Carsten Henneges

Efficacy and Safety of the Coadministration of Tadalafil Once Daily with Finasteride for 6 Months in Men with Lower Urinary Tract Symptoms and Prostatic Enlargement Secondary to Benign Prostatic Hyperplasia

PURPOSE Medical treatment for men with lower urinary tract symptoms and prostatic enlargement secondary to benign prostatic hyperplasia is 5α-reductase inhibitor monotherapy or coadministration with an α-blocker. We assessed the effects of tadalafil 5 mg coadministered with finasteride 5 mg during 26 weeks on lower urinary tract symptoms and sexual symptoms. MATERIALS AND METHODS In an international, randomized, double-blind, parallel study of men 45 years old or older who were 5α-reductase inhibitor naïve and had an I-PSS (International Prostate Symptom Score) of 13 or greater and prostate volume 30 ml or greater, 350 were treated with placebo/finasteride and 345 received tadalafil/finasteride for 26 weeks. Changes in lower urinary tract symptoms secondary to benign prostatic hyperplasia were assessed with the I-PSS, erectile dysfunction improvements were assessed with the IIEF-EF (International Index of Erectile Function-Erectile Function) in sexually active men and safety was assessed by evaluating adverse events. RESULTS Least squares mean changes from baseline in I-PSS after 4, 12 and 26 weeks of tadalafil/finasteride coadministration were -4.0, -5.2 and -5.5, respectively. Corresponding values for placebo/finasteride coadministration were -2.3, -3.8 and -4.5 (p ≤ 0.022 at all visits favoring tadalafil/finasteride coadministration). I-PSS subscores (storage and voiding) and quality of life index were also numerically improved with tadalafil/finasteride coadministration. Least squares mean changes from baseline in IIEF-EF with tadalafil/finasteride coadministration were 3.7 after 4 weeks, and 4.7 after 12 and 26 weeks. Corresponding values for placebo/finasteride coadministration were -1.1, 0.6 and -0.0 (p <0.001 at all visits favoring tadalafil/finasteride coadministration). Tadalafil/finasteride coadministration was well tolerated and most adverse events were mild/moderate. CONCLUSIONS The coadministration of tadalafil/finasteride provides early improvement in lower urinary tract symptoms in men with benign prostatic hyperplasia and prostatic enlargement. Tadalafil/finasteride coadministration also improves erectile function in men who have comorbid erectile dysfunction.

Sexual Function in Men with Lower Urinary Tract Symptoms and Prostatic Enlargement Secondary to Benign Prostatic Hyperplasia: Results of a 6‐Month, Randomized, Double‐Blind, Placebo‐Controlled Study of Tadalafil Coadministered with Finasteride

INTRODUCTION Tadalafil (TAD) 5 mg coadministered with finasteride (FIN) 5 mg significantly improves lower urinary tract symptoms (LUTS) in men with benign prostatic hyperplasia (BPH) and prostatic enlargement. However, its effects on erectile/sexual function have yet to be fully described. AIM Assess the effects of TAD/FIN coadministration (compared with placebo [PBO]/FIN) on erectile and sexual function in sexually active men with LUTS and prostatic enlargement secondary to BPH with or without baseline comorbid erectile dysfunction (ED). METHODS A randomized, double-blind, PBO-controlled study of 695 men (610 sexually active; 450 with baseline ED; 404 sexually active with baseline ED) conducted at 70 sites in 13 countries. TAD 5 mg or PBO once daily coadministered with FIN 5 mg once daily for 26 weeks. MAIN OUTCOME MEASURES International Index of Erectile Function (IIEF) domain and single-item scores; proportions of patients who demonstrated minimal clinically important differences (MCIDs) in IIEF-Erectile Function domain scores (IIEF-EF; MCID defined as ≥4-point improvement); and sexual dysfunction adverse events (AEs). RESULTS Compared with PBO/FIN, TAD/FIN resulted in improvements for all IIEF domain and single-item scores assessed among patients with baseline ED (P ≤ 0.002 for all measures) and among patients without baseline ED (P ≤ 0.041 for all measures). Compared with PBO/FIN, significantly larger percentages of sexually active men with baseline ED treated with TAD/FIN achieved an IIEF-EF MCID after 4, 12, and 26 weeks of therapy (P < 0.001 for odds ratio comparisons between TAD/FIN and PBO/FIN at all 3 three postbaseline timepoints). The incidence of sexual AEs was low: five TAD/FIN patients and seven PBO/FIN patients reported sexual AEs, including ED, decreased/lost libido, and ejaculation disorders. CONCLUSIONS TAD/FIN coadministration for the treatment of men with LUTS and prostatic enlargement secondary to BPH concurrently leads to statistically significant improvements in erectile/sexual function and is well-tolerated, regardless of the presence/absence of ED at treatment initiation.

Tadalafil Once Daily in Men with Erectile Dysfunction: An Integrated Analysis of Data Obtained from 1913 Patients from Six Randomized, Double-blind, Placebo-controlled, Clinical Studies

BACKGROUND This analysis explores tadalafil once-daily treatment for 12 wk in clinical subpopulations of men with erectile dysfunction (ED). OBJECTIVE Assess the efficacy and safety of once-daily tadalafil 2.5mg and 5mg in patients with different ED characteristics and comorbidities. DESIGN, SETTING, AND PARTICIPANTS This analysis integrated data from six randomized, double-blind, placebo-controlled studies that assigned 1913 men with ≥3-mo history of ED either to once-daily placebo (n=596), tadalafil 2.5mg (n=394), or tadalafil 5mg (n=923). Clinical factors examined included: ethnicity, age, obesity, alcohol consumption, smoking, comorbidities, concomitant medication, and ED characteristics (etiology, duration, severity). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Descriptive statistics were reported for efficacy and safety, including International Index of Erectile Function Erectile Function Domain (IIEF-EF) scores and Sexual Encounter Profile question 3 (SEP3) responses. Clinical factors were included in analysis of covariance models using last observation carried forward for SEP3 and IIEF-EF scores. RESULTS AND LIMITATIONS Both tadalafil doses significantly improved SEP3 responses (least-squares [LS] mean change: 17.8% and 23.6%, respectively) and IIEF-EF scores (LS mean change: 4.2; 5.4) compared with placebo (p<0.01). Treatment with 2.5mg and 5mg tadalafil resulted in IIEF-EF LS mean improvements ≥4 (minimal clinically important difference [MCID]) in patients with hypertension (4.3 [95% confidence interval (CI), 2.9-5.7]; 4.7 [95% CI, 3.5-5.8]), cardiac disorder (7.0 [95% CI, 4.7-9.3]; 6.3 [95% CI, 4.4-8.2]), or hyperlipidemia (5.3 [95% CI, 3.4-7.1]; 5.8 [95% CI, 4.3-7.4]). Obese patients (4.7 [95% CI, 3.4-6.0]), smokers (4.8 [95% CI, 3.0-6.7]), and psychogenic ED (7.3 [95% CI, 5.0-9.6]) reached MCID only after treatment with 5mg tadalafil. Severity-specific MCID (IIEF-EF change ≥7) was achieved by 44.5% of patients with severe baseline ED treated with tadalafil 5mg, compared with 11.6% of placebo-treated patients. No unexpected safety findings were observed. These analyses were performed on integrated data and can only provide descriptive results to guide further investigations. CONCLUSIONS Treatment with tadalafil 2.5mg or 5mg once daily was well tolerated and resulted in clinically important improvements in patients with mild (54.3% and 74.8%, respectively), moderate (51.3% and 63.1%, respectively), or severe (33.7% and 44.5%, respectively) ED.

Treatment satisfaction and clinically meaningful symptom improvement in men with lower urinary tract symptoms and prostatic enlargement secondary to benign prostatic hyperplasia: Secondary results from a 6-month, randomized, double-blind study comparing finasteride plus tadalafil with finasteride plus placebo

To report the secondary analyses of treatment satisfaction and clinically meaningful improvements in a randomized study comparing coadministration of tadalafil 5 mg with finasteride 5 mg versus finasteride alone in men with prostatic enlargement secondary to benign prostatic hyperplasia.

Effect of Tadalafil on Male Lower Urinary Tract Symptoms: An Integrated Analysis of Storage and Voiding International Prostate Symptom Subscores from Four Randomised Controlled Trials☆

BACKGROUND The international prostate symptom score (IPSS) evaluates lower urinary tract symptoms (LUTS) in men with suspected benign prostatic hyperplasia (BPH); the total score does not differentiate between storage and voiding and is unevenly weighted (four questions [57%] on voiding, three questions [43%] on storage). OBJECTIVE To evaluate the relative contributions of storage and voiding IPSS subscores to total IPSS at baseline and in response to treatment with tadalafil. DESIGN, SETTING, AND PARTICIPANTS Integrated analysis of data from four placebo-controlled, 12-wk studies of tadalafil (5mg once daily) in 1499 men with LUTS/BPH. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Relationships between total IPSS and the storage and voiding subscores were assessed using graphical exploration and linear regression modelling. Linear modelling was performed for the baseline and endpoint and for changes in subscores. The optimal storage subscore to total IPSS (S:T) ratio for IPSS improvement was identified using nonparametric regression and gradient-descent optimisation. RESULTS AND LIMITATIONS The contribution of storage and voiding subscores at baseline and endpoint was 38.8% and 61.2%, and 39.2% and 60.7%, respectively. This intuitive 40:60 storage-to-voiding ratio was similar at baseline and endpoint by treatment group and for changes in subscores, but spanned the entire range for individuals. Changes in total IPSS were greatest for a storage subscore percentage contribution to total IPSS of 42.7%. There was no statistical association between S:T ratio (≥ 40% vs < 40%) at baseline and response to tadalafil. The main limitation was the use of unvalidated storage and voiding IPSS subscores. CONCLUSIONS A constant S:T ratio of 4:10 was observed at baseline and endpoint. The greatest effect on total IPSS was noted for an S:T percentage contribution of 42.7%. Tadalafil efficacy was unaffected by the level of storage dysfunction at baseline. PATIENT SUMMARY This analysis shows that for men with BPH, improvements during treatment with tadalafil apply to both storage and voiding symptoms at a constant ratio. The extent of storage dysfunction before treatment did not affect the response to treatment.

PDE5 Inhibitor Treatment Persistence and Adherence in Brazilian Men: Post-hoc Analyses from a 6-Month, Prospective, Observational Study

PURPOSE Characterize persistence and adherence to phosphodiesterase type - 5 inhibitor (PDE5I) on-demand therapy over 6 months among Brazilian men in an observational, non-interventional study of Latin American men naïve to PDE5Is with erectile dysfunction (ED). MATERIALS AND METHODS Men were prescribed PDE5Is per routine clinical practice. Persistence was defined as using ≥ 1 dose during the previous 4 - weeks, and adherence as following dosing instructions for the most recent dose, assessed using the Persistence and Adherence Questionnaire. Other measures included the Self - Esteem and Relationship (SEAR) Questionnaire, and International Index of Erectile Function (IIEF). Multivariate logistic regression was used to identify factors associated with persistence/adherence. RESULTS 104 Brazilian men were enrolled; mean age by treatment was 53 to 59 years, and most presented with moderate ED (61.7%). The prescribed PDE5I was sildenafil citrate for 50 (48.1%), tadalafil for 36 (34.6%), vardenafil for 15 (14.4%), and lodenafil for 3 patients (2.9%). Overall treatment persistence was 69.2% and adherence was 70.2%; both were numerically higher with tadalafil (75.0%) versus sildenafil or vardenafil (range 60.0% to 68.0%). Potential associations of persistence and/or adherence were observed with education level, ED etiology, employment status, and coronary artery disease. Improvements in all IIEF domain scores, and both SEAR domain scores were observed for all treatments. Study limitations included the observational design, brief duration, dependence on patient self - reporting, and limited sample size. CONCLUSION Approximately two-thirds of PDE5I-naive, Brazilian men with ED were treatment persistent and adherent after 6 months. Further study is warranted to improve long-term outcomes of ED treatment.

Decision tree analyses of key patient characteristics in Middle Eastern/North African and Latin American men treated with long-acting and short-acting PDE5 inhibitors for erectile dysfunction

Abstract Background: Phosphodiesterase type 5 (PDE5) inhibitors have discontinuation rates as high as 60% in men with erectile dysfunction. Treatment satisfaction has been significantly associated with treatment continuation. Understanding key characteristics in terms of treatment preference, relationship, and lifestyle issues could provide direction on how to improve compliance with PDE5 inhibitor treatment globally. Objective: The objective was to identify subgroups of interest in the pooled database of two observational studies conducted in Latin America (LA) and Middle East/North Africa (MENA) exploring patient characteristics and prescription of either a long- or short-acting PDE5 inhibitor at baseline. Methods: Two identical prospective, non-interventional, observational, studies in MENA (N = 493) and LA (N = 511) treated men with an ‘on demand’ (pro re nata, PRN) PDE5 inhibitor (sildenafil, tadalafil, vardenafil, or lodenafil) during 6 months. In this post-hoc meta-analysis of two observational studies with equal design, pooled data were analyzed to determine patient characteristics and PDE5 inhibitor prescribed/used most likely to be associated with patient expectations, satisfaction, self-esteem, and patient–partner relationships. Decision tree analyses, with and without weighting, were used to identify and describe key features. Results: In each analysis of patient expectations, patient–partner relationship, and self-esteem, we describe the two major subgroups at baseline for each decision tree. Analyses of patient expectations and sexual self-esteem revealed that patients prescribed long-acting PDE5 inhibitors (59%) highlighted the importance of treatment effect duration, second to partner satisfaction with treatment, while patients prescribed short-acting PDE5 inhibitors (32%) placed less importance on treatment effect duration but considerable importance on treatment effect lasting until intercourse completion. Further insights regarding patients, partner relationship characteristics, and treatment expectations were identified. Conclusion: Our analyses have described key characteristics, such as self- and partner perceptions, sexual attitudes, and treatment expectations in relation to the patients’ country and prescribed treatment, which might guide treatment decisions in MENA and LA men with ED.

Reply from Authors re: Arthur L. Burnett. Erection Rehabilitation After Radical Prostatectomy: Definite Purpose, Indefinite Strategy. Eur Urol 2014;65:597–8: Although Erection Rehabilitation After Prostatectomy Remains Indefinite, the Most Effective Treatment, the Earliest Recovery, and the Preservation of Erectile Function Remain a Definite Goal

efforts to set proper expectations and provide necessary education surrounding the reality and circumstances of ED after RP. Strategies that emphasize effective communication, coaching, and monitoring of functional progress postoperatively remain central to EF recovery. With counseling, some patients should be prepared to explore temporary and reversible ED-specific therapies postoperatively. Reversible options are ideal for the patient possessing intact erections preoperatively who was able to undergo nerve-sparing RP and had favorable risk factors for regaining natural EF in time after the surgery. A forward perspective is to continue to support scientific investigation to develop optimal strategies for postoperative EF recovery. Investigation should continue into the pathophysiologic derangements associated with ED in this setting and will likely advance scientifically targeted treatments. It is understandable that current ED-specific therapies have been brought forward initially for this purpose, although their roles in this arena would best be defined by success in restoring erection mechanisms or preventing their loss rather than by eliciting on-demand erectogenic effects alone. Several therapeutic prospects carry interest for erection rehabilitation purposes in the future. These may include not just pharmacotherapies but also growth factor therapies, gene therapies, tissue engineering, stem cell therapies, and possibly local energybased technologies, any of which may be smartly applied before or possibly during the course of RP surgery, aiming for maximal therapeutic benefit. Our responsibility is to continue to investigate and establish the effectiveness of all suggested therapies with rigorous scientific standards to confirm their EF restorative and preventative roles. The best strategy for EF preservation after RP will require proficiently performed anatomic nerve-sparing surgery when indicated, coupled with health and physical fitness optimization by the patient, to which proven pathophysiology-specific interventions can be added. This