Tamsulosina en urolitiasis 1

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Original article Comparison of tamsulosin with extracorporeal shock wave lithotripsy in treating distal ureteral stones ZHANG Meng-yuan, DING Sen-tai, LÜ Jia-ju, LUE Yan-he, ZHANG Hui and XIA Qing-hua Keywords: tamsulosin; distal ureteral stones; extracorporeal shockwave lithotripsy; expulsive therapy Background Tamsulosin, an alpha-1 receptor antagonist, has been demonstrated effective in promoting distal ureteral stone passage and in reducing pain associated with stone expulsion. This study aimed to evaluate the effect of tamsulosin in comparison with nifedipine and extracorporeal shock wave lithotripsy (ESWL) on the expulsion rate of distal ureteral stones at different sizes.

Methods We assigned 314 patients to three categories: I, the stone with maximal diameter of 4.0–5.9 mm; II, 6.0–7.9 mm, and III, 8.0–9.9 mm. Patients in each category were randomly subdivided into three treatment subgroups: group A (nifedipine group), group B (tamsulosin group), and group C (ESWL group). Stone-free rate and the dose of analgesics were recorded weekly during the 4-week follow-up period.

Results Three hundred and three patients completed the study. The results showed that nifedipine and tamsulosin treatments promoted a small (4–8 mm, categories I and II) stone expulsive rate that was comparable with ESWL treatment. Nonetheless, when the stone diameter was 8.0–9.9 mm, ESWL showed a greater stone free rate than nifedipine and tamsulosin treatments; no significant difference existed between the latter two therapies. Although the ESWL treatment group required the least analgesics, tamsulosin treatments required less pain medication than nifedipine (P <0.05).

Conclusions Tamsulosin treatment is recommended for patients with the stone diameter smaller than 8 mm because of its feasibility, effectiveness and safety. ESWL is more appropriate than tamsulosin therapy for the patients whose stones are larger than 8 mm.

Chin Med J 2009;122(7):798-801

T

he worldwide incidence of urinary stone disease (urolithiasis) is estimated to be about 4% to 15% in the lifetime of the population. Ureteral stones account for 20% of urolithiasis, and 70% of ureteral stones are located in the lower third part of the ureter, known as distal ureteral stones.

Nearly all ureteral stones are supposed to be expelled spontaneously when their diameters are smaller than 4 mm.1 However, the spontaneous expulsion rate of distal ureter stones is about 25% if their sizes are between 4–6 mm and 5% if greater than 6 mm.1 And calculi over 8 mm are very rarely eliminated spontaneously.2 Therefore, active treatments are recommended for individuals with larger stones, especially their sizes are greater than 5 mm.3 In many institutions extracorporeal shock wave lithotripsy (ESWL), which has a shorter observation period and is less invasive, has been recommended as the first line treatment option for patients with stones greater than 20 mm. The stone free rate of ESWL treatment in patients with distal ureteral stones varies from 49.9% to 91%, and decreases as the stone diameter increases.3-6 Moreover, there are also some limitations for ESWL management, including a higher percentage of side effects and sometimes multiple treatments are needed.5,7 As a result, ureteroscopy (URS) has become an additional first-line treatment in some centers in order to achieve

better stone free rates.3,8 In comparison with ESWL, URS is a more invasive procedure, and may cause post-operative complications. Anesthesia, expertise and costly equipment are required for effective URS treatment.9,10 It is generally believed that conservative medical treatment should be applied (which is also the wish of most patients) first, and if it is unsuccessful, ESWL or URS treatment can then be utilized.11 A growing body of recent studies has investigated medical-expulsive therapy (MET) aimed at facilitating spontaneous passage of distal ureteral stones.

Tamsulosin, an alpha 1-adrenoceptor blocker, has been used in several current MET experiments and shows an excellent expulsive effectiveness for distal ureteral stones that are smaller than 10 mm. The results of these experiments indicate a high expulsion rate (>80%), a shortened expulsion time, and a marked reduction in the DOI: 10.3760/cma.j.issn.0366-6999.2009.07.007 Department of Urology, Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, China (Zhang MY, Ding ST, Lü JJ, Zhang H and Xia QH) Division of Endocrinology, Department of Medicine, Los Angeles Medical Center and Los Angeles Biomedical Research Institute at Harbor University of California, Los Angeles Medical Center, Torrance, California, 90502, USA (Lue YH) Correspondence to: Dr. LÜ Jia-ju, Department of Urology, Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, China (Tel: 86-531-85186310. Fax: 86-531-87037504. Email: kyoto2310@hotmail.com)

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frequency and intensity of the painful episodes.11-18 However, it remains unclear whether tamsulosin treatment for patients with distal ureteral stones would improve the stone free rate as the stone diameter increases.

Accordingly, when the distal ureteral stones are from 4 mm to 10 mm, it seems to be difficult to make a decision between less invasive therapy (ESWL) and MET with tamsulosin. Therefore, we performed a randomized study to evaluate and compare the effects of the tamsulosin with ESWL to help us choose the optimal active management of these distal ureteral stones. Furthermore, the variations of the two protocols′ efficacies are also investigated when the stone size increases up to 10 mm.

METHODS Subjects All patients, enrolled from Provincial Hospital Affiliated to Shandong University between January 2004 and April 2008, were diagnosed of distal ureteral stones based on plain abdominal X-rays, urinary ultrasonography and with helical computed tomography when necessary.

Additionally, the patients underwent a series of measurements, including case history, physical examination, complete blood cell count, blood electrolytes, and routine urinalysis as well as serum urea and creatinine. Patients were excluded if they had any of the following: history of a urinary system stone, previous surgery on urinary tract, multiple stones, nonopaque stones, urinary tract infection, severe hydronephrosis, a solitary kidney, diseases such as diabetes, peptic ulcers, hypotension or hypertension treated with alphaadrenoceptor blocker or calcium-antagonists, severe obesity, kidney failures, or pregnancy. The ethics committees at Provincial Hospital affiliated to Shandong University approved our study protocols. All subjects signed written informed consent and we discussed with them in detail the potential side effects and complications.

All patients′ plain abdominal X-rays and urinary ultrasonography results were reviewed and confirmed by two experienced radiologists, and the stone diameter was measured with ultrasonography.

Grouping and treatments Based on the maximal diameter of stones, the patients were first assigned to 3 categories: I (4.0–5.9 mm), II (6.0–7.9 mm), and III (8.0–9.9 mm), then the patients of each category were randomized into three treatment subgroups A, B and C. In group A (nifedipine group), the patients received nifedipine (30 mg, orally, tid), and patients in group B were given tamsulosin 0.4 mg/d (OMNIC 0.4). In Group C, the patients were treated a single session of ESWL with the Dornier Compact Delta Lithotripter (Dornier MedTech System GmbH, Wessling, Germany). Additionally, from the day of treatment, all patients received the conventional treatment with 2500 ml hydration daily and levofloxacin (0.1 g orally, twice a day) for the first 7 days. During the

4-week treatment period, diclofenac sodium (75 mg intramuscular injection, once a day) was given to the patients as analgesic therapy if needed.

Follow-up All patients were followed up weekly for 4 weeks or until an alternative treatment was applied. For each follow-up visit, a routine examination was performed with plain abdominal X-rays, urinary ultrasonography, urinalysis, serum urea and creatinine. At each follow-up, stone-free condition, dose of analgesic injections, any side effects and complications were recorded. A stone-free condition, as a main outcome from the treatment was defined as the complete absence of any stone based on plain abdominal X-rays. In this study, the presence of asymptomatic stone fragments less than 3 mm in diameter after ESWL was also considered as stone-free.

Patients who did not have a stone-free condition at the end of this treatment underwent ureteroscopy as a substitutive therapy. During the period of treatment, patients who suffered from attacks of uncontrollable renal colic, or who had apparent drug side effects, were excluded from the study.

Statistical analysis Statistical analyses were performed using Student′s t test, analysis of variance (ANOVA) test, chi-square test, and Fisher′s exact test. SPSS 11.5 was used to perform the analysis. Two-tailed tests were used for all comparisons and P <0.05 was considered as statistical significance.

RESULTS Baseline characteristics We enrolled 314 patients in this study and a total of 303 patients completed the study. Eleven patients withdrew from the study due to severe renal colic, infection or tamsulosin′s side effects (Table 1). All these 11 patients underwent ureteroscopy to remove the stones. There was no statistical difference in patients′ age, sex distribution and diameter of the stones between groups A, B and C (P <0.05, Table 2) in each stone-diameter category (P <0.05, Table 3).

Table 1. The causes of withdrawal during the study Causes Severe renal colic Urinary infection Dizziness Nausea Total

Patient numbers (n) 6 2 1 1 1 11

Groups A C A B B

Stone free rates among the three treatment groups When the stone size ranges were from 4–10 mm, ESWL treatment showed a greater stone free rate (87.5%) than MET, nifedipine (68.0%) and tamsulosin therapy (73.5%) (P=0.011 and P=0.001, respectively), while there was no significant difference between the nifedipine and

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tamsulosin therapy groups (P=0.394). When the dose of diclofenac was compared among the 3 treatment groups, patients given ESWL needed the least analgesic, and the nifedipine group needed more analgesic than the tamsulosin group (P <0.05, Table 2). When the stone size was from 4 mm to 8 mm in categories I and II, however, ESWL had no a significantly better stone free rate than the MET groups, but when the stone diameter was 8.0–9.9 mm in category III, ESWL showed a greater stone free rate. Meanwhile, there was not a significant difference between nifedipine and tamsulosin therapy in this regard (P <0.05, Table 3, Figure).

Table 2. Patients′ characteristics and follow-up in the three treatment groups Characteristics Age (years) Sex (n) Male Female Stone diameter (mm) Stone free rate (n (%)) Analgesic mean use (mg)

Group A (n=97) 36.3±9.7

Group B (n=102) 34.6±11.4

Group C (n=104) 36.6±11.1

68 29 6.8±1.6 66 (68.0) 88.3

63 29 6.9±1.6 75 (73.5) 34.6

68 36 6.9±1.6 91 (87.5) 15.7

Figure. Correlation between stone free rates after 4-week treatment and the stone diameters.

Additionally, the expulsion rate of the patients given nifedipine and tamsulosin indicated no statistically significant decreases when the stone diameter increased from category I to category II (P=0.246 and P=0.479 respectively). On the contrary, it dropped significantly when the stone diameter increased from category II to category III (both P <0.05). For patients receiving ESWL in group C, the stone free rate remained stable when the stone size increased from category I to category III (P <0.05) (Table 3, Figure).

DISCUSSION Numerous studies have recently demonstrated promising results in increasing the expulsion rate with the addition of drugs for MET, including corticosteroids, glyceryl trinitrate, prostaglandin synthesis inhibitors, calcium channel blockers and alpha-adrenoceptor blockers. Treatments with a calcium channel blocker or an alpha-blocker are suggested by a recent meta-analysis of nine randomized controlled trials showing that both of these MET improve the spontaneous expulsion rate of small ureteral stones by 65%, obviating the need for surgical treatment.12 Cervenakov et al11 demonstrated that tamsulosin treatment decreased the expulsion time and the frequency of renal

colic attacks compared with conservative treatment. Others have studied the results of treatment with tamsulosin when compared with other medical therapies. Porpiglia et al13 confirmed that both nifedipine and tamsulosin could achieve an excellent expulsion rate with less need of additional pain medication during the treatment of distal ureteral stones.

However, patients receiving tamsulosin could have the shortest expulsion time. Many investigators, including Dellabella et al14 compared tamsulosin with corticosteroids, Autorino et al15 employed diclofenac (100 mg/d) plus aescin (80 mg/d), and Erturhan et al16 used tolterodine, did not find a significant difference between two different MET regarding the expulsion time. Interestingly, tamsulosin treatment significantly decreased either the expulsion time or the frequency and intensity of pain episodes.

In this study, tamsulosin therapy was more effective in reducing the use of analgesics than nifedipine therapy.

Although patients treated with tamsulosin needed higher dose of diclofenac than ESWL, only two patients from the tamsulosin therapy group withdrew from the study due to uncontrollable renal colic while 6 from the nifedipine group withdrew for this reason. In our study, the stone free rate in the tamsulosin group appears to be lower than previous reports. One reason may be that we did not treat our patients with anti-inflammatory drug.

We investigated the variability of tamsulosin treatment in accelerating expulsion rate of the distal ureteral stone; tamsulosin treatment had a similar effectiveness as ESWL when the stone diameter ranged 4–8 mm. For stones

Table 3. Patients′ characteristics and clinical follow-up results in the three stone-diameter categories Characteristics Patient numbers (n) Age (years) Sex (n) Male Female Stone diameter (mm) Stone free rate (n (%))

Category I (4.0–5.9 mm) Group A Group B Group C 34 36 36 35.6±9.9 35.2±10.5 35.9±11.1

Category II (6.0–7.9 mm) Group A Group B Group C 36 37 38 37.2±10.7 34.6±12.0 39.3±10.6

Category III (8.0–9.9 mm) Group A Group B Group C 27 29 30 35.9±8.3 34.0±12.1 34.1±11.3

22 12 5.0±0.5 30 (88.2)

27 9 6.9±0.6 28 (77.8)

19 8 8.9±0.5 8 (29.6)

26 10 5.2±0.5 32 (88.9)

23 13 5.1±0.5 33 (91.7)

27 10 6.9±0.6 30 (81.1)

24 14 6.8±0.5 33 (86.8)

20 9 8.8±0.6 13 (44.8)

21 9 9.0±0.5 25 (83.3)

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larger than 8 mm, ESWL administration showed a greater stone expulsive rate than tamsulosin treatment. Consistent with previous studies, we demonstrated that tamsulosin treatment has fewer side effects than ESWL.11,13-19 The minor side effects, such as dizziness and nausea, caused by tamsulosin are tolerable and usually needed no further medical intervention. We choose a 4-week study period because we found that about 20% patients had complications if the treatment went beyond 4 weeks, which is consistent with previous reports.14 We treated patients with the antibiotic, levofloxacin, to reduce the risk of urinary infection and stone retention.15

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The mechanism of accelerating stone passage by tamsulosin has been revealed in recent studies. Alpha 1-adrenoceptors fall into three subtypes α1A, α1B and α1D, which are prevalent in the distal part of the ureter with a density order of α1D >α1A >α1B.20 Tamsulosin is a selective blocker for α1A and α1D over α1B-adrenoceptors, which is able to inhibit basal tone, ureteral contractions and peristaltic activity, and, in turn, dilating the ureteral lumen and facilitating stone passage14 with a reduction of the algogenic stimulus. Apart from adrenoceptor subtype-selectivity, a smooth pharmacokinetic profile of its modified-release formu- lation and a selective accumulation in target tissues may contribute to an excellent efficacy tolerability ratio.

In conclusion, we demonstrate that the tamsulosin medical therapy is effective in accelerating distal ureteral stone passage and in reducing the use of analgesics. We recommend that tamsulosin therapy should be used for patients with distal ureteral stone smaller than 8 mm.

Although equivalent to ESWL in treating smaller stones, tamsulosin therapy appears to be more safe and feasible than ESWL administration. In addition, we demonstrate that ESWL is more effective for the patients with ureteral stones larger than 8 mm. It is tempting to speculate that combined ESWL with tamsulosin treatment may markedly improve the distal ureteral stone expulsive rate.

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(Received September 11, 2008) Edited by SUN Jing