Alfuzosin Treatment Improves The Rate and Time for Stone Expulsion in Patients with Distal Uretral Stones: A Prospective Randomized Controlled Study Nouran O. El Said,1 Lamia El Wakeel,2,* Khaled M. Kamal,3 and Abd El Reheem Morad4 1
Department of Pharmacy Practice and Clinical Pharmacy, Faculty of Pharmacy, Future University, Cairo, Egypt; 2 Department of Clinical Pharmacy, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt; 3Department of Urology, Faculty of Medicine, Ain Shams University, Cairo, Egypt; 4Department of Clinical Pharmacy, Faculty of Pharmacy, Misr University for Science & Technology, Cairo, Egypt
OBJECTIVE To evaluate the safety and efficacy of alfuzosin treatment on rate and time of stone expulsion in patients with uncomplicated distal ureteral stones. PATIENTS AND METHODS Prospective, randomized, open-label, controlled study. Patients > 18 years of age presenting to the outpatient urology clinic with uncomplicated radio-opaque stones located in the distal third of the ureter and of size ≤ 10 mm were included. Patients were randomly assigned to either a control group (n=26) and received standard of care management (daily oral hydration and diclofenac 75 mg IM on demand) or to the alfuzosin group (n=28) and received alfuzosin SR 5 mg twice daily in addition to standard of care management. Patients were followed weekly at office visits and twice weekly by telephone for 4 weeks or until stone expulsion. Assessments included stone passage rate and time, and patients were monitored for occurrence of adverse drug events, complications, number of pain episodes, analgesic consumption, and number of hospital revisits. Mann–Whitney, v2, and Fisher exact test were used for data analysis. RESULTS All 54 patients completed the study. Stone expulsion rate was higher in the alfuzosin arm (53.6%, 15/28) compared to the control arm (26.9%, 7/26, p=0.04). Median stone passage time was lower in the alfuzosin group than in the control group (9 vs 19 days, respectively, p=0.006). Ureteral sepsis, uncontrollable pain, and hospitalization readmissions were reported in the control group only. There were no differences between groups in number of pain episodes, pain scores, or analgesic consumption. Alfuzosin therapy was tolerable with only minor adverse effects (headache, dizziness, mild postural hypotension, and rhinitis). CONCLUSION Alfuzosin is safe and effective in increasing stone expulsion rates and shortening stone passage times for uncomplicated distal ureteral stones. KEY WORDS alfuzosin, distal uretral stones, expulsion time. (Pharmacotherapy 2015;35(5):470–476) doi: 10.1002/phar.1593
Urolithiasis is a common urological condition. The Afro-Asian stone-forming belt stretches from Sudan and Egypt to the Philippines. In this area of the world the prevalence of stones ranges *Address for correspondence: Lamia M. El Wakeel, 4 street 292, New Maadi, Cairo, Egypt; e-mail: [email protected]. Ó 2015 Pharmacotherapy Publications, Inc.
from 4% to 20%.1 In the United States, kidney stones affect approximately 1 in 11 people, with an estimated prevalence of 8.4%.2 The incidence and prevalence of kidney stones is increasing globally and these increases are seen across sex, race, and age groups.3 In the U.S., urolithiasis was the primary diagnosis for almost 2 million office visits, more than 600,000 emergency department visits, and more than 177,000
ALFUZOSIN IMPROVES DISTAL URETERAL STONE EXPULSION El Said et al hospitalizations, totaling more than $2 billion in annual expenditures in the year 2000.4 The majority of ureteral stones (70%) are found in the lower third of the ureter at the time of presentation to the emergency department because the ureterovesical junction is one of the three narrowest points in the ureter where the majority of stones are most likely to lodge.5, 6 An observational approach based only on the pharmacological control of pain has been traditionally considered to be effective because pain relief is the most urgent need in patients with an acute stone episode.7 Stone passage is dependent on a variety of factors including stone size and location.8 However, the watchful waiting approach can result in complications, such as urinary tract infection, hydronephrosis, and loss of kidney function. Therefore it is recommended that the observation period does not exceed 4 weeks.9 Medical expulsive therapy (MET) has emerged as an appealing option for the management of ureteral stones that can potentially avoid the need for surgical intervention. The European guidelines for urolithiasis recommend MET as an option for newly diagnosed ureteral stones < 10 mm in patients without the need for urgent urologic intervention who have well-controlled pain, are not septic, have good renal function, and are followed with periodic imaging to monitor stone position and assess hydronephrosis.10 Several pharmacological approaches designed to act on possible causes of stone retention have been proposed. These pharmacological agents include calcium channel blockers, steroids, and a1 adrenergic antagonists.11 Because a1 receptors are abundant in the ureteral smooth muscle, receptor blockade using a1 antagonists inhibits basal tone, peristaltic activity, and ureteral contractions, therefore providing the basis of medical expulsive therapy using these agents.12 Specific adrenoreceptor subtypes a1a and a1d are prevalent in the distal part of the ureter. The a1d receptor is the most prevalent subtype, whereas the a1a receptor is the primary subtype in the stromal portion of the prostate.13, 14 Therefore, the majority of clinical trials have studied the effect of tamsulosin, a selective a1a and a1d antagonist, with promising results regarding distal ureteral stone passage.15–17 Another a1 antagonist, alfuzosin has been shown to have a lower incidence of ejaculatory disorders compared with tamsulosin.18 Only a few studies have assessed the use of alfuzosin as MET, and the results regarding efficacy in stone
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expulsion are inconsistent.19–22 This mandates the conduction of sufficient studies to clearly evaluate the potential beneficial role of alfuzosin in the management of distal ureteral stones. The aim of the current study was to report our experience with the effect of alfuzosin treatment of uncomplicated distal ureteral stones in the outpatient setting, on clinical efficacy, pain control, and patient outcome. Patients and Methods This was a prospective, randomized, open– label, controlled study conducted at the urology outpatient department of Ain Shams University Hospital in Egypt. The local ethical committee approved the study protocol, and the study was performed in accordance with the Declaration of Helsinki. All patients provided written informed consent. The primary efficacy outcomes were stone expulsion rate and stone passage time. Secondary outcomes were the number of pain episodes, pain scores, analgesic consumption, hospitalization rate, number of complications, adverse drug effects, and the need for ureteroscopy. Patients older than 18 years presenting with radio-opaque stones ≤ 10 mm in size and located in the distal third of the ureter were included. Exclusion criteria included urinary tract infections, ureteral strictures, renal impairment, solitary functioning kidney, hepatic insufficiency, severe hydronephrosis, multiple stones, peptic ulcers, diabetes mellitus, hypotension, pregnancy, lactation, and sensitivity to a1 blockers. Patients were also excluded if they were receiving a1 blockers, nitrates, calcium channel blockers, steroids, beta blockers, sildenafil, ketoconazole, itraconazole, or ritonavir. All patients underwent a full medical history and physical examination. Laboratory evaluations included urine analysis, serum creatinine measurement, and liver function tests. Imaging studies were intravenous urography (IVU), plain radiograph of the kidney, ureter and bladder (KUB), and ultrasound (US). The stone size and position and side of obstruction were recorded for all patients at baseline. A total of 54 patients fulfilled the inclusion criteria and were randomly assigned to either the control group or the alfuzosin group based on a computer-generated random table. The control group (n=26) received standard of care treatment (oral hydration with ≥ 2 L of water daily and diclofenac 75 mg IM on demand). The
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alfuzosin group (n=28) received the same standard of care treatment in addition to alfuzosin sustained release (SR) 5 mg twice daily after meals. Treatment duration was 28 days or until stone expulsion. Patients in both groups were educated by the clinical pharmacist about potential adverse events, methods of reporting adverse events, self-reporting of pain on the visual analogue scale, importance of adherence to medications, and maintaining a minimum of 2 L daily water intake. Patients were assessed weekly in the outpatient clinic and followed up on the 2nd and 5th day of each week via phone calls during the treatment duration. During the weekly follow up visits, patients were assessed for development of complications or stone expulsion by means of US and plain KUB. Serum creatinine levels were measured, and urine analysis was performed. For patients with a stone-free ureter on final KUB but unnoticed stone expulsion, the date of the negative stone status was recorded as the time of stone passage. During telephone interviews, patients were followed for compliance with medications and fluid intake, adverse drug events, pain episodes, and any unscheduled hospital revisits. Pain levels were determined by visual analogue scale and by recording the dose of analgesics required (number of vials used). Patient-reported stone passage was recorded. Treatment failure was defined as no stone expulsion within 28 days or treatment discontinuation due to development of urinary tract infection, uncontrollable pain, severe hydronephrosis, or renal insufficiency. Patients who failed treatment were scheduled to receive ureteroscopic intervention. Statistical analysis was performed using the SPSS statistical program (v.20; SPSS, Chicago, IL). Data were expressed as median with range
for quantitative nonparametric measures, as mean and standard deviation (SD) for parametric data, and as numbers and percentage for categorical data. The Mann–Whitney test was used to compare nonnormally distributed variables between the two groups, while v2 test and Fisher exact test were used for analysis of nominal parameters. A p-value of 0.05 was considered significant and 0.001 highly significant. Results Of 85 patients screened, 54 fulfilled eligibility criteria and were randomly assigned to either the control or alfuzosin group. Baseline evaluation demonstrated no significant differences between groups for demographic features or clinical characteristics (Table 1). At the end of the study, the number of patients with stone expulsion was significantly higher in the alfuzosin group than in the control group (53.6% vs 26.9%, p=0.04). The median time for stone expulsion was significantly lower in the alfuzosin group versus the control group (9 days vs 19 days, p=0.006). There was no significant difference between-groups in the mean size of expelled stones for the alfuzosin (5.5 1.8 mm) and control groups (4.5 1 mm, p=0.383) (Table 2). There was no significant difference in stone expulsion rate between the alfuzosin and control groups for patients with stones < 5 mm (p=0.335). Moreover, the stone expulsion rate for larger stones (≥ 5 mm) in the alfuzosin group (42.1%) was more than double that in the control group (16.7%), yet this difference did not achieve statistical significance (p=0.091) (Table 3). For both control and alfuzosin groups combined, failure rates for stone expulsion were significantly higher in patients with stone sizes
Table 1. Demographics and Clinical Characteristics Parameters
Alfuzosin Group (n=28)
Control Group (n=26)
p Value
Age (years), mean SD (range) Sex; n (%) Male Female Stone size (mm), mean SD Size < 5 mm, n (%) Size ≥ 5 mm, n (%) Stone location, n (%) Left side Right side
32.8 9.5 (19–67)
32.1 9.2 (17–65)
0.828a
18 (64.3%) 10 (35.7%) 6.3 2.1 9 (32.1) 19 (67.9)
16 (61.5%) 10 (38.5%) 5.9 1.9 8 (30.8) 18 (69.2)
0.835b
8 (28.6%) 20 (71.4%)
9 (34.6%) 17 (65.4%)
Statistical tests: aMann–Whitney; bv2.
0.583a
0.633b
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Table 2. Incidence and Time of Stone Expulsion Parameters Stone expulsion, n (%) No Yes Stone expulsion time (days), median (min–max) Mean stone size in patients with stone expulsion(mm), n (mean SD)
Alfuzosin Group (n=28)
Control Group (n=26)
p Value
13 (46.4%) 15 (53.6%) 9 (5–18)
19 (73.1%) 7 (26.9%) 19 (8–25)
0.04a 0.006b
15 (5.5 1.8)
7 (4.5 1)
0.383b
Statistical tests: av2, bMann–Whitney.
Table 3. Comparing Stone Expulsion between Alfuzosin and Control in Patients with Different Stone Sizes Groups Stone size < 5 mm
Stone expulsion; n (%)
≥ 5 mm
Stone expulsion; n (%)
a
No Yes No Yes
Alfuzosin
Control
Total
p Value
2 (22.2%) 7 (77.8%) 11 (57.9%) 8 (42.1%)
4 (50.0%) 4 (50.0%) 15(83.3%) 3 (16.7%)
6 (35.3%) 11 (64.7%) 26 (70.3%) 11 (29.7%)
0.335a 0.091a
Fisher exact test.
Table 4. Relationship Between Stone Expulsion and Patient Characteristics Stone Expulsion Parameters Age (years), mean SD Sex; n (%) Female Male Stone location, n (%) Left Right Stone size (mm) Mean SD < 5 mm, n (%) ≥ 5 mm, n (%) Stone history (weeks), mean SD) Number of pain episodes, Median (range) VAS Pain score (cm), Median (range) No. of analgesic vials, Median (min–max) Analgesic dose (mg); Median (min–max)
No
Yes
p Value
32.5 8.4
32.3 10.6
0.679a
10 (31.3%) 22 (68.8%)
10 (45.5%) 12 (54.5%)
0.288b
9 (28.1%) 23 (71.9%) 6.8 2
8 (36.4%) 14 (63.6%) 5.2 1.6
0.522b
6 (18.8%) 26 (81.3%) (1.15 1.91) 1 (0–7) 5.5 (0–9) 1 (0–9) 75 (75–675)
11 (50%) 11 (50%) (0.13 0.33) 1 (0–5) 6 (0–9) 1(0–7) 75 (75–525)
0.004a 0.015b 0.006a 0.697 a 0.714a 0.693a 0.826a
Statistical tests: aMann–Whitney; bv2.
≥ 5 mm versus those with stone size < 5 mm (81.3% and 18.8% respectively, p=0.015). The mean stone size was significantly lower in patients who passed their stones versus patients who did not (5.2 1.6 mm vs 6.8 2 mm respectively, p=0.004). The time with symptoms prior to therapy initiation was significantly lower in patients who achieved stone expulsion (0.13 0.33 weeks) versus those patients who did not have stone expulsion (1.15 1.91 weeks, p=0.006) (Table 4). There was no significant difference between control and alfuzosin groups for number of
reported pain episodes, VAS pain scores, or number of analgesic vials consumed. Four patients in the alfuzosin group reported adverse drug events, all of which were tolerable and did not result in treatment discontinuation. The adverse events in the alfuzosin group were headache (n=2, 7.1%), dizziness (n=1, 3.6%), mild postural hypotension (n=3, 10.7%), and rhinitis (n=1, 3.6%); no patient reported retrograde ejaculation. None of the patients in the control group reported adverse events. The overall complication rate was 2 (7.7%) in the control group versus 0% in the alfuzosin
Alfuzosin Treatment Improves The Rate and Time for Stone Expulsion in Patients with Distal Uretral Stones: A Prospective Randomized Controlled Study Nouran O. El Said,1 Lamia El Wakeel,2,* Khaled M. Kamal,3 and Abd El Reheem Morad4 1
Department of Pharmacy Practice and Clinical Pharmacy, Faculty of Pharmacy, Future University, Cairo, Egypt; 2 Department of Clinical Pharmacy, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt; 3Department of Urology, Faculty of Medicine, Ain Shams University, Cairo, Egypt; 4Department of Clinical Pharmacy, Faculty of Pharmacy, Misr University for Science & Technology, Cairo, Egypt
OBJECTIVE To evaluate the safety and efficacy of alfuzosin treatment on rate and time of stone expulsion in patients with uncomplicated distal ureteral stones. PATIENTS AND METHODS Prospective, randomized, open-label, controlled study. Patients > 18 years of age presenting to the outpatient urology clinic with uncomplicated radio-opaque stones located in the distal third of the ureter and of size ≤ 10 mm were included. Patients were randomly assigned to either a control group (n=26) and received standard of care management (daily oral hydration and diclofenac 75 mg IM on demand) or to the alfuzosin group (n=28) and received alfuzosin SR 5 mg twice daily in addition to standard of care management. Patients were followed weekly at office visits and twice weekly by telephone for 4 weeks or until stone expulsion. Assessments included stone passage rate and time, and patients were monitored for occurrence of adverse drug events, complications, number of pain episodes, analgesic consumption, and number of hospital revisits. Mann–Whitney, v2, and Fisher exact test were used for data analysis. RESULTS All 54 patients completed the study. Stone expulsion rate was higher in the alfuzosin arm (53.6%, 15/28) compared to the control arm (26.9%, 7/26, p=0.04). Median stone passage time was lower in the alfuzosin group than in the control group (9 vs 19 days, respectively, p=0.006). Ureteral sepsis, uncontrollable pain, and hospitalization readmissions were reported in the control group only. There were no differences between groups in number of pain episodes, pain scores, or analgesic consumption. Alfuzosin therapy was tolerable with only minor adverse effects (headache, dizziness, mild postural hypotension, and rhinitis). CONCLUSION Alfuzosin is safe and effective in increasing stone expulsion rates and shortening stone passage times for uncomplicated distal ureteral stones. KEY WORDS alfuzosin, distal uretral stones, expulsion time. (Pharmacotherapy 2015;35(5):470–476) doi: 10.1002/phar.1593
Urolithiasis is a common urological condition. The Afro-Asian stone-forming belt stretches from Sudan and Egypt to the Philippines. In this area of the world the prevalence of stones ranges *Address for correspondence: Lamia M. El Wakeel, 4 street 292, New Maadi, Cairo, Egypt; e-mail: [email protected]. Ó 2015 Pharmacotherapy Publications, Inc.
from 4% to 20%.1 In the United States, kidney stones affect approximately 1 in 11 people, with an estimated prevalence of 8.4%.2 The incidence and prevalence of kidney stones is increasing globally and these increases are seen across sex, race, and age groups.3 In the U.S., urolithiasis was the primary diagnosis for almost 2 million office visits, more than 600,000 emergency department visits, and more than 177,000
ALFUZOSIN IMPROVES DISTAL URETERAL STONE EXPULSION El Said et al between stone history (time prior to starting therapy) and failure of stone expulsion, possibly explaining our results. We stratified patients according to stone size (ie, < 5 mm vs ≥ 5 mm). For patients with stone sizes < 5 mm, there were no significant differences in the rate of stone expulsion between alfuzosin and control. The loss of treatment effect as the size of the stones decreased can be attributed to the high spontaneous expulsion rate of small stones. This finding agrees with that reported by another group where there was no significant difference in stone expulsion between groups for stones < 5 mm. However, for stones > 5 mm, in the current study, the stone expulsion rate was increased by 25.4%, from 16.7% in the control group to 42.1% in the alfuzosin group, yet these results did not reach statistical significance. These findings are different from those observed by the other study which could be attributed to the small sample size of this stratified population.22 No significant differences were reported in pain episodes and analgesic consumption between the alfuzosin and control groups unlike a previous study.19 Similarly, other studies reported nonsignificant reduction in colic pain with alfuzosin use.21, 22 This could be explained by the fact that ureteral stone pain is attributable to edema, inflammation, infection, and spasms following obstruction. a1 blockers are not efficacious against all causes of colic, as they are believed to reduce ureteral colic through inhibition of peristalsis only rather than through reduction in inflammation or edema. A previous group reported a nonsignificant difference in the analgesic and morphine equivalent consumption between alfuzosin and placebo. However, there was a greater improvement in pain scores from baseline after treatment in the alfuzosin arm.20 In another study, the alfuzosin group significantly consumed fewer NSAIDs.21 In our study, patients received only diclofenac sodium 75 mg IM on demand, while in the other study patients received dologesic (paracetamol + dextropropoxyphene) on demand for 2 weeks and if pain control was suboptimal, diclofenac sodium SR 100 mg on demand for an additional 2 weeks. Hence, the difference in those findings is attributed only to NSAID consumption and not dologesic intake. The adverse effects experienced by patients receiving alfuzosin in our study (postural hypotension, dizziness, headache, rhinitis) were unre-
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markable and did not require treatment discontinuation. Similarly, all previously MET published studies using alfuzosin for treatment of ureteral stones, reported similar adverse events that were reversible, tolerable, and did not require therapy discontinuation.19, 21, 22, 26 An exception is a single study where 12% of patients treated with alfuzosin discontinued therapy because of side effects even though they were minor (dizziness and transient orthostatic hypotension) and reversible.20 Retrograde ejaculation occurs with a1-adrenergic antagonists because of relaxation of the bladder neck, allowing semen to flow into the bladder during ejaculation. As a result, patients complain of decreased ejaculate volume. In the current study, none of the patients in the alfuzosin group experienced retrograde ejaculation. Similarly, a previous study followed more than 7000 alfuzosin treated patients over 3 years, and none reported ejaculation disorders related to alfuzosin.28 On the other hand, only two patients in a single study reported retrograde ejaculation with alfuzosin use. However, none required therapy discontinuation implying that alfuzosin is associated with a low incidence of retrograde ejaculation.26 In contrast, tamsulosin is reported to result in higher frequency of retrograde ejaculation.19 In the current study, none of the patients in the alfuzosin group required hospitalization during the study period, while three (11.5%) patients in the control group were hospitalized. The overall complication rate was 0% in the alfuzosin group compared to 7.7% in the control group. We found that alfuzosin significantly reduced the need for intervention using endoscopic procedures for stone removal compared to standard therapy (42.9% vs 73.1% respectively), which can eventually lead to a reduction in complication rate and morbidity associated with ureteroscopy.29 Conclusion Administration of alfuzosin 5 mg twice daily improved stone passage rate and reduced stone expulsion time for distal ureteral stones ≤ 10 mm in size with no effect on pain intensity or analgesic consumption. Alfuzosin therapy was tolerable and reported adverse effects were minor, reversible, and did not require treatment discontinuation.
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Source of Support No pharmaceutical or industrial support. Disclosure of Funding No source of funding from National Institute of Health (NIH); Welcome Trust: Howard Hughes Medical Institute (HHMI) and others. Conflict of Interest None. References 1. Hussain M, Lal M, Ali B, et al. Management of urinary calculi associated with renal failure. J Pak Med Assoc 1995;45:205–8. 2. Scales CD Jr, Smith AC, Hanley JM, Saigal CS. Urologic diseases in America. Prevalence of kidney stones in the United States. Eur Urol 2012;62:160. 3. Romero V, Akpinar H, Assimos DG. Kidney stones: a global picture of prevalence, incidence, and associated risk factors. Rev Urol 2010;12:e86. 4. Litwin MS, Saigal CS, Yano EM, et al. Urologic diseases in America project: analytical methods and principal findings. J Urol 2005;173:933–7. 5. Pak CYC. Kidney stones. Lancet 1998;351:1797–801. 6. Tanagho EA, McAninch JW. Smith’s general urology. Columbus, Ohio: McGraw Hill, 2004. 727. 7. Phillips E, Kieley S, Johnson EB, Monga M. Emergency room management of ureteral calculi: current practices. J Endourol 2009;23:1021–4. 8. Miller OF, Kane CJ. Time to stone passage for observed ureteral calculi: a guide for patient education. J Urol 1999;162: 688–91. 9. Lingeman JE, Matlaga BR, Evan AP. Surgical management of upper urinary tract calculi. In: Wein AJ, Kavoussi LR, Novick AC, Partin AW, Peters CA, eds. Campbell-Walsh urology, 9th ed. Philadelphia: Saunders, 2007. 1448–1507. 10. Turk C, Knoll T, Petrik A, et al. Guidelines on urolithiasis. Eur Urol 2013;5:19–21. 11. Hollingsworth JM, Rogers MA, Kaufman SR, et al. Medical therapy to facilitate urinary stone passage: a meta-analysis. Lancet 2006;368:1171–9. 12. Sigala S, Dellabella M, Milanese G, et al. Evidence for the presence of a1 adrenoceptor subtypes in the human ureter. Neurourol Urodyn 2005;24:142–8. 13. Itoh Y, Kojima Y, Yasui T, Tozawa K, Sasaki S, Kohri K. Examination of alpha 1 adrenoceptor subtypes in the human ureter. IJU 2007;14:749–53. 14. Roehrborn CG, Schwinn DA. a 1-Adrenergic receptors and their inhibitors in lower urinary tract symptoms and benign prostatic hyperplasia. J Urol 2004;171:1029–35.
15. Al-Ansari A, Al-Naimi A, Alobaidy A, Assadiq K, Azmi MD, Shokeir AA. Efficacy of tamsulosin in the management of lower ureteral stones: a randomized double-blind placebo-controlled study of 100 patients. Urology 2010;75:4–7. 16. Arrabal-Martin M, Valle-Diaz de la Guardia F, Arrabal-Polo MA, Palao-Yago F, Mijan-Ortiz JL, Zuluaga-Gomez A. Treatment of ureteral lithiasis with tamsulosin: literature review and meta-analysis. Urol Int 2010;84:254–9. 17. Lojanapiwat B, Kochakarn W, Suparatchatpan N, Lertwuttichaikul K. Effectiveness of low-dose and standard-dose tamsulosin in the treatment of distal ureteric stones: a randomized controlled study. J Int Med Res 2008;36:529–36. 18. Hellstrom WJ, Sikka SC. Effects of acute treatment with tamsulosin versus alfuzosin on ejaculatory function in normal volunteers. J Urol 2006;176:1529. 19. Agrawal M, Gupta M, Gupta A, Agrawal A, Sarkari A, Lavania P. Prospective randomized trial comparing efficacy of alfuzosin and tamsulosin in management of lower ureteral stones. Urology 2009;73:706–9. 20. Pedro RN, Hinck B, Hendlin K, Feia K, Canales BK, Monga M. Alfuzosin stone expulsion therapy for distal ureteral calculi: a double-blind, placebo controlled study. J Urol 2008;179:2244–7. 21. Chau LH, Tai DCK, Fung BTC, Li JCM, Fan CW, Li MKW. Medical expulsive therapy using alfuzosin for patient presenting with ureteral stone less than 10 mm: a prospective randomized controlled trial. IJU 2011;18:510–4. 22. Ahmed A, Al-sayed A. Tamsulosin versus alfuzosin in the treatment of patients with distal ureteral stones: prospective, randomized, comparative study. Korean J Urol 2010;51:193–7. 23. Weiss RM. Physiology and pharmacology of the renal pelvis and ureter. In: Wein AJ, Kavoussi LR, Novick AC, Partin AW, Peters CA, eds. Campbell-Walsh, 9th ed. Philadelphia: Saunders, 2007. 377–403. 24. Morita T, Wada I, Saeki H, et al. Ureteral urine transport: changes in bolus volume, peristaltic frequency, intraluminal pressure and volume of flow resulting from autonomic drugs. J Urol 1987;137:132–5. 25. Cha WH, Choi JD, Kim KH, Seo YJ, Lee K. Comparison and efficacy of low-dose and standard-dose tamsulosin and alfuzosin in medical expulsive therapy for lower ureteral calculi: prospective, randomized, comparative study. Korean J Urol 2012;53:349–54. 26. Ibrahim AK, Mahmood IH, Mahmood NS. Efficacy and safety of tamsulosin versus alfuzosin as medical expulsive therapy for ureteric stones. Arab J Urol 2013;11:142–7. 27. Hermanns T, Sauermann P, Rufibach K, Frauenfelder T, Sulser T, Strebel RT. Is there a role for tamsulosin in the treatment of distal ureteral stones of 7 mm or less? Results of a randomised, double-blind, placebo-controlled trial. Eur Urol 2009;56:407–12. 28. Lukacs B, Grange JC, Comet D, McCarthy C. History of 7,093 patients with lower urinary tract symptoms related to benign prostatic hyperplasia treated with alfuzosin in general practice up to 3 years. Euro Urol 2000;37:183–90. 29. Hong YK, Park DS. Ureteroscopic lithotripsy using Swiss Lithoclast for treatment of ureteral calculi: 12-years experience. J Korean Med Sci 2009;24:690–4.
Department of Pharmacy Practice and Clinical Pharmacy, Faculty of Pharmacy, Future University, Cairo, Egypt; 2 Department of Clinical Pharmacy, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt; 3Department of Urology, Faculty of Medicine, Ain Shams University, Cairo, Egypt; 4Department of Clinical Pharmacy, Faculty of Pharmacy, Misr University for Science & Technology, Cairo, Egypt
OBJECTIVE To evaluate the safety and efficacy of alfuzosin treatment on rate and time of stone expulsion in patients with uncomplicated distal ureteral stones. PATIENTS AND METHODS Prospective, randomized, open-label, controlled study. Patients > 18 years of age presenting to the outpatient urology clinic with uncomplicated radio-opaque stones located in the distal third of the ureter and of size ≤ 10 mm were included. Patients were randomly assigned to either a control group (n=26) and received standard of care management (daily oral hydration and diclofenac 75 mg IM on demand) or to the alfuzosin group (n=28) and received alfuzosin SR 5 mg twice daily in addition to standard of care management. Patients were followed weekly at office visits and twice weekly by telephone for 4 weeks or until stone expulsion. Assessments included stone passage rate and time, and patients were monitored for occurrence of adverse drug events, complications, number of pain episodes, analgesic consumption, and number of hospital revisits. Mann–Whitney, v2, and Fisher exact test were used for data analysis. RESULTS All 54 patients completed the study. Stone expulsion rate was higher in the alfuzosin arm (53.6%, 15/28) compared to the control arm (26.9%, 7/26, p=0.04). Median stone passage time was lower in the alfuzosin group than in the control group (9 vs 19 days, respectively, p=0.006). Ureteral sepsis, uncontrollable pain, and hospitalization readmissions were reported in the control group only. There were no differences between groups in number of pain episodes, pain scores, or analgesic consumption. Alfuzosin therapy was tolerable with only minor adverse effects (headache, dizziness, mild postural hypotension, and rhinitis). CONCLUSION Alfuzosin is safe and effective in increasing stone expulsion rates and shortening stone passage times for uncomplicated distal ureteral stones. KEY WORDS alfuzosin, distal uretral stones, expulsion time. (Pharmacotherapy 2015;35(5):470–476) doi: 10.1002/phar.1593
Urolithiasis is a common urological condition. The Afro-Asian stone-forming belt stretches from Sudan and Egypt to the Philippines. In this area of the world the prevalence of stones ranges *Address for correspondence: Lamia M. El Wakeel, 4 street 292, New Maadi, Cairo, Egypt; e-mail: [email protected]. Ó 2015 Pharmacotherapy Publications, Inc.
from 4% to 20%.1 In the United States, kidney stones affect approximately 1 in 11 people, with an estimated prevalence of 8.4%.2 The incidence and prevalence of kidney stones is increasing globally and these increases are seen across sex, race, and age groups.3 In the U.S., urolithiasis was the primary diagnosis for almost 2 million office visits, more than 600,000 emergency department visits, and more than 177,000
ALFUZOSIN IMPROVES DISTAL URETERAL STONE EXPULSION El Said et al hospitalizations, totaling more than $2 billion in annual expenditures in the year 2000.4 The majority of ureteral stones (70%) are found in the lower third of the ureter at the time of presentation to the emergency department because the ureterovesical junction is one of the three narrowest points in the ureter where the majority of stones are most likely to lodge.5, 6 An observational approach based only on the pharmacological control of pain has been traditionally considered to be effective because pain relief is the most urgent need in patients with an acute stone episode.7 Stone passage is dependent on a variety of factors including stone size and location.8 However, the watchful waiting approach can result in complications, such as urinary tract infection, hydronephrosis, and loss of kidney function. Therefore it is recommended that the observation period does not exceed 4 weeks.9 Medical expulsive therapy (MET) has emerged as an appealing option for the management of ureteral stones that can potentially avoid the need for surgical intervention. The European guidelines for urolithiasis recommend MET as an option for newly diagnosed ureteral stones < 10 mm in patients without the need for urgent urologic intervention who have well-controlled pain, are not septic, have good renal function, and are followed with periodic imaging to monitor stone position and assess hydronephrosis.10 Several pharmacological approaches designed to act on possible causes of stone retention have been proposed. These pharmacological agents include calcium channel blockers, steroids, and a1 adrenergic antagonists.11 Because a1 receptors are abundant in the ureteral smooth muscle, receptor blockade using a1 antagonists inhibits basal tone, peristaltic activity, and ureteral contractions, therefore providing the basis of medical expulsive therapy using these agents.12 Specific adrenoreceptor subtypes a1a and a1d are prevalent in the distal part of the ureter. The a1d receptor is the most prevalent subtype, whereas the a1a receptor is the primary subtype in the stromal portion of the prostate.13, 14 Therefore, the majority of clinical trials have studied the effect of tamsulosin, a selective a1a and a1d antagonist, with promising results regarding distal ureteral stone passage.15–17 Another a1 antagonist, alfuzosin has been shown to have a lower incidence of ejaculatory disorders compared with tamsulosin.18 Only a few studies have assessed the use of alfuzosin as MET, and the results regarding efficacy in stone
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expulsion are inconsistent.19–22 This mandates the conduction of sufficient studies to clearly evaluate the potential beneficial role of alfuzosin in the management of distal ureteral stones. The aim of the current study was to report our experience with the effect of alfuzosin treatment of uncomplicated distal ureteral stones in the outpatient setting, on clinical efficacy, pain control, and patient outcome. Patients and Methods This was a prospective, randomized, open– label, controlled study conducted at the urology outpatient department of Ain Shams University Hospital in Egypt. The local ethical committee approved the study protocol, and the study was performed in accordance with the Declaration of Helsinki. All patients provided written informed consent. The primary efficacy outcomes were stone expulsion rate and stone passage time. Secondary outcomes were the number of pain episodes, pain scores, analgesic consumption, hospitalization rate, number of complications, adverse drug effects, and the need for ureteroscopy. Patients older than 18 years presenting with radio-opaque stones ≤ 10 mm in size and located in the distal third of the ureter were included. Exclusion criteria included urinary tract infections, ureteral strictures, renal impairment, solitary functioning kidney, hepatic insufficiency, severe hydronephrosis, multiple stones, peptic ulcers, diabetes mellitus, hypotension, pregnancy, lactation, and sensitivity to a1 blockers. Patients were also excluded if they were receiving a1 blockers, nitrates, calcium channel blockers, steroids, beta blockers, sildenafil, ketoconazole, itraconazole, or ritonavir. All patients underwent a full medical history and physical examination. Laboratory evaluations included urine analysis, serum creatinine measurement, and liver function tests. Imaging studies were intravenous urography (IVU), plain radiograph of the kidney, ureter and bladder (KUB), and ultrasound (US). The stone size and position and side of obstruction were recorded for all patients at baseline. A total of 54 patients fulfilled the inclusion criteria and were randomly assigned to either the control group or the alfuzosin group based on a computer-generated random table. The control group (n=26) received standard of care treatment (oral hydration with ≥ 2 L of water daily and diclofenac 75 mg IM on demand). The
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alfuzosin group (n=28) received the same standard of care treatment in addition to alfuzosin sustained release (SR) 5 mg twice daily after meals. Treatment duration was 28 days or until stone expulsion. Patients in both groups were educated by the clinical pharmacist about potential adverse events, methods of reporting adverse events, self-reporting of pain on the visual analogue scale, importance of adherence to medications, and maintaining a minimum of 2 L daily water intake. Patients were assessed weekly in the outpatient clinic and followed up on the 2nd and 5th day of each week via phone calls during the treatment duration. During the weekly follow up visits, patients were assessed for development of complications or stone expulsion by means of US and plain KUB. Serum creatinine levels were measured, and urine analysis was performed. For patients with a stone-free ureter on final KUB but unnoticed stone expulsion, the date of the negative stone status was recorded as the time of stone passage. During telephone interviews, patients were followed for compliance with medications and fluid intake, adverse drug events, pain episodes, and any unscheduled hospital revisits. Pain levels were determined by visual analogue scale and by recording the dose of analgesics required (number of vials used). Patient-reported stone passage was recorded. Treatment failure was defined as no stone expulsion within 28 days or treatment discontinuation due to development of urinary tract infection, uncontrollable pain, severe hydronephrosis, or renal insufficiency. Patients who failed treatment were scheduled to receive ureteroscopic intervention. Statistical analysis was performed using the SPSS statistical program (v.20; SPSS, Chicago, IL). Data were expressed as median with range
for quantitative nonparametric measures, as mean and standard deviation (SD) for parametric data, and as numbers and percentage for categorical data. The Mann–Whitney test was used to compare nonnormally distributed variables between the two groups, while v2 test and Fisher exact test were used for analysis of nominal parameters. A p-value of 0.05 was considered significant and 0.001 highly significant. Results Of 85 patients screened, 54 fulfilled eligibility criteria and were randomly assigned to either the control or alfuzosin group. Baseline evaluation demonstrated no significant differences between groups for demographic features or clinical characteristics (Table 1). At the end of the study, the number of patients with stone expulsion was significantly higher in the alfuzosin group than in the control group (53.6% vs 26.9%, p=0.04). The median time for stone expulsion was significantly lower in the alfuzosin group versus the control group (9 days vs 19 days, p=0.006). There was no significant difference between-groups in the mean size of expelled stones for the alfuzosin (5.5 1.8 mm) and control groups (4.5 1 mm, p=0.383) (Table 2). There was no significant difference in stone expulsion rate between the alfuzosin and control groups for patients with stones < 5 mm (p=0.335). Moreover, the stone expulsion rate for larger stones (≥ 5 mm) in the alfuzosin group (42.1%) was more than double that in the control group (16.7%), yet this difference did not achieve statistical significance (p=0.091) (Table 3). For both control and alfuzosin groups combined, failure rates for stone expulsion were significantly higher in patients with stone sizes
Table 1. Demographics and Clinical Characteristics Parameters
Alfuzosin Group (n=28)
Control Group (n=26)
p Value
Age (years), mean SD (range) Sex; n (%) Male Female Stone size (mm), mean SD Size < 5 mm, n (%) Size ≥ 5 mm, n (%) Stone location, n (%) Left side Right side
32.8 9.5 (19–67)
32.1 9.2 (17–65)
0.828a
18 (64.3%) 10 (35.7%) 6.3 2.1 9 (32.1) 19 (67.9)
16 (61.5%) 10 (38.5%) 5.9 1.9 8 (30.8) 18 (69.2)
0.835b
8 (28.6%) 20 (71.4%)
9 (34.6%) 17 (65.4%)
Statistical tests: aMann–Whitney; bv2.
0.583a
0.633b
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Table 2. Incidence and Time of Stone Expulsion Parameters Stone expulsion, n (%) No Yes Stone expulsion time (days), median (min–max) Mean stone size in patients with stone expulsion(mm), n (mean SD)
Alfuzosin Group (n=28)
Control Group (n=26)
p Value
13 (46.4%) 15 (53.6%) 9 (5–18)
19 (73.1%) 7 (26.9%) 19 (8–25)
0.04a 0.006b
15 (5.5 1.8)
7 (4.5 1)
0.383b
Statistical tests: av2, bMann–Whitney.
Table 3. Comparing Stone Expulsion between Alfuzosin and Control in Patients with Different Stone Sizes Groups Stone size < 5 mm
Stone expulsion; n (%)
≥ 5 mm
Stone expulsion; n (%)
a
No Yes No Yes
Alfuzosin
Control
Total
p Value
2 (22.2%) 7 (77.8%) 11 (57.9%) 8 (42.1%)
4 (50.0%) 4 (50.0%) 15(83.3%) 3 (16.7%)
6 (35.3%) 11 (64.7%) 26 (70.3%) 11 (29.7%)
0.335a 0.091a
Fisher exact test.
Table 4. Relationship Between Stone Expulsion and Patient Characteristics Stone Expulsion Parameters Age (years), mean SD Sex; n (%) Female Male Stone location, n (%) Left Right Stone size (mm) Mean SD < 5 mm, n (%) ≥ 5 mm, n (%) Stone history (weeks), mean SD) Number of pain episodes, Median (range) VAS Pain score (cm), Median (range) No. of analgesic vials, Median (min–max) Analgesic dose (mg); Median (min–max)
No
Yes
p Value
32.5 8.4
32.3 10.6
0.679a
10 (31.3%) 22 (68.8%)
10 (45.5%) 12 (54.5%)
0.288b
9 (28.1%) 23 (71.9%) 6.8 2
8 (36.4%) 14 (63.6%) 5.2 1.6
0.522b
6 (18.8%) 26 (81.3%) (1.15 1.91) 1 (0–7) 5.5 (0–9) 1 (0–9) 75 (75–675)
11 (50%) 11 (50%) (0.13 0.33) 1 (0–5) 6 (0–9) 1(0–7) 75 (75–525)
0.004a 0.015b 0.006a 0.697 a 0.714a 0.693a 0.826a
Statistical tests: aMann–Whitney; bv2.
≥ 5 mm versus those with stone size < 5 mm (81.3% and 18.8% respectively, p=0.015). The mean stone size was significantly lower in patients who passed their stones versus patients who did not (5.2 1.6 mm vs 6.8 2 mm respectively, p=0.004). The time with symptoms prior to therapy initiation was significantly lower in patients who achieved stone expulsion (0.13 0.33 weeks) versus those patients who did not have stone expulsion (1.15 1.91 weeks, p=0.006) (Table 4). There was no significant difference between control and alfuzosin groups for number of
reported pain episodes, VAS pain scores, or number of analgesic vials consumed. Four patients in the alfuzosin group reported adverse drug events, all of which were tolerable and did not result in treatment discontinuation. The adverse events in the alfuzosin group were headache (n=2, 7.1%), dizziness (n=1, 3.6%), mild postural hypotension (n=3, 10.7%), and rhinitis (n=1, 3.6%); no patient reported retrograde ejaculation. None of the patients in the control group reported adverse events. The overall complication rate was 2 (7.7%) in the control group versus 0% in the alfuzosin
Alfuzosin Treatment Improves The Rate and Time for Stone Expulsion in Patients with Distal Uretral Stones: A Prospective Randomized Controlled Study Nouran O. El Said,1 Lamia El Wakeel,2,* Khaled M. Kamal,3 and Abd El Reheem Morad4 1
Department of Pharmacy Practice and Clinical Pharmacy, Faculty of Pharmacy, Future University, Cairo, Egypt; 2 Department of Clinical Pharmacy, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt; 3Department of Urology, Faculty of Medicine, Ain Shams University, Cairo, Egypt; 4Department of Clinical Pharmacy, Faculty of Pharmacy, Misr University for Science & Technology, Cairo, Egypt
OBJECTIVE To evaluate the safety and efficacy of alfuzosin treatment on rate and time of stone expulsion in patients with uncomplicated distal ureteral stones. PATIENTS AND METHODS Prospective, randomized, open-label, controlled study. Patients > 18 years of age presenting to the outpatient urology clinic with uncomplicated radio-opaque stones located in the distal third of the ureter and of size ≤ 10 mm were included. Patients were randomly assigned to either a control group (n=26) and received standard of care management (daily oral hydration and diclofenac 75 mg IM on demand) or to the alfuzosin group (n=28) and received alfuzosin SR 5 mg twice daily in addition to standard of care management. Patients were followed weekly at office visits and twice weekly by telephone for 4 weeks or until stone expulsion. Assessments included stone passage rate and time, and patients were monitored for occurrence of adverse drug events, complications, number of pain episodes, analgesic consumption, and number of hospital revisits. Mann–Whitney, v2, and Fisher exact test were used for data analysis. RESULTS All 54 patients completed the study. Stone expulsion rate was higher in the alfuzosin arm (53.6%, 15/28) compared to the control arm (26.9%, 7/26, p=0.04). Median stone passage time was lower in the alfuzosin group than in the control group (9 vs 19 days, respectively, p=0.006). Ureteral sepsis, uncontrollable pain, and hospitalization readmissions were reported in the control group only. There were no differences between groups in number of pain episodes, pain scores, or analgesic consumption. Alfuzosin therapy was tolerable with only minor adverse effects (headache, dizziness, mild postural hypotension, and rhinitis). CONCLUSION Alfuzosin is safe and effective in increasing stone expulsion rates and shortening stone passage times for uncomplicated distal ureteral stones. KEY WORDS alfuzosin, distal uretral stones, expulsion time. (Pharmacotherapy 2015;35(5):470–476) doi: 10.1002/phar.1593
Urolithiasis is a common urological condition. The Afro-Asian stone-forming belt stretches from Sudan and Egypt to the Philippines. In this area of the world the prevalence of stones ranges *Address for correspondence: Lamia M. El Wakeel, 4 street 292, New Maadi, Cairo, Egypt; e-mail: [email protected]. Ó 2015 Pharmacotherapy Publications, Inc.
from 4% to 20%.1 In the United States, kidney stones affect approximately 1 in 11 people, with an estimated prevalence of 8.4%.2 The incidence and prevalence of kidney stones is increasing globally and these increases are seen across sex, race, and age groups.3 In the U.S., urolithiasis was the primary diagnosis for almost 2 million office visits, more than 600,000 emergency department visits, and more than 177,000
ALFUZOSIN IMPROVES DISTAL URETERAL STONE EXPULSION El Said et al between stone history (time prior to starting therapy) and failure of stone expulsion, possibly explaining our results. We stratified patients according to stone size (ie, < 5 mm vs ≥ 5 mm). For patients with stone sizes < 5 mm, there were no significant differences in the rate of stone expulsion between alfuzosin and control. The loss of treatment effect as the size of the stones decreased can be attributed to the high spontaneous expulsion rate of small stones. This finding agrees with that reported by another group where there was no significant difference in stone expulsion between groups for stones < 5 mm. However, for stones > 5 mm, in the current study, the stone expulsion rate was increased by 25.4%, from 16.7% in the control group to 42.1% in the alfuzosin group, yet these results did not reach statistical significance. These findings are different from those observed by the other study which could be attributed to the small sample size of this stratified population.22 No significant differences were reported in pain episodes and analgesic consumption between the alfuzosin and control groups unlike a previous study.19 Similarly, other studies reported nonsignificant reduction in colic pain with alfuzosin use.21, 22 This could be explained by the fact that ureteral stone pain is attributable to edema, inflammation, infection, and spasms following obstruction. a1 blockers are not efficacious against all causes of colic, as they are believed to reduce ureteral colic through inhibition of peristalsis only rather than through reduction in inflammation or edema. A previous group reported a nonsignificant difference in the analgesic and morphine equivalent consumption between alfuzosin and placebo. However, there was a greater improvement in pain scores from baseline after treatment in the alfuzosin arm.20 In another study, the alfuzosin group significantly consumed fewer NSAIDs.21 In our study, patients received only diclofenac sodium 75 mg IM on demand, while in the other study patients received dologesic (paracetamol + dextropropoxyphene) on demand for 2 weeks and if pain control was suboptimal, diclofenac sodium SR 100 mg on demand for an additional 2 weeks. Hence, the difference in those findings is attributed only to NSAID consumption and not dologesic intake. The adverse effects experienced by patients receiving alfuzosin in our study (postural hypotension, dizziness, headache, rhinitis) were unre-
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markable and did not require treatment discontinuation. Similarly, all previously MET published studies using alfuzosin for treatment of ureteral stones, reported similar adverse events that were reversible, tolerable, and did not require therapy discontinuation.19, 21, 22, 26 An exception is a single study where 12% of patients treated with alfuzosin discontinued therapy because of side effects even though they were minor (dizziness and transient orthostatic hypotension) and reversible.20 Retrograde ejaculation occurs with a1-adrenergic antagonists because of relaxation of the bladder neck, allowing semen to flow into the bladder during ejaculation. As a result, patients complain of decreased ejaculate volume. In the current study, none of the patients in the alfuzosin group experienced retrograde ejaculation. Similarly, a previous study followed more than 7000 alfuzosin treated patients over 3 years, and none reported ejaculation disorders related to alfuzosin.28 On the other hand, only two patients in a single study reported retrograde ejaculation with alfuzosin use. However, none required therapy discontinuation implying that alfuzosin is associated with a low incidence of retrograde ejaculation.26 In contrast, tamsulosin is reported to result in higher frequency of retrograde ejaculation.19 In the current study, none of the patients in the alfuzosin group required hospitalization during the study period, while three (11.5%) patients in the control group were hospitalized. The overall complication rate was 0% in the alfuzosin group compared to 7.7% in the control group. We found that alfuzosin significantly reduced the need for intervention using endoscopic procedures for stone removal compared to standard therapy (42.9% vs 73.1% respectively), which can eventually lead to a reduction in complication rate and morbidity associated with ureteroscopy.29 Conclusion Administration of alfuzosin 5 mg twice daily improved stone passage rate and reduced stone expulsion time for distal ureteral stones ≤ 10 mm in size with no effect on pain intensity or analgesic consumption. Alfuzosin therapy was tolerable and reported adverse effects were minor, reversible, and did not require treatment discontinuation.
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Source of Support No pharmaceutical or industrial support. Disclosure of Funding No source of funding from National Institute of Health (NIH); Welcome Trust: Howard Hughes Medical Institute (HHMI) and others. Conflict of Interest None. References 1. Hussain M, Lal M, Ali B, et al. Management of urinary calculi associated with renal failure. J Pak Med Assoc 1995;45:205–8. 2. Scales CD Jr, Smith AC, Hanley JM, Saigal CS. Urologic diseases in America. Prevalence of kidney stones in the United States. Eur Urol 2012;62:160. 3. Romero V, Akpinar H, Assimos DG. Kidney stones: a global picture of prevalence, incidence, and associated risk factors. Rev Urol 2010;12:e86. 4. Litwin MS, Saigal CS, Yano EM, et al. Urologic diseases in America project: analytical methods and principal findings. J Urol 2005;173:933–7. 5. Pak CYC. Kidney stones. Lancet 1998;351:1797–801. 6. Tanagho EA, McAninch JW. Smith’s general urology. Columbus, Ohio: McGraw Hill, 2004. 727. 7. Phillips E, Kieley S, Johnson EB, Monga M. Emergency room management of ureteral calculi: current practices. J Endourol 2009;23:1021–4. 8. Miller OF, Kane CJ. Time to stone passage for observed ureteral calculi: a guide for patient education. J Urol 1999;162: 688–91. 9. Lingeman JE, Matlaga BR, Evan AP. Surgical management of upper urinary tract calculi. In: Wein AJ, Kavoussi LR, Novick AC, Partin AW, Peters CA, eds. Campbell-Walsh urology, 9th ed. Philadelphia: Saunders, 2007. 1448–1507. 10. Turk C, Knoll T, Petrik A, et al. Guidelines on urolithiasis. Eur Urol 2013;5:19–21. 11. Hollingsworth JM, Rogers MA, Kaufman SR, et al. Medical therapy to facilitate urinary stone passage: a meta-analysis. Lancet 2006;368:1171–9. 12. Sigala S, Dellabella M, Milanese G, et al. Evidence for the presence of a1 adrenoceptor subtypes in the human ureter. Neurourol Urodyn 2005;24:142–8. 13. Itoh Y, Kojima Y, Yasui T, Tozawa K, Sasaki S, Kohri K. Examination of alpha 1 adrenoceptor subtypes in the human ureter. IJU 2007;14:749–53. 14. Roehrborn CG, Schwinn DA. a 1-Adrenergic receptors and their inhibitors in lower urinary tract symptoms and benign prostatic hyperplasia. J Urol 2004;171:1029–35.
15. Al-Ansari A, Al-Naimi A, Alobaidy A, Assadiq K, Azmi MD, Shokeir AA. Efficacy of tamsulosin in the management of lower ureteral stones: a randomized double-blind placebo-controlled study of 100 patients. Urology 2010;75:4–7. 16. Arrabal-Martin M, Valle-Diaz de la Guardia F, Arrabal-Polo MA, Palao-Yago F, Mijan-Ortiz JL, Zuluaga-Gomez A. Treatment of ureteral lithiasis with tamsulosin: literature review and meta-analysis. Urol Int 2010;84:254–9. 17. Lojanapiwat B, Kochakarn W, Suparatchatpan N, Lertwuttichaikul K. Effectiveness of low-dose and standard-dose tamsulosin in the treatment of distal ureteric stones: a randomized controlled study. J Int Med Res 2008;36:529–36. 18. Hellstrom WJ, Sikka SC. Effects of acute treatment with tamsulosin versus alfuzosin on ejaculatory function in normal volunteers. J Urol 2006;176:1529. 19. Agrawal M, Gupta M, Gupta A, Agrawal A, Sarkari A, Lavania P. Prospective randomized trial comparing efficacy of alfuzosin and tamsulosin in management of lower ureteral stones. Urology 2009;73:706–9. 20. Pedro RN, Hinck B, Hendlin K, Feia K, Canales BK, Monga M. Alfuzosin stone expulsion therapy for distal ureteral calculi: a double-blind, placebo controlled study. J Urol 2008;179:2244–7. 21. Chau LH, Tai DCK, Fung BTC, Li JCM, Fan CW, Li MKW. Medical expulsive therapy using alfuzosin for patient presenting with ureteral stone less than 10 mm: a prospective randomized controlled trial. IJU 2011;18:510–4. 22. Ahmed A, Al-sayed A. Tamsulosin versus alfuzosin in the treatment of patients with distal ureteral stones: prospective, randomized, comparative study. Korean J Urol 2010;51:193–7. 23. Weiss RM. Physiology and pharmacology of the renal pelvis and ureter. In: Wein AJ, Kavoussi LR, Novick AC, Partin AW, Peters CA, eds. Campbell-Walsh, 9th ed. Philadelphia: Saunders, 2007. 377–403. 24. Morita T, Wada I, Saeki H, et al. Ureteral urine transport: changes in bolus volume, peristaltic frequency, intraluminal pressure and volume of flow resulting from autonomic drugs. J Urol 1987;137:132–5. 25. Cha WH, Choi JD, Kim KH, Seo YJ, Lee K. Comparison and efficacy of low-dose and standard-dose tamsulosin and alfuzosin in medical expulsive therapy for lower ureteral calculi: prospective, randomized, comparative study. Korean J Urol 2012;53:349–54. 26. Ibrahim AK, Mahmood IH, Mahmood NS. Efficacy and safety of tamsulosin versus alfuzosin as medical expulsive therapy for ureteric stones. Arab J Urol 2013;11:142–7. 27. Hermanns T, Sauermann P, Rufibach K, Frauenfelder T, Sulser T, Strebel RT. Is there a role for tamsulosin in the treatment of distal ureteral stones of 7 mm or less? Results of a randomised, double-blind, placebo-controlled trial. Eur Urol 2009;56:407–12. 28. Lukacs B, Grange JC, Comet D, McCarthy C. History of 7,093 patients with lower urinary tract symptoms related to benign prostatic hyperplasia treated with alfuzosin in general practice up to 3 years. Euro Urol 2000;37:183–90. 29. Hong YK, Park DS. Ureteroscopic lithotripsy using Swiss Lithoclast for treatment of ureteral calculi: 12-years experience. J Korean Med Sci 2009;24:690–4.
