The efficacy of alpha-1A blocker (tamsulosin), antimuscarinic (solifenacin) and their combination in the management of double-J stent-related lower urinary tract symptoms: a randomized controlled study

The insertion of a double-J (DJ) stent is considered a routine and necessary urological procedure. It can cause lower urinary tract symptoms (LUTS). Pharmacologic management is one of many trials that were done to improve these symptoms, particularly the administration of alpha-1A blockers and antimuscarinics medications. This trial aimed to evaluate the efficacy of alpha-1A blocker (tamsulosin), antimuscarinic (solifenacin), and their combination in managing DJ stent-related LUTS. This prospective, randomized, comparative, and nonblinded trial was conducted between November 2016 and October 2018. Eligible patients were between 18 and 50 years of both genders who underwent temporary retrograde unilateral Double-J stent fixation. Patients were randomized to four groups; group I was control (drug-free), group II received tamsulosin 0.4 mg, group III received solifenacin 5 mg, and group IV received the combination of tamsulosin and solifenacin. All patients completed the IPSS, QoL, and VAS questionnaires at both pre-insertion day of the stent and 2 weeks postoperatively; the data obtained were compared to all four groups. The study included 143 patients (78 males, 65 females). There was no statistically significant difference between the four groups regarding age, sex, side, and DJ placement indications. In comparison with the control group, there were statistically significant differences in all scores in favor of groups II, III, and IV. Compared to groups II and III, there were statistically significant differences in overall IPSS, QoL, and VAS scores in group IV. No significant differences were found between the tamsulosin and solifenacin groups. The alpha-1A blocker (tamsulosin) or antimuscarinic (solifenacin) monotherapy effectively improves the DJ stent-related LUTS and the QoL of patients with no advantage with either drug. The combination therapy of both pharmacotherapies is significantly effective than drug monotherapy.

of a DJ stent is considered a routine and necessary urological procedure, which can be used in different ways to treat urinary tract diseases [2]. For instance, it is used to relieve ureteral obstruction due to stones or tumors, post-ureteroscopic lithotripsy, pre-shockwave lithotripsy, or post-percutaneous nephrolithotomy (PNL). The DJ ureteral stent can cause lower urinary tract symptoms (LUTS) even with its beneficial effects, such as frequency, dysuria, urgency, urge incontinence, and suprapubic pain that affects sexual health and quality of life (QoL) in 70-80% of cases [3].
Trials to overcome DJ stent-related LUTS included using the DJ stent's precise length, appropriate placement of upper and lower coil, changing stent material from polyurethane to silicone or other polymers, changing the coating substance or stent design [4]. Pharmacologic management is one of many trials that were done to improve these symptoms, particularly the administration of alpha-1A blockers and antimuscarinics medications [5].
The basis for administering alpha-1A blockers based on the DJ stent-related symptoms' resemblance to benign prostatic hyperplasia-related LUTS [6]. The antimuscarinics (tolterodine and solifenacin) stimulate the muscarinic receptors to control the involuntary contractions of vesical smooth muscle that is a cause of LUTS [7,8].
Therefore, this trial aimed to evaluate the efficacy of alpha-1A blocker (tamsulosin), antimuscarinic (solifenacin), and their combination in the management of double-J stent-related lower urinary tract symptoms using the International Prostate Symptom Score (IPSS), QoL score, and Visual Analog Scale (VAS).

Methods
This prospective, randomized, comparative, and nonblinded trial was conducted between November 2016 and October 2018. Eligible patients were between 18 and 50 years of both genders who underwent temporary retrograde unilateral Double-J stent fixation.
Patients who had bladder pathology (like bladder tumor), age less than 18 years, bilateral stents, urethral stricture, benign prostatic hyperplasia, prior use of alpha-blocker and anticholinergics drugs, urinary tract infection, pregnant women, overactive bladder (OAB), history of previous ureteral stenting or long-term stenting were excluded from the study. The local ethics committee approved the research procedure.
An informed consent form was signed by eligible patients who decided to participate in the trial. Patients that developed complications associated with stents were excluded.
A computer randomization software (http://www. rando mizat ion.com/) was used to assign patients to four groups: group I control group did not receive any medications, group II received tamsulosin 0.4 mg once daily, group III received solifenacin 5 mg once daily, and group IV received both tamsulosin and solifenacin. The medication was used until the DJ stent was removed.
All patients were evaluated by medical and surgical history, examination, and routine laboratory investigations. In all cases, PercuflexTM 6F DJ ureteral stents (Boston Scientific, USA) were used. The DJ length was determined by the marks on the ureteric catheter inserted from the ureteral orifice to the renal pelvis before the DJ stent fixation.
Routinely, abdominal X-ray film was done to confirm proper DJ positioning before home discharge. The day before operation and 2 weeks after stent fixation, each patient completed written validated IPSS, QoL, and VAS questionnaires.
The VAS is a validated, subjective measure for pain. Scores are verified by creation a hand-written mark on a 10-cm line that denotes a range between "no pain" and "pain as bad as it could possibly be" [9]. We compare the total scores between groups on the pre-insertion day of the stent and after 2 weeks.
The data collected and analyzed by SPSS (version 24.0, IBM Corporation; Armonk, NY, USA). Categorical variables were compared between treatment groups by Chi-square or Fisher exact tests. Comparisons between multiple groups were made using the Kruskal-Wallis test, and post hoc comparisons were made with adjustment for multiple comparisons. The sample size was calculated with ClinCalc Sample Size Calculator. A sample size of 130 patients was calculated for the power of 0.8, alpha error probability 0.05 and 20% drop-out.

Results
The total studied patients for eligibility were 252 cases. A total of 164 cases were included in the trial, but 143 patients completed the study. Eleven patients lost to follow up, and ten patients discontinue the treatment. The CONSORT Flow Diagram of the patients through the trial is illustrated in Fig. 1.
The study included 143 patients (78 males, 65 females). There was no statistically significant difference between the four groups regarding age, sex, side, and DJ placement indications. The most frequent indication was ureteroscopy (URS), 65% (Table 1). There was no statistically significant difference between groups as regards stone size and operative time in URS cases.
Regarding IPSS scores, initially (pre-insertion day), there was no statistically significant difference between the four groups. In contrast, after 2 weeks, there was an overall significant difference between the four groups ( Table 2). The control group was significantly different from all the other three groups. The combined therapy group was also statistically significantly different from both tamsulosin and solifenacin monotherapy.
The difference between the tamsulosin and solifenacin groups was not statistically significant. That means tamsulosin alone or solifenacin alone improves DJ stent-related symptoms with no advantage with either medication. At the same time, their combination does a better result than either drug alone in improving DJ stent-related LUTS.
Regarding QoL score and VAS, pre-insertion day of DJ stent, there was no significant difference between the four groups. Meanwhile, after 2 weeks, there was an overall statistically significant difference between the four groups. The control group was statistically significantly different from all the other three groups.
The tamsulosin group was also statistically significantly different from the combination treatment group. The solifenacin group was also statistically significantly different from the combination treatment group. There was  no statistically significant difference between the tamsulosin group and the solifenacin group. That means both tamsulosin and solifenacin improve the QoL and VAS of patients with no advantage of either medication, while their combination is better than either medication alone (Table 3).

Discussion
DJ ureteral stenting has become a routine practice for every urologist. The main advantages of stenting are preventing ureteral obstruction, permitting ureteral healing, and preventing ureteral stricture. Despite its useful effects, short-term use of a double-J stent is associated with mild complications. In contrast, the complications became more severe in long-term usage, particularly when placed for more than 6 months. Patients usually complain of various stent-related symptoms, such as frequency, urgency, dysuria, incomplete emptying, flank pain, suprapubic pain, incontinence, and hematuria. These symptoms negatively affect the patient's activities, work performance, and QoL [10]. The pathogenesis of the DJ stent-related LUTS has not been verified. Multiple theories were proposed to describe these symptoms' mechanisms; it might be due to smooth muscle spasm in the lower ureter, irritation of nerve endings located in the trigone of urinary bladder submucosa, and bladder instability [11][12][13].
Trials to overcome the DJ stent-related LUTS included using the suitable length of the stent, appropriate placement of upper and lower coils, changing stent material from polyurethane to silicone or other polymers, changing the coating substance or stent design. Pharmacologic management is one of many trials to improve those problems; many medical drugs have been tested, such as anticholinergics, analgesics, and alpha-blockers.
In this trial, we aimed to evaluate the efficacy of alpha-1A blocker (tamsulosin), antimuscarinic (solifenacin), and their combination in the management of DJ stentrelated LUTS, using IPSS, QoL, and VAS questionnaires.
Our analysis found that, relative to the control group, both alpha-1A blocker (tamsulosin) and antimuscarinic (solifenacin) monotherapy improved patients' DJ stentrelated LUTS using IPSS, QoL, and VAS questionnaires. However, their combination was much better than either drug alone. These results were consistent with other studies; Lim et al. conducted a retrospective study that stated

QoL
Pre-insertion 0 (0-0) 0 (0-1) 0 (0-1) 0 (0-1) 0.31 that combined treatment with tamsulosin and solifenacin improved LUTS more than in the other groups (control, tamsulosin, and solifenacin monotherapy) [14]. In a prospective, randomized, and controlled study by Shalaby et al., combined treatment with tamsulosin and solifenacin was confirmed to be substantially better than either drug alone in relieving the DJ stents-related LUTS [11]. EL-Nahas et al. indicated that in patients with DJ stents, tamsulosin alone or solifenacin alone could improve the QoL by reducing LUTS related to DJ stents. Solifenacin has shown better efficacy than tamsulosin. They did not study the efficacy of combined treatment [15].
A meta-analysis performed by Zhou et al. proved a substantial advantage of combined treatment of alphablockers and antimuscarinics compared with alphablockers monotherapy. Also, they stated a beneficial effect of alpha-blockers alone and antimuscarinics alone in relieving the ureteric stent-related LUTS. After all, higher quality, randomized controlled trials have been recommended to deal with this subject [16].
Liu et al. reported that in the first few days, combination therapy was affected quicker than monotherapy. Based on this analysis, the combination treatment was suggested for patients with severe symptoms at the start [17]. Another study by Dellis et al. reported that tamsulosin and solifenacin monotherapy or combined treatment relieve the DJ stent-related LUTS and improve the QoL [18].
In contrast, Lee et al., a prospective randomized study using a combined treatment of tamsulosin and tolterodine, informed no statistically significant difference compared to placebo. The combined treatment showed no benefit when compared to tamsulosin alone. In their view, the DJ stent's correct positioning was more important than pharmacotherapy for relieving the DJ stentrelated LUTS [19].
Also, Park et al. have performed randomized clinical trials to test the effectiveness of tamsulosin, solifenacin and combined treatment in relieving DJ stent-related LUTS. They concluded that neither tamsulosin nor solifenacin positively affected relieving the DJ stent LUTS [20].
Another study reported that anticholinergic (tolterodine) was not different from anti-inflammatory, spasmolytic, and alpha-blockers regulating DJ stent-related LUTS [21]. In contrast to this result, a prospective randomized controlled study by Park et al. stated that the anticholinergic (tolterodine ER) and alpha-blocker (alfuzosin) relieving the DJ stent-related urinary symptoms [8].
The heterogeneity due to differences in surgical procedures was the key drawback of our report. For instance, post-ureteroscopy DJ placement leads to less pain and hematuria than post-PNL.

Conclusion
The alpha-1A blocker (tamsulosin) or antimuscarinic (solifenacin) monotherapy effectively improves the DJ stent-related LUTS and the QoL of patients with no advantage with either drug. On the other hand, both pharmacotherapies' combination therapy is significantly effective than drug monotherapy in improving DJ stentrelated LUTS and the patients' QoL.