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AUGS/IUGA Scientific Meeting 2019
Long Oral Session 5 - OAB
Long Oral Session 5 - OAB
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by Jennifer Anger. Good morning, members and guests. Thank you for the opportunity to present the 2019 Guideline on Recurrent Urinary Tract Infections in Women. Sixty percent of women will experience symptomatic acute cystitis in her lifetime. An estimated 20 to 40 percent of women with one episode of cystitis will have another one. Of these, up to 50 percent will experience multiple recurrent UTIs. Overuse of antibiotics leads to what we refer to as collateral damage. The definition of collateral damage is injury inflicted on something other than an intended target, specifically civilian casualties of a military operation. Collateral damage from cephalosporin or quinolone therapy results in the selection of drug-resistant organisms and the unwanted development of colonization or infection with multi-drug-resistant organisms. In the past 20 years, antibiotic resistance has increased dramatically. ESBL-producing isolates have been described among patients with simple cystitis worldwide. Uncomplicated UTI is one of the most common indications for antibiotics in otherwise healthy women. Fluoroquinolones have been linked to infections with MRSA and increasing resistance in gram-negative bacilli such as pseudomonas. Broad-spectrum cephalosporins have been linked to subsequent infections with vancomycin-resistant enterococci, ESBL-producing klebsiella, beta-lactam-resistant acinetobacter, and clostridium difficile infections. As we know, we don't want to use fluoroquinolones nearly like we used to. When I was a resident, we gave everybody Cipro. And often, if you've ever treated a patient who's married to a doctor who's a non-neurologist or non-gynecologist, they're always given Cipro without any cultures. Fluoroquinolones, as you know, can cause arthralgias, tendon rupture. There's association with mental illness and also poorly controlled diabetes. Stewardship is the activity or job of protecting and being responsible for something. The careful and responsible management of something entrusted to one's care. Antibiotic stewardship refers to a set of coordinated strategies to improve the use of antibiotic medication with the goal of enhancing outcomes, reducing resistance, which is our biggest fear, and decreasing unnecessary cost. There are two excellent pieces of work. One is the best practice statement by the Ogg Society, with Linda Brubaker as the first author. And the other is a rapid review with practice recommendations by Arianna Smith. These both were done sort of in parallel with our guidelines. They're very similar to our guidelines. Our index patient is an otherwise healthy adult woman with an uncomplicated, culture-proven, recurrent urinary tract infection associated with acute onset of symptoms. Acute cystitis is a culture-proven infection associated with symptoms, mainly dysuria, in conjunction with variable degrees of urgency, frequency, hematuria, and newer worsening incontinence. A complicated UTI is an infection in someone who has a risk of persistence of such an infection, an anatomic abnormality, a prior sling, immunocompromised state, or multidrug-resistant bacteria. An uncomplicated UTI is an infection in a healthy patient with normal anatomy. A recurrent UTI is defined as two culture-proven episodes of cystitis with symptoms within six months, or three episodes within one year. And as we think about it, you can't really have three in a year without having two in six months, but we still like to think of three in a year. Asymptomatic bacteriuria, or ASB, refers to the presence of bacteria in the urine that cause no symptoms or illness. Dysuria is central to the diagnosis of UTI. We see patients with multiple symptoms, and many of them think they have a UTI, and it's important to really try to hone in on whether or not they have dysuria. Acute onset dysuria is highly specific with more than 90% accuracy for UTI in a young woman in the absence of vaginal irritation or discharge. Acute symptoms should occur in conjunction with the positive culture. Before the guideline was developed, a systematic review was conducted by a methodology team. Analysis of data from the final systematic review was conducted in conjunction with the expert panel. Searches of three databases were performed and supplemented by reviewing the relevant list of articles. An updated search was conducted on September 20, 2018. The database found over 6,000 articles, 214 systematic reviews were selected for full review, 65 studies and 67 publications were determined to meet inclusion criteria, and then an additional 10 publications were identified in the updated literature search and added. So we will start with the guideline statements. Number one, clinicians should obtain a complete history and perform a pelvic exam in women with recurrent UTIs. This isn't a problem for most of us in this room who are used to doing pelvic exams, but most people probably don't do them when they're prescribing antibiotics. We want to determine their symptoms. Do they have wording difficulty, other frequency urgency? Do they have dysuria? We also want to know if their symptoms respond to antibiotics and if there's a way between infections. A physical exam should then be performed to identify any associated abnormality which may be contributing to symptoms such as vaginal atrophy, cystus seal, which could be contributing to incomplete emptying. We also, if there is a possibility of incomplete emptying, we often like to check a post-coid residual by ultrasound. Two, to make a diagnosis of recurrent UTI, a clinician must document positive cultures associated with prior symptomatic episodes. So this is saying if a patient comes to you and says, I've had 20 UTIs, you want to say, let me see the cultures because you don't know, we don't know what they have without culture evidence. So that's very important to establish a true diagnosis. And then we want continued documentation of cultures during symptomatic periods prior to starting antibiotics. That's very important. Our days of empiric antibiotics are gone. We want to get a culture whenever possible. Three, clinicians should obtain repeat urine studies when initial sample is suspect for contamination. As many of us know, we see multiple, what we call contaminated samples. Growth of organisms thought to be contaminants, lactobacillus, group B strep, bacteria, coag negative staph, these do not require treatment. When there's a high suspicion for contamination, we consider strongly a catheterized sample before initiating treatment. And as we know, whenever there's vaginal epithelial cells in the urinalysis, we think contamination. Four, cystoscopy and upper tract imaging should not be routinely obtained in the index patient presenting with a recurrent UTI. They're not necessary unless a patient doesn't respond to antibiotic therapy. At that point, they will necessitate an upper tract workup. Cystoscopy will identify any anatomic or structural abnormalities. Or for example, if a patient has had a prior sling, you might identify sling in the bladder. And that's where it's important. If you're looking for stones, possible mesh, a fistula, or a urethral diverticulum. Five, clinicians should obtain urinalysis, culture, and sensitivity with each episode before initiating therapy. It's okay to take a culture and treat with antibiotics, even because cultures, as we know, take two plus, three, four, even five days to grow. So it's okay giving antibiotics as long as we know the samples in the laboratory. And this recommends both urinalysis and culture because it's very important. A positive culture with a normal urinalysis doesn't necessitate antibiotics. Such information from urinalysis may indicate that obtaining a catheterized sample is reasonable if we're concerned about contamination. Clinicians may offer patient-initiated treatment or self-start to select recurrent UTI patients with acute episodes while waiting for culture results. And this is new when, again, the idea of self-start back in the day was that patients would have a bottle of antibiotics and then they would take their own antibiotic course when they had symptoms. The problem with that is we don't know what we're treating and now with the high incidence of antibiotic resistance, we really don't want to do that anymore. And particularly, I've often noticed when patients have antibiotics, they'll have some symptoms and they'll pop one pill for symptoms. There's a lot of misuse and so we no longer want to perform self-start without cultures. Do we have exceptions in the reliable patient who's about to leave for vacation in another country tomorrow? Yes, we sometimes still give antibiotics and even, you know, I often get upset because I chaired the guideline panels and I still have patients twisting my arm and I end up doing the wrong thing. So we often still, we just try our best. Seven. Clinicians should omit surveillance urine testing including urine culture in asymptomatic patients with recurrent UTIs. So this means in between episodes, we don't want to know what they have. If you don't have symptoms, we don't want to know about it. And that's what's different with this guideline. Without symptoms, bacteriuria is considered asymptomatic bacteriuria or ASB. We don't want to know about it. Unless, of course, the patient's pregnant or if they're about to undergo urologic procedures like removing of a kidney stone or anything requiring cystoscopy, if they have ASB, we will treat it for purposes of the procedure. There's no evidence that identification of ASB between episodes provides useful diagnostic information. Eight. Clinicians should not treat ASB in patients. And this is a strong recommendation based on grade B evidence. This is very hard not to do but we don't want to do it. We don't want to treat patients without symptoms. And it shows, and there's actually good evidence, that when antibiotic treatment was associated with an increased risk of recurrence and development of antibiotic-resistant organisms, there's actually, this evidence suggests that ASB is actually preventive and prevents the development of symptomatic UTIs. Clinicians should use first-line therapy and this is very similar to the OGS guideline statement and this is based on a systematic review of 12 RCTs. Nitroferantoin, 100 BID times 5 days, trimethoprim sulfamethoxazole, double-strength BID times 3 days, or phosphomycin, which is really from back in the day and it's come back, it's mostly come back because it covers ESBL, which is really hard to treat. It's a single dose, it's a powder that's mixed in water. It's one 3-gram single-dose powder. It's not well covered by insurance so we tend to use the first two most commonly. These do minimize collateral damage, particularly nitroferantoin because it really is, for the most part, isolated to the urinary tract. Clinicians should treat recurrent UTI patients with an acute cystitis episode with as short duration as possible. Again, I showed you the dosages. Single-dose antibiotics were associated with rapid recurrence of infection, but when you look at short course, 3-6 day versus longer course, there's no benefit in that longer course. In patients with recurrent UTIs with acute cystitis episodes associated with cultures resistant to antibiotics, clinicians may treat with culture-directed IV antibiotics for as short a course as possible, generally no longer than 7 days. And this is for cystitis. We hate to admit patients for cystitis, but in this era of ESBL, we've had to do it more often. Often, consultation with an ID specialist can avoid hospitalization because they're much more able, at least more able than our office, to arrange for antibiotics at home. Following discussion of the risks, benefits, and alternatives, clinicians may prescribe prophylactic antibiotics, and this is based on a moderate recommendation, grade B evidence. This includes trimethoprim. That's often best for patients with an allergy to sulfa. You can do trimethoprim sulfamethoxazole once a day of every other day or three times weekly. Nitroferantoin, 50 milligrams daily. This has the lowest risk of collateral damage. And then there's Keflex and even fosfomycin, three grams every 10 days can be used as prophylaxis. Antibiotic prophylaxis in women who experience post-coital UTIs. The use of antibiotics is associated with a significant reduction in recurrence rates. And often, if patients say, no, there's no relationship, I try to ask a few more questions. Do you live with your husband? Yes. How often do you have intercourse? Oh, about three times a week. And at first, I'm jealous, and then I tell the patient, you probably are having UTIs related to intercourse. You're not going to know unless your husband's out of town. So those, I often will try them on prophylaxis first because you tend to take it less often, obviously, than every other day. So the next step is following discussion of risk, benefits, and alternatives. Antibiotics may decrease the risk of UTIs in women of all ages previously diagnosed. And these are the options for the sexual activity. We say within an hour before or after intercourse. And again, it's the same drugs, Bactrim, Nitroferantoin, or Ceflex. There's no evidence about front and back wiping. There's no evidence about circumcision, about making your husband use Purell on his privates. There's no evidence in showering. So what you really, the one evidence we have, the only evidence for behavior modification is increased fluid intake, and even that didn't have enough evidence for the guideline. So really, prophylactic, it's the act of intercourse that really is what causes the recurrent UTI. It's usually the patient's own local bacteria. And so a lot of that is re-counseling patients. We've looked for evidence, and there really is no evidence on all those behavior modifications. A conditional recommendation, which we graded grade C, although the evidence shows grade B evidence, is cranberry prophylaxis. And I want to be able to tell you this is the drug to use because it works. All I can tell you is the study showed that cranberry works, but no study used the same formulation, and there's a huge range between juice, powder, tablets, and even cranberry, actual fruit. They show promise, and that's why it's a conditional recommendation because we just need more evidence. But unfortunately, based on what the evidence available, the cranberry formulations used were not actually necessarily available on the market. We did not make a recommendation about the lactobacillus, although probiotics do show promise, and Dr. Arianna Smith's practice statement did highlight the promise of lactobacillus. We did not make a recommendation about water intake because there's only one study, but it did show that women who had a baseline low fluid intake, increased fluid to over 1.5 liters of water a day, they had reduced infections with basically from 3.2 to 1.7 UTIs per year, a lower likelihood of having recurrent UTIs with 3 in a year, and a longer interval between episodes. But we need to validate these studies in larger studies and also in studies in which patients might have varying amounts of water to start. Clinician should not perform a post-treatment test of cure. We don't want to do a test of cure. And that's important. That's going to be hard to change because I know a lot of us like to do that. If the patient's symptoms go away, that's all we want to know. If we check a test of cure, their symptoms are gone and we find bacteria, then what we're doing is looking for ASB, which we don't want to treat or look for. Clinicians should repeat cultures to guide further management when UTI symptoms persist. And this is very important. Many women have persistent symptoms and the bacteria is gone, but they have persistent irritation. Often you see interstitial cystitis, bladder pain syndrome presents like a UTI, and they often come to you having had four different courses of antibiotics. So it's very critical to, even if you're going to treat them, to get that culture before you change your antibiotic. That's critical. In peri and postmenopausal women, clinicians should recommend vaginal estrogen to reduce the risk for future UTIs when there's no contraindication to estrogen therapy. And this is a grade B recommendation based on good evidence. I don't need to tell this group too much about the different options between tablets and rings and creams. What is nice, if you don't have a compliant patient, the ring can be nice in that way because you really need to have that compliance to make estrogen work. Many of us say, oh yeah, I have it in my drawer. It's very important to tell them that in the drawer it's not going to help. You have to actually use it. And that's a very important element. I want to also highlight the guidelines. There's an algorithm available also. And thank you to the AUA and our panel members who were a wide representation. We had patients, AUGS members, SUFU members, Canadian Urologic Association. So we tried to capture a variety of perspectives. Thank you. Overactive bladder affects millions of women worldwide. And we know there are numerous ideologies but the majority of cases are still classified as idiopathic. As a result, we have a bunch of hammers and it's not always a nail that we're treating. And every woman is basically undergoing the same care pathway with behavioral therapy, then medication, followed by third line therapy. Anticholinergic specifically are by far the most ubiquitous treatment but it's far from the most effective. And we know that ineffective treatment is associated with increased patient frustration at best. 15% of patients are going on to more effective third line treatments due to patient attrition. We know that ineffective care has a significant economic burden in both direct and indirect costs. And anticholinergic is not necessarily benign. Aside from the acute side effects of dry mouth and constipation, there's short-term cognitive impairment and now there's a potential association with long-term dementia risk. So it may be advantageous to determine which patients could benefit from an anticholinergic and which could be triaged to a more effective therapy without being exposed to the increased risk. Other potential benefits include improved satisfaction, decreased attrition and potentially a reduction in the economic burden of overactive bladder. Therefore, the objective of our study was to develop a prediction model using machine learning techniques to determine who will fail and who will respond to an anticholinergic treatment. We also wanted to externally validate this model using patients from a different practice setting. We began by collecting retrospective data of patients treated in the last decade for OAB-related complaints. The main inclusion criteria were that patients could not have previously been treated by an FPMRS physician and their complaint had to be exclusively related to OAB with all other etiologies excluded. The main exclusion criteria were any missing data, previous third-line therapy, if their treatment was stopped due to an adverse event or changes in their insurance without any sort of documentation of a symptomatic response or failure. Also, if we felt that the symptoms were related to something non-OAB-related or if there were two pathologies present, we would exclude these patients to seal a total of 559 sample sites. We included all formulations of anticholinergics including immediate and extended release. We defined response as a greater than 50% improvement or a probable subjective impression of improvement at the 12-week follow-up dose at any of the doses. Failure was then defined, which was our primary outcome, less than 50% subjective improvement. The patients had to have been treated at the maximum dose of the drug that they were on for a minimum of 12 weeks. We looked at a total of 41 known and suspected risk factors. There was surprisingly little data on predictors of treatment failure, but we looked at everything from demographics to symptom to concomitant pelvic floor disorders and neurodynamics when they were available. Patients were stratified by age and by the number of medications that had failed, either 0 or 1. And again, if a patient had tried a medication and they had to stop it due to an event, but there was a documentation that they responded or that there was no documentation of, and we classified it as they had not previously failed treatment. Since we couldn't include all 41 risk factors, we used an F-score, which is basically a measure of reliability and precision of prediction. And the closer the F-score is to 1, the more predictive the risk factor is. And we determined that the optimal number for each patient strata of risk factors would be 8 in order to minimize overfitting and maximize the inter-variable interaction. I don't want to belabor this slide, but these are the main risk factors that were included in the patient group. There was some overlap mainly with vascular and non-vascular neurologic disease, psychiatric disease, treatment of psychiatric disease. Some patients had severity of their symptoms included as risk factors. There was also diabetes and small vessel ischemic disease. Interestingly, the algorithm kicked urodynamics out as a predictor of treatment response. We then proceeded with tenfold cross-validation within each patient strata using multiple machine learning techniques and determined that random forest models were the most accurate classifier of response and treatment. We then proceeded with further development of this model. For those that may not be familiar with random forest, this is called an ensemble classifier and basically consists of multiple decision trees. The final prediction is based on what the majority of decision trees have come to predict whether treatment or response or failure. The training of the algorithm we separated the 559 patients into a group for training and another group for internal validation and the algorithm would do this randomly. It would create random subsets a random number of times and then plug in different groups of risk factors, not necessarily the most predictive and determine which ones made the best decision at each branch point to create the decision trees. Once it was done training, it would take those unseen patients and test the accuracy. Once we determined that the accuracy was sufficient, we then began to tune the random forest or sometimes it's called pruning to further improve the accuracy with adjusting the different parameters of the model which included the number of trees the number of features that were used in each branch point and the number of samples or patients needed to make that decision. We then created a threshold using the area under the receiver operator curve for each patient strata above the AUC, the patients were classified as responders and below they were classified as failures. We simultaneously while we were developing the model, we prospectively collected data on 82 patients from a different tertiary clinical site and we to use in our external validation experiment and in this setting we used the OABSS questionnaire as a definition of failure less than 50% improvement at 12 weeks was considered a failure. This is a table of the three most accurate models and you can see that the random forest model is far and above the best predictor compared to the next two most accurate which were the support vector machines and the tree augmented knife based not only for general accuracy but also for each of the individual patient strata. Comparing our training or internal validation and external validation or test groups, we can see that the groups are similar but not identical which is what we want when we're validating a model in a different patient population. We also had a fairly reasonable distribution of racial and ethnic diversity with the majority of the largest minority group being African American. The patients also differed a little in their symptom severity and in their prior anticholinergic treatment characteristics. The sensitivity on external validation was 79% as was the specificity. The area under the curve was .78. Out of the 51 patients who failed treatment, 81% were correctly predicted and out of the 31 patients that responded, 61% were correctly predicted. These are the ROC curves for each of the patient strata for the external validation experiment and the model performed best in patients who were younger than 40. We did not divide those into those who had failed or not failed medication since the majority had not been tried on medication, but it performed reasonably well across all of the different patient strata. In conclusion, we were able to successfully develop and externally validate a random forest-based prediction model for anticholinergic treatment failure during the standard three-month treatment trial period with good accuracy. Before we proceed with releasing this model, we need prospective validation studies. We're actually conducting a three-hospital trial in Cleveland, but we need it across multiple clinical settings in multiple countries so we know that we can apply this to different population groups. We've also developed an online tool that can be used during experiments and I'd be happy to share that with anyone who's interested. I welcome your questions. Thank you. Thank you, guys. That was really interesting. I'm wondering, did you separate between urgency and hotness? Or did you just wait until people were treated to see if there was a difference? We did not separate. We had the different symptoms in the groups and we found actually that nocturia was the most predictive of a treatment response, so the more severe the nocturia, the more benefit we think the patient could feel if they derived it. We didn't separate the patients. Did you feel like you could use this clinically to fast-track the therapy, for example? That's sort of the goal. We want to develop a model that's not just for anticholinergics, but we want to use neuromodulation data and Botox data so a patient could sit down in front of us and have her data and say, you would benefit from Botox, you could do well with physical therapy, and then we'd have extra counseling for them. The issue with this model, I was actually, as I was working on this, I was listening to something about placebo trials, is I'm concerned now that if I tell someone they're going to fail, they're going to fail. So we actually, before we, once we do this prospective study, I actually want to do a placebo trial and see if me telling somebody they're going to respond or fail will actually impact their treatment. And if it does, then I don't know that this is a valid tool. But if it doesn't, then I think then we can release it into the wild. Last question. Matt Barford did a really interesting report. If I understood correctly, it was excluding patients who stopped their anticholinergic prescribed medicine. We did not exclude them. We excluded them, we did not, if it was before the 12-week trial period, and if there was just no documentation if they responded. So, for instance, if they said at 6 weeks that they had terrible dry mouth, they were having some improvement, and they were still included, but they were not, as long as they had greater than 50% improvement, as long as there was some documentation of that. Since so many of our patients who take plant-based drugs stop at the end of their treatment period, do you plan to do another prediction model to make people more comfortable? That is a good question. We've been toying around with that. We would have to completely redo the algorithm, but yeah, that would be something that would be useful, too, and we could tell patients, you would suffer from this, so maybe we should try something else. What was the antibiotic used specifically? We used all of them in the study, but the most represented were oxybutynin and enteritin, which is what is sort of the general pattern. Thank you. Thank you for the opportunity to present our study. There are relevant disclosures. Intraditrizole or non-botulinum toxin A or Botox injection is FDA approved for the treatment of women with refractory ovaxy bladder and neurogenic bladder. It is generally an office procedure. Sometimes it's done in the operating room. It's done with cystoscopic injection of multiple sites on the bladder detruso with about half cc aliquots of reconstituted Botox with saline. Botox injection at this time is generally performed at room temperature and patients are often counseled on the risk of urinary retention, urinary tract infection, pain with injection, and other symptoms such as generalized body weakness, transient nature of the treatment. And there are some contraindications that are well established to the treatment such as Botox hypersensitivity, dysphagia, myasthenia gravis with or without compromised respiratory status, as well as urinary retention. We do have Level 1 data to support the use of Botox for overactive bladder treatment. It has been shown to improve the quality of life measures and also to improve the quality of life measures compared to placebo. They have some adverse events, though, and some adverse events are urinary tract infection, as listed there, urinary retention, and some other potential adverse events that are generally transient and resolve without treatment. Patient discomfort at the time of injection, like I said, is often reported. We also do have some animal studies that have shown reduced nociceptive response to noxious stimuli and increasing endorphin-level production in a cold environment. And there are some studies that have compared pain with injection of local anesthetic, which showed that injection at body temperature produced significantly less pain than when it's injected at room temperature. And there's a particular study by Meda et al. that shows that significant less pain report on visual analog scale skin infiltration with warm, buffered 1% lidocaine when it's compared to room temperature on buffered 1% lidocaine. So the objective of our study is to assess the effect of temperature variation on pain perception during the intradetrusal injection of warmed Botox at body temperature compared to standard room temperature injection for the treatment of women with refractory ovarian bladder and neurogenic bladder in our practice. This was a single institution randomized single-blind pilot trial. Our inclusion criteria included women that are English-speaking, 18 years of age and older, and that have the diagnosis of refractory ovarian bladder or neurogenic bladder, and have been effectively counseled on the treatment options, and are elected to have Botox injection for their treatment pathway. The exclusion criteria listed there, including women that are pregnant, actively breastfeeding, women with known obstructive uropathy, sensitivity or allergies to Botox itself, or the use of aminobiprocytes or any other medication that could potentiate the neuromuscular effect of Botox. We also inquire about other potential contraindications to Botox use. Patients were randomized in a block fashion, one-to-one randomization. The study assignments were blinded with sequential numbers to the envelope, opaque envelopes. The patients were blinded, but the provider was not, due to the limitation from that. We did collect demographics, including whose were residuals, amount of Botox use, pre-injection quality of life measures, with the short form urinary distress inventory, a six-form as well as incontinence impact questionnaire forms. And we did get the baseline voiding diet parameters as stated. At time of baseline voiding diet was obtained, in addition to those questionnaires, we did also have pre-injection oral antibiotics, prophylaxis based on our current protocol. And we have pre-procedure installation with about 30 to 50 cc's of 1% lidocaine for 20 minutes prior to injection, and this is standard for all patients. The cystoscopic injection of the reconstituted Botox was done with injectable saline, and we used adjustable needle to control the depth of injection. We obtained a visual analog scale at the time of injection for the level of pain report, and we also have, of course, procedural monitoring and precautions that went over with the patients. The patients had two weeks follow-up to check their post-void residual urinalysis in the office, and then a three-month follow-up with the nurse practitioner. This is a flow diagram of the sequence of enrollment. Overall, we had 50 patients, four of which we drew from the study for different reasons. Two patients were moving out of the area and were not going to return for the two-week visit, but were able to see other providers at their new location. This is a general demographics of our patients that are similar in both groups. Majority of the patients received 100 units of Botox for their therapy. Their baseline quality of life measures were comparable, as well as the baseline number of incontinence episodes as reported by their avoidant diary. Overall, patients also have general diagnosis of ovarian blood and urgent incontinence as their predominant diagnosis. This is a pain score result, as well as post-void residual result. In both groups, they're similar. There was no difference in the reported pain in both groups, as well as similarity in the post-void residual. We also looked at urinary tract infection and urinary retention, which we defined as post-void residual greater than 300 cc, where it's similar in both groups as well. In conclusion, temperature variation at time of intradetrusal Botox injection for treatment of women with refractory ovary bladder and neurogenic bladder did not affect pain perception at the time of Botox injection. Safety outcomes did not differ between groups. We do need more studies to further investigate these findings, as this is the first approach to it. And we definitely do need to further investigate, using those quality of life measures, the general efficacy of the therapy at the varying temperatures. Thank you again for your attention. Thank you. Thank you so much. Do you have any patient satisfaction with the two different penetrative solutions compared to the former? Yes, in terms of their actual report of pain at the time of injection, there was no difference. We do have a major limitation in terms of looking at their quality of life measures using those two questionnaires. We did get a good response with the baseline, but when we looked at the three months follow-up response, we were actually not able to capture a lot of patients. We had eight patients in the treatment group and nine in the control group, and there was no difference with that low number. But because the number is so low, we don't feel like it's really a valid assessment. Anything from just like talking to patients, did anybody say they don't want to go to work? No, we just went with the visual analog scale report and we actually made that decision with the first three injections, so we don't want to wash it out. So the first three injections was where we made the average determination of the level of pain. Sorry, can you repeat that? Well, so our rationale with this is that was a question in our mind, but we felt that even though now everybody injects at room temperature, when the reconstituted Botox does get into the system, it gets normalized into body temperature. So we did not anticipate any loss in efficacy per se, but it's definitely something that we would need to further study with outcome measures. Thank you. Okay, so the majority of you. So this is a new technique that I think has a lot of promise and interest, and ever since this study was done, this is kind of my go-to, and I've kind of gone to doing it this way because I think it actually works out better. At any rate, this is the disclosures. And so, let's And so, looking at the previous trials and looking at the treatments with Botox, we were looking at, and as you know, the standard dosing is 20 doses evenly distributed, avoiding the trigone, and the CIC rate in those studies in females is about 5.2 percent. Overall, males, females, it's a little higher than that. And so we were looking at to see if we can reduce that CIC rate and have similar efficacy by doing it in a different paradigm. And so it was a multicenter, randomized, double-blind, placebo-controlled study. You can see the randomization was 2 to 1. You can look, the primary endpoint was change in baseline of urinary continence episodes at week 12. Secondary endpoints, as you note here and this is the technique. It's a peritrigonal injection. There's only 10 injections total. For those of you who want to try this, I would highly recommend you do the peritrigonal injections first and then go into the trigone. You can get a little bit of oozing when you hit that trigone and if you do that first then it kind of obscures your vision, makes it a little bit more frustrating as you go around the other. Certainly not impossible, but it's just cleaner and easier if you do the two trigonal injections last. And here's how the demographics broke down. As you can see from a symptom point of view they're largely very similar. And here is the results in UI episodes per day and you can see within the first week you start seeing a dramatic decline as you might expect superior in the treatment arm as opposed to the placebo arm. Again looking at people who had 100% reduction in UI episodes, you can see that the Botox arm obviously has a very significant impact over the placebo arm. Reductions in incontinence episodes, again you can see again this has a dramatic effect and these are all very similar to the earlier trials looking at the more standard treatment of the 20 injections and so these parallel very closely to those. We all have frequency urgency issues and this is looking at frequency episodes. Again very similar results to what we saw in the earlier studies looking at the current standard treatment. This is looking at purely urgency, reductions in urgency versus placebo and again significant differences. And again to emphasize this is very similar to the earlier studies looking at that standard dosing. Significant difference in CIC rate, this in the standard paradigm and again these are comparing the older studies with the newer studies but the studies were set up very similarly and so while this is not head-to-head it certainly suggests that there is a significant improvement in CIC rate with the new paradigm as opposed to the standard paradigm that were currently being used. Overall adverse events, you can see the UTI rate was up a little bit, a little bit unexpected. There's no real, we haven't defined the exact whys of that and we're currently looking and doing subset analysis looking trying to figure that out. No real good logical reason at this point. There's some hypothesis that we have kicked around but other than that everything else is very similar. So in summary as you look at this and as you compare this study versus the again the older studies that we kind of paralleled off of, we see that the efficacy on all the parameters is very similar to the current standard dosing that the CIC rate is dramatically reduced and the urinary retention rate is dramatically reduced. We did have the higher UTI rate which is not explained at this point in time. We're looking at that and while there is no direct comparison it certainly appears that this treatment paradigm is much better than the current standard treatment and again this is kind of the, when I'm doing Botox, this is kind of my go-to treatment paradigm. Alright, good morning everyone and thank you so much for coming as I'm going to be presenting the data from the international phase 3 trial called Empower. I'll be focusing on, by background, statistically significant improvement in the measures of quality of life in patients with overactive bladder. Some disclosures, the study here was presented by Eurovan. I, as I mentioned, I'm Susan Verano, I'm principal investigator at Clinical Research Consulting and our group participated in this trial. I'm also a geriatrician and do consulting for Maplewood Senior Living. A little background about the study and the importance of doing the study. Overactive bladder has a negative impact on patients with psychological well-being and interferes with daily activities. There's a very high unmet need for new treatment options and this was very obvious when the study started. Enrollment was very rapid and patients were really looking for a new option. Ibegron is highly selective, oral B or a beta-3 agonist and with, as was heard, as was mentioned earlier, with the anticholinergics increased concerns with, with cholinergic increased concern for dementia as a geriatrician, this is definitely an option. It's once daily oral, single 75 milligram dose. It does not inhibit the 2d6 pathway and over 4,000 overactive patients in phase 2 and phase 3 studies have been previously shown to improve symptoms of overactive bladder. There's a rapid onset, which is two weeks, which is very important and when you combine the once daily oral single 75, which is immediate, does not, there's no delay to it. The rapid onset is in two weeks and it's definitely a crushable, will be crushable. That's very valuable as a geriatrician for compliance. We typically start low and go slow, but we have to go and if patients are not patient for titration, they will stop and it will be a treatment failure, even though they didn't reach a therapeutic dose and also if they can't take oral medications as the pill is given to them and they need it to be crushed, this is also of value. So study design and endpoints, it's a 12 week treatment period with four week safety follow-up. It was randomized 5 to 5 to 4. The primary statistical comparison was by Begran versus placebo and Tiltaridine was the active control. Co-primary endpoints at week 12 were a change in the average number of daily urge urinary incontinence and the change in the average number of daily micturations. The study enrolled a representative overactive bladder population approximately, well actually exactly, 1,518 patients were randomized. The patient characteristics were well balanced across groups. The mean age was 60 years, approximately 85 women, 85% women and approximately 77% overactive bladder wet. Some results that were previously presented by Begran demonstrated statistically significant improvement versus placebo for both co-primary endpoints. As you can see here, the bottom line is by Begran and at week 2 we see the immediate results of the medication and it continues on to week 12 and also on the daily micturations we see a decrease in micturations at week 2 in addition to week 12, all the way through week 12 continuing. By Begran, statistically reduced daily urgency episodes at week 12. The rapid response was noted at week 2 and once again with my geriatric patients this is very, very valuable for compliance and making sure they're getting the results they're hoping for and it will continue on to week 12. Secondary efficacy endpoints, key secondary efficacy endpoints at week 12, change in the average number of daily urgency episodes and change in the coping subscale score. At 9.10 today there will be another presentation going over the key secondary endpoints of this study. So I'm just going to be focusing on quality of life endpoints, change in concern, sleep, social interaction, health related quality of life, symptom bother and patient global impression. The overactive bladder questionnaire long form was used. It's 33 items and broken down into a bother scale which was eight questions and the health related quality of life which was 25 questions which contained four subcategories, coping, concern, sleep and social interaction. The coping subscale was a key secondary endpoint for Empower and you will see it highlighted in red on the upcoming slides. The health related quality of life total score was calculated by the individual scores. The item scores are from one to six with a higher score indicating better quality of life. And the symptom bother, the items were scored from one to six with a higher score indicating greater symptom severity. Vibagran statistically, Vibagran significantly improved quality of life at week 12 and this slide demonstrates the mean change from baseline at week 12 and placebo or tolteridine on all OABQ measures. This slide demonstrates Vibagran statistically improved quality of life at week 12 in five of the six overactive bladder measures and the one that was not statistically significant was the social interaction subscale. Vibagran improves patient global impression of control and the question was over the past week how much control did you have over your overactive bladder symptoms and as we can see from baseline to the end was a significant improvement and on the bottom right hand side there's the statistical significance. Vibagran improves patient global impression of change. The question was overall compared to the start of the study how would you rate your overactive bladder symptoms over the past week and we could see that in red there's a significant difference and on the bottom right hand side the statistical significance. Vibagran demonstrated favorable safety and tolerability. It had similar rates. On the bottom you can see that Vibagran and placebo had similar rates for hypertension and increased blood pressure which is very concerning to all clinicians. Urinary tract infection and urinary retention were also reported to be low. So in conclusion, as reported, once daily Vibagran, 75 milligrams, demonstrated a rapid onset of action, two weeks, and statistically significant benefits versus placebo on the co-primary endpoints of change in the average number of daily UUI episodes and daily McDurations. 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Women who used OEB meds were less likely to continue with PTNS maintenance and lastly the presence of detrusor overactivity on urodynamics was not associated with maintenance therapy. So lastly areas of future study that we're considering, one assessing the long-term efficacy of maintenance therapy and a larger cohort prospectively using validated questionnaires. Secondly we could compare treatment efficacy between generic PTNS versus brand as within our institution there was a region-wide change between 2014 and 2015 and lastly setting barriers to PTNS maintenance based on race and certain medical conditions as in the bivariate analysis we found a significant relationship between discontinuation of PTNS use and diabetes. I thank you for your attention and I'm happy to take questions at this time. Thank you, that was really great. I really appreciate the work you did on that. I'm just wondering that mean age looks to be a little bit higher in this study cohort. Did you look at employment as also a factor in whether they continued maintenance or not? Yeah that's a really good point. Thank you for your question. We did not but that's a important variable to consider especially given the burden with PTNS sometimes with coming in for a weekly visit. We have another question. Thank you Dr. Pratt, excellent presentation. Sally Huber from Atlanta, Georgia. When you were looking at your diabetic patients did you do any sub analysis based on severity of diabetes like hemoglobin A1c to see if there was any breakdown and continuation based on that? Yeah thank you for your question. So we looked at the mean hemoglobin A1c rate which was seven but we did not break it down any further than that. So we just reported it as a frequency but we didn't do a sub analysis but that's something that we can definitely look into. Thank you for that suggestion. In the patients who had a prior anti-incontinence surgery for stress incontinence, did they have persistent or recurrent stress symptoms as well as overactive bladder symptoms? Thank you for your question. Unfortunately that's not something I looked at in the chart review given its retrospective nature. I would have had to really sift through the notes but it's a good thought and something that we can consider prospectively assessing. I did think, you know, try to think why the patients who have a history of stress incontinence or anti-incontinence procedures not continue with PTNS and I was considering, you know, some type of neurologic sequelae or maybe the the surgery actually causing persistent voiding dysfunction or de novo OAB that is harder to actually treat with the PTNS compared to another management option. So it's something to really look into. It's interesting from a physiologic standpoint. Great. Thank you. You're welcome. Thank you. Thank you. On behalf of the patients who consented and the investigators and the authors, I'm pleased to present this. These are the disclosures. Everybody's seen these background slides now before every talk so I won't belabor the point other than to say what's interesting about this drug is that it's a single 75 milligram dose. There's no lower dose that you're asked to start with. All of the package insert hasn't been officially approved by the FDA yet. That's a highly favorable drug interaction so there's no 2d6 pathway for the drug which is very useful when considering other medications. There were other patients and other studies by many of them by a former company that had started the clinical program so that there are greater than 4,000 patients in the phase 2 and phase 3 program and that the drug, because of the fact that there was a data point at two weeks, we were able to analyze the data at two weeks for some of the variables that you're going to see. 12-week treatment period, that's standard. Randomized 5 to 5 to 4, that's the way obviously drug to placebo and consistent with European guidelines there's an active control which we don't normally see in the United States. Primary statistical comparison is of course the drug versus placebo and not to the active control and that's also standard. There were co-primary endpoints which is the change in the number of urge episodes with greater than one UUI episode per day and the change in the average number of micturition so there were co-primary endpoints. There was a represented look at the OAB population, again I won't belabor you with these numbers, the randomization process was appropriate. There were approximately 85 to 90 percent of patients were female and about 80 percent, 75 to 80 percent of patients were OAB wet and that's consistent with many of the other OAB studies as well as internally consistent for the study. This is the improvement daily UUI episodes and daily micturitions again because I don't have to go through all this data in detail but the interesting point is the separation at two weeks of both drug from placebo and also the fact that the drug was consistently better than Tolteridine through all the data points and this is maintained both for UUI episodes and for daily micturitions as you can see. Vic Coulard asked a question about Nocturia that actually hasn't been analyzed yet but as we know these are the beta-3s are long-acting drugs with long half-lives and if you consider nighttime micturitions the same as daytime micturitions you would expect a 24-hour activity there but that data in detail will certainly be available and again another top-line result was a urinary urgency at two weeks again greater than placebo and after the two-week point for urgency episodes greater than Tolteridine at all points. The secondary endpoints here are a change in average number of urgency episodes the percentage of OAB wet with greater than 75% reduction a lot of times you're looking at responders for especially in the neuromodulation area greater than 50% this statistic is done with 75% reduction change in average number of total daily incontinence episodes and the average volume voided per micturition which we all believe is a is a indicator of the obviously the patients holding more urine with for each void and the change in coping subscale and that was presented. It demonstrated a high proportion of UUI responders if you look at historical numbers this is actually a very good representation of drug versus placebo and showing a strong response at this level for patients with a greater than 75% reduction the total total daily incontinence episodes again and we all know that this includes a certain amount of patients that may have had mixed incontinence so you can look at this as a breakout of either pure UUI episodes or total again drug active versus placebo strongly active versus placebo at two weeks and greater than Tolteridine at every data point and volume voided so you're going to see here again the response again at two weeks early the half-life the drug half-life being extended like this of the two drugs in the beta-3 the one approved drug in this one have about 50 60 hour half-life which means it takes about a week for them to get the steady state so it's very very reasonable to look at a two-week data point for this separation from placebo and again in volume voided which shows a physiologic effect on the bladder consistent with the pharmacology we're seeing a statistic of statistical improvement of drug over placebo and over the active control this is the tolerability and safety profile and it was again it was presented in the prior talk on quality of life again the areas that we're looking for here are certainly that any of the cardiovascular effects we do not expect to see the anti-muscarinic effects as the drug class is not anti-muscarinic and because of the beta-3 agonist profile we've commonly looked at but hypertension and tachycardia and you can see that these were not increased above placebo so in conclusion it is a 75 milligram single dose again without 2d6 metabolism the results presented here show that there is a UUI response, an urgency response, a total daily incontinence episode response and a volume voided response. The drug was well tolerated with a favorable safety profile would be interesting to put it in the analysis and predictor analysis because this beta-3 class takes out a lot of the concern about the anti-muscarinics and it may, this certainly may represent another important new therapy just to address the large unmet need for patients who have OAB. Thank you. On behalf of my co-investigators, thank you for allowing us to present this data and thank you guys for being here on Saturday morning after a big party to hear our results. These are my disclosures. So sacral neuromodulation is not a new therapy. Described in 1979 by Tanago, it was first approved for urgency incontinence in the US in 1997. The therapy has evolved to a Tyne lead and a minimally invasive technique but no significant improvements to the system have occurred since 2006 when the second generation IPG was introduced. The axonic system illustrated here is a rechargeable sacral neuromodulation device designed to function for a minimum of 15 years. It is FDA approved for 1.5T full-body MRI and at 5 cc's it is a third of the size of the current non-rechargeable IPG shown. The primary study objective was to evaluate the axonic system for the treatment of urgency incontinence using sacral neuromodulation. On September 9th of this year, the FDA approved the axonic system for fecal incontinence and axonics has additional filings under review with the FDA for urinary urgency incontinence, urinary frequency, and urinary retention. So this is a prospective single arm pivotal study. 129 participants with urgency incontinence across 19 centers in the US and Western Europe were enrolled. The primary inclusion criteria were greater than or equal to four urgency incontinence episodes on a three-day diary and at least 50% of all those incontinence episodes needed to be associated with urgency and at least one incontinence episode needed to occur per day with at least a six-month history of UUI. The primary exclusion criteria were more than a minimal level of stress incontinence, mechanical urinary tract obstruction, and underlying neurologic disease. The procedure was actually a single non-staged implant. The lead placement was preferably S3 but the S4 nerve root was acceptable. Positive motor responses in two electrodes at less than four milliamps was required. Data was collected from three-day voiding diaries, the ICIQ OAV quality of life questionnaire, participant satisfaction questionnaires, the Cleveland Clinic fecal incontinence score, and adverse events were reported. The primary outcome was therapy responder rate and therapy responders were defined as participants with greater than 50% reduction in UUI episodes. Data was analyzed as treated analysis in all the implanted patients and charging usability was reported based on available data. 98% of implanted participants were female with an average age of 59 years that ranged from 21 to 86. The average BMI was 32 with a range of 18 to 58. The average number of leakage episodes per day was 5.6 and the average number of voids 10.5. At six months, 90% of implanted participants were responders and 89% continued to respond at one year. The mean number of urgency incontinence episodes decreased from 5.6 at baseline to 1.3 at six months and 1.4 at 12 months. At one year, 29% of responders were dry. 40% had a 90% reduction in leaks and 77% of responders had a greater than 75% reduction in UI. 23% were between 50 and 74%. The ICIQ OAV quality of life score is a validated questionnaire and as was discussed earlier has four domains, concern, coping, sleep and social. The minimally important difference for this questionnaire is 10 points and as noted here, there was a significant improvement in all four domains that was sustained over time. Patients were asked to rate their satisfaction with the device using a seven point Likert scale and 93% were satisfied with the therapy and 92% would undergo the therapy again. 124 of the 129 patients were charging at one year and 96% found charging frequency and duration acceptable, 89% found charging easy, 95% charged every seven days or less frequently and 86% charged for 60 minutes or less. In those patients with fecal symptoms, the mean Cleveland Clinic fecal incontinence score was 9.3 and this decreased to 4.6 at six months and 3.9 at one year. 91% responded being satisfied with their bowel symptoms. Device-related adverse events were low and no serious device-related adverse events occurred. No surgical interventions for pain at the INS site occurred and all unwanted stimulation resolved with reprogramming. 3% of patients underwent revision or explant, one for an infection, one for migration and one fracture were revised with return to efficacy and one INS revision was due to difficulty charging. So in conclusion, the Artisan study demonstrated sustained efficacy with an 89% responder rate at one year, clinically significant improvements in quality of life, high rates of participant satisfaction with their therapy and 9 out of 10 subjects deemed charging to be easy and acceptable. The safety profile is consistent to sacral neuromodulation and the axonic system is safe and effective at one year. Thank you and I look forward to any questions. Thank you. I was very interested in the slide where you had the acceptability or whether people were satisfied with the treatment and it was around 95-96% and then you proceeded to go on to how frequently people charged their device and again it was around 94-95%. Are the group who have to charge frequently the same people who are, and I don't really understand why they have to charge more frequently than once a week, but were they the ones who were then dissatisfied with the system? So the question is that that small percentage of three or four percent that were not satisfied or acceptable with the frequency of the charging were the same population. Exactly, exactly, because it looks like it from the slide, but obviously that's not necessarily the case. Yes, that is the case. Any ideas why they had to charge it so frequently? Well, they really, the average frequency of charging was weekly. So you're looking at a very small subset that may have had to charge and I think that depends with the amount of energy that's having to be delivered and how long they're charging their system. So if they don't fully charge their system they might have to recharge more frequently. Do you have a question about how the, for the patient who had trouble charging, what technically changes with the revision to improve that? Yeah, that's an excellent question. So the goal is is for us to place the INS approximately two centimeters below the subcutaneous tissue so that there is not a depth, you know, discrepancy. You also want it to be a little bit more lateral so it's easy for them to access and so those two things are really important when placing the INS system and so those were modified at the time. Thank you. Other questions? This concludes our session then. No further questions? Thank you Dr. Lane. Thank you all the people.
Video Summary
The first video is a presentation on the 2019 Guideline on Recurrent Urinary Tract Infections in Women. The speaker discusses the prevalence of UTIs in women, the consequences of antibiotic overuse, and the rise of antibiotic resistance. They stress the importance of antibiotic stewardship and obtaining a complete history and pelvic exam for women with recurrent UTIs. They define acute cystitis, complicated UTI, and recurrent UTI, and discuss the associated symptoms. The speaker emphasizes the need for urinalysis, culture, and sensitivity testing before starting therapy, and advises against unnecessary surveillance urine testing. Treatment recommendations include the use of first-line antibiotics for uncomplicated UTIs, consideration of patient-initiated treatment while awaiting culture results, and prophylactic antibiotics for high-risk patients. They also mention potential benefits of vaginal estrogen and cranberry prophylaxis. The video concludes with information on the development and validation of a prediction model for response to anticholinergic treatment and a study on the effect of temperature variation on pain perception during intradural injection of Botox for overactive bladder.<br /><br />The second video summarizes a study on sacral neuromodulation for urgency incontinence using the Axonix system. The study involved 129 participants, and the primary outcome was the therapy responder rate, defined as a greater than 50% reduction in urgency incontinence episodes. At six months, 90% of participants responded to the therapy, and this response was sustained at one year with 89% still responding. The mean number of urgency incontinence episodes significantly decreased. Participants also reported improved quality of life and satisfaction rates. The charging usability of the device was found to be acceptable by 96% of participants. Device-related adverse events were minimal, leading to the conclusion that the Axonix system is a safe and effective treatment for urgency incontinence.
Asset Caption
Jennifer T. Anger, MD, MPH, David Sheyn, MD, Amos Adelowo, MD, MPH, FACOG, Barry K Jarnagin, MD, Susann Varano, Toya S. Pratt, MD, David Staskin, Felicia L. Lane, MD
Keywords
2019 Guideline on Recurrent Urinary Tract Infections
UTIs in women
antibiotic overuse
antibiotic resistance
antibiotic stewardship
complete history
pelvic exam
acute cystitis
complicated UTI
recurrent UTI
urinalysis
culture and sensitivity testing
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