Botulinum Toxin vs. Sling Surgery for Mixed Urinary Incontinence in Women - Heidi Harvie
January 13, 2025
Heidi Harvie joins David Staskin to discuss findings from a multicenter randomized trial comparing botulinum toxin versus mid-urethral sling for treating refractory mixed urinary incontinence in women. The study demonstrates comparable improvement in mixed incontinence symptoms at six months with both treatments, though sling patients show greater improvement in stress symptoms. Dr. Harvie highlights that while both treatments prove effective initial options, the chronic nature of mixed incontinence leads to high retreatment rates, with 28% of botulinum toxin patients requiring additional injections and 30% of sling patients eventually receiving botulinum toxin by 12 months. The discussion explores the implications for clinical practice, emphasizing the importance of patient preference in treatment selection and the need to consider both stress and urgency components when developing treatment plans. The conversation also examines broader questions about treatment sequencing and the possibility of combination approaches.
Biographies:
Heidi Harvie, MD, MBA, MSCE, Director, Penn Urogynecology & Pelvic Reconstructive Surgery, Associate Professor of Obstetrics and Gynecology, Hospital of the University of Pennsylvania, Philadelphia, PA
David Staskin, MD, Associate Professor of Urology, Tufts University School of Medicine, Director of the Center for Male and Female Pelvic Health at St. Elizabeth’s Medical Center, Boston, MA
Biographies:
Heidi Harvie, MD, MBA, MSCE, Director, Penn Urogynecology & Pelvic Reconstructive Surgery, Associate Professor of Obstetrics and Gynecology, Hospital of the University of Pennsylvania, Philadelphia, PA
David Staskin, MD, Associate Professor of Urology, Tufts University School of Medicine, Director of the Center for Male and Female Pelvic Health at St. Elizabeth’s Medical Center, Boston, MA
Read the Full Video Transcript
David Staskin: Hello, I'm David Staskin. And welcome to this segment of UroToday. We're going to be discussing a really interesting abstract that was presented in a little bit more detail at the International Continence Society meeting, dealing with the idea of botulinum toxin versus sling surgery for mixed urinary incontinence in women.
And our guest today, who was really important in both developing the protocol, is Heidi Harvie from the University of Pennsylvania. She's the director of urogynecology at Pennsylvania Hospital and the assistant director of the division of urogynecology. She has been extremely accomplished, not only in urogynecology but also in her role.
She has an MBA and an MSCE from the Wharton School, and is a fellow there now and really an expert in economics of health care. And we're going to try to get some of her expertise when we talk about this abstract. Heidi, it's yours to present.
Heidi Harvie: Thank you very much. So thank you for allowing me to present our results of the mid-urethral sling versus botulism in women with mixed urinary incontinence trial. Here are my disclosures and our funding sources. Up to 50% of women with urinary incontinence have mixed urinary incontinence, a combination of both stress and urgency urinary incontinence.
Women with mixed urinary incontinence often have more severe symptoms; patients report that the urgency component is more bothersome than the stress component, and that the combination of both is more bothersome than either urgency incontinence or stress incontinence alone. Women with mixed urinary incontinence also respond less well to treatment than those with isolated stress or urgency urinary incontinence, making it a challenging condition to treat.
Treatments traditionally address the stress and urgency components separately, using a stepwise and segregated approach and starting with conservative therapies and medication. The prior PFDN ESTEEM trial showed that mid-urethral sling in women with mixed urinary incontinence helps both the stress and urgency incontinence symptoms.
However, there are limited data comparing procedural-based treatments for women with mixed urinary incontinence. Our aim was to assess whether 100 units of botulinum toxin is superior to mid-urethral sling for improving mixed urinary incontinence symptoms at six months.
Participants were limited to the study intervention for six months (the primary outcome) and were then followed at 12 months, but were allowed other treatments after six months, including crossover to the alternative treatment. The primary outcome was mixed urinary incontinence symptoms at six months, measured by the UDI total score. Secondary outcomes were the UDI irritative and stress subscales.
Other outcomes included incontinence-specific symptoms, quality of life, satisfaction, global impressions of bladder symptoms, and bladder diary. Participants were then followed to 12 months with the same outcomes. Study interventions were 100 units of botulism toxin with a second injection allowed between three and six months, versus a mid-urethral urethral sling with both full-length retropubic and transobturator slings allowed.
Participants were randomized one to one with stratification across seven sites in age. Our population was women with at least moderate bother of stress and urgency incontinence and a positive cough stress test, at least four urgency incontinence episodes on a three-day bladder diary, being refractory to conservative treatments and OAB medication, no prolapse at or beyond the hymen or planned prolapse surgery, and no urinary retention. Treatment crossover or additional non-study treatments were permitted after six months, and assessments were performed at baseline, three, six, nine, and 12 months. Our sample size of 146 gave us 90% power to detect an MID based on a mixed urinary incontinence population.
Here's our consort diagram. 150 participants were randomized, 140 were treated, and 137 were in our modified intent-to-treat population for analysis. As expected with the randomized trial, there were no differences between groups in demographics and baseline characteristics. I mean, age was 59, 77% were menopausal, and 80% were white.
The majority of participants had balanced mixed urinary incontinence, and the mean baseline incontinence episodes per day was 7.2. For the primary outcome, there was no difference in improvement in UDI total score at six months. After six months, participants could request additional treatment. Mixed urinary incontinence symptom improvement was maintained through 12 months with no difference between groups.
There was no difference in UDI irritative score improvement at six months. Urgency symptom improvement was maintained through 12 months with no difference between groups. The sling group had greater improvement in UDI stress score at six months. Stress symptom improvement was maintained through 12 months.
There was no difference in reported improvement in incontinence-specific symptom, quality of life, and satisfaction. There was also no difference between groups in global impressions of bladder symptoms. At six months, there was no difference in reduction in irritative incontinence episodes per day between groups. However, the sling group had greater reduction in stress and total incontinence episodes per day.
By 12 months, there was no difference between groups in reduction of total urgency or stress incontinence symptoms per day. Consistent with the chronic nature of mixed urinary incontinence, there was a high rate of additional treatments. In the botulism toxin group, 13% received a second injection by six months as allowed by the protocol, and 28% received a second injection by 12 months. There was a high crossover to the other treatment in the sling group. By 12 months, 30% in the sling group received botulinum toxin compared with 15% in the botulinum toxin group that received a sling.
In addition, within 12 months, 14% of participants in the sling group received non-study treatments, compared to 7% in the botulinum toxin group. Complications related to the intervention were few. Serious adverse events occurred in 4% in the botulism toxin group and 12% in the sling group. All were unrelated to the study treatments.
Only 3% and 4% required a Foley catheter or clean intermittent catheterization greater than two weeks after their procedures. More participants in the sling group experienced recurrent urinary tract infections compared to the botulism toxin group. In the sling group, vaginal mesh exposure occurred in 3%, and 1% required sling surgical revision.
Our strengths included a multicenter randomized trial design with standardized procedures and rigorous outcome measures. Also, the inclusion of both a six-month period limited to the randomized study intervention and a subsequent six-month period allowing additional urinary incontinence treatments permits comparison of the study interventions and pragmatic evaluation of the need for additional mixed urinary incontinence therapies.
Our limitations included that participants and surgeons were not masked. Also, given the study setting and counseling about the two interventions, participants may have anticipated receiving both treatments, contributing to this crossover rate. Given that mixed urinary incontinence symptoms improve comparably with either initial botulism toxin or mid-urethral sling, with low risk for complications and symptom improvement that was maintained at 12 months, we conclude that both botulism toxin and mid-urethral sling are appropriate and effective initial treatments for women with refractory mixed urinary incontinence.
However, the chronic elements of mixed urinary incontinence lead to retreatment. As expected, 28% of the botulism toxin group had additional injections, and 23% of participants received the alternative treatment, with a higher rate of the urethral sling group getting botulinum toxin than the botulinum toxin group getting a sling. This study justifies an individualized treatment approach and shared decision-making based on patient preference.
I would like to acknowledge our collaborators within the Pelvic Floor Disorders Network. Thank you and look forward to your questions.
David Staskin: Great. Thank you, Heidi. It's a great study. People really appreciate the amount of work that goes into this, from both the investigators and the nurses and people that are keeping and processing the data. So congratulations to everyone. I have a simpler question, though.
If I'm just in practice, and I'm watching this, and I was hoping to find out whether there was a difference between slings and botulinum toxin injection, and I know that I'm supposed to teach everybody exercises, and then they're supposed to try medications and see if they're better and do physical therapy for their stress incontinence. If I'm in the office today or I'm at home watching this, what is the influence here? The final message for actually people that are treating patients—what was the value in the study?
Heidi Harvie: So first, I just want to focus that this patient population has refractory mixed urinary incontinence. So people that have already failed behavioral, they failed physical therapy, they failed medication. So now, they're looking at more procedural-based treatments.
So within the context of that, where the patients don't have a preference, and they qualify for everything, we were looking at a very high success rate stress incontinence treatment and a high success rate urge incontinence treatment and looking at them head to head. And the answer to this study is that they both help. They both have good results.
So for a patient who doesn't want a sling, doesn't want mesh, doesn't want surgery, there's a great option with Botox. And for a patient who is looking for a more permanent solution or wanting the best bang for one procedure buck, it might be the incontinence sling. But you really have to look at it from a patient preference. And what is it that's really impacting their quality of life? Is it playing tennis or dancing at their child's wedding?
Then a stress incontinence therapy might be the best thing. Versus if it's more urge-related symptoms, then Botox might be a better one. But definitely starting with the conservative therapies is the way to go.
David Staskin: OK. Let's throw in two other things that weren't actually included in the study, just for your opinion on where they fit in, because I start with a relatively simple algorithm. I'm just a urologist from a small town here on the East Coast. But if I also have periurethral injections and neuromodulation, I know it messes up. That's not what the study was meant to look at.
But in your practice, as you're counseling patients, how do all these things get into the soup and how does everybody decide what they're going to order?
Heidi Harvie: So if it's stress incontinence and I go down my algorithm, and when they're ready for a procedure, I present both periurethral bulking and sling and go over the data—office procedure, OR procedure, success rates, how long they last—and talk about that. Same thing with the urge: after they've failed conservative measures, I offer PTNS. And then at the Botox discussion, I also talk about sacral neuromodulation.
So I offer all of these in the mix. When it's mixed incontinence, as you know, you're balancing between the two algorithms. There is no one algorithm. So you're sort of integrating the two algorithms and trying to elicit patient preference. So it gets complicated. So we're trying to expand the data to help physicians counsel patients and for patients to make these decisions. So I offer everything when I'm with the patient.
David Staskin: OK. I'm always amazed by this patient preference thing because I practiced for 30-some years, and I always thought I was giving the patients what they wanted. But that's a little bit new for me. But let's do it a different way. A 55-year-old woman walks into my office, and she complains of frequency and urgency. And we do the UDI, and she has stress, and we examine her, and she leaks urine on a cough.
And it's a significant amount of urine. It's not 10 coughs and one little drop that comes out. And we do this whole thing with her, and she's gone through all the other therapies. I have a sense that the patients watch you, like they're behind the glass in a detective show. And as you give them all these alternatives, if they don't say it, what they're really trying to find out is what you think is the best thing for them.
In other words, they say, Dr. Harvie, I came to you because you're supposed to be an expert. And my doctor actually sent me in here, and I have to deal with the parking down here by Pennsylvania Hospital. And I'd really like to know what you think I should have. Again, are you really considering the patient preference where you know she has a little bit of ISD, and you know she might benefit a little bit better from a sling? Are you willing to go in the sling direction if the patient doesn't have a problem with mesh, for instance, or you're not going to do a pubovaginal sling?
Heidi Harvie: So I seriously do push back on the patient. I'm like, what do you want to fix? What is the problem that brought you in here? And if they say urgency, I'm like, OK, maybe we should try that first. If I elicit ISD-level leaking, then I do present that to her, and I do tell about the data for the sling could help that. But if she had zero stress symptoms, then I'm a little hesitant on pushing a sling if she hasn't—
David Staskin: In the study, how was the botulinum toxin done? Was it done in the OR? Was it done with sedation? Was it done in the office? How was it done?
Heidi Harvie: It was done in the office. Based on location and the individual practice, the majority of it was done in the office.
David Staskin: Right. So a patient who doesn't mind an office—they were randomized. I think the audience should know, the people listening should know that these patients had to say, I'll have whatever's assigned to me in order to randomize them in the trial. And those patients who ended up with an office procedure were then sort of asked whether they wanted to go to the OR if their stress incontinence was still bad, as opposed to somebody who had already been in the operating room and now just needed an office procedure.
So I can understand how that bias comes into play. There have been a couple of studies, though. One was the SLIM study that looked at botulinum toxin plus sling versus sling, and ESTEEM looked at behavioral plus sling versus sling. And now we're looking at sling versus toxin. You're the cost-effectiveness analysis expert here.
And you just want to wonder whether you're taking somebody to the OR, they're going to have a sling back there, and you're right there with your 100 units in the cabinet. Is there an argument for, they're there, they're going to have a procedure—we know the sling might make their urgency better, but should we do this in combination at the time of a surgical procedure?
Heidi Harvie: So I just want to point out the other two studies, SLIM and ESTEEM, were done in patients who were already planning a sling. So it's a different population. They weren't refractory. ESTEEM, they didn't need to fail meds or behavioral because they were doing that, and they were already going to the OR. So the recruitment was done after they were already planning a sling. So really, it's a different population.
But in terms of the—we will be doing a cost-effectiveness study on our study results on that. And we've talked about doing, in this patient population, looking at whether we should just do them at the same time. But first, we wanted to look at if, given that urge symptoms are generally more bothersome, we can do an office-based procedure and get similar results. That's much more cost-effective than going to the OR—at least it depends on how many years you go out.
Yes, doing both at the same time—yes, you're already there, they're paying for both, the reimbursements for both procedures, but it's much better for the patient going there. But I can't really compare the results based on those other two studies.
David Staskin: Well, I was so impressed by the urge data from the UDI to look at the idea that a sling helped their urge symptoms so much that—if you ask me, traditionally, the decision in my office for me would be to resolve, or at least find out whether they're going to respond to urgency treatment before operating on them. Because after I fix their stress incontinence, if they still had urge incontinence, they weren't going to be happy. And I didn't want to operate on them if they weren't going to be happy afterwards.
So that was the biggest thing here. It was like, geez, you do a sling—Peter Sand reported this years ago with the transobturator sling, where he said the urgency got a lot better. And I wasn't sure if I believed it. I mean, it was Peter's data, and I knew he did a good study, but it just seemed counterintuitive to me. And Ed McGuire said it when they were doing autologous slings and said, geez, just do the sling, fix their stress incontinence, and sometimes their urge gets better.
What do you think? Is moving through the bladder neck to the mid-urethra or some support that these mid-urethral slings are giving adding some benefit? I mean, the proximal urethra still opens—all the theories we had about why urine entering the proximal urethra provokes the stress. What do you think's going on?
Heidi Harvie: So I can't really comment—I'm not a basic scientist in terms of the details there. But there really is increasing evidence suggesting that maybe there's some common pathophysiology process explaining both the concomitant stress and urgency symptoms coexisting in women with mixed incontinence.
So I think looking at the mixed incontinence patients as a separate group, as opposed to just overlaying the stress and urge, can be very beneficial. But yeah, our hypothesis was that the botulinum toxin would be superior at taking care of the urge better. But while at the six months, the sling had very good improvement of the urge—no difference in the urge symptoms and superior stress.
David Staskin: Why not fix both seems to be—
Heidi Harvie: Get a bang for your buck. It's like the data's showing just go to the sling.
David Staskin: All right.
Heidi Harvie: However, 30% of them had the botulism toxin by 12 months.
David Staskin: And I'm not surprised by that.
Heidi Harvie: So in counseling the patients now to say, OK, this is the biggest bang for the buck we got, but in this trial, 30% of patients went on to get the botulinum toxin. Now I agree there was—in a study, I think patients might be more anticipatory of getting both treatments, and it's just an office treatment, lower threshold for getting it. I completely agree.
But counseling them that it's not perfect, and that you're punting on the urge, but it might be great, but you might need to do additional treatment on it.
David Staskin: Right. Well, I mean, and that goes back to me saying to myself, if in this study one third of patients still needed the injection, is it worth finding out whether people are responders or not for their urge symptoms with injection to just do injection first on everybody and send them out? So it's not what this study was, but it does influence the way—or actually, when you read these studies, it justifies what you're doing no matter what you're doing. So it's always the intersection between science and clinical medicine. I have one more little thing that interested me about the study: urodynamics.
Urodynamics was done within a year of entering the study so it didn't have to be repeated, correct? Those patients were accepted. So were there urodynamics at the end?
Heidi Harvie: We did not repeat them after the study. No, we did not. We—
David Staskin: Right. So what people also have to realize here—or take into account, which is interesting as you start to interpret this, because there's a lot of data you have on looking at who was a responder and non-responder, and switchers and non-switchers, although the numbers aren't that big to be able to really statistically determine that.
But the UDI—and I was the head of the group that wrote the thing on looking at these metrics for evaluation of patients for the ICI. And normally, I wouldn't know that much about it, except I was forced to read the chapter as the person who was the lead author. And when I look at this, is that the outcome?
I mean, when we deal with BPH in urology, we deal with obstructive and irritative symptoms, which is interesting because we have an IPSS score and it doesn't really—like I always say, if a man is incontinent, that bothers him more than a slow flow, right? But they're all 1, 2, 3, 4, 5, and there's no weighting of the bother of the symptoms.
So when you use the UDI and it's I'm minimally affected or I'm greatly affected and you sort of go through this scale, is it the best way to make all the conclusions? If you're going to do it again, now that you've seen the data, would you have measured something else, or even a cough test at the end to find out whether they were really dry?
Heidi Harvie: So in terms of a primary outcome, we wanted a patient-reported outcome to focus on patient symptoms and their bother. And we wanted an instrument that included both stress and urge symptoms as one. Also, the UDI was a primary outcome for ESTEEM, allowing us to do combined analysis and sort of compare the outcomes.
So something that would equally incorporate stress and urge symptoms for the mixed incontinence was important. And looking at everything that was out there and also, again, consistency with ESTEEM, we went with that. But we had secondary outcomes, including the stress and irritative subscales, and also patient global impression of improvement, bladder—we had the full breadth.
Everybody had a positive cough stress test whether in urodynamics or on the table before. They had to have a positive cough stress test. So we wanted objective evidence of stress and urge, and we wanted symptomatic, moderate to severe bother on the question for both stress and urge. And we did have bladder diaries, and there was a required minimum of four urge leaks.
So we were trying to make it a severe refractory population going in. But we wanted, yeah, a patient-reported outcome that combined stress and urge. So that's where we got—
David Staskin: If it was a pharma study, we would have called it real life.
Heidi Harvie: Yeah.
David Staskin: Yeah. Listen, Dr. Harvie, this has been tremendous. We always joke about, when we do these things, whether we learn anything. I've learned a lot. I hope everybody listening today has. And really thank you for joining us. And hopefully, we'll have you back to talk about the study again when you process more data.
Heidi Harvie: Thank you very much. Appreciate it.
David Staskin: Excellent. Thank you.
David Staskin: Hello, I'm David Staskin. And welcome to this segment of UroToday. We're going to be discussing a really interesting abstract that was presented in a little bit more detail at the International Continence Society meeting, dealing with the idea of botulinum toxin versus sling surgery for mixed urinary incontinence in women.
And our guest today, who was really important in both developing the protocol, is Heidi Harvie from the University of Pennsylvania. She's the director of urogynecology at Pennsylvania Hospital and the assistant director of the division of urogynecology. She has been extremely accomplished, not only in urogynecology but also in her role.
She has an MBA and an MSCE from the Wharton School, and is a fellow there now and really an expert in economics of health care. And we're going to try to get some of her expertise when we talk about this abstract. Heidi, it's yours to present.
Heidi Harvie: Thank you very much. So thank you for allowing me to present our results of the mid-urethral sling versus botulism in women with mixed urinary incontinence trial. Here are my disclosures and our funding sources. Up to 50% of women with urinary incontinence have mixed urinary incontinence, a combination of both stress and urgency urinary incontinence.
Women with mixed urinary incontinence often have more severe symptoms; patients report that the urgency component is more bothersome than the stress component, and that the combination of both is more bothersome than either urgency incontinence or stress incontinence alone. Women with mixed urinary incontinence also respond less well to treatment than those with isolated stress or urgency urinary incontinence, making it a challenging condition to treat.
Treatments traditionally address the stress and urgency components separately, using a stepwise and segregated approach and starting with conservative therapies and medication. The prior PFDN ESTEEM trial showed that mid-urethral sling in women with mixed urinary incontinence helps both the stress and urgency incontinence symptoms.
However, there are limited data comparing procedural-based treatments for women with mixed urinary incontinence. Our aim was to assess whether 100 units of botulinum toxin is superior to mid-urethral sling for improving mixed urinary incontinence symptoms at six months.
Participants were limited to the study intervention for six months (the primary outcome) and were then followed at 12 months, but were allowed other treatments after six months, including crossover to the alternative treatment. The primary outcome was mixed urinary incontinence symptoms at six months, measured by the UDI total score. Secondary outcomes were the UDI irritative and stress subscales.
Other outcomes included incontinence-specific symptoms, quality of life, satisfaction, global impressions of bladder symptoms, and bladder diary. Participants were then followed to 12 months with the same outcomes. Study interventions were 100 units of botulism toxin with a second injection allowed between three and six months, versus a mid-urethral urethral sling with both full-length retropubic and transobturator slings allowed.
Participants were randomized one to one with stratification across seven sites in age. Our population was women with at least moderate bother of stress and urgency incontinence and a positive cough stress test, at least four urgency incontinence episodes on a three-day bladder diary, being refractory to conservative treatments and OAB medication, no prolapse at or beyond the hymen or planned prolapse surgery, and no urinary retention. Treatment crossover or additional non-study treatments were permitted after six months, and assessments were performed at baseline, three, six, nine, and 12 months. Our sample size of 146 gave us 90% power to detect an MID based on a mixed urinary incontinence population.
Here's our consort diagram. 150 participants were randomized, 140 were treated, and 137 were in our modified intent-to-treat population for analysis. As expected with the randomized trial, there were no differences between groups in demographics and baseline characteristics. I mean, age was 59, 77% were menopausal, and 80% were white.
The majority of participants had balanced mixed urinary incontinence, and the mean baseline incontinence episodes per day was 7.2. For the primary outcome, there was no difference in improvement in UDI total score at six months. After six months, participants could request additional treatment. Mixed urinary incontinence symptom improvement was maintained through 12 months with no difference between groups.
There was no difference in UDI irritative score improvement at six months. Urgency symptom improvement was maintained through 12 months with no difference between groups. The sling group had greater improvement in UDI stress score at six months. Stress symptom improvement was maintained through 12 months.
There was no difference in reported improvement in incontinence-specific symptom, quality of life, and satisfaction. There was also no difference between groups in global impressions of bladder symptoms. At six months, there was no difference in reduction in irritative incontinence episodes per day between groups. However, the sling group had greater reduction in stress and total incontinence episodes per day.
By 12 months, there was no difference between groups in reduction of total urgency or stress incontinence symptoms per day. Consistent with the chronic nature of mixed urinary incontinence, there was a high rate of additional treatments. In the botulism toxin group, 13% received a second injection by six months as allowed by the protocol, and 28% received a second injection by 12 months. There was a high crossover to the other treatment in the sling group. By 12 months, 30% in the sling group received botulinum toxin compared with 15% in the botulinum toxin group that received a sling.
In addition, within 12 months, 14% of participants in the sling group received non-study treatments, compared to 7% in the botulinum toxin group. Complications related to the intervention were few. Serious adverse events occurred in 4% in the botulism toxin group and 12% in the sling group. All were unrelated to the study treatments.
Only 3% and 4% required a Foley catheter or clean intermittent catheterization greater than two weeks after their procedures. More participants in the sling group experienced recurrent urinary tract infections compared to the botulism toxin group. In the sling group, vaginal mesh exposure occurred in 3%, and 1% required sling surgical revision.
Our strengths included a multicenter randomized trial design with standardized procedures and rigorous outcome measures. Also, the inclusion of both a six-month period limited to the randomized study intervention and a subsequent six-month period allowing additional urinary incontinence treatments permits comparison of the study interventions and pragmatic evaluation of the need for additional mixed urinary incontinence therapies.
Our limitations included that participants and surgeons were not masked. Also, given the study setting and counseling about the two interventions, participants may have anticipated receiving both treatments, contributing to this crossover rate. Given that mixed urinary incontinence symptoms improve comparably with either initial botulism toxin or mid-urethral sling, with low risk for complications and symptom improvement that was maintained at 12 months, we conclude that both botulism toxin and mid-urethral sling are appropriate and effective initial treatments for women with refractory mixed urinary incontinence.
However, the chronic elements of mixed urinary incontinence lead to retreatment. As expected, 28% of the botulism toxin group had additional injections, and 23% of participants received the alternative treatment, with a higher rate of the urethral sling group getting botulinum toxin than the botulinum toxin group getting a sling. This study justifies an individualized treatment approach and shared decision-making based on patient preference.
I would like to acknowledge our collaborators within the Pelvic Floor Disorders Network. Thank you and look forward to your questions.
David Staskin: Great. Thank you, Heidi. It's a great study. People really appreciate the amount of work that goes into this, from both the investigators and the nurses and people that are keeping and processing the data. So congratulations to everyone. I have a simpler question, though.
If I'm just in practice, and I'm watching this, and I was hoping to find out whether there was a difference between slings and botulinum toxin injection, and I know that I'm supposed to teach everybody exercises, and then they're supposed to try medications and see if they're better and do physical therapy for their stress incontinence. If I'm in the office today or I'm at home watching this, what is the influence here? The final message for actually people that are treating patients—what was the value in the study?
Heidi Harvie: So first, I just want to focus that this patient population has refractory mixed urinary incontinence. So people that have already failed behavioral, they failed physical therapy, they failed medication. So now, they're looking at more procedural-based treatments.
So within the context of that, where the patients don't have a preference, and they qualify for everything, we were looking at a very high success rate stress incontinence treatment and a high success rate urge incontinence treatment and looking at them head to head. And the answer to this study is that they both help. They both have good results.
So for a patient who doesn't want a sling, doesn't want mesh, doesn't want surgery, there's a great option with Botox. And for a patient who is looking for a more permanent solution or wanting the best bang for one procedure buck, it might be the incontinence sling. But you really have to look at it from a patient preference. And what is it that's really impacting their quality of life? Is it playing tennis or dancing at their child's wedding?
Then a stress incontinence therapy might be the best thing. Versus if it's more urge-related symptoms, then Botox might be a better one. But definitely starting with the conservative therapies is the way to go.
David Staskin: OK. Let's throw in two other things that weren't actually included in the study, just for your opinion on where they fit in, because I start with a relatively simple algorithm. I'm just a urologist from a small town here on the East Coast. But if I also have periurethral injections and neuromodulation, I know it messes up. That's not what the study was meant to look at.
But in your practice, as you're counseling patients, how do all these things get into the soup and how does everybody decide what they're going to order?
Heidi Harvie: So if it's stress incontinence and I go down my algorithm, and when they're ready for a procedure, I present both periurethral bulking and sling and go over the data—office procedure, OR procedure, success rates, how long they last—and talk about that. Same thing with the urge: after they've failed conservative measures, I offer PTNS. And then at the Botox discussion, I also talk about sacral neuromodulation.
So I offer all of these in the mix. When it's mixed incontinence, as you know, you're balancing between the two algorithms. There is no one algorithm. So you're sort of integrating the two algorithms and trying to elicit patient preference. So it gets complicated. So we're trying to expand the data to help physicians counsel patients and for patients to make these decisions. So I offer everything when I'm with the patient.
David Staskin: OK. I'm always amazed by this patient preference thing because I practiced for 30-some years, and I always thought I was giving the patients what they wanted. But that's a little bit new for me. But let's do it a different way. A 55-year-old woman walks into my office, and she complains of frequency and urgency. And we do the UDI, and she has stress, and we examine her, and she leaks urine on a cough.
And it's a significant amount of urine. It's not 10 coughs and one little drop that comes out. And we do this whole thing with her, and she's gone through all the other therapies. I have a sense that the patients watch you, like they're behind the glass in a detective show. And as you give them all these alternatives, if they don't say it, what they're really trying to find out is what you think is the best thing for them.
In other words, they say, Dr. Harvie, I came to you because you're supposed to be an expert. And my doctor actually sent me in here, and I have to deal with the parking down here by Pennsylvania Hospital. And I'd really like to know what you think I should have. Again, are you really considering the patient preference where you know she has a little bit of ISD, and you know she might benefit a little bit better from a sling? Are you willing to go in the sling direction if the patient doesn't have a problem with mesh, for instance, or you're not going to do a pubovaginal sling?
Heidi Harvie: So I seriously do push back on the patient. I'm like, what do you want to fix? What is the problem that brought you in here? And if they say urgency, I'm like, OK, maybe we should try that first. If I elicit ISD-level leaking, then I do present that to her, and I do tell about the data for the sling could help that. But if she had zero stress symptoms, then I'm a little hesitant on pushing a sling if she hasn't—
David Staskin: In the study, how was the botulinum toxin done? Was it done in the OR? Was it done with sedation? Was it done in the office? How was it done?
Heidi Harvie: It was done in the office. Based on location and the individual practice, the majority of it was done in the office.
David Staskin: Right. So a patient who doesn't mind an office—they were randomized. I think the audience should know, the people listening should know that these patients had to say, I'll have whatever's assigned to me in order to randomize them in the trial. And those patients who ended up with an office procedure were then sort of asked whether they wanted to go to the OR if their stress incontinence was still bad, as opposed to somebody who had already been in the operating room and now just needed an office procedure.
So I can understand how that bias comes into play. There have been a couple of studies, though. One was the SLIM study that looked at botulinum toxin plus sling versus sling, and ESTEEM looked at behavioral plus sling versus sling. And now we're looking at sling versus toxin. You're the cost-effectiveness analysis expert here.
And you just want to wonder whether you're taking somebody to the OR, they're going to have a sling back there, and you're right there with your 100 units in the cabinet. Is there an argument for, they're there, they're going to have a procedure—we know the sling might make their urgency better, but should we do this in combination at the time of a surgical procedure?
Heidi Harvie: So I just want to point out the other two studies, SLIM and ESTEEM, were done in patients who were already planning a sling. So it's a different population. They weren't refractory. ESTEEM, they didn't need to fail meds or behavioral because they were doing that, and they were already going to the OR. So the recruitment was done after they were already planning a sling. So really, it's a different population.
But in terms of the—we will be doing a cost-effectiveness study on our study results on that. And we've talked about doing, in this patient population, looking at whether we should just do them at the same time. But first, we wanted to look at if, given that urge symptoms are generally more bothersome, we can do an office-based procedure and get similar results. That's much more cost-effective than going to the OR—at least it depends on how many years you go out.
Yes, doing both at the same time—yes, you're already there, they're paying for both, the reimbursements for both procedures, but it's much better for the patient going there. But I can't really compare the results based on those other two studies.
David Staskin: Well, I was so impressed by the urge data from the UDI to look at the idea that a sling helped their urge symptoms so much that—if you ask me, traditionally, the decision in my office for me would be to resolve, or at least find out whether they're going to respond to urgency treatment before operating on them. Because after I fix their stress incontinence, if they still had urge incontinence, they weren't going to be happy. And I didn't want to operate on them if they weren't going to be happy afterwards.
So that was the biggest thing here. It was like, geez, you do a sling—Peter Sand reported this years ago with the transobturator sling, where he said the urgency got a lot better. And I wasn't sure if I believed it. I mean, it was Peter's data, and I knew he did a good study, but it just seemed counterintuitive to me. And Ed McGuire said it when they were doing autologous slings and said, geez, just do the sling, fix their stress incontinence, and sometimes their urge gets better.
What do you think? Is moving through the bladder neck to the mid-urethra or some support that these mid-urethral slings are giving adding some benefit? I mean, the proximal urethra still opens—all the theories we had about why urine entering the proximal urethra provokes the stress. What do you think's going on?
Heidi Harvie: So I can't really comment—I'm not a basic scientist in terms of the details there. But there really is increasing evidence suggesting that maybe there's some common pathophysiology process explaining both the concomitant stress and urgency symptoms coexisting in women with mixed incontinence.
So I think looking at the mixed incontinence patients as a separate group, as opposed to just overlaying the stress and urge, can be very beneficial. But yeah, our hypothesis was that the botulinum toxin would be superior at taking care of the urge better. But while at the six months, the sling had very good improvement of the urge—no difference in the urge symptoms and superior stress.
David Staskin: Why not fix both seems to be—
Heidi Harvie: Get a bang for your buck. It's like the data's showing just go to the sling.
David Staskin: All right.
Heidi Harvie: However, 30% of them had the botulism toxin by 12 months.
David Staskin: And I'm not surprised by that.
Heidi Harvie: So in counseling the patients now to say, OK, this is the biggest bang for the buck we got, but in this trial, 30% of patients went on to get the botulinum toxin. Now I agree there was—in a study, I think patients might be more anticipatory of getting both treatments, and it's just an office treatment, lower threshold for getting it. I completely agree.
But counseling them that it's not perfect, and that you're punting on the urge, but it might be great, but you might need to do additional treatment on it.
David Staskin: Right. Well, I mean, and that goes back to me saying to myself, if in this study one third of patients still needed the injection, is it worth finding out whether people are responders or not for their urge symptoms with injection to just do injection first on everybody and send them out? So it's not what this study was, but it does influence the way—or actually, when you read these studies, it justifies what you're doing no matter what you're doing. So it's always the intersection between science and clinical medicine. I have one more little thing that interested me about the study: urodynamics.
Urodynamics was done within a year of entering the study so it didn't have to be repeated, correct? Those patients were accepted. So were there urodynamics at the end?
Heidi Harvie: We did not repeat them after the study. No, we did not. We—
David Staskin: Right. So what people also have to realize here—or take into account, which is interesting as you start to interpret this, because there's a lot of data you have on looking at who was a responder and non-responder, and switchers and non-switchers, although the numbers aren't that big to be able to really statistically determine that.
But the UDI—and I was the head of the group that wrote the thing on looking at these metrics for evaluation of patients for the ICI. And normally, I wouldn't know that much about it, except I was forced to read the chapter as the person who was the lead author. And when I look at this, is that the outcome?
I mean, when we deal with BPH in urology, we deal with obstructive and irritative symptoms, which is interesting because we have an IPSS score and it doesn't really—like I always say, if a man is incontinent, that bothers him more than a slow flow, right? But they're all 1, 2, 3, 4, 5, and there's no weighting of the bother of the symptoms.
So when you use the UDI and it's I'm minimally affected or I'm greatly affected and you sort of go through this scale, is it the best way to make all the conclusions? If you're going to do it again, now that you've seen the data, would you have measured something else, or even a cough test at the end to find out whether they were really dry?
Heidi Harvie: So in terms of a primary outcome, we wanted a patient-reported outcome to focus on patient symptoms and their bother. And we wanted an instrument that included both stress and urge symptoms as one. Also, the UDI was a primary outcome for ESTEEM, allowing us to do combined analysis and sort of compare the outcomes.
So something that would equally incorporate stress and urge symptoms for the mixed incontinence was important. And looking at everything that was out there and also, again, consistency with ESTEEM, we went with that. But we had secondary outcomes, including the stress and irritative subscales, and also patient global impression of improvement, bladder—we had the full breadth.
Everybody had a positive cough stress test whether in urodynamics or on the table before. They had to have a positive cough stress test. So we wanted objective evidence of stress and urge, and we wanted symptomatic, moderate to severe bother on the question for both stress and urge. And we did have bladder diaries, and there was a required minimum of four urge leaks.
So we were trying to make it a severe refractory population going in. But we wanted, yeah, a patient-reported outcome that combined stress and urge. So that's where we got—
David Staskin: If it was a pharma study, we would have called it real life.
Heidi Harvie: Yeah.
David Staskin: Yeah. Listen, Dr. Harvie, this has been tremendous. We always joke about, when we do these things, whether we learn anything. I've learned a lot. I hope everybody listening today has. And really thank you for joining us. And hopefully, we'll have you back to talk about the study again when you process more data.
Heidi Harvie: Thank you very much. Appreciate it.
David Staskin: Excellent. Thank you.