The objective of this study was to determine whether retropubic midurethral sling (MUS) combined with onabotulinumtoxinA (ONA) is more effective than MUS alone in improving mixed urinary incontinence (MUI) symptoms. We hypothesize that a combined treatment approach for women with MUI is superior to treating with MUS alone.  Specifically, women with MUI undergoing MUS with concomitant intradetrusor ONA will have greater improvement in incontinence symptoms at 3-months postoperatively than women undergoing MUS alone.

We conducted a prospective, double-blind, randomized, controlled trial of women with MUI planning to undergo MUS from March 2016 to November 2019. Participants all had positive cough stress tests. Women who responded “somewhat,” “moderately,” or “quite a bit” bothered to both questions 2 and 3 on the Urinary Distress Inventory-6 (UDI) were recruited. These questions assess urinary urgency and stress symptoms respectively. Patients were excluded if they (1) had previous incontinence surgery or intradetrusor ONA, (2) taken overactive bladder medications within 2-months, or (3) found to have a post void residual (PVR)  greater than 150ml. Participants were randomly assigned on the day of MUS surgery to receive 100U of intradetrusor ONA or placebo (10ml of normal saline). Participants completed the Patient Global Impression of Severity (PGI-S) for overall incontinence symptoms and subscales for SUI and UUI symptoms, UDI, and Pelvic Floor Impact Questionnaire-7 (PFIQ) before and 3-months after MUS surgery. They also completed the Patient Global Impression of Improvement (PGI-I) for overall incontinence symptoms and subscales for SUI and UUI symptoms at 3-months postoperatively. Adverse events were recorded. Our primary outcome was improvement in PGI-I scores. Secondary outcomes included incontinence symptom severity and quality of life measures.  Assuming a PGI-I of “very much better” or “much better” in 66% of women in MUS and 93% in MUS with ONA, 68 women were needed to show a significant difference with 80% power at 0.05 significance level.

103 women were enrolled and 78 were randomized (ONA: 41; placebo: 37). The mean age was 51±10 years, and median BMI was 29.1 (IQR 25.7, 34.9) kg/m2. The majority was Caucasian (76.9%) and 20.5% had urodynamically proven DO. Neither demographics nor baseline incontinence survey data differed between the groups (TABLE 1). At 3-months, UDI, PFIQ, and PGI-S scores improved significantly from baseline in both groups. Those who responded “very much better” or “much better” on PGI-I did not differ between groups 3-months after treatment (82.9% vs. 83.8%, p=1.0). Similarly, UDI and PFIQ scores did not differ (TABLE 2). Median PGI-S scores were significantly lower for UUI, indicating less severe symptoms, at 3-months for the ONA group than the placebo group (1.0 IQR 1.0, 2.0 vs. 2.0 IQR 1.0, 3.0, p=0.03). Similarly, median PGI-I scores for UUI were significantly lower for the ONA group, indicating greater symptom improvement (1.0 IQR 1.0, 3.0 vs. 2.0 IQR 0, 3.0, p=0.03). Rates of immediate postoperative voiding dysfunction did not differ between groups (5.4% placebo; 7.3% ONA, p=1.0) nor did the proportion of women requiring ISC within the 2-weeks after surgery (5.6% placebo; 12.5% ONA, p=0.5). Between 2-weeks and 3-months, more women in the ONA arm initiated ISC (2.7% placebo; 20.0% ONA, p=0.05). UTI was experienced more frequently in the ONA group at 3-months, but this did not reach statistical significance (5.4% placebo; 22.5% ONA, p=0.07).

While our primary outcome of a difference in overall PGI-I scores between groups at 3-months did not meet statistical significance, there were secondary outcomes that did show differences between the ONA and placebo groups. The median PGI-S and PGI-I scores specifically for the UUI subscale were significantly better for the ONA group indicating that adding ONA at the time of MUS may decrease the severity of urgency symptoms. Notably, all survey scores improved significantly from baseline for both groups implying that significant improvement can be expected in all MUI symptoms with MUS alone. 
As expected, there were no differences in immediate postoperative voiding dysfunction, given that ONA does not take effect immediately. Between 2-weeks and 3-months, the ONA group had more patients initiate ISC and a higher rate of UTI, though this did not reach statistical significance. These findings are in line with previous data on intradetrusor ONA.[1]

Women with MUI undergoing MUS report significant improvement in overall incontinence symptoms, regardless of addition of ONA. However, women who received concurrent ONA reported less UUI symptom severity and more improvement in urgency symptoms, without a significant increase in adverse outcomes. Some patients with MUI may benefit from concomitant ONA with MUS, but most will improve with MUS alone.

Visco AG, Brubaker L, Richter HE, et al. Anticholinergic therapy vs. onabotulinumtoxina for urgency urinary incontinence. The New England journal of medicine 2012;367:1803-13.