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This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library 2009, Issue 4 http://www.thecochranelibrary.com
Naftopidil for the treatment of lower urinary tract symptoms compatible with benign prostatic hyperplasia (Review) Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
TABLE OF CONTENTS HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . AUTHORS CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 1.1. Comparison 1 Pooled adverse events: Naftopidil versus tamsulosin, Outcome 1 Adverse events - any. ADDITIONAL TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . WHATS NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . NOTES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 1 2 2 3 3 4 7 8 8 9 10 16 16 16 20 20 20 20 20 21 21
Naftopidil for the treatment of lower urinary tract symptoms compatible with benign prostatic hyperplasia (Review) Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
[Intervention Review]
Naftopidil for the treatment of lower urinary tract symptoms compatible with benign prostatic hyperplasia
Pranav S. Garimella2 , Howard A Fink3 , Roderick MacDonald1 , Timothy J Wilt1
1 General
Internal Medicine (111-0), VAMC, Minneapolis, Minnesota, USA. 2 John H. Stroger Hospital of Cook County, Chicago, Illinois, USA. 3 Geriatric Research Education and Clinical Center, Box 11G, VA Medical Center, Minneapolis, Minnesota, USA
Contact address: Timothy J Wilt, General Internal Medicine (111-0), VAMC, One Veterans Drive, Minneapolis, Minnesota, 55417, USA. Tim.Wilt@med.va.gov. Editorial group: Cochrane Prostatic Diseases and Urologic Cancers Group. Publication status and date: Edited (no change to conclusions), published in Issue 2, 2012. Review content assessed as up-to-date: 15 June 2009. Citation: Garimella PS, Fink HA, MacDonald R, Wilt TJ. Naftopidil for the treatment of lower urinary tract symptoms compatible with benign prostatic hyperplasia. Cochrane Database of Systematic Reviews 2009, Issue 4. Art. No.: CD007360. DOI: 10.1002/14651858.CD007360.pub2. Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
ABSTRACT Background Benign prostatic hyperplasia (BPH) is a common condition in aging men causing lower urinary tract symptoms (LUTS). Treatment aims are to relieve symptoms and prevent disease progression. Of the different -1 adrenergic receptors (ARs) in the prostate, -1a receptors are known to be central to prostatic smooth-muscle contraction. Recent studies have shown that patients with BPH may also have a predominance of -1d receptors. Objectives To evaluate the efcacy and adverse effects of naftopidil, a selective -1d oral alpha-blocking agent for the treatment of LUTS associated with BPH. Search methods Systematic review of trials published January 1950 to January 2009. Sources included MEDLINE and bibliographies of retrieved articles and review articles. Selection criteria Eligible trials included: men diagnosed with symptomatic BPH; compared Naftopidil to placebo, control, or combination therapy; evaluated clinically relevant outcomes between randomized groups; had at least 4-weeks follow up; and were published in English language. Data collection and analysis Participant demographics and comorbidities, enrollment criteria, outcomes, adverse events, numbers and reasons for dropouts were extracted onto standardized extraction forms by one reviewer. The mean change and per cent improvement from baseline in AUA (American Urological Association Symptom Score) and IPSS (International Prostate Symptom Score) scores and other efcacy outcomes for treatment and control groups were calculated. If feasible, the efcacy outcomes and adverse events data were pooled.
Naftopidil for the treatment of lower urinary tract symptoms compatible with benign prostatic hyperplasia (Review) Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 1
Main results Eight trials were eligible (N = 744 participants). All trials were conducted in Japan. Study duration ranged from 4 to 17 weeks. The mean age of participants was 68 years; pretreatment mean IPSS = 17.8 and mean peak urine ow (Qmax) = 9.5 mL/s (milliliters/ second). No trials compared naftopidil to placebo. In 5 trials (N = 419), naftopidil in doses of 25 to 75 mg/d (milligrams/day) showed a mean IPSS improvement similar to low-dose tamsulosin (0.2 mg/d) (8.4 versus 8.9 points). Compared to a phytotherapy preparation (eviprostat), naftopidil signicantly improved total IPSS (-5.9 versus 0.4; P < 0.0002). In one trial, the addition of anticholinergic drugs (oxybutynin or propiverine hydrochloride) to naftopidil did not offer any signicant improvement for IPSS or Qmax in comparison to treatment with naftopidil alone. Although IPSS did not signicantly differ between high- (75 mg/d) and low-dose (25mg/d) naftopidil, high dose signicantly improved Qmax compared to low dose (1.2 mL/s versus 0.2 mL/s). Adverse events reported were few, mild and similar to those seen with 0.2 mg/d tamsulosin. Authors conclusions There are no data from placebo controlled trials regarding the efcacy of naftopidil in men with symptomatic BPH. Limited information suggests that treatment with naftopidil provides short-term improvement in urinary symptom-scale scores (total IPSS/AUA), QoL (quality of life) score, and urinary symptoms from baseline comparable to low-dose tamsulosin. Adverse effects due to naftopidil were few and usually mild.
PLAIN LANGUAGE SUMMARY Naftopidil for the treatment of benign prostatic hyperplasia Benign prostatic hyperplasia (BPH) can cause bothersome lower urinary tract symptoms such as increased frequency, urgency, nighttime urinations, straining and hesitancy. BPH is common in older males and its symptoms can affect quality of life. This review of eight trials evaluated naftopidil for the treatment of BPH. Current evidence is sparse. We did not identify any placebo-controlled trials. Naftopidil had a similar short-term efcacy and adverse-effect prole compared to low-dose tamsulosin, and better efcacy than phytotherapy (eviprostat). Adverse effects of naftopidil were few, most commonly dizziness and hypotension. Prior to wide-spread use, more long-term, randomized, controlled studies compared to standard therapy are needed.
BACKGROUND
-1a ARs (Lepor 2006). Of the different subtypes of -1 ARs, -1a ARs are known to be central to human prostatic smoothmuscle contraction, although the exact receptor involved in LUTS is unknown (Lepor 2006).
Naftopidil for the treatment of lower urinary tract symptoms compatible with benign prostatic hyperplasia (Review) Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Secondary outcomes
OBJECTIVES
To evaluate the efcacy and adverse effects of naftopidil in the treatment of LUTS associated with BPH.
Secondary outcome measures included: change in Qmax, reported in milliliters per second (mL/s); change in LUTS-related Quality of Life (QoL) score; change in post-void residual volume (PVR), reported in milliliters; change in progressive nocturia and BPH leading to the need for surgical intervention; and development of acute urinary retention. Included harms were (1) adverse events, (2) treatment discontinuations. Outcomes were assessed according to predened subgroups, if feasible: race; age (greater than or equal to 65 versus less than 65 years old); baseline AUA/IPSS severity ((IPSS range = 0 to 35) mild 8, moderate 9 to 19, and severe > 18); measures of prostate size; and baseline PSA values (less than 4 versus 4 ng/mL (nanograms/ milliliter) or greater).
Types of studies Trials were eligible for inclusion if they: (1), were randomized; (2) compared naftopidil to placebo or other controls; (3) enrolled men with symptomatic BPH; (4) had treatment of at least 4 weeks; and (5) were published in English.
Types of participants Men diagnosed with symptomatic BPH randomized to naftopidil versus control or placebo with minimum treatment duration of 4 weeks.
Searching other resources Bibliographies of retrieved trials and of review articles were examined.
Types of interventions Any form of drug or phytotherapy for the treatment of urinary symptoms due to BPH.
Primary outcomes
Primary efcacy was change in the AUA/IPSS scores and the per cent of individuals who had a clinically signicant improvement (i.e. at least a four-point decrease).
Naftopidil for the treatment of lower urinary tract symptoms compatible with benign prostatic hyperplasia (Review) Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Selection of studies Study eligibility was individually determined by the reviewers. Trials were eligible for inclusion if they: (1) were randomized, (2) compared naftopidil to placebo, control or combination therapy, (3) enrolled men who had been diagnosed with symptomatic BPH, (4) had treatment duration of at least 4 weeks, and (5) were published in English. For each trial, one reviewer independently assessed study eligibility and this was veried by a second reviewer. Differences in eligibility assessments were resolved by discussion.
Assessment of heterogeneity A xed-effects model was used if there was no evidence of heterogeneity between the studies, and was based on the I2 test (DerSimonian 1986; Higgins 2003). In the event of signicant heterogeneity between studies (I2 > 50%), we would have used a random- effects model.
Assessment of reporting biases Due to the limited number of studies, assessment of reporting/ publication bias could not be assessed.
Data extraction and management Participant demographics and comorbidities, enrollment criteria, outcomes, adverse events, numbers and reasons for dropouts were extracted onto standardized extraction forms by two reviewers (PG and RM) independently. Any differences of opinion were resolved by discussion. Data synthesis We compared mean change in outcome variables from baseline as this yields smaller condence intervals and standard errors.
Subgroup analysis and investigation of heterogeneity Assessment of risk of bias in included studies We assessed the quality of concealment of randomized treatment allocation according to a scale developed by Schulz, assigning scores of 1 for poorest quality and 3 for best quality (Schulz 1995), Additional means of measuring study quality and/or clinical generalizability included: blinding methods of participants, investigators and assessors; whether intention-to-treat (ITT) analysis was used; use of run-in periods; and per cent withdrawal. Subgroup analysis according to predened criteria was performed where feasible.
Sensitivity analysis Sensitivity analysis could not be conducted due to the limited number of studies, their small size, and data presented.
Measures of treatment effect Weighted mean differences (WMD), the difference between treatment and control pooled means at endpoint, with 95% CI, were calculated for continuous variables where possible. Weighted RR increases, comparing study intervention subjects to control subjects, and their 95% CI, were calculated for categorical data.
RESULTS
Description of studies
See: Characteristics of included studies; Characteristics of excluded studies.
Unit of analysis issues For crossover trials, the observations at the end of the rst treatment phase were considered for analysis, where provided. In situations where repeated observations were provided, the last observation was considered during analysis.
Results of the search Fourteen citations were identied through an initial electronic literature search covering January 1950 through June 2008. After review of all titles and abstracts, eight articles were retrieved for detailed review, of which all eight met inclusion criteria.
Dealing with missing data Missing or additional information was sought from authors. No response was obtained from the authors who were contacted. As no trials provided all three means and standard deviations (SD) (baseline, nal and change of mean) needed to calculate correlation coefcient, a SD for change of mean could not be calculated for trials that did not provide it.
Included studies Eight trials (N = 744 participants, range 34 to 185) met inclusion criteria (Table 1). Treatment duration with naftopidil ranged from 4 to 16 weeks. Five trials compared naftopidil to low-dose tamsulosin (0.2 mg/d) (a dose not approved for use in the United States) (Momose 2007; Nishinio 2006; Gotoh 2005; Ikemoto 2003; Ukimura 2008). One compared naftopidil to an
4
Naftopidil for the treatment of lower urinary tract symptoms compatible with benign prostatic hyperplasia (Review) Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
unknown dose (6 tablets/day) of eviprostat (a compound phytotherapy product containing plant extracts from Phila umbellata, Populus tremula, Pulsatilla pratensis mill and wheat-germ oil), the most commonly used agent for treating LUTS of BPH in Japan (Yamanishi 2004). One compared low- versus high-dose naftopidil (25 mg/d versus 75 mg/d) (Yokoyama 2006), and one compared naftopidil monotherapy to naftopidil plus either of two antimuscarinic agents, oxybutynin or propiverine (Maruyama 2006). All trials were published in peer-reviewed, English-language journals. Five trials (Gotoh 2005; Yamanishi 2004; Yokoyama 2006; Maruyama 2006; Ukimura 2008) used a parallel treatment design (N = 569 participants, range 49 to 185) and 3 trials (Nishinio 2006; Momose 2007; Ikemoto 2003) used a crossover design (N = 175 participants, range 34 to 96). The Nishinio 2006 study had 2 groups of 17 participants each. One group initially received naftopidil 50 mg/d for 4 weeks followed by tamsulosin 0.2 mg/d for 4 weeks. The other group initially received tamsulosin 0.2 mg/d for 4 weeks followed by naftopidil 50 mg/d for 4 weeks. The crossover to alternate treatment occurred after a one-week washout period. Only Momose 2007 performed a statistical analysis evaluating residual effect of interventions from Period 1 to Period 2 and found no signicant residual effect of the rst drug on the second. Two crossover trials (Nishinio 2006; Momose 2007) were analyzed using the outcomes at the end of the rst treatment phase (4 weeks of treatment). Ikemoto 2003 had two treatment groups; the rst group received naftopidil 25 mg daily for 2 weeks, followed by 50 mg/d for 6 weeks. The participants were then switched to tamsulosin 0.2 mg/d for 8 weeks. The second group received tamsulosin 0.2 mg/d for 8 weeks and was then switched to 25 mg/d naftopidil for 2 weeks, followed by 50 mg/d for 6 weeks. The trial did not provide data on outcomes at the end of the rst treatment phase and hence the analysis was done using data at baseline and at end of second treatment phase (16 weeks). One trial (Yamanishi 2004) stated that the dosage of naftopidil was increased initially from 25 mg/d to 50 mg/d after 2 weeks following which the dose was further increased to 75 mg/ d if the patient was not satised with the improvement in symptoms. No information is provided whether the code was broken and treatment carried out in a non randomized manner.
LUTS. The mean baseline peak urinary ow was 9.4 mL/s (range 8.7 to 11.1). Excluded studies Studies that were excluded after detailed review were non English language publications (n = 7) or non randomized trials (n = 5). Abstracts of these studies were reviewed to compare their results to the included trials.
Allocation All trials indicated that they were randomized, but only one reported adequate method of randomization, by Zelens method (Yokoyama 2006). One trial (Yamanishi 2004) stated that randomization was done by using an envelope but no details were provided. Randomization was clearly inadequate (odd-even numbers) in two trials that randomized participants based on patient hospital numbers (Maruyama 2006) and birth dates (Ukimura 2008). Blinding Four studies reported blinding of which two studies were doubleblinded (Gotoh 2005; Nishinio 2006) and two were single-blinded (Ikemoto 2003; Yamanishi 2004). One trial (Yamanishi 2004) stated that the dosage of naftopidil was increased initially from 25 mg/d to 50 mg/d after 2 weeks following which the dose was further increased to 75 mg/d if the patient was not satised with the treatment. No information was provided whether the code was broken and treatment carried out in a non randomized manner. Incomplete outcome data Baseline total IPSS, mean change and/or post treatment total IPSS was reported by all trials allowing for the computation of per cent change in symptom score from baseline. Change in the following secondary outcomes couldnt be calculated because of inadequate data; Qmax (Momose 2007; Yokoyama 2006); QoL (Ikemoto 2003); nocturia (Yamanishi 2004); PVR (Ikemoto 2003; Maruyama 2006; Momose 2007; Yokoyama 2006). Intention to treat (ITT) analysis was not performed in any of the trials. Gotoh 2005 performed data analysis on 144 of the 185 subjects randomized, and although reasons for exclusion were stated, the number of excluded subjects in each treatment arm is unclear. In two trials, although the total number of registered subjects at start of the study was stated, the number randomized to each treatment arm was unclear (Ukimura 2008; Yokoyama 2006).
5
Baseline characteristics
A total of 744 men were included in the review. The mean age was 68.3 years. The dose of naftopidil used was between 25 to 50 mg/d, except in 2 studies, Yamanishi 2004 and Yokoyama 2006. In Yokoyama a high dose naftopidil (75 mg/d) was administered as a comparison to 25 mg/d of naftopidil, and in Yamanishi the dose of naftopidil was increased to 75 mg/d if the patient was not satised with the improvement in symptoms. Severity of LUTS at baseline did not differ by treatment group based on symptom scores and peak urine-ow rates. Mean baseline IPSS in the 8 trials was 17.8 points (range 15.6 to 20.4) indicating moderately severe
Naftopidil for the treatment of lower urinary tract symptoms compatible with benign prostatic hyperplasia (Review) Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Selective reporting One of the crossover trials (Ikemoto 2003) did not provide interim data at the end of the rst treatment phase and only reported data at the end of both treatment phases. Other potential sources of bias Due to the differences in reporting of results we were unable to pool data to estimate overall effect size for main outcomes. Where poolable (adverse events), the effect sizes seen were on both sides of the null with wide condence intervals. All studies of naftopidil published in English were from Japan with no published trials outside Japan and China.
a signicant difference in post treatment PVR between groups. It did not provide numerical values for the change. Naftopidil versus phytotherapy Total IPSS and QoL score signicantly improved in participants treated with naftopidil compared with eviprostat. Signicant within group differences in mean change of IPSS, Qmax and QoL score (P < 0.0001 for all) were seen in the naftopidil group compared to the phytotherapy group. Naftopidil signicantly improved total IPSS score compared to phytotherapy (-5.9 versus 0.4, P < 0.0002) (Table 2). The improvement in the QoL score seen with naftopidil (1.5 points) was also statistically signicant (P = 0.0018) when compared to phytotherapy, which showed no change from baseline. Change in Qmax did not differ signicantly between naftopidil and phytotherapy groups (3.7 mL versus 0.5 mL, P = 0.088) (Table 3). Naftopidil and eviprostat decreased post void residual volume by 28.1 mL (P = 0.009) and 5.3 mL (P = 0.81), respectively. The authors reported no signicant difference in PVR change between the two groups (P = 0.3072). Naftopidil monotherapy versus co therapy with anticholinergic The improvement in symptoms seen with combined therapy of naftopidil plus an anticholinergic, oxybutynin or propiverine hydrochloride was similar to the improvement seen with naftopidil therapy alone (Table 2). Total IPSS showed an improvement of 6.3 and 5.0 points with monotherapy and combined therapy, respectively (P = 0.98). This change from baseline was statistically signicant in both groups (P < 0.005). The improvement in Qmax was small in both groups and did not change signicantly from baseline. Naftopidil monotherapy improved Qmax by 1.1 mL/ s while combined therapy showed an improvement of 0.6 mL/s (between group P = 0.43). QoL improved by 1.5 points in the monotherapy group and by 1.1 points in the combined therapy group. While these changes were signicantly different from baseline, a comparison between treatment groups failed to show and statistical evidence of a difference (P = 0.28). Improvement of nocturia was 1 point and signicant in both treatment groups (Table 3). Among the 75 patients in whom both pre and post treatment PVR was recorded, the median PVR at baseline was 19.6 mL for the monotherapy group and 35.0 mL for the combined therapy group. While this difference was not statistically signicant at baseline, the median PVR post therapy was signicantly higher (P = 0.02) in the combined therapy group (45.0 mL) as compared to the monotherapy group (13.5 mL). Low-dose (LD) versus high-dose (HD) naftopidil High-dose (75 mg) naftopidil showed similar efcacy outcomes for IPSS and QoL as compared to low dose (25 mg) (Table 2). Total IPSS showed a 4.5 point change in the LD group compared
6
Effects of interventions
Naftopidil versus tamsulosin Men randomized to naftopidil showed statistically signicant within-group improvement in IPSS, QoL, urinary ow rate, and PVR, improvements similar to those experienced by men allocated to low-dose tamsulosin. None of the ve trials found naftopidil statistically superior to tamsulosin in improving symptoms, peak urine ow, or QoL (Table 2). The mean change in IPSS from baseline was -8.4 points (range -5.9 to -11.5) for naftopidil and 8.9 points (range -7.3 to -11.1) for tamsulosin therapy. Four studies (Gotoh 2005; Momose 2007; Nishinio 2006; Ukimura 2008) reported statistically signicant intra group changes from baseline. The change in QoL from baseline as reported by four studies (Gotoh 2005; Ikemoto 2003; Nishinio 2006; Ukimura 2008), was statistically signicant with a mean of +1.5 points (range 0.6 to 2.3) for naftopidil and +1.4 points (range 0.7 to 2.2) for tamsulosin therapy. Mean change in Qmax from baseline averaged +2.1 mL/s (range 2.1 to 3) for naftopidil and +2.8 mL/s (range 2.1 to 3.0) for tamsulosin in four trials (Gotoh 2005; Ikemoto 2003; Nishinio 2006; Ukimura 2008). This change was statistically signicant for both treatments in three of the trials (Gotoh 2005; Ikemoto 2003; Nishinio 2006). Decrease in nocturia averaged -0.9 points (range -0.7 to -1.9) for naftopidil and -0.7 points (-0.3 to -1.7) for tamsulosin among all ve trials, with only 1 trial (Nishinio 2006) reporting a signicant reduction (P < 0.001) with naftopidil when compared to tamsulosin (Table 3). Improvement in PVR from baseline with naftopidil therapy in three trials (Gotoh 2005; Nishinio 2006; Ukimura 2008) was signicant (P < 0.05), averaging -24.0 mL (range; -13.6 to -42.7), while the same trials averaged a -19.2 mL (range -3.5 to -44.7) improvement with tamsulosin, which was not statistically signicant. One trial (Ikemoto 2003), which had signicantly different PVR (P = 0.048) between naftopidil (86.8 mL) and tamsulosin (32.8 mL) groups at baseline, also reported a signicant improvement from baseline with naftopidil therapy and was the only trial reporting
Naftopidil for the treatment of lower urinary tract symptoms compatible with benign prostatic hyperplasia (Review) Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
to a 5.4 point change in the HD group (P value stated as not signicant).The QoL score improved by 0.9 and 1 points in the LD and HD groups, respectively. HD naftopidil improved Qmax compared to LD naftopidil (1.2 mL/s versus 0.2 mL/s, respectively (P < 0.05)). Nocturia improved signicantly from baseline in both groups (1.1 points in LD and 1 point in HD) (Table 3). Subgroup analyses was presented based on age of patients (<70 years and > 70 years) and prostate volume (<30 mL and >30 mL). IPSS (range 7 to 9 points), QoL score, Qmax (range 0.5 to 2.3mL), and subjective symptoms did not differ signicantly in the two age subgroups (P > 0.05). Patients with prostate volume < 30 mL had a 2.3 mL improvement in Qmax with HD naftopidil, which was signicantly different (P = 0.005) from the 0.4 mL improvement in Qmax seen with LD naftopidil. Those with prostate volume > 30 mL showed similar Qmax improvements with HD and LD naftopidil. No other differences in IPSS improvement (range 4 to 5 points), QoL score or subjective symptoms were seen between the two groups based on prostate volume.
Adverse Effects and Withdrawals Adverse effects due to therapy occurred among 34 (15%) participants in 5 trials. The most common adverse effect associated with naftopidil were dizziness and hypotension. One study reported numbness of the tongue in four patients taking naftopidil (Gotoh 2005). The most commonly reported adverse effects due to tamsulosin were hypotension, dizziness and headache. No studies reported statistically signicant differences in adverse events between the treatment and control groups. No signicant difference in the incidence of adverse events was seen after pooling data from three trials comparing naftopidil to tamsulosin (RR 1.01; 95% CI 0.47 to 2.18) (Gotoh 2005; Ikemoto 2003; Momose 2007). Fifteen per cent (100/663) of all patients randomized withdrew before the studies ended. Three trials (Momose 2007; Nishinio 2006; Yamanishi 2004) did not have any dropouts. No trials reported data on signicant differences between withdrawals. Withdrawals due to adverse effects averaged 2.3% (13/663) in the 7 trials. Of these thirteen who withdrew due to adverse effects, six (two subjects each in three trials) were on naftopidil therapy (Ikemoto 2003; Maruyama 2006; Yokoyama 2006), three on combination therapy with naftopidil and anticholinergic (Maruyama 2006), while one trial reported that two subjects withdrew due to adverse effects but did not provide information about their treatment group (Gotoh 2005). Three studies (Gotoh 2005: Ikemoto 2003; Maruyama 2006) reported the need for surgical intervention to relieve urinary symptoms.
DISCUSSION
Naftopidil for the treatment of lower urinary tract symptoms compatible with benign prostatic hyperplasia (Review) Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
the current reviews results. None of the included trials compared naftopidil to placebo. Comparison to placebo would provide evidence for statistically and clinically signicant differences in treatment outcomes with naftopidil, if they exist. In addition, most of the studies were underpowered, which can hide clinically important differences due to small sample sizes. All trials were performed in Japan and the dosage of tamsulosin used in all trials (0.2 mg/d) was lower than the dosage recommended and widely utilized to treat BPH symptoms (Helfand 2007). Therefore, the generalizability of results is uncertain. Although adverse events were few and naftopidil was not shown to have serious or life threatening adverse events, the results were based on small, short-term, trials with a mean duration of only 9.7 weeks. None of the included trials were designed to assess or report data on the ability of naftopidil to prevent long-term complications of BPH progression, including UTI (urinary tract infection) and need for surgical intervention. Data from one long-term trial (Masumori 2007), in which all participants received 25 mg/d naftopidil, showed 81% participant discontinuation over a period of 4 years. The high rate of discontinuation included 48% loss to follow up due to unknown causes and 17% treatment failure, which included conversion to other medical treatment (7.7%) and surgery (9.3%).
in QoL index after naftopidil therapy (50 to 75 mg/d for more than 4 weeks) were switched to tamsulosin (0.1 to 0.2 mg/d) and compared with participants receiving naftopidil, who had earlier reported no benet with tamsulosin therapy (Hayashi 2002). Results from this trial suggest that while improvements were seen with both drugs, tamsulosin was superior to naftopidil for ow symptoms while naftopidil was better at improving nocturia. A third trial that compared naftopidil (25 to 75 mg/d) to prazosin hydrochloride (0.5 to 1 mg 3 times per day) reported similar improvements in urine ow rates, PVR (post and global improvement of symptoms with both treatments (Yamaguchi 1992). Four trials (Awa 2008; Takahashi 2006; Masumori 2007; Yasuda 1994) in which all participants received only naftopidil (no control group) reported a signicant improvement in IPSS, Qmax, nocturia and QoL score at the end of therapy when compared to baseline values.
ACKNOWLEDGEMENTS
Supported by the National Institute of Diabetes and Digestive and Kidney Diseases under the following grant number: DKR01 063300-01A2.
Naftopidil for the treatment of lower urinary tract symptoms compatible with benign prostatic hyperplasia (Review) Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
REFERENCES
Naftopidil for the treatment of lower urinary tract symptoms compatible with benign prostatic hyperplasia (Review) Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
urinary tract symptoms suggestive of benign prostatic hyperplasia. Scandinavian Journal of Urology and Nephrology 2007;41:422429. Sugino 2003 {published data only} Sugino Y, Fukuzawa S, Takeuchi H, Taki Y, Hashimura T, Soeda T, Araki I. Clinical effects of naftopidil on nocturia associated with benign prostatic hyperplasia. Hinyokika Kiyo - Acta Urologica Japonica 2003;49(8):4459. Takahashi 2006 {published data only} Takahashi S, Tajima A, Matsushima H, Kawamura T, Tominaga T, Kitamura T. Clinical efcacy of an alpha1A/ D-adrenoceptor blocker (naftopidil) on overactive bladder symptoms in patients with benign prostatic hyperplasia. Internal Journal of Urololgy 2006;13(1):1520. Yamaguchi 1992 {published data only} Yamaguchi O, Fukaya Y, Shiraiwa Y, Kaneko S, Yachiku S, Yasuda K, Shimazaki J, Takagi R, Sato S, Kondo A, Miyake K, Taira N. Clinical Evaluation of Naftopidil (KT611) on Urinary Obstruction Caused by Benign Prostatic Hypertrophy: Double-Blind Comparative Study Compared with Prazosin Hydrochloride [Zenritsusen Hidaisho ni Tomonau Hainyo Shogai ni Taisuru Nafutopijiru (KT611) no Rinsho Hyoka: Ensan Purazoshin o Taishoyaku to Shita Niju Moken Hikaku Shiken]. Rinsho Iyaku [Journal of Clinical Therapeutics and Medicines] 1992;8(3):699722. Yasuda 1994 {published data only} Yasuda K, Yamanishi T, Tojo M, Nagashima K, Akimoto S, Shimazaki J. Effect of naftopidil on urethral obstruction in benign prostatic hyperplasia: assessment by urodynamic studies. Prostate 1994;25(1):4652.
DerSimonian 1986 DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clinical Trials 1986, (7):17788. Helfand 2007 Helfand M, Muzyk T, Garzotto M. Comparative Effectiveness Review. Benign Prostatic Hyperplasia (BPH) Management in Primary Care- Screening and Therapy. Department of Veteran Affairs HSR&D. Final report February 2007. Higgins 2003 Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ 2003;323: 55760. Kojima 2006 Kojima Y, Sasaki S, Shinoura H, Hayashi Y, Tsujimoto G, Kohri K. Quantication of alpha1-adrenoceptor subtypes by real-time RT-PCR and correlation with age and prostate volume in benign prostatic hyperplasia patients. Prostate 2006;66(7):7617. Lepor 2006 Lepor H. The Evolution of Alpha blockers for the Treatment of Benign Prostatatic Hyperplasia. Reviews in Urology 2006; 8(suppl 4):S3S9. Madersbacher 2004 Madersbacher S, Alivizatos G, Nordling J, Sanz CR, Emberton M, de la Rosette JMCH. EAU 2004 Guidelines on Assessment, Therapy and Follow-Up of Men with Lower Urinary Tract Symptoms Suggestive of Benign Prostatic Obstruction (BPH Guidelines). European Urology 2004;46: 54754. Review Manager 2008 Review Manager (RevMan). Version 5.0. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration 2008. Schulz 1995 Schulz KF, Chalmers I, Hayes RJ, et al.Empirical evidence of bias. Dimensions of methodological quality associated with estimates of treatment effects in controlled trials. Journal of the American Medical Association 1995;273:408. Indicates the major publication for the study
Additional references
Andersson 2007 Andersson KE. LUTS Treatment: Future Treatment Options. Neurourology and Urodynamics 2007;26:93447. AUA Guideline 2003 AUA Guideline on the Management of Benign Prostatic Hyperplasia: Diagnosis and Treatment Recommendations. 2003.
Naftopidil for the treatment of lower urinary tract symptoms compatible with benign prostatic hyperplasia (Review) Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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CHARACTERISTICS OF STUDIES
Interventions
Outcomes
Notes
Ikemoto 2003 Methods Participants Randomized crossover trial. No blinding methods reported. N = 96 Japanese men, mean age 65 years, with symptomatic BPH; (IPSS > 8 points; peak urine ow < 12 mL/s; voided volume of > 150 mL) / Mean IPSS = 17.1 and peak urine ow = 9.2 mL/s. Intervention:naftopidil -tamsulosin (N = 43) naftopidil 25 mg/d x 2 weeks followed by 50 mg/d x 6 weeks then switched to tamsulosin 0.2 mg/d x 8 weeks Control: tamsulosin - naftopidil group (N = 53) tamsulosin 0.2 mg/d x 8 weeks followed by naftopidil 25 mg/d x 2 weeks followed by 50 mg/d x 6 weeks Study duration: 16 weeks (8 x 2, with no washout period) Symptom score as assessed by IPSS scale, Qmax (peak urine ow), QoL score, PVR (post void residual volume) and adverse events No information on analysis of crossover or period effect.
Interventions
Outcomes
Notes
Maruyama 2006 Methods Participants Randomized controlled parallel trial. No blinding methods reported N = 101 Japanese men, mean age 67.3 years, with storage symptoms BPH (IPSS > 8 points with a frequency score > 3 and a nocturia score > 2). Mean IPSS = 17.1 and peak urine ow = 11.1 mL/s.
Naftopidil for the treatment of lower urinary tract symptoms compatible with benign prostatic hyperplasia (Review) Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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Maruyama 2006
(Continued)
Interventions
Intervention:Monotherapy (N = 53) with naftopidil 25 to 75 mg/d x 12 weeks Control: Co therapy (N = 48) with naftopidil 25 to 75 mg/d x 12 weeks plus oxybutynin hydrochloride 4 to 8 mg/d or propiverin hydrochloride 10 to 20 mg/d x 12 weeks Study duration: 12 weeks Symptom score as assessed by IPSS scale, Qmax (peak urine ow), QoL score, PVR (post void residual volume) and adverse events Naftopidil dosage varied between 25 to 75 mg/d within the treatment arms. There is no information as to whether this allocation was done in a randomized fashion within treatment groups. Also the rationale behind the allocation of oxybutynin or propiverine in the co therapy arm is unclear
Outcomes
Notes
Risk of bias Bias Allocation concealment (selection bias) Authors judgement High risk Support for judgement Clearly inadequate. Patients divided into two groups based on medical chart numbers. Naftopidil monotherapy was administered to odd-numbered patients and combination therapy to even-numbered patients
Momose 2007 Methods Participants Randomized controlled crossover trial. No blinding methods reported N = 45 Japanese men, mean age 67 years, with symptomatic BPH diagnosed at the outpatient clinic; Mean IPSS = 18.9 and peak urine ow = 9.3 mL/s Intervention: naftopidil - tamsulosin (N = 20) naftopidil 50 mg/d x 4 weeks followed by tamsulosin 0.2 mg/d x 4 weeks Control: tamsulosin - naftopidil group (N = 25) tamsulosin 0.2 mg/d x 4 weeks followed by naftopidil 50 mg/d x 4 weeks Study duration: 8 weeks (4 x 2 weeks; no washout period) Symptom score as assessed by IPSS scale, Qmax (peak urine ow), QoL score, PVR (post void residual volume) and adverse events
Interventions
Outcomes
Notes
Naftopidil for the treatment of lower urinary tract symptoms compatible with benign prostatic hyperplasia (Review) Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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Nishinio 2006 Methods Participants Randomized controlled crossover trial. No blinding methods reported N = 34 Japanese men, mean age 72.4 years (range 66 to 79), with symptomatic BPH (IPSS > 7 points; peak urine ow > 15 mL/s) / Mean IPSS = 20.4 and peak urine ow = 9.9 mL/s Intervention: naftopidil - Tamsulosin (N = 17) Naftopidil 50 mg/d x 4 weeks followed by tamsulosin 0.2 mg/d x 4 weeks Control: tamsulosin - naftopidil group (N = 17) tamsulosin 0.2 mg/d x 4 weeks followed by naftopidil 50 mg/d x 4 weeks Study duration: 9 weeks (4 x 2, plus 1 week washout between treatments) Symptom score as assessed by IPSS scale, Qmax (peak urine ow), QoL score, PVR (post void residual volume) and adverse events Authors report that residual effects of the rst drug were analyzed and no statistically signicant results were obtained
Interventions
Outcomes
Notes
Ukimura 2008 Methods Participants Randomized controlled parallel trial. No blinding methods reported N = 81 Japanese men. Data reported only for 59 participants. Mean age 69 years, with symptomatic BPH (IPSS > 8 points; peak urine ow < 15 mL/s with a voided volume of > 150 mL); residual volume < 50 mL and a QoL index > 3 / Mean IPSS = 18.3 and peak urine ow = 9.7 mL/s. Intervention: naftopidil (N = 31) 50 mg/d Control: tamsulosin (N = 28) 0.2 mg/d Study duration: 6 to 8 weeks Symptom score as assessed by IPSS scale, Qmax (peak urine ow), QoL score, PVR (post void residual volume) Authors state that 81 patients were registered (randomized) for the trial. The data at baseline is however reported only for the 59 participants who were included for analysis
Interventions
Outcomes
Notes
Risk of bias Bias Allocation concealment (selection bias) Authors judgement High risk Support for judgement Clearly inadequate. Patients were randomized into two groups: one for patients whose birthdays were odd numbers, for administration of 50 mg Naf; and the other for patients whose birthdays were even numbers, for administration of 0.2 mg Tam
Naftopidil for the treatment of lower urinary tract symptoms compatible with benign prostatic hyperplasia (Review) Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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Yamanishi 2004 Methods Participants Randomized controlled parallel trial. Single-blind study. N = 49 Japanese men, mean age 68 years, with symptomatic BPH (IPSS > 8 points; peak urine ow > 12 mL/s; prostate volume > 15 mL) / Mean IPSS = 15.6 and peak urine ow = 9.5 mL/s. Intervention: naftopidil (N = 36) 25 mg/d x 2 weeks followed by 50 mg/d x 2 weeks and then increased to 75 mg/d x 2 weeks if the patient was not satised with the improvement in symptoms Control: eviprostat (N = 13) 6 tablets/d x 6 weeks Study duration: 6 weeks Symptom score as assessed by IPSS scale, Qmax (peak urine ow), QoL score, PVR (post void residual volume) and adverse events Dosage of eviprostat was not mentioned.
Interventions
Outcomes
Support for judgement The study mentions that randomization was done using enveloped indicating one of the two groups
Yokoyama 2006 Methods Participants Randomized controlled parallel trial. No blinding methods reported N = 153 Japanese men , aged 50 to 80 years (mean 69.9), with symptomatic BPH (IPSS > 8 points; nocturia > 3 per night; prostate volume > 20 mL) / Mean IPSS = 19.0 and peak urine ow = 8.7 mL/s. Intervention1: Naftopidil Low Dose (N = 72) 25 mg/d x 4 weeks Intervention2: Naftopidil High Dose (N = 67) 75 mg/d x 4 weeks Study duration: 4 weeks Symptom score as assessed by IPSS scale, Qmax (peak urine ow), QoL score, PVR (post void residual volume) and adverse events Data presented was for the 139 participants included in the efcacy analysis
Interventions
Outcomes
Naftopidil for the treatment of lower urinary tract symptoms compatible with benign prostatic hyperplasia (Review) Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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Study Awa 2008 Furuya 2005 Hayashi 2002 Ju 2002 Kaplan 2005 Kosugi 2007 Li 2007 Masumori 2007 Sugino 2003 Takahashi 2006 Yamaguchi 1992 Yasuda 1994
Reason for exclusion Not an RCT Non English language- Japanese, Not an RCT Non English language - Japanese, Randomization not stated Non English Language - Chinese Comment Non English language- Japanese, Randomization not stated Non English Language - Chinese Not an RCT Non English language - Japanese, Not an RCT Not an RCT Non English language- Japanese, Randomization not stated Not an RCT
Naftopidil for the treatment of lower urinary tract symptoms compatible with benign prostatic hyperplasia (Review) Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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No. of studies 3
Analysis 1.1. Comparison 1 Pooled adverse events: Naftopidil versus tamsulosin, Outcome 1 Adverse events - any.
Review: Naftopidil for the treatment of lower urinary tract symptoms compatible with benign prostatic hyperplasia
Comparison: 1 Pooled adverse events: Naftopidil versus tamsulosin Outcome: 1 Adverse events - any
Study or subgroup
Naftopidil n/N
Weight
153
173
100.0 %
Total events: 11 (Naftopidil), 12 (Control) Heterogeneity: Chi2 = 1.41, df = 2 (P = 0.49); I2 =0.0% Test for overall effect: Z = 0.03 (P = 0.98) Test for subgroup differences: Not applicable
0.01
0.1
10
100
Favours experimental
Favours control
Naftopidil for the treatment of lower urinary tract symptoms compatible with benign prostatic hyperplasia (Review) Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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ADDITIONAL TABLES
Table 1. Overview of randomized controlled trials of Naftopidil
Study characteristic
Overall Per cent or mean (range) 34 to 185 34 to 96 49 to 185 9.3 (4 to 17) 68.3 (65 to 72.4) 36.5 (29.6 to 54.0) 17.8 (15.6 to 20.4) 9.5 (8.7 to 11.1) 4.5 (3.9 to 4.8) 2.9 (2.0 to 3.5)
Number of subjects
Total # of subjects randomized Crossover design (# subjects) Parallel design (# subjects) Study duration (weeks) Mean age (years) Prostate volume (ml) Total IPSS Peak urine ow (Qmax) Quality of life (QoL) Nocturia
744 175/744 569/744 744 722/744 489/663 641/744 588/744 645/744 566/695 610/744
8 3 5 8 8 6 8 8 8 7 8
Post void residual volume 41.4 (19.4 to 57.2) (PVR) (ml) Study withdrawals (%) 16.3 (0 to 31.3)
122/744 13/663
8 7
Table 2. Primary outcomes data from individual studies of naftopidil for treating LUTS
Study
Momose 2007
-6.7a
NR
-0.60a
-7.3a
-39.36
9.2
NR
4.8
-0.70a
-14.58
Naftopidil for the treatment of lower urinary tract symptoms compatible with benign prostatic hyperplasia (Review) Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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Table 2. Primary outcomes data from individual studies of naftopidil for treating LUTS
(Continued)
Nishinio 2006
Naftopidil
20.4
-11.5a
-56.37
9.9
3.0a
36.60
4.9
-2.30a
-46.90
-11.1a
-54.41
9.0
3.0a
33.30
4.9
-2.20a
-44.90
-5.9a
-38.06
9.3
2.1a
22.5
4.5
-1.30a
-28.89
-8.4a
-50.00
9.3
2.1a
22.58
4.4
-1.40a
-31.82
-8.5a
-49.12
8.8
2.1a
23.86
4.4
NR
-8.3
-47.43
9.1
2.9a
31.87
4.6
NR
-9.4a
-54.65
10.7
1.3
12.14
4.7
-2.2a
-46.80
Low Dose 18.9 Tamsulosin Nafto17.5 Maruyama pidil 2006 Monotheray Cother16.6 apy with ACHLc Yamanishi 2004 Naftopidil Eviprostat 15.4
-9.7a
-51.32
11.8
2.8
23.72
4.8
-2.0a
-41.66
-6.3a
-36.00
10.5
1.1
10.48
4.4
-1.50a
-34.09
-5.0a
-30.12
11.8
0.60
5.08
4.4
-1.10a
-25.00
5.9ab
-38.31
9.8
3.7a
37.76
3.9
1.50ab
38.46
16.0
-0.4b
-2.50
8.5
0.5
5.88
4.2
0.00b
0.00
-4.5a
-23.94
8.0
b NR
4.7
-0.90a
-19.15
-5.4a
-27.98
8.6
ab
NR
4.7
-1.00a
-21.18
Naftopidil for the treatment of lower urinary tract symptoms compatible with benign prostatic hyperplasia (Review) Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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Table 2. Primary outcomes data from individual studies of naftopidil for treating LUTS
(Continued)
pidil reported signicant within group change from baseline (P<0.05) reported signicant between group differences (p<0.05) c combination of Naftopidil and Anti-Cholinergic agent NR value not reported
b a
Table 3. Secondary outcomes data from studies of naftopidil for treating LUTS of BPH
Study
Drug and Nocturia Control Baseline Score 2.4 2.4 3.4 3.4 2.5 2.6 2.0 1.9 3.5 3.4 3.0
PVR Mean % (decrease) Baseline Score (mL) -25.0 -25.0 -32.3b -8.8b -28.0 -34.6 -24.0 -13.1 -54.28 -50.00 -33.3 26.3 30.2 54.1 54.1 46.6 42.5 86.8 32.8 19.3 19.6 45.0 Mean % (decrease)
Momose 2007 Naftopidil Tamsulosin Nishinio 2006 Naftopidil Tamsulosin Gotoh 2005 Naftopidil Tamsulosin Ikemoto 2003 Naftopidil Tamsulosin Ukimura 2008 Naftopidil Tamsulosin Maruyama 2006 Naftopidil Monotheray Cotherapy with ACHLc Yamanishi 2004 Naftopidil Eviprostat Yokoyama 2006
-0.6a -0.6a -1.1 -0.3 -0.7a -0.9a -0.5a -0.2. -1.9a -1.7a -1a
NR NR -42.7 -44.7 -13.6a -9.6 NR NR -15.9a -3.5 NR -82.38 -17.85 -78.9 -82.6 -29.1 -22.5
2.9
-1a
-34.4
55.8
NR
NR NR
NR NR -1.1a -30.5
-28.1a -5.3 NR
-58.6 -8.8
Naftopidil for the treatment of lower urinary tract symptoms compatible with benign prostatic hyperplasia (Review) Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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Table 3. Secondary outcomes data from studies of naftopidil for treating LUTS of BPH
(Continued)
-1.0a
-28.5
28.1
NR
reported signicant within group change from baseline (P < 0.05) signicant between group differences (P < 0.05) c combination of naftopidil and anti-cholinergic agent NR value not reported
WHATS NEW
Last assessed as up-to-date: 15 June 2009.
Event Amended
HISTORY
Protocol rst published: Issue 4, 2008 Review rst published: Issue 4, 2009
CONTRIBUTIONS OF AUTHORS
Pranav Garimella: Acquisition of data, abstraction of data, analysis and interpretation of data, preparation of manuscript. Roderick MacDonald: Acquisition of data, conception and design of study, analysis and interpretation of data, critical review of manuscript. Timothy Wilt: Design of study, Critical review of analysis and manuscript preparation. Howard Fink: Design of study, Critical review of analysis and manuscript preparation.
DECLARATIONS OF INTEREST
None.
Naftopidil for the treatment of lower urinary tract symptoms compatible with benign prostatic hyperplasia (Review) Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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External sources
Grant no. 5R01DK63300-4, USA. Editing support was in part provided by the National Institutes of Health (NIH), and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK).
NOTES
None.
Naftopidil for the treatment of lower urinary tract symptoms compatible with benign prostatic hyperplasia (Review) Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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