Do Patients on Alpha-Blockers for the Treatment of Benign Prostatic Hyperplasia Have Better Results After Shockwave Lithotripsy of Urinary Stones?

Abstract

Purpose:

To investigate whether patients who are on alpha 1-adrenergic receptor (alpha 1-AR) antagonists for the treatment of benign prostatic hyperplasia (BPH) had better results after extracorporeal shockwave lithotripsy (SWL).

Patients and Method:

We retrospectively reviewed the records of male patients older than 50 years who underwent SWL. Clinical characteristics, including the use of alpha 1-AR antagonists for BPH were analyzed. Mann–Whitney U test was used for data not normally distributed and student's t test for data normally distributed. The categorical variables were analyzed by the Chi-square test. A multiple logistic regression analysis was used to analyze the associations of variables on successful treatment.

Results:

A total of 264 renal units were treated. Complete stone clearance was achieved in 167 RUs (63.3%) and 28 RUs (10.6%) had clinically insignificant residual fragments. In 69 RUs (26.1%), SWL failed. More patients were on alpha 1-AR antagonists for BPH in the successfully treated group (p=0.028). The multivariate analysis revealed that the use of alpha 1-AR antagonists had significant effects on the success of SWL (p=0.047). SWL was performed to 34 RUs of 33 patients who were on alpha 1-AR antagonists and it was successful in 30 RUs (88.2%). In the remaining 230 RUs, stone-free state was achieved in 165 RUs (71.7%) (p=0.028). Stone-free rates were similar for patients on alfuzosine, tamsulosine, and doxazosine (p=0.310).

Conclusion:

Patients who are being treated with alpha 1-AR antagonist agents for BPH have better results after SWL treatment, compared to patients not receiving alpha 1-AR antagonist. The improved results are independent of the type of alpha 1-AR antagonist.

Introduction

E xtracorporeal shockwave lithotripsy (SWL) is the first-line treatment option for most patients with kidney and ureteral stones due to its noninvasive nature and satisfactory results.¹ The success of SWL depends on fragmentation of the stones followed by clearance of fragments. Recently, pharmacological treatment with alpha 1-adrenergic receptor (alpha 1-AR) antagonists has been shown to facilitate passage of fragments, thereby increasing the success rate after SWL. The most commonly used agent was tamsulosin which is a specific alpha 1A- and alpha 1D-AR antagonist.

We aimed to investigate whether patients who are already on alpha 1-AR antagonist medication for the treatment of benign prostatic hyperplasia (BPH) had better results after SWL. We retrospectively compared the results of SWL of male patients older than 50 years of age and analyzed the factors that affect the outcome of SWL, including the use of AR antagonists for the treatment of BPH.

Patients and Methods

We retrospectively reviewed the records of all male patients older than 50 years of age who underwent SWL for the treatment of urinary stone diseases at our department, between January 2008 and December 2011. We excluded patients who had lower pole kidney stones. We identified 248 patients. 16 patients had bilateral stones so a total of 264 renal units (RUs) were treated. All patients were treated by a third generation lithotripter with an undertable electromagnetic shock head module (Siemens Lithostar Uro Modularis; Siemens, Erlangen, Germany). All treatments were carried out under fluoroscopic control as an outpatient procedure. Evaluation of the patients before SWL included medical history, physical examination, renal function tests, urinalysis, and urine culture. Patients were evaluated by intravenous urography (IVU) or by computed tomography (CT) and plain X-ray graph of the abdomen. The follow-up after SWL consisted of plain X-ray, usually 10–14 days after treatment for renal stones and 1 week for ureteral stones, and was carried on according to disintegration and clearance. Stone-free state was confirmed with IVU, or X-ray and CT in all patients. Residual fragments smaller than 4 mm were accepted as clinically insignificant residual fragments (CIRF) for renal stones. RUs with complete stone clearance (stone-free) or CIRF were accepted as successfully treated. All other RUs were considered as failed treatments.

Clinical characteristics were patient age, number and size of stones, the location of the stones inside the urinary tract, number of SWL sessions, number of delivered shock waves, mean shock wave energy levels, development of steinstrasse, presence of medical comorbidities, and use of alpha 1-AR antagonists for the treatment of BPH. Patients with diabetes, high blood pressure, chronic kidney disease, history of cerebrovascular accident, chronic respiratory disease, and coronary artery disease were defined as having medical comorbidities.

Statistical analysis was performed using the statistical package SPSS v 17.0. For each continuous variable, normality was checked by Kolmogorov Smirnov and Shapiro–Wilk tests and by histograms. Comparison between groups was made with Mann–Whitney U test for data not normally distributed and with student's t test for data normally distributed. The categorical variables between the groups were analyzed by the Chi-square test. A multiple logistic regression analysis was used to analyze the associations of variables on successful treatment. Values of p<0.05 were considered statistically.

Results

We identified 248 patients. 16 patients had bilateral stones so a total of 264 RUs were treated. Complete stone clearance was achieved in 167 RUs (63.3%) and 28 RUs (10.6%) had CIRF. Thus, 195 RUs were succesfully treated (73.9%). Time to stone clearance in the successfully treated RUs was between 7 to 120 days (43.6±38.4). In this group, stone density and skin-to-stone distance (SSD) values were available in 97 patients (49.7%) and measured as 430.5±112.3 Hounsfield Units (HU) and 95.7±20.4 mms, respectively. Residual fragments were present in 57 RUs (21.6%) and no fragmentation could be achieved in 12 RUs (4.5%). These 69 RUs (26.1%). made up the treatment failure group. In the failure group, stone density and SSD values were available in 31 patients (44.9%) and measured as 450.5±105.4 HU and 89.4±23.6 mms, respectively. The SSD and HU measurements were similar between the successfully treated and failure groups (p=0.097, and p=0.136, respectively). In this group, 12 RUs were treated with ureteroscopic stone removal, 4 with percutaneous nephrostolithotomy, and 2 RUs with ureterolithotomy. Fourty-three patients were followed without further treatment because they were asymptomatic and had no obstruction. Eight patients were lost to follow-up.

Double pigtail stents were placed in 80 RUs and percutaneous nephrostomy tubes placed in 4 RUs before SWL. Steinstrasse developed in 38 RUs (14.4%). Twelve of these were treated by ureteroscopic removal, 16 with SWL, 2 with percutaneous removal, and 8 with conservative methods.

Table 1 shows patients characteristics and the results of univariate analysis for the effect of clinical variables on treatment success. Number of shock waves delivered and the number of SWL treatment sessions were significantly higher in the failed group. More patients were on alpha 1-AR antagonists for the treatment of BPH in the successfully treated group.

Table 1.

Patient Characteristics and Results of Univariate Analysis for the Effect of Clinical Variables on Shockwave Lithotripsy Success

	Total	Success	Treatment failure	p
Number of patients	264	195 (73.9%)	69 (26.1%)
Age (years)	59.2±7.3	59.1±7.6	59.3±6.3	0.886^a
Stone lateralization
Right	132	96	36
Left	132	99	33
Stone localization
Kidney	196	143	53	0.331⁺
Ureter	62	46	16
Kidney and ureter	6	6	-
Number of stones	1.4±0.8	1.4±0.8	1.4±0.7	0.530^b
Stone size (mm)	13.2±4.7	13.0±4.6	13.8±5.2	0.080^b
Number of SWL sessions	1.8±0.9	1.6±0.8	2.2±1.0	0.001 ^b
Number of shockwaves	5652.0±3244	5134.6±2913	7115±3682	0.001 ^b
Mean energy level	3.1±0.4	3.1±0.4	3.2±0.4	0.098^a
Comorbid disease	108 (40.1%)	76 (38.9%)	32 (46.4%)	0.175⁺
Alpha 1-AR antagonists	34 (12.9%)	30 (15.4%)	4 (5.8%)	0.028⁺

Student's t.

Mann–Whitney U, ⁺Chi-square.

Bold data indicate significant values.

Data presented as mean±standard deviation or numbers with percentages in parentheses.

Alpha 1-AR=alpha 1-adrenergic receptor; SWL=shockwave lithotripsy.

The effect of age, stone size, and alpha-blockers on SWL success was analyzed with multivariate analysis. The multivariate analysis revealed that the use of alpha 1-AR antagonist agents for the treatment of BPH had significant effects on the success of SWL (Table 2).

Table 2.

Results of Multivariate Analysis for the Effect of Clinical Variables on the Success of Shockwave Lithotripsy

			95% Confidence interval
Clinical variables	p-Value	Odds ratio	Lower	Upper
Age	0.570	1.011	0.973	1.050
Stone size	0.392	1.001	0.999	1.003
Stone localization	0.992
Kidney	0.999	0.000	0.000	-
Ureter	0.999	0.000	0.000	-
Number of SWL sessions	0.329	0.546	0.162	1.842
Number of shockwaves	0.890	1.000	1.000	1.000
Alpha 1-AR antagonists	0.047	3.139	1.014	9.712

Bold data indicate significant values.

Thirty-three patients were on alpha 1-AR antagonists for the treatment of BPH. One of these patients, underwent SWL for both kidneys so 34 RUs were treated. SWL was successful in 30 RUs (88.2%). In the remaining 230 RUs of patients who were not on alpha 1-AR antagonists, stone-free state was achieved in 165 RUs (71.7%). This difference between the success rates of patients who were and were not on alpha 1-AR antagonists was statistically significant (p=0.028). Stone size, number of SWL sessions, number of shock waves, and stone localization were not statistically different between these two groups (Table 3). The mean age of patients on alpha 1-AR antagonists was significantly higher than those who were not (p=0.001). When the types of alpha 1-AR antagonists were analyzed 18, 8, and 8 RUs belonged to patients on alfuzosine, tamsulosine, and doxazosine treatment, respectively. Stone-free rates for these groups were 88.9%, 75%, and 75%, respectively. The differences were not statistically significant (p=0.310).

Table 3.

The Comparison of Clinical Characteristics of Patients Who Were and Were Not on Alpha 1-Adrenergic Receptor Antagonist Medication for the Treatment of Benign Prostatic Hyperplasia

	Alpha 1-AR antagonist (+)	Alpha 1-AR antagonist (−)	p
Number of RUs	34	230
Stone free status	30 (%88.2)	165 (%71.7)	0.028⁺
Age (years)	63.2±6.7	58.6±7.2	0.001 ^a
Stone size (mm)	12.6±5.3	13.3±4.7	0.189^b
Number of SWL sessions	1.5±0.7	1.8±0.9	0.123^b
Number of shock waves	4676±2588	5796±3310	0.095^b
Stone localization
Kidney	28 (82.4%)	168 (73.0%)	0.407⁺
Ureter	6 (17.6%)	56 (24.4%)
Kidney and ureter	-	6 (2.6%)

Student's t.

Mann–Whitney U, ⁺Chi-square.

Bold data indicate significant values.

Data presented as mean±standard deviation or numbers with percentages in parentheses.

Discussion

Alpha −1D ARs are known to be effective in the relaxation of the detrusor and the spasm of the distal thirds and the intramural part of the ureter.^2,3 Other studies have shown that alpha −1A, −1B, and −1D AR subtypes are localized in human ureter irrespective of location.⁴ Several studies have demonstrated the utility of pharmacological therapy with specific alpha 1A- and alpha 1D-AR antagonist tamsulosin in promoting spontaneous ureteral stone passage and in reducing the time for and pain associated with stone expulsion.^5
–7 This further led to the idea of adjunctive medical therapy with tamsulosin after SWL treatment of ureteral and kidney stones, to facilitate the clearance of fragments. Two groups reported conflicting results for tamsulosin as adjunctive treatment after SWL of ureteral stones.^8,9 Küpeli et al reported that addition of tamsulosin to conventional treatment of hydration and diclofenac sodium after SWL was beneficial in terms of stone clearance of lower ureteral stones.⁸ In patients with ureteral stones 6–15 mm, their stone-free rates were 33% for patients who received diclofenac sodium, and 70.8% for patients who received diclofenac sodium and tamsulosin. Although the stone-free rate of 33% is lower than expected, this was the first study to report the beneficial effect of tamsulosin for the clearance of fragments after SWL. On the other hand, Gravas et al reported results of patients with lower ureteral stones ≥6 mm who underwent SWL and received diclofenac only or diclofenac and tamsulosin after treatment.⁹ The stone-free rates were 51.6% for patients who did not receive tamsulosin and 63.3% for patients who did receive tamsulosin (p>0.05). They concluded that adjunctive medical therapy with tamsulosin does not improve the success rate.

Gravina et al administered tamsulosin as an adjunctive treatment after a single SWL session for the treatment of solitary radiopaque renal stones 4 to 20 mm in size.¹⁰ After treatment patients received standart medical therapy (oral methylprednisolone twice daily and intramuscular diclofenac injections on demand) either alone or with the addition of tamsulosin 0.4 mg once a day. The clinical success rate was 78.5% for patients receiving standard therapy and tamsulosin and 60% for patients receiving standard therapy alone. (p=0.037) Among patients with stone size 11 to 20 mm the difference in success rate was even greater (81% vs. 55%, p=0.009). Occurence of colicky pain and cumulative diclofenac dose were also more favorable for patients receiving tamsulosin in addition to standard treatment.

Zhu et al published a meta-analysis of seven randomized controlled trials in which AR antagonists were evaluated after SWL.¹¹ The AR antagonist used was tamsulosin in all trials. The pooled results included 240 patients treated with tamsulosin and 244 controls. The pooled absolute risk difference of the clearance rate was 16% (95% confidence interval [CI] 5, 27), indicating an increase in clearance rate in the tamsulosin group compared to controls. The absolute risk difference was 19% (95% CI 10, 29) for the subgroup analysis for patients on tamsulosin 0.4 mg daily. Schuler et al also published a systematic review and meta-analysis of four randomized trials evaluating medical expulsive therapy as an adjunct to improve SWL outcomes.¹² This analysis revealed that medical therapy results a 17% risk difference of post-SWL success in favor of adjunctive medical expulsive therapy. This favorable effect was more pronounced for stones larger than 10 mm with an absolute risk difference of 26%.

Naja et al evaluated the role of tamsulosin in the clearance of fragments after SWL treatment of renal stones.¹³ The study included 139 patients with a single radiopaque renal stone 5 to 20 mm. The patients were randomized into two groups to either receive or not receive 0.4 mg tamsulosin once daily after SWL. The success rate after 1, 2, and 3 SWL sessions was greater in patients receiving tamsulosin than patients not receiving tamsulosin (52.9%, 78.4%, and 94.1% vs. 30.8%, 52.3%, and 75.4%, p=0.016, p=0.004, and p=0.007, respectively). The total days required for success, total number of sessions required for success, and the pain experienced were also significantly less in patients receiving tamsulosin after SWL. They also reported that, although not statistically significant, fewer patients receiving adjunctive tamsulosin treatment developed steinstrasse and when they did, spontaneous clearance was more likely.

Georgiev et al reported in a similar study that adjunctive tamsulosin oral controlled absorption system in addition to standard medical care (corticosteroids and analgesics) after SWL improves stone clearance rate, interval to elimination, rehospitalization rate, and occurrence of renal colic.¹⁴ Vicentini et al randomized patients with kidney stones 5–20 mm in size to receive tamsulosin, nifedipine, or placebo after 1 session of SWL.¹⁵ They analyzed the results from 111 patients who completed 30 days of follow-up. The success rate was 60.5% in the tamsulosin group, 48.6% in the nifedipine group, and 36.8% in the placebo group and was not significantly different across the groups (p=0.118). On the other hand subgroup analysis revealed that stones 10–20 mm had significantly greater success rate in the tamsulosine (61.9%), and nifedipine (60%) groups, compared with the placebo group (26.1%), (p=0.024). Nifedipine was associated more adverse effects than placebo. The difference in the subgroup analysis seems to be caused by unusually low success rate achieved in the placebo group. Nonetheless, the results reported by both Gravina et al and Vicentini et al point that adjunctive tamsulosin treatment seems to be most beneficial after SWL treatment of stones 10 to 20 mm in size.

The prospective studies were performed on patients who were not already on treatment with alpha 1-AR antagonists. The purpose was to evaluate the role of adjunctive alpha 1-AR antagonists after SWL. In the present study, we investigated whether patients who are already on alpha 1-AR antagonist medication for the treatment of BPH had better results after SWL. Our results showed improved success rate after SWL in patients who were already being treated with alpha 1-AR antagonists for BPH. Alfuzosin appears to have higher success rates than tamsulosin and doxazosin. This was not statistically significant, probably due to the small numbers involved. Yılmaz et al have previously compared the efficacy of 3 different alpha blocking agents (tamsulosin, terazosin, and doxazosin) for increasing the rate of spontaneous passage of distal ureteral stones.¹⁶ They found that all three agents increased the frequency of spontaneous passage of stones in distal ureter and were equally efficacious. Thus, if a patient is being treated with an alpha-blocker for BPH, and is also scheduled for SWL for urinary stone disease, there does not seem to be any reason to switch the type of medication to achieve better results.

There are inherent limitations to this study. The main limitation is its retrospective nature. Selection bias cannot be ruled out. It is also possible that use of alpha 1-AR antagonists may not be totally accurate in patient files, this may have caused some patients who are actually on alpha 1-AR antagonists be mistakenly included in the control group. The effect of alpha 1-AR antagonists on multivariate analysis was barely significant. The small sample size in the group using alpha 1-AR antagonists may have caused insufficient statistical power to detect the advantage of these drugs on the success rate of SWL.

Conclusions

Patients older than 50 years of age who are being treated with alpha 1-AR antagonist agents for BPH have better results after SWL treatment of kidney or ureter stones, when compared to patients in the same age group but are not receiving alpha 1-AR antagonist treatment for BPH. These improved results are independent of the type of alpha 1-AR antagonist being used.

Footnotes

Disclosure Statement

No competing financial interests exist.

Abbreviations Used

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