The pathophysiology of stress urinary incontinence (SUI) includes loss of urethral support resulting from weakness of the pelvic floor fascia and musculature, as well as weakening of the urethral sphincter, known as intrinsic sphincter deficiency (ISD). The urethral sphincter function depends on the muscular component and the mucosal or intrinsic component, which lines the urethra and contributes to urethral coaptation and closure. 
Intravaginal IncontiLase® treatment using the non-ablative Erbium YAG laser has been previously shown to be effective and safe for treatment of mild and moderate SUI (1). Intraurethral treatment using the same laser source has also shown benefit for treatment of patients with symptoms of ISD and menopause-related urinary symptoms (2,3). Because non-ablative Er:YAG treatment results with thickening and remodelling of the mucosal layer, it can lead to improvement in the urethral closure mechanism. We hypothesized that the intraurethral treatment would add benefit in treating patients with stress-predominant urinary incontinence with ISD component. 
Primary objective of this study was to assess the tolerability and safety of the combination of intraurethral and intravaginal non-ablative Er:YAG laser techniques for the treatment of women with SUI symptoms with an ISD component, and compare to intravaginal-only and sham treatments. Secondary objective was to assess the effectiveness of the combined intraurethral + intravaginal laser treatment and intravaginal-only treatment using relevant subjective and objective measures and compare to sham treatment through 6-months follow up. The duration of effect was assessed by extending the active group follow up (including the cross-over subjects from the sham group) to 12 months.

This study was designed as a prospective, randomized, 3-arm parallel pilot study. Included study subjects were women experiencing SUI and stress-predominant mixed urinary incontinence (SMUI) with a degree of ISD for a minimum duration of 6 months prior to enrolment. Diagnosis of SUI with a degree of ISD was performed using urodynamic and clinical assessment. 
The study followed the Declaration of Helsinki and was approved by an Ethics Committee. Patients who met inclusion criteria and signed informed consent were randomly allocated into combination of intraurethral and intravaginal treatment (Group 1, n=20), intravaginal treatment only (Group 2, n=20) and sham control (Group 3, n=15). Treatment in both active groups was performed using the 2940 nm Er:YAG laser (Fotona, Slovenia) at two sessions, 4 weeks apart. The study was single-blinded (patient only). The control arm underwent a sham intravaginal treatment with an inactive laser setting and parameter presentations masked. The sham arm subjects were followed out to 6 months and were then offered the active treatment; ten patients were crossed over to the Group 1 and five patients to Group 2. The subjects in active groups (including crossed-over subjects) were followed out to 12 months post-treatment (1 week telephone follow up and 3-, 6- and 12-month clinical visits). 
Tolerability of the intra-urethral/intravaginal Er:YAG laser treatments was assessed by VAS pain scale and by monitoring the use of pain relieving medication post treatment. Safety of the study intervention was assessed by recording the incidence and severity of adverse events. Effectiveness endpoints included reduction of leakage measured by 24-hour pad weight test and number of used pads, reduction in number of incontinence episodes measured by 3-day voiding diary, reduction of SUI symptoms measured by ICIQ-UI SF questionnaire and patient satisfaction measured by patient global impression of improvement (PGI-I).
Clinical success was defined for this proposed study as a > 50% reduction from baseline in mean 24-hour pad weight; or > 50% reduction in incontinence episodes from baseline to 6 months post-treatment.

55 patients were recruited to the study and randomized into three groups, as described above. 54 patients completed the trial, while one patient discontinued the study because of pregnancy. 15 patients from Group 3 (sham treatment) were followed out to 6 months and then randomized to either Group 1 (10) or Group 2 (5) and followed out to further 12 months. The final analysed number of patients in each group were therefore 30 in Group 1, 24 in Group 2 (which had 1 dropout due to pregnancy) and 15 in the Group 3.
During the study, 13 patients reported adverse events that were either possibly, probably, or definitely related to the procedure. Of those, 9 were considered mild, 4 moderate and none as severe. All adverse events were resolved in up to one week’s time. 5 patients (1 from Group 1 and 4 from Group 2) reported transient increase in UI that was resolved in a couple of days. Two patients (1 in Group 1 and 1 in Group 2) reported urinary tract infection for which antibiotics were prescribed. Six women (4 in Group 1 and 2 in Group 3) reported post-op discomfort, soreness or pain that was managed by oral ibuprofene or acetaminophene in 3 cases, while others did not require medication.
In this preliminary analysis, we analysed and compared the results for three effectiveness endpoints: 24-hour pad test, ICIQ-UI SF questionnaire and incontinence episodes as recorded by the 3-day voiding diary. 
At the 6-months follow up clinical, median pad-weight decrease in Group 1 (combined treatment) was 56.7%, in Group 2 (intravaginal treatment only) 33.3%, while in Group 3,10.1% median increase in pad weight was observed.
Median reduction in incontinence episodes at 6 months was also highest in Group 1 (50%), followed by Group 2 (43.6%) and Group 3 (20.4%).
ICIQ-UI SF assay at the 6-months follow up showed a median decrease of 4 points in Group 1, 3.5 in Group 2 and 0 in Group 3, when compared to baseline.
The complete statistical analysis of all safety and effectiveness endpoints is underway.

The analysis of procedure-related adverse events has shown that most of the recorded events were mild, transient and did not require medical assistance. There were no differences in the incidence of adverse events between active groups (Groups 1 and 2). 
As the included patients all had a degree of ISD, it was expected that the population would include more patients with moderate and severe incontinence. In previous studies, the intravaginal treatment was shown to be most effective for mild and moderate incontinence, and less effective in incontinence with intrinsic sphincter deficiency. 
A degree of placebo effect was seen in the sham group (Group 3), but it consistently diminished by the 6-months follow up. The treatment results of both active treatments persisted up to 12 months, some showing a decline in effectiveness between 6- and 12-months follow up. This was expected from previous studies. Based on other studies, increasing the number of treatments to 3–5 could add additional improvement in efficacy. 
Our results show that in patients with a degree of ISD, combining intraurethral and intravaginal treatments (Group 1) improves the efficiency of the laser procedure and at the same time does not result with additional or more frequent adverse events.

Combination of intraurethral and intravaginal non-ablative Er:YAG treatments seems to be a safe and effective method for treatment of SUI with a component of ISD. It is a minimally invasive treatment without implants or injectables and should be considered as a first line treatment especially in those women, which do not want to have more invasive procedures are not suitable candidates for those.

Kuszka A, Gamper M, Walser C, Kociszewski J, Viereck V. Erbium:YAG laser treatment of female stress urinary incontinence: midterm data. Int Urogynecol J. 2020 Sep;31(9):1859–66.
Gaspar A, Brandi H. Non-ablative erbium YAG laser for the treatment of type III stress urinary incontinence (intrinsic sphincter deficiency). Lasers Med Sci [Internet]. 2017;32(3):685–91.
Gaspar A, Maestri S, Silva J, Brandi H, Luque D, Koron N, et al. Intraurethral Erbium:YAG laser for the management of urinary symptoms of genitourinary syndrome of menopause: A pilot study. Lasers Surg Med [Internet]. 2018;50(8):802–7.

Continence 7S1 (2023) 100778
DOI: 10.1016/j.cont.2023.100778