Urodynamic outcomes of tamsulosin in the treatment of primary bladder neck obstruction in men.

INTRODUCTION: Alpha blockers are widely used in the treatment of primary bladder neck obstruction; however, evidence for objective urodynamic efficacy is scarce. We studied the effect of the uroselective α1-blocker tamsulosin on urodynamic parameters in male patients with type I primary bladder neck obstruction.
METHODS: A single center prospective observational study was carried out from July 2013 to February 2015. Male patients (18-50 years) with type 1 primary bladder neck obstruction were recruited. Selected patients were started on tablet tamsulosin 0.4 mg once daily for 3 months. International prostate symptom score (IPSS), uroflow and urodynamic studies were done pre- and post-treatment. Primary outcome was decreased in minimum detrusor pressure at maximum flow rate by 15%. Wilcoxon-matched pair signed-rank test was used.
RESULTS: Of 39 patients recruited, 21 patients completed the follow-up as per protocol and were analyzed. Mean age was 41 years. 57% patients achieved the primary outcome (median detrusor pressure pre- and post-treatment were 71 and 56 cm of water, P < 0.001). Similarly, median values for bladder outlet obstruction index (BOOI) and IPSS decreased from 59 to 38 (P < 0.001) and 22 to 12 (P < 0.001), respectively. Median maximum flow rate increased from 8 to 10 ml (P = 0.05). Pretreatment BOOI of >60 was associated with poor outcomes.
CONCLUSIONS: Tamsulosin 0.4 mg once a day is effective in reducing bladder outlet obstruction on pressure flow studies in patients with primary bladder neck obstruction type 1.

INTRODUCTION

Primary bladder neck obstruction (PBNO) is a rare but now well-recognized entity. The presence of high voiding pressure accompanied by poor flow and narrowing at bladder neck with concomitant silent external sphincter on electromyography (EMG) defines primary bladder neck obstruction.[1]

PBNO is further classified into three subgroups by Nitti et al. Type 1 includes the presence of classical high-pressure low flow (bladder outlet obstruction index [BOOI] >40).[2]

The treatment options available are observation with follow-up, alpha blockers, clean intermittent catheterization, or bladder neck incision. Most studies on the efficacy of pharmacological treatment have been small and nonrandomized. The results of these studies have been variable,[3456] and objective urodynamic evaluation of success has been lacking[278] as success of the treatment has been defined variably by different authors [Supplementary Table S1]. There are few studies which have reported pressure flow study outcomes after alpha blockers.[910] This study aims to objectively study the efficacy of alpha blockers in primary bladder neck obstruction and its impact on urodynamic parameters.

Defining successful outcomes in various studies

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METHODS

A single center prospective observational study was carried out from November 2013 to February 2015. Institutional Review Board approval was obtained. Men aged 18–50 years, who were diagnosed as having PBNO type 1 based on videourodynamic evaluation and consented to be part of the study, were included. Exclusion criteria included absolute indication for surgical intervention (e.g., obstructive uropathy), coexisting neurological disease, diabetes mellitus, bladder stones, urethral stricture, pelvic surgery, or allergy to α-adrenoceptor antagonists or sulfa drugs.

Evaluation protocol for young males with lower urinary tract symptoms at our center is as follows: patient undergoes detailed clinical history and examination including focal neurological examination. International prostate symptom score (IPSS) is documented. Urine routine and microscopy, serum creatinine, and urine cultures (where indicated) are done. All patients underwent uroflowmetry. A representative flow with a minimum voided volume of 150 ml is recorded. Kidney, ureter, bladder, and prostate are imaged with ultrasonography. Ascending urethrogram or cystoscopy is done to rule out urethral stricture. If all the above investigations are normal, patients are subjected to videourodynamics.

The selected patients were started on tablet tamsulosin 0.4 mg to be taken at bed time and followed up after 3 months, when uroflowmetry, IPSS, and pressure flow study were repeated.

Videourodynamics was conducted in accordance with International Continence Society (ICS) document on good urodynamics practices, unless specifically stated.[11] A 6 Fr infant feeding tube was used as vesical pressure measurement line; eight Fr infant feeding tube was used for bladder filling, which was removed before giving voiding command. Surface electrodes were used for EMG.

Decrease in minimum detrusor pressure at maximum flow rate (PdetQmax)[12] during voiding phase by 15% from baseline was the primary endpoint. This pressure was noted during the videourodynamic study being done for diagnosis of PBNO and compared with repeat urodynamic study after 3 months.

Secondary endpoints recorded in the study were (1) BOOI reduction to <40; BOOI was calculated as follows: PdetQmax − 2Qmax (men were considered obstructed if BOOI was > 40; unobstructed if BOOI was <20, and equivocal if BOOI was 20–40). (2) Percentage reduction in BOOI posttreatment of ≥ 15%. (3) Improvement in maximum flow rate (Qmax) by 2.5 ml/s. (4) IPSS score reduction by 25%. (5) Decrease in the postvoid residue - the amount of urine remaining in the bladder immediately after the completion of micturition.

Two post hoc analyses were performed to see if patients who had subjective improvement also showed objective (based on pressure flow study parameters) improvement. This analysis is important especially as there was no placebo used in this study and subjective improvement may be due to placebo effect. Second, to see if any urodynamic parameter could predict those who failed medical managevment (based on objective criteria as defined in the primary endpoint of the study) as there were studies in literature which showed varied results to this question.

Based on available studies in literature,[4710] mean PdetQmax before and after intervention were assumed at 71 cm and 60 cm of water, respectively. Keeping alpha and beta errors at 5% and 20%, respectively, sample size calculated using two-sided test was 28 patients.

Statistical Package for Social Sciences Version 16 (SPSS Inc. Chicago) was used for statistical analysis. Measures of central tendency were reported as median (as data had skewed distribution) with interquartile range (IQR). To show that there is a statistical significant difference between the pre-and post-test values, Wilcoxon-matched pair signed-rank test was used. Fisher's exact test was used to check association of preoperative urodynamic parameters with successful outcomes. P ≤ 0.05 was taken as statistically significant.

RESULTS

During the period of the study, a total of 96 patients were diagnosed as PBNO. Details of patients excluded are given in Figure 1. Only the outcome data of 21 patients who completed follow-up urodynamics study were analyzed.

Figure 1

Study flow and details of patients excluded, PBNO: Primary bladder neck obstruction type 1 (original)

The mean age of study group was 41 years; the age distribution of the study population is shown in Figure 2. Average duration of symptoms was 50 months before they came for evaluation to our hospital. The pre- and post-treatment outcomes are detailed in Table 1.

Figure 2

Distribution of study population in various age groups (original)

Table 1

Outcome parameters, pre- and post-treatment

Twelve (57.2%) patients had fall in detrusor pressure by more than 15%. Nine patients (42.8%) who failed to achieve the primary outcome had a pretreatment PdetQmax of more than 60 cm of water.

Median percentage reduction in BOOI posttreatment was 23.2% with IQR of 0.8%–69.8%. Eleven patients (52.3%) had posttreatment BOOI of <40. Eighteen patients (85%) showed some improvement in BOOI after the treatment; however, only three patients (14%) became unobstructed, i.e., BOOI <20 [Figure 3].

Figure 3

Bladder outlet obstruction index before and after treatment. Y axis shows BOOI: Bladder outlet obstruction index and X axis shows the individual patients. Blue bars represent pretreatment BOOI and purple bars represent posttreatment BOOI (original)

On subgroup analysis, of twelve patients who had initial BOOI in the range of 40–60 (mild obstruction), three patients achieved BOOI of <20, eight patients had BOOI in equivocal range 20–40, and one patient remained obstructed with final BOOI of >40 after treatment. All nine patients who had pretreatment BOOI above 60 remained obstructed (BOOI >40) after the treatment. A pretreatment BOOI of >60 was also significantly associated with <15% reduction in BOOI posttreatment (P = 0.01).

Nine patients (42.85%) achieved an improvement in Qmax of ≥2.5 ml/s. Seventeen patients (80%) showed IPSS reduction of >25%. All four patients who did not achieve at least 25% of reduction in IPSS had pretreatment BOOI of more than 60. Improvement was seen in both storage and voiding subset of IPSS score. Twelve patients (57%) had improvement in global quality of life, and change in pre- and post-treatment score was statistically significant [Table 1].

Tablet tamsulosin was well tolerated. Ten patients (47.6%) complained of abnormal ejaculation. Three patients had some giddiness during the initial few days of treatment which subsided with time. One patient who could not tolerate the drug because of severe giddiness discontinued the treatment and was excluded from final analysis.

Out of 21 patients who had completed the follow-up protocol, five patients had bladder neck incision and the rest continued with medical treatment after completion of 3-month follow-up. Patients who showed subjective improvement but failed to show objective improvement were kept under close follow-up.

DISCUSSION

All the patients in our study were diagnosed as primary bladder neck obstruction based on videourodynamic study. Following diagnosis, all of them were started on tamsulosin, as this was the most commonly used alpha blocker at the time of study in our hospital. Other studies on the subject, both retrospective[3410] and prospective,[57] are compared with the present study. The number of patients enrolled varied from 9 to 41. The mean age ranged from 32 to 43 years. The drugs used were phenoxybenzamine, prazosin, terazosin, doxazosin, alfuzosin, and tamsulosin. The mean age of study population in the present study was 41 years, and tamsulosin was used in this study [Supplementary Table S2].

Comparing drugs used, number of individuals enrolled, and mean age at presentation among various studies and the present study

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Similar to our study, other studies in literature[47] have shown comparable subjective improvement. The improvement in mean AUA-6/IPSS score varies from 6.9 to 9.2 points in these studies [Supplementary Table S3].

Comparing symptoms score improvement among various studies

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Variable improvement in the mean Qmax ranging from 4 ml/s to 11 ml/s following treatment with alpha blockers has been shown previously.[347] Improvement in mean Qmax in the present study was 2.3 ml/s [Supplementary Table S4]. It would not be possible to compare these studies, as there are many confounding variables such as type of alpha blockers used. However, it would be safe to assume that most alpha blockers cause clinically and statistically significant improvement in flow rates in this group of patients.

Comparing the pre- and post-treatment maximum flow rates and postvoid residue among various studies

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As most of these studies are not placebo control trials, subjective improvement may be confounded by placebo effect. Documentation of the simultaneous objective urodynamic effect would be desirable. An elegant study by Yamanishi et al. had provided the proof of concept that alpha blockers relax the bladder neck and decrease the energy loss due to obstruction in patients with bladder neck obstruction as compared to normal controls.[9] Our study also showed clinically and statistically significant improvement in urodynamic pressure flow parameters indicating reduction in outlet obstruction.

In our study, on post hoc analysis, we found patients who had <25% improvement in IPSS score (four patients) had both pre- and post-treatment BOOI of >60 cm of water. The association of pretreatment BOOI >60 and lack of subjective improvement was statistically significant (P = 0.02). On the other hand, there were five other patients who had pre- and post-treatment BOOI of >60 and had improvement in IPSS of more than 25%. These five patients who had only subjective improvement (without accompanied objective urodynamically demonstrable improvement) suggest a placebo effect of these medications. This is an important reminder of the fact that even if the patient feels subjectively better, his underlying pathophysiology may be unaltered and may result in obstructive nephropathy in the long term. Other studies have not made an attempt to associate the individual subjective and objective improvements in the outcomes.

Cisternino et al. and Yang et al. had attempted to see if there were any urodynamic predictors of success.[710] Cisternino et al. did not find any clinical or urodynamic baseline parameters which would predict the outcome of alpha blockers in their study group. On the other hand, Yang et al. found that higher baseline grade of obstruction (Schafer grade [3–4 vs. 0–2]) predicted better response to alpha blocker. BOOI of 40 on the ICS nomogram corresponds to the line dividing grade 2 and grade 3 obstructions on Schafer nomogram. In our study, we did not include patients with initial BOOI of <40 cm of water (grade 1 or 2 obstruction on Schafer nomogram) on initial pressure flow study (type 2 and 3 PBNO patients were excluded as there was difficulty in documenting the improvement objectively based on urodynamic parameters as we do not measure the cross-sectional area of bladder neck on imaging, and existing literature suggests that these patients have poor outcomes with alpha blocker[7] further bringing into question the true underlying pathophysiology).

On excluding grade 1 and 2 obstruction (Schafer) from Yang et al.'s data, decrease in improvement response with increasing grade of obstruction (grade 3 showed 83% improvement rate vs. 75% in grade 4) was seen. A similar trend was noted in our study. Patients with initial BOOI of >60 cm of water showed poor response. These patients should be counseled appropriately and kept on close follow-up if they are under medical therapy.

We found a good number of young patients had abnormal ejaculation on taking tamsulosin 400 μg daily. The side effects of alpha blockers in young adults with PBNO are not well documented by other studies in literature [Supplementary Table S5]. In our study, about half of the study population reported these minor side effects; we should forewarn our patients about abnormal ejaculation before starting them on this drug.

Comparing the adverse effect of the drug with other studies

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Our study has the following limitations. Primary endpoint as reduction in BOOI would unquestionably be a better choice as it more appropriately reflects reduction in outlet resistance. However, we could not find relevant data from the existing literature to calculate number needed for the study based on BOOI reduction. The only retrospective study which had done posttreatment urodynamic study[10] had not given data for the whole study group and only presented data in the form of median improvement in Schafer grade of obstruction in those with successful and unsuccessful outcomes.

Poor follow-up compliance of patients was another drawback as out of 39 recruited, only 21 completed the follow-up protocol. Most of our patients were from far off places and had to travel long distances for review. However, it is unlikely that continuing the study further would have changed outcomes as results of the study are statistically significant even at this point.

The database generated by this study (pre- and post-treatment) BOOI can be used to further study the subgroup which is likely to benefit from alpha blockers.

CONCLUSIONS

In our study, we found that tamsulosin 400 μg once a day is effective in reducing the bladder outlet obstruction on pressure flow studies in patients with primary bladder neck obstruction type 1. Subjective and objective improvements may not match especially in those with higher grade of obstruction (placebo effect). Patients with initial BOOI of >60 cm of water are less likely to respond to alpha blockers. Significant number of younger patients experience abnormal ejaculation on tamsulosin.