also now have a rechargeable device that is commercially available in Europe that has a minimum battery life of up to 15 years and actually designs some user-friendly programs that, when we place that, actually can inform the physician what programs to choose. Now, Dr. Visco talked about cost-effective. And let's look at cost-effective versus cost-savings. In the short term, he's absolutely right. Botox is certainly more cost-effective. It's more cost-savings as well. But this isn't a short-term disease. Again, this is a chronic disease. At five years out, sacral nerve modulation actually becomes more cost-effective, and that includes the quality-adjusted life years, where the cost-savings, the actual cost itself, it could be plus or minus depending on which study you look at. As we get out longer, it's very, very clear. Sacral nerve modulation is both cost-effective and cost-savings. And we just published our data looking at the rechargeable device, and actually we become more cost-effective and cost-savings if we have the rechargeable device. So, again, in just thinking about why we might choose Intersim over Botox, it restores function. It treats multiple pelvic floor disorders. We have a trial period. We have long-term benefits. And, again, if you're having any adverse events, you can simply turn that off. Thank you. Well, it was interesting to hear all the additional benefits. It was almost like an ad for – I thought this was just a debate. If we can pull up the next ones. She's taking the high road. We have a different definition of that then. Let's go a little further. Okay. So despite Dr. Noblitt's presentation, I have a very different conclusion. So I still contend that Botox is far superior to Intersim. Trying to do an analogy between the Insight trial that 28 percent didn't even have incontinence and ABC where the average patient had five incontinence episodes per day and all patients leaked is just incorrect. The issue of intermittent self-cath is a critically important issue, and I'd like to just highlight ABC versus Rosetta. So if you look over at the six-month time period, 100 units of Botox results in a 1 percent risk of intermittent self-cath at six months, and Rosetta at 200 units had a 2 percent rate of intermittent self-cath at six months. Now, the important distinction, nobody wants to catheterize, right? I get that, and my patients understand that. But if that happens, does it really impact quality of life? And this was a really interesting study that was done. This is a focus on the 200-unit dosing. The two lines are those that did and did not require intermittent self-cath, and you can see that there was a really significant improvement in quality of life and essentially identical between those two groups. So I'm with you. I don't want to have to catheterize. The patients don't want to have to catheterize, but it still improves quality of life significantly. In a randomized trial, again, the only randomized trial that compared Botox to InterStim, it had significant improvements not only in urgent incontinence episodes, and it also had a significant improvement in symptom bother. So Botox had a greater improvement than InterStim, had greater patient satisfaction in both of those groups, and they were more likely to recommend it to a friend or family member. We had very experienced implanters, so we had a minimum of ten implants required. They had to be ongoing implanters. We used a very standardized regimen in the OR that assessed both motor and sensory function. And importantly, 84% of there was an 84% clinical response in the stage one that led to stage two. So there's that strong evidence that we had experienced implanters. In summary, it's pretty clear to me that Botox is simple, efficient, and effective. Botox is expensive, complicated, and doesn't work as well. You decide. Before we start the rebuttal timing, if I just may have a moment, I think they're not starting. I'll have to go through. Let's see. Go back. Here we go. So before we start the timing of this, I just want to, for some of the younger members in our audience who may not know how Dr. Visco really wanted to start his earlier career, he really started out in Hollywood, and he starred in an iconic movie in the 1980s called Say Anything. And I am no way implying what his current behavior is, but I just thought this would be something of interest for our younger members who may not have known this about Dr. Visco. So when we look, again, this is a chronic therapy, so we know the sacral neuromodulation is far more durable when correcting for steady dropouts. You can see in Vic Nitti's study in the long-term follow-up in the Botox trial, only 44% or 372 of 839 actually had three or more treatments at three-and-a-half years follow-up. And if you take it out, if patients had perfect treatment out to that sixth treatment, only 16% were compliant. And if we look at an intent-to-treat analysis in the Insight trial, we have a 60% compliance rate and also success. So not only do we have 83% still continuing, but of those, when we do an intent-to-treat, 60% are successful. So let's just think, again, this is a chronic disease, and let's take an average patient, 50 years old, and we're treating her to 65. Now, that's conservative, correct? So over that 15-year span, she's going to have to come in and have 30 treatments, 30 treatments. That means when she comes in, she has a catheter placed to put the anesthetic in. She has to wait the 30 to 40 minutes. Then she has a cystoscopy done. Then she comes back two weeks for a PVR check. Now she's got 60 visits in 15 years. With the primary cell interstem device, she'll have the first one placed and then come back maybe two more times for a battery change. And we heard Dr. Hale say yesterday, that's a very easy procedure to do. We go into the rechargeable that's now commercially available with a minimum 15-year life. Patient has maybe one procedure in that 15 years. When we look at head-to-head studies, again, we brought up the Rosetta. Looking at SING study, this is out of the Mayo Clinic, much higher success rate in the interstem group versus Botox. And, again, we looked at the Rosetta trial, and that slide looks very, very similar to the ABC trial. And the six-month difference, about a half a leak per day, is that really clinically significant? Maybe it's statistically significant, but is that really clinically significant? And you can see it approaching the same decrease in incontinence episodes at that six-month period. And, of course, the limitation, it's a non-FDA-approved dose, which is unfortunate. I mean, it was a great study, and that's just an unfortunate timing of things. And also the lead that was recommended was the extended lead, which is no longer commercially available. So this is limited data that we can actually apply to our patients now. Adverse events are minor. We see that at the 36 months, only 3% were actually explanted due to lack of efficacy. Again, I believe that interstem, sacro-neuromodulation, for all the different reasons, should be chosen over Botox. It's restorative, treats multiple pelvic floor disorders, sustained results for a chronic condition, more cost-effective over time, has a trial phase, and is the only third-line therapy shown to be superior. Thank you very much. I believe Elvis is about to leave the building. Wow. I think both of them, let's give a big round of applause. I think it was excellent. I think due to time, we'll move on to the next presentation. But thank you, everybody, and awesome job, both.

refractory overactive bladder

Botox

sacral neuromodulation

efficacy

cost-effectiveness

patient preferences