PDE-5Is have beneficial effects on LUTS with or without comorbid ED and therefore should be offered to men with LUTS/BPH. The mechanism of action of this PDE-5I effect is only partially understood, but there is emerging clinical evidence of their effect on LUTS/BPH (alone or in combination with other agents) as summarized below. PDE-5Is versus Placebo A meta-analysis by Gacci et al. made up of RCTs has demonstrated that PDE-5Is, in addition to significant improvement in International Index of Erectile Function (IIEF) score, reduce IPSS, storage and voiding LUTS, and improve quality of life with no significant difference in Qmax compared to placebo.158 A systematic review by Brasure et al. identified nine RCTs comparing tadalafil to placebo.141 At three-month follow-up, tadalafil treatment was associated with a small improvement in symptom scores and quality of life. Tadalafil improved IPSS by 5.5 points versus 3.4 points with placebo. There was an increase in withdrawal due to adverse events in the treatment group. Short-term, serious adverse effects were rare and reported in similar proportions with tadalafil and placebo. Long-term experience with tadalafil in men with LUTS is limited, with no data reporting efficacy or tolerability greater than one year.159 PDE-5Is + Beta-3 Agonists versus PDE-5Is One RCT (n=161) assessed the effectiveness of a PDE-5I plus a beta-3 agonist versus PDE-5I monotherapy.160 Men with persistent LUTS, despite being on tadalafil treatment for at least 8 weeks, were randomized to either tadalafil plus mirabegron combination therapy or tadalafil monotherapy with a 12-week follow-up.160 While there was no significant difference observed in urinary flow rates, the combination showed a greater patient-reported treatment satisfaction. PDE-5Is + ABs versus Anticholinergics + ABs One RCT (n=75) compared 5 mg tadalafil add-on therapy with 5 mg solifenacin add-on therapy in patients with a poor response to AB monotherapy.161 Men in both tadalafil and solifenacin groups had similar improvements in LUTS and quality of life based on the IPSS; clinical progression and sexual function outcomes were not reported. Men in the solifenacin group were more likely to withdraw from the study due to adverse events, primarily due to urinary retention, voiding difficulty, or constipation.