Rapid Communication Efficacy of Tamsulosin in the Management of Lower Ureteral Stones: A Randomized Double-blind Placebo-controlled Study of 100 Patients Abdulla Al-Ansari, Abdulla Al-Naimi, Abdulkader Alobaidy, Khalid Assadiq, Mohamed D. Azmi, and Ahmed A. Shokeir OBJECTIVE METHODS

RESULTS

CONCLUSIONS

To study the impact of tamsulosin on the rate of spontaneous passage of distal ureteral stones. A total of 100 patients with stones sized 10 mm or smaller, located in the distal part of the ureter were included. Patients were randomly assigned to 2 equal groups. Group 1 received 0.4 mg tamsulosin once daily and group 2 received placebo. The investigators and the patients were masked to the type of treatment. Patients were followed-up until passage of the stone, or for a maximum of 4 weeks. The number of pain episodes, need for analgesia, stone expulsion rate and time, and possible side effects of medications were observed in both groups. Apart from 4 patients in the placebo group who were lost to follow-up, all patients complied with the prescribed medications and continued the study. Stone expulsion occurred in 41 of 50 patients (82%) in group 1 and in 28 of 46 patients (61%) in group 2 (P ⫽ .02). The chance of stone expulsion was 3 times higher in the tamsulosin group (relative risk [RR] ⫽ 2.93; 95% CI, 1.152-7.45). In group 1, patients with stones sized ⱕ5 mm showed a significantly higher expulsion rate compared to those with larger stones (⬎5 mm). Age, gender, and stone laterality had no significant impact on the expulsion rate. The expulsion time was significantly shorter in the tamsulosin group (6.4 ⫾ 2.77 days vs 9.87 ⫾ 5.4 days for groups 1 and 2, respectively). Moreover, the frequency of pain episodes, the need for diclofenac, and its total dosage were significantly lower in the tamsulosin group. Side effects observed in both groups were comparable and mild, and no patient withdrew because of them. Tamsulosin is a safe and effective drug that enhances spontaneous passage of distal ureteral stones sized 10 mm or smaller. UROLOGY 75: 4 – 8, 2010. © 2010 Elsevier Inc.

tudies have shown an increased density of ␣-adrenergic receptors in the distal ureter. It has been proved that ␣1-adrenergic antagonists cause inhibition of the basal tone, peristaltic frequency, and contractions in the lower ureter.1 Therefore, tamsulosin, a specific antagonist of ␣1-adrenergic receptors, is used for treatment of distal ureteral stones. Several randomized controlled trials (RCTs) using ␣1adrenergic antagonists for the treatment of lower ureteral stones have demonstrated good results.2-11 Nevertheless, randomization or maskings were not complete in the vast majority of the previous RCTs. We know of only 2 randomized double-blind placebo-controlled studies for alpha blocker therapy of distal ureteral stones; one used alfuzosin12 and the second used tamsulosin.13 The stone

S

From the Department of Urology, Hamad General Hospital, Doha, Qatar Reprint requests: Ahmed A. Shokeir, M.D., Ph.D., F.E.B.U., Urology and Nephrology Center, Department of Urology, Mansoura, Egypt. E-mail: ahmedshokeir@ hotmail.com Submitted: August 19, 2009, accepted (with revisions): September 10, 2009

4

© 2010 Elsevier Inc. All Rights Reserved

size in both the studies was relatively small, and in one study the exact time of stone passage was not known in 32% of the patients.13 Herein, we present a randomized double-blind placebocontrolled study of 100 patients with lower ureteral stones, 10 mm or smaller when measured by the largest diameter, treated using either placebo or tamsulosin. To the best of our knowledge, the present study is the third randomized double-blind placebo-controlled study on this topic.

PATIENTS AND METHODS Patients Between May 2007 and May 2009, 100 consecutive patients with ureteral stones of 10 mm or smaller in largest diameter located below the common iliac vessels, as assessed on noncontrast computed tomography (NCCT), were included in this study. There were 67 men and 33 women with a mean age of 36.7 ⫾ 9.35 years (range, 21-55 years). All patients had single, radiopaque, unilateral stones, and presented with normal renal function and no urinary tract infection (UTI). All patients pre0090-4295/10/$34.00 doi:10.1016/j.urology.2009.09.073

Table 1. Characteristics of patients in both groups Variable Age (y), mean ⫾ SD Gender (n) Male Female Stone side Right Left Stone size (mm), mean ⫾ SD (range) Stone size (n) ⱕ5 mm ⬎5 mm

Tamsulosin (n ⫽ 50) 37.18 ⫾ 9.38

P

36.13 ⫾ 9.32

.83

32 (64%) 18 (36%)

35 (70%) 15 (30%)

.85

34 (68%) 16 (32%) 5.88 ⫾ 2.39 (2-10)

29 (58%) 21 (42%) 6.04 ⫾ 2.5 (3-10)

sented with acute flank pain at the emergency room and none received shock wave lithotripsy (SWL) before presentation.

Exclusion Criteria Exclusion criteria consisted of age below 18 years, nonradiopaque stones, multiple stones, UTI, severe hydronephrosis, pregnancy, hypotension, peptic ulcer, and a history of endoscopic or open ureteral surgery. Patients taking calcium antagonist medications and those who refused to participate in the study were also excluded.

Study Design The study design was fully explained to the patients before obtaining a valid informed consent. The study was approved by the local ethics committee. Before patient recruitment, the sample size needed in each arm was calculated on the basis of previous studies that estimated stone expulsion rate to be 90% and 65% in patients with and without tamsulosin, respectively, with a difference of 25%.2,5,9,12,13 A sample size of 43 in each arm was found to give a power of 80% with type II statistical error ⬍20% and type I ⬍5%. Fifty patients per group were finally randomized, which allowed for a maximum drop-out rate of 14%. Patients were randomized between study and placebo medications using a computer-generated random number assignment, adjusted at a ratio of 1:1. Doctors at the local pharmacy generated the labels of pill bottles that contained capsules of identical appearance and taste. The investigators and patients were masked to the type of the treatment throughout the study. Randomization data were kept strictly confidential, in sealed envelops, accessible only to the pharmacist at the end of the study. Group 1 (50 patients) received 0.4 mg tamsulosin once daily and group 2 (50 patients) received placebo. All the patients were allowed to use symptomatic therapy with injection of 75 mg diclofenac (on demand) and were advised to drink a minimum of 2 L of water daily. Furthermore, they were advised to filter their urine to detect spontaneous calculus passage. When the stone was expelled, the patients stopped taking the medications.

Intervention All patients were evaluated using x-rays of the kidney, ureter, and bladder (KUB), urinary system ultrasonography (US), and NCCT before treatment. Moreover, biochemical and hematological evaluation of the patients were obtained before therapy. UROLOGY 75 (1), 2010

Placebo (n ⫽ 50)

24 26

27 23

.39 .75 .48

In addition, complete urine analyses were carried out before, during, and after treatment. Patients were followed-up with KUB films, US, and urine analysis every week until passage of the stone or for a maximum duration of 4 weeks. The number of pain episodes, the need of diclofenac injection, the total diclofenac dosage, stone expulsion rate, time for spontaneous passage of the stone, blood pressure, and possible side effects of the medications were observed. The time for spontaneous passage was defined as the day the patient reported the passage of a stone and the report was confirmed by absence of the radiopaque calculi shadow on KUB. If a 4-week treatment failed to relieve the patient of the stone, pain was uncontrolled by therapy, fever appeared, serum creatinine increased (⬎2 mg/dL), or severe hydronephrosis occurred, further course of treatment was decided upon for the patient.

Statistical Analysis Statistical analysis was carried out using ␹2 test, t test, and univariate logistic regression as appropriate. A P value ⬍.05 was considered significant.

RESULTS Patient Characteristics Both groups were comparable regarding age, sex, mean stone size, and stone localization (left vs right) (Table 1). Moreover, the number of patients with smaller stones (ⱕ5 mm) and larger (⬎5 mm) stones were also comparable in both groups (Table 1). Four patients in the placebo group were lost to follow-up. The rest of the patients complied with the prescribed medications and continued the schedule of follow-up. Stone Expulsion Rate Spontaneous expulsion was observed in 41 of 50 patients (82%) in the tamsulosin group and 28 of 46 patients (61%) in the placebo group, with a statistically significant difference of P ⫽ .02 (Table 2). Univariate logistic regression showed that the chance of expulsion of the stones was 3 times higher in the tamsulosin group than in the placebo group (RR ⫽ 2.93; 95% CI, 1.152-7.45; P ⬍.001). The stone expulsion rate in the tamsulosin 5

Table 2. Overall results

Expulsion rate (n) Expulsion time (d), mean ⫾ SD Pain episodes, mean ⫾ SD Need for injection, mean ⫾ SD Dose of injection (mg), mean ⫾ SD Side effects (n) Retrograde ejaculation Dizziness Headache Rhinitis Fatigue Postural hypotension Total

Tamsulosin (n ⫽ 50)

Placebo (n ⫽ 46)

P

41/50 (82%) 6.4 ⫾ 2.77 1.6 ⫾ 1.3 0.9 ⫾ 0.93 67.5 ⫾ 69.8

28/46 (61%) 9.87 ⫾ 5.4 2.3 ⫾ 1.4 1.8 ⫾ 1.3 127.2 ⫾ 89.3

.02 .001 .02 .001 .001

1 2 2 1 2 1 9

0 2 2 0 1 0 5

Table 3. Analysis of the results of tamsulosin group according to patients and stone characteristics Variable Age (n) ⱕ40 y ⬎40 y Gender (n) Male Female Stone localization Left Right Stone size (n) ⱕ5 mm ⬎5 mm

Expulsion Rate

P .46

27/31 (87%) 14/19 (73%) .37 25/32 (78%) 16/18 (89%) .76 14/16 (87.5%) 27/34 (79%) .01 23/24 (96%) 18/26 (69%)

group (6.4 stones/d) was 2.3 times more than that in the placebo group (2.8 stones/d). In the tamsulosin group, further analysis of the factors that may influence the chance of spontaneous passage of the stones showed that patients with smaller stones (ⱕ5 mm) had significantly higher expulsion rate than those with larger ones (⬎5 mm). On the other hand, age, gender, and stone localization had no significant impact on the rate of spontaneous passage of the stones (Table 3). Stone Expulsion Time The mean stone expulsion time was 6.4 ⫾ 2.77 days in the tamsulosin group and 9.87 ⫾ 5.4 days in the placebo group, indicating a difference of high statistical significance in favor of the tamsulosin group (P ⫽ .001, Table 2). The breakdown of the expulsion time for stones ⱕ5 mm was 6 and 10 days and for stones ⬎5 mm was 9 and 13 days for the tamsulosin and placebo groups, respectively. Pain Episodes, Diclofenac Injection, and Side Effects In the tamsulosin group, the mean number of pain episodes (1.6 ⫾ 1.3) was significantly less than that in the placebo group (2.3 ⫾ 1.4) (P ⫽ .02, Table 2). Also, the 6

need for diclofenac injection and the total dosage of diclofenac were less in the tamsulosin group (Table 2). Side effects observed in the study and placebo groups were comparable and mild, and no patient withdrew because of them (Table 2).

End Point of the Study During the course of the study, none of the patients experienced intractable pain that required urgent intervention and none developed fever, severe hydronephrosis, or marked increase of serum creatinine (⬎2 mg/dL). Patients who did not pass the stone within the 4-week duration of follow-up (9 in the tamsulosin and 18 in the placebo) were kept under continued observation (10) or treated using SWL (5) or ureteroscopy (12).

COMMENT The probability of spontaneous passage of distal ureteral stones less than 5 mm in diameter is 71%-98%, and observation is recommended for such patients.14 Distal stones ⬎5 mm had lower spontaneous passage rate of 25%-51%.14 The conservative approach for lower ureteral stones may be complicated by UTI, hydronephrosis, and deterioration of renal function. In complete obstruction, signs of renal injury appear in 3-4 weeks. Therefore, the waiting period for the spontaneous passage of the stones is 4 weeks.8,10 Parsons et al15 performed meta-analysis of 11 randomized clinical trials (911 participants) using ␣-blockers for the treatment of ureteral stones. Patients receiving conservative therapy plus ␣-blockers were 44% more likely to spontaneously expel the stones (RR ⫽ 1.44; 95% CI, 1.31-1.59; P ⬍.001) compared to patients receiving conservative therapy only. A similar result was shown in the present study in which patients under tamsulosin had a significantly higher stone expulsion rate compared with those under placebo. Other studies did not demonstrate a significant advantage of using tamsulosin and conservative therapy over conservative therapy alone in terms of stone expulsion rate at 6 weeks.12,13 Differences in the UROLOGY 75 (1), 2010

results could be attributed to differences in patients and stone characteristics. We have demonstrated, as do others, that tamsulosin therapy had better results regarding the frequency of episodes of renal colic, the need for injection of diclofenac, and its total dose.7,8,10,12,13 These results demonstrate that tamsulosin probably decreases the frequency of phasic peristaltic contractions in the ureter. Several studies have emphasized that tamsulosin reduces expulsion time compared with conservative therapy.5,8 The present study also demonstrated that tamsulosin decreased the stone expulsion time by 40%. Most studies demonstrated that stone size has a significant impact on the rate of spontaneous passage of distal ureteral stones. Some studies showed that age, gender, and stone laterality do not affect the spontaneous passage of the stones. Nevertheless, Tekin et al4 emphasized that the ratio of spontaneous passage of the stones decreases in patients older than 50 years of age. We have shown that stone size is the only variable that may affect the rate of stone expulsion in the tamsulosin group. The side effects reported in the present series are similar to those in the published data.7 Apart from 1 patient in the tamsulosin group, who experienced retrograde ejaculation, the side effects encountered in the study group were generally mild and did not require cessation of therapy in any patient. Several RCTs were carried out to study the impact of alpha blockers on the rate of spontaneous passage of distal ureteral stones. However, randomization was not complete in the vast majority of these studies.2-11 We know of only 2 randomized double-blind placebo-controlled studies investigating the alpha blocker therapy of distal ureteral stones.12,13 Both studies showed no significant difference in the stone expulsion rate between the study and placebo groups. This could be explained by the relatively small size of the stones in both the studies (mean size ⱕ4.1 mm in both studies). The mean stone size was more than 5 mm in both groups of our study population. Furthermore, in the study of Hermanns et al,13 the exact time of stone passage was not available in 32% of patients; therefore, these patients needed to be censored at the last known date of stone passage. The present study has an added advantage in that the time of stone expulsion was known in all patients. In the study by Pedro et al,12 9.2% patients were excluded after randomization while the exclusion rate in our study was only 4%.

CONCLUSIONS In this randomized double-blind placebo-controlled study, we have demonstrated that tamsulosin is a safe and effective drug that can be used to enhance spontaneous passage of distal ureteral stones sized 10 mm or smaller when measured by the largest diameter. UROLOGY 75 (1), 2010

References 1. Obara K, Takeda M, Shimura H, et al. Alpha-1 adrenoreceptor subtypes in the human ureter. Characterization by RT-PCR and in situ hybridization. J Urol. 1996;155(suppl ):472A; abstract: 646. 2. Dellabella M, Milanese G, Muzzoinigro G. Efficacy of tamsulosin in the medical management of juxtavesical ureteral stones. J Urol. 2003;170:2202-2205. 3. Kupeli B, Irkilata L, Gurocak S, et al. Does tamsulosin enhance lower ureteral stone clearance with or without shock wave lithotripsy. J Urol. 2004;64:1111-1115. 4. Tekin A, Alkan E, Beysel M, et al. Alpha-1 receptor blocking therapy for lower ureteral stones: a randomized prospective trial. J Urol. 2004;171(suppl):304; abstract: 1152. 5. Porpiglia F, Ghignone G, Fioric C, et al. Nifedipine versus tamsulosin for the management of lower ureteral stones. J Urol. 2004; 172:568-571. 6. Dellabella M, Milanese G, Muzzonigro G. Randomized trial of the efficacy of tamsulosin, nifedipine and phloroglucinol in medical expulsive therapy for distal ureteral calculi. J Urol. 2005;174:167172. 7. Resim S, Ekerbicer H, Ciftci A. Effect of tamsulosin on the number and intensity of ureteral colic in patients with lower ureteral calculus. Int J Urol. 2005;12:615-620. 8. Yilmaz E, Batislam E, Basar MM, et al. The comparison and efficacy of 3 different alpha-1 adrenergic blockers for distal ureteral stones. J Urol. 2005;173:2010-2012. 9. De Sio M, Autorino R, Di Lorenzo G, et al. Medical expulsive treatment of distal ureteral stones using tamsulosin: a single-center experience. J Endourol. 2006;20:12-16. 10. Agrawal M, Gupta M, Gupta A, et al. Prospective randomized trial comparing efficacy of alfuzosin and tamsulosin in management of lower ureteral atones. Urology. 2009;73:706-709. 11. Porpiglia F, Vaccino D, Billia M, et al. Corticosteroids and tamsulosin in the medical expulsive therapy for symptomatic distal ureter stones: single drug or association? Eur Urol. 2006;50:339-344. 12. Pedro RN, Hindlin K, Feia K, et al. Alfuzosin stone expulsion therapy for distal ureteral calculi: a double-blind, placebo controlled study. J Urol. 2008;179:2244-2247. 13. Hermanns T, Sauermann P, Rufibach K, et al. Is there a role for tamsulosin in the treatment of distal ureteral stones of 7 mm or less? Results of a randomized, double-blind, placebo-controlled trial. Eur Urol. 2009;56:407-412. 14. Segura JW, Preminger GM, Assimos DG, et al. Ureteral stones clinical guidelines panel summary report on the management of ureteral calculi. J Urol. 1997;158:1915-1921. 15. Parsons JK, Hergan LA, Sakamoto K, et al. Efficacy of ␣-blockers for the treatment of ureteral stones. J Urol. 2007;177:983-987.

EDITORIAL COMMENT The authors report a randomized, double-blinded, placebo-controlled trial of medical expulsive therapy (MET) using tamsulosin in patients with distal ureteral stones sized ⬍10 mm. They demonstrate that tamsulosin safely increases spontaneous expulsion of distal ureteral stones in addition to decreasing time to expulsion, pain episodes, and need for and dose of analgesic. These results nicely confirm earlier nonrandomized trials using various ␣-blockers in MET. Nevertheless, there are a few recent trials that have not shown effectiveness of ␣-blockers in stone expulsion and have called into question the proper role of these medications.1-3 Such discrepancy could be explained by several reasons but stone size is likely to play a major role. The stones were small in the negative studies (mean size ⬍4 mm) and would be likely to 7