Busetto_Stesura Seveso 10/01/20 08:48 Pagina 205 DOI: 10.4081/aiua.2019.4.205 ORIGINAL PAPER Efficacy and safety of Finasteride (5 alpha-reductase inhibitor) monotherapy in patients with benign prostatic hyperplasia: A critical review of the literature Gian Maria Busetto 1, Francesco Del Giudice 1, Daniele D’Agostino 2, Daniele Romagnoli 2, Andrea Minervini 3, Bernardo Rocco 4, Alessandro Antonelli 5, Antonio Celia 6, Riccardo Schiavina 7, Luca Cindolo 8, Benjamin I. Chung 9, Jae Heon Kim 10, Martina Maggi 1, Alessandro Sciarra 1, Ettore De Berardinis 1, Angelo Porreca 2 1 Department of Maternal-Child and Urological Sciences, Sapienza Rome University, Policlinico Umberto I Hospital, Rome, Italy; 2 Department of Urology, Policlinico Abano Terme, Abano Terme (PD), Italy; 3 Department of Urology, University of Florence, Unit of Oncologic Minimally-Invasive Urology and Andrology, Careggi Hospital, Florence, Italy; 4 Department of Urology, University of Modena and Reggio Emilia, Modena, Italy; 5 Department of Urology, Azienda Ospedaliera Universitaria Integrata (A.O.U.I.), Verona, Italy; 6 Department of Urology, San Bassiano Hospital, Bassano Del Grappa, Italy; 7 Department of Urology, University of Bologna, Bologna, Italy; 8 Department of Urology, Villa Stuart Hospital, Rome, Italy; 9 Department of Urology, Stanford Medical Center, Palo Alto, CA, USA; 10 Department of Urology, Soonchunhyang University Seoul Hospital, Soon Chun Hyang University College of Medicine, Seoul, Korea. Summary Background: Combination therapy with 5 teride monotherapy were demonstrated, the effective size of the alpha-reductase inhibitor (5-ARI) and available reports included in the analysis is limited. Additional alpha-blocker can be considered as a gold standard interven- head-to-head studies would be needed to re-evaluate clinical tion for medical management of lower urinary tract symptoms efficacy and safety of 5-ARI in combination or not with alpha related to benign prostatic hyperplasia (LUTS/BPH). On the blockers. other hand, 5-ARI monotherapy and in particular Finasteride KEY WORDS: Benign prostatic hyperplasia; 5 alpha-reductase alone is currently getting focus of attention especially due to lack of systematic reviews investigating efficacy outcomes inhibitor; Finasteride; Side effects. and/or adverse events associated. Submitted 27 November 2019; Accepted 7 December 2019 Objectives: Aim of the present critical review was to analyze current knowledge of clinical efficacy and incidence of adverse events associated with 5-ARI treatment for LUTS/BPH. INTRODUCTION Materials and methods: A systematic review of clinical trials of Benign prostatic hyperplasia (BPH) with lower urinary tract the literature of the past 20 years was performed using data- symptoms (LUTS) is one of the most common diseases base from PubMed, Cochrane Collaboration and Embase. A prevalent in elderly men. Prevalence of BPH among men total of 8821 patients were included in this study and inclusion in their 50s and 60s is 50% rising to 90% by the age of criteria for studies selection were: data from randomized clini- 80s with significant consequent impact on Quality of Live cal trials (RCTs) focusing their attention on the clinical role of (QoL) outcomes (1, 2). Five Alpha-Reductase Inhibitors Finasteride monotherapy for symptomatic BPH. Parameters of (5-ARI) block the conversion of testosterone to dihy- research included prostate specific antigen (PSA), prostate vol- ume (PV), International Prostate Symptom Score (IPPS), post- drotestosterone, which accounts for the efficacy of its void residual urine (PVR), voiding symptoms of IPSS (voiding use in the treatment of BPH/LUTS, by reducing prostate volume (3, 4). To date, there are two types of 5-ARIs: IPSS), maximum urinary flow rate (Qmax), and adverse events (AEs). finasteride and dutasteride. While finasteride inhibits Results: Overall 12 original articles were included and critical- only type 2 5-ARI, dutasteride inhibits both type 1 and ly evaluated. Sample sizes of patient actively treated with 2, but both medications have shown similar efficacy (5). finasteride varied from 13 to 1524 cases analyzed in a single Primary medical management of men with BPH/LUTS study. Follow-up after treatments ranged from 3 to 54 months. include alpha-blockers and 5-ARI as standard therapy The effect of finasteride in reducing prostate volume (PV) was and Serenoa repens with more limited efficacy (6-8). moderate (standardized mean difference (SMD) effect between Combination treatment with alpha blockers have been 0.5 to 0.8 for all trials evaluable) while the effect on IPSS score and Qmax was considered significant (SMD in the 0.2 to demonstrated to be able to significantly decrease prostate 0.5 variation range). No severe AEs and/or psychiatric disor- volume (PV), improve International Prostate Symptom ders were retrieved among the studies. Sexual health dysfunc- Score (IPSS), improve Qmax, decrease risk of acute urinary tions were significantly influenced by finasteride therapy when retention (AUR) and operative procedures related with compared with placebo treated patients. BPH/LUTS better than finasteride alone. Even studies on Conclusions: Although significant clinical benefits of finas- 5-ARI monotherapy resulted, especially for finasteride, No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2019; 91, 4 205 Busetto_Stesura Seveso 10/01/20 08:48 Pagina 206 G.M Busetto, F. Del Giudice, D. D’Agostino, et al. in a significant improvement in all BPH related symp- literature search. Accordingly, we searched publications toms by long-term treatment (9, 10). However, decision using the following primary and secondary fields: “benign of implementing a 5-ARI monotherapy regimen of treat- prostatic hyperplasia” and “low tract urinary symptoms” ment should be cautiously evaluated by urologists due to and “5 alpha-reductase inhibitor” and “finasteride” and “5- recent warning data suggesting adverse clinical implica- ARI monotherapy” and “side effects” (primary fields); “PSA tions of such drugs including the events of erectile dys- reduction” and “placebo controlled” and “randomized clini- function, decreased libido, clinically significant prostate cal trials” (secondary fields). For all studies, we evaluat- cancer increase of incidence, gynecomastia, and anxiety ed the level of evidence (LE) according to the European (11-15). Moreover, in their recent systematic review and Association of Urology (EAU) guidelines (Table 1) (20). metanalysis Kim et al. (16) clearly raised the correlation on 5-ARI administration and possible risk for suicidal Selection of the studies, criteria of inclusion, attempts and depression, showing also a considerable analysis of the outcomes number of men reporting intolerable adverse effects after Entry into the analysis was restricted to data collected initiating finasteride therapy, and continuing to experi- from original studies, including data from BPH sympto- ence these effects after treatment withdrawal (10, 11). matic men trials implementing finasteride as per stan- These peripheral or secondary effects have undesirable dard of treatment compared with a placebo arm. Two consequences that are collectively becoming known as authors (FDG and GMB) independently screened the post-finasteride syndrome (17-19). titles and abstracts of all articles using predefined inclu- Considering the social burden of BPH significant symp- sion criteria. The full-text articles were examined inde- toms on the worldwide QoL scenario in men, together pendently by three authors (AP, FDG, and EDB) to with the wide prescription/assumption of these medica- determine whether or not they met the inclusion criteria. tions, more evidence is needed in order to develop bet- Then, two authors (FDG and BIC) extracted data from ter information for both clinicians and patients, which the selected articles. Final inclusion was determined by could have benefits regarding shared decision making consensus of all investigators. Study inclusion criteria about 5-ARI use. were: 1) randomized controlled clinical trials (RCTs) with Aim of our analysis was to critically update current 5-ARI and placebo administration; 2) daily 5-ARI treat- knowledge specifically for the efficacy and safety profile ment; 3) disease indication of BPH/LUTS; 4) types of of finasteride 5-ARI monotherapy in men with functional outcomes measures including at least one of BPH/LUTS through a critical review of available RCTs these: prostate specific antigen (PSA), prostate volume (PV), which have systematically implemented the use of finas- International Prostate Symptom Score (IPPS), post-void teride as per standard of reference. In particular we ana- residual urine (PVR), voiding symptoms of IPSS (Voiding lyzed the impact of finasteride monotherapy on urody- IPSS), maximum urinary flow rate (Qmax), and adverse namics variables (PV; Qmax), questionnaire score (IPSS) events (AEs). and secondary outcomes (comparison with Placebo). At To evaluate the effect of the different continuous vari- the same time, we carried out a review of the drug toler- ables analyzed, standardized mean difference (SMD) was ability and sides effects profile. identified from the studies included as was recently reported by the systematic review and metanalysis of Kim et al. on 5-ARI monotherapy in patients with BPH (21). MATERIALS AND METHODS In their analysis, SMDs were calculated as the difference between the mean change in the treatment and placebo Evidence acquisition groups divided by the pooled standard deviation (SD). We performed