This section details the standard criteria necessary for any clinical study on BPH.
Recommendations for Phase 3 clinical studies on medical treatments include; (i) double-blinded RCT using placebos or standard treatments as the control group; and (ii) monitoring of efficacy and safety for up to 12 months, with the primary end-points evaluated at 3 months.
Clinical question (CQ) 1: When is a bladder diary recommended as part of the assessment of BPH?
A bladder diary is recommended for men with daytime or nocturnal frequency (Grade B). The diary records individual voiding prospectively, enabling the accurate evaluation of voiding time, individual volumes voided, and total urinary volume. This information is useful for the differential diagnosis of urinary frequency, which can be classified as a decrease in the volume voided, polyuria, or both.2,101,102 Ideally, the diary should be kept over a period of 3–7 days, although keeping the diary for over 1 or 2 days may be sufficient.4
CQ 2: What examination is recommended for the anatomical evaluation of the prostate?
Ultrasonography is recommended for the anatomical evaluation of the prostate (Grade A). Compared with a digital rectal examination and other imaging tests, ultrasonography is more accurate and minimally invasive.2,100,102 Trans-abdominal ultrasonography is easily performed and readily able to detect bladder pathology, whereas trans-rectal ultrasonography permits the detailed imaging of the inner structures. The type of ultrasonography performed depends on the equipment available, as well as on the objective of the examination. PV is predictive of both clinical progression and the therapeutic outcomes of surgical or medical treatment.102,103
CQ 3: When and how is evaluation of the upper urinary tract recommended?
Evaluation of the upper urinary tract is not to be performed routinely. It is recommended for men with abnormal urinalysis, a large amount of PVR, renal insufficiency, or a history of other urological diseases (Grade B). In these cases, ultrasonography is recommended as the initial method of assessment.2,102 Renal ultrasonography in 556 men with BPH detected hydronephrosis, renal cysts, and renal cancer in 2.5, 11.7 and 0.18% of men, respectively.104
CQ 4: What considerations are recommended when assessing serum PSA values?
Serum PSA concentrations should be determined because higher PSA concentrations are indicative of prostatic cancer and enlarged PV.2,102 Serum PSA concentrations are increased in men with enlarged adenoma, prostate cancer, urinary retention, and prostatitis, but can be reduced approximately to 50% by long-term treatment with anti-androgens or 5α-reductase inhibitors25,97,102 (Grade A).
CQ 5: Is long-term therapy with α1-adrenoceptor antagonists recommended?
The efficacy and safety of α1-adrenoceptor antagonists up to 1 year has been reported in many studies. However, there is a relative paucity of long-term data over 3 years regarding the maintained efficacy of these drugs (Grade B). Most long-term studies into the efficacy of α1-adrenoceptor antagonists are open-label extensions of previous short-term trials or retrospective studies in real-life clinical practice. The study designs are not consistent. In long-term studies (over 3 years; range 4–10 years), approximately 18, 64, and 36–80% of patients withdrew from the studies after 2, 3, and >4 years, respectively. The risk factors for treatment failure were severe LUTS, low urinary flow rate, large prostate (>30–40 mL), large PVR or a history of urinary retention, concomitant OAB symptoms, urodynamically proven BOO, and insufficient effects with short-term therapy.105–108
CQ 6: Is combination therapy with α1-adrenoceptor antagonists and anticholinergics recommended for men with OAB?
There is adequate evidence supporting the efficacy and safety of combination therapy with α1-adrenoceptor antagonists and anticholinergics for BPH associated with OAB (BPH or OAB; Grade A).
For male OAB symptoms, monotherapy with α1-adrenoceptor antagonists is effective and may be a first-line treatment,2 although the efficacy of α1-adrenoceptor antagonists is limited for patients with detrusor overactivity (DO).109 The efficacy and safety of anticholinergic monotherapy have also been confirmed in the treatment of BPH and OAB.49 Combined therapies with anticholinergics and α1-adrenoceptor antagonists are more effective than monotherapy with α1-adrenoceptor antagonists in improving storage symptoms, with urinary retention being rare.48,110–112 However, it should be noted that most of these studies were conducted in Caucasian men, with strict exclusion criteria, specialist supervision, and relatively short-term observational periods. There remains a concern about the exacerbation of voiding difficulties and possible urinary retention in a practice setting.2
Note: two recent Japanese studies reported that combination therapies with tamsulosin plus anticholinergics are more effective for BPH and OAB than tamsulosin monotherapy, with lower doses of anticholinergics associated with better outcomes.113,114
CQ 7: Is combination therapy with an α1-adrenoceptor antagonist and a 5α-reductase inhibitor recommended?
Combination therapy is recommended for relatively severe disease, e.g. prostatic volume ≥30 mL (Grade B). The combination therapy with dutasteride and tamsulosin (CombAT) study randomly assigned men with BPH (N = 4844, prostatic volume ≥30 mL, 1.5 ≤ PSA ≤ 10 ng/mL, 5 ≤ maximal urine flow ≤ 15 mL/s) to either dutasteride, tamsulosin or combination therapy for 4 years.115 The average change in the IPSS and the cumulative incidence of clinical progression, −6.3 points and 12.6% in the combination therapy group, respectively, were significantly better than in other groups. Men on combination therapy for 24 weeks were randomly assigned to either continued combination therapy or dutasteride monotherapy for 36 weeks.116 Of 82 men with a pretreatment IPSS, ≥20 symptom aggravation was reported in 14% of the continued combination therapy group and 42.5% of the dutasteride monotherapy group. A study of finasteride (not indicated for BPH in Japan), the Medical Therapy of Prostatic Symptoms (MTOPS) study, randomly assigned 3047 men with BPH (IPSS ≥8 points, 4 ≤ maximal urine flow ≤ 15 mL/s) to placebo, doxazosin, finasteride or combination therapy.117 The risk of clinical progression during 4.5 years (5%) was significantly less in the combination therapy group. A similar additive effect of combination therapy is suggested in Japanese men,25,118 although trials on its efficacy and cost effectiveness in Japanese men are awaited.
CQ 8: What urodynamic test is recommended for men undergoing surgical treatment for BPH?
BOO, DU, and DO are all important prognostic variables for the surgical outcomes of BPH.119 Symptom improvement is less likely for men with no or equivocal BOO compared with men with evident BOO.120 Both DU without BOO and DO without BOO strongly predict treatment failure for TURP.121 A higher degree of BOO without DO or DU, or both, is associated with improvements in both symptoms and QOL.122 Thus, urodynamic examinations, including pressure-flow studies and cystometry, are recommended to delineate BOO, DU, and DO (Grade B). Predicting BOO using simpler parameters such as uroflowmetry and PV may be a viable alternative.123
CQ 9: What measures are recommended for persistent symptoms after surgical treatment (predominantly TURP)?
Appropriate treatments should be selected after evaluating possible causes other than BOO using urodynamic studies, including pressure-flow studies and recording a frequency and volume chart (Grade B). DO induced by BOO generally improves postoperatively, but DO without accompanying BOO often persists after surgery,121 or DO may arise independently as a result of the surgery.124 DU is present in 20–30% of men with LUTS,125 and the surgical outcome for these patients is poor.119 In a long-term postoperative study, BOO recurred in only 12.4% of patients treated with TURP, whereas DU was present in 36.5% of the men complaining of LUTS after surgery.124 Nocturia is a symptom with low specificity for BPH126 that is often caused by polyuria. Thus, the postoperative recurrence of LUTS is not necessarily attributable to BOO, but rather to overlooked or developing DO, DU, or polyuria.
CQ 10: What treatments are recommended for urinary retention by BPH?
Either insertion of an indwelling catheter or intermittent catheterization should be indicated. After this, catheter removal may be attempted after administration of an α1-adrenoceptor antagonist. Surgical intervention is likely to be necessary for a large prostate (Grade B). It is recommended to use intermittent catheterization only for urinary retention due to transient causes (e.g. the use of anaesthetic or α-sympathomimetic agents) and an α1-adrenoceptor antagonist at an attempt to remove the indwelling catheter.3 A retrospective survey on 248 patients in whom indwelling catheters were successfully removed after treatment with an α1-adrenoceptor antagonist, with a mean follow-up period of 33 months, reported a failure rate of 11.6, 14.3, 28.4, and 50.5% at 6, 12, 24 and 60 months, respectively.127 Multivariate analysis revealed a prostatic volume ≥50 mL, and a PSA level ≥10 ng/mL at the time of acute urinary retention, as predictive factors for surgical intervention. Another multivariate analysis of 72 patients showed that those with PSA >2.9 ng/mL, a large prostate size on digital rectal examination, and a volume drained at the time of catheterization >1000 mL, were best managed by surgical intervention.128
CQ 11: What measures are recommended for men with symptomatic BPH in whom usual treatments are not indicated due to deteriorating activities in daily life?
Urethral stents, intermittent catheterizaion, and indwelling urethral or suprapubic catheters should be considered as management options for such men (Grade B). Although stenting is an effective, less invasive procedure for improving symptoms,87 its utility is limited by the associated complications, including encrustation, discomfort or urethral pain, UTI, bleeding, and stent migration.4,88,89,129,130 Intermittent self-catheterization is safe and useful with minimal complications,57 although it requires manual dexterity. Urethral indwelling catheters are useful for prompt management, yet are associated with inevitable UTI, urethral erosion, strictures, and fistula formation. Suprapubic cystostomy is an alternative measure that avoids the complications caused by indwelling urethral catheters.
CQ 12: What therapeutic strategies are recommended to avoid sexual dysfunction as an adverse event?
Surgical treatment or α1-adrenoceptor antagonists are recommended to avoid erectile dysfunction (ED). To prevent ejaculatory dysfunction, surgical treatment, α1A-adrenoceptor antagonists, 5α-reductase inhibitors or anti-androgens should be avoided. To retain libido, 5α-reductase inhibitors or anti-androgens especially should be avoided (Grade B). ED as an adverse event is rare for surgery (0–12.5%),4,96 and is comparable with placebo for α1-adrenoceptor antagonists.4 Ejaculatory dysfunction has been reported to be 50–80% post-surgery,3,4,95,96 and 1.6 to 22.3% in Japanese men using α1-adrenoceptor antagonists, particularly α1A-adrenoceptor antagonists.29,131 Decreased libido and ejaculatory dysfunction are observed in men taking 5α-reductase inhibitors or anti-androgens,37,97 with more pronounced in the latter.122