Hypothesis / aims of study
To investigate the add-on effects of tadalafil for tamsulosin-treated patients with benign prostatic hyperplasia (BPH) suffering from residual lower urinary tract symptoms by a randomized, placebo-controlled, double-blind, crossover study.
Study design, materials and methods
From September 2014 to July 2018, we evaluated patients who were treated with tamsulosin for mild BPH for at least 4 weeks and were still suffering from residual lower urinary tract symptoms in our hospital. The key inclusion criteria were: 1) Patients who agree with this study; 2) 50 years old men and elder; 3) Diagnosed as benign prostatic hyperplasia using a standard method; 4) Prostatic volume is between 20 ml and 40 ml; 5) Patients who have IPSS total score no less than 8 and QOL no less than 3 under treatment of tamsulosin 0.2 mg for at least 4 weeks. The key exclusion criteria were: 1) Patients with prostate cancer, neurogenic bladder, urethral stricture, chronic prostatitis, urinary tract infections, urinary tract stones or interstitial cystitis; 2) Patients with a contraindication for tadarafil; 3) Patients taking silodosin or naftopidil, or within 2 weeks after stopping those two; 4) Patients taking dutasteride, or within 3 months after stopping dutasteride; 5) Patients taking anticholinergics, or within 2 weeks after stopping them; 6) Patients who are considered as not applicable to this study by an attending doctor. Patients were randomized into two groups: one was dosed with tadalafil of 5 mg once daily for 6 weeks followed by placebo for 6 weeks (Tadalafil-placebo group), and the other was set in placebo for 6 weeks followed by tadalafil 5 mg once daily for 6 weeks (Placebo-tadalafil group). Patients visited to our outpatient clinic after 2 weeks, 6 weeks, 8 weeks and 12 weeks. Questionnaires of IPSS, IPSS-QOL and OABSS were obtained each time, and uroflowmetry and voiding diary were retrieved at week 6 just before alternating tadalafil/placebo and at week 12 as the end of the treatment period.
The primary endpoint of this study was for differences of total IPSS score from baseline to cross over treatment of tadalafil and placebo for 6 weeks each. Secondary endpoints were: 1) Changes in questionnaire parameters (IPSS each score, IPSS-QOL, OABSS, IIEF-5); 2) Changes in uroflowmetry parameters (Qmax, residual urine); 3) Changes in voiding diary (frequency per day, frequency at daytime, frequency at night, urine volume per day and average voided volume); 4) Safety, adverse events and side effects. The data of two groups were integrated and reclassified as combination therapy of tamsulosin with tadalafil and monotherapy of tamsulosin with placebo.
Thirteen patients each belonged to tadalafil-placebo group and for placebo-tadalafil group (total 26 patients), respectively, and the median age (range) of the patients were 70 (65–85) and 73 (50–80). The median prostatic volumes were 30.0 (22.0–39.7) and 32.0 (20.1–39.5), and the median IPSS total score were 15.5 (10–27) and 16 (10–24). The primary endpoint, the total IPSS mean changes from the baseline were -1.75 in placebo and -3.5 in tadalafil, which was statistically significant (difference: -1.75 95% CI -3.27, -0.23, p = 0.026). This explained that the tadalafil add-on for 6 weeks had a greater effect on the improvement of total IPSS compared to the placebo (difference: -1.75 95% CI -3.27, -0.23, p = 0.026). As for secondary endpoints, the significant difference was observed only in the IPSS item 3 (intermittency) with -0.15 in placebo and -0.54 in tadalafil (difference: -0.38 95% CI -0.73, -0.04, p = 0.030). Other scores of each IPSS items, OABSS, maximal urine flow rate and residual urine did not show any significant difference. No complaint for side effects was obtained.
Interpretation of results
This explained that the tadalafil add-on for 6 weeks had a greater effect on the improvement of total IPSS compared to the placebo