OnabotulinumtoxinA is a well tolerated and effective treatment for refractory overactive bladder in real-world practice

Overactive bladder (OAB) is a syndrome characterized by the International Continence Society as “urinary urgency, usually accompanied by frequency and nocturia, with or without urgency urinary incontinence, in the absence of urinary tract infection or other obvious pathology” [1]. An estimated 546 million people worldwide are affected by symptoms consistent with OAB; approximately 423 million have urinary incontinence (UI) [2].

UI as a result of OAB can significantly affect quality of life (QoL) and, as a result of social embarrassment, many patients can suffer from low self-esteem resulting in avoidance and limited social behavior. Many aspects of daily life can be impacted by UI including physical activity, travel, relationships, sexual activity, and quality of sleep [3], and it is also associated with further medical problems such as falls and dermatitis [4, 5]. There is also a substantial direct cost to the patient with UI primarily from the use of absorbent products [6] as well as indirect sequelae costs [7].

First-line pharmacological treatments for OAB with UI include anticholinergic medications and beta-3 agonists. Anticholinergic medications are not always effective over time and can be associated with side effects of dry mouth, constipation, blurred vision [8], and an increased risk of dementia [9]. Beta-3 agonists have been associated with side effects of constipation, dry mouth, headaches, and an increased risk of hypertension [10].

OnabotulinumtoxinA 100 U is approved in many countries for the treatment of OAB with symptoms of urge UI, urgency, and frequency in adults who have an inadequate response to or are intolerant of ≥ 1 anticholinergic [11]. In two large, randomized, placebo-controlled phase 3 studies, onabotulinumtoxinA has been demonstrated to be well tolerated and to improve urinary symptoms and QoL in patients with OAB who were refractory to anticholinergic medications [12, 13].

However, efficacy and safety data with onabotulinumtoxinA for the treatment of OAB in real-world clinical practices are limited, as is information regarding the ongoing concomitant use of other OAB medications and incontinence product use after treatment.

The objective of this study was to evaluate the real-world use of onabotulinumtoxinA up to 1 year in the treatment of patients with idiopathic OAB including the evaluation of changes in urinary symptoms, QoL, incontinence product usage, OAB medication use, and treatment procedures.

This was a large, prospective, observational, non-randomized multinational study (GRACE; ClinicalTrials.​gov, NCT02161159) performed in four European countries: Germany (31 sites), Spain (nine sites), Sweden (six sites), and the UK (seven sites).

Patients were enrolled who were aged ≥ 18 years with OAB with UI and who were intolerant to and/or inadequately managed with ≥ 1 anticholinergic medication; all were naive to botulinum toxin type A for the treatment of OAB.

Exclusion criteria included: treatment with any botulinum toxin type A in the prior 18 months for any condition, if the patient was not willing or unable to initiate clean intermittent catheterization (CIC) after onabotulinumtoxinA treatment, or if they were currently taking part in other clinical studies.

Both efficacy and safety analyses were conducted on the safety population (patients who received at least one dose of onabotulinumtoxinA).

Treatment with onabotulinumtoxinA was performed per the physician’s normal clinical practice and based on local summaries of product characteristics (SMPC). Patients were then followed up for 12 months with three scheduled follow-up visits (FU: FU1 approximately 12 weeks, FU2 any time point after FU1, FU3 approximately 12 months after baseline).

Patients could have completed an optional paper diary. Data entered into the diary were analyzed according to predefined documentation time points. Patients could document the following data into the diary at specific time points, which were not necessarily linked with a particular visit: UI, micturition, urgency and nocturia frequency (baseline and weeks 1 and 12 post-injection); Treatment Benefit Scale (TBS, week 12 post-injection only); incontinence product usage (baseline and weeks 12, 20, 28, 36, and 52 post-injection); ongoing OAB medication use (weeks 1, 12, 20, 28, 36, and 52 post-injection).

This real-world study is the largest prospective, multinational, observational study performed to date and was designed to evaluate the efficacy and safety of treatment with onabotulinumtoxinA in patients with OAB as well as the treatment methodologies used by the physicians in their day-to-day clinical practices.

When treating patients with OAB with onabotulinumtoxinA in their clinical practices, the majority of physicians in this study administered a dose of 100 U while using a rigid cystoscope for injection. Local anesthesia instillation into the bladder was the most commonly employed anesthesia.

Physicians appear to have refined their process versus the label with injections in < 20 sites, mainly submucosally and distributed between both the trigone and trigone-sparing regions. Moreover, a small study of patients with idiopathic detrusor overactivity (n = 22) or neurogenic detrusor overactivity (n = 23) demonstrated efficacy and tolerability with as little as one to three intradetrusor injections. These results were comparable to those seen using the established technique of 20 intradetrusor injections [15]. As physicians gain more experience with the use of onabotulinumtoxinA they can learn how to optimize the administration and effectiveness to better treat OAB patients with their bothersome symptoms.

In this study, all patients had previously failed treatment with anticholinergic therapy, and by the time they received onabotulinumtoxinA many had been receiving anticholinergics for 24 weeks, with approximately 15% discontinuing those medications prior to baseline.

After onabotulinumtoxinA treatment, significant improvements were observed in UI as early as within week 1 (−2.4 episodes/day). These improvements were sustained to at least week 12 (−3.0) and were similar to those observed in phase 3 trials at week 12 (−2.7 to −3.2) [12, 13, 16]. While all patients were required to have UI to be included in this study, more than one in five reported that urgency was their primary symptom, indicating that UI was less bothersome to them than the urge to void. In this study, not only was UI frequency improved but also other urinary symptoms including urgency, suggesting improvement in other pertinent symptoms in this cohort of patients. The improvement in urinary symptoms was accompanied by an improvement in QoL measured by TBS; most patients expressed a positive response 12 weeks following treatment. This was higher than the response observed in previous clinical studies (62.8% and 60.8%) [12, 13]. There was also a reduced reliance upon incontinence products which would be associated with significant cost savings. The Prospective Urinary Incontinence Research study, which looked at the economic burden in women with UI in various European countries (Germany, Spain, UK/Ireland), showed the cost of incontinence products was a large contributor to the overall cost of UI management with more than half of the patients paying out of pocket [17].

The reduction in ongoing medication use observed during this study could indicate that onabotulinumtoxinA-treated patients may decrease or even discontinue their prior OAB medications as they are achieving sufficient control with onabotulinumtoxinA alone. This also emphasizes the benefits of treating patients sooner with onabotulinumtoxinA as opposed to cycling on oral medications. The slight increase in solifenacin use observed between weeks 24 and 28 is consistent with the expected duration of onabotulinumtoxinA and the time at which patients requested retreatment in this study. The reduction in medication use aligns with the reduction in incontinence pad usage, further confirming the efficacy of onabotulinumtoxinA and potentially a better cost-effective option than oral therapy for OAB patients as has been suggested in previous studies [18‐20].

It is noteworthy that there was a delay of about 1 month between a patient’s request for retreatment and the patient actually receiving retreatment. This reinforces how important it is to treat patients optimally so they do not experience full reoccurrence of their symptoms. Suffering through multiple “peaks” and “troughs” can be highly discouraging for the patients. To avoid this, healthcare providers may wish to take a proactive approach with patients and schedule follow-up appointments/retreatments every 6 to 7 months.

No new safety signals related to onabotulinumtoxinA treatment were identified, and the rates of AEs were low. In particular, the incidence of urinary retention and urinary tract infections, the definitions of which were discussed and approved by the US Food and Drug Administration, throughout the 52 weeks was very low (1.0% and 0.4%, respectively). In the phase 3 RCTs over the 24 weeks of these studies urinary retention was 5.8% to 6.9% and urinary tract infection was 24.1% to 25.5% [12, 13, 16]. While direct comparisons cannot be made the differences between this real-world study and the data from the phase 3 studies may in part reflect the more conservative criteria that were developed for the purpose of those clinical trials. Specifically, in the RCTs urinary retention was defined as a post-void residual urine volume ≥ 200 ml that required CIC, and urinary tract infection was defined as both a positive urine culture (bacteriuria count of > 10⁵ colony forming units/ml) and leukocyturia (> 5 cells per high power field) regardless of clinical symptoms. In this real-world study, no such specific criteria were required for documentation of urinary retention or urinary tract infection which was diagnosed under the discretion of the physician, and may be reflective of real-world AEs associated with onabotulinumtoxinA treatment. Results from a retrospective review of electronic health records from 99 women evaluated 2 weeks after receiving onabotulinumtoxinA 100 U demonstrated CIC was required following 1.6% of injections (3/187). As with this current study, it was suggested that the low CIC rate was reflective of the less rigorous criteria for CIC initiation compared with prior studies [21]. Previous studies have demonstrated that antibiotic prophylaxis can mitigate the risk for developing urinary tract infections following onabotulinumtoxinA treatment [22, 23], and for the majority of injections performed in this real-world study patients did receive antibiotic pretreatment.

Limitations of this study may be associated with the observational nature of the study design, such as the lack of randomization and a comparator group. In addition, while some patients appear to be restarting other OAB medications after about 7 months following initial treatment, no data are available to specifically identify which patients have or have not been retreated with onabotulinumtoxinA so as to better determine if the retreated group of patients was not reinitiating OAB medications. In contrast to clinical trials, there were no exact evaluation time points in this non-interventional study, as data were collected by the physicians from all clinic visits that occurred as per normal practice in the 12 months that followed the baseline visit.

The results from this real-world trial may better inform physicians about what to expect following onabotulinumtoxinA treatment for OAB in their day-to-day clinical practice. The data add to the growing body of evidence that onabotulinumtoxinA can improve urinary symptoms and QoL in most patients with OAB symptoms who had not seen lasting benefit with other OAB medications [24]. In addition, the reduction in oral medications and incontinence product usage may provide significant cost savings for the patients.

The low rates of urinary retention and urinary tract infection seen in this study suggest that onabotulinumtoxinA treatment may be better tolerated in clinical practice than previously suggested from the results reported for RCTs.

Physicians may wish to consider proactively scheduling a structured time frame for follow-up/retreatment to avoid a lag time between the patients requesting and actually receiving retreatment, thus preventing a potential recurrence of OAB symptoms.

Given how well tolerated onabotulinumtoxinA was over the 52 weeks of this study, and the sustained efficacy with regard to UI and QoL out to at least 12 weeks, healthcare providers may wish to consider moving patients to onabotulinumtoxinA sooner as opposed to cycling on oral medications.