|Year : 2018 | Volume
| Issue : 2 | Page : 86-90
Do 5α-reductase inhibitors prevent secondary benign prostate hyperplasia-related urinary retention?
Chi-Fong Lu1, Chun-You Chen2, Liang-Ming Lee3, Ke-Hsun Lin3, Yung-Wei Lin3, Chi-Hao Hsiao3, Yu-Ching Wen3
1 Department of Urology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
2 Department of Radiation Oncology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
3 Department of Urology, Wan Fang Hospital; Department of Urology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
|Date of Web Publication||30-Apr-2018|
Department of Urology, Wan Fang Hospital, Taipei Medical University, No. 111, Sec. 3, Xinglong Rd., Taipei 11696
Source of Support: None, Conflict of Interest: None
Objective: The objective of this study is to determine whether 5α-reductase inhibitors (5ARIs) prevent secondary benign prostate hyperplasia (BPH)-related acute urinary retention (AUR) after the first episode of urine retention. Materials and Methods: In total, 1161 patients were enrolled using the International Classification of Diseases, Ninth Revision (ICD-9) codes as having AUR (ICD-9 code 788.20) and BPH, with or without lower urinary tract symptoms (ICD-9 codes 600.0 and 600.1) between January 2006 and June 2016. After excluding patients with bladder and external sphincter dysfunction, we enrolled 128 patients in this study. Patients were divided into two groups: Group 1 comprising 33 patients receiving 5ARI (dutasteride) and α-blocker treatment, and Group 2 comprising 95 patients receiving α-blocker treatment alone. Patient characteristics, namely, age, prostate size, maximal urinary flow rate (Qmax), prostate-specific antigen (PSA) level, and duration of dutasteride treatment, were recorded and compared. Patients were followed for at least 6 months to a maximum period of 24 months if no event occurred. Events of secondary BPH-related AUR and surgery were recorded. Results: All patient characteristics, except for prostate size, were similar between the two groups (Group 1 vs. Group 2: 65.0 vs. 36.9 mL, P = 0.001). In total, 43 patients (32%) experienced secondary AUR within 24 months. The rate of secondary BPH-related AUR was significantly lower in the Group 1 than in the Group 2 (18.2% vs. 39.4%, P = 0.030). The rate of BPH-related surgery was lower in the Group 1 (9.1% vs. 14.9%, P = 0.410), although the difference was not significant. Prostate size and PSA levels were significantly lower in the Group 1 (23.5%) than in the Group 2 (60.4%) (P < 0.001). Conclusions: Using 5ARIs to treat patients with first episodes of BPH-related AUR significantly prevents secondary AUR.
Keywords: Benign prostate hyperplasia, dutasteride, secondary acute urine retention
|How to cite this article:|
Lu CF, Chen CY, Lee LM, Lin KH, Lin YW, Hsiao CH, Wen YC. Do 5α-reductase inhibitors prevent secondary benign prostate hyperplasia-related urinary retention?. Urol Sci 2018;29:86-90
|How to cite this URL:|
Lu CF, Chen CY, Lee LM, Lin KH, Lin YW, Hsiao CH, Wen YC. Do 5α-reductase inhibitors prevent secondary benign prostate hyperplasia-related urinary retention?. Urol Sci [serial online] 2018 [cited 2018 Aug 15];29:86-90. Available from: http://www.e-urol-sci.com/text.asp?2018/29/2/86/228289
| Introduction|| |
Benign prostate hyperplasia (BPH) is a common chronic disease in aging men. The disease is usually progressive and often accompanied by irritating lower urinary tract symptoms (LUTS). The symptoms including acute urinary retention (AUR) and surgery for BPH are undesirable events and may cause complications and medical expenditure. Nevertheless, α blockers have been proven to increase the chances of a successful trial without catheter (TWOC) following AUR. However, in a recent study, the medical failure rates of α blockers after AUR were reported to be 28.4% and 50.5% at 24 and 60 months, respectively, with the most frequent cause of failure being recurrent AUR. 5α-reductase inhibitors (5ARIs) are well-recognized agents for the treatment of symptomatic BPH. In a previous study, dutasteride was reported to reduce the rate of AUR or BPH-related surgery. A combination of BPH-related surgery and α blockers such as tamsulosin was also demonstrated to reduce the relative risk of AUR, BPH-related surgery, and BPH clinical progression in men with moderate-to-severe LUTS caused by BPH. However, according to our review of the literature, studies describing the effect of dutasteride after the first episode of AUR are scant. Thus, the aim of this study was to explore the effectiveness of dutasteride in preventing urine retention after the first BPH-related AUR.
| Materials and Methods|| |
We searched for patient data from our hospital using International Classification of Diseases, Ninth Revision (ICD-9) codes. Patients diagnosed as having AUR (ICD-9 code 788.20) and BPH, with or without LUTS (ICD-9 codes 600.0 and 600.1) between January 2006 and June 2016 were enrolled in this study. The exclusion criteria were as follows: (1) previous BPH-related surgery; (2) long-term catheter use; (3) prostatic malignancy; (4) urine retention secondary to other causes such as neurogenic bladder, infection, or urethral stricture; and (5) insufficient data.
Information regarding basic patient characteristics, including age, prostate size, prostate-specific antigen (PSA) levels, and maximum urinary flow rate (Qmax) was recorded if available. Patients were then divided into two groups: Group 1 consisting of patients who received dutasteride and α blocker (including alfuzosin, doxazosin, and tamsulosin) treatment, and Group 2 consisting of patients who received only α blocker treatment. And by following the reimbursement criteria of the Taiwan National Health Insurance program, all the patients using dutasteride in the Group 1 with PSA level above 4 underwent prostate biopsy to exclude prostate cancer.
Patients were followed for at least 6 months, to a maximum follow-up period of 24 months if no episode occurred. Episodes such as secondary urine retention and BPH-related surgery were recorded. Follow-up was discontinued after the patients encountered either episode. In the Group 1, the posttreatment prostate size, PSA level, and treatment duration were recorded if available.
The characteristics of patients in the two groups were compared. The rate of secondary AUR within 24 months and the rate of BPH-related surgery within 24 months in the two groups were compared. Other comparisons involved the relationships between the prevention rate and prostate size as well as PSA levels. The differences in prostate size or PSA levels before and after dutasteride treatment were also compared.
We used the statistical software package SPSS version 23.0 (IBM Corp., Armonk, NY, USA) for our analysis. Patient characteristics were compared using a paired t-test. For comparison of the prevention rate of AUR or BPH-related surgery, survival analysis was conducted using the Chi-square test. For the comparison of the average time to develop secondary AUR or BPH-related surgery, Kaplan–Meier method was used. The log-rank test was used to obtain P values. For determining the relationships between prevention rate and prostate size or PSA levels, the Cox regression method was used. For comparing factors such as prostate size or PSA levels before and after treatment, a paired t-test was used.
| Results|| |
We included a total of 1161 patients diagnosed with urine retention between January 2006 and June 2016. After excluding patients according to the mentioned criteria, we enrolled 128 patients in our study. The enrolled patients were divided into two groups; Group 1 comprised 33 patients who received dutasteride and α-blocker treatment, and Group 2 comprised 95 patients who received only α blocker treatment [Figure 1].
The mean age, prostate size, PSA levels, and Qmax in our study were 77.7 years, 45.4 mL, 11.69 ng/dL, and 9.8 mL/s, respectively. The mean ages were 77.9 years in the Group 1 and 77.6 years in the Group 2 (P = 0.886). The mean prostate size was significantly larger in the Group 1 than in the Group 2 (65.1 vs. 36.9 mL, P = 0.001). PSA levels and Qmax were similar in both groups (5.45 vs. 14.97 ng/dL, P = 0.371; 9.72 vs. 9.9 mL/s, P = 0.893, respectively) [Table 1]. The mean treatment duration in the Group 1 was 13.8 months.
In total, 43 patients (33.6%) experienced secondary AUR within 24 months. The secondary AUR rate in the Group 1 (18.2%) was lower than that in the Group 2 (38.9%) (P = 0.030) [Table 2]. According to our data, dutasteride treatment reduced the risk of secondary AUR by 20.7%.
Groups 1 and 2 exhibited BPH-related surgery rates of 9.1% and 14.7%, respectively. However, the difference between these groups did not reach statistical significance (P = 0.410) [Table 2]. When secondary AUR and BPH-related surgery were combined as an end event, the use of dutasteride reduced the risk of secondary AUR or BPH-related surgery to 27.3% in the Group 1 and 50.5% in the Group 2 (P = 0.021) [Table 2]. However, there were five patients in Group 1 experienced recurrent AUR- or BPH-related surgery within 6 months after dutasteride usage.
The average time without secondary AUR development was 18.5 months. It was longer in the group 1 then the Group 2 (20.5 vs. 17.8 months, P = 0.031) [Table 3] and [Figure 2]a. The average time without BPH-related surgery was 21.3 months, and there was no significant difference between two groups (22.6 vs. 20.9 months, P = 0.340) [Table 3] and [Figure 2]b. When secondary AUR- and BPH-related surgery were combined as an end event, the average time without secondary AUR- or BPH-related surgery was 16.7 months. It was also longer in the Group 1 then the Group 2 (19.5 vs. 16.0 months, P = 0.030) [Table 3] and [Figure 2]c.
|Figure 2: Kaplan–Meier curves of cumulative episode-free rate between the two treatment groups: a. secondary AUR; b. BPH-related surgery; c. secondary AUR or BPH-related surgery|
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The prostate size and PSA levels before and after dutasteride treatment in the Group 1 were compared. According to our results, dutasteride treatment reduced the prostate size by 23.7% (from 65.1 to 49.7 mL, P < 0.001) and the PSA level by 55.8% (from 5.45 to 2.41 ng/dL, P < 0.001). By contrast, the prostate size and PSA levels in the Group 2 did not reveal significant changes (prostate size: 36.9–50.1 mL, P = 0.328; PSA: 14.97–7.65 ng/dL, P = 0.204).
| Discussion|| |
In clinical trials conducted over the past decade, 5ARIs have been demonstrated as effective agents for the treatment of BPH., Previous randomized clinical trials, such as the Medical Therapy of Prostatic Symptoms and Combination of Avodart and Tamsulosin studies,, have demonstrated that combination therapy of 5ARIs with α blockers was significantly more effective in reducing symptoms and lowering the rates of AUR and BPH-related surgery, compared with either component alone, within a 24-month follow-up period.
A study conducted in Japan investigated the success rate of TWOC in patients receiving dutasteride (0.5 mg) and silodosin (8 mg) daily after the first episode of BPH-related AUR; the study attempted TWOC every 2 weeks until 12 weeks after medication was initiated and recorded the catheter-free rate at the end of 12 weeks. The study demonstrated that the success rate of TWOC at 12 weeks was 88%. However, no control group was used in the study. In the current study, patients receiving only α blockers represented the control group. Our study focused on the preventive effects of the additional use of 5ARIs with α blockers. Compared with the use of only α blockers, we observed that the additional use of dutasteride might reduce the rate of secondary AUR- or BPH-related surgery by 23.2%.
Roehrborn et al. reported that adding dutasteride to tamsulosin monotherapy resulted in a 66% reduction in AUR- or BPH-related surgery after 4 years of follow-up. However, the study design mainly focused on primary BPH-related AUR or BPH-related surgery. All patients enrolled in our study had previous episodes of AUR, which may be considered more severe in patients with BPH. Previous studies have also mentioned detrusor dysfunction after AUR. Saito et al. studied the change in bladder detrusor after AUR in rat models, and they reported detrusor dysfunction with mechanisms involving free radicals and increased fibrosis in the submucosal layer. Due to the possible physiological change in the bladder caused by fibrosis and associated detrusor dysfunction, the rate of secondary AUR may increase, and this would explain the lower preventive effect of dutasteride in our study than that observed in previous studies, which focused on primary AUR.
In a previous study, the use of 5ARIs could reduce the prostate size by approximately 18%–28% after 6–12 months of treatment. Roehrborn et al. also reported a 27.3% reduction in prostate volume after combination therapy of dutasteride and tamsulosin and a 4.6% increase in prostate volume (P< 0.001) after tamsulosin treatment alone after 48 months. Tsukamoto et al. studied 378 Japanese patients treated with dutasteride with or without tamsulosin treatment, and they reported a 23.7% reduction in prostate volume in 52 weeks; the dutasteride-treated groups exhibited significant differences compared with the placebo group developed after 24 weeks of dutasteride treatment. In the current study, we observed a 23.4% reduction in prostate volume after 24 months, and our finding is similar to the previously reported results.
In our study, all the characteristics were comparable between the two groups, except for the prostate size. The average prostate size was significantly larger in Group 1 (additional dutasteride therapy) than in Group 2 (α-blocker therapy only). The main reason for this difference could be a possible patient selection bias. The physician may have had a higher preference to prescribe dutasteride combined with α-blocker treatment over α-blocker treatment alone for AUR in patients with a large prostate size. The 2016 European Association of Urology guideline for nonneurogenic male LUTS recommends the provision of 5ARIs to patients with severe LUTS and a prostate volume of >40 mL. Furthermore, according to the reimbursement criteria of the Taiwan National Health Insurance program, the use of dutasteride would be reimbursed for patients with a prostate size of >30 mL. In this study, the mean prostate size in the group 1, using dutasteride, was 65.1 mL, compared with 36.9 mL in the Group 2; this thus demonstrates adherence of clinical practice to the guideline. With our current results, we can assume that the differences of the rate of secondary AUR- and BPH-related surgery would be more significant if the control group had a mean prostate size similar to the study group.
The subgroup analysis of BPH-related surgery failed to reach statistical significance. The trend favored the use of dutasteride. This trend may be related to the preference of physicians and communication between the physicians and patients in our hospital. Moreover, according to the EAU guidelines, clinical effects relative to placebo are seen after a minimum treatment duration of at least 6–12 months. The effect of the drug may fail to reach significance before symptom recurrence. However, with higher case numbers, the differences between the two groups may reach statistical significance. Further study is therefore warranted.
This study has limitations. First, our study group is relatively small compared with the previous large randomized control trials. Second, our study applied a retrospective design; the guidelines followed, physicians' preferences and treatment strategy are liable to change with time. Therefore, future studies can use larger samples and apply prospective designs to verify the findings of the current study.
| Conclusions|| |
Our study demonstrated that the use of 5ARIs in patients with first episodes of BPH-related AUR significantly prevented secondary AUR. Additional studies with higher numbers of patients and prospective randomized controlled trials are still required for obtaining further evidence of the preventive effect of 5ARIs.
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Conflicts of interest
There are no conflicts of interest.
| References|| |
Roehrborn CG, Nickel JC, Andriole GL, Gagnier RP, Black L, Wilson TH, et al.
Dutasteride improves outcomes of benign prostatic hyperplasia when evaluated for prostate cancer risk reduction: Secondary analysis of the REduction by DUtasteride of prostate Cancer Events (REDUCE) trial. Urology 2011;78:641-6.
Alan McNeill S. The role of alpha-blockers in the management of acute urinary retention caused by benign prostatic obstruction. Eur Urol 2004;45:325-32.
Lo KL, Chan MC, Wong A, Hou SM, Ng CF. Long-term outcome of patients with a successful trial without catheter, after treatment with an alpha-adrenergic receptor blocker for acute urinary retention caused by benign prostatic hyperplasia. Int Urol Nephrol 2010;42:7-12.
Andriole GL, Bostwick DG, Brawley OW, Gomella LG, Marberger M, Montorsi F, et al.
Effect of dutasteride on the risk of prostate cancer. N
Engl J Med 2010;362:1192-202.
Siami P, Roehrborn CG, Barkin J, Damiao R, Wyczolkowski M, Duggan A, et al.
Combination therapy with dutasteride and tamsulosin in men with moderate-to-severe benign prostatic hyperplasia and prostate enlargement: The CombAT (Combination of Avodart and Tamsulosin) trial rationale and study design. Contemp Clin Trials 2007;28:770-9.
Roehrborn CG, Boyle P, Nickel JC, Hoefner K, Andriole G, ARIA3001 ARIA3002 and ARIA3003 Study Investigators, et al.
Efficacy and safety of a dual inhibitor of 5-alpha-reductase types 1 and 2 (dutasteride) in men with benign prostatic hyperplasia. Urology 2002;60:434-41.
Debruyne F, Barkin J, van Erps P, Reis M, Tammela TL, Roehrborn C, et al.
Efficacy and safety of long-term treatment with the dual 5 alpha-reductase inhibitor dutasteride in men with symptomatic benign prostatic hyperplasia. Eur Urol 2004;46:488-94.
McConnell JD, Roehrborn CG, Bautista OM, Andriole GL Jr., Dixon CM, Kusek JW, et al.
The long-term effect of doxazosin, finasteride, and combination therapy on the clinical progression of benign prostatic hyperplasia. N
Engl J Med 2003;349:2387-98.
Roehrborn CG, Siami P, Barkin J, Damião R, Major-Walker K, Morrill B, et al.
The effects of dutasteride, tamsulosin and combination therapy on lower urinary tract symptoms in men with benign prostatic hyperplasia and prostatic enlargement: 2-year results from the CombAT study. J Urol 2008;179:616-21.
Hagiwara K, Koie T, Iwamura H, Imai A, Hatakeyama S, Yoneyama T, et al.
Efficacy and safety of silodosin and dutasteride combination therapy in acute urinary retention due to benign prostatic hyperplasia: A Single-arm prospective study. Biomed Res Int 2016;2016:4975851.
Roehrborn CG, Siami P, Barkin J, Damião R, Major-Walker K, Nandy I, et al.
The effects of combination therapy with dutasteride and tamsulosin on clinical outcomes in men with symptomatic benign prostatic hyperplasia: 4-year results from the CombAT study. Eur Urol 2010;57:123-31.
Saito M, Shimizu S, Kinoshita Y, Satoh I, Shomori K, Dimitriadis F, et al.
Bladder dysfunction after acute urinary retention in the rats: A novel over active bladder model. Mol Cell Biochem 2010;333:109-14.
Naslund MJ, Miner M. A review of the clinical efficacy and safety of 5alpha-reductase inhibitors for the enlarged prostate. Clin Ther 2007;29:17-25.
Tsukamoto T, Endo Y, Narita M. Efficacy and safety of dutasteride in Japanese men with benign prostatic hyperplasia. Int J Urol 2009;16:745-50.
Gratzke C, Bachmann A, Descazeaud A, Drake MJ, Madersbacher S, Mamoulakis C, et al.
EAU guidelines on the assessment of non-neurogenic male lower urinary tract symptoms including benign prostatic obstruction. Eur Urol 2015;67:1099-109.
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3]