A review of the use of tadalafil in the treatment of benign prostatic hyperplasia in men with and without erectile dysfunction
Abstract
Epidemiological data link erectile dysfunction (ED) and benign prostatic hyperplasia (BPH)-associated lower urinary tract symptoms (LUTS), two highly prevalent conditions in aging men, assuming common pathophysiological pathways. Tadalafil 5 mg once daily has been approved for the treatment of men with LUTS with or without comorbid ED. The aim of this review is to provide an overview of current knowledge on the epidemiological and pathophysiological links between ED and LUTS and to focus on tadalafil as a new treatment option in men with BPH-associated LUTS.
A Medline search was completed using the Medical Subject Headings (MESH® keywords) ‘prostatic hyperplasia’ and ‘phosphodiesterase inhibitors’. This search revealed 125 relevant references (entire Medline database up to 11 March 2014). The efficacy of tadalafil 5 mg once daily for the treatment of LUTS has been reported by several well-designed studies. Tadalafil improves significantly the total International Prostate Symptom Score (IPSS), the voiding and storage subscores, the IPSS Quality of Life (QoL) and the BPH Impact Index (BII). Its efficacy is irrelevant to the erectile function status of the patients. However, in the majority of these studies tadalafil is not associated with improvement in maximum urine flow or post-void residual volume (PVR). Its safety profile is well established and no new or unexpected adverse events other than those reported in ED studies have been recorded. Tadalafil is today a new treatment alternative to other established drugs for LUTS such as the α-adrenergic antagonists or 5α-reductase inhibitors. However, it is not just an alternative, since sexual adverse events associated with these drugs are avoided and tadalafil is the only drug that can treat both ED and LUTS at the same time.
Introduction
Erectile dysfunction (ED) and lower urinary tract symptoms (LUTS) are highly prevalent conditions associated with a significant negative impact on patients’ quality of life [Rosen et al. 2003, Robertson et al. 2007]. For a long time, ED and LUTS were considered to be two distinct clinical entities with an increasing prevalence in aging men despite the fact that almost all treatment modalities for benign prostatic hyperplasia (BPH)-associated LUTS have some negative impact on patients’ sexual function [Gacci et al. 2011]. This common belief has been rejected by several epidemiological studies showing a strong relationship between them and that they share several comorbidities and lifestyle factors [Rosen et al. 2005; Roehrborn et al. 2007]. While it is not clear how they are associated, there are emerging data supporting common pathophysiological mechanisms [McVary, 2005].
Phosphodiesterase type 5 inhibitors (PDE5i) are the current first-line treatment option for the majority of men with ED due to their excellent efficacy and safety profile [Hatzimouratidis et al. 2010]. Early clinical research showed that all PDE5i are also beneficial for the treatment of LUTS [McVary et al. 2007a, 2007b; Stief et al. 2008]. However, only tadalafil 5 mg once daily has been approved for the treatment of BPH-associated LUTS in men with or without ED. These new data provided new treatment options in the urologic armamentarium but also further promoted clinical research aiming to better understand the pathophysiology of LUTS.
The aim of this review is to provide an update on the current knowledge on the rationale for the use of tadalafil for the treatment of BPH-associated LUTS, and its efficacy and safety. A Medline (http://www.ncbi.nlm.nih.gov) search was completed using the Medical Subject Headings (MESH® keywords) ‘prostatic hyperplasia’ and ‘phosphodiesterase inhibitors’ in the English language only. This search revealed 125 relevant references (entire Medline database up to 11 March 2014).
The rationale for the use of tadalafil in the treatment of BPH-associated LUTS
Ep >Several epidemiological studies have reported a strong correlation between ED and LUTS. The National Health and Social Life Survey (NHSLS) [Laumann et al. 1999] demonstrated an increasing prevalence of ED in men with age, ranging from 7% to 18%. In the Cologne Male Survey [Braun et al. 2000, 2003] the overall prevalence of ED was 19.2%. The EDEM study [Martin-Morales et al. 2001] reported an ED prevalence rate of 12.1%. The Krimpen study [Blanker et al. 2001a, 2001b] showed that the overall prevalence of significant (severe) ED was 11%. The UrEpik study [Boyle et al. 2003] reported that the overall prevalence of ED was 21%. The Cross National Study on the Epidemiology of ED and its Correlates [Nicolosi et al. 2003a, 2003b] reported an overall prevalence of moderate or complete ED of 16%. The Multinational Survey of the Aging Male (MSAM-7) [Rosen et al. 2003] reported an overall prevalence of ED (difficulty achieving an erection) of 48.7% with 10% of men reporting complete absence of erections. In a population-based study in Denmark, the prevalence of ED was 28.8% while the prevalence of LUTS was 39.1% [Hansen, 2004]. Finally, in the Boston Area Community Health (BACH) study [Brookes et al. 2008] the overall prevalence of ED was 47% (less than 10% reported moderate or severe dysfunction) while the overall prevalence of LUTS was 81% (only 19% reported moderate or severe symptoms). In all of these studies LUTS were a significant risk factor for ED, but in the majority of them, LUTS were also an independent risk factor [Blanker et al. 2001; Braun et al. 2003; Nicolosi et al. 2003a; Rosen et al. 2003; Hansen, 2004]
These studies can be criticized due their cross-sectional design which cannot address the temporal relationship between LUTS and ED. Therefore, it is not possible to establish a definite causal association between LUTS and ED. There are only two longitudinal, prospective studies assessing the causal relationship between LUTS and ED. Shiri and colleagues [Shiri et al. 2005b], in a population-based study in Tampere (Finland), reported that the 5-year incidence of ED was greater in men reporting LUTS at baseline. Compared with men with no LUTS (IPSS: 0), the incidence of ED was 2.7 times higher among men with IPSS 7–11, and 3.1 times higher in men with IPSS 12 or more. Men with mild bother scores were at higher risk of ED than those with mild symptoms scores [Shiri et al. 2005a] while the incidence of LUTS was higher in men with moderate or severe ED than in those free of ED at baseline [Shiri et al. 2007]. In the Health Professionals Follow-Up Study (HPFS) [Mondul et al. 2008], men with severe LUTS in 1994 or earlier had a statistically significant 40% higher risk of ED subsequently compared with men without LUTS when assessed in year 2000. The risk of ED increased with increasing LUTS severity and the positive association between LUTS and ED was stronger in younger than in older men.
Common pathophysiological pathways
While the common pathophysiological pathways between ED and LUTS are not clear, four theories have been described and reviewed in the literature [McVary, 2005; Ponholzer and Madersbacher, 2007; Kohler and McVary, 2009; Gacci et al. 2011]. The first hypothesis includes impaired nitric oxidase synthase (NOS) in the endothelium of the pelvis including the prostate, bladder and penis. The second hypothesis is based on increased Rho-kinase activation resulting in decreased smooth muscle relaxation with consecutive increased bladder outlet resistance and impaired erection. The third hypothesis is based on the autonomic hyperactivity and metabolic syndrome effects on LUTS, prostate growth and ED. Finally, the fourth hypothesis illustrates atherosclerosis as a common mechanism for LUTS and ED. These theories are compatible and may overlap substantially [Kohler and McVary, 2009]. The theories of impaired NOS and reduced NO levels, increased Rho-kinase activation and atherosclerosis and pelvic ischemia are linked by common vascular risk factors. Atherosclerosis may reduce NO levels and Rho-kinase activation and may result in loss of smooth muscle from the bladder detrusor and prostate fibrosis associated with loss of bladder compliance and increased urethral resistance, respectively.
What is the evidence on tadalafil based on these four theories? The upregulation of the NO/cGMP activity is probably the most important. Preclinical studies reported partial reversal of norepinephrine- and endothelin-1-reduced prostatic tissue contraction [Kedia et al. 2009] and an antiproliferative effect on cultured prostate and bladder smooth muscle cells [Filippi et al. 2007]. These mechanisms may decrease smooth muscle tension in the prostatic stroma and capsule and attenuate cellular proliferation associated with prostate/bladder hypertrophy, respectively. An assessment of the activity of PDE5i on endothelin-1-induced contraction of human prostatic tissue (mediated by ROCK pathway) showed that tadalafil had greater activity when compared with sildenafil or vardenafil and among PDE5i, only tadalafil achieved >50% relaxation of the precontracted strips [Kedia et al. 2009]. Evidence on the efficacy of tadalafil in the modulation of autonomic nervous system overactivity and afferent nerve activity is very limited. PDE5i cause an inhibitory effect of NO on ion channels in afferent neurons and on afferent nerve activity in the bladder. Calcium channels in bladder afferent neurons are inhibited by NO [Yoshimura et al. 2001]. Moreover, vardenafil reduces nonvoiding contractions associated with bladder afferent nerve firing [Behr-Roussel et al. 2011]. Tadalafil inhibits in vitro PDE5 activity, prominently expressed in the human vesicular-deferential arteries and increases prostate tissue oxygenation in spontaneously hypertensive rats [Morelli et al. 2011]. Moreover, tadalafil increased prostatic blood perfusion in a preliminary evaluation of men using contrast-enhanced ultrasound [Bertolotto et al. 2009]. Finally, tadalafil attenuates the expression of various inflammatory markers (tumor necrosis factor [TNF]-α, interleukin [IL]-1β and IL-8) and therefore may reduce atherosclerotic damage and overall inflammation by reducing leukocyte recruitment [Roumeguere et al. 2010]. Tadalafil’s proposed mechanism of action based on current data is presented in Figure 1 [Andersson et al. 2011].
Mechanisms by which tadalafil may reduce benign prostatic hyperplasia (BPH)-associated lower urinary tract symptoms.
Clinical data on the efficacy and safety of tadalafil in men with BPH-associated LUTS
Efficacy data of PDE5i in the treatment of LUTS
McVary and colleagues [McVary et al. 2007b] reported on the first double-blind, placebo-controlled trial with tadalafil in men with both ED and LUTS. A total of 281 men were randomized in a 1:1 ratio to receive 5 mg of tadalafil daily (138 men, mean age: 61 years) followed by dose escalation to 20 mg for 6 weeks or 12 weeks of placebo (143 men, mean age: 62 years). Tadalafil significantly improved the mean change from baseline in IPSS at 6 weeks (5 mg tadalafil −2.8 versus placebo -1.2) and at 12 weeks (5/20 mg tadalafil −3.8 versus placebo −1.7). Larger changes were observed with inclusion of the placebo run-in at 12 weeks (5/20 mg tadalafil −7.1 versus placebo −4.5). Mean irritative and obstructive IPSS subscores, the IPSS QoL index, a question about urinary symptom improvement and the BPH Impact Index (BII) significantly improved versus placebo. IPSS and International Index of Erectile Function (IIEF) scores significantly improved in the 56% of men with LUTS who were sexually active and had ED. No differences in uroflowmetry parameters were recorded in the placebo and tadalafil groups. Moreover, no change in PVR was recorded in the tadalafil group.
Roehrborn and colleagues [Roehrborn et al. 2008] reported data from a dose finding study with tadalafil in men with ED and LUTS. A total of 1058 patients were included in a randomized, double-blind, placebo-controlled, parallel design, 12-week study (211 in the placebo group, 208 in the tadalafil 2.5 mg daily group, 212 in the tadalafil 5 mg daily group, 216 in the tadalafil 10 mg daily group and 209 in the tadalafil 20 mg daily group). The IPSS least-squares mean change from baseline to end point was significantly improved for 2.5 (−3.9, p = 0.015), 5 (−4.9, p
Porst and colleagues [Porst et al. 2013a] also presented subgroup analyses demonstrating that IPSS improvements were significant regardless of baseline LUTS severity (IPSS 65 years), recent previous use of α-adrenergic antagonists or PDE5i, total testosterone level ( 40 ml). The rates of treatment emergent adverse events were comparable between all subgroups but were somewhat higher in patients with recent previous α-adrenergic antagonists use.
Improvement in International Prostate Symptom Score (IPSS) in all patients treated with tadalafil 5 mg versus placebo (p
Improvement in Benign Prostatic Hyperplasia Impact Index (BII) in all patients treated with tadalafil 5 mg versus placebo (p
A recent meta-analysis [Dong et al. 2013] reported that after pooling four doses (2.5, 5, 10 and 20 mg), tadalafil failed to produce a significant outcome in Qmax although it was improved (mean difference = +0.26 ml/s, p = 0.14), but 5 mg of tadalafil significantly improved Qmax (mean difference = +0.63 ml/s, p = 0.04).
Is there any explanation for these findings? The answer is currently no. McVary commented that it might be a potential new basic pathophysiology paradigm in which the impact of PDE5 activity on LUTS symptoms may reveal an alternate explanation for the etiology of LUTS not involving relaxation of prostatic smooth muscle but bladder compliance changes, improvement in bladder wall perfusion or central nervous system impact [McVary, 2006]. While the answer to this question is of the highest importance in understanding the mechanisms of LUTS and the effect of new treatments, its importance from a clinical point of view may be less significant since symptom alleviation is the primary treatment target in the majority of patients.
Long-term efficacy of tadalafil
While the efficacy of tadalafil was established from placebo-controlled studies, it is unknown whether this positive effect is maintained through time. This is important to know since LUTS are a chronic condition and treatments must be efficacious also in the long-term. In this context, Donatucci and colleagues [Donatucci et al. 2011] reported on the long-term efficacy of tadalafil. A total of 427 men who completed the 12-week, placebo-controlled, dose-finding study assessing once-daily tadalafil (2.5, 5, 10 or 20 mg) or placebo elected to continue into the open-label extension period using tadalafil 5 mg. Changes in the total IPSS, IPSS irritative and obstructive subscores, IPSS health-related QoL and BII were maintained after 1 year and were similar despite the tadalafil dose administered during the double-blind study. During the open-label extension period, mean PSA increased from 1.6 ± 1.3 to 1.8 ± 1.4 ng/ml. Mean PVR was 61.1 ± 60.4 ml at study entry and 42.2 ± 64.1 ml after the open-label extension period. Therefore, it can be concluded that the efficacy of tadalafil is maintained for at least 1 year.
Comparative data on the efficacy of tadalafil and tamsulosin
Another important question that rises up is the efficacy of tadalafil compared with an established treatment for BPH-associated LUTS such as an α-adrenergic antagonist. In this context, Oelke and colleagues [Oelke et al. 2012], reported on a randomized, double-blind, international, placebo-controlled, parallel-group study including tamsulosin as an active control. A total of 511 men with BPH/LUTS were randomized to placebo (n = 172), tadalafil 5 mg (n = 171) or tamsulosin 0.4 mg (n = 168) once daily for 12 weeks following a 4-week run-in period. This study was not designed for statistical testing of noninferiority or superiority between tadalafil and tamsulosin but it was adequately powered for the comparison of each active treatment with placebo. IPSS scores significantly improved versus placebo with tadalafil (−2.1; p = 0.001) and tamsulosin (−1.5; p = 0.023). This improvement was ev > 0.1). Surprisingly, given the data from previously published studies, Qmax increased significantly versus placebo with both tadalafil (2.4 ml/s; p = 0.009) and tamsulosin (2.2 ml/s; p = 0.014). PVR decrease was higher with tamsulosin but statistical significance was not reached by either treatment versus placebo.
As expected, the IIEF erectile function domain improved versus placebo with tadalafil (4.0; p
These are the only studies published so far showing that tadalafil improves LUTS to a similar extent as tamsulosin, an α-adrenergic antagonist that is widely prescribed for this condition. These are also the only studies showing a statistically significant increase in Qmax that is similar for both active treatments. Although these studies cannot give an answer comparing the two active treatments directly, tadalafil seems to be at least as efficient as tamsulosin while having an extra benefit in improving all aspects of sexual life.
Safety issues
All of these studies reported that tadalafil is not only efficacious but also a safe treatment. As in the classic ED trials, the most common side effects were headache, dyspepsia, nasal congestion, flushing and back pain. In the pooled analysis of data from four randomized, double-blind, placebo-controlled, 12-week, parallel-design, multinational LUTS/BPH studies, the incidence of headache, back pain and dyspepsia was 3.8%, 2.5%, 2.1% and 2.6%, 1.2%, 0.2% for the tadalafil 5 mg and placebo group, respectively. Treatment discontinuation rates due to adverse events were 2.7% and 1.2% for the tadalafil 5 mg and placebo group, respectively [Porst et al. 2013b]. Brock and colleagues [Brock et al. 2013] reported similar findings without any significant difference in adverse events between patients with or without ED. In the open-label extension study, no new or unexpected adverse event was recorded while treatment discontinuation due to adverse events was 5.2% without significant differences between placebo and all tadalafil doses used [Donatucci et al. 2011].
For several years, well before data became available, concerns were raised in terms of combining an α-adrenergic antagonist with a PDE5i. Giuliano and colleagues [Giuliano et al. 2006], in a randomized, double-blind, placebo-controlled, crossover study in 18 healthy m >
Is there still a role for combination therapy?
Since the coadministration of tadalafil and α-adrenergic antagonists is safe when following the proper instructions, another question that arises is the possible role of combination treatment in patients with BPH-associated LUTS, especially using the new more uroselective α-adrenergic antagonists.
Animal and clinical data have provided preliminary evidence for the benefits of combining α-adrenergic antagonists and PDE5i [Giuliano, 2008; Oger et al. 2008]. Bechara and colleagues [Bechara et al. 2008] reported on the combination of tadalafil (20 mg/day) plus tamsulosin (0.4 mg/day) to tamsulosin alone in 20 men with LUTS. This was a randomized, double-blind, crossover design, 12-week study. Improvements of IPSS score and IPSS QoL were significant with both treatments but greater with the drug combination. Both regimens similarly improved the maximum flow rate and decreased the PVR from baseline (p 0.05). The IIEF improved with tamsulosin plus tadalafil (p 0.05). The General Assessment Question (GAQ) showed that all patients preferred the combination scheme. No serious adverse events were recorded while only two patients (one in each group) discontinued treatment due to an adverse event (headache and cutaneous rash, respectively). Regadas and colleagues [Regadas et al. 2013], compared the combination therapy of tamsulosin/tadalafil taken daily to tamsulosin/placebo. A total of 40 men with BPH-associated LUTS were randomized to tamsulosin 0.4 mg/tadalafil 5 mg or tamsulosin 0.4 mg/placebo once daily for 30 days. The primary end point was to demonstrate changes in urodynamic variables in the vo >
Recently, data on the combination of tadalafil with finasteride (a 5α-reductase inhibitor) have been published [Casabe et al. 2014]. This study was an international, randomized, double-blind, parallel study including men with prostate volumes 30 ml or greater. The combination of tadalafil 5 mg and finasteride 5 mg improved IPSS significantly compared with finasteride monotherapy at all time points (4, 8 and 16 weeks; p ≤ 0.022). IPSS improved by 1.7, 1.4 and 1 more in the combination group compared with the finasteride-only group at the above time points, respectively. As expected, IIEF improved significantly in the combination group (p Andersson K., De Groat W., McVary K., Lue T., Maggi M., Roehrborn C., et al. (2011) Tadalafil for the treatment of lower urinary tract symptoms secondary to benign prostatic hyperplasia: pathophysiology and mechanism(s) of action . Neurourol Urodyn 30 : 292–301 [PubMed] [Google Scholar]
