Impact of cardiovascular risk factors and related comorbid conditions and medical therapy reported at baseline on the treatment response to tadalafil 5 mg once-daily in men with lower urinary tract symptoms associated with benign prostatic hyperplasia: an integrated analysis of four randomised, double-blind, placebo-controlled, clinical trials.

PURPOSE: The influence of cardiovascular risk factors/comorbidities on response to oral once-daily tadalafil 5 mg was explored in men with lower urinary tract symptoms associated with benign prostatic hyperplasia (LUTS/BPH). METHODS: This post hoc analysis pooled data from four double-blind studies in which 1498 men with > 6-mo history of LUTS/BPH were randomised and received either once-daily placebo (n = 746) or tadalafil 5 mg (n = 752) for 12 weeks. Descriptive statistics were reported for changes in total International Prostate Symptom Score (IPSS), IPSS voiding and storage subscores, and IPSS quality-of-life (QoL) index. Treatment group differences by baseline clinical and cardiovascular factors and medical therapies were examined using analysis of covariance. RESULTS: Tadalafil was effective in men with LUTS/BPH and cardiovascular risk factors/comorbidities except for patients receiving > 1 antihypertensive medication. Placebo-adjusted least squares (LS) mean improvements in total IPSS were -1.2 (95% CI: -2.5 to -0.0) in men taking > 1 antihypertensive medication vs. -3.3 (95% CI: -4.4 to -2.1) in men taking one medication (interaction p = 0.020). In addition, placebo-adjusted LS mean improvements in total IPSS were -0.2 (95% CI, -2.1 to 1.7) in men who reported use of diuretics vs. -2.8 (95% CI, -3.7 to -1.9) in men who reported taking other antihypertensive medications vs. -2.3 (95% CI, -3.2 to -1.5) in men who reported not using any antihypertensive drug (p-value for interaction = 0.053). CONCLUSIONS: Once-daily tadalafil 5 mg improved LUTS/BPH, regardless of severity, in men with coexisting cardiovascular risk factors/comorbidities, except for patients with history of > 1 drug for arterial hypertension. Use of diuretics may contribute to patients' perception of a negated efficacy of tadalafil on LUTS/BPH. Comorbidities should be considered when choosing the optimal medicine to treat men with LUTS/BPH.

Impact of behaviour and lifestyle on bladder health.

Bladder conditions, including UTI, UI, and bladder cancer, are highly prevalent and affect a wide range of populations. There are a variety of modifiable behavioral and lifestyle factors that influence bladder health. Some factors, such as smoking and obesity, increase the risk or severity of bladder conditions, whereas other factors, such as pelvic floor muscle exercise, are protective. Although clinical practice may be assumed to be the most appropriate ground for education on behavioral and lifestyle factors that influence bladder health, it is also crucial to extend these messages into the general population through public health interventions to reach those who have not yet developed bladder conditions and to maximize the prevention impact of these behaviors. Appropriate changes in these factors have the potential for an enormous impact on bladder health if implemented on a population-based level.

Complex cases in primary care: report of a CME-certified series addressing patients with multiple comorbidities.

AIM: To assess whether participation in a series of continuing medical education-certified activities presenting complicated case scenarios resulted in evidence-based decision making for patients with chronic comorbid conditions. METHODS: A series of interactive live workshops and online case studies presented evidence-based, practical information addressing the care of patients with multiple chronic diseases to primary care physicians. Clinical case vignettes were used to assess workshop participant knowledge and competence. Results were compared with those of matched non-participant controls. Online participants were surveyed to evaluate immediate knowledge gains from the activity. RESULTS: Overall, physician workshop participants were 27% more knowledgeable of evidence-based treatment decisions. Participants were more likely to refer a patient with rheumatoid arthritis to a rheumatologist (57% vs. 36%; p = 0.035) and showed better recognition of medications that can contribute to overactive bladder symptoms (36% vs. 18%; p = 0.043) compared with non-participant controls. Non-significant differences in favour of participants included evidence-based decisions regarding the management of osteoporosis, attention deficit hyperactivity disorder in adults and type 2 diabetes mellitus in adolescents. Online participants demonstrated significant knowledge gains (p < 0.001) on 17 of 18 assessment questions across all therapeutic areas. DISCUSSION: Chronic comorbid conditions afflict a sizable minority of patients. However, specific recommendations and education surrounding patient management are often overlooked because of the inherent difficulty of treating this group. Highly interactive educational activities can improve participant knowledge and competency in treating these patients by providing an opportunity to interact with faculty experts, receive immediate feedback and practice new skills. CONCLUSION: Interactive educational activities that discuss complicated case scenarios can improve participant application of evidence-based medicine for patients with multiple chronic comorbidities.

A practical guide to male hypogonadism in the primary care setting.

There is a high prevalence of hypogonadism in the older adult male population and the proportion of older men in the population is projected to rise in the future. As hypogonadism increases with age and is significantly associated with various comorbidities such as obesity, type 2 diabetes, hypertension, osteoporosis and metabolic syndrome, the physician is increasingly likely to have to treat hypogonadism in the clinic. The main symptoms of hypogonadism are reduced libido/erectile dysfunction, reduced muscle mass and strength, increased adiposity, osteoporosis/low bone mass, depressed mood and fatigue. Diagnosis of the condition requires the presence of low serum testosterone levels and the presence of hypogonadal symptoms. There are a number of formulations available for testosterone therapy including intramuscular injections, transdermal patches, transdermal gels, buccal patches and subcutaneous pellets. These are efficacious in establishing eugonadal testosterone levels in the blood and relieving symptoms. Restoration of testosterone levels to the normal range improves libido, sexual function, and mood; reduces fat body mass; increases lean body mass; and improves bone mineral density. Testosterone treatment is contraindicated in subjects with prostate cancer or benign prostate hyperplasia and risks of treatment are perceived to be high by many physicians. These risks, however, are often exaggerated and should not outweigh the benefits of testosterone treatment.

Biology and natural history of prostate cancer and the role of chemoprevention.

Androgens not only play an important role in the development and function of the prostate but they are also intimately involved in the development and progression of prostate cancer (PCa). Within the prostate, testosterone is converted to the more potent androgen dihydrotestosterone (DHT) via the action of 5α-reductase enzymes. DHT is the primary prostatic androgen and promotes the growth and survival of normal, hyperplastic and malignant prostate tissues. Throughout the different stages of PCa [prostatic intraepithelial neoplasia (PIN), localised, recurrent, and metastatic] there is an increase in expression of 5α-reductase enzymes, particularly in localised high-grade carcinoma. Specifically inhibiting 5α-reductase may reduce the production of DHT in the prostate while maintaining other endogenous hormone levels. Clinical studies have shown significant PCa risk reduction by blocking this pathway with 5α-reductase inhibitors (5ARIs). However, this comes at a risk, albeit low, with sexual side effects, gynaecomastia and cardiac failure. In addition, one study has shown a slight, but significant, risk of high-grade PCa. The currently available evidence does not support the routine use of 5α-reductase inhibitors to prevent PCa in the general population. It could, however, be considered as an individual option for high-risk or concerned patients with appropriate education from the prescribing provider.

STEP: simplified treatment of the enlarged prostate.

We propose a simple and practical approach to the identification, evaluation and treatment of lower urinary tract symptoms (LUTS) resulting from an enlarging and obstructive prostate. The proposed Simplified Treatment for Enlarged Prostate (STEP) plan is a logical guide to patient management by the primary care provider (PCP). Symptoms of enlarged prostate (EP) are common and may frequently progress into a condition with profound adverse effects on quality of life. Despite the high prevalence, EP is underdiagnosed and undertreated. This situation may result from patient- and provider-related issues. Assessment of symptoms of EP should be initiated with a discussion of LUTS. Evaluation includes a focused history, physical examination and selected laboratory tests. Certain factors put the symptomatic patient at risk for disease progression; however, not all factors can be readily evaluated in the PCP setting. The serum prostate-specific antigen (PSA) level acts both as an indicator of prostatic size and a screening tool for prostatic cancer, and thereby provides an important tool for PCPs. The STEP plan is a logical guide to patient management. Step 1, watchful waiting, is appropriate in patients with symptoms that are not bothersome. If symptoms cause bother, the initiation of an alpha-blocker (AB) in step 2, provides relatively rapid symptom improvement. Patients with bothersome symptoms and a PSA > or = 1.5 ng/ml are at risk for progression and consideration should be given to combination treatment with an AB and a 5alpha-reductase inhibitor (step 3). Patients with refractory symptoms should be referred to a urologist (step 4). Identification, evaluation and management of EP are within the domain of the primary care setting. The STEP approach provides a simple and practical framework for PCPs to manage most men with symptoms of EP.

The role of tramadol ER in the treatment of chronic pain.

Despite its high prevalence, chronic pain is suboptimally treated in approximately one half of affected patients. Failure to recognise and manage comorbid physical and psychosocial impairments may contribute to the perpetuation of chronic pain. Knowledge of the potential advantages and disadvantages of available analgesic medications will permit informed selection of the appropriate medication for the individual chronic pain patient. Ultimate therapeutic goals will also influence analgesic medication selection. For the patient with chronic pain requiring analgesic treatment for an extended period of time, long-acting analgesics are recommended. Theoretically, these agents will provide sustained analgesia by minimising the end-of-dose pain that is often seen with short-acting medications, with improved patient convenience and a potential for reduced risk of adverse events. The extended-release formulation of tramadol (tramadol ER) has proven efficacy in chronic pain conditions such as osteoarthritis and low back pain, as well as a favourable tolerability profile. In addition, tramadol ER has been shown in clinical trials to improve pain-related sleep disturbances and physical function in patients with chronic pain from osteoarthritis and low back pain.

Improvement in duration of erection following phosphodiesterase type 5 inhibitor therapy with vardenafil in men with erectile dysfunction: the ENDURANCE study.

OBJECTIVE: The ENDURANCE study evaluated the efficacy of vardenafil, a phosphodiesterase type 5 (PDE5) inhibitor, in men with erectile dysfunction (ED), by measuring the duration of erection leading to successful intercourse using a stopwatch as the assessment instrument. METHODS: This was a randomised, multicentre, double-blind, placebo-controlled, crossover study consisting of a 4-week treatment-free run-in phase after which patients were randomised to either fixed-dose vardenafil 10 mg or placebo (to be administered 60 min prior to intercourse) and entered the first of the two 4-week double-blind treatment periods, separated by a 1-week washout. The primary efficacy end-point was the stopwatch-assessed duration of erection, which was defined as the time from erection perceived hard enough for penetration until withdrawal from the partner's vagina leading to successful intercourse as measured by Sexual Encounter Profile Question 3 (SEP-3). Secondary efficacy end-points included SEP-2 and SEP-3 success rates, the erectile function domain of the International Index of Erectile Function, global assessment questionnaire, change from baseline in duration of erection and duration of erection not leading to successful intercourse. Safety was assessed by adverse events (AEs), laboratory samples, vital signs and ECGs. RESULTS: Of the 191 men included in the safety population, 40% had moderate ED and 33% had severe ED at baseline. The duration of erection (least squares mean +/- SE) leading to successful intercourse was longer with vardenafil than with placebo (12.81 +/- 1.00 min vs. 5.45 +/- 1.00 min; p < 0.001). The differences recorded for all secondary end-points were statistically significant in favour of vardenafil compared with placebo (p < 0.001), with the exception of duration of erection not leading to successful intercourse. Vardenafil was well tolerated in this study; the majority of AEs being mild-to-moderate in intensity. CONCLUSION: Vardenafil 10-mg therapy provided a statistically superior duration of erection leading to successful intercourse in men with ED compared with placebo.

Trospium chloride once-daily extended release is effective and well tolerated for the treatment of overactive bladder syndrome: an integrated analysis of two randomised, phase III trials.

BACKGROUND: Trospium chloride is an antimuscarinic agent with a hydrophilic polar quaternary amine structure that is minimally metabolised by hepatic cytochrome P450 and is actively excreted in the urine, each of which confers a potential benefit with regard to efficacy and tolerability. PURPOSE: We analysed pooled data from two identically designed phase III trials of a once-daily, extended-release (XR) formulation of trospium chloride (trospium XR 60-mg capsules) in subjects with overactive bladder syndrome (OAB). METHODS: Adults with OAB of > or = 6 months' duration with urinary urgency, frequency and > or = 1 urge urinary incontinence (UUI) episode/day were enrolled in these multicentre, parallel-group, double-blind trials. Participants were randomised (1 : 1) to receive trospium XR 60 mg or placebo for 12 weeks. Primary efficacy variables were changes in urinary frequency and the number of UUI episodes/day. Adverse events (AEs) were recorded throughout. RESULTS: In total, 1165 subjects were randomised (trospium XR, 578; placebo, 587). At baseline, subjects averaged 12.8 toilet voids/day and 4.1 UUI episodes/day. Compared with placebo, subjects treated with trospium XR had significantly greater reductions from baseline in the mean number of toilet voids/day (-1.9 vs. -2.7; p < 0.001) and UUI episodes/day (-1.8 vs. -2.4; p < 0.001) at week 12. The most frequent AEs considered possibly related to study treatment were dry mouth (trospium XR, 10.7%; placebo, 3.7%) and constipation (trospium XR, 8.5%; placebo, 1.5%). Notably, rates of central nervous system (CNS) AEs were lower with trospium XR vs. placebo (dizziness: 0.2% vs. 1.0%; headache: 1.4% vs. 2.4%). CONCLUSIONS: Treatment with trospium XR resulted in statistically significant improvements in both of the dual primary and all of the secondary outcome variables. Trospium XR demonstrated favourable rates of AEs, particularly CNS AEs (numerically lower than with placebo) and dry mouth (lower than previously reported with trospium immediate-release, although not compared in a head-to-head study).

Benign prostatic hyperplasia evaluation, treatment and association with sexual dysfunction: practice patterns according to physician specialty.

AIMS: Lower urinary tract symptoms suggestive of benign prostatic hyperplasia (LUTS/BPH) are a common problem in ageing men and are accompanied by sexual dysfunction (SD) in 40-70% of men evaluated in large-scale epidemiological studies. One year after the 2003 American Urological Association (AUA) guideline on BPH management was published, a survey of US urologists (UROs) and primary care physicians (PCPs) was conducted to ascertain physician knowledge of the AUA guideline and practice patterns regarding LUTS/BPH diagnosis, treatment and association with SD. METHODS: A 19-question qualitative survey, sponsored by the American Foundation of Urologic Disease, was mailed April 2004 to 7500 UROs and 17,500 PCPs, with responses collected until May 2004. RESULTS: A total of 788 surveys were returned (437 UROs; 351 PCPs). Only 62% of PCPs were aware of and only 41% of PCPs used the AUA-Symptom Index/International Prostate Symptom Score (AUA-SI/IPSS) to assess LUTS compared with 97% and 81% of UROs respectively. Alpha-blocker monotherapy was the treatment of choice for both UROs and PCPs. Compared with UROs, PCPs reported higher rates of SD in association with LUTS or BPH (37% vs. 27%) and BPH pharmacotherapy (27% vs. 21%). UROs and PCPs reported higher rates of SD side effects [ejaculatory dysfunction (EjD) and erectile dysfunction (ED)] for tamsulosin (EjD: UROs 22%, PCPs 12%; ED: UROs 7%, PCPs 10%) and doxazosin (EjD: UROs 14%, PCPs 10%; ED: UROs 7%, PCPs 12%) than for alfuzosin (EjD: UROs 6%, PCPs 4%; ED: UROs 4%, PCPs 5%). CONCLUSIONS: The results suggest that many PCPs are not using the AUA-SI/IPSS to assess LUTS in their ageing male patients. Both UROs and PCPs appear to be underestimating the prevalence of SD in men with LUTS/BPH relative to prevalence rates reported in large-scale epidemiological studies.

Comparison of laparoscopic and open retropubic urethropexy for treatment of stress urinary incontinence.

OBJECTIVES: Laparoscopic retropubic urethropexy has recently been described as an alternative method to the surgical correction of pure stress urinary incontinence. This study compares the operative technique and results of laparoscopic colposuspension with traditional open Burch urethropexy to treat women with stress urinary incontinence. METHODS: We assessed the short-term results of 12 women who underwent a modified laparoscopic Burch urethropexy for the correction of stress urinary incontinence and compared these with a similar contemporary group of 10 women who underwent a traditional open Burch colposuspension procedure. RESULTS: Ten women (83%) who underwent the laparoscopic procedure are continent with a mean follow-up of 20.8 months, and 7 women (70%) who had an open Burch colposuspension are continent at a mean follow-up of 35.6 months. The laparoscopic procedure took an average of 1.5 hours longer than the open repair (P < 0.01). Patients who underwent the laparoscopic urethropexy required less postoperative analgesia (mean, 14.2 mg morphine equivalents versus 131.4 mg; P < 0.01), shorter length of hospitalization (mean, 1.9 days versus 4.9 days; P < 0.01), and a more expedient return to normal activity when compared with those who underwent open Burch colposuspension. CONCLUSIONS: Laparoscopic bladder neck suspension offers a less invasive approach to the surgical correction of stress urinary incontinence and can provide successful outcomes in properly selected patients.

Stopwatch-assessed duration of erection: a new measure of the efficacy of erectile dysfunction treatments.

Results are reported from the first two adequate trials of the PDE-5 inhibitor vardenafil using a stopwatch to precisely measure erection duration in men with ED. Two randomized, multicenter, double-blind, placebo-controlled trials were conducted: a crossover 4-week treatment in men with ED (ENDURANCE) and a parallel group, 12-week treatment in men with ED and dyslipidemia (the dyslipidemia study). Stopwatch-assessed duration of erection leading to successful intercourse measured by Sexual Encounter Profile question-3 (SEP-3) was the primary end point in ENDURANCE and one of the secondary end points in the dyslipidemia study. Other efficacy end points included responses to SEP-2, SEP-3 and International Index of Erectile Function-Erectile Function (IIEF-EF) domain scores. Adverse events were recorded. Duration of erection (least squares mean ± s.e.) leading to successful intercourse was statistically superior in men receiving vardenafil versus placebo (12.8 ± 1.0 versus 5.5 ± 1.0 min; p<0.001 in ENDURANCE and 10.0 ± 0.8 versus 3.4 ± 0.8; p<0.001 in the dyslipidemia study), with a difference of 7.4 and 6.6 min, respectively, between treatment groups. Results for SEP-2, SEP-3 and IIEF-EF domain scores were consistent across studies and with stopwatch-assessed measures for duration of erection. Vardenafil was well tolerated. Duration of erection leading to successful intercourse is an important indicator of the efficacy of ED treatment. The stopwatch approach offers an alternative, precise and reproducible measure of efficacy. We propose this approach as a potential new paradigm for assessing the efficacy of ED treatments.

Effects of oxybutynin transdermal system on health-related quality of life and safety in men with overactive bladder and prostate conditions.

AIMS: Overactive bladder (OAB) is common in men and may exist concomitantly with benign prostatic hyperplasia (BPH) and obstruction. We present a subanalysis of results from men with OAB in a 6-month, open-label study of treatment with the oxybutynin transdermal system (OXY-TDS). Broad entry criteria were incorporated to yield a clinically representative population. METHODS: All participants received OXY-TDS 3.9 mg/day. Effectiveness was assessed by changes in scores on validated questionnaires, which included the single-item Patient Perception of Bladder Condition (PPBC), the King's Health Questionnaire (KHQ) and the Beck Depression Inventory-II (BDI-II). RESULTS: The proportion of men (n=369; mean age=69.6 years) who reported that their bladder condition caused moderate, severe or many severe problems (PPBC>or=4) improved from 77.3% at baseline to 38.1-53.6% in subsequent months. Mean KHQ scores decreased significantly (p12 (associated with a diagnosis of depression) decreased from 23.9% to 17.9% (p=0.0055). Men with a history of 'prostate problems' or use of 'BPH medication' (32.2%) had KHQ domain changes that were similar (p>or=0.1016) to those of other men. Most men (76.2%) reported no treatment-related adverse events; two men (0.5%) experienced symptoms of mild urinary retention, but neither required catheterisation. CONCLUSIONS: Oxybutynin transdermal system treatment of men with OAB was effective and well tolerated, regardless of history of prostate condition.