Phosphodiesterase type 5 (PDE-5) inhibitors
Several trials have shown subjective benefit to tadalafil for LUTS. Gacci et al reported on a meta-analysis that pooled 3,214 men. Seven of the trials compared PDE-5 inhibitors with placebo and five compared PDE-5 inhibitors plus alpha blockers with placebo.13 Median follow up was 12 weeks.
There was a significant improvement in erectile function based on the International Index of Erectile Function (IIEF) and AUA-SS. Although there were statistically significant improvements in subjective parameters, there were no improvements in objective parameters.
Although no direct relationship has been proven, PDE-5 inhibitors appear to improve BPH-related LUTS. Although subjective improvement has been reported via improvement in IPSS scores, no improvement in objective parameters such Qmax (maximal flow rate) or post-void residual (PVR) volume, however, was seen in these studies. As such, the use of PDE-5 inhibitors remains to be determined and should not be used as first-line therapy.
In addition, long-term experience with PDE-5 inhibitors to treat LUTS is still lacking. As a warning, all PDE-5 inhibitors should not be used in patients who are taking the alpha blockers doxazosin or terazosin due to the risk of hypotension.
Alpha blockers with 5-ARIs. The Medical Therapy of Prostatic Symptoms (MTOPS) trial was the first study to demonstrate the efficacy of combination therapy over alpha blocker or 5-alpha-reductase monotherapy.14 This study was followed by a 4,844-patient trial eval- uating the efficacy of combination therapy using dutasteride and tamsulosin in men with moderate-to- severe LUTS secondary to BPH.15 This multicenter, randomized, double-blind trial demonstrated that combination treatment achieved significantly greater mean reductions in both voiding and storage symp- toms than either monotherapy at 24 months. Dutasteride alone was as effective as tamsulosin for controlling storage symptoms, but provided significantly greater relief of void- ing symptoms at 24 months. At this time point, combination therapy was more effective than monotherapy for voiding symptoms in men with prostate volumes of 30-42 cm3.
Moreover, combination therapy led to significant increases in patient-reported, disease-specific QoL.16 At four years, the study demonstrated that patients taking dutasteride significantly increased their time to first episode of acute urinary retention (AUR) or BPH-related surgery compared with tamsulosin alone.17
Alpha blockers and PDE-5 inhibitors. Combination therapy using both alpha blockers and PDE-5 inhibitors for LUTS and erectile dysfunction (ED) is gaining interest because of the increasing frequency of co-prescription in the aging population. In a study by Kaplan et al, 62 men with previously untreated LUTS and ED were randomized to daily 25 mg sildenafil versus 10 mg alfuzosin versus combination therapy.18 Combination therapy was associated with greater improvement in IPSS and IIEF scores over either monotherapy. The most common adverse effects included dyspepsia, dizziness, and flushing.
Several single-arm trials have shown benefit of onabotulinumtoxinA (Botox) injection to the prostate either through a transrectal or transperineal route. In a multicenter, double blind, phase 2 dose-finding study, 380 men were randomized to receive either placebo or onabotulinumtoxin A either through a transperineal or transrectal route.19 All patients experienced an improvement in all parameters, including AUA-SS and Qmax. There was a large placebo effect noted from both transperineal and transrectal injections.
Minimally invasive therapy
Transurethral microwave therapy (TUMT). In a Cochrane Review published in 2012, researchers reviewed 15 studies of TUMT involving 1,585 patients. These studies included six comparisons of TUMT with transurethral resection of the prostate (TURP), eight comparisons with sham thermotherapy procedures, and one comparison with an alpha blocker.20
Study durations ranged from 3-60 months. The pooled mean urinary symptom scores decreased by 65% with TUMT. The pooled mean peak urinary flow increased by 70% with TUMT. Compared with TURP, TUMT was associated with decreased risks for retrograde ejaculation, treatment for strictures, hematuria, blood transfusions, and the transurethral resection (TUR) syndrome, but increased risks for dysuria, urinary retention, and retreatment for BPH symptoms. No studies evaluated the effects of symptom duration, patient characteristics, PSA levels, or prostate volume on treatment response.
Prostatic urethral lift (Urolift)
The prostatic urethral lift system is a relatively new non-ablative technique that uses solely mechanical compression to open the prostatic urethra. A handheld delivery device is fired with transurethral sutures at the anterolateral lobes of the prostate.
In a smaller prostate (e.g. 60 grams), two to four sutures are needed, whereas larger glands require more sutures. A relative contraindication for the prostatic urethral lift system is a large median lobe.
The device has been tested in other countries, but has not been approved by the FDA. Initially the safety of the device was tested in 19 men with moderate-to-severe LUTS.21 All patients tolerated the procedure with no serious or unexpected adverse events. The most common adverse event was hematuria (63%) or dysuria (58%) that resolved in three to five days.
The device was then evaluated in a prospective multicenter trial in Australia that enrolled 64 men with moderate to severe LUTS.22 The study demonstrated a 42% improvement at two years in IPSS and 30% improvement in peak flow.
About half of the patients did not have a post-operative catheter, and three quarters of the patients requiring post-operative catheters had the catheters removed the next day.
In addition, there were no reports of anejaculation or retrograde ejaculation.
Erectile function as measured using the Sexual Health Inventory for Men (SHIM) questionnaire, was slightly improved from baseline. The most common adverse effects included irritative symptoms and hematuria that resolved within the first few weeks.
This initial data from this multicenter single-arm trial seems promising. The prostatic urethral lift system does require physician education, ease with insertion, and reproducibility.
Furthermore, the device requires rigid cystoscopy in an awake male, which itself is a challenge.