Relief of double-J stent-related symptoms: a comparison between mirabegron, tamsulosin and solifenacin

Background Inserting ureteral stents is a routine intervention that often results in problems. The cornerstone for treating stent-related symptoms is pharmacological therapy. This study was conducted to evaluate and to compare the effectiveness of mirabegron, tamsulosin, solifenacin and control in reducing double-J stent-related symptoms. Results Patients were evaluated preoperatively, one week after stent insertion and two weeks after the start of medications by the Ureteral Stent Symptom Questionnaire (USSQ), International Prostate Symptom Score (IPSS), overactive bladder questionnaire (OAB-q) and visual analogue pain scale (VAPS). Solifenacin and mirabegron groups had significantly lower sexual scores after the 1st and 2nd weeks post-operatively (PO) when compared with the control group. Mirabegron group had significantly lower sexual scores after 1st and 2nd weeks PO when compared with patients in tamsulosin and solifenacin groups. Patients in mirabegron group had significantly fewer additional problems after the 1st and 2nd weeks PO when compared with patients in the control and tamsulosin groups. Conclusions To sum up, mirabegron was found to be superior to solifenacin in lowering urinary symptoms scores, sexual performance scores and work performance scores at both first and second weeks post-operatively. Mirabegron is a good alternative choice for SRSs when tamsulosin or solifenacin is ineffective or not tolerated.


Background
Double-J stents (DJS) are crucial to avoid or treat ureteral blockage [1,2].However, some patients may have stent-related morbidities including urinary tract infections (UTI), lower urinary tract symptoms (LUTS), general or pelvic discomfort and hematuria.In both men and women, such morbidities represent a prevalent problem with significant impacts on life quality, sexual matters, general health situation and regular work performance [3].Stent length, girth modification and avoiding the distal end crossing the midline are crucial and considerably lessen the discomfort associated with stents [4].
Tamsulosin is a medication that specifically inhibits alpha-1a/1d receptors; it works on the contracting smooth muscles of the distal ureter, bladder trigone and bladder neck [5].Relaxing these smooth muscles is thought to reduce voiding pressure and bladder outlet resistance, which has a beneficial effect in relieving LUTS related to DJ stents [6].
Solifenacin is a medication that specifically blocks the M1/M3 cholinergic receptors.It is prescribed to treat patients with overactive bladder (OAB) and may be beneficial for relieving stent-related symptoms [7,8].
Alpha blockers and antimuscarinics may have adverse effects.Alpha blockers may lead to postural hypotension, asthenia, headache and ejaculatory abnormalities [9].Antimuscarinics might result in dry mouth, constipation, disorientation, headache and an elevated risk of urine retention [10].
Mirabegron is a selective β3-adrenergic receptor agonist agent; it has a favorable safety profile and higher tolerability than antimuscarinics.Headache, hypertension and dry mouth are only experienced by a small number of patients [11].Recently, mirabegron has demonstrated efficacy in relieving SRSs [3].
This study aimed to evaluate and to compare the effectiveness of mirabegron, tamsulosin, solifenacin in reducing double-J SRSs.

Methods
This prospective cohort study (observations on already operated subjects) was performed in June 2020 in Urology Outpatient Clinic our University Hospital.Patients who underwent temporary ureteral stent placement were assessed for eligibility to the study.

Inclusion criteria
Patients aged > 18-year planning ureteral stenting for > 5 days and experienced double-J SRSs.

Exclusion criteria
Patients with bilateral stents.History of bladder or prostate surgery.Patients with contraindications for receiving either tamsulosin or mirabegron or solifenacin (i.e.end-stage renal disease, urinary retention, orthostatic hypotension, known QT prolongation, uncontrolled hypertension, severe aortic regurgitation), significant cognitive impairment, presence of neurogenic bladder, OAB syndrome, in addition to active urinary tract infection.

Methodology
A total of 200 patients with 6F polyurethane D-J stent were included in this study.The surgeon markings on the ureteric catheter that was inserted from the ureteral orifice to the renal pelvis were used to estimate the proper stent length in each patient.Patients were selected as four groups of 50 each; patients in group one served as controls and did not take any medications (control nonexposed arm).Patients in group two received 0.4 mg tamsulosin once daily, while those in group three patients received 5 mg solifenacin once daily, and those in group four received 50 mg mirabegron once daily.The medications were taken one week after stent placement for those who experienced DJ-related symptoms till removal of the stent.
The researchers observed patients preoperatively, one week after stent insertion and two weeks after the start of medications, by filling out the validated USSQ, the IPSS, OAB-q and VAPS questionnaire forms.

Perioperative assessment
The researchers obtained the history of all patients' demographics including age and sex from patient records.Then they recorded the operative details including indication of ureteric stenting, laterality and length of the stents used.Urine analysis and culture were performed to ensure that patients have sterile urine before the procedure.KUB was done before discharge to confirm the exact position of the stent.Urine analysis was done to exclude any existing infection.The patients were discharged when they were vitally stable and after removal of the urethral catheter.

Sample size
Using the G*Power 3.1.9.4 program, the sample size was determined to be 212 for the necessary sample and 220 for any data loss.Selected people were then randomly assigned to the study's four groups.

Statistical data analysis
SPSS for Windows, version 23, was used to tabulate, code and analyze the data that had been obtained.Categorical data were reported as percentages, whereas continuous variables were shown as mean values standard deviation (SD).Chi-square test and Fisher test were used to compare qualitative data.Independent sample t test was used to compare groups in quantitative data.Appropriate statistical tests of significance were utilized for further statistical analysis.Statistics were deemed significant for P values under 0.05.

Results
The results of demographic and anthropometric data are recorded in Table 1.The clinical data showed insignificant difference between the four studied groups as shown in Table 2.In the present study, patients in solifenacin and mirabegron groups had significantly lower urinary symptoms scores 1 week post-operative as well as 2 weeks post-operative (Table 3) when compared with patients in control group (P < 0.001 for both).Moreover, patients in solifenacin and mirabegron groups had significantly lower urinary symptoms scores 1 week post-operative as well as 2 weeks post-operative when compared with patients in tamsulosin group (P < 0.001 for both).Regarding pain score, patients in solifenacin and mirabegron groups had significantly lower body pain 1 week post-operative as well as 2 weeks post-operative when compared with patients in control group (P < 0.001 for both) (Table 4).Patients in solifenacin and mirabegron groups in the present study had significantly lower body pain 1 week post-operative as well as 2 weeks post-operative when compared with patients in tamsulosin group (P = 0.026 for both and P = 0.012 for both, respectively).General health index scores are recorded in Table 5. Patients in solifenacin and mirabegron groups had significantly lower general health index scores 1 week post-operative as well as 2 weeks post-operative when compared with patients in control group (P = 0.003 for both and P < 0.001 for both, respectively).In addition, no significant difference was reported between patients in solifenacin and tamsulosin groups regarding general health either 1 week or 2 weeks post-operative.It is worth noting that patients in mirabegron group had significantly lower general health index scores 1 week post-operative as well as 2 weeks post-operative when compared with patients in tamsulosin group (P = 0.012 for both).Work performance score results are recorded in Table 6.Patients in mirabegron group had significantly lower work performance scores 1 week post-operative as well as 2 weeks post-operative when compared with patients in control and solifenacin groups (P < 0.001 for both and P = 0.050 for both, respectively).Regarding sexual scores   (Table 7), patients in solifenacin group had significantly lower sexual scores 1 week post-operative as well as 2 weeks post-operative when compared with patients in control group (P = 0.001 for both and P < 0.001 for both, respectively).Patients in mirabegron group had significantly lower sexual performance 1 week post-operative as well as 2 weeks post-operative when compared with patients in tamsulosin and solifenacin groups (P < 0.001 for both and P = 0.004 for both, respectively).Patients in mirabegron group in the current study had significantly lower additional problems 1 week post-operative as well as 2 weeks post-operative when compared with patients in tamsulosin group (P = 0.009 for both) (Table 8).

Discussion
The use of indwelling DJ stents, a frequent urological technique, has seen an increase in justifications in the era of minimally invasive procedures.It is very important to avoid or treat ureteral obstruction in a variety of circumstances.However, during the stenting phase, this intervention is often linked to stent-related symptoms (SRS), which are responsible for patients' pain and have a detrimental impact on quality of life [12].Alpha blockers and antimuscarinics are the cornerstones of pharmaceutical therapy of SRSs.It is believed that alpha blockers may reduce voiding pressures and reflux by relaxing the smooth muscles in the ureter, trigonal and prostatic regions [13].Antimuscarinics work by similar processes to those used to treat overactive bladder (OAB) by decreasing bladder spasms [7].A beta-3 adrenoceptor agonist called mirabegron is authorized for use in treating OAB patients [14].
The mucosa and muscle layers of the bladder as well as the ureter express beta-3 adrenoceptors.Therefore, it is anticipated that beta-3 agonists would reduce SRSs via comparable processes.Alpha blockers and antimuscarinics, however, have related adverse effects.Alpha blockers may induce postural hypotension, asthenia, headaches and ejaculatory abnormalities, while antimuscarinics may result in dry mouth, constipation, disorientation, headaches and a higher risk of urine retention [15].
In contrast, mirabegron has a superior safety record and tolerance than antimuscarinics; only a small proportion of patients experience headache, hypertension, or dry mouth [14].Mirabegron has shown efficacy in  treating SRSs [16].There are currently published openlabel trials comparing mirabegron to hydration and the combination of tamsulosin and solifenacin [3].A controlcontrolled single-blinded study compared mirabegron to tamsulosin [17].
In the present study, patients in solifenacin group had significantly lower urinary symptoms scores 1 week postoperative as well as 2 weeks post-operative when compared with patients in control group (P < 0.001 for both).In agreement with our study, Dellis et al. [17] reported that patients receiving solifenacin expressed significantly lower urinary scores when compared with control group.
We noticed that patients in solifenacin group had significantly lower urinary symptoms scores 1 week post-operative as well as 2 weeks post-operative when compared with patients in tamsulosin group (P < 0.001 for both).In line with our study, El-Nahas et al. [18] demonstrated better efficacy in alleviating stent-related symptoms when compared with tamsulosin, while Dellis et al. [17]; Abdelaal et al. [19] studies revealed that solifenacin The effectiveness of combining tamsulosin and solifenacin in treating SRS is becoming more and more clear.According to Jian et al. [20] meta-analysis, the most effective treatment for treating urinary symptoms was a combination of tamsulosin and solifenacin, followed by solifenacin and tamsulosin monotherapy.
Moreover, patients in mirabegron group in the current study had significantly lower urinary symptoms scores 1 week post-operative as well as 2 weeks post-operative when compared with patients in control group (P < 0.001 for both).In agreement with our study, Galal et al. [12] in their study that compared patients who received mirabegron with patients who received no treatment as control group reported that the mirabegron group had significantly lower daytime frequency, nocturia and urgency.
Otsuki et al. [21], in contrast to our research, showed no significant difference for frequency and nocturia, and urgency levels in the USSQ urine symptom subscore were not substantially lower in the mirabegron group as compared to the control group.The authors hypothesized that increasing water consumption may have had an impact on patients undergoing ureteroscopy and having an indwelling ureteric stent, and that the accompanying polyuria may have decreased the reaction to the medication.
In the current study, patients in mirabegron group had significantly lower urinary symptoms scores 1 week post-operative as well as 2 weeks post-operative when compared with patients in tamsulosin group (P < 0.001 for both).Also, patients in mirabegron group had significantly lower urinary symptoms scores 1 week post-operative as well as 2 weeks post-operative when compared with patients in solifenacin group (P = 0.002 for both).
In agreement with our research, Sahin et al. [3] verified mirabegron as a single treatment with superior outcomes in treating OAB symptoms associated with DJ stents than other medications, since postoperative OAB-q levels in the tamsulosin group were greater than in the mirabegron group.The postoperative OAB-q value in the oral hydration group was 29, tamsulosin 23 and mirabegron 18, respectively.Their results also demonstrate that mirabegron can improve OAB-q results.
Regarding comparison between mirabegron and tamsulosin, Yavuz et al. [16] control-controlled study reported that while mirabegron has no impact on ureteral stent-related symptoms, it does reduce the demand for analgesics.Tamsulosin only alleviates urine symptoms caused by the ureteral stent while increasing the need for analgesics.
Our results do not line up with those of Chandna et al. [14], who found mirabegron to be on par with solifenacin and tamsulosin in terms of urine index score at 10 days and 4 weeks after ureteric stent installation.But when the urine index score's subscores for storage symptoms were evaluated, mirabegron and solifenacin both showed considerably lower scores than tamsulosin at the second visit and over the course of four weeks, indicating their superiority.The discrepancy may be ascribed to the research by Chandna et al. [14] having a longer period of follow-up.
In disagreement with our study, Alexander et al. [22] reported that in groups with tamsulosin 5 mg/day treatment compared with mirabegron 50 mg/day gives a good effect in lowering the complaint score lower urinary tract symptoms for four weeks post-installation of double-J (DJ) stent, urinary symptoms concluding that tamsulosin therapy compared with mirabegron can effectively cure complaints of post-installation lower urinary tract symptoms.The difference can be attributed to smaller sample size in Alexander [22] study (25 patients in each group in Alexander study [22] vs 50 patients in our study).
We noticed that patients in solifenacin group had significantly lower body pain 1 week post-operative as well as 2 weeks post-operative when compared with patients in control group (P < 0.001 for both).In line with our study, Dellis et al. [17] reported that patients receiving solifenacin expressed significantly lower pain when compared with control group.
We found that patients in mirabegron group had significantly lower body pain 1 week post-operative as well as 2 weeks post-operative when compared with patients in control group (P < 0.001 for both).This was in line with what Galal et al. [12] reported, as for stent-related pain, mirabegron group had significantly less flank and abdominal pain.Additionally, Yavuz et al. [16] discovered that the control group's analgesic need was higher than that of the mirabegron group's.Furthermore, mirabegron reportedly reduced body and total pain ratings, according to Tae et al. study [15].
Patients in solifenacin group in the present study had significantly lower body pain 1 week post-operative as well as 2 weeks post-operative when compared with patients in tamsulosin group (P = 0.026 for both).In line with our study, El-Nahas et al. [18] reported superiority of solifenacin over tamsulosin in relieving pain, albeit.
In contrast, Chandna et al. [14] reported comparable pain index score at both visits across mirabegron, solifenacin and tamsulosin groups.The difference can be attributed to longer duration of follow-up in Chandna et al. [14] study.
Moreover, solifenacin was found to be comparable with tamsulosin and alfuzosin in Jian et al. [20] meta-analysis.
Moreover, we found that patients in mirabegron group had significantly lower body pain 1 week post-operative as well as 2 weeks post-operative when compared with patients in tamsulosin group (P = 0.012 for both).In agreement with our study, Yavuz et al. [16] reported that patients in mirabegron group had less need for analgesics when compared with patients in tamsulosin group.Moreover, a significant improvement in pain index score for mirabegron over control was noted by Tae et al. [15].On the other hand, Yavuz et al. [16] demonstrated comparable pain index score scores but lower analgesic requirement for mirabegron and tamsulosin over control.
In discordance with our study, Alexander et al. [22] reported that in groups with tamsulosin 5 mg/day treatment compared with mirabegron 50 mg/day gives a significantly better effect in lowering the pain.The difference can be attributed to the smaller sample size in Alexander study [22].
In the present study, patients in solifenacin group had significantly lower general health index scores 1 week post-operative as well as 2 weeks post-operative when compared with patients in control group (P = 0.003 for both).In agreement, Dellis et al. [17] reported that patients receiving solifenacin expressed significantly lower general health index scores.
In the current study, no significant difference was reported between patients in solifenacin and tamsulosin groups regarding general health either 1 week or 2 weeks post-operative.Similarly, superiority of solifenacin over tamsulosin was not observed in Chandna et al. [14] study.On the contrary, Jian et al. [20] demonstrated lower general health index score with solifenacin monotherapy over tamsulosin.
Patients in mirabegron group in the current study had significantly lower general health index scores 1 week post-operative as well as 2 weeks post-operative when compared with patients in control group (P < 0.001 for both).On the contrary, Tae et al. [15] found no significant differences in the general health index score between mirabegron and control groups.
Moreover, we found that patients in mirabegron group had significantly lower general health index scores 1 week post-operative as well as 2 weeks post-operative when compared with patients in tamsulosin group (P = 0.012 for both).This was in agreement with Chandna et al. [14] study, patients in the mirabegron group illustrated significantly better general health index score in Chandna et al. [14] study, at the 1st visit and over 4 weeks of follow-up as well as well as less side effects as compared to the other drugs may account for better general health in these patients.
In our study, patients in mirabegron group had significantly lower work performance scores 1 week post-operative as well as 2 weeks post-operative when compared with patients in control group (P < 0.001 for both).In line with our finding, Galal et al. [12] reported that mirabegron versus control group showed significant difference in mean quality of life scores during the stenting period.On the contrary, Tae et al. [15] found no significant differences in the work performance score between mirabegron and control groups.
Moreover, the current study reported that patients in mirabegron group had significantly lower work performance 1 week post-operative as well as 2 weeks postoperative when compared with patients in solifenacin group (P = 0.050 for both).In concordance with our study, Palinrungi [23] reported that when mirabegron 50 mg/day and therapy with 5 mg/day of solifenacin were compared, the latter had significantly superior results in terms of reducing work activity score (2.08 vs. 2.04, P = 0.044).
Patients in mirabegron group had significantly lower work performance 1 week post-operative as well as 2 weeks post-operative when compared with patients in tamsulosin group (P < 0.001 for both).In discordance with our study, work performance index score was comparable across the mirabegron, solifenacin and tamsulosin groups in Chandna et al. [14] study.The difference can be attributed to the longer duration of follow-up in Chandna et al. [14] study (4 weeks).
According to the present study, patients in solifenacin group had significantly lower sexual scores 1 week postoperative as well as 2 weeks post-operative when compared with patients in control group (P = 0.001 for both).This was in line with what Dellis et al. [17] reported, as sexual life was positively influenced in patients receiving solifenacin.
Moreover, we noticed that patients in mirabegron group had significantly lower sexual scores 1 week postoperative as well as 2 weeks post-operative when compared with patients in control group (P < 0.001 for both).The mirabegron group scored lower than the control group in Tae's et al. [15] research when comparing sexual activity to the percentage of stent-related sexual abstention, although the difference was not statistically significant.The Tae et al. [15] research's lack of statistical significance may be attributable to its lower sample size than our investigation (only 45 patients).
According to the present study, patients in mirabegron group had significantly lower sexual performance 1 week post-operative as well as 2 weeks post-operative when compared with patients in tamsulosin group (P < 0.001 for both).Moreover, patients in mirabegron group had significantly lower sexual performance 1 week postoperative as well as 2 weeks post-operative when compared with patients in Solifenacin group (P = 0.004 for both).Contrary to our research, the research by Chandna et al. [14] found that sexual scores and other factors were similar among the three groups.At 10 days, sexual abstinence was noted in 83.3 percent of tamsulosin arm patients, 69.6 percent of solifenacin arm patients and 57.7 percent of mirabegron arm patients, with no discernible difference between the 3 groups.
Subjects in mirabegron group in the current study had significantly lower additional problems 1 week post-operative as well as 2 weeks post-operative when compared with patients in tamsulosin group (P = 0.009 for both).
In disagreement with our study, Alexander et al. [22] reported superiority of tamsulosin over mirabegron in reduction of additional problems.The difference can be attributed to the smaller sample size in Alexander study [22].
Furthermore, additional matters were comparable across the mirabegron, solifenacin and tamsulosin groups in Chandna et al. [14] study.The difference can be attributed to longer duration of follow-up in Chandna et al. [14] study.

Conclusion
In comparison with tamsulosin, solifenacin and mirabegron significantly lowered urinary symptoms scores, and body pain score 1 week post-operative as well as 2 weeks post-operative.In comparison with tamsulosin, mirabegron was found to significantly lower additional problems, sexual performance scores, general health index scores and work performance scores 1 week post-operative as well as 2 weeks post-operative.Finally, mirabegron was found to be superior to solifenacin in lowering urinary symptoms scores, sexual performance scores and work performance scores 1 week post-operative as well as 2 weeks post-operative that makes its use a good alternative choice for SRSs when tamsulosin or solifenacin is ineffective or not tolerated.

Table 1
Comparison of demographic, anthropometric data and stent length between the studied.groups P values less than 0.05 were considered as statistically significant, SD

Table 2
Comparison of clinical data between the 4 studied groups P values less than 0.05 were considered as statistically significant, SD: standard deviation

Table 3
Comparison of urinary symptoms between the 4 studied groups Bold and asterisk indicates statistically significant data P values less than 0.05 were considered as statistically significant, PO post-operative, SD standard deviation

Table 4
Comparison of body pain between groups Bold and asterisk indicates statistically significant data P values less than 0.05 were considered as statistically significant, PO post-operative, SD standard deviation

Table 5
Comparison of general health between groupsBold and asterisk indicates statistically significant data P values less than 0.05 were considered as statistically significant, PO post-operative, SD standard deviation

Table 6
Comparison of work performance between groupsBold and asterisk indicates statistically significant data P values less than 0.05 were considered as statistically significant, PO post-operative, SD standard deviation

Table 7
Comparison of sexual performance between groupsBold and asterisk indicates statistically significant data P values less than 0.05 were considered as statistically significant, PO post-operative, SD standard deviation

Table 8
Comparison of additional problems between groups