Giulia Ippolito: Thank you so much for this opportunity to present and work with UroToday. This Cochrane review started back in 2018 when I was a fellow in neurourology and pelvic reconstruction here and doing a master's. And it really came out of my interest into better understanding vaginal lasers, but also the methodology of systematic reviews and meta-analysis. I want to highlight what you mentioned, that this was an abridged Cochrane review published to the Journal of Urology and the full review is available through the Cochrane Library that has much, much more details than we could include in the Journal of Urology review. So why do we care about vaginal lasers for stress incontinence and how could they work to treat this condition? So lasers are used in a number of treatments throughout the body and the mechanism for lasers is a controlled heating of tissues, which leads to new collagen growth, which for the urethra is hypothesized to potentially decrease urethral hypermobility, which would then help with stress urinary incontinence.
When we think about lasers, there are many different types. We know the medium can change, there are CO2 lasers or Er:YAG. Both of these are used for vaginal procedures. And then we look more into how these lasers affect the tissue. So ablative lasers are generally more harsh. So they vaporize the tissue and they cause a surface reaction that requires more recovery time. Whereas non-ablative lasers, which are what typically are used for vaginal procedures for stress incontinence, heat deeper and leave the superficial skin intact so that there's less of a reaction and less local side effects, but it takes more time to achieve that effect. And then there's this concept of conventional versus fractional. So conventional lasers, if you have a surface that the laser is targeting, the conventional lasers will apply treatment to the entire surface, whereas fractional lasers, as they're named, only cover like a certain part of that surface. So they have a way to target just portions of the entire surface. And it's important to know that there are these differences because when we think about systematic reviews and meta-analysis, every time there's heterogeneity in how something can be done, then that adds a little bit of heterogeneity and uncertainty to our results.
And so that is important to keep in mind with this review. And a lot of the premise behind why we did this systematic review was that vaginal lasers have a potential to provide an office-based solution for stress incontinence. And a lot of people have been exploring them in clinical use, but there really wasn't a lot of robust evidence behind them. And in 2018, the FDA actually put out a letter to the device manufacturers that weren't against the marketing of lasers for symptoms that they were calling vaginal rejuvenation, including menopause, incontinence, or sexual function. And our societies really have not recommended the use of vaginal lasers because there wasn't great data one way or another to make our recommendations. The only guidelines that mention lasers for incontinence are the NICE guidelines, and those are really only in the context of a trial. So we had this situation where we have a potential technology that could be helpful, but the data is unclear, and there were multiple trials in this data. So we looked at this as a opportunity to perform a systematic review. And when thinking about the timeline of this, this 2018 FDA letter was a little bit what spurred me to do this review. It came out in 2018, which is when I started this project.
So the main goals of this systematic review was to assess the effect of vaginal lasers specifically for stress urinary incontinence. And we also attempted to perform an economic evaluation, but there really wasn't enough data to provide any evidence for that. We included just RCTs of women with SUI, and we assessed vaginal lasers compared to sham or control treatments or topical lubricants. So this would have been like estrogen or some studies randomized people to like moisturizers. And what we found were, overall, we came up with nine studies of just shy of 700 women. Five of these used CO2 lasers and four used the Er:YAG lasers. The follow-up time on the whole was short, so usually on the span of three. There were a couple of studies that provided 12-month data. But for the most part, the data was less than one year follow-up. And we'll talk about this more, but when we assessed the evidence for the outcomes that we were looking at, overall, every outcome had very low certainty of evidence.
I spoke that we started this review in 2018, so Cochrane is very robust in requiring a systematic review to be up-to-date. So we've updated our search several times before publishing, and the most recent search was done April of 2024. When we think about outcomes for systematic review, we really want to focus on patient relevant outcomes. So the primary outcomes we chose were the number of continent women after treatment, the improvement in urinary incontinence as measured by patient-reported outcome measures, and the number of major adverse events. There were many more secondary outcomes, but these were the primary outcomes that we were focused on. And we talked a little bit about the certainty of evidence, but we used for the systematic review, the GRADE approach, which is a transparent and structured process to develop certainty of evidence based on four main domains, which are risk of bias, inconsistency, indirectness, and imprecision. And you'll see in the review, there is a summary of findings table and there are these little symbols about what the quality or the grading of the certainty of evidence is.
And these are meant to communicate to readers how certain we feel in the results of this systematic review. And it's really important to keep in mind that every single outcome had very low certainty of evidence. And so that means that we're very uncertain to where the true effect is of the finding and could be substantially different from what we're reporting here. We briefly touched on this before, but we started with 271 records and after excluding studies, we came down to nine studies. And one thing I want to highlight is that unfortunately we had to exclude randomized trials of vaginal lasers that were done in women with genitourinary syndrome of menopause, many of which who did also have incontinence because we were not able to tease out the data of the stress incontinence separate from maybe urgency incontinence or their other symptoms. And so that was one of the limitations that we couldn't include all of the studies of vaginal lasers because they weren't reporting separately on those with stress incontinence. When we looked at our risk of bias, the main source of bias in these studies was there was a lack of blinding of participants and personnel. So even though in some studies, they did blind, they did have a sham control trial, while the participants were blinded, the personnel might have not been, or the outcome assessor. So it increased the risk of bias. Okay. So sort of let's get back to our primary outcomes and the results.
What did we find? So for the number of continent women after treatment, and this was in the short term, less than one year, and reported by the trialists, we had three studies, and we found that there was no evidence of a difference in the number of continent women between those who underwent laser and those who underwent sham. And again, this was very low certainty of evidence due to the risk of bias between studies and also the inconsistency or the width of the confidence interval that spanned the null. We also looked at patient-reported improvement incontinence and many more studies reported on this. So we had a total of eight studies and we were able to do... We had pre-planned in our pre-published protocol a subgroup analysis looking by type of laser.
So I was happy that we could report based on laser type. And we did find that while vaginal lasers may improve patient-reported incontinence measures based on the ICIQ-UI short form, the point estimates, so if you can see here, improving it by two points, didn't meet the previously published thresholds of the minimally important difference, which is usually a five point decrease. So while it could have a improvement in patient-reported urinary incontinence, that improvement might not be clinically significant and patients might not be able to detect that difference. And sorry, going back to that, when we looked at the subgroup analysis, there are tests to see whether the subgroups were different than the overall, and we found that actually the subgroup didn't show any difference between the different lasers and the overall finding that it's the same conclusion, that it didn't meaningfully change the patient-reported improvement in urinary incontinence.
Overall, when we're looking at our summary of findings for vaginal lasers, and this is compared to sham, we did a separate analysis comparing to estrogen, which had very limited data, so I won't present it here. I think the things for readers to keep in mind is that one, the certainty of evidence is very low. So the true effect might be substantially different from what we found. But we didn't find a difference in the number of continent women as reported by trialist. And even though there might be a difference in patient-reported incontinence, it does not appear to be clinically significant. And then for major adverse events, one thing that we could find is there were no major adverse events reported among any of the studies. So while there were minor adverse events, so I think the studies were reporting adverse events, there were just none that were major. So that means that it's unlikely that you're going to suffer a major adverse event from this therapy based on the data that we have. So that's the recap of this study. I'm happy to take any questions.
Alan Wein: Great. So in these studies, was this one treatment or a series of treatments?
Giulia Ippolito: Yeah, that's a great question. So most of the studies did three treatments, a couple did two, and usually it's about 30 days apart, but that was another source of heterogeneity. So most of the studies did three treatments that were about 30 to 45 days apart.
Alan Wein: And in the ones that reported positive effects, even though they didn't meet the level of clinically significant, was that right away or did that take a while to do? The follow-up extended for 12 months, so was that the final determination of outcome in most of these at 12 months?
Giulia Ippolito: So actually only one, I believe only one study had a 12-month follow-up. Most of the studies were in the short term, so three to just shy of 12 months. I'm going to re-share because one of the figures has the granular data in there. So you can see in the footnotes when everything was measured. And for this, we used the longest follow-up time that that study had for this analysis that was within the short-term period. So I think I mentioned before, most of these studies did not report beyond three to six months data.
Alan Wein: Right. Was the rationale when the lasers were used that you could come back, let's say in the people that reported a positive result and then it disappeared, was it possible for them to come back again and get retreated or not? In other words, was this meant to be a repetitive treatment when it wore off or was it meant to be one treatment, one series of treatments, and that's it, and then if you weren't satisfied, you had to go on to something else?
Giulia Ippolito: So in these studies, they had a protocol that had a set series of treatments. So they were randomized and they underwent either two or three treatments based on the protocol. There are some observational studies where they looked at repeated treatments or sort of like what we call maintenance treatments, but we didn't include those in this data. This was all randomized to a certain treatment protocol. And there were no studies that I can recall that pulled out people or continued therapy for people if they had a positive effect. That wasn't something that I saw.
Alan Wein: Were there any studies that you saw either, well, looking at the studies that you included or just looking at the literature on vaginal lasers that actually looked at urethral mobility before and after, since that was one of the rationales for shrinking this tissue?
Giulia Ippolito: I do not think there were any studies that I can call off the top of my mind that measured urethral mobility. There were some studies that did tissue biopsies to look at collagen, and there's some studies that look at the genitourinary syndrome of menopause, they have a score based on the tissue properties. But I actually don't recall that any studies looked at tissue mobility as a objective measure. That is actually a really interesting thing to look at to understand the mechanism of how this could work.
Alan Wein: Yeah. I mean, most of the time, I mean, my impression is that most of the time if you shrink something, if you shrink collagen containing tissues, that eventually if you keep stressing, it wears off and it goes back to the way it was before, except maybe it's a little more wrinkled. That's just kind of my impression. Did the studies that included patients with GSM, genitourinary syndrome of menopause, did they show any improvement versus sham treatments or versus estrogen cream or anything like that?
Giulia Ippolito: So there are studies that show some improvement, but I would say I would redirect readers to the AUA guidelines on GSM. They looked at that data very thoroughly through a separate systematic review that was done by AHRQ and they put out, they have two statements in the guidelines. So their main statement is that clinicians should counsel patients that the evidence doesn't support these lasers for GSM related symptoms, especially the dryness, irritation, discomfort, quality of life, or dyspareunia. So the AUA guidelines looking at all that data said that it doesn't support its use. However, there were some studies that found that there was no difference between lasers and vaginal estrogens for certain GSM symptoms, especially dryness, discomfort, dysuria, and dyspareunia. So the guidelines also go on to say that using shared decision making and disclosing to patients that these are experimental outside of clinical trials, you could consider these in people who are not candidates for estrogen because there were some data to show that it's not different from estrogen.
Alan Wein: Gotcha. Did any of these studies look at, besides subjective evaluations of the patient-related outcomes, did they look at pad weight or anything like that or just sort of total dryness? Or in other words, the ones that were said to be totally dry, were they said to be totally dry because they subjectively said, "I'm totally dry," or was it actually measured in some way?
Giulia Ippolito: So the outcome determined by the trialist, that primary outcome was cough stress test or pad weight.
Alan Wein: Ah, okay.
Giulia Ippolito: Those were what I recall as being the ways that we said the objective measure of dryness as... And so they would do a cough stress test usually or pad weight.
Alan Wein: Right. Do you remember what the percent was that were, the average percent that was totally dry?
Giulia Ippolito: So there were three trials that looked at that and the total number of people in the laser group were about a hundred, and there were 47 dry people in the laser group, so about 50%. And then in the sham group, there were 26 out of 95. But even when you pulled that data and weighted it based on the studies, it came out that it really wasn't a difference and it spanned the null. So if you put all that together, so I think the question you're asking was the proportion of people dry in the laser group, and it seemed to be about 50%.
Alan Wein: They didn't say how long it lasted?
Giulia Ippolito: So that data was, one trial was three months and it was a cough stress test and then the other were four and six months of outcomes. So it would've been at the six-month point. And we don't have data beyond 12 months, so that was the longest study.
Alan Wein: I mean, do you think you could go back and do it again in the ones that were dry and then got wet again?
Giulia Ippolito: Yeah. I mean, I think the mechanism is that you could repeat this, especially because it seems fairly well-tolerated. There are no major adverse events. It's an office-based procedure. So I do think that it is something that you can offer. I know that for other uses of lasers, people will have repeated treatments. And one thing I would worry about is, and I think maybe that's the difference between ablative and non-ablative, is that non-ablative is more gentle. Maybe repeated treatments can happen if it's helpful. But at this point I'd be pretty hesitant to recommend it at all outside of a trial. I do think we need people to think through the questions you're asking is if we're going to trial this, what is the correct protocol to trial it? And if people have a success in that trial, should we design the trial in such a way that we can do maintenance or repeat it or look at people in the long term?
Alan Wein: Right. Great. Well, thanks very much. I think everyone has improved their knowledge about vaginal lasers for stress incontinence. And thanks to you for spending the time to do those reviews, because I know that they must be terribly arduous and take a very long time.
Giulia Ippolito: Thank you so much.
Alan Wein: Thank you so much.
Giulia Ippolito: All right. See you.