Several large, well-known studies found statistically significant improvements with combination therapy in overall IPSS as well as quality of life, however in some, the benefits were small and of questionable clinical significance. More significantly, however, is the risk reduction patients experience in terms of reduced rates of urinary retention and progression to surgical intervention as cited in the MTOPS trial.166 While combination therapy is generally considered safe, there is a risk for potentiated hypotension that is higher with non-selective ABs and requires monitoring. CombAT was a 4-year randomized, double-blinded, parallel group study of 4,844 men ≥50 years of age with moderate to severe LUTS/BPH, IPSS ≥12 points, prostate volume ≥30 cc, and a serum PSA 1.5-10 ng/mL. Participants were randomized to dutasteride in combination with tamsulosin or either drug alone. Combination therapy provided better relief than tamsulosin alone in terms of both LUTS and quality of life as evidenced by reduced IPSS and better urinary flow rates, as well as better clinical outcomes (decreased need for surgery and urinary retention). CombAT did not show clinically important differences in symptoms or quality of life between combination therapy and dutasteride alone, and there was some limited evidence of better clinical outcomes with combination therapy. Combination therapy was well-tolerated with a safety profile consistent with the individual medications.174 Furthermore, during this study, prostate biopsies were done only for significant changes in PSA and did not show a higher rate of high-grade prostate cancer. The REDUCE trial noted men on dutasteride had a lower incidence of low-grade prostate cancer by approximately 23% but found an increase in cases of high-grade prostate cancer. The exact mechanism is unknown and remains debated.175 The MTOPS trial evaluated the effectiveness of finasteride, doxazosin, and their combination in managing BPH symptoms. This was a 4-year multicenter, randomized, double-blinded, placebo-controlled trial that included 3,047 men ≥50 years of age with BPH symptoms identified by an IPSS ≥8 points. Participants also had a prostate volume ≥30 cc and Qmax ≤15 mL/s. The combination group that received finasteride with doxazosin was found to have significantly improved symptoms (7-point improved AUA-SS score versus baseline), reduced risk of urinary retention (81% risk reduction versus placebo; 0.1 versus 0.6 cases/100 person-years), and decreased need for surgical intervention (near 67% risk reduction versus placebo). Symptom improvement with combination therapy was similar to that with doxazosin (-7 points versus -6 points at year 4), and slightly better than that with finasteride (-7 points versus -5 points). Clinical outcomes were better with combination therapy than with doxazosin alone, but similar between combination therapy and finasteride. Although not a primary endpoint, there was superior flow rate improvement with combination therapy compared to both monotherapies as well.116, 166 The CONDUCT trial found improved IPSS, quality of life, and rates of clinical progression associated with immediate combination therapy of dutasteride plus tamsulosin compared with watchful waiting and delayed tamsulosin therapy. However, the study also noted increased withdrawal rates in the combination group for ED, EjD, and rarely cardiovascular adverse events.187, 188 Most of the side effects related to the pharmacotherapy for treatment of LUTS/BPH will be resolved after discontinuation of medication, however, some long-term effects have been associated with these medications and the Panel believes it is important that discussion should take place for proper shared decision-making. There continues to be a paucity of large studies regarding the initiation of combination therapy with the intention of later withdrawal or discontinuation of the AB medication. This has been referred to as “Withdrawal Therapy” in the previous Guideline.14 Rationale for this approach is for men to benefit from the AB’s earlier onset while the 5-ARI benefit is slower to appreciate. The strategy then is to remove the AB and maintain adequate symptom control. Barkin et al. was a small study that had patients with lower IPSS (<20 points) and were without noticeable deterioration in their symptoms when stopping tamsulosin after dual therapy (dutasteride and tamsulosin) for 12 weeks.189 Lee et al. had different findings in a small RCT that looked at the withdrawal of either AB or 5-ARI medication following a period of success with combination therapy. Both groups had similar IPSS deterioration (≥2 points) at 24 months (27.8% in the AB group and 26.4% in the 5-ARI withdrawal group).190 Similarly, Lin et al. also demonstrated progression of BPH symptoms in patients on combination therapy with the discontinuation of either medication. Furthermore, patients with a larger prostate volume had a greater need for resuming 5-ARI therapy or needing a TURP.191 While the strategy of withdrawal seems reasonable in theory, the concept has not been studied sufficiently to determine the utility of this approach or the optimal durations of combination therapy before the cessation of the AB. Clinicians should follow general guidelines on PSA screening when initiating therapy with 5-ARIs as it is widely accepted that this medication will influence one’s future PSA measurements.54