SYSTEMATIC REVIEW

Tadalafil – a therapeutic option in the management of BPH-LUTS C. C. Carson,1 M. Rosenberg,2 J. Kissel,3 D. G. Wong3

1

University of North Carolina, Chapel Hill, NC, USA 2 Mid-Michigan Health Centers, Jackson, MI, USA 3 Eli Lilly and Company, Indianapolis, IN, USA Correspondence to: Culley C. Carson III, M.D., F.A.C.S., Rhodes Distinguished Professor of Urology, University of North Carolina, 2113 Physicians Office Building, Chapel Hill, NC 27599-7235, USA Tel.: 919 966 2574 Fax: 919 966 0098 Email: [email protected]. edu

Disclosures Culley Carson: None. Matt Rosenberg: Consultant for Eli Lilly and Company. Jay Kissel and David Wong: Employees and stockholders of Eli Lilly and Company.

SUMMARY

Introduction and background Benign prostatic hyperplasia (BPH) is a histological diagnosis characterised by the proliferation of smooth muscle and epithelial cells within the prostatic transition zone, and can be associated with bothersome lower urinary tract symptoms (LUTS), including urinary frequency, urgency, intermittence, nocturia, straining, incomplete emptying or a weak urinary stream (1). LUTS in men becomes increasingly common with age, reaching a prevalence of 45% or greater for moderate to severe LUTS in men over 70 years of age (2). Additionally, bothersome LUTS is known to interfere with normal daily activities and sleep patterns, thus negatively impacting quality of life (QOL) (3).

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Background/Aims: Men with signs of benign prostatic hyperplasia (BPH) may experience lower urinary tract symptoms (LUTS) such as urinary frequency, urgency, intermittence, nocturia, straining, incomplete emptying or a weak urinary stream. The effective management of LUTS suggestive of BPH (BPH-LUTS) requires careful consideration of several factors, including the severity of a patient’s symptoms, concurrent or other coexisting medical conditions, the ability to improve symptoms and impact quality of life (QOL), as well as the potential side effects of available treatment options. Several clinical studies have assessed phosphodiesterase type 5 (PDE5) inhibitors in reducing LUTS; however, tadalafil is the only PDE5 inhibitor approved for the treatment of signs and symptoms of BPH, as well as in men with both erectile dysfunction (ED) and the signs and symptoms of BPH. This review examined articles that assessed tadalafil in patients with signs and symptoms of BPH, with or without erectile dysfunction (ED), which led to regulatory approval in the United States and Europe. Results: In dose-ranging and confirmatory studies, results demonstrate that tadalafil significantly improved total International Prostate Symptom Score (IPSS) following 12 weeks of treatment with once daily tadalafil 5 mg. Statistically significant improvements in Benign Prostatic Hyperplasia Impact Index (BII), IPSS subscores, IPSS QOL and International Index of Erectile Function (IIEF) were also observed. Improvement in urinary symptoms occurred regardless of age, previous treatment with an a1-adrenergic blocker, BPH-LUTS severity at baseline or ED status. Conclusions: While tadalafil is most frequently recognised as a standard treatment option for men with ED, it also represents a well-tolerated and effective treatment option in men with moderate to severe BPH-LUTS.

Literature was obtained via Medline searches and from the individual reviewers’ files. Articles were selected that assessed tadalafil in patients with signs and symptoms of benign prostatic hyperplasia (BPH), with or without erectile dysfunction (ED), which led to regulatory approval in the USA and Europe.

Message for the clinic Once daily tadalafil represents a well-tolerated and effective treatment option in men with moderate to severe BPH-LUTS. As BPH-LUTS and ED often appear concurrently in ageing men, a treatment option that is able to treat the signs and symptoms of both conditions is of significant value to clinicians. Tadalafil is the first and only therapy approved to treat both BPH-LUTS and ED.

Concurrence of BPH and ED Erectile dysfunction (ED) and LUTS suggestive of BPH (BPH-LUTS) commonly coexist in ageing men (2,4). The link between BPH-LUTS and ED is well supported by epidemiologic, pathophysiologic and treatment studies (2,5–7). In the Multinational Survey of the Ageing Male (MSAM-7), erection problems were significantly more common in men with LUTS and were strongly related to the severity of urinary symptoms, independent of age and other comorbidities (2). In men with mild, moderate and severe LUTS, erection problems were reported by 43.3%, 65.8% and 81.9% of the men, respectively (2). Over the last decade, population and practicebased studies have continued to provide consistent evidence of an association between BPH-LUTS and ª 2013 John Wiley & Sons Ltd Int J Clin Pract, January 2014, 68, 1, 94–103. doi: 10.1111/ijcp.12305

Tadalafil treatment for BPH-LUTS and ED

sexual dysfunction in ageing men that is independent of age, other comorbidities and lifestyle factors (4,8). A recent review of the coexistence of ED and LUTS has suggested that a co-diagnosis of these conditions is important for both the patient and their partner (9).

Overview of tadalafil for treatment of BPH-LUTS Primary care physicians (PCPs) are often responsible for the identification and treatment of BPH-LUTS. Often, the identification of patients with urinary symptoms may prove challenging as many men do not volunteer such information to their healthcare providers, and may incorrectly believe that changes in their urinary function are a normal part of ageing, are embarrassed about their condition, or fear the need for surgery (10,11). Over the last 20 years, BPH-LUTS treatment paradigms have shifted from surgical interventions to first line pharmacologic therapy, with treatment choices and success measured against goals of symptom reduction and improvement in QOL, thereby allowing the PCP to evaluate the patient and treat them without referral. Medical management options of bothersome BPHLUTS include a1-adrenergic blocker (alpha-blocker) and phosphodiesterase type 5 (PDE5) inhibitors; in men with an enlarged prostate, a 5a-reductase inhibitor (5ARI) may be considered or, the combination of treatment with an alpha-blocker and 5ARI for the management of bothersome BPH-LUTS. While effective, alpha-blockers and 5ARIs have also been associated with sexual dysfunction such as loss of libido, ED and ejaculatory disorders (9,12). Several clinical studies have assessed PDE5 inhibitors, including vardenafil, sildenafil and tadalafil, in reducing LUTS (13–20); however, tadalafil is the only PDE5 inhibitor approved for the treatment of signs and symptoms of BPH. Tadalafil was first approved for as needed treatment of ED in 2003. The 17.5-hour halflife allowed for the evaluation and approval of tadalafil for the once daily treatment for ED in 2008. In 2011, tadalafil was further approved for the treatment of signs and symptoms of BPH, as well as in men with both ED and signs and symptoms of BPH.

Tadalafil – mechanism of action Phosphodiesterases (PDEs) are enzymes that metabolise the second messenger molecules cyclic adenosine monophosphate and cyclic guanosine monophosphate (cGMP). PDE5 is specific for cGMP and tadalafil is a selective inhibitor of PDE5. The PDE5 isoenzymes have been found in human tissues including the smooth muscle cells of the corpus ª 2013 John Wiley & Sons Ltd Int J Clin Pract, January 2014, 68, 1, 94–103

cavernosum, vascular and visceral smooth muscle, skeletal muscle, platelets, kidney, lung, cerebellum and pancreas, as well as in the bladder, prostate, urethra and their vasculature (21–23). The mechanism of action of PDE5 inhibitors for the treatment of ED has been well characterised. Following the local release of nitric oxide (NO) during sexual stimulation, cGMP concentration is increased as a result of PDE5 inhibition, causing relaxation of the smooth muscle cells promoting flow of blood into the penile tissues, thereby facilitating an erection. The presence of the nitric oxide/cGMP (NO/ cGMP) signalling pathway and the presence of PDE5 in the urogenital tract are well established and are reviewed elsewhere (12,24,25). Within the lower urinary tract (LUT), nitric oxide/cGMP signalling has been linked to prostate smooth muscle relaxation (21,26,27) and to the reduction of detrusor muscle overactivity in the bladder body and neck (23). Vasculature smooth muscle relaxation mediated through PDE5 inhibition may also provide improved blood flow to the LUT. PDE5 inhibitors have been shown to attenuate alpha-adrenergic induced contraction of isolated human prostate strips in a concentrationdependent manner (21). These results support the role of the NO/cGMP pathway and the role that PDE5 inhibitors may have in regulating LUT smooth muscle cell contraction. Additional research suggests the pathophysiology may be multifactorial and include other pathways such as enhancement of Rho-A-Rho-kinase (ROCK) signalling, autonomic hyperactivity and pelvic atherosclerosis in addition to the NO/cGMP pathway (9,25).

Study design and patient population – tadalafil efficacy studies Several randomised, double-blind, placebo-controlled, multinational trials have investigated the efficacy and safety of tadalafil in the treatment of BPH-LUTS, as well as in the treatment of men with ED and with BPH-LUTS, leading to regulatory approvals in the USA and Europe. Key trial design details are summarised in Table 1. The designs of these studies were similar and included a screening period followed by a washout period of up to 4 weeks, if needed, for washout of therapies, such as alpha-blockers and PDE5 inhibitors. The screening/washout period was followed by a 4-week single-blind, placebo lead-in period. Initial Phase 2/3 clinical investigation of tadalafil included a dose-ranging trial evaluating the following once daily doses: 2.5, 5, 10 and 20 mg with confirmatory Phase 3 trials evaluating 5 mg for BPH-LUTS and 2.5 and 5 mg in the evaluation of men with both BPH-LUTS and ED. All trials were placebo-controlled,

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Tadalafil treatment for BPH-LUTS and ED

Table 1 Trial designs of pivotal tadalafil BPH-LUTS clinical trials

Treatment groups/Doses

Treatment period

Tadalafil 2.5 mg Tadalafil 5 mg Tadalafil 10 mg Tadalafil 20 mg Placebo Tadalafil 5 mg Placebo

12 weeks

606

Tadalafil 2.5 mg Tadalafil 5 mg Placebo

12 weeks

Men with BPH-LUTS for > 6 months

511

Tadalafil 5 mg Tamsulosin 0.4 mg Placebo

12 weeks

Men with BPH-LUTS for > 6 months who completed 12-week doubleblind treatment study*

427

Tadalafil 5 mg

52 weeks

Reference

Title

Patient population

N

Roehrborn et al. (13)

Tadalafil administered once daily for lower urinary tract symptoms secondary to benign prostatic hyperplasia: a dose finding study

Men with BPH-LUTS for > 6 months

1058

Porst et al. (19)

Efficacy and safety of tadalafil once daily in the treatment of men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia: results of an international randomised, double-blind, placebo-controlled trial Tadalafil 2.5 or 5 mg administered once daily for 12 weeks in men with both erectile dysfunction and signs and symptoms of benign prostatic hyperplasia: results of a randomised, placebo-controlled, double-blind study Monotherapy with tadalafil or tamsulosin similarly improved lower urinary tract symptoms suggestive of benign prostatic hyperplasia in an international, randomised, parallel, placebo-controlled clinical trial Tadalafil administered once daily for lower urinary tract symptoms secondary to benign prostatic hyperplasia: a 1-year, open-label extension study

Men with BPH-LUTS for > 6 months

325

Men with BPH-LUTS for > 6 months and ED for ≥ 3 months

Egerdie et al. (20)

Oelke et al. (18)

Donatucci et al. (28)

12 weeks

*Patient population included men with BPH-LUTS for > 6 months who completed the 12-week double-blind, dose finding study (Roehrborn et al.), and who were from the USA or Canada. BPH, benign prostatic hyperplasia; ED, erectile dysfunction; LUTS, lower urinary tract symptoms; N, number of randomised subjects.

double-blinded and study end-points were assessed after 12 weeks of treatment. Additionally, a 1-year open-label extension trial was conducted to investigate the long-term safety and efficacy of tadalafil in patients with BPH-LUTS. The demographic characteristics of the patients participating in these trials are shown in Table 2. In general, the study population included men with moderate to severe BPH-LUTS as assessed by the International Prostate Symptom Score (IPSS) with an IPSS > 13, and verified bladder outlet obstruction as assessed by uroflowmetry, maximum urinary flow rate (Qmax) of ≥ 4 to ≤ 15 ml/s. Patients with comorbidities that could impact the safety of the population and efficacy interpretations, such as prostate malignancy, urinary tract infection, urinary retention and severe cardiovascular disease, were excluded. In the one study evaluating BPH-LUTS and ED, men were required to be sexually active with a female partner and were expected to remain sexually active for the duration of the study (20).

Efficacy of tadalafil in the treatment of BPH-LUTS Primary and key secondary efficacy measures Primary and key secondary efficacy measures included the IPSS, the Benign Prostatic Hyperplasia Impact Index (BII), and the International Index of Erectile Function-Erectile Function domain (IIEFEF). The IPSS is a 4-week recall questionnaire that scores the responses to seven component questions that assess the severity of voiding and storage LUTS and was included as a primary measure in all efficacy studies. The total IPSS range is 0–35 with higher scores indicating more severe symptoms. IPSS changes alone may not fully describe the patient’s morbidity and degree of bother because of BPH symptoms; as such the BII was assessed as a secondary end-point. The BII is a 4-item questionnaire developed to determine the degrees to which urinary problems affect various domains of health and impact the perception of health in a given individual. Higher scores indicate increased bother or problems ª 2013 John Wiley & Sons Ltd Int J Clin Pract, January 2014, 68, 1, 94–103

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66.8 33.2 31.11 55.56 13.33 29.33 NR 30.77

64.9

35.1

26.76 57.75 15.49 29.86

NR

26.54

26.42

NR

28.47 56.94 14.58 27.83

33.5

66.5

84.4

62.0 (8.2) 67.9

TAD (5 mg)

22.69

NR

37.33 48.00 14.67 26.85

33.3

66.2

80.6

62.2 (7.2) 69.4

TAD (10 mg)

28.23

NR

27.59 54.48 17.93 30.14

32.5

67.5

77.0

62.6 (8.1) 69.4

TAD (20 mg)

20.7

NR

35.7 52.7 11.6 31.1

32.9

67.1

78.7

64.6 (10.0) 68.3

PBO

Porst

24.8

NR

30.4 54.5 15.2 29.8

37.9

62.1

79.5

65.1 (8.4) 69.6

TAD (5 mg)

TAD (2.5 mg

TAD (5 mg)

30.5

28.0

46.5 24.5 29.0 23.0

39.0

61.0

26.3

24.2

52.5 23.2 24.2 20.2

37.6

62.4

28.8

27.4

47.6 26.0 26.4 26.9

40.4

59.6

62.9 (8.2) 62.2 (7.6) 62.5 (8.4) Patients required to have ED per study entry criteria Patients required to be sexually active per study entry criteria

PBO

Egerdie

13.4

NR

30.0 53.3 16.7 26.2

31.4

68.6

84.3

63.7 (8.7) 69.8

PBO

Oelke

12.3

NR

31.4 53.7 14.9 24.0

28.1

71.9

83.6

63.5 (8.1) 70.8

TAD (5 mg)

12.5

NR

28.4 51.7 19.8 25.6

29.2

70.8

82.7

63.5 (7.8) 69.0

TAM (0.4 mg)

*Moderate BPH (IPSS < 20) for Roehrborn et al., Egerdie et al., Oelke et al., studies. †ED severity for Porst et al., study represents subject-reported severity at screening. ‡ED severity defined as mild (IIEF-EF domain 17–30), moderate (IIEF-EF domain 11–16), severe (IIEF-EF domain 1–10) for Egerdie et al. study. §Previous ED therapy includes: alprostadil, sildenafil, tadalafil, vardenafil, yohimbine (Oelke et al.); alprostadil, arginine aspartate, arginine glutamate, ifenprodil, papaverine, sildenafil, tadalafil, testosterone, vardenafil, yohimbine (Egerdie et al.). BPH, Benign prostatic hyperplasia; ED, Erectile dysfunction; IPSS, International Prostate Symptom Score; LUTS, lower urinary tract symptoms; NR, Not reported; PBO, Placebo; PDE5, Phosphodiesterase type 5 (inhibitor); SD, standard deviation; TAD, tadalafil; TAM, tamsulosin.

80.8

80.1

Sexually active, yes (%) BPH severity, % Mild–Moderate (IPSS < 20)* Severe (IPSS ≥ 20) ED severity, %†,‡ Mild Moderate Severe Prior alpha-blocker use, yes (%) Prior PDE5 inhibitor use Prior ED therapy§, yes (%)

62.0 (8.4) 64.9

61.8 (7.7) 67.3

TAD (2.5 mg)

Age, mean (SD) ED status, yes (%)

PBO

Roehrborn

Table 2 Baseline characteristics of patients in Phase 3 clinical studies of tadalafil for the treatment of BPH-LUTS

Tadalafil treatment for BPH-LUTS and ED 97

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associated with urinary symptoms. Lastly, the IIEF is a 15-item questionnaire evaluating sexual function and satisfaction and the IIEF-EF was a co-primary end-point in one trial (20) and a secondary end-point in the others. The IIEF-EF domain is comprised of questions 1–5 and question 15 with higher scores indicating greater erectile function. The IIEF questionnaire was administered to men who were sexually active and expected to remain sexually active.

Efficacy results Four randomised, double-blind, placebo-controlled studies demonstrated the efficacy and safety of tadalafil once daily in men with BPH-LUTS; one trial was conducted in men with both BPH-LUTS and ED; and one trial included tamsulosin as an active comparator (13,18–20). The persistence of efficacy and long-term safety of tadalafil once daily for the treatment of men with BPH-LUTS was demonstrated in a 1-year open-label extension study (28). Efficacy results for these studies are summarised in Table 3.

Total IPSS In all tadalafil trials, after 12 weeks of treatment, the total IPSS least squares (LS) mean change from baseline was significantly greater in patients receiving

tadalafil 5 mg once daily vs. placebo (Table 3) (13,18–20). In the dose-ranging study reported by Roehrborn et al., a significant improvement in LS mean change from baseline to end-point was observed for the 2.5, 5, 10 and 20 mg tadalafil dose groups compared with placebo. After 12 weeks of treatment, clinically meaningful changes in IPSS were observed for all tadalafil doses with tadalafil 5 mg having a marked improvement compared with 2.5 mg; higher doses of tadalafil (10 and 20 mg) showed similar improvement as seen with tadalafil 5 mg. Additionally, IPSS improvements at 4, 8 and 12 weeks were significant for all tadalafil doses. Among the doses studied in the dose-ranging study, tadalafil 5 mg was confirmed as the dose for additional study based on the risk-benefit profile. The improvement in BPH symptoms was also observed at the earliest measured time points. Statistically significant improvement (as measured by the total IPSS LS mean change from baseline) in patients receiving tadalafil 5 mg once daily vs. placebo was observed as early as 1 week posttreatment initiation in one trial (p < 0.01) (18) and at 2 weeks posttreatment initiation (p < 0.001) (20). In the long-term evaluation of tadalafil treatment for BPH-LUTS, the improvement in IPSS after

Table 3 Mean changes from baseline to end-point in BPH-LUTS and erectile function measures in Phase 3 clinical

studies of tadalafil for the treatment of BPH-LUTS in men with and without ED

Total IPSS

IPSS storage subscore

IPSS voiding subscore

BII

IIEF-EF†

Study

Treatment

N

Roehrborn et al.

Placebo Tadalafil, Tadalafil, Tadalafil, Tadalafil,

2.5 mg 5.0 mg 10 mg 20 mg

210 208 212 216 208

2.27 3.88* 4.87*** 5.17*** 5.21***

0.99 1.58 1.89** 1.96** 2.07**

1.26 2.23* 2.94*** 3.13*** 3.12***

0.83 0.96 1.40* 1.38 1.45*

2.20 5.59*** 6.97*** 7.98*** 8.34***

Porst et al.

Placebo Tadalafil, 5.0 mg

164 161

3.6 5.6**

1.3 2.3**

2.3 3.3*

1.3 1.8

2.0 6.7***

Egerdie et al.

Placebo Tadalafil, 2.5 mg Tadalafil, 5.0 mg

200 198 208

3.8 4.6 6.1***

1.6 1.9 2.5***

2.2 2.7 3.6***

1.2 1.6 2.1***

1.8 5.2*** 6.5***

Oelke et al.

Placebo Tadalafil, 5.0 mg Tamsulosin, 0.4 mg

172 171 167

4.2 6.3*** 5.7*

1.6 2.2* 2.2*

2.6 4.1*** 3.5*

0.9 1.7* 1.5*

2.1 6.0*** 1.7

Donatucci et al. (1-year Open-Label Extension Study)

Tadalafil, 5.0 mg

427

5.0

1.9

3.1

1.3

5.9

Values are LS mean, except where noted. *p < 0.05, **p < 0.01, ***p < 0.001 vs. placebo. †Only reported in men with ED who were sexually active and who expected to remain sexually active during the duration of the study. BII, BPH Impact Index; BPH, benign prostatic hyperplasia; ED, erectile dysfunction; IIEF-EF, International Index of Erectile Function-Erectile Function Domain; IPSS, International Prostate Symptom Score; LS, least squares; LUTS, lower urinary tract symptoms; NR, Not Reported.

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12 weeks of treatment was maintained during a 1year open-label extension study in which patients who were treated with tadalafil 5, 10 or 20 mg for 12 weeks in the dose-ranging trial received 5 mg daily in the open-label extension. Patients previously taking placebo or tadalafil 2.5 mg experienced numerical improvement in total IPSS within the first month of treatment with 5 mg tadalafil; this improvement was maintained during the remainder of the open-label extension (28). Men who received 5, 10 or 20 mg in the double blind period maintained the improvement through the open-label extension.

IPSS subscores Subscores of the IPSS questionnaire (storage and voiding) were included as secondary objectives in all studies. The storage subscore, comprised of questions 2, 4 and 7 assesses the irritative symptoms (i.e., frequency, urgency and nocturia) associated with BPHLUTS. The voiding subscore, comprised of questions 1, 3, 5 and 6, assesses the obstructive symptoms (i.e., incomplete emptying, intermittency, weak stream and straining) associated with BPH-LUTS. Treatment with tadalafil 5 mg once daily resulted in statistically significant improvements in both the IPSS storage as well as voiding subscores after 12 weeks of treatment in all trials (Table 3).

BII The impact of urinary symptoms on overall health and activity was assessed with the BII. In three of the double-blind, placebo-controlled trials, BII was significant improvement in men treated with tadalafil 5 mg once daily vs. placebo after 12 weeks of treatment (Table 3) (13,18,20). In the trial reported by Porst et al., the improvement in BII was statistically significant compared with placebo at week 4, but not statistically different than placebo at week 12. In the dose-ranging trial reported by Roehrborn et al., improvements in BII were statistically significant at tadalafil doses of 5 mg or greater compared with placebo at weeks 4, 8 and 12 (non-significant for 10 mg at week 12) (13). In the trial reported by Oelke, BII significantly improved vs. placebo at week 4 with both tadalafil and tamsulosin and remained significantly improved throughout week 12 for both treatments compared with placebo (18). Similarly, in men with both ED and signs and symptoms of BPHLUTS, BII was significantly improved in tadalafil at weeks 4, 8 and 12 (20). Changes in BII were maintained over an openlabel, 1-year extension period during which men received tadalafil 5 mg once daily (28).

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IIEF In all tadalafil BPH-LUTS trials, tadalafil treatment significantly improved (p < 0.001) the IIEF-EF domain score compared with placebo in sexually active men with ED following 12 weeks of treatment (13,18–20). Three of the tadalafil trials did not require men to have ED or be sexually active; however, the percentage of men in those trials who were sexually active ranged from 77.0% to 84.4%, and the percentage of men with ED ranged from 64.9% to 70.8% (Table 2). One trial required that men have both ED and BPH-LUTS at screening; in that trial, IIEF-EF was significantly improved in patients with tadalafil 5 mg vs. placebo from week 4 (p < 0.001) through end-point (p < 0.001) (20). In the 1-year open-label extension study, improvements in IIEF-EF were maintained (28). In the trial that included an active comparator, tadalafil 5 mg (p < 0.001) significantly improved IIEF-EF domain compared with placebo after 12 weeks whereas, tamsulosin did not (p = 0.699) (18).

Quality of life measures The IPSS QOL question, “If you were to spend the rest of your life with your urinary condition just the way it is now, how would you feel about that?” was collected in all studies. In the study of tadalafil in men with symptoms of coexisting ED and BPH, neither the tadalafil 2.5 mg (p = 0.38) nor the 5 mg dose (p = 0.082) significantly improved the IPSS QOL index (20). Statistically significant improvements at end-point were observed following treatment with tadalafil 5 mg once daily in the following trials: Roehrborn et al., p = 0.002; Porst et al., p = 0.013 and Oelke et al., p = 0.022 (13,18,19). In the study reported by Oelke et al., the IPSS QOL index improved significantly vs. placebo with tadalafil, but not with tamsulosin (18). To further evaluate the impact of tadalafil therapy on QOL, the Patient Global Impression of Improvement (PGI-I) and the Clinician Global Impression of Improvement (CGI-I) were collected in two of the randomised, placebo-controlled trials (19,20). In both trials, after 12 weeks of treatment with tadalafil 5 mg, more subjects felt their symptoms had improved with tadalafil 5 mg compared with placebo (p = 0.003 and p < 0.001). Similarly, clinicians also felt that more of their tadalafil 5-mg treated subjects’ symptoms had improved compared with placebo after 12 weeks of treatment in both trials (p = 0.009 and p < 0.001). In the study reported by Egerdie et al., treatment with tadalafil 2.5 also resulted in both subjects and clinicians reporting that symptoms had improved with tadalafil treatment compared

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with placebo at end-point (PGI-I, p = 0.009; CGI-I, p = 0.011) (20).

Subgroup analysis To improve the understanding of the relationship between tadalafil’s known effects on ED and improvements in BPH-LUTS, subgroup analyses were conducted to evaluate whether the response to tadalafil was the same for men in different subgroups. These analyses were assessed in each of the randomised, placebo-controlled trials and looked at age (≤ 65 years, > 65 years; and < 75 years, ≥ 75 years), LUTS severity (IPSS ≥ 20 and IPSS < 20), previous alpha-blocker therapy, previous PDE5-inhibitor therapy, ED status (yes/no) and baseline ED severity (mild, moderate, severe). In general, the baseline characteristics across the studies were comparable (Table 2), with similar percentages of men reporting being sexually active, having previously received treatment with an alpha-blocker, or having previously received treatment for their ED. Overall, treatment with tadalafil 5 mg improved total IPSS in each subgroup (vs. placebo) (13,18–20) and results indicated no differences in treatment effect across subgroups. Additionally, in men with both signs and symptoms of BPH and ED, treatment with tadalafil 5 mg improved total IIEF-EF in each subgroup (20).

Safety and tolerability of tadalafil in the treatment of BPH-LUTS In the studies described here, once daily tadalafil 5 mg was generally well tolerated, and the safety profile was consistent with that seen in previous trials in men with ED alone (29). A summary of common treatment-emergent adverse events (TEAEs) reported in two of the placebo-controlled studies conducted in patients with BPH (13,19) and one randomised, placebo-controlled trial conducted in patients with signs and symptoms of BPH and ED (20) is provided in Table 4. In these three studies, the most commonly reported TEAEs, reported in ≥ 1% of patients receiving tadalafil, included headache, dyspepsia, back pain, nasopharyngitis, diarrhoea, pain in extremity, myalgia and dizziness (30). Overall, the incidence of TEAEs was low in subjects receiving tadalafil, and > 90% of the events were mild or moderate in severity. In the studies conducted in patients with BPH, the discontinuation rate because of adverse events in patients treated with tadalafil was 4.0% compared with 1.6% in placebo-treated patients (p = 0.045) (13,19). In the study conducted in patients with signs and symptoms of BPH and ED, the discontinuation rate because of adverse events was 2.9%

Table 4 Common treatment-emergent adverse events (TEAEs) reported in ≥ 1% of patients with BPH-LUTS (with and without ED) treated with 5 mg tadalafil, once daily for 12 weeks (13, 19, 20)

TEAE (preferred term)

Placebo N = 576 (%)

Tadalafil 5 mg N = 581 (%)

Headache Dyspepsia Back pain Nasopharyngitis Diarrhoea Pain in extremity Myalgia Dizziness

2.3 0.2 1.4 1.6 1.0 0.0 0.3 0.5

4.1 2.4 2.4 2.1 1.4 1.4 1.2 1.0

BPH, Benign prostatic hyperplasia; ED, erectile dysfunction; N, number of randomised subjects; TEAE, treatment-emergent adverse event.

compared with 1.5% in placebo-treated patients (p = 0.504) (20). There were no clinically significant events of urinary retention or increased postvoid residual (PVR) volume, and there were no clinically significant changes in prostate specific antigen (PSA) (13,18–20). Long-term safety/tolerability was assessed in the 1year open-label extension study (28). In this study, TEAEs were reported by 57.6% of patients, however, the majority were mild (44%) or moderate (45%) in severity. The most common TEAEs (≥ 2%) were dyspepsia, gastro-oesophageal reflux disease, back pain, headache, sinusitis, hypertension and cough. Of note, these TEAEs represent treatment-emergent events, regardless of causality. Consistent with the randomised, placebo-controlled trials of 12 weeks’ duration, there were no clinically relevant changes in mean PSA, mean PVR volume or clinically significant events of urinary retention observed in the open-label extension study. Haemodynamic effects (specifically, treatmentemergent dizziness) were evaluated in a study investigating the safety of daily co-administration of alpha-blockers with tadalafil 5 mg (31). Results indicated that the proportion of patients who reported treatment-emergent dizziness was not significantly different between tadalafil and placebo treatment groups.

Peak urinary maximum flow rate (Qmax) It is generally recognised that there is poor correlation between Qmax and subjective symptoms such as severity and frequency of bother, QOL, residual urine or prostate size (3). Furthermore, guidelines state that in the management of patients with bothersome LUTS, Qmax is an optional measure to be considered ª 2013 John Wiley & Sons Ltd Int J Clin Pract, January 2014, 68, 1, 94–103

Tadalafil treatment for BPH-LUTS and ED

should patients be a candidate for surgical procedures (3,32). As such, Qmax was included as an efficacy measure in the early dose-ranging study reported by Roehrborn et al. (13), and was performed as a safety end-point in the Phase 3 randomised, placebo-controlled studies to ensure there was no detrimental effect of tadalafil on urinary flow rate (18–20). Results from these trials demonstrated that although Qmax improved from baseline in all trials, improvement was typically not statistically significant compared with placebo (Table 5). Despite the small Qmax changes, study results consistently demonstrate significant and clinically meaningful improvement in urinary symptoms as measured by IPSS. Specifically, in a post hoc analysis reported in the Roehrborn study to assess change in Qmax by IPSS subgroups, results indicated that once daily tadalafil did not significantly change Qmax or voiding efficiency, although there were dose-dependent improvements in IPSS (33). The reason for the improvement in urinary symptoms despite nonsignificant changes in urinary flow is not fully understood. In an article by Giuliano et al., the modest Qmax changes observed in trials assessing alpha-blocker therapy were attributed to relaxation of the bladder neck/prostatic smooth muscle cell layer. Similarly, in vitro studies have also found that PDE5 inhibitors relax the bladder/prostatic smooth muscle cell layers. The improvement in both the IPSS storage and voiding subscores suggests that

Table 5 Mean changes from baseline to end-point in

maximum urinary flow rate (Qmax) in Phase 3 clinical studies of tadalafil for the treatment of BPH-LUTS in men with and without ED Study

Treatment

N

Qmax

Roehrborn et al.

Placebo Tadalafil, 2.5 mg Tadalafil, 5.0 mg Tadalafil, 10 mg Tadalafil, 20 mg Placebo Tadalafil, 5.0 mg Placebo Tadalafil, 2.5 mg Tadalafil, 5.0 mg Placebo Tadalafil, 5.0 mg Tamsulosin, 0.4 mg

210 208 212 216 208 164 161 200 198 208 172 171 168

1.24 1.41 1.64 1.58 1.96 1.1 1.6 1.2 1.7* 1.6 1.2 2.4** 2.2*

Porst et al. Egerdie et al.

Oelke et al.

*p < 0.05, **p < 0.01 vs. placebo; Qmax units provided as ml s 1. BPH, benign prostatic hyperplasia; ED, erectile dysfunction; LUTS, lower urinary tract symptoms; Qmax, maximum urinary flow rate.

ª 2013 John Wiley & Sons Ltd Int J Clin Pract, January 2014, 68, 1, 94–103

tadalafil may impact not only the bladder neck and prostatic smooth muscle cells but also relaxation of the detrusor muscle (24). Additional research to define the mechanism of action is warranted.

Discussion and conclusions Primary care physicians and urologists have a number of elements to consider when treating and managing BPH-LUTS, including the severity of a patient’s symptoms, concurrence of other coexisting medical conditions, the ability to improve symptoms and impact QOL, as well as the potential side effects of available treatment options. In the studies presented here, results demonstrate that tadalafil was effective in treating men with BPH-LUTS. The mean change from baseline to week 12 in total IPSS was significantly greater in those treated with once daily tadalafil 5 mg than with placebo. Improvements in total IPSS that occurred over the initial 12 weeks of tadalafil treatment were maintained over a 1-year open-label extension period (28), and improvements were seen at the earliest measured time points: 1 week (18) and 2 weeks (20). Additionally, improvement in urinary symptoms was observed in tadalafil-treated patients across subgroups, regardless of age, previous treatment with an alpha-blocker, BPH-LUTS severity at baseline or ED status. While tadalafil is most frequently recognised as a standard pharmacological treatment option for men with ED, results from the clinical studies presented here demonstrate that tadalafil is additionally a well-tolerated and effective treatment option in men with moderate to severe BPH-LUTS with current guidelines placing tadalafil in the treatment algorithm for patients with bothersome LUTS (32). The pathophysiologic mechanism explaining the association between BPH-LUTS and ED is not entirely certain; however, the NO/cGMP signalling pathway appears to be a common link between the two conditions. Previous research indicates that reduced levels of nitric oxide in the penis can lead to ED. Reduced levels of NO in the prostate and bladder can increase smooth muscle tone of the bladder neck and urethra and may stimulate prostatic smooth muscle cell proliferation that results in increased outlet resistance (34). The pathophysiologic rationale for the use of tadalafil to relieve BPH-LUTS in men with and without ED is, in part, based on findings that show the expression of the PDE5 enzyme in the bladder and urethra, as well as in the prostatic glandular, stromal, smooth muscle and vascular tissues. PDE5 isoenzymes are highly expressed in human LUT tissues, thus PDE5 inhibition results in smooth muscle relaxation and may increase pelvic

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blood perfusion, which is suspected to affect smooth muscle tone (24). As PDE5 inhibitors have been investigated as a means of increasing cellular cGMP concentrations, thereby amplifying smooth muscle relaxation and vasodilation, tadalafil may target the common NO/cGMP signalling pathway linking the conditions of BPH-LUTS and ED. As expected, and in addition to the improvement observed in BPH-LUTS, treatment with tadalafil significantly improved (p < 0.001) the IIEF-EF domain score compared with placebo in sexually active men with ED after 12 weeks (18,19). The concurrence of ED and BPH-LUTS in ageing men is well known (2,4), and previous studies have indicated that the impact of coexisting BPH-LUTS and ED on a man’s QOL seems to be directly dependent on the severity of the conditions, independent of the effects of age (2,4). As described by Seftel et al., in a systematic review of coexisting BPH-LUTS and ED epidemiological data, the prevalence and severity of coexisting LUTS and ED increase as men move across the healthcare system from being in the general population to being treatment seeking for BPH-LUTS or ED (7). Additionally, for both LUTS and ED independently, the most important motivations for seeking treatment are the severity and degree of bother associated with the symptoms (7). As the prevalence of coexisting LUTS and ED increases with age, and the severity of one condition typically correlate with the severity of the other, the increasing severity of the conditions typically leads to reduced QOL and an increased degree of bother. Furthermore, among men from the general population assessed in MSAM7, the bothersomeness of ED was inversely related to age and increased in men with moderate to severe LUTS compared with mild or no LUTS (2).

References 1 Wei JT, Calhoun E, Jacobsen SJ. Urologic diseases in America project: benign prostatic hyperplasia. J Urol 2005; 173: 1256–61. 2 Rosen R, Altwein J, Boyle P et al. Lower urinary tract symptoms and male sexual dysfunction: the multinational survey of the aging male (MSAM-7). Eur Urol 2003; 44: 637–49. 3 American Urological Association (AUA) Benign Prostatic Hyperplasia (BPH) Guideline Update Panel. American Urological Association Guideline: Management of Benign Prostatic Hyperplasia (BPH). American Urological Association. 2010. 3-27-2010. 4 Rosen RC, Wei JT, Althof SE, Seftel AD, Miner M, Perelman MA. Association of sexual dysfunction with lower urinary tract symptoms of BPH and BPH medical therapies: results from the BPH Registry. Urology 2009; 73: 562–6. 5 McVary KT. BPH: epidemiology and comorbidities. Am J Manag Care 2006; 12(5 Suppl.): S122–8.

From a safety perspective, tadalafil was well tolerated in patients with BPH-LUTS (with or without ED) and few patients discontinued from the study because of adverse events. Overall, the rate of treatment-emergent adverse events suggests that the safety profile for 5 mg tadalafil once daily in men with BPH-LUTS is similar to observations from long-term studies of 5 mg of tadalafil once daily in men with ED. As treatment options for men with BPH-LUTS evolve, the PCP is in a position to offer a variety of choices to the patient. The specific benefit of tadalafil to treat both ED and BPH-LUTS is unique and presents the only single medical therapy option approved to treat men with both conditions, thus simplifying the medical treatment of commonly coexisting conditions.

Acknowledgements Eli Lilly and Company helped provide support for this study. All co-authors participated in the preparation, review and approval of the manuscript. The authors acknowledge Stephanie Brillhart (inVentiv Health, Indianapolis, IN) for writing and editorial assistance.

Author contributions Culley Carson: Interpretation of data, drafting article, critical revision of article, approval of article. Matt Rosenberg: Interpretation of data, drafting article, critical revision of article, approval of article. Jay Kissel: Interpretation of data, drafting article, critical revision of article, approval of article. David Wong: Interpretation of data, drafting article, critical revision of article, approval of article.

6 Kohler TS, McVary KT. The relationship between erectile dysfunction and lower urinary tract symptoms and the role of phosphodiesterase type 5 inhibitors. Eur Urol 2009; 55: 38–48. 7 Seftel AD, de la Rosette J, Birt J, Porter V, Zarotsky V, Viktrup L. Coexisting lower urinary tract symptoms and erectile dysfunction: a systematic review of epidemiological data. Int J Clin Pract 2012; 67: 32–45. 8 Rosen RC. Update on the relationship between sexual dysfunction and lower urinary tract symptoms/ benign prostatic hyperplasia. Curr Opin Urol 2006; 16: 11–9. 9 Kirby M, Chapple C, Jackson G et al. Erectile dysfunction and lower urinary tract symptoms: a consensus on the importance of co-diagnosis. Int J Clin Pract 2013; 67: 606–18. 10 Naslund MJ, Costa FJ, Miner MM. Managing enlarged prostate in primary care. Int J Clin Pract 2006; 60: 1609–15. 11 Rosenberg MT, Staskin DR, Kaplan SA, MacDiarmid SA, Newman DK, Ohl DA. A practical guide to the evaluation and treatment of male lower uri-

12

13

14

15

nary tract symptoms in the primary care setting. Int J Clin Pract 2007; 61: 1535–46. Gacci M, Eardley I, Giuliano F et al. Critical analysis of the relationship between sexual dysfunctions and lower urinary tract symptoms due to benign prostatic hyperplasia. Eur Urol 2011; 60: 809–25. Roehrborn CG, McVary KT, Elion-Mboussa A, Viktrup L. Tadalafil administered once daily for lower urinary tract symptoms secondary to benign prostatic hyperplasia: a dose finding study. J Urol 2008; 180: 1228–34. Mulhall JP, Guhring P, Parker M, Hopps C. Assessment of the impact of sildenafil citrate on lower urinary tract symptoms in men with erectile dysfunction. J Sex Med 2006; 3: 662–7. McVary KT, Monnig W, Camps JL Jr., Young JM, Tseng LJ, van den Ende G. Sildenafil citrate improves erectile function and urinary symptoms in men with erectile dysfunction and lower urinary tract symptoms associated with benign prostatic hyperplasia: a randomized, double-blind trial. J Urol 2007; 177: 1071–7.

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Tadalafil treatment for BPH-LUTS and ED

16 Stief CG, Porst H, Neuser D, Beneke M, Ulbrich E. A randomised, placebo-controlled study to assess the efficacy of twice-daily vardenafil in the treatment of lower urinary tract symptoms secondary to benign prostatic hyperplasia. Eur Urol 2008; 53: 1236–44. 17 Gacci M, Vittori G, Tosi N et al. A randomized, placebo-controlled study to assess safety and efficacy of vardenafil 10 mg and tamsulosin 0.4 mg vs. tamsulosin 0.4 mg alone in the treatment of lower urinary tract symptoms secondary to benign prostatic hyperplasia. J Sex Med 2012; 9: 1624–33. 18 Oelke M, Giuliano F, Mirone V, Xu L, Cox D, Viktrup L. Monotherapy with tadalafil or tamsulosin similarly improved lower urinary tract symptoms suggestive of benign prostatic hyperplasia in an international, randomised, parallel, placebo-controlled clinical trial. Eur Urol 2012; 61: 917–25. 19 Porst H, Kim ED, Casabe AR et al. Efficacy and safety of tadalafil once daily in the treatment of men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia: results of an international randomized, double-blind, placebo-controlled trial. Eur Urol 2011; 60: 1105–13. 20 Egerdie RB, Auerbach S, Roehrborn CG et al. Tadalafil 2.5 or 5 mg administered once daily for 12 weeks in men with both erectile dysfunction and signs and symptoms of benign prostatic hyperplasia: results of a randomized, placebo-controlled, double-blind study. J Sex Med 2012; 9: 271–81. 21 Uckert S, Kuthe A, Jonas U, Stief CG. Characterization and functional relevance of cyclic nucleotide phosphodiesterase isoenzymes of the human prostate. J Urol 2001; 166: 2484–90.

ª 2013 John Wiley & Sons Ltd Int J Clin Pract, January 2014, 68, 1, 94–103

22 Morelli A, Sarchielli E, Comeglio P et al. Phosphodiesterase type 5 expression in human and rat lower urinary tract tissues and the effect of tadalafil on prostate gland oxygenation in spontaneously hypertensive rats. J Sex Med 2011; 8: 2746–60. 23 Filippi S, Morelli A, Sandner P et al. Characterization and functional role of androgen-dependent PDE5 activity in the bladder. Endocrinology 2007; 148: 1019–29. 24 Giuliano F, Uckert S, Maggi M, Birder L, Kissel J, Viktrup L. The mechanism of action of phosphodiesterase type 5 inhibitors in the treatment of lower urinary tract symptoms related to benign prostatic hyperplasia. Eur Urol 2013; 63: 506–16. 25 Andersson KE, de Groat WC, McVary KT et al. Tadalafil for the treatment of lower urinary tract symptoms secondary to benign prostatic hyperplasia: pathophysiology and mechanism(s) of action. Neurourol Urodyn 2011; 30: 292–301. 26 Uckert S, Sormes M, Kedia G et al. Effects of phosphodiesterase inhibitors on tension induced by norepinephrine and accumulation of cyclic nucleotides in isolated human prostatic tissue. Urology 2008; 71: 526–30. 27 Kedia GT, Uckert S, Jonas U, Kuczyk MA, Burchardt M. The nitric oxide pathway in the human prostate: clinical implications in men with lower urinary tract symptoms. World J Urol 2008; 26: 603–9. 28 Donatucci CF, Brock GB, Goldfischer ER et al. Tadalafil administered once daily for lower urinary tract symptoms secondary to benign prostatic hyperplasia: a 1-year, open-label extension study. BJU Int 2011; 107: 1110–6.

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29 Curran MP. Tadalafil: in the treatment of signs and symptoms of benign prostatic hyperplasia with or without erectile dysfunction. Drugs Aging 2012; 29: 771–81. 30 Cialis (tadalafil) Tablets, for Oral Use [package insert]. Indianapolis, IN: Eli Lilly nd Company; 2011. http://pi.lilly.com/us/cialis-pi.pdf. 31 Goldfischer E, Kowalczyk JJ, Clark WR et al. Hemodynamic effects of once-daily tadalafil in men with signs and symptoms of benign prostatic hyperplasia on concomitant alpha1-adrenergic antagonist therapy: results of a multicenter randomized, double-blind, placebo-controlled trial. Urology 2012; 79: 875–82. 32 Oelke M, Bachmann A, Descazeaud A et al. EAU guidelines on the treatment and follow-up of non-neurogenic male lower urinary tract symptoms including benign prostatic obstruction. Eur Urol 2013; 64: 118–40. 33 Roehrborn CG, Kaminetsky JC, Auerbach SM, Montelongo RM, Elion-Mboussa A, Viktrup L. Changes in peak urinary flow and voiding efficiency in men with signs and symptoms of benign prostatic hyperplasia during once daily tadalafil treatment. BJU Int 2010; 105: 502–7. 34 McVary KT. Erectile dysfunction and lower urinary tract symptoms secondary to BPH. Eur Urol 2005; 47: 838–45.

Paper received June 2013, accepted August 2013

Tadalafil - a therapeutic option in the management of BPH-LUTS.

Men with signs of benign prostatic hyperplasia (BPH) may experience lower urinary tract symptoms (LUTS) such as urinary frequency, urgency, intermitte...
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