NIFEDIPINE VERSUS TAMSULOSIN FOR THE MANAGEMENT OFLOWER URETERAL STONES

FRANCESCO PORPIGLIA,* GIANPAOLO GHIGNONE, CRISTIAN FIORI, DARIO FONTANAAND ROBERTO MARIO SCARPA

From the Division of Urology, Department of Clinical and Biological Sciences, University of Turin, “San Luigi” Hospital and Division ofUrology, University of Turin, “San Giovanni Battista” Hospital (DF), Orbassano (Turin), Italy

ABSTRACT

Purpose: We evaluate and compare the effectiveness of 2 different medical therapies duringwatchful waiting in patients with lower ureteral stones.

Materials and Methods: A total of 86 patients with stones less than 1 cm located in the lowerureter (juxtavesical or intramural tract) were enrolled in the study and were randomly dividedinto 3 groups. Group 1 (30) and 2 (28) patients received daily oral treatment of 30 mg deflazacort,(maximum 10 days). In addition group 1 patients received 30 mg nifedipine slow-release (max-imum 28 days) and group 2 received 1 daily oral therapy of 0.4 mg tamsulosin (maximum 28days), Group 3 patients (28) were used as controls. Statistical analyses were performed usingStudent’s test, ANOVA test, chi-square test and Fisher’s exact test.

Results: The average stone size for groups 1 to 3 was 4.7, 5.42 and 5.35 mm, respectively, whichwas not statistically significant. Expulsion was observed in 24 of 30 patients in group 1 (80%), 24of 28 in group 2 (85%) and 12 of 28 in group 3 (43%). The difference in groups 1 and 2 with respectto group 3 was significant. Average expulsion time for groups 1 to 3 was 9.3, 7.7 and 12 days,respectively. A statistically significant difference was noted between groups 2 and 3. Meansodium diclofenac dosage per patient in groups 1 to 3 was 19.5, 26, and 105 mg, respectively. Astatistical significant difference was observed between groups 1 and 2 with respect to group 3.

Conclusions: Medical treatments with nifedipine and tamsulosin proved to be safe and effectiveas demonstrated by the increased stone expulsion rate and reduced need for analgesic therapy.Moreover medical therapy, particularly in regard to tamsulosin, reduced expulsion time.

KEY WORDS: ureter, urinary calculi, nifedipine, corticosteroids

Urinary stone disease is a common condition affecting upto 12% of the population and accounting for 122 of 100,000outpatient visits in the United States. Furthermore its inci-dence is growing in western countries.1–3 Ureteral stonesoccupy an important place in daily urological practice, andclinicians are frequently asked to choose adequate treat-ment.4 The efficacy of mini-invasive therapies, such as extra-corporeal shock wave lithotripsy (ESWL, Dornier MedicalSystems, Marrieta, Georgia) and ureteroscopy, has beenproven by several studies.5, 6 Nevertheless these techniquesare not risk-free, are problematic and are quite expensive.7

On the other hand, a watchful waiting approach can beused in a large number of cases, as demonstrated by severalstudies that revealed spontaneous passage rates of up to 98%for small distal ureteral stones.8–10 Moreover, even the sim-ple watchful waiting approach can result in complications,such as infection of the urinary tract, hydronephrosis andrenal function effects.9 Therefore, it is difficult to choosebetween mini-invasive therapies and a watchful-waiting ap-proach, especially when patients report few symptoms and/orstones are small.

Recently, use of the watchful waiting approach has beenextended by using pharmacological therapy, which can re-duce symptoms and facilitate stone expulsion.11–14 We previ-ously reported our results using a combination of corticoste-roid and calcium antagonist.12 Some authors reportedimproved spontaneous stone passage rate using an � blocker

agent (tamsulosin)13, 14 on the basis of the evidence that �-1receptors have an important role in expulsion of lower ure-teral physiology.15, 16 Therefore, we decided to perform a com-parative study to evaluate the safety and effectiveness ofthese therapies for the treatment of lower ureteral stones.

MATERIAL AND METHODS

The population of our study was composed of patients withstones in the lower tract of the ureter (juxtavesical tract andureterovesical junction) 1 cm or less in size. Subjects withurinary tract infection, ureterohydronephrosis, diabetes, ul-cer disease, history of hypersensitivity to nifedipine or corti-costeroid, or history of spontaneous stone expulsion and hy-potension or diagnosed during examination, and pregnantwomen were excluded from study. All patients were referredto our department by the emergency department staff, andwere examined in the outpatient Division of Urology betweenSeptember 2002 and September 2003. Stone presence andcharacteristics were diagnosed with abdominal ultrasonog-raphy. An x-ray of the kidneys, ureters and bladder andexcretory urography were used when necessary.

A total of 86 patients were randomly divided into group 1(30 patients), group 2 (28) and group 3 (28). The number ofincluded patients was estimated using statistical programsplus 1.0 and plus 2.10 for randomization. Patients in groups1 and 2 received 30 mg deflazacort daily for a maximum of 10days. In addition, patients in group 1 received 30 mg nifedi-pine (slow-release) daily for a maximum of 28 days, whilepatients in group 2 received 0.4 mg tamsulosin for a maxi-mum of 28 days. Each patient in groups 1 and 2 also received200 �g mysoprostol twice daily. Patients in group 3 were

Accepted for publication March 12, 2004.* Correspondence: Division of Urology, Department of Clinical and

Biological Sciences, University of Turin, “San Luigi” Hospital, Re-gione Gonzole 10, 10043 Orbassano (Turin), Italy (telephone:390119026558; FAX: 390119038654; e-mail: porpiglia@libero.it).

0022-5347/04/1722-0568/0 Vol. 172, 568–571, August 2004THE JOURNAL OF UROLOGY® Printed in U.S.A.Copyright © 2004 by AMERICAN UROLOGICAL ASSOCIATION DOI: 10.1097/01.ju.0000132390.61756.ff

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used as controls and did not receive any expulsive medicaltherapy (only symptomatic therapy).

All patients were allowed to use symptomatic therapy withinjections of 75 mg diclofenac (on demand) and were requiredto drink a minimum of 2 l of water daily. The followup waslimited to 4 weeks. Patients who failed to expel the stonewithin 4 weeks underwent ESWL or ureteroscopy. To high-light possible stone expulsion, all patients were required tofilter the urine. All patients were examined weekly usingx-ray of the kidneys, ureters and bladder and ultrasonogra-phy. Side effects of the expulsive therapy were also recordedduring followup visits if present. Statistical analyses wereperformed with Student’s t test, ANOVA, chi-square andFisher’s exact test using the parameters of stone size, expul-sion rate, time to expulsion, amount of analgesic consumedand side effects.

RESULTS

Of the 86 enrolled patients 84 completed the study. Onepatient in group 1 (3.3%), and one patient in group 2 (3.5%)had to cease medical therapy due to side effects and, there-fore, dropped out of this study. All patients in group 3 com-pleted the study. Group 1 consisted of 19 men and 11 women(average age 45.6 � 12 years), group 2 consisted of 18 menand 10 women (50.5 � 17 years) and group 3 consisted of 16men and 12 women (42.7 � 16 years). No significant statis-tical difference was observed in patient age and gender dis-tribution (p � 0.3).

Average stone size was 4.7 mm � 1.47 mm (range 3.5 to 10)for group 1, 5.42 mm � 1.54 mm (3 to 10) for group 2 and 5.35mm � 1.49 for group 3. ANOVA test and Student’s t test didnot reveal any significant statistical difference among thegroups (p � 0.2).

Stone expulsion was observed in 24 patients in group 1(80%), 24 in group 2 (85%) and 12 in group 3 (43%). Asignificant statistical difference was noted between groups 1and 3 (p �0.01), and groups 2 and 3 (p �0.001), whereas nodifference was recorded between groups 1 and 2 (p � 0.5, seefigure). Average time to expulsion was 9.3 days (range 3 to20) in group 1, 7.9 days (1 to 15) in group 2 and 12 days (3 to20) in group 3. A significant statistical difference was ob-served in times to expulsion between groups 2 and 3(p � 0.02), whereas no significant statistical difference was

noted between groups 1 and 2 (p � 0.2) or between groups 1and 3 (p � 0.09). The difference between the mean size ofexpelled and retained stones was statistically significant onlyin group 3 (p � 0.03). No significant differences were ob-served in expulsion rates between males and females andbetween right and left sides.

Mean sodium diclofenac dosage was 19.5 mg (range 0 to150) per patient in group 1, 26 mg (0 to 150) in group 2 and105 mg (0 to 450) in group 3. No significant statistical differ-ence was observed between groups 1 and 2 (p �0.05) while itwas noted between groups 1 and 3 and groups 2 and 3(p �0.0001 and p �0.0001, respectively). No patient washospitalized for recurrent colic, no urosepsis was recordedand no narcotics drugs were administered.

Only 1 group 1 patient experienced serious side effectsassociated with the medical expulsive therapy (transient hy-potension, systolic blood pressure less than 100 mm Hg, andpalpitations), whereas 1 group 2 patient reported severe as-thenia (p � 0.9). Both patients suspended medical therapyand the side effects disappeared. Another 3 patients in group1 (10%) and 3 in group 2 (10%) (p � 0.9) reported minor sideeffects but did not need to interrupt therapy. Patients (6 ingroup 1, 4 in group 2 and 16 in group 3) who were notstone-free after the 4 weeks of followup were successfullytreated with ureteroscopy (20) or ESWL (6).

DISCUSSION

The literature provides a variety of results regarding spon-taneous ureteral stone passage. Ueno et al evaluated morethan 500 patients and reported a spontaneous stone expul-sion rate of 57% for 5 mm stone calculi.9 However, Morse andResnick reported that a 6 mm stone in the distal ureter wasspontaneously expelled in 35% of cases at the expense ofrecurrent ureteral colic.17 Kinder et al focused on lower ure-teral calculi and calculated a 94% frequency of passage ofstones less than or equal to 5 mm and 45% for calculi greaterthan 5 mm.18 Therefore, it is difficult to choose betweenESWL or ureteroscopy and observation, although the latterapproach can be improved by the addition of pharmacologicaltherapy which can help stone expulsion and reduce renalcolic.

Various medications have been used to assist the passageof ureteral stones. Bajor showed that a � blocker reduced the

Percentages of patients with ureteral stones as function of days of observation

MEDICAL THERAPY FOR LOWER URETERAL STONES 569

time for stone passage from 11 to 5.2 days in 86 patients withlower ureteral stones without encountering any serious sideeffects.19 Borghi et al demonstrated the beneficial effect ofcalcium antagonist (nifedipine) in reducing time to stonepassage and improving expulsion rates.11 We previously re-ported our experience with nifedipine and a corticosteroidagent (deflazacort).12 This expulsive therapy was safe andeffective as demonstrated by the increased expulsion rate,decreased expulsion time and reduced need for analgesictherapy with respect to our control group. The rationale ofour medical therapy is to use deflazacort to reduce the edemaand administer nifedipine to inhibit the stone-induced ure-teral spasm maintaining the peristaltic rhythm.

On the basis of the evidence that �-1 receptors have animportant role in expulsion of lower ureteral physiology,some authors have more recently proposed the use of � block-ers with the aim of facilitating lower ureteral stone expul-sion.13–16 In particular Ukhal et al reported positive resultsin accelerating lower tract ureter stone passage (juxtavesicaltract and ureterovesical junction) using �-1 blockers.14 Cer-venakov et al in a randomized study registered a significantstatistical difference in stone expulsion rate between thegroup treated with tamsulosin and the control group.13 Sim-ilar results have been reported in a recent study.20

To our knowledge, no comparative studies exist that inves-tigate different expulsive medical therapies, which led us toour current comparative study of the safety and effectivenessof nifedipine and deflazacort versus tamsulosin and deflaza-cort for the treatment of lower ureteral stones. We usednifedipine based on our historical positive results and tam-sulosin was used based on the literature and �-1 receptorsselectivity.11–14 Our study was limited to patients affected bylower ureteral stones (juxtavesical tract and ureterovesicaljunction) with size equal to or less than 10 mm. The successof these particular medical therapies for this kind of stonewas encouraging, and we were further motivated by thepositive results with tamsulosin due to the higher density of�-1 receptor in the lower part of the ureter.15, 16 We decidedon a maximum observation period of 4 weeks because longerperiods can increase complication rates by up to 20%.8

The medical therapy based on a combination of nifedipineand deflazacort (group 1) demonstrated positive results in80% of patients, whereas the combination of tamsulosin anddeflazacort (group 2) demonstrated positive results in 85% ofpatients. These figures do not demonstrate any significantdifference. However, differences were evident in stone expul-sion between groups 1 and 3 (80% versus 43%) and betweengroups 2 and 3 (85% versus 43%). These results confirmedthat medical therapy with either nifedipine or tamsulosincan improve stone expulsion.

As far as expulsion time was concerned, we observed spon-taneous stone passage after 9 days in group 1, 7.9 days ingroup 2 and 12 days in group 3. A significant statisticaldifference was noted between groups 2 and 3. The resultsdemonstrate that use of tamsulosin reduced expulsion timessignificantly in respect to the control group (3) and confirmthe positive results obtained in reducing stone passage timesby others.13, 14, 20 Adding also the fact that stone size and thepercentage of expulsion rate were greater in group 2, even ifnot significantly in comparison to group 1, we hypothesizethat tamsulosin is more effective for the treatment of thistype of ureteral stone than nefedipine. Further evaluationusing larger groups will provide an opportunity to confirmthese findings.

Moreover, the combination of nifedipine and deflazacort,and tamsulosin and deflazacort was effective in pain reduc-tion and decreased the amount of analgesic administered asdemonstrated by information gathered from groups 1 and 2with respect to quantities administered to patients in group3. We did not observe any statistical difference between theaverage size of expelled and not expelled stones in the treated

patients. In addition, no relationship between stone size andtime to expulsion was evident. Gender and stone side ap-peared not to influence the stone expulsion rate. As previ-ously reported, these data suggest that not only stone sizeinfluences expulsion times, but also other factors, such asstone shape and edema around the stone.12

We encountered 2 cases of serious side effects of medicalexpulsive therapy (hypotension accompanied by heart palpi-tations, and severe asthenia), which required its suspension.Minor therapy related side effects were observed in 6 pa-tients (in 3 group 1, 3 in group 2) but they were able tocomplete the study. No clinical side effect was observed re-lated to use of corticosteroid drug. With regard to safety, bothcombinations were well tolerated by the patients. Patientswho were not stone-free after the 4-week followup were suc-cessfully treated with ureteroscopy or ESWL. These datademonstrate that neither watchful waiting nor medical ther-apy seems to negatively affect the success rate of stone re-moval.

CONCLUSIONS

The results of this study indicate that lower tract ureteralstones can be treated with an expulsive medical therapy inpatients when a watchful waiting approach is possible. In ourstudy medical treatments with nifedipine and tamsulosincombined with deflazacort proved to be safe and effective asdemonstrated by the low incidence of side effects and theincreased stone expulsion rate. Moreover, medical therapy,particularly in regard to tamsulosin, seems to reduce expul-sion times.

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