Introduction
Ureteral stones account for 22 % of all urinary tract stones with 68 % of them being located in the distal ureter [
1]. Conservative management strategies such as observation or medical expulsive therapy (MET) using pharmacological agents to facilitate spontaneous passage of ureteral stones have gained popularity in the management of ureteral stones during the recent years [
2]. Evidence on the association of stone size with spontaneous stone passage rates is scarce. 95 % of stones up to 4 mm are estimated to pass within 40 days. Moreover, stones <10 mm can be considered to pass spontaneously [
3]. There is a growing body of evidence on the clinical benefit of the α-blockers in the patients with distal ureteral calculi. Specifically, the administration of α-blockers is related to a higher stone expulsion rate and shorter time periods for stone passage when compared to observation [
1,
4].
The mechanism of action behind the above effects is associated with the presence of adrenergic receptors (ARs) in the ureteric smooth muscle cells with the α1-adrenergic receptors to be the most abundant [
5]. α1A-, α1B- and α1D-ARs are the three types of α1-ARs that are expressed in the human ureter with the following order of abundance α1D > α1A > α1B. The blocking of these receptors results in selective relaxation of the ureteric smooth muscle and, therefore, causes ureteric lumen dilatation. The latter phenomenon results in facilitation of stone expulsion. [
6‐
8].
The most commonly used α-blocker for MET is tamsulosin, but similar effects have been shown by other α-blockers such as terazosin and doxazosin, indicating a possible class effect [
3]. Silodosin has been also proposed for MET instead of tamsulosin but studies comparing these substances for MET are scarce. In this systematic review and meta-analysis we aim to review current literature and compare the success rates of silodosin to tamsulosin for MET of ureteral stones.
Discussion
Tamsulosin is a selective α1-blocker with tenfold greater affinity to α1A- and α1D- AR subtypes in comparison to α1B -AR subtype, whereas the affinity of silodosin to α1A-AR subtype is about 162-fold and 50-fold greater than its affinity to α1B- and α1D-AR subtypes, respectively [
18]. Silodosin has shown superior results in the treatment of benign hyperplasia of the prostate when compared with tamsulosin in terms of efficacy and safety [
19]. The above differences in the affinity of the tamsulosin and silodosin to the respective receptors may be related to the observed differences in the clinical outcome of these pharmaceutical substances for MET.
The expulsive effect for ureteral stones of silodosin has been proposed in a RCT comparing silodosin to observation treatment [
20]. 112 patients were randomized into 8 mg of silodosin or observation. Both groups were directed to take 2 L of water/day. Silodosin showed superior expulsion rates especially for stones ≥5 mm. The stones of 17.9 % (
n = 28) of the patients of the observation group and 75.9 % (
n = 29) of the silodosin group were successfully expelled (
p = 0.001). The expulsion time was 13.40 ± 5.90 and 9.29 ± 5.91 days, respectively (
p = 0.012). Analgesics were required 1.5 ± 3.1 and 0.3 ± 0.9 times, respectively (
p = 0.382). The stone size of the expulsion cases showed significant difference with 3.64 ± 1.25 and 5.23 ± 2.32 mm for the observation and silodosin groups, respectively (
p = 0.003). The authors concluded that the administration of silodosin facilitated the expulsion of 1.5 mm or larger distal ureteral stones, as compared to the control group which did not include any medical intervention for stone expulsion [
20].
The available evidence in the literature regarding the superiority of silodosin over tamsulosin for the MET of ureteral stones has been controversial. One of the studies that compare the effect of silodosin to the most commonly used substance for MET was reported by Imperatore et al. [
21] The investigators retrospectively collected observational data from patients who received either silodosin or tamsulosin within a period of 1 year. The authors found no significant difference between the two groups in terms of stone expulsion rates (88 and 82 %, respectively) or mean stone expulsion times (6.7 and 6.5 days, respectively). Nevertheless, the inclusion of 50 patients in each group, despite the retrospective nature of this study, raised the question of a possible selection bias. Due to its retrospective nature, the above study was not included in the current meta-analysis.
Another study not included in the current meta-analysis was conducted by Rathi et al. [
22] The study was presented as an abstract in an International Congress. The investigators randomized 87 patients with distal ureteral stones of <10 mm into three groups. Group I (
n = 29) received 8 mg silodosin daily, group II (
n = 30) received 0.4 mg tamsulosin daily and group III patients (
n = 28) were not given any of the above substances. Patients in all groups received diclofenac sodium regularly for 1 week and then on demand. The follow-up period was 4 weeks. The stone expulsion rates for groups I, II and III were 86.2, 76.6 and 50 %, respectively. The difference in groups I and II with respect to group III was significant (
p = 0.0028 and 0.035, respectively). The expulsion time was significantly shorter in groups I and II than in group III (
p = 0.0097 and 0.026, respectively). Patients taking silodosin and tamsulosin had fewer pain attacks than group III patients. No side effects were reported in silodosin or tamsulosin groups.
The authors concluded the use of α-blockers for MET of lower ureteric stones to be safe and effective without any significant benefit of silodosin over tamsulosin.
On contrast to the above studies, the current meta-analysis showed superior stone expulsion rates and faster stone expulsion times for silodosin when compared with tamsulosin. Our pooled data showed a lack of heterogeneity for the expulsion rate calculations with an I
2 value of 0 % indicating reliable results. On the other hand, a high level of heterogeneity was calculated for stone expulsion times with an I
2 value of 89 %, but I
2 can be misleading as the magnitude and directions of the effects may influence its value and the p value from the χ
2 test or the CI may be related to strength of evidence of heterogeneity. When the p value of the χ
2 (p < 0.0001) and the CI [−2.49 (−3.40, −1.58)] are considered, it is clear that the expulsion time is shorter for silodosin in the current analysis. Moreover, the quality of the included studies was high according to the Jadad score (>3). When considering the low heterogeneity and the quality of the included studies, the presented results in favor of silodosin should probably be considered as reliable and accurate.
A similar meta-analysis was published recently evaluating the efficacy and safety of silodosin for MET [
23]. In contrast to the current meta-anlaysis, seven studies were included. Two of the included studies were conducted by the same working group (Itoh et al.) and were published with a difference of 2 years. The investigators did not indicate in these two studies the time period for patient recruitment and it is likely that these studies may be overlapping. In addition, the aforementioned study by Imperatore et al. is not a RCT but a retrospective observational study which reduces the quality of the included studies. As a result, we could advocate that the current meta-analysis provided evidence of higher quality despite the low number of studies which were included. In fact, the latter issue is probably the major drawback of the current meta-analysis. Nevertheless, the low level of heterogeneity detected by
I
2 test, especially for the primary endpoint, renders the current data to be representative. Larger scale RCTs are necessary for the confirmation of the current findings.
An important aspect of MET is the effect in the reduction of colic episodes. Kumar et al. [
16] advised their patients to receive 50 mg of diclofenac on demand during MET. The mean number of pain episodes for the silodosin group was significantly lower than that for the tamsulosin group, 0.8 (SD ± 0.9) and 1.7 (SD ± 1.2), respectively (
p < 0.001). A significantly lower requirement of analgesia was noted for silodosin (mean = 195 ± 10.2 mg) in comparison to tamsulosin (mean = 220 ± 10.8 mg) (
p < 0.001). Similarly, Gupta et al. [
17] was able to demonstrate lower analgesic use for the silodosin group. On the contrary, Imperatore et al. [
21] showed no significant difference in terms of mean number of pain episodes and need for analgesics while Dell’atti et al. [
15] reported infrequent and mild colic episodes in both groups that were manageable with analgesics that allowed continuation of MET. Thus, a possible but not clear reduction of colic events could be advocated for silodosin in comparison to tamsulsosin.
The evaluation of side effects is an important aspect of any medical therapy. In the case of silodosin and tamsulosin, abnormal ejaculation was the most predominant side effect observed for both silodosin and tamsulosin [
15‐
17]. This difference was significant in the study of Dell’Atti et al. [
15] which showed a significantly higher incidence of abnormal ejaculation in the silodosin group in comparison to the tamsulosin group with 22.7 and 10.2 % of the patients having experienced the side effect, respectively (
p < 0.002). Imparatore et al. [
21] also demonstrated a significantly higher incidence of abnormal ejaculation in the silodosin group when compared to tamsulosin group (
p < 0.05). In the remaining studies, the difference among the two substances did not reach any significance. Other common side effects for both groups were orthostatic hypotension, headache, dizziness and diarrhea without any statistical difference or clinical consequence [
15‐
17]. On the other hand, a significantly lower incidence of peripheral vasodilatation-related complications was observed for the silodosin group when compared to the patients who received tamsulosin [
17,
21]. Considering the above evidence, it seems that the use of silodosin may be related to a higher incidence of ejaculation disturbances in comparison to the use of tamsulosin without any other significant difference in the side effects. The ejaculatory issues represent side effects that are reversible after the withdrawal from the MET and may not compromise the general health of the patients. Thus, the use of either substances for MET could be considered as safe.