Tamsulosin or Silodosin Adjuvant Treatment Is Ineffective in Improving Shockwave Lithotripsy Outcome: A Short-Term Follow-Up Randomized,Placebo-Controlled Study

Abstract

Introduction:

The role of α-blockers after shockwave lithotripsy (SWL) is controversial. The aim of our study was to evaluate the effect of tamsulosin and silodosin after SWL for kidney stones.

Methods:

From 2012 onward, a consecutive series of patients undergoing SWL were prospectively enrolled and randomized by closed envelopes in three groups receiving tamsulosin 0.4 mg (A), silodosin 8 mg (B), and placebo (C) daily for 21 days after SWL. Anthropometrics, stone size, and location were recorded before SWL. Visual analogue scale (VAS) score was collected at 6, 12, and 24 hours after treatment to evaluate patients’ discomfort. Stone-free rate was assessed 1 and 3 weeks postoperatively. Complications and medical treatment–related adverse events (AEs) were recorded. Differences in VAS score, stone-free rate, and complications were compared among the groups.

Results:

Overall, 60 patients were enrolled. Mean stone sizes were 10.28 ± 2.46 mm, 10.45 ± 1.73 mm, and 9.23 ± 2.04 mm in groups A, B, and C, respectively (p = 0.474). There was no significant difference between the three groups with regard to stone location. Comparable energy was used to treat patients from the three groups. The overall 3-week stone-free rate was 53%: 58% in the tamsulosin group, 47% in the silodosin group, and 55% in the placebo group (p = 0.399). No significant differences were observed in the VAS scores reported by the groups at 6 hours (p = 1.254), 12 hours (p = 0.075), and 24 hours (p = 0.490). Overall, 12 complications were reported: 11 patients (7 in group C and 4 in group B) needed analgesics for colic, and 1 patient (group B) was surgically treated for Steinstrasse. Tamsulosin was superior to placebo (p = 0.008) and silodosin (p = 0.021) in preventing complications; no difference between silodosin and placebo (p = 0.629) was noted.

Conclusions:

Tamsulosin and silodosin are ineffective in increasing stone-free rate as well as early patients’ discomfort after extracorporeal lithotripsy.

Introduction

Urolithiasis is a frequent disease, with a prevalence ranging from 1% to 15%, and its incidence is increasing, mostly in Western countries. It is threefold more frequent in men than in women, mainly in patients between 20 and 40 years of age.¹

According to the American Urological Association (AUA) and the European Association of Urology (EAU), extracorporeal shockwave lithotripsy (SWL) is indicated for renal stones of <20 mm in diameter.² Management of residual fragment after SWL is still a major concern as it may eventually cause pain and require reintervention. Elimination of residual fragments depends on various parameters, such as size, number, location in the urinary tract, patient's anatomy, and ureteral peristaltic capability.²

Medical expulsive therapy (MET) is an established therapeutic approach based on the use of various drugs acting on the ureter promoting, by different mechanisms, the spontaneous passage of ureteral stones, thus reducing the need for minimally invasive surgery.¹ It has been lately used with controversial results as an adjuvant treatment after SWL, aiming to enhance stone-free rates and decrease expulsion time.² The role of calcium channel blockers, α-blockers (αBs), corticosteroids, and nonsteroidal anti-inflammatory drugs in improving SWL outcomes has been already investigated. Particularly, tamsulosin has been proven to increase the stone expulsion rate and decrease expulsion time, while few studies have investigated the role of silodosin in ureteral stone expulsion,¹ and no study evaluated the possible differences between tamsulosin and silodosin adjuvant treatments post-SWL.

The aim of the present prospective, randomized, placebo-controlled study was to compare silodosin and tamsulosin as adjuvant treatments after SWL for kidney stones.

Materials and Methods

From January 2012 to March 2015, a consecutive series of patients undergoing SLW for a single radiopaque renal stone (0.5–2 cm) were prospectively enrolled. Informed consent was signed by each single patient. Patients with congenital or acquired urinary anomalies, severe vertebral malformation, renal impairment, hydronephrosis, ureteral stent, urinary tract infection, previous SLW, ureterolithotripsy (ULT), or recent open/endoscopic surgical intervention and those on calcium channel blocker or α-adrenergic antagonist and corticosteroids were excluded from the study.

A complete medical history along with anthropometric parameters was routinely collected. Body mass index (BMI) was calculated as weight in kilograms divided by height in meters squared (kg/m²). Blood samples were taken and tested for blood count and serum creatinine. Urinalysis and urine culture were also performed before SWL. Stone number, size, and location were assessed preoperatively by means of a low-dose noncontrast-enhanced computed tomography (CT) scan, the most accurate imaging modality to define stone size and location.³ By closed envelopes, patients were randomized into three groups: those receiving tamsulosin 0.4 mg were allocated to group A, those receiving silodosin 8 mg daily to group B, and those receiving placebo to group C. Drug/placebo administration was started immediately after the SWL and continued, daily, for 21 days. EDAP integrated Sonolith 4000 plus (EDAP TMS, France) was used for SWL treatment. The procedure started with a low energy level in each pulse and was then gradually increased with the aim of maximizing stone fragmentation and reducing the morbidity of the procedure.⁴ A maximum of 3500 shocks (SWs) at a rate of 60–90 shocks/minute per session were delivered.⁵ Patients were given intravenous analgesia (tramadol) along with intravenous antiemetic (metoclopromide) during each SWL session in case of pain and nausea. No perioperative antibiotic prophylaxis was administered. After lithotripsy session, patients were informed regarding how to complete a visual analogue scale (VAS) (0: no pain, 1–4: mild, 5–6: moderate, and 7–10: severe) and provided with 3 paper copies, so that they could mark the intensity of pain at 6, 12, and 24 hours after treatment. Stone-free rate was evaluated 1 and 3 weeks after treatment by means of urinary tract ultrasound (US). A low-dose CT was also performed 3 weeks after treatment in patients with any suspicion of residual fragments on US. Differences in VAS score and stone-free rate were compared among the three groups. Complications were recorded and evaluated using the modified Clavien classification system.⁶ Medical treatment–related adverse events (AEs) were also recorded.

Statistical analysis

Statistical analysis was performed using SPSS 12.0 software. Evaluation of data distribution showed a nonnormal distribution of the study data set. Differences between groups of patients in medians for quantitative variables and differences in distributions for categorical variables were tested with Kruskal–Wallis test and χ ² test, respectively. An α value of 5% was considered as threshold for significance.

Before the study start, a power calculation was performed based on the assumption of an increase in the stone-free rate from 55% to 75% per person in both treatment arms.⁷ To detect such a difference with 80% power⁸ using a two-tailed test at 5% significance level,⁹ it was estimated that 18 evaluable patients per group were needed. To consider possible dropout, 22 patients per group were planned.

Results

Overall, 66 patients were enrolled, but six were excluded as they did not complete the VAS score (three patients) or the follow-up evaluation (three patients). Overall, 60 patients (32 males and 28 females) completed the study: 19 were included each in groups A and B and 22 in group C. The three groups were comparable with regard to their baseline demographic and clinical characteristics (Table 1).

Table 1.

Patients’ Characteristics

	Overall (N = 60)	Group A, tamsulosin (n = 19)	Group B, silodosin (n = 19)	Group C, placebo (n = 22)	p Value
Gender, n (%)
Male	32 (53)	11 (58)	12 (63)	9 (41)	0.271
Female	28 (47)	8 (42)	7 (37)	13 (59)
Age, years	48.12 ± 14.72 (48; 40/59)	46.95 ± 12.14 (47; 40/53)	45.53 ± 13.79 (46; 40/55)	51.36 ± 17.36 (51; 42/66)	0.293
BMI, kg/m²	24.61 ± 3.77 (24.5; 22/26.7)	25.04 ± 4.11 (24.9; 20/27.6)	24.2 ± 3.03 (24.5; 22/25.8)	24.62 ± 4.17 (24.06; 22/27)	0.563
Side, n (%)
Right	26 (43)	8 (42)	9 (47)	9 (41)	0.818
Left	34 (57)	11 (58)	10 (53)	13 (59)
Site, n (%)
Upper	9 (15)	2 (10.5)	2 (10.5)	5 (23)	0.107
Mid	17 (28)	7 (37.5)	4 (21)	6 (27)
Lower	16 (27)	5 (26)	9 (47.5)	2 (9)
Pelvis	18 (30)	5 (26)	4 (21)	9 (41)
Size, mm	9.95 ± 2.13 (10; 8/11.75)	10.28 ± 2.46 (10; 8.7/11.2)	10.45 ± 1.73 (10; 9.25/12)	9.23 ± 2.04 (8.5; 8/11.25)	0.474

Data are presented as mean ± SD (median; Q1/Q3).

BMI = body mass index; CD = Clavien–Dindo classification; AE = adverse events.

The mean age was 46.95 ± 12.14 years in group A, 45.53 ± 13.79 years in group B, and 51.36 ± 17.36 years in group C (p = 0.293). Mean BMIs were 25.04 ± 4.11 kg/m², 24.2 ± 3.03 kg/m², and 24.62 ± 4.17 kg/m² in the three groups, respectively (p = 0.563). Mean stone sizes were 10.28 ± 2.46 mm, 10.45 ± 1.73 mm, and 9.23 ± 2.04 mm in the previously mentioned groups, respectively (p = 0.474). Similarly, there was no statistically significant difference between the three groups with regard to side and site of stones (Table 1). Comparable energy was used to treat patients with a mean of 3120 ± 520 SWs delivered to those in group A, 3070 ± 590 SWs to those in group B, and 2880 ± 610 SWs to those in the control group (p = 0.679). Treatment outcomes and complications are summarized in Table 2. The overall 3-week stone-free rate was 53% (32/60): 58% (11/19) in the tamsulosin group, 47% (9/19) in the silodosin group, and 55% (12/22) in the placebo group (p = 0.399). Because of residual fragment, 8 patients in group A, 10 in group B, and 10 in group C were scheduled for a second SWL treatment. The mean intensity of pain patients experienced according to the VAS was assessed at 6, 12, and 24 hours after treatment. Median VAS scores of 4 (IQR: 1–6), 3 (IQR: 1–4), and 1 (IQR: 1–4) were reported, respectively, by patients in group A; 5 (IQR: 1–9), 3 (IQR: 1–7), and 2 (IQR: 1–4) by those in group B; and 6 (IQR: 1–9), 2 (IQR: 1–8), and 1 (IQR: 1–7) by subjects in group C. No significant differences among the three groups were observed when VAS score was stratified (no/mild pain = VAS 0–3 and moderate/severe pain = VAS 4–10) (Table 2). Overall, 12 complications in 12 of 60 patients were reported: 11 patients (7 in the placebo group and 4 in the silodosin group) reported renal colic and needed analgesics on demand, and 1 patient (group B) was diagnosed with Steinstrasse and therefore was further hospitalized to perform ULT under general anesthesia. A statistically significant difference was found in terms of complication rate between the three groups (p = 0.031). Compared one to one, tamsulosin was found to be superior to placebo (p = 0.008) and silodosin (p = 0.021) in reducing the overall complications rate, whereas no statistically significant difference was noted between silodosin and placebo (p = 0.629). Overall, 3 of 60 patients reported retrograde ejaculation: one (5%) in group A and two (10%) in group B (p = 0.813); no patients in the control group experienced the same disorder.

Table 2.

Extracorporeal Shockwave Lithotripsy Outcomes and Complications

	Overall (N = 60)	Group A, tamsulosin (n = 19)	Group B, silodosin (n = 19)	Group C, placebo (n = 22)	p Value
Operative time, minutes	39.59 ± 10.92 (45; 30/45)	41.32 ± 11.64 (45; 30/45)	39.25 ± 10.29 (42; 30/45)	38.41 ± 11.16 (45; 25/45)	0.559
Shocks, thousands	3.02 ± 0.58 (3; 2.5/3.5)	3.12 ± 0.52 (3; 2.5/3.5)	3.07 ± 0.59 (3; 3/3.5)	2.88 ± 0.61 (3; 2.5/3.5)	0.679
VAS 6 hours	5 (IQR: 1–8)	4 (IQR: 1–6)	5 (IQR: 1–9)	6 (IQR: 1–9)	1.254
No/mild pain (VAS 0–3), n (%)	25 (42)	7 (37)	9 (47)	9 (41)	0.604
Moderate/severe pain (VAS 5–10)	35 (58)	12 (63)	10 (53)	13 (59)
VAS 12 hours	3 (IQR: 1–6)	3 (IQR: 1–4)	3 (IQR: 1–7)	2 (IQR: 1–8)	0.075
No/mild pain (VAS 0–3), n (%)	33 (55)	11 (58)	10 (53)	12 (55)	0.926
Moderate/severe pain (VAS 5–10)	27 (45)	8 (42)	9 (47)	10 (45)
VAS 24 hours	1 (IQR: 1–4)	1 (IQR: 1–4)	2 (IQR: 1–4)	1 (IQR: 1–7)	0.490
No/mild pain (VAS 0–3), n (%)	37 (62)	13 (68)	11 (58)	13 (59)	0.703
Moderate/severe pain (VAS 5–10)	23 (38)	6 (32)	8 (42)	9 (41)
Stone-free rate, n (%)	32 (53)	11 (58)	9 (47)	12 (55)	0.399
Complications, n (%)
CD grades I–II	11 (18)	0	4 (21)	7 (32)	0.031
CD grades III–IV	1 (1.6)	0	1 (5)	0
Total	12 (19.6)	0	5 (26)	7 (32)	0.029
Drug-related AEs, n (%)	3 (8)	1 (5)	2 (10)	0	0.331

Data are presented as mean ± SD (median; Q1/Q3).

Discussion

Urinary stone disease presents an important impact in daily urologic practice, affecting 1%–15% of the population.¹ Since its introduction in the 1980s,¹⁰ SWL has changed the noninvasive treatment of renal and ureteral stones, being considered for years the main modality of treating renal concretions <2.0 cm. In our series, the stone-free rate in the placebo group was 55%, in line with the meta-analysis published by Lingeman et al.¹¹ that reported a success rate of 56% for patients with stones <2 cm treated with SLW alone. Conversely, after a single session of SWL, Wiesenthal et al.¹² reported a significantly higher stone-free rate (70.2%): this result can be due to the considerably longer (3 months) follow-up period. In our experience, although MET was well tolerated, it did not influence the SWL outcome. The 3-week stone-free rate did not differ between the three groups, being 58% in patients treated with tamsulosin, 47% in those treated with silodosin, and 55% in the placebo population (p = 0.399). The rationale to use αBs as adjuvant treatment post-SWL to improve stone clearance dates back to 1970 when Malin first described the role of adrenergic receptors (ARs) in the human ureter.¹³ There are also several studies and meta-analysis supporting that αBs produce relaxation of the human ureter by reducing smooth muscle tone, thus providing clinical benefit in patients with ureteral stones or kidney stone treated with SLW.^{1,2,14

–17} Although most of the studies used tamsulosin, a selective α1A/α1D AR antagonist, the efficacies of other αBs as silodosin were also recently investigated.^{14,18

–22}

Despite all these evidences, the effectiveness and role of αBs as adjuvant treatment in improving stone clearance after SLW remain controversial.

Recent data from the SUSPEND (Spontaneous Urinary Stone Passage Enabled by Drugs) trial, a large, multicenter, randomized, placebo-controlled trial, do not support the effectiveness of MET in assisting stone clearance. Particularly, the rate for spontaneous stone passage did not differ between the MET and control groups (p = 0.78; RR 0.9, 95% [CI]: 5.1, 6.8). Moreover, no differences were recorded with regard to time to stone passage (p = 0.71; RR 0.6, 95% [CI]: − 2.6, 4.0) and days of analgesic use (p = 0.45; RR 0.6, 95% [CI]: − 1.6, 2.8).²³ In this study, however, the effect of silodosin was not assessed.

Moreover, in our study, MET does not seem to be effective in reducing the intensity of pain experienced by patients in the first hours after SLW. In fact, the treatment was considered uncomfortable by the majority of the overall population as 35 of 60 (58%) patients reported moderate/severe pain 6 hours after SLW, and the number slightly decreased to 27 of 60 (45%) at 12 hours and 23 of 60 (38%) at 24 hours. No statistically significant differences were observed in the VAS scores reported by the three groups when assessed. Our results are difficult to compare with the available evidence as few studies have evaluated using a VAS the potential role of MET after SLW treatment. Most of them evaluated the VAS at baseline and 8 weeks after treatment²⁴ or observed a statistically significant but probably clinically nonrelevant difference of about 1 point between patients receiving treatment and the control group, with no changes in patients with moderate pain.²⁵

In the present study, the overall complication rate, classified according to the Clavien classification system, was 19.6%. Most of the complications were low grade and included a renal colic requiring analgesics on demand in 11 of 60 (18%) patients. In only one patient, from the silodosin group, we performed an ULT for a Steinstrasse. Our overall complication rate is lower than those reported by other authors, and it could be explained with the characteristics of our study population: small series, no significant comorbidities, nonobese population, and small kidney stone. However, the incidence of colicky pain in our control group (32%) is similar to the one reported by Salem et al.²⁶ (40%) in a population of 3241 patients with a radiologic diagnosis of renal stones treated by SLW not followed by MET.

Comparing silodosin with tamsulosin showed that the latter was superior to the former (p = 0.021) and placebo (p = 0.008) in preventing low-grade complication. This result is in line with the finding by Gravina that reported a lower incidence of renal colic (26.1% versus 76.9%, p < 0.001) in the tamsulosin group.²⁷ However, considering our small population and the small number of complications reported, a comparison between tamsulosin and silodosin to placebo in the efficacy of preventing complications when administered after SLW might be misleading and was out from the aim of our study. We must acknowledge some limitations of our study. Our series is a small group of well-selected patients with kidney stones <2 cm and no significant comorbidities. Furthermore, patients were followed up for only 3 weeks, and no data are available regarding stone composition. However, notwithstanding all these limitations, our study is the only available randomized, placebo-controlled study comparing the two most commonly αBs used as adjuvant SWL treatment. Another peculiar characteristic of our study was that we evaluated the stone-free rate as well as the possible early pain relief associated with MET treatment using three VAS score evaluations in the first 24 hours after treatment when pain perception could be more important. Although a high-quality confirmatory trial with a large number of patients and using different SWL machines is warranted, our experience suggests that αBs should not be offered to patients post-SWL and that further in vitro end in vivo studies are needed to identify new possible medical treatments improving stone clearance after SWL.

Conclusions

To our knowledge, this is the first prospective, randomized, placebo-controlled trial comparing silodosin and tamsulosin as adjuvant MET after SLW for kidney stones. We highlighted that both the drugs are ineffective in increasing stone-free rate as well as early patients’ discomfort after extracorporeal lithotripsy. Further confirmatory studies should clarify the role of αBs as adjuvant treatment post-SWL.

Footnotes

Author Disclosure Statement

No competing financial interests exist.

Abbreviations Used

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