European Urology

In this edition of the journal, Oelke and colleagues report the results of an interesting study contrasting the efficacy of tadalafil 5 mg or tamsulosin 0.4 mg versus placebo over a 12-wk period after 4 wk of placebo run-in [1]. This is the first study to synchronously contrast these two agents with placebo.

They evaluated 510 men who were started on the study drug with a 1:1:1 randomisation. It is important to emphasise that this study was not powered to contrast the active drugs with each other, but just with placebo. Using the International Prostate Symptom Score (IPSS) and the International Index of Erectile Function–Erectile Function Domain (IIEF-ED) as parameters, they demonstrated improved efficacy of tadalafil 5 mg (n = 171) and tamsulosin 0.4 mg (n = 168) compared with placebo (n = 172) at 12 wk. IPSS for tadalafil 5 mg was −2.1 (p = 0.001) and −1.5 for tamsulosin 0.4 mg (p = 0.023). Efficacy was evident at 1 wk after starting therapy and was equal in both groups (−1.5; p = 0.01). The IIEF-ED improved with tadalafil versus placebo (−4.0; p < 0.001), but not with tamsulosin (−0.4; p = 0.699). It is notable that the maximum flow rate (Q_max) improved with tadalafil (2.4 ml/s; p = 0.009) and tamsulosin (2.2 ml/s; p = 0.14). More consistent improvements in quality of life (QOL) were seen with tadalafil than with tamsulosin as compared to placebo.

There are four published studies contrasting combination therapy with these two classes of drug versus monotherapy [2], [3], [4], and [5]. Two of these studies evaluated tadalafil at a dose of 20 mg daily and 20 mg on alternate days, respectively [3] and [4], and two studies evaluated sildenafil 25 mg [2] and [5]. The efficacy of the phosphodiesterase type 5 inhibitor (PDE5-I) alone for improving IPSS appeared less pronounced with sildenafil [2] and [5]. Somewhat more equivocal findings were reported for tadalafil at a higher dose of 20 mg, with positive results for one study [3] but not for the other [4].

In the study by Kaplan et al, which was the first published combination study [2], men aged 50–76 yr with untreated erectile dysfunction (ED) and lower urinary tract symptoms (LUTS) were randomised to receive alfuzosin (n = 20), sildenafil (n = 21), or combination therapy (n = 21) for 12 wk. The IPSS was significantly improved with the three treatments but was greatest with the combination (−24.1%) compared with alfuzosin (−15.6%) and sildenafil (−11.8%) alone (p < 0.03). Improvement in the IIEF was slight with alfuzosin (16.7%), marked with sildenafil (49.7%), and greatest with the combination (58.6%).

In the study by Bacharach et al. [3], 27 men > 50 yr old and with a history of LUTS of ≥6 mo were randomised into two groups: tamsulosin 0.4 mg/d versus tamsulosin 0.4 mg/d plus tadalafil 20 mg/d for 45 d, and then switched in this crossover study to the other treatment for 45 d. Improvements in IPSS score and IPSS-QOL were significant with both treatments but were greater with the drug combination. Both regimens similarly improved the Q_max and decreased the postvoid residual (PVR) volume from baseline with no significant differences between tamsulosin alone versus tamsulosin and tadalafil (p > 0.05). The IIEF-ED improved with tamsulosin plus tadalafil (p < 0.001), but not with tamsulosin alone (p > 0.05).

The study by Liguori et al. [4] used a randomised, open-label, three-arm design including 66 men complaining of LUTS and ED. Patients were randomly allocated to either alfuzosin 10 mg once daily (n = 22), tadalafil 20 mg on alternative days (n = 21), or a combination of both (n = 23). After 12 wk, IPSS was significantly improved by alfuzosin (27.2%), more markedly with combination therapy (41.6%), and to a lesser extent with tadalafil (8.4%). The IIEF improved slightly with alfuzosin alone (+15%), and to a greater extent with tadalafil alone (+36.3%) and the combination therapy (+37.6%). Improvement in Q_max was observed in all groups, but patients receiving combination therapy had greater improvement (29.6%) than patients receiving either alfuzosin (21.7%) or tadalafil (9.5%).

Tuncel and colleagues [5] studied a total of 60 men with LUTS randomised to receive sildenafil 25 mg four times per week (n = 20), tamsulosin 0.4 mg (n = 20), and the combination of both (n = 20) for 8 wk. Improvement of IPSS was more marked with the combination (40.1%) and tamsulosin (36.2%) groups in contrast to sildenafil alone (28.2%). Improvement of Q_max and PVR was greater with tamsulosin only and the combination than in the sildenafil-only group, although there was a greater improvement in ED with either combination or sildenafil alone.

Although there is a suggestion from these underpowered pilot studies of the potential benefit of adding a PDE5-I to an α-blocker in terms of treating both LUTS and ED, it is clear that great caution must be exercised in drawing any conclusion on comparative efficacy not only because of the small number of patients studied but also because of the different doses of drug used and the differing study designs.

The study by Oelke et al. [1] clearly confirms the findings of the previously published studies with tadalafil 5 mg/d in terms of its efficacy in improving both LUTS and ED [6], [7], [8], and [9]. In one of these studies, a subgroup analysis demonstrated no evidence of any differences in efficacy as judged by improvement in IPSS, whether or not the men had underlying ED [8]. None of these studies, however, demonstrated any evidence of an increase in Q_max with 5 mg/d tadalafil. The Oelke et al. study [1] is the first to report an increase in Q_max, and as such, it must be interpreted with caution until confirmed by other studies, particularly as this was not previously seen with doses ≤20 mg [6], [7], and [9].

Dmochowski and coworkers [10] reported on a multicentre, randomised, double-blind, placebo-controlled clinical trial in which they evaluated once-daily tadalafil 20 mg versus placebo over 12 wk in men with LUTS and with or without bladder outlet obstruction. They documented both invasive and noninvasive urodynamics and IPSS. The primary end point was change in detrusor pressure at maximum urinary flow rate (PDet Q_max). Urodynamic measures were not significantly changed during the study, with no difference found between tadalafil and placebo in change in Pdet Q_max (mean difference between treatments: −2.2 cm H₂O; p = 0.33) or any other urodynamic parameter assessed, including Q_max, maximum detrusor pressure, bladder outlet obstruction index, or bladder capacity (all measures p≥ 0.13).

Clearly the available evidence would support potential efficacy for tadalafil 5 mg as a useful addition to the therapeutic armamentarium of patients with both LUTs and ED. The finding of what appears to be comparable efficacy to an α-blocker will, however, need to be confirmed in an adequately powered head-to-head study. There remains no universally accepted principal mode of action for tadalafil's effect on LUTS. The study by Dmochowsky et al, in failing to demonstrate any significant effect on either the bladder or its outflow, would certainly lend support to the hypothesis that it may be an effect mediated by altering afferent nerve function [11] and [12].

Conflicts of interest

The author has served as an advisor and researcher for Astellas Pharma Inc., Allergan Inc., Pfizer Inc., and Recordati S.p.A.