Introduction

Nonneurogenic lower urinary tract symptoms (LUTS) have a high prevalence in men after middle ages, whose number is expected to grow very rapidly over the next decades as a result of the gradual aging of the population [ ]. LUTS can be progressive affecting quality of life (QoL) and may lead to urinary retention and surgical intervention [ ]. During the last decades, the medical therapy of male LUTS has progressively expanded and it is currently including different novel class of drugs, mainly represented by α1-blockers (AB) and 5α-reductase inhibitors (5ARI). Of note, the efficacy of monotherapy with such medications has been well documented in randomized control trial [ ]. Based on the mechanism of action, several associations of different drugs have been tested in specific clinical setting. In the present chapter, the following combination therapies will be considered: AB + 5ARI, AB associated with antimuscarinic agents or β3-adrenoreceptor agonist, 5ARI + phosphodiesterase 5 inhibitors (PDE5Is), plant extracts combined to other agents.

AB + 5ARI

Although there is a strong rationale for this association therapy, determined by the different mechanism of action of AB and 5ARI, three studies in the past (VA-COOP, ALFIN, and PREDICT) failed to demonstrate a benefit of the combination compared to monotherapy. In the Veteran Affairs Cooperative (VA-COOP) study, terazosin was significantly more effective than finasteride monotherapy, both for symptom reduction and for peak urinary-flow rates improvement [ ]. The combination was no more effective than terazosin alone. No threshold level of prostatic enlargement was required, the baseline characteristic were the following: mean prostatic volume 37 cm ³ , mean PSA level 2.3 ng/mL, and mean International Prostate Symptom Score (IPSS) score 16.2.

In the ALFIN study patients received sustained release (SR) alfuzosin or finasteride, or both drugs for 6 months [ ]. Primary efficacy criteria were symptomatic improvement and maximum flow rate. In this 6-month trial, SR alfuzosin was more effective than finasteride, with no additional benefit in combining both drugs. Even in the PREDICT study, monotherapy of doxazosin has been shown to be more effective in improving symptoms and urinary flow compared to finasteride and placebo, but the combination of doxazosin + finasteride did not produce any better results with respect to monotherapies [ ]. In this study, the prostate volume was measured only by digital rectal examination with a mean value of 36 g. Mean baseline PSA was 2.6 ng/mL and mean IPPS score was 17.3.

The main limitations of the earlier-mentioned studies were a short follow-up schedule (6 months-1 year), the inclusion criteria were not defined in details, patients were not selected for risk of progression, and finally clinical progression was not considered a study endpoint [ ].

The Medical Therapy of Prostatic Symptoms (MTOPS) study was the first to conclude that 5ARI (finasteride) + AB (doxazosin) administered for over 4.5 years are significantly more effective than single drug therapy, in patients with mild-to-severe benign prostatic hyperplasia (BPH) [ ]. Combination therapy provided a significantly greater reduction in the overall risk of surgical treatment and clinical progression (defined as an increase above baseline of at least four points in the American Urological Association symptom score, acute urinary retention (AUR), urinary incontinence, renal insufficiency, or recurrent urinary tract infection) than either drug alone. The number needed to treat to prevent one instance of overall clinical progression was 8.4 for combination therapy, 13.7 for doxazosin, and 15.0 for finasteride. In a preplanned secondary analysis, among men who had serum PSA levels of more than 4.0 ng per milliliter or a baseline prostate volume of more than 40 mL on transrectal ultrasonography, the number needed to treat decrease to 4.7 and 4.9, respectively, for combination therapy and 7.2 for both subgroups for finasteride therapy. Treatment with finasteride and combination therapy significantly reduced the risk of receiving invasive therapy, by 64% and 67%, respectively, as compared with placebo. The number needed to treat to prevent 1 patient from undergoing invasive therapy was 25.9 for combination therapy and it dropped to 23.1 and 15.9 in men with initial serum PSA levels of more than 4.0 ng per milliliter and in those with a prostate volume of more than 40 mL at baseline. In contrast, doxazosin did not significantly reduce the cumulative incidence of invasive therapy [ ].

The study demonstrated the long-term safety of doxazosin, finasteride, and combination therapy, with incidence rates of the typical adverse effects similar to those reported in prior studies [ ]. The adverse events negatively affecting sexual function were significantly more common in the combination arm. A subsequent analysis confirmed that the greater reductions in symptoms and the risk of progression with combination therapy compared with either drug alone were significant in men with a prostate volume of at least 25 cm ³ [ ].

The MTOPS study differed from the previous three studies mainly in duration (average follow-up 4.5 years), while mean prostate volume (36.3 cm ³ ), mean IPSS score (16.9), and mean PSA value (2.4 ng/mL) at baseline were substantially overlapping.

The CombAT ( Comb ination of A vodart and T amsulosin) trial is a long-term (4-year), international, multicenter, randomized, double-blind, parallel-group study investigating the efficacy and safety of treatment with dutasteride and tamsulosin, alone and in combination, in improving symptoms and reducing the risk of AUR and disease-related surgery in men with moderate-to-severe BPH [ , ]. In this study 4844 subjects over the age of 50 were randomized.

Compared to the MTPOS study, in the CombAT study there were more narrow selection criteria, with PSA and prostate volume thresholds, so that patients with higher risk of progression of BPH were recruited; prostate volume was ≥ 30 cm ³ (mean value 55.0 cm ³ ), mean PSA at baseline was 4.0 ng/mL, and IPSS was ≥ 12 [ , ]. The population of the CombAT study should be the one that gets the most benefit from combination therapy. In CombAT, there are two separate primary endpoints for symptoms (at 2 years) and the risk of AUR and surgery (at 4 years).

The results at 2 years showed that association therapy significantly improved symptomatology compared with only dutasteride, starting from 3 months and with only tamsulosin, starting from 9 months. Significant reduction in IPSS was found in comparison with baseline values with combined therapy (mean reduction of 6.2 units) compared with dutasteride monotherapy (mean reduction of 4.9 units) or tamsulosin (average reduction of 4.3 units) [ ] ( Fig. 11.1 ).

CombAT study, 2-year results. Adjusted mean change from baseline IPSS in the three study arms.

In addition, the pharmacological association has been significantly superior to monotherapy for improved urinary flow. The increase in the maximum flow rate compared to the baseline value was significantly greater with the combination therapy than the single agents since the first 6-month evaluation, and then maintained up to 2 years when the flow increased by more than 3 mL/s. in 39% of the patients in the combined therapy arm and 35% and 27%, respectively, with dutasteride alone and tamsulosin ( Fig. 11.2 ).

CombAT study, 2-year results. Q _max increase from baseline in the three study arms.

Combination therapy was significantly superior to tamsulosin monotherapy with regard to prostate volume reduction from baseline at 12 months and 24 months (− 27% vs. 0% at month 24). Even with regard to QoL, combination therapy has proven to be more effective (reduction in the BPH Impact Index score and IPSS Q8 score). There was a statistically significant increase in any-drug related adverse event in association therapy compared to each monotherapy, which was mostly driven by an increased incidence of ejaculatory disorders and erectile dysfunction [ ]. The incidence of erectile dysfunction and ejaculatory disorders was 7.4% and 9.4% respectively, in association therapy versus 6.0% and 1.8% for dutasteride alone and 3.8% and 3.0% for tamsulosin alone [ ].

Overall, however, the profile of adverse events for combined therapy was similar to that reported for monotherapy and they are cumulative and did not seem synergistically potentiated. The incidence of any-drug related adverse event leading to withdrawal was 5%, 3%, and 3% in the combination therapy, dutasteride and tamsulosin groups, respectively. Only 1% of subjects in the combination therapy group discontinued treatment as a result of an ejaculatory disorder [ ].

The results at 4 years demonstrated that combination therapy was significantly superior to tamsulosin monotherapy but not dutasteride monotherapy at reducing the relative risk of AUR or BPH-related surgery [ ]. Combination therapy reduced the relative risk of AUR or BPH-related surgery by 65.8% compared with tamsulosin ( Fig. 11.3 ).

CombAT study. Four-year incidences of acute urinary retention (AUR) or benign prostatic hyperplasia (BPH)-related surgery with combination therapy versus each monotherapy.

In the selected population for CombaAT trial, the number needed to treat with combination therapy to prevent a single man from developing symptom deterioration by IPSS ≥ 4 points was 22.3 versus dutasteride and 17.9 versus tamsulosin. To prevent 1 patients developing AUR and/or undergoing BPH invasive treatment, the number needed to treat over 4-year therapy was 11.1 versus tamsulosin and 54.8 versus dutasteride. Starting at 8 months, a higher incidence of AUR or BPH-related surgery was seen in the tamsulosin arm compared with the combination and dutasteride arms. Combination therapy was also significantly superior to both monotherapies at reducing the relative risk of BPH clinical progression, mainly represented by IPSS symptom score deterioration (relative risk reduction 44.1% compared with tamsulosin and 31.2% compared with dutasteride) [ ]. Combination therapy provided significantly greater symptom benefit than either monotherapy starting from month 9 versus tamsulosin and from month 3 versus dutasteride, and it was maintained for the study duration. Combination therapy also significantly improved Q _max at month 48 compared with tamsulosin but not with dutasteride. The Q _max improvement at month 24 was maintained at month 48 in the combination and dutasteride groups but decreased in the tamsulosin group. The adverse events were consistent with the previous at 2-year report [ , ].

A post hoc analysis of the 4-year study data demonstrated that combination therapy resulted in a significantly greater improvement from baseline IPSS at 48 months versus tamsulosin monotherapy independently of prostate volume, PSA, and IPSS baseline characteristics. The benefit of combination therapy over dutasteride was confined to groups with lower baseline prostate volume (< 60 mL) and PSA (< 4 ng/mL). Between 2 and 4 years, combination therapy was significantly more effective than dutasteride monotherapy in improving symptoms in all baseline subgroups, apart from in patients with baseline prostate volume ≥ 60 mL beyond 12 months, or beyond 15 months in subgroups with baseline PSA ≥ 4 ng/mL, where dutasteride monotherapy was as effective as combination therapy. Combination therapy resulted in significantly improved Q _max compared with tamsulosin but not dutasteride monotherapy. Q _max improvement appeared to increase with prostate volume and PSA level in combination therapy subjects [ ].

Roehrborn et al. published the CONDUCT study that investigated whether a fixed-dose combination (FDC) of 0.5 mg dutasteride and 0.4 mg tamsulosin is more effective than watchful waiting (WW) plus initiation of tamsulosin therapy if subsequent IPSS score remained the same or worsened in time (WW-All), in men with moderately symptomatic BPH at risk of progression [ ]. Results at 24 months showed that improvement of symptoms and reduction of risk of progression were significantly greater for FDC than WW-All (IPSS − 5.4 points vs. − 3.6 points; progression 18% vs. 29%). Improvements in QoL were seen in both groups but were significantly greater with FDC. The results of this study reinforce the concept of synergistic action of 5ARI and AB with better results of combination therapy in selected patients [ ].

Several studies explored the possibility to withdraw the AB after a period of combination therapy [ ]. The studies are different in terms of design (inclusion criteria, study duration, time of combination therapy and AB withdrawal, endpoints, subgroups analysis) and number of patients enrolled. The study with the greatest number of patients (Symptom Management After Reducing Therapy, SMART-1) suggested that, following a period of combination therapy of 6 months, it may be feasible to withdraw the AB and carry on with 5-ARI therapy, particularly in the case of moderate symptoms [ ]. However, the duration of this study was only 9 months. Although the CombAT study does not address this issue directly, it does suggest that in those men with a larger prostate volume or a greater PSA, the contribution of the AB to long-term symptom control is more modest [ , ]. However, regardless of baseline symptom score, prostate volume, or PSA, combination therapy versus either monotherapy is superior with regard to the improvement in symptoms and Q _max from baseline, and that this superiority is maintained till 48 months [ ].

In patients with moderate-to-severe BPH symptoms and enlarged prostate gland, the evidence supports a sustained use of combination therapy providing the most favorable outcome, compared with either monotherapy. The decision to withdraw one of the two agents must be made on an individual basis in full consultation with the patient [ ].

The clinical benefit of combination therapy should be balanced with additional cost, the possible reduce long-term compliance of patients taking two drugs instead of one, and the increase rate of side effect, mainly in the sexual domain.

There is a lack of high-level cost-effectiveness trials to assess whether observed benefits justify the added cost. Ismaila A. et al. studied with a Markov model if FDC therapy (0.5 mg dutasteride + 0.4 mg tamsulosin) of male with moderate-to-severe BPH-LUTS can be convenient over each monotherapy in terms of quality adjusted life year at 10 years and over a patient’s lifetime [ ]. In the Canadian health care system at a willingness to pay CAN$50,000 per QALY, the probability of combination therapy being cost-effective relative to tamsulosin and dutasteride monotherapy was about 99.6% and 99.8%, respectively. A similar study evaluating a different combination therapy (doxazosin and finasteride compared to doxazosin monotherapy) found a baseline incremental cost-effectiveness ratio less than CAN$40,000 [ ].

FDC therapy has been also proved to be more cost-effective than monotherapy, according to results of studies conducted in Greece, Spain, Scandinavia, and the United Kingdom [ ].

In a decision-analytical Markov model, DiSantostefano et al. compared the expected costs and effectiveness of six treatments (WW, AB, 5ARI, AB + 5ARI, transurethral microwave thermotherapy, and transurethral resection of the prostate) for urinary symptoms from BPH over a 20-year period [ ]. Only men with uncomplicated, moderate-to-severe BPH were included. The base-case was the cohort of men aged 65 years old who could switch among pharmaceuticals and WW if they did not respond to treatment or require TURP. Expected costs for each treatment over time were based on 2004 costs (US $). For the base case, the costs of treatment over 20 years ranged from $4.4 million for men initially treated by WW to $11.6 million for men initially treated with combined therapy. The incremental cost-effectiveness ratios showed that the most cost-effective treatment alternative depends on the severity of baseline symptoms. AB and TURP were the most cost-effective treatments for BPH relative to the alternatives for patients with moderate and severe symptoms, respectively.

All these cost-effectiveness studies have a number of limitations and the conclusions could vary considerably among different national health care systems [ ].

Furthermore, Cindolo et al. demonstrated that adherence to pharmacological therapy of BPH-associated LUTS is low and varies depending on drugs class [ ]. Patients under combination therapy have a higher likelihood of discontinuing (91% at 1 year), with detrimental effects on BPH progression. Other authors founded lower but still significant rate of drug discontinuation [ , ]. The problem of progressive discontinuation of pharmacological treatment of male LUTS has to be taken into account in studies dealing with cost-effectiveness. Although in clinical trial the rate of patients withdrawal due to side effects is low (< 10%), it could not be excluded that in the real clinical practice this percentage would be higher. Combination therapy with AB and 5ARIs results in a threefold increased risk of ejaculatory dysfunction as compared with each drug alone [ ]. The prevalence of erectile dysfunction is significantly greater with the combination treatment than with both AB and 5-ARI monotherapy (odds ratio 1.81 vs. AB and 1.25 vs. 5ARI) [ ]. The combination therapy significantly increases the risk of libido alterations compared to monotherapy with AB (odds ratio 1.58) [ ].

In summary, patients with moderate-to-severe LUTS associated with enlarged prostates (> 30–40 mL) and intended long-term treatment (> 1 year) benefit from 5ARI/AB combination therapy. Proper patients counseling in term of cost-benefit is important in order to improve the treatment adherence.

Anticholinergic Agents and AB

Over the last decade, the pathophysiology of male LUTS has been thoroughly revisited, and there is current strong evidence supporting the role of BPH, bladder, and afferent nervous system as key players [ ]. Given such findings, the clinical management of male LUTS has changed and the barrier precluding physicians to treat men with BPH and obstructive/storage symptoms with anticholinergic drugs has been broken. Although for many years antimuscarinic agents were avoided in men with bladder outlet obstruction (BOO) with/without overactive bladder (OAB) due to the concern of causing AUR, there is indeed current strong evidence supporting the safety and efficacy of this class of drugs among these patients [ ].

Antimuscarinic drugs bind the muscarinic receptors of the parasympathetic system and antagonize the neurotrasmitter acetylcholine, leading to detrusor smooth muscle relaxation by reducing intracellular level of calcium via L-type channel [ ]. Different muscarinic receptor subtypes have been described, including M1, M2, M3, M4, and M5 subtypes, with M3 receptors being the most actively involved in the physiology of micturition resulting in bladder voiding [ ].

Current antimuscarinic agents approved by the FDA include oxybutinin, tolterodine, solifenacin, darifenacin, trospium, propiverine, and fesoterodine [ ]. Agents carry different affinity for muscarinic receptor subtypes, with darifenacin as the only drug with high selectivity for the M3 over the M2 receptor [ ]. Fesoterodine is metabolized rapidly and extensively to the active metabolite 5-hydroxymethyl tolterodine and does not discriminate between the receptor subtypes, while oxybutynin and solifenacin show fractional selectivity for M3 receptors [ ]. Chapple and Novara conducted two metaanalysis to assess the clinical efficacy of antimuscarinic drugs among patients with LUTS and/or OAB. The authors concluded that antimuscarininc agents can reduce micturition episodes of 0.5–1.3 and incontinence episodes of 0.4–1.1 episodes per day. Changes in QoL with improvement of self-administered QoL questionnaire such as the Incontinence Impact Questionnaire, King’s Health Questionnaire and Urogenital Distress Inventory were reported over placebo [ , ].

Scientific evidence concerning the efficacy of combining anticholinergic drugs with AB has been growing over the last 15 years resulting in retrospective, observational, prospective, and randomized studies. Given that randomized controlled trials provide superior level of evidence compared to other type of studies, the analysis will be focused on the outcomes of currently published randomized controlled trials, whenever available.