Heidi Harvey: Thank you for allowing me to present our results of the Midurethral Sling versus OnabotulinumtoxinA in Women with Mixed Urinary Incontinence trial. As you know, 50% of women with urinary incontinence have mixed urinary incontinence, a combination of stress and urgency urinary incontinence. Women with mixed urinary incontinence often have more severe symptoms, and 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 incontinence, making it a challenging condition to treat. Treatments traditionally address stress and urgency components separately using a stepwise and segregated approach, starting with conservative therapies and medication. The prior PFDN ESTEEM trial showed that a midurethral sling in women with mixed urinary incontinence helps both the stress and urgency incontinent symptoms. However, there's limited data comparing procedure-based treatment for women with mixed urinary incontinence.
The study interventions were a hundred units of botulinum toxin with a second injection allowed between three and six months versus midurethral 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 for stress and urgency incontinence and a documented positive cough stress test, at least four urgency incontinence episodes on a three-day bladder diary, being refractory to conservative treatments and OAB medications, no prolapse at or beyond the hymen, and no planned prolapse surgery, and no urinary retention. Treatment crossover or additional non-study treatments were permitted after six months. Assessments were performed at baseline, three, six, nine, and 12 months, and our sample size gave us 90% power to detect an MID based on a mixed 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, representing those who had treated and having post-baseline efficacy data. As expected with the randomized trial, there were no differences between groups in demographics and baseline characteristics. Mean age was 59, 77% were menopausal, and 80% were white.
The majority of participants had balanced mixed incontinence, and the mean baseline incontinence episodes per day were 7.2. For the primary outcome, we chose the UDI or urinary distress inventory total score, which would represent the impact of mixed urinary incontinence, both the stress and urgency components, on our patients. There was no difference in improvement in total UDI score at six months. After six months, participants could request additional treatment. The mixed urinary incontinence symptom improvement was maintained through 12 months with no difference between groups. The sling group had a greater improvement in the UDI stress score at six months. Stress symptom improvement was maintained through 12 months. Other outcomes showed that there was no difference in reported improvement in incontinence-specific symptoms, quality of life, and satisfaction. There was also no difference between groups in global impressions of bladder symptoms. We also looked at bladder diary outcomes. 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 episodes per day. Consistent with the chronic nature of mixed urinary incontinence, there was a high rate of additional treatments. In the botulinum 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 rate of 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 study received non-study treatments compared to 7% in the botulinum toxin group. Complications related to the interventions were few. Serious adverse events occurred in 4% in the botulinum 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 self-catheterization greater than two weeks after their procedures. More participants in the sling group experienced recurrent urinary tract infections compared to the botulinum toxin group. In the sling group, vaginal mesh exposure occurred in 3%, and only 1% required sling revision.
Given that mixed urinary incontinence symptoms improved comparably with either botulinum toxin or midurethral sling, with low risk for complications and symptom improvement that was maintained at 12 months, we conclude that both botulinum toxin and midurethral 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, 20% of the botulinum toxin group had additional injections, but 23% of participants received the alternative treatment, with a higher rate of the midurethral sling group getting botulinum toxin than the botulinum toxin group getting a sling. But this study justifies an individualized treatment approach and shared decision-making based on patient preference. I'd like to acknowledge our collaborators in the PFDN. Thank you and appreciate your questions.
Alan Wein: Yeah, so the editorial states that 30% of women over age 65 have mixed urinary incontinence that's pretty significant. Is that an accurate number?
Heidi Harvey: That data wasn't taken from our studies.
Alan Wein: No, I know that. Yeah.
Heidi Harvey: We took it from other studies. But yeah, that is the information that we have at this date.
Alan Wein: Gotcha. So why do you suppose the botulinum toxin injections improved the stress urinary incontinence at all? Is that just a placebo effect?
Heidi Harvey: That's an excellent question. And we've talked about that and debated that internally ourselves. One thought was that women with severe mixed urinary incontinence can't always distinguish the type of leakage-
Alan Wein: Right.
Heidi Harvey: ... that they're really responding to their global improvement in their incontinence and that the botulinum toxin does such a great job on the urge component. And the urge component is generally more bothersome quality-of-life-wise, and the stress that they perceived that their overall leakage or their overall incontinence symptoms were improved. That's why we use the UDI total score-
Alan Wein: Yeah.
Heidi Harvey: ... as our primary outcome because we wanted to assess the total impact on women's incontinence.
Alan Wein: So if Angela was a patient with stress urinary incontinence and urgency urinary incontinence and they were severe like the parameters that you used, I mean, how would you talk to her in a patient physician setting about the advantages and disadvantages of choosing one approach or the other approach?
Heidi Harvey: I still try to elicit what has the greatest impact on the patient's quality of life in terms of the specific instance where they're leaking. But I do present for women with significant mixed urinary incontinence that there are treatments designed for the stress incontinence component and for the urge incontinence component and sort of go through the risk benefits of all of them. But for women who have been refractory to meds and the conservative treatments and all, then I do present the sort of data from this trial a bit saying that an incontinence sling can help really good with the stress incontinence. And you might get a pickup, it should help some on the urge symptoms versus a botulinum toxin injection is an office-based procedure, no mesh, no surgery, and it can also get really good results and then let them think about it. Now, the sling might be the biggest thing we have to the one-and-done kind of approach. But you have to counsel these patients that they still will have to work on the urge component because by one year in the MUSA trial, a large number of patients in the sling group had crossed over to get the Botox as well. So obviously, they still had some urge symptoms that were unmet.
Alan Wein: So for the ones that got Botox who didn't require a second injection, let's say up to 12 months, do you anticipate that those people are going to require an injection at some point or did they just sort of improve for whatever reason on a semi-permanent basis?
Heidi Harvey: I would expect they would need another injection.
Alan Wein: Yeah.
Heidi Harvey: We were actually surprised at how low the re-injection number was-
Alan Wein: Right.
Heidi Harvey: ... because we counsel them, this is a recurring treatment, and we were surprised because they could have had a free injection by the three months and only a small percentage of them took advantage of that. I mean, it was covered by the study, so that was surprising. But yeah, I do with the chronic nature of mixed incontinence, particularly the urge symptoms, that I expect them to need continued treatment.
Alan Wein: So one last question that has nothing to do with your study. In this particular group of people that had pretty clear symptomatology, do you think that urodynamics would've been of benefit? In other words, complex urodynamics, either just pressure-flow or videos?
Heidi Harvey: Excellent question. Everyone received urodynamics-
Alan Wein: Right. Yep. Yep. Yep.
Heidi Harvey: ... that was required for the study, and that paper is forthcoming.
Alan Wein: Right.
Heidi Harvey: Because one thing we are trying to look at is what are predictors from the urodynamics-
Alan Wein: Right.
Heidi Harvey: ... that might help inform which patients would do better with which treatments.
Alan Wein: Any hints?
Heidi Harvey: It is not. No, not yet.
Alan Wein: Because that'll be really very interesting-
Heidi Harvey: Yes.
Alan Wein: ... as to whether that changed in any way what you were going to do or when you described the results to the patients, whether they change their mind as to whatever they were going to do. I'll look forward to that one, and we'll probably have you back to discuss that. Okay?
Heidi Harvey: Absolutely. Would love to. Thank you.
Alan Wein: So listen, thank you so much. And really, I think that was a great paper and I really enjoy the discussion on camera.
Heidi Harvey: Thank you.
Alan Wein: Take care.
Heidi Harvey: Thanks a lot.
Alan Wein: Bye.
Heidi Harvey: Take care, Alan.