In several countries, current guidelines for the treatment of benign prostatic hyperplasia (BPH) recommend the use of alpha-1 receptor blockers or phosphodiesterase 5 (PDE5) enzyme inhibitors in patients with lower urinary tract symptoms ( LUTS) indicative of this prostate condition (LUTS-BPH).
Tadalafil is the only PDE5 inhibitor approved for the treatment of BPH-LUTS; This drug can act through different mechanisms, such as relaxing the tone of the prostate smooth muscle and the bladder neck, increasing blood perfusion to the organs that make up the urinary system, inhibiting afferent nerve fibers and suppressing inflammation due to decreased Rho-kinase activity.
In placebo-controlled clinical trials, subjective symptomatic improvement was observed, but not in objective parameters such as urinary flow, although there is no long-term information that evaluates its effect on the emptying and storage functions of the bladder. For this reason, the authors decided to evaluate the efficacy of oral monotherapy with thaladafil on bladder functions in men with LUTS-BPH through a urodynamic study.
| Materials and methods |
The reference study, with an open and prospective design, included 105 Japanese men aged 50 years or older, without previous treatment and with the following criteria: score on the International Prostate Symptom Score (IPSS) scale ≥ 8; IPSS score related to quality of life (IPSS-QOL) ≥ 3; prostate volume ≥ 25 ml; maximum urinary flow (Qmax) < 15 ml/s with a voided volume ≥ 100 ml, and residual volume < 150 ml.
In those participants with prostate-specific antigen values greater than 4 ng/ml, a biopsy was performed to rule out prostate cancer.
Cases of neurogenic bladder, severe heart disease, deterioration of renal function with serum creatinine ≥ 2 mg/dl or alterations in the hepatogram were excluded , as well as those treated with drugs that could affect the results (alpha-adrenergic blockers, antidepressants, anxiolytics, nitroglycerin, among others).
Participants who met all inclusion criteria and none of the exclusion criteria received tadalafil 5 mg orally daily for 12 months.
The IPSS, IPSS-QOL, Overactive Bladder Symptom Scores (OABSS) and BPH Impact Index (BII) scores were assessed before the start of treatment, and then at 3 and 12 months.
In the same periods, a urodynamic study was carried out, in which, as parameters of the storage function, the first desire to void (FDV), the maximum cystometric capacity (MCC, maximum cystometric capacity) and detrusor overactivity (HD), while the bladder emptying parameters analyzed were Qmax, post-void residual urine volume (PVR), detrusor pressure at the time of Qmax (PdetQmax) and the bladder outlet obstruction index (BOOI).
The results found are presented as mean ± standard deviation, and the Wilcoxon and McNemar tests were used to evaluate the subjective changes and objective parameters. A value of p < 0.05 was considered statistically significant.
| Results |
Five participants discontinued treatment due to side effects, such as headaches, dizziness, and erection disorders; another two presented urinary retention, and in four the study of urinary flow pressure was not carried out during follow-up, so the data were analyzed based on the information obtained in 94 patients, in whom their average age was 70.7 years old and his average prostate volume was 44.5 ml.
The treatment caused significant improvements in the subjective evaluation carried out using the IPSS, OABSS, IPSS-QOL and BII questionnaires at 3 months, which were accentuated at 12 months of the study; A global reduction in the mean scores of 6.9, 2.0, 1.9 and 3.2 points, respectively, was determined (p < 0.001 for all the scales mentioned when comparing the initial score with the final score).
Likewise, objective parameters such as FDV and MCC presented a statistically significant improvement in the first evaluation carried out, which expanded after 12 months of treatment (p= 0.004 and p= 0.02, when comparing the initial values with the final ones); Furthermore, the disappearance of OD was observed in 15 (30.6%) and 22 (44.9%) patients after 3 and 12 months, respectively.
The Qmax value increased by 2.9 ml/s throughout the study, a fact that was considered significant (p < 0.001), while the PVR presented a decrease, also significant, at 3 (p = 0.02) and 12 months (p = 0.002).
In absolute terms, the decrease in this variable was 20 ml between the initial value and that calculated at 3 months, and 27 ml at the end of the study.
The PdetQmax parameter also presented a significant reduction of 10.9 cm of water, compared to the value obtained at the beginning (p= 0.002).
Regarding the BOOI index, a reduction in its score of 13.8 and 16.6 points was observed at 3 and 12 months of the study, values that were considered statistically significant (p= 0.001 and p< 0.001, respectively).
| Discussion and Conclusions |
The authors explain that this was the first work to evaluate the objective effects of the daily administration of 5 mg of tadalafil on the storage and emptying functions of the bladder in patients with LUTS-BPH for more than 3 months, since in a study controlled with placebo, Dmochowski and collaborators reported the urodynamic effect of this agent used for 3 months, while other studies detected a significant improvement in subjective symptoms of the lower urinary tract with the use of this PDE5 inhibitor as monotherapy, for a period of 3 months. intermediate period.
After 12 months of treatment, the mean values of PdetQmax, Qmax, and BOOI showed an improvement of 10.9 cm water, 2.9 ml/s, and 16.6, respectively, data that were considered statistically significant.
Due to the lack of similar studies, the authors comment that they cannot compare these data with those of other published works, although they mention that, previously, they themselves carried out a research in which the alpha-1 blocker was used. adrenergic silodosin, and determined a change in the mean PdetQmax of -12.6 cm water (p< 0.001), a mean increase in Qmax of 1.8 ml/s (p< 0.001) and a mean change in the BOOI index of -16.2 (p < 0.001).
When comparing the two studies, the beneficial effects were practically identical, so they consider it likely that the use of tadalafil is associated with similar efficacy in relation to parameters such as Qmax and bladder outlet obstruction.
Beyond the improvement in bladder capacity, the incidence of HD disappearance was 30.6% after 3 months, and increased to 44.9% at 12 months, a difference that they considered significant, they add.
Likewise, they consider that their findings provide evidence-based guidance for physicians when they need to implement treatment for patients with LUTS-BPH.
In the literature, discordant data were reported in relation to the use of tadalafil and Qmax, since, in a placebo-controlled study, this drug was associated with significant improvements in this parameter, although other studies could not corroborate the difference from the statistical point of view.
One limitation they mention about the work carried out is the lack of a placebo group. This is why the placebo effect cannot be excluded regarding changes in subjective symptoms and urodynamic parameters; However, they consider that this effect is probably minimal when an analysis of objective parameters is carried out, such as those used in this work.
Furthermore, the habituation effect could have played a role when carrying out repeated urodynamic assessments, although in other investigations that used placebo, the influence of this effect was insignificant, which is why they consider that it did not cause a major problem in terms of the objectivity of the work they did.
The authors consider it necessary to carry out studies with a longer treatment period to analyze, in greater depth, the long-term effects of this PDE5 inhibitor on the function and obstruction of the bladder outlet tract.
| Based on the results obtained, the authors conclude that the use of tadalafil for 12 months significantly improved LUTS-BPH and urodynamic parameters such as bladder capacity, HD, Qmax and BOOI at 3 months, and continued to improve until the end of the study period. |
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