ORIGINAL PAPER
Effect of tamsulosin on stone expulsion in proximal ureteral calculi: an open-label randomized controlled trial S. W. Lee,1 S. H. Woo,2 D.-S. Yoo,2 J. Park2
1
Department of Urology, Hanyang University Guri Hospital, Guri, Korea 2 Department of Urology, Eulji University Hospital, Daejeon, Korea Correspondence to: Jinsung Park, MD, PhD, Department of Urology, Eulji University Hospital, Eulji University College of Medicine, 1306 Dunsan-dong, Seo-gu, Daejeon, 302-799, Korea Tel.: 82-42-611-3533 Fax: 82-42-259-1326 Email: [email protected]; [email protected] Disclosures All authors declare no competing financial interests. All authors declare no conflict of interests.
SUMMARY
Introduction According to the 2007 AUA guidelines for ureteral calculi (UC), medical expulsive therapy (MET) using a-blockers is a reasonable treatment option for distal UC that are less than 10 mm in diameter (1). Several studies shows that MET with a1a blockers augments stone expulsion and reduces the time to stone expulsion (2–6). a1 blockers may facilitate stone passage by decreasing ureteral peristaltic contraction force and frequency, which in turn may reduce the intra-ureteral pressure and thus increase the volume of the fluid bolus that is transported down the ureter (7).
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What’s known
Aim: Medical expulsive therapy (MET) using alpha-blockers is effective for distal ureteral calculi (UC). We aimed to evaluate the efficacy of tamsulosin for proximal UC expulsion. Materials and methods: An open-label randomized controlled trial was conducted with 108 patients who agreed to conservative management for single, radiopaque, proximal UC ≤ 6 mm and were randomized into group A (n = 54, conservative managements only) or B (n = 54, 0.2 mg tamsulosin once a day). The primary end-point was stone passage rates (SPR) in the intention-totreat population in 4 treatment weeks. The secondary end-points were estimated in per-protocol population and were time to stone passage, post-trial Euro-qualityof-life (EuroQOL) score, oral analgesic requirements, and willingness to undergo conservative treatment again. Results: The two groups were well balanced in terms of baseline patient and stone characteristics. Seventy nine patients (73.2%; 35 of group A and 44 of group B) completed the study protocol. The overall SPR was 60.2% (65/108). Group B had a higher SPR (74.1%; 40/54) than group A (46.3%; 25/54; p = 0.003) and a significantly shorter time to stone passage (mean days, A: 19.6 vs. B: 14.3, p = 0.005). The groups did not differ in post-trial EuroQOL score or oral analgesic requirements, whereas 74.3% (26/35) of group A and 90.9% (40/44) of group B were willing to undergo conservative treatment again (p = 0.048). Univariate logistic regression analysis showed that stone size (OR = 1.447, p = 0.045) and tamsulosin treatment (OR = 3.314, p = 0.004) significantly predicted stone expulsion. On multivariate analysis, only tamsulosin was statistically significant (OR=3.198, p = 0.021). Conclusions: Tamsulosin was associated with significantly higher stone expulsion rate and shorter expulsion time in proximal UC ≤ 6 mm compared with conservative managements only. Our results indicate that similar to patients with distal UC, MET using tamsulosin is a reasonable treatment option for patients with proximal UC.
According to the 2007 AUA guidelines for ureteral calculi (UC), medical expulsive therapy using ablockers is a reasonable treatment option for distal UC < 10 mm. However, given the ureter locationdependent differences in a1 receptor distribution and density and the fact that a proximal UC must pass through the entire ureter to pass spontaneously, it remains unclear whether a1 blockers may also be effective for the expulsion of proximal UC.
What’s new By this prospective randomized open-label multicenter trial, we found that tamsulosin was associated with significantly higher stone expulsion rate and shorter expulsion time in proximal UC ≤ 6 mm compared with conservative managements only. Our results indicate that similar to patients with distal UC, MET using tamsulosin is a reasonable treatment option for patients with proximal UC.
Gene-cloning studies have identified three a1 receptor subtypes, namely a1a, a1b, and a1d (8). The distributions and densities of these a1 receptors along the ureter differ depending on the location. While the a1d receptor is the most predominant receptor on the entire human ureter, the a1a receptor is expressed at higher levels in the distal ureter than in the proximal or mid ureter (9–11). Given these ureter location-dependent differences in a1 receptor distribution and density and the fact that a proximal UC must pass through the entire ureter to pass spontaneously, it remains unclear whether a1 blockers may also be effective for the expulsion of proximal UC. In the present study, we evaluated the ª 2013 John Wiley & Sons Ltd Int J Clin Pract, February 2014, 68, 2, 216–221. doi: 10.1111/ijcp.12271
Medical expulsive therapy in proximal ureteral calculi
efficacy of tamsulosin on stone expulsion in proximal UC.
Materials and methods Patients and study design This prospective, randomized, open-label, multicenter trial was conducted at two university hospitals from July 2010 to August 2012. Written informed consent was obtained from each patient before screening. The study protocol was approved at the Institutional Review Board of each institute, and approval for off label use of tamsulosin and the study protocol was obtained from the Korea Food and Drug Administration (clinical trial registration no. 1656). Eligible patients were 18 years or older, had presented with renal colic, were diagnosed to have a single, unilateral, radiopaque, proximal UC ≤ 6 mm in diameter, and agreed to undergo conservative management. The proximal ureter was defined as the segment between the ureteropelvic junction and the upper border of the sacroiliac joint. Exclusion criteria included the following: (i) UC ≥ 7 mm or multiple UC; (ii) febrile urinary tract infection; (iii) single kidney; (iv) non-functioning kidney; (v) pregnancy; (vi) azotemia (creatinine > 1.8 mg/dl); (vii) ureteral stricture; (viii) severe hydronephrosis; (ix) current treatment with medications that could affect stone passage, such as a-blockers, calcium channel blockers, steroids, or nitrates; and (x) patients who wanted immediate stone removal because of colic. Patients were randomized (1:1 ratio) to one of the two groups: group A (conservative managements only) or group B (0.2 mg tamsulosin once a day). A predefined randomization sequence was created by a computer random number generator using a block size of 4. Approved initial tamsulosin dosage for Korean patients with benign prostatic hyperplasia is 0.2 mg. Therefore, that dosage was used instead of 0.4 mg, standard dosage used in the Western countries. At enrollment, all patients were assessed with plain abdominal radiography kidney ureter bladder (KUB) and non-contrast CT to evaluate stone size and location. These procedures were performed in an emergency setting. Stone size was determined based on the longest diameter on CT after magnifying three to four times on a picture archiving communication system at our institution (12). Patients were asked to complete the validated Korean version of the Euroquality-of-life (EuroQOL) questionnaire (13) and a baseline visual pain score (VPS). At discharge, all patients were instructed to drink 2 l water daily, and were given an oral painkiller (Ultracet ER) and were told to take the medication on demand. Group B patients were instructed to take tamsulosin ª 2013 John Wiley & Sons Ltd Int J Clin Pract, February 2014, 68, 2, 216–221
approximately 30 min after dinner, as recommended by the drug package. To assess the sole effect of tamsulosin on stone passage and patient perception, none of the patient was treated with concomitant antibiotics, anti-emetics, or spasmolytics (2,14). This obviated possible confounding effects on efficacy outcomes. Patients were evaluated by KUB and urine analysis every 5 days at the outpatient clinic until stone expulsion or to post-trial 4 weeks (2). In some patients who had no symptom and no visible stone in the KUB but had haematuria on urinalysis, final non-contrast CT was taken to confirm the stone passage. During follow-up, patients with persistent symptoms, such as intractable pain, severe nausea, vomiting, or voiding symptoms, were given the opportunity to seek active treatments (shock wave lithotripsy or ureteroscopy). Some of these patients indeed converted to active treatment on the basis of their own desires and the clinician’s decision. At study completion, the patients were asked to complete a specifically tailored questionnaire (15) regarding oral analgesic requirements, adverse events after tamsulosin, and willingness to undergo conservative treatment again. A post-trial EuroQOL questionnaire was also administered. The primary end-point was cumulative stone passage rate (SPR) over 4 weeks of treatment. The secondary end-points were time to stone passage, posttrial EuroQOL score, oral analgesic requirements, and willingness to undergo conservative treatment again. Time to stone passage was defined as the number of days from the date of study enrollment to the date when patients identified their stone passage, or the date of the follow-up visit when the imaging study no longer detected a visible stone.
Outcomes analysis The primary outcome analyses were based on the intention-to-treat population, namely those patients who had a baseline assessment and were randomized. The secondary end-points analyses were based on the patients who completed the study protocol. As described in our previous EuroQoL study (16), the small number of missing post-trial data for EuroQOL was imputed by using the individual’s mean and whole unanswered questionnaires were omitted from the analysis. There were no missing data regarding the questions regarding oral analgesic requirements or willingness to undergo conservative treatment again.
Sample size and statistical analysis From several studies and a meta-analysis, a-blocker treatment in distal UC resulted in an absolute
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increase in the SPR of 29%, compared with control (placebo: 50–60% vs. a-blocker: 80–90%) (2–6). We hypothesized that tamsulosin for proximal UC would be associated with the same degree of benefit (approximately 30%) as for distal UC; however, the SPR of proximal UC would be 20–30% lower than the SPR of the distal UC (group A: 30% vs. group B: 60%). On the basis of this assumption, and using a two-tailed a-level of 0.05 with 80% power, it was calculated that 42 patients per group were required. Planning for a possible 20% drop-out rate, the aim was to enroll 100 patients (50 per group). To compare the groups, Fisher’s exact or v2 tests were used with categorical variables and Student’s ttest was used with continuous variables. To identify significant predictors of stone expulsion, logistic regression analysis with various clinical and stone factors was performed. All statistical analyses were two-sided with p < 0.05 being defined as statistically significant. The data are expressed as the mean SD or median and range. Statistical analyses were performed by using SPSS 18.0 software (SPSS Inc., Chicago, IL).
Results Cohort and group characteristics Of the 116 patients who were screened, 108 satisfied the inclusion and exclusion criteria and were randomly assigned to group A or B (n = 54 in both groups). The mean patient age of the whole cohort was 45.8 years, the mean body mass index was 23.8 kg/m2, the mean baseline VPS was 7.76, the
mean EuroQOL score was 5.88, and the mean stone size ( SD) was 3.53 1.10 mm. The two groups were well balanced in terms of baseline patient and stone characteristics (Table 1): in particular, the mean stone sizes of groups A and B were 3.65 1.15 and 3.41 1.04 mm, respectively (p = 0.256). Figure 1 depicts a study flow diagram. Of the 108 patients randomized, 79 (73.2%) completed the study. Analysis of the two groups revealed that the group B patients tended to be more likely to complete the study (81.5%) than the group A patients (64.8%; p = 0.051). While the two groups did not differ significantly in terms of loss to follow-up (A: 14.8% vs. B: 11.1%, p = 0.567), the group A patients tended to be more likely to convert to active treatment (A: 20.4% vs. B: 7.4%, p = 0.051).
Efficacy outcomes The cumulative SPR of the whole cohort was 60.2% (65/108). The cumulative SPR of group B was significantly higher than the group A [B: 74.1% (40/54) vs. A: 46.3% (25/54), p = 0.003]. Secondary endpoints are summarized in Table 2. Group B also had a significantly shorter time to stone passage than group A (A: 19.6 8.5 days vs. B: 14.3 7.9 days, p = 0.005). The two groups did not differ significantly in terms of post-trial EuroQOL score and oral analgesic requirements but 74.3% (26/35) of group A and 90.9% (40/44) of group B were willing to undergo conservative treatment again (p = 0.048). In group B, serious tamsulosin-related adverse events were not observed.
Table 1 Baseline patient and stone characteristics
Age (year), mean SD Sex Male, n (%) Female, n (%) Body mass index (kg/m2), mean SD Past stone history No, n (%) Yes, n (%) Baseline VPS, mean SD Baseline EuroQOL, mean SD Baseline VSS, mean SD Stone site Right, n (%) Left, n (%) Stone size (mm), mean SD
Total (n = 108)
Group A (n = 54)
Group B (n = 54)
p-value
45.8 12.1
47.9 11.4
43.6 12.4
0.061
68 (63.0) 40 (37.0) 23.8 2.7
33 (61.1) 21 (38.9) 24.3 2.8
35 (64.8) 19 (35.2) 23.4 2.6
0.690
81 (75.0) 27 (25.0) 7.76 2.19 5.88 0.94 69.2 14.3
39 (72.2) 15 (27.8) 7.96 2.06 5.83 0.75 67.2 15.2
42 (77.8) 15 (22.2) 7.56 2.31 5.92 1.10 71.3 13.2
0.505
56 (51.9) 52 (48.1) 3.53 1.10
32 (59.3) 22 (40.7) 3.65 1.15
24 (44.4) 30 (55.6) 3.41 1.04
0.123
0.116
0.346 0.614 0.145
0.256
Group A = conservative management only, Group B = tamsulosin 0.2 mg once a day medication. VPS, visual pain score; VSS, visual satisfaction score; QOL, quality of life; SD, standard deviation.
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Medical expulsive therapy in proximal ureteral calculi
Discussion
Figure 1 Study flow diagram
Table 3 describes the univariate and multivariate logistic regression analyses of factors that predict stone expulsion. Stone size (OR = 1.447; 95% CI, 1.007–2.079; p = 0.045) and tamsulosin medication (OR = 3.314; 95% CI, 1.474–7.452; p = 0.004) were significant predictors of stone expulsion on univariate analysis. However, on multivariate analysis, only tamsulosin remained statistically significant (OR = 3.198; 95% CI, 1.193–8.572; p = 0.021).
This prospective, randomized, open-label, multicenter study evaluated the effect of tamsulosin on stone expulsion in proximal UC ≤ 6 mm and found that tamsulosin 0.2 mg once daily for a maximum of 4 weeks resulted in a significantly higher stone expulsion rate compared with conservative treatment alone. Of note, overall cumulative SPR was 60.2% while group A and B had an SPR of 46.3% and 74.1%, respectively. These rates are lower than the SPRs reported for MET in the distal UC, which range from 80% to 100% (2–4,17). In other words, about one-quarter of patients taking tamsulosin failed to be stone-free after 4 weeks of medication. This observation can be explained by the fact that a proximal UC must traverse through the entire ureter before it can be passed spontaneously. Thus, the SPR of proximal UC, even after tamsulosin treatment, is likely to be more affected by the internal anatomical structure of the ureter than the distal UC SPR (18). Supporting this are our observations of the 15 patients who converted to active treatments during follow-up. Of these, eight underwent ureteroscopic surgery and the operative findings indicated that
Table 2 Comparison of efficacy outcomes
Variables
Primary end-point* Cumulative stone passage rates, % (n) Secondary end-points† Time to stone passage (days), mean SD Post-trial EuroQOL, mean SD Post-trial VSS, mean SD Requirements of oral analgesics, mean SD Willingness to undergo conservative treatment again, % (n)
Group A
Group B
p-value
46.3 (25/54)
74.1 (40/54)
0.003
7.9 0.6 15.2 3.8 (40/44)
0.005 0.531 0.723 0.379 0.048
19.6 5.5 76.3 4.3 74.3
8.5 0.8 11.8 4.2 (26/35)
14.3 5.4 77.4 3.5 90.9
Group A = conservative management only, Group B = tamsulosin 0.2 mg once a day medication. QOL, quality of life; VSS, visual satisfaction score; SD, standard deviation. *Based on the intention-to-treat population. †Based on the per-protocol population.
Table 3 Univariate and multivariate logistic regression analysis for stone expulsion
Variables
Univariate OR 95% CI
p-value
Multivariate OR 95% CI
p-value
Age (as continuous variable) Sex (male vs. female) Body mass index (as continuous variable) Past stone history (no vs. yes) Stone size (as continuous variable) Tamsulosin medication (no vs. yes)
1.004 0.857 0.982 1.579 1.447 3.314
0.822 0.706 0.827 0.309 0.045 0.004
0.993 0.577 0.950 1.398 1.475 3.198
0.724 0.306 0.603 0.565 0.078 0.021
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0.972–1.036 0.384–1.911 0.837–1.153 0.655–3.803 1.007–2.079 1.474–7.452
0.953–1.034 0.201–1.655 0.784–1.152 0.447–4.374 0.958–2.271 1.193–8.572
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seven had reactive mucosal change around the stone, ureteral kink, ureteral stricture below the stone or intrinsic ureteral narrowness. As the internal anatomical structures cannot be determined on the basis of the clinical data alone, we recommend that patients who choose MET for proximal UC should be informed of a relatively higher failure rate compared with the patients with distal UC. Of the secondary outcomes that were examined, tamsulosin treatment was associated with a significantly shorter expulsion time: groups A and B had mean stone passage times ( SD) of 19.6 ( 8.5) and 14.3 ( 7.9) days, respectively. Studies of distal UC reported mean stone expulsion time that ranged from 3 to 7 days (2–4,17). Thus, compared with distal UC passage, at least one extra week is required for the passage of a proximal UC. Notably, although the aforementioned studies of distal UC found that tamsulosin reduced pain (as assessed by oral analgesic requirements) (2–4,17), the present study did not find this. This may reflect, at least in part, the longer time to stone passage in proximal UC. Relatively higher drop-out rate in group A, largely because of conversion into active treatments, may also have affected the results concerning pain and patient EuroQOL. If these patients had completed the study protocol, it is possible that groups A and B would have differed significantly in terms of pain and EuroQOL. Despite many prior studies regarding MET using a-blockers in the distal UC, there is only one report to date on the efficacy of MET in proximal UC (19). In the study, 0.4 mg tamsulosin was associated with a higher SPR and shorter time to stone passage compared with control group. Of note, in the study by Yencilek et al. (19), benefit of tamsulosin in spontaneous stone passage was limited to patients having stones < 5 mm (71.4% vs. 50%, p < 0.001). Taken together with our results including patients with ≤ 6 mm in diameter and the study of Yencilek et al. (19), MET using tamsulosin is appropriate treatment option for patients with proximal UC not exceeding 7 mm. Several studies have investigated the distributions and densities of a1 receptors along the human ureter based on mRNA level (9,10) or protein expression (11). While the two methodologies differ slightly in terms of their estimation of the relative expressions of the a1a, a1b, and a1d receptors in each ureter location, those studies (9–11) show that the distal ureter has the highest density of a1 receptors and a1d is the most common receptor in all portions of the human ureter at both the mRNA and protein levels. Of note, the a1a receptor is expressed at much lower levels in the proximal ureter than in the distal
ureter (9,11). In addition, the distal ureter is covered by three muscular layers while the proximal ureter only contains two relatively thin, interlacing layers (20). From these findings, it may be questionable whether MET with tamsulosin promotes proximal UC expulsion by relaxing the ureteral smooth muscle. It has also been proposed previously that because tamsulosin mainly targets a1a receptors, it would have maximal efficacy in the distal UC (2). However, our results show that tamsulosin also facilitates proximal UC expulsion. We hypothesize that tamsulosin promotes proximal UC expulsion by blocking the a1d receptors. Supporting this is that although tamsulosin is a selective a1a blocker, it also has affinity for a1d receptors (21,22). Further studies of the key receptors at the molecular level are needed to elucidate the mechanism behind our findings. We confirmed the efficacy of tamsulosin in promoting stone expulsion by multivariate analysis adjusted for other clinical and stone parameters. No other clinical or stone parameters were predictive of stone expulsion. A recent study by Bensalah et al. showed that MET with tamsulosin for distal UC is more cost-effective as an initial treatment than ureteroscopy (23). On the other hand, Lotan et al. showed that when a conservative approach to UC as the initial management option is followed by stone expulsion, it is less costly than ureteroscopy or shock wave lithotripsy (24). As the SPR of proximal UC after MET using tamsulosin was lower than the SPR of distal UC, further comparisons between tamsulosin and minimally invasive procedures are necessary in terms of cost and efficacy. Limitations of the present study include the absence of a placebo control group and the higher drop-out rate than initial assumption, specifically in the group A. As our primary end-point was SPR, which was an objective outcome based on imaging studies, the bias because of the absence of a placebo control might be minimal. In addition, in contrast to our study in which 0.2 mg tamsulosin was used, 0.4 mg tamsulosin is standard-dose in Western countries. Thus, optimal dosage of MET is open for debate, and further studies are required to address this issue. Countering the possible limitation is that our results are based on a homogeneous population of patients with proximal UC. We believe that our results are helpful in guiding MET in proximal UC.
Conclusion Tamsulosin was associated with significantly higher stone expulsion rate and shorter expulsion time in proximal UC ≤ 6 mm compared with conservative ª 2013 John Wiley & Sons Ltd Int J Clin Pract, February 2014, 68, 2, 216–221
Medical expulsive therapy in proximal ureteral calculi
managements only. Our results indicate that similar to patients with distal UC, MET using tamsulosin is a reasonable treatment option for patients with proximal UC. Meanwhile, as overall SPR was lower than the SPRs reported for MET in the distal UC, we recommend that patients who choose MET for proximal UC should be informed of a relatively higher
References 1 Preminger GM, Tiselius HG, Assimos DG et al. 2007 guideline for the management of ureteral calculi. J Urol 2007; 178: 2418–34. 2 Dellabella M, Milanese G, Muzzonigro G. Efficacy of tamsulosin in the medical management of juxtavesical ureteral stones. J Urol 2003; 170: 2202–5. 3 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: 12–6. 4 Yilmaz E, Batislam E, Basar MM et al. The comparison and efficacy of 3 different alpha1-adrenergic blockers for distal ureteral stones. J Urol 2005; 173: 2010–2. 5 Seitz C, Liatsikos E, Porpiglia F et al. Medical therapy to facilitate the passage of stones: what is the evidence? Eur Urol 2009; 56: 455–71. 6 Hollingsworth JM, Rogers MA, Kaufman SR et al. Medical therapy to facilitate urinary stone passage: a meta-analysis. Lancet 2006; 368: 1171–9. 7 Morita T, Ando M, Kihara K, Oshima H. Function and distribution of autonomic receptors in canine ureteral smooth muscle. Neurourol Urodyn 1994; 13: 315–21. 8 Hieble JP, Bylund DB, Clarke DE et al. International Union of Pharmacology. X. Recommendation for nomenclature of alpha 1-adrenoceptors: consensus update. Pharmacol Rev 1995; 47: 267–70. 9 Sigala S, Dellabella M, Milanese G et al. Evidence for the presence of alpha1 adrenoceptor subtypes
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failure rate compared with the patients with distal UC.
Acknowledgements This study was supported by research grant of Korean Astellas Pharm, Co.
in the human ureter. Neurourol Urodyn 2005; 24: 142–8. Itoh Y, Kojima Y, Yasui T et al. Examination of alpha 1 adrenoceptor subtypes in the human ureter. Int J Urol 2007; 14: 749–53. Park HK, Choi EY, Jeong BC et al. Localizations and expressions of alpha-1A, alpha-1B and alpha-1D adrenoceptors in human ureter. Urol Res 2007; 35: 325–9. Park J, Hong B, Park T, Park HK. Effectiveness of noncontrast computed tomography in evaluation of residual stones after percutaneous nephrolithotomy. J Endourol 2007; 21: 684–7. Lee WJ, Song KH, Noh JH et al. Health-related quality of life using the EuroQol 5D questionnaire in Korean patients with type 2 diabetes. J Korean Med Sci 2012; 27: 255–60. Cooper JT, Stack GM, Cooper TP. Intensive medical management of ureteral calculi. Urology 2000; 56: 575–8. Park J, Shin DW, Chung JH, Lee SW. Shock wave lithotripsy versus ureteroscopy for ureteral calculi: a prospective assessment of patient-reported outcomes. World J Urol 2012. doi:10.1007/s00345012-0966-2. Park J, Shin DW, You C et al. Cross-cultural application of the Korean version of Ureteral Stent Symptoms Questionnaire. J Endourol 2012; 26: 1518–22. Porpiglia F, Ghignone G, Fiori C et al. Nifedipine versus tamsulosin for the management of lower ureteral stones. J Urol 2004; 172: 568–71.
18 Miller OF, Kane CJ. Time to stone passage for observed ureteral calculi: a guide for patient education. J Urol 1999; 162: 688–90; discussion 90-1. 19 Yencilek F, Erturhan S, Canguven O et al. Does tamsulosin change the management of proximally located ureteral stones? Urol Res 2010; 38: 195–9. 20 Hanna MK JR, Sturgess JM, Barkin M. Ureteral structure and ultrastructure. Part I. The normal human ureter. J Urol 1976; 116: 718–24. 21 Richardson CD, Donatucci CF, Page SO et al. Pharmacology of tamsulosin: saturation-binding isotherms and competition analysis using cloned alpha 1-adrenergic receptor subtypes. Prostate 1997; 33: 55–9. 22 Kojima Y, Sasaki S, Kubota Y et al. Up-regulation of alpha1a and alpha1d-adrenoceptors in the prostate by administration of subtype selective alpha1-adrenoceptor antagonist tamsulosin in patients with benign prostatic hyperplasia. J Urol 2011; 186: 1530–6. 23 Bensalah K, Pearle M, Lotan Y. Cost-effectiveness of medical expulsive therapy using alpha-blockers for the treatment of distal ureteral stones. Eur Urol 2008; 53: 411–8. 24 Lotan Y, Gettman MT, Roehrborn CG et al. Management of ureteral calculi: a cost comparison and decision making analysis. J Urol 2002; 167: 1621–9.
Paper received June 2013, accepted July 2013
Effect of tamsulosin on stone expulsion in proximal ureteral calculi: an open-label randomized controlled trial S. W. Lee,1 S. H. Woo,2 D.-S. Yoo,2 J. Park2
1
Department of Urology, Hanyang University Guri Hospital, Guri, Korea 2 Department of Urology, Eulji University Hospital, Daejeon, Korea Correspondence to: Jinsung Park, MD, PhD, Department of Urology, Eulji University Hospital, Eulji University College of Medicine, 1306 Dunsan-dong, Seo-gu, Daejeon, 302-799, Korea Tel.: 82-42-611-3533 Fax: 82-42-259-1326 Email: [email protected]; [email protected] Disclosures All authors declare no competing financial interests. All authors declare no conflict of interests.
SUMMARY
Introduction According to the 2007 AUA guidelines for ureteral calculi (UC), medical expulsive therapy (MET) using a-blockers is a reasonable treatment option for distal UC that are less than 10 mm in diameter (1). Several studies shows that MET with a1a blockers augments stone expulsion and reduces the time to stone expulsion (2–6). a1 blockers may facilitate stone passage by decreasing ureteral peristaltic contraction force and frequency, which in turn may reduce the intra-ureteral pressure and thus increase the volume of the fluid bolus that is transported down the ureter (7).
216
What’s known
Aim: Medical expulsive therapy (MET) using alpha-blockers is effective for distal ureteral calculi (UC). We aimed to evaluate the efficacy of tamsulosin for proximal UC expulsion. Materials and methods: An open-label randomized controlled trial was conducted with 108 patients who agreed to conservative management for single, radiopaque, proximal UC ≤ 6 mm and were randomized into group A (n = 54, conservative managements only) or B (n = 54, 0.2 mg tamsulosin once a day). The primary end-point was stone passage rates (SPR) in the intention-totreat population in 4 treatment weeks. The secondary end-points were estimated in per-protocol population and were time to stone passage, post-trial Euro-qualityof-life (EuroQOL) score, oral analgesic requirements, and willingness to undergo conservative treatment again. Results: The two groups were well balanced in terms of baseline patient and stone characteristics. Seventy nine patients (73.2%; 35 of group A and 44 of group B) completed the study protocol. The overall SPR was 60.2% (65/108). Group B had a higher SPR (74.1%; 40/54) than group A (46.3%; 25/54; p = 0.003) and a significantly shorter time to stone passage (mean days, A: 19.6 vs. B: 14.3, p = 0.005). The groups did not differ in post-trial EuroQOL score or oral analgesic requirements, whereas 74.3% (26/35) of group A and 90.9% (40/44) of group B were willing to undergo conservative treatment again (p = 0.048). Univariate logistic regression analysis showed that stone size (OR = 1.447, p = 0.045) and tamsulosin treatment (OR = 3.314, p = 0.004) significantly predicted stone expulsion. On multivariate analysis, only tamsulosin was statistically significant (OR=3.198, p = 0.021). Conclusions: Tamsulosin was associated with significantly higher stone expulsion rate and shorter expulsion time in proximal UC ≤ 6 mm compared with conservative managements only. Our results indicate that similar to patients with distal UC, MET using tamsulosin is a reasonable treatment option for patients with proximal UC.
According to the 2007 AUA guidelines for ureteral calculi (UC), medical expulsive therapy using ablockers is a reasonable treatment option for distal UC < 10 mm. However, given the ureter locationdependent differences in a1 receptor distribution and density and the fact that a proximal UC must pass through the entire ureter to pass spontaneously, it remains unclear whether a1 blockers may also be effective for the expulsion of proximal UC.
What’s new By this prospective randomized open-label multicenter trial, we found that tamsulosin was associated with significantly higher stone expulsion rate and shorter expulsion time in proximal UC ≤ 6 mm compared with conservative managements only. Our results indicate that similar to patients with distal UC, MET using tamsulosin is a reasonable treatment option for patients with proximal UC.
Gene-cloning studies have identified three a1 receptor subtypes, namely a1a, a1b, and a1d (8). The distributions and densities of these a1 receptors along the ureter differ depending on the location. While the a1d receptor is the most predominant receptor on the entire human ureter, the a1a receptor is expressed at higher levels in the distal ureter than in the proximal or mid ureter (9–11). Given these ureter location-dependent differences in a1 receptor distribution and density and the fact that a proximal UC must pass through the entire ureter to pass spontaneously, it remains unclear whether a1 blockers may also be effective for the expulsion of proximal UC. In the present study, we evaluated the ª 2013 John Wiley & Sons Ltd Int J Clin Pract, February 2014, 68, 2, 216–221. doi: 10.1111/ijcp.12271
Medical expulsive therapy in proximal ureteral calculi
efficacy of tamsulosin on stone expulsion in proximal UC.
Materials and methods Patients and study design This prospective, randomized, open-label, multicenter trial was conducted at two university hospitals from July 2010 to August 2012. Written informed consent was obtained from each patient before screening. The study protocol was approved at the Institutional Review Board of each institute, and approval for off label use of tamsulosin and the study protocol was obtained from the Korea Food and Drug Administration (clinical trial registration no. 1656). Eligible patients were 18 years or older, had presented with renal colic, were diagnosed to have a single, unilateral, radiopaque, proximal UC ≤ 6 mm in diameter, and agreed to undergo conservative management. The proximal ureter was defined as the segment between the ureteropelvic junction and the upper border of the sacroiliac joint. Exclusion criteria included the following: (i) UC ≥ 7 mm or multiple UC; (ii) febrile urinary tract infection; (iii) single kidney; (iv) non-functioning kidney; (v) pregnancy; (vi) azotemia (creatinine > 1.8 mg/dl); (vii) ureteral stricture; (viii) severe hydronephrosis; (ix) current treatment with medications that could affect stone passage, such as a-blockers, calcium channel blockers, steroids, or nitrates; and (x) patients who wanted immediate stone removal because of colic. Patients were randomized (1:1 ratio) to one of the two groups: group A (conservative managements only) or group B (0.2 mg tamsulosin once a day). A predefined randomization sequence was created by a computer random number generator using a block size of 4. Approved initial tamsulosin dosage for Korean patients with benign prostatic hyperplasia is 0.2 mg. Therefore, that dosage was used instead of 0.4 mg, standard dosage used in the Western countries. At enrollment, all patients were assessed with plain abdominal radiography kidney ureter bladder (KUB) and non-contrast CT to evaluate stone size and location. These procedures were performed in an emergency setting. Stone size was determined based on the longest diameter on CT after magnifying three to four times on a picture archiving communication system at our institution (12). Patients were asked to complete the validated Korean version of the Euroquality-of-life (EuroQOL) questionnaire (13) and a baseline visual pain score (VPS). At discharge, all patients were instructed to drink 2 l water daily, and were given an oral painkiller (Ultracet ER) and were told to take the medication on demand. Group B patients were instructed to take tamsulosin ª 2013 John Wiley & Sons Ltd Int J Clin Pract, February 2014, 68, 2, 216–221
approximately 30 min after dinner, as recommended by the drug package. To assess the sole effect of tamsulosin on stone passage and patient perception, none of the patient was treated with concomitant antibiotics, anti-emetics, or spasmolytics (2,14). This obviated possible confounding effects on efficacy outcomes. Patients were evaluated by KUB and urine analysis every 5 days at the outpatient clinic until stone expulsion or to post-trial 4 weeks (2). In some patients who had no symptom and no visible stone in the KUB but had haematuria on urinalysis, final non-contrast CT was taken to confirm the stone passage. During follow-up, patients with persistent symptoms, such as intractable pain, severe nausea, vomiting, or voiding symptoms, were given the opportunity to seek active treatments (shock wave lithotripsy or ureteroscopy). Some of these patients indeed converted to active treatment on the basis of their own desires and the clinician’s decision. At study completion, the patients were asked to complete a specifically tailored questionnaire (15) regarding oral analgesic requirements, adverse events after tamsulosin, and willingness to undergo conservative treatment again. A post-trial EuroQOL questionnaire was also administered. The primary end-point was cumulative stone passage rate (SPR) over 4 weeks of treatment. The secondary end-points were time to stone passage, posttrial EuroQOL score, oral analgesic requirements, and willingness to undergo conservative treatment again. Time to stone passage was defined as the number of days from the date of study enrollment to the date when patients identified their stone passage, or the date of the follow-up visit when the imaging study no longer detected a visible stone.
Outcomes analysis The primary outcome analyses were based on the intention-to-treat population, namely those patients who had a baseline assessment and were randomized. The secondary end-points analyses were based on the patients who completed the study protocol. As described in our previous EuroQoL study (16), the small number of missing post-trial data for EuroQOL was imputed by using the individual’s mean and whole unanswered questionnaires were omitted from the analysis. There were no missing data regarding the questions regarding oral analgesic requirements or willingness to undergo conservative treatment again.
Sample size and statistical analysis From several studies and a meta-analysis, a-blocker treatment in distal UC resulted in an absolute
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increase in the SPR of 29%, compared with control (placebo: 50–60% vs. a-blocker: 80–90%) (2–6). We hypothesized that tamsulosin for proximal UC would be associated with the same degree of benefit (approximately 30%) as for distal UC; however, the SPR of proximal UC would be 20–30% lower than the SPR of the distal UC (group A: 30% vs. group B: 60%). On the basis of this assumption, and using a two-tailed a-level of 0.05 with 80% power, it was calculated that 42 patients per group were required. Planning for a possible 20% drop-out rate, the aim was to enroll 100 patients (50 per group). To compare the groups, Fisher’s exact or v2 tests were used with categorical variables and Student’s ttest was used with continuous variables. To identify significant predictors of stone expulsion, logistic regression analysis with various clinical and stone factors was performed. All statistical analyses were two-sided with p < 0.05 being defined as statistically significant. The data are expressed as the mean SD or median and range. Statistical analyses were performed by using SPSS 18.0 software (SPSS Inc., Chicago, IL).
Results Cohort and group characteristics Of the 116 patients who were screened, 108 satisfied the inclusion and exclusion criteria and were randomly assigned to group A or B (n = 54 in both groups). The mean patient age of the whole cohort was 45.8 years, the mean body mass index was 23.8 kg/m2, the mean baseline VPS was 7.76, the
mean EuroQOL score was 5.88, and the mean stone size ( SD) was 3.53 1.10 mm. The two groups were well balanced in terms of baseline patient and stone characteristics (Table 1): in particular, the mean stone sizes of groups A and B were 3.65 1.15 and 3.41 1.04 mm, respectively (p = 0.256). Figure 1 depicts a study flow diagram. Of the 108 patients randomized, 79 (73.2%) completed the study. Analysis of the two groups revealed that the group B patients tended to be more likely to complete the study (81.5%) than the group A patients (64.8%; p = 0.051). While the two groups did not differ significantly in terms of loss to follow-up (A: 14.8% vs. B: 11.1%, p = 0.567), the group A patients tended to be more likely to convert to active treatment (A: 20.4% vs. B: 7.4%, p = 0.051).
Efficacy outcomes The cumulative SPR of the whole cohort was 60.2% (65/108). The cumulative SPR of group B was significantly higher than the group A [B: 74.1% (40/54) vs. A: 46.3% (25/54), p = 0.003]. Secondary endpoints are summarized in Table 2. Group B also had a significantly shorter time to stone passage than group A (A: 19.6 8.5 days vs. B: 14.3 7.9 days, p = 0.005). The two groups did not differ significantly in terms of post-trial EuroQOL score and oral analgesic requirements but 74.3% (26/35) of group A and 90.9% (40/44) of group B were willing to undergo conservative treatment again (p = 0.048). In group B, serious tamsulosin-related adverse events were not observed.
Table 1 Baseline patient and stone characteristics
Age (year), mean SD Sex Male, n (%) Female, n (%) Body mass index (kg/m2), mean SD Past stone history No, n (%) Yes, n (%) Baseline VPS, mean SD Baseline EuroQOL, mean SD Baseline VSS, mean SD Stone site Right, n (%) Left, n (%) Stone size (mm), mean SD
Total (n = 108)
Group A (n = 54)
Group B (n = 54)
p-value
45.8 12.1
47.9 11.4
43.6 12.4
0.061
68 (63.0) 40 (37.0) 23.8 2.7
33 (61.1) 21 (38.9) 24.3 2.8
35 (64.8) 19 (35.2) 23.4 2.6
0.690
81 (75.0) 27 (25.0) 7.76 2.19 5.88 0.94 69.2 14.3
39 (72.2) 15 (27.8) 7.96 2.06 5.83 0.75 67.2 15.2
42 (77.8) 15 (22.2) 7.56 2.31 5.92 1.10 71.3 13.2
0.505
56 (51.9) 52 (48.1) 3.53 1.10
32 (59.3) 22 (40.7) 3.65 1.15
24 (44.4) 30 (55.6) 3.41 1.04
0.123
0.116
0.346 0.614 0.145
0.256
Group A = conservative management only, Group B = tamsulosin 0.2 mg once a day medication. VPS, visual pain score; VSS, visual satisfaction score; QOL, quality of life; SD, standard deviation.
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Discussion
Figure 1 Study flow diagram
Table 3 describes the univariate and multivariate logistic regression analyses of factors that predict stone expulsion. Stone size (OR = 1.447; 95% CI, 1.007–2.079; p = 0.045) and tamsulosin medication (OR = 3.314; 95% CI, 1.474–7.452; p = 0.004) were significant predictors of stone expulsion on univariate analysis. However, on multivariate analysis, only tamsulosin remained statistically significant (OR = 3.198; 95% CI, 1.193–8.572; p = 0.021).
This prospective, randomized, open-label, multicenter study evaluated the effect of tamsulosin on stone expulsion in proximal UC ≤ 6 mm and found that tamsulosin 0.2 mg once daily for a maximum of 4 weeks resulted in a significantly higher stone expulsion rate compared with conservative treatment alone. Of note, overall cumulative SPR was 60.2% while group A and B had an SPR of 46.3% and 74.1%, respectively. These rates are lower than the SPRs reported for MET in the distal UC, which range from 80% to 100% (2–4,17). In other words, about one-quarter of patients taking tamsulosin failed to be stone-free after 4 weeks of medication. This observation can be explained by the fact that a proximal UC must traverse through the entire ureter before it can be passed spontaneously. Thus, the SPR of proximal UC, even after tamsulosin treatment, is likely to be more affected by the internal anatomical structure of the ureter than the distal UC SPR (18). Supporting this are our observations of the 15 patients who converted to active treatments during follow-up. Of these, eight underwent ureteroscopic surgery and the operative findings indicated that
Table 2 Comparison of efficacy outcomes
Variables
Primary end-point* Cumulative stone passage rates, % (n) Secondary end-points† Time to stone passage (days), mean SD Post-trial EuroQOL, mean SD Post-trial VSS, mean SD Requirements of oral analgesics, mean SD Willingness to undergo conservative treatment again, % (n)
Group A
Group B
p-value
46.3 (25/54)
74.1 (40/54)
0.003
7.9 0.6 15.2 3.8 (40/44)
0.005 0.531 0.723 0.379 0.048
19.6 5.5 76.3 4.3 74.3
8.5 0.8 11.8 4.2 (26/35)
14.3 5.4 77.4 3.5 90.9
Group A = conservative management only, Group B = tamsulosin 0.2 mg once a day medication. QOL, quality of life; VSS, visual satisfaction score; SD, standard deviation. *Based on the intention-to-treat population. †Based on the per-protocol population.
Table 3 Univariate and multivariate logistic regression analysis for stone expulsion
Variables
Univariate OR 95% CI
p-value
Multivariate OR 95% CI
p-value
Age (as continuous variable) Sex (male vs. female) Body mass index (as continuous variable) Past stone history (no vs. yes) Stone size (as continuous variable) Tamsulosin medication (no vs. yes)
1.004 0.857 0.982 1.579 1.447 3.314
0.822 0.706 0.827 0.309 0.045 0.004
0.993 0.577 0.950 1.398 1.475 3.198
0.724 0.306 0.603 0.565 0.078 0.021
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0.972–1.036 0.384–1.911 0.837–1.153 0.655–3.803 1.007–2.079 1.474–7.452
0.953–1.034 0.201–1.655 0.784–1.152 0.447–4.374 0.958–2.271 1.193–8.572
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seven had reactive mucosal change around the stone, ureteral kink, ureteral stricture below the stone or intrinsic ureteral narrowness. As the internal anatomical structures cannot be determined on the basis of the clinical data alone, we recommend that patients who choose MET for proximal UC should be informed of a relatively higher failure rate compared with the patients with distal UC. Of the secondary outcomes that were examined, tamsulosin treatment was associated with a significantly shorter expulsion time: groups A and B had mean stone passage times ( SD) of 19.6 ( 8.5) and 14.3 ( 7.9) days, respectively. Studies of distal UC reported mean stone expulsion time that ranged from 3 to 7 days (2–4,17). Thus, compared with distal UC passage, at least one extra week is required for the passage of a proximal UC. Notably, although the aforementioned studies of distal UC found that tamsulosin reduced pain (as assessed by oral analgesic requirements) (2–4,17), the present study did not find this. This may reflect, at least in part, the longer time to stone passage in proximal UC. Relatively higher drop-out rate in group A, largely because of conversion into active treatments, may also have affected the results concerning pain and patient EuroQOL. If these patients had completed the study protocol, it is possible that groups A and B would have differed significantly in terms of pain and EuroQOL. Despite many prior studies regarding MET using a-blockers in the distal UC, there is only one report to date on the efficacy of MET in proximal UC (19). In the study, 0.4 mg tamsulosin was associated with a higher SPR and shorter time to stone passage compared with control group. Of note, in the study by Yencilek et al. (19), benefit of tamsulosin in spontaneous stone passage was limited to patients having stones < 5 mm (71.4% vs. 50%, p < 0.001). Taken together with our results including patients with ≤ 6 mm in diameter and the study of Yencilek et al. (19), MET using tamsulosin is appropriate treatment option for patients with proximal UC not exceeding 7 mm. Several studies have investigated the distributions and densities of a1 receptors along the human ureter based on mRNA level (9,10) or protein expression (11). While the two methodologies differ slightly in terms of their estimation of the relative expressions of the a1a, a1b, and a1d receptors in each ureter location, those studies (9–11) show that the distal ureter has the highest density of a1 receptors and a1d is the most common receptor in all portions of the human ureter at both the mRNA and protein levels. Of note, the a1a receptor is expressed at much lower levels in the proximal ureter than in the distal
ureter (9,11). In addition, the distal ureter is covered by three muscular layers while the proximal ureter only contains two relatively thin, interlacing layers (20). From these findings, it may be questionable whether MET with tamsulosin promotes proximal UC expulsion by relaxing the ureteral smooth muscle. It has also been proposed previously that because tamsulosin mainly targets a1a receptors, it would have maximal efficacy in the distal UC (2). However, our results show that tamsulosin also facilitates proximal UC expulsion. We hypothesize that tamsulosin promotes proximal UC expulsion by blocking the a1d receptors. Supporting this is that although tamsulosin is a selective a1a blocker, it also has affinity for a1d receptors (21,22). Further studies of the key receptors at the molecular level are needed to elucidate the mechanism behind our findings. We confirmed the efficacy of tamsulosin in promoting stone expulsion by multivariate analysis adjusted for other clinical and stone parameters. No other clinical or stone parameters were predictive of stone expulsion. A recent study by Bensalah et al. showed that MET with tamsulosin for distal UC is more cost-effective as an initial treatment than ureteroscopy (23). On the other hand, Lotan et al. showed that when a conservative approach to UC as the initial management option is followed by stone expulsion, it is less costly than ureteroscopy or shock wave lithotripsy (24). As the SPR of proximal UC after MET using tamsulosin was lower than the SPR of distal UC, further comparisons between tamsulosin and minimally invasive procedures are necessary in terms of cost and efficacy. Limitations of the present study include the absence of a placebo control group and the higher drop-out rate than initial assumption, specifically in the group A. As our primary end-point was SPR, which was an objective outcome based on imaging studies, the bias because of the absence of a placebo control might be minimal. In addition, in contrast to our study in which 0.2 mg tamsulosin was used, 0.4 mg tamsulosin is standard-dose in Western countries. Thus, optimal dosage of MET is open for debate, and further studies are required to address this issue. Countering the possible limitation is that our results are based on a homogeneous population of patients with proximal UC. We believe that our results are helpful in guiding MET in proximal UC.
Conclusion Tamsulosin was associated with significantly higher stone expulsion rate and shorter expulsion time in proximal UC ≤ 6 mm compared with conservative ª 2013 John Wiley & Sons Ltd Int J Clin Pract, February 2014, 68, 2, 216–221
Medical expulsive therapy in proximal ureteral calculi
managements only. Our results indicate that similar to patients with distal UC, MET using tamsulosin is a reasonable treatment option for patients with proximal UC. Meanwhile, as overall SPR was lower than the SPRs reported for MET in the distal UC, we recommend that patients who choose MET for proximal UC should be informed of a relatively higher
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Acknowledgements This study was supported by research grant of Korean Astellas Pharm, Co.
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Paper received June 2013, accepted July 2013
