The Serendipitous Story of Sildenafil: An Unexpected Oral Therapy for Erectile Dysfunction.

INTRODUCTION: The serendipitous discovery of sildenafil (Viagra [sildenafil citrate]) as a treatment for erectile dysfunction (ED) is one of the most fascinating drug development stories of our time. When sildenafil was approved by the U.S. Food and Drug Administration in 1998, it revolutionized the treatment protocol for men with ED, once considered a psychological issue or an inevitable part of aging. AIM: To review the discovery of sildenafil and its role in changing the field of sexual medicine in the context of the epidemiology and history of treatment for ED. METHODS: For this narrative review, a literature search was conducted to identify essential articles and was supplemented by author observations from a historical perspective. MAIN OUTCOME MEASURE: A broad overview of ED and its past, current, and future treatments. RESULTS: ED is a prevalent condition for which medical treatment had been limited to genitally localized interventions, including surgery, vacuum pumps, injectable therapies, and intraurethral suppositories. The discovery of sildenafil provided a safe, oral pharmacotherapy for the treatment of ED, sparking greater understanding of the science behind ED and its role in men's overall health. CONCLUSION: The approval of sildenafil initiated a global conversation about ED that had profound implications for patients, methods of clinical practice, and academic sexual medicine. These changes will catalyze continued advances in ED treatment. Goldstein I, Burnett AL, Rosen RC, et al. The serendipitous story of sildenafil: an unexpected oral therapy for erectile dysfunction. Sex Med Rev 2019;7:115-128.

The pharmacist's role in improving the treatment of erectile dysfunction and its underlying causes.

Erectile dysfunction (ED), which worldwide is likely to affect in excess of 300 million men by 2025, is often either untreated or insufficiently treated. It can be a prelude to other serious illnesses and may be a cause or consequence of depression in affected individuals. Among men younger than 60 years of age, ED can be a robust early-stage indicator of vascular disease and type 2 diabetes. Untreated or inadequately treated ED can also be a sign of poor communication between health professionals and service users of all ages. Improved treatment of ED could cost-effectively prevent premature deaths and avoidable morbidity. The extension of community pharmacy‒based health care would enable more men living with ED to safely access effective medications, along with appropriate diagnostic services and support for beneficial lifestyle changes such as smoking cessation in conveniently accessible settings. The task of introducing improved methods of affordably addressing problems linked to ED exemplifies the strategic challenges now facing health care systems globally. Promoting professionally supported self-care in pharmacies has the potential to meet the needs of aging populations in progressively more effective ways.

Predictors of Erectile Function Normalization in Men With Erectile Dysfunction Treated With Placebo.

BACKGROUND: Clinical study and practice data have shown sildenafil improves sexual function in men with erectile dysfunction (ED). However, some men treated with placebo in double-blind, placebo-controlled sildenafil studies also report improved erectile function as measured by International Index of Erectile Function (IIEF)-Erectile Function Domain (EFD) scores. AIM: This analysis estimated the relationship between post-baseline IIEF-EFD scores and demographic variables, including co-morbidities, in men with ED receiving placebo in flexible-dose sildenafil studies. METHODS: Placebo-treated participants in the intent-to-treat population of 42 double-blind, placebo-controlled, flexible-dose, sildenafil studies were included. A participant was classified as a placebo responder if the IIEF-EFD score was ≥26 at the last visit. OUTCOMES: Variables assessed were age (<45, 45-64, ≥65 years), race, body mass index, co-morbidities (cardiovascular disease/hypertension, diabetes mellitus, depression), date the last study dose was taken, study completion date, ED etiology (psychogenic, organic, mixed), history of cigarette smoking, ED duration, baseline IIEF-EFD score (≤10, 11-16, ≥17), and treatment duration. Stepwise multivariate logistic regression models assessed the odds of being a responder vs a non-responder for each variable. RESULTS: A total of 4,360 men were included; 13.5% were responders. Odds estimates indicated the largest likelihood of placebo response occurred in men who were black (odds = 20.2, P < .0001), were younger than 45 years (odds = 7.3, P < .0001), had mild ED (baseline IIEF-EFD ≥17; odds >100, P < .0001), and did not have diabetes (odds = 4.5, P < .0001). The likelihood of a placebo response decreased as ED duration increased (odds = 0.74, P < .0001). The frequency of common adverse events was similar between placebo responders and non-responders. CLINICAL TRANSLATION: These findings contribute to the improved understanding of predictors of placebo response in sildenafil clinical studies. Elucidation of these factors may contribute to the development of further interventions and treatment strategies and best practices for clinical trials. STRENGTHS AND CONCLUSIONS: Strengths of this analysis include the large and diverse population and the duration of follow-up. Limitations include those associated with retrospective analyses and the inability to ascertain to what extent other demographic factors might have contributed to the placebo responses or how these placebo responses might be related to the natural course of ED. CONCLUSIONS: Certain demographics, co-morbidities, and condition characteristics predicted the odds of a placebo response in sildenafil clinical studies of ED. Underlying reasons behind a placebo response warrant further evaluation. Mulhall JP, Carlsson M, Stecher V, et al. Predictors of Erectile Function Normalization in Men With Erectile Dysfunction Treated With Placebo. J Sex Med 2018;15:866-872.

Enriching the Interpretation of the Erectile Dysfunction Inventory of Treatment Satisfaction: Characterizing Success in Treatment Satisfaction.

BACKGROUND: Patient-reported outcomes, such as the Erectile Dysfunction Inventory of Treatment Satisfaction (EDITS) index, are essential for successful evaluation and treatment of patients with erectile dysfunction. AIM: To enrich interpretation of the EDITS index score and to complement the existing 0 to 100 scoring. METHODS: This supplemental analysis evaluated EDITS questionnaire data (11 items; index score range = 0-100; higher scores indicate more treatment satisfaction) after completion of an 8-week double-blinded trial of 279 men 18 to 65 years old with erectile dysfunction randomized to sildenafil 100 mg, sildenafil 50 mg, or placebo. Response options for each EDITS item were grouped into "success" (the 2 most satisfied or favorable responses) and "no success" (the remaining 3 responses). The binary response (success or no success) for each item was expressed as a function of overall EDITS score in a simple logistic regression model with all treatments combined. OUTCOMES: Odds ratios and success probabilities (using Wald χ2 tests) were calculated for specified point differences and total EDITS index scores, respectively. RESULTS: EDITS index score increases corresponded with significant increases in odds of success in different EDITS aspects (P < .0001 for all comparisons). For instance, a 10-point EDITS index score difference was associated with odds ratios of 11.3, 42.0, 17.7, and 6.8 for overall treatment satisfaction, treatment meeting expectations, satisfaction with treatment quickness, and satisfaction with how long treatment lasts, respectively. For a given EDITS index score, likelihood of success was determined for different aspects of treatment satisfaction. For example, a mean EDITS index score of 78 (sildenafil 100 mg; SD = 18) corresponded to 96%, 88%, 94%, and 88% chances of success for the 4 EDITS items referenced earlier, respectively. Corresponding probabilities for a mean EDITS index score of 50 (placebo; SD = 18) were 3%, less than 0.1%, 1%, and 4%, respectively. CLINICAL IMPLICATIONS: Interpretation of the EDITS index score can be augmented using key aspects of treatment satisfaction as reported by the patient. STRENGTHS AND LIMITATIONS: This analysis used a well-established anchor-based approach to interpret EDITS index scores. The methodology used and corresponding results are appropriate for clinical practice and clinical trial settings. Limitations include data evaluation only for the Patient EDITS and not the complementary Partner EDITS and use of data from a clinical trial enrolling a well-defined patient population only in stable relationships. CONCLUSION: These results enable a meaningful interpretation of EDITS index scores, facilitating decision making by stakeholders for better-informed health care choices. Cappelleri JC, Tseng L-J, Stecher V, Goldstein I. Enriching the Interpretation of the Erectile Dysfunction Inventory of Treatment Satisfaction: Characterizing Success in Treatment Satisfaction. J Sex Med 2018;15:732-740.

Real-world observational results from a database of 48 million men in the United States: Relationship of cardiovascular disease, diabetes mellitus and depression with age and erectile dysfunction.

AIMS: To evaluate the relationship of comorbidities (cardiovascular disease [CVD], diabetes mellitus [DM] and depression) with erectile dysfunction (ED) and age using real-world claims data from 48 million men in the United States. METHODS: This was a cross-sectional, non-interventional study in men aged ≥18 years using data from the Truven Health MarketScan® and Medicare Supplemental Research Databases from January 2010 to December 2015, with an observational period of January 2011 to December 2014 to allow for 12 months pre- and post-index. Comorbidity rate was compared between ED and non-ED groups by age using the χ2 (bivariate) test. Comorbidity relationship to ED after controlling for categorical variables was assessed using logistic regression analysis. RESULTS: In all, 48 004 379 men were in the database. Of the 9 839 578 who met the inclusion criteria, 573 313 (6%) were ED patients and 9 266 265 (94%) were non-ED patients. ED diagnosis increased decade to decade from 18-29 years to 50-59 years but decreased from 60-69 years to ≥90 years. ED patients had a higher prevalence of CVD, DM and depression than non-ED patients in all periods (P < .0001). After controlling for potential demographic and baseline confounders, the association between ED and CVD, DM and depression remained significant for each age group beginning at 30-39 years (P < .0001). DISCUSSION: Conversations with patients concerning ED should be comprehensive regardless of patient age, in particular in those who have CVD, DM and/or depression. CONCLUSIONS: In the real-world setting, ED diagnosis was associated with CVD, DM and depression across age groups, suggesting a need for inquiry about the potential for comorbidities among these men as a preventative measure against potentially serious future events.

Clinically important difference on the Erectile Dysfunction Inventory of Treatment Satisfaction questionnaire in patients with erectile dysfunction.

AIM: To determine what constitutes a clinically important difference (CID) on the Erectile Dysfunction Inventory of Treatment Satisfaction (EDITS), an 11-item validated questionnaire assessing treatment satisfaction used in clinical trials for patients with erectile dysfunction (ED). METHODS: Erectile Dysfunction Inventory of Treatment Satisfaction data were evaluated from a double-blind, fixed-dose trial of 279 men aged 18-65 years with ED who were treated with sildenafil 50 or 100 mg or placebo. The primary anchor measure was the erectile function (EF) domain of the International Index of Erectile Function (IIEF), which has a 4-point minimal CID. The CID on the EDITS index score was determined using a regression analysis comparing EDITS and IIEF EF scores at the end of the 8-week treatment. A similar analysis was performed for EDITS and the Erection Hardness Score (EHS) instrument, a single-item questionnaire measuring hardness, which was used as a secondary anchor measure. RESULTS: Erectile Dysfunction Inventory of Treatment Satisfaction and IIEF EF domain scores were highly correlated (Pearson correlation coefficient = 0.75). EDITS total scores across treatments at week 8 averaged (mean ± standard deviation [SD]) 67.5 ± 21.6 (range, 0-100; higher scores indicate greater treatment satisfaction); IIEF EF domain scores averaged 22.2 ± 6.9 (range, 1-30; higher scores indicate higher erectile functioning). The calculated CID for EDITS scores was 9.5 (95% CI, 8.5-10.4; 0.44 SD units), corresponding to a medium effect size. EDITS and EHS instrument scores also correlated highly (Pearson correlation coefficient = 0.64). Placebo-adjusted EDITS mean scores were more than twice the CID, at 23 (95% CI, 17-28) and 28 (95% CI, 23-33) for the 50- and 100-mg doses, respectively. CONCLUSION: Approximately 10 points on the EDITS index score is considered a CID. Serving as a benchmark, this finding aids interpretation of the clinical relevance of a difference in mean EDITS index scores between treatments for patients with ED.

Quality of erections by age group in men with erectile dysfunction.

AIMS: The aim of this study was to assess erection quality with sildenafil vs placebo and adverse events (AEs) according to age (≤45, 46-55 and ≥56 years) in 997 men with erectile dysfunction (ED) using pooled data from four randomized, double-blind, placebo-controlled, flexible-dose trials. METHODS: The trials included 6- to 10-week treatment periods. The starting sildenafil dose was 50 mg, taken ~1 hour before sexual activity but not more than once daily, with subsequent adjustment to 100 or 25 mg based on efficacy and safety. Exclusion criteria included blood pressure <90/50 or >170/110 mmHg, taking nitrate therapy or nitric oxide donors, severe cardiac failure/unstable angina or recent stroke or myocardial infarction. Changes from baseline in Quality of Erection Questionnaire (QEQ), International Index of Erectile Function (IIEF) and Erectile Dysfunction Inventory of Treatment Satisfaction (EDITS) scores were analysed. RESULTS: Improvements in QEQ scores with sildenafil vs placebo were significant (P<.0001) for the overall sample (33.7 sildenafil; 8.1 placebo) and each age group (≤45 years: 38.5 sildenafil, 13.9 placebo; 46-55 years: 34.9 sildenafil, 5.8 placebo; ≥56 years: 26.9 sildenafil, 4.9 placebo). IIEF Erectile Function domain (P<.0001), question 3 (achieving erection; P<.003), and question 4 (maintaining erection; P<.001) scores also improved significantly for the overall sample and each age group. Treatment satisfaction was significantly greater (P<.0001) with sildenafil vs placebo for the overall sample and each age group. The most common AEs with sildenafil were headache, flushing and nasal congestion in all age groups. CONCLUSIONS: Sildenafil significantly improved erection quality across all age groups of men with ED. Efficacy improvements with sildenafil were consistent with the QEQ, IIEF, and EDITS. AEs were comparable across age groups. ClinicalTrials.gov ID: NCT00159900, NCT00147628, NCT00301262, NCT00343200.

Ethnicity and age as factors in sildenafil treatment of erectile dysfunction.

INTRODUCTION: Sildenafil has been evaluated in >16 000 men with erectile dysfunction (ED) in double-blind, placebo-controlled trials. AIM: To assess efficacy and safety of sildenafil in ED by ethnicity (white, black Asian) and age (≤45, 46-60, ≥61 years). METHODS: Data were pooled from 38 double-blind, placebo-controlled, flexible-dose trials. Most had starting sildenafil doses of 50 mg once daily, ~1 hour before sexual activity, with adjustment to 100 or 25 mg as needed. MAIN OUTCOME MEASURES: Change from baseline in International Index of Erectile Function erectile function (IIEF-EF) domain score assessed with analysis of covariance and a Global Assessment Question (GAQ; "Did the treatment improve your erections?") at endpoint assessed with logistic regression analysis. RESULTS: 4120 and 3714 men received sildenafil and placebo, respectively (2740 and 2671 White; 407 and 385 Black; 973 and 658 Asian). For sildenafil vs. placebo groups, overall treatment differences for IIEF-EF domain and GAQ were significant for each ethnic and age group (P<.0001); significant treatment-by-ethnicity and treatment-by-age interactions were also observed for change in IIEF-EF domain scores (P<.05), with differences significantly greater for White vs. Black (P<.0001), White vs. Asian (P=.0163), and Asian vs. Black (P=.0036) men. A significant treatment-by-ethnicity interaction was observed for GAQ (P=.0004). The OR comparison for GAQ was significantly greater (P=.0001) with sildenafil vs. placebo in White (OR=11.2) or Asian (OR=12.4) men vs. Black men (OR=5.1). Adverse-event rates were generally similar, with some age variations. CONCLUSIONS: Sildenafil is effective and well-tolerated regardless of ethnicity or age; however, treatment effects can vary.

Treatment response to sildenafil in men with erectile dysfunction relative to concomitant comorbidities and age.

AIM: To evaluate treatment response in men with erectile dysfunction (ED) and concomitant comorbidities. METHODS: Data were pooled from 42 placebo-controlled, flexible-dose sildenafil trials. In most trials, the sildenafil dose was 50 mg, taken ~1 hour before sexual activity but not more than once daily, with adjustment to 100 or 25 mg as needed. The overall population (N=9413) was stratified by age (<45, 46-64, ≥65 years). Treatment response was defined as a minimal clinically important difference (MCID) from baseline in the International Index of Erectile Function-Erectile Function (IIEF-EF) domain score of >2, >5 and >7 for men with mild, moderate and severe ED at baseline, respectively, or an IIEF-EF domain score ≥26 (no ED) at end-point. RESULTS: In the overall population, treatment response using the IIEF-EF MCID definition was significantly greater (P<.0001) with sildenafil vs placebo in men with no comorbidity (77% vs 33%), cardiovascular disease/hypertension only (71% vs 27%), diabetes only (63% vs 24%) or depression only (78% vs 29%). Using an IIEF-EF score ≥26, treatment response was significantly greater (P<.0001) with sildenafil vs placebo in men with no comorbidity (49% vs 17%), cardiovascular disease/hypertension only (48% vs 12%), diabetes only (40% vs 12%) or depression only (60% vs 17%). With each definition, the treatment response for each age and comorbidity was significantly greater (P≤.0065) with sildenafil vs placebo. CONCLUSION: The treatment response was significantly greater with sildenafil vs placebo in men with ED and each comorbidity regardless of age.

Efficacy and Safety of Sildenafil in Men With Sexual Dysfunction and Spinal Cord Injury.

INTRODUCTION: Spinal cord injury (SCI) is estimated to affect approximately 276,000 individuals in the United States. Since 2010, the mean age of individuals at the time of the SCI has been 42 years, with nearly 80% of cases involving men. This means that individuals with SCI generally are young men who typically place a great deal of importance on normal sexual and reproductive function. AIM: To assess the effect of sildenafil treatment on erectile function and the frequency of ejaculation in men with SCI. METHODS: This study was a post hoc analysis of pooled data from two randomized, double-blinded, placebo-controlled, flexible-dose, crossover sildenafil trials conducted in Europe, Australia, and Turkey. Two hundred forty-eight men at least 18 years old with traumatic SCI of at least 6 months' duration, with erectile dysfunction solely attributed to SCI, and in a stable heterosexual relationship were treated sequentially with sildenafil and placebo. Exclusion criteria included taking nitrate therapy, severe cardiac failure, and recent stroke or myocardial infarction. The starting sildenafil dose was 50 mg, taken approximately 1 hour before sexual activity, with subsequent dose adjustment to 100 or 25 mg based on efficacy and safety during treatment. There was a 2-week washout between 6-week treatments. MAIN OUTCOME MEASURES: Change from baseline in International Index of Erectile Function question 3 (frequency of penetration), question 4 (maintaining erection after penetration), question 9 (frequency of ejaculation), and erectile function domain scores; intercourse success; and treatment preference. RESULTS: All International Index of Erectile Function outcomes, including achieving and maintaining erections and ejaculation frequency, were statistically significantly greater with sildenafil vs placebo, including the subgroup with complete SCI (P < .01 for all comparisons). The percentage of successful intercourse attempts with sildenafil (53% vs 12%) and preference for sildenafil (96% vs 4%) vs placebo were significant (P < .001), including the subgroup with complete SCI. The most common all-cause adverse events with sildenafil were headache (16.1%) and urinary tract infection (11.6%). CONCLUSION: Sildenafil significantly improves erections, intercourse success, and ejaculation frequency vs placebo, including in men with complete SCI. Sildenafil is an effective and well-tolerated treatment for sexual dysfunction in men with SCI. The increase in frequency of ejaculation could allow the possibility of having children without medical intervention in this patient population. Ohl DA, Carlsson M, Stecher VJ, Rippon GA. Efficacy and Safety of Sildenafil in Men With Sexual Dysfunction and Spinal Cord Injury. Sex Med Rev 2017;5:521-528.

Quantifying Barriers to Improvement of Treatment Satisfaction in Men With Erectile Dysfunction: Use of Person-Item Maps.

INTRODUCTION: Patient-reported outcomes are a valuable tool used to gauge treatment satisfaction in different conditions, including erectile dysfunction (ED). AIM: To use person-item maps to quantify barriers to improvement of treatment satisfaction in men with ED. METHODS: Men 18 to 65 years old with documented ED received sildenafil 50 mg, sildenafil 100 mg, or placebo for 8 weeks in a double-blinded manner. Post hoc analyses were conducted on Erectile Dysfunction Inventory of Treatment Satisfaction (EDITS) data (11 items rating treatment satisfaction; each item score range = 0-4). MAIN OUTCOME MEASURES: Person-item maps were developed based on Rasch models. To quantify barriers to improvement of treatment satisfaction, responses to the 11 items of the EDITS questionnaire were dichotomized to indicate improvement (responses of 3 or 4 were combined to a score of 1) vs no change or worsening (responses of 0, 1, or 2 were combined to a score of 0). RESULTS: Analyses were conducted using data from 278 men who completed the EDITS questionnaire at the end of double-blinded treatment. The person-item map indicated that EDITS item 4 (ease of use of treatment) was the easiest barrier to overcome, whereas the most difficult barrier to improvement of treatment satisfaction was EDITS item 2 (degree to which treatment met expectations). Most men in the sildenafil 100-mg group endorsed most EDITS items, consistent with substantial improvement. The sildenafil 50-mg group was similar, but with smaller frequencies for endorsing improvement of the more difficult EDITS items. In contrast, men receiving placebo endorsed mainly the easiest EDITS items, with only a small number of men endorsing the difficult items. CONCLUSION: A person-item map is a useful means for quantifying barriers to improvement of treatment satisfaction represented by EDITS items in patients with ED.

Relationship between age and erectile dysfunction diagnosis or treatment using real-world observational data in the USA.

AIMS: With self-reporting of erectile dysfunction (ED) in population-based surveys, men with ED may not represent men who are bothered sufficiently to seek an ED diagnosis and treatment. We used real-world observational data to assess: 1) the prevalence of ED diagnosis or treatment by age subgroups; and 2) the relationship of age with ED diagnosis or treatment after controlling for ED-related comorbidities in the USA. METHODS: This cross-sectional study used de-identified claims data (MarketScan® databases; primary analysis). Sensitivity analysis was conducted using electronic health records (Humedica® database). Inclusion criteria were men aged ≥18 years with a 360-day continuous enrollment before the index date. We assessed the prevalence of ED diagnosis or phosphodiesterase type 5 inhibitor (PDE5I) prescription by age and the risk for ED diagnosis or treatment by age after controlling for comorbidities (hypertension, other cardiovascular disease, diabetes mellitus, depression and benign prostatic hyperplasia). RESULTS: Of 19,833,939 men meeting inclusion criteria in the primary analysis, only 1 108 842 (5.6%) had an ED diagnosis or PDE5I prescription (mean [SD] age: 55.2 [11.2] years). Prevalence of ED diagnosis or treatment increased from age 18-29 years (0.4%) to 60-69 years (11.5%), then decreased in the seventh (11.0%), eighth (4.6%), and ninth (0.9%) decades. Men with ED diagnosis or treatment had a higher prevalence of any comorbidity (63.1% vs 29.3% for men without ED) and of each comorbid condition. In multivariate analyses, age was an independent risk factor for ED diagnosis or treatment. Sensitivity analysis provided consistent results. CONCLUSIONS: In a real-world setting in the USA, the prevalence of ED diagnosis or PDE5I treatment is generally low, increases with age, decreases in very old men, and is associated with increased prevalence of comorbidities. Age is an independent risk factor for ED diagnosis or treatment after controlling for comorbidities.

Efficacy and Safety of Sildenafil by Age in Men With Erectile Dysfunction.

INTRODUCTION: Sildenafil, an oral phosphodiesterase type 5 inhibitor, has been extensively investigated for the treatment of erectile dysfunction in randomized controlled trials. AIM: To assess the efficacy and safety of sildenafil vs placebo according to age subgroups (<65, 65-74, and ≥75 years) in 11,364 men with erectile dysfunction using pooled data from 48 randomized, double-blinded, placebo-controlled, parallel-group, flexible-dose trials. METHODS: Most trials had a 12-week treatment duration. The starting sildenafil dose was 50 mg, taken 1 hour before sexual activity, with subsequent adjustment to 100 or 25 mg based on efficacy and safety. Men taking nitrate therapy or nitric oxide donors and men with severe cardiac failure, unstable angina, or recent stroke or myocardial infarction were excluded. Efficacy analyses included all subjects with baseline and at least one postrandomization evaluation. Safety analyses included subjects who received study medication. MAIN OUTCOME MEASURES: The International Index of Erectile Function and a global assessment question ("Did the treatment improve your erections?"). RESULTS: Mean International Index of Erectile Function scores for question 3 (frequency of penetration), question 4 (maintenance of erections after penetration), and the erectile function domain were statistically significantly improved with sildenafil vs placebo for each age subgroup; orgasmic function, intercourse satisfaction, sexual desire, and overall satisfaction domain scores also were statistically significantly improved with sildenafil vs placebo. The percentage of men reporting improved erections on the global assessment question was statistically significantly higher with sildenafil vs placebo for all age subgroups; the percentage with sildenafil tended to decrease with increasing age (<65 years, 80%; 65-74 years, 69%; ≥75 years, 59%). The most common adverse events with sildenafil were headache and flushing in each age subgroup. CONCLUSION: Sildenafil is an effective and well-tolerated treatment for erectile dysfunction regardless of patient age, including men at least 75 years old.

Simplified Interpretation of the Erectile Function Domain of the International Index of Erectile Function.

INTRODUCTION: This report describes a post hoc analysis of data from a randomized, double-blinded, placebo-controlled, flexible-dose, sildenafil trial in men with erectile dysfunction. AIMS: To simplify interpretation of erectile function (EF) domain scores of the International Index of Erectile Function (IIEF). METHODS: Men at least 18 years old with erectile dysfunction were randomized to receive sildenafil or placebo for 12 weeks. Men taking nitrates or nitric oxide donors were excluded. Responses for each IIEF EF domain question (questions 1-5 and 15) were combined into two broad categories ("success" for responses of the two most favorable categories of a question and "no success" for other responses). Each question was expressed in a logistic regression model (sildenafil and placebo groups combined) as a function of overall EF domain score. MAIN OUTCOME MEASURES: IIEF EF domain score and items. RESULTS: A four-point increase in the IIEF EF domain score was associated with an odds ratio of success of 6.1 for getting an erection, 29.2 for having a firm erection, 10.0 for able to penetrate,12.8 for maintaining erection, 4.0 for maintaining erection to completion, and 3.7 for erection confidence. An EF domain score of 22 was associated with a probability of success of 81% for getting an erection, 86% for having a firm erection, 89% for able to penetrate, 67% for maintaining an erection, 70% for maintaining an erection to completion, and 32% for erection confidence. For an EF domain score of 16, the corresponding probabilities of success were 22%, 4%, 20%, 4%, 22%, and 6%, respectively. CONCLUSION: These results provide stakeholders with a simplified and meaningful interpretation of IIEF EF domain scores based on six key aspects of EF.

Further Understanding of the International Index of Erectile Function at 15+ Years: Confirmatory Factor Analysis and Multidimensional Scaling.

The objective of this study was to describe confirmatory factor analysis (CFA) and multidimensional scaling (MDS) on the International Index of Erectile Function (IIEF) to confirm the structure and to enrich understanding of the IIEF, thereby heightening appreciation of the factors and responses underlying sexual functioning for men with erectile dysfunction. Baseline, end of double-blind, and end of open-label data sets were derived from all data from 2 previously published sildenafil trials. For the CFA model, an acceptable fit of the data was shown for each data set, as indicated by a Bentler comparative fit index >0.9, statistically significant path coefficients ( t values >1.96), and (except for IIEF item 6 at baseline) statistically significant standardized path coefficients ≥0.4. For MDS modeling, the distance matrix created for each data set, based on polychoric correlations, interpreted relationships between the IIEF items in 2-dimensional space across the "sexual intercourse interference" dimension (horizontal axis) and the "sexual satisfaction" dimension (vertical axis). The 5-factor structure of the IIEF was confirmed by CFA and enriched with visual interpretation by MDS.

Improvement in erection hardness and intercourse success with first dose of sildenafil citrate 100 mg.

PURPOSE: To determine, in men with erectile dysfunction (ED), the extent of improvement in erection hardness and in the rate of successful sexual intercourse (SSI) during the final intercourse attempt using sildenafil 50 mg compared with the subsequent initial attempt after a dose increase to 100 mg. PATIENTS AND METHODS: This post hoc analysis used data from two randomized, double-blind, placebo-controlled studies of flexible-dose sildenafil for the treatment of men with ED, who were given sildenafil 50 mg or matching placebo, to be taken as needed before sexual intercourse. After 2 weeks, those with no tolerability concerns were titrated up to 100 mg, forming the subgroup of this analysis. The main outcome measures were event log data, including an Erection Hardness Score (EHS) and a question on SSI ("Did your erection last long enough for you to have successful sexual intercourse?"), for each attempt at sexual intercourse, analyzed by study and treatment group (sildenafil or placebo). Statistical comparisons were conducted by using the Fisher's exact test. RESULTS: In both studies, the sildenafil group had a larger proportion of EHS4 (completely hard and fully rigid) erections (P < 0.001) and SSI (P < 0.005) compared with the placebo group, both before and after the dose increase. Between the final 50 mg sildenafil dose and the initial 100 mg sildenafil dose, the outcomes improved and significantly so in the larger study. CONCLUSION: The improved efficacy with sildenafil 100 mg versus 50 mg, which occurs rapidly, suggests that patients should be encouraged to use 100 mg if they are unable to achieve completely hard and fully rigid erections or SSI with the 50 mg dose.

Adulteration of purported herbal and natural sexual performance enhancement dietary supplements with synthetic phosphodiesterase type 5 inhibitors.

INTRODUCTION: Many products labeled "herbal" or "all natural" (herbal/natural) that claim to enhance sexual performance and imply use for the treatment of erectile dysfunction (ED) are marketed as over-the-counter (OTC) dietary supplements. However, adulteration with undeclared phosphodiesterase type 5 (PDE5) inhibitors appears widespread. AIM: To assess the availability, cost, origin, categorical content, and adulteration with PDE5 inhibitors of purported herbal/natural OTC dietary supplements claiming to naturally enhance sexual performance. METHODS: Pfizer Global Security coordinated sample collection (all from convenience stores and filling stations in two U.S. metropolitan areas except for seven from U.S. Customs seizures) and liquid chromatography/mass spectrometry examination. MAIN OUTCOME MEASURE: Adulteration with synthetic PDE5 inhibitors. RESULTS: Ninety-one samples labeled as 58 distinct products and priced from $2.99 to $17.99 were evaluated. Origin/manufacture was claimed as United States (n = 62), apparently Asian (n = 15), and not clearly identified (n = 14). Although no sample claimed to include synthetic substances, 74 (81%) contained PDE5-inhibitor pharmaceutical ingredients, including tadalafil and/or sildenafil (n = 40, of which 18 contained >110% of the highest approved drug product strength) or PDE5-inhibitor analogs (n = 34). Pronounced heterogeneity of contents between samples within individual products indicated minimal quality control during manufacture. Labeling was inadequate (e.g., lacking lot number and/or expiry date) for 17 products (23 samples) and inconsistent between samples within a given product (e.g., in manufacturer, lot number, and/or expiry date) for seven of 17 products having multiple samples. Only 14 samples warned against concomitant nitrate use. CONCLUSIONS: Ethical pharmaceutical companies are concerned for an unsuspecting public when their products are counterfeited, mislabeled, and illegally offered for sale in an unsafe manner. Because of the dangers of adulteration with synthetic PDE5 inhibitors, absent safety warnings, and lack of quality or consistent manufacture, men with ED unknowingly risk their health by using OTC herbal/natural products that claim to enhance sexual performance.

Phosphodiesterase type 5 inhibitors improve endothelial function and may benefit cardiovascular conditions.

The effects of phosphodiesterase type 5 inhibitors on vasodilation mediated via nitric oxide-cyclic guanosine monophosphate are well described. Less is known about other mechanisms through which phosphodiesterase type 5 inhibitors benefit endothelial function, including normalization of serum biomarkers, increased levels of endothelial progenitor cells, ischemia-reperfusion protection mechanisms, and other actions specific to patients with diabetes. These various mechanisms are reviewed. Their impact on several cardiovascular diseases, including erectile dysfunction, pulmonary hypertension, heart failure, high-altitude pulmonary edema, Raynaud's phenomenon, coronary artery disease, diabetes, and atherosclerosis, is presented.

Multi-domain Longitudinal Modeling: An Application to the International Index of Erectile Function.

Individual domains of multi-domain, patient-reported outcome instruments are typically analyzed independently, without considering inherent interdependency. The authors assessed correlations across time (longitudinal) and across domains of a multi-domain instrument, simultaneously, in a single, unified, and cohesive integrated model. International Index of Erectile Function (IIEF) data from a trial of sildenafil in erectile dysfunction were used. For the multi-domain longitudinal modeling, covariance of response was constructed using (1) the Kronecker product of an unstructured covariance matrix to model across domains, with an unstructured covariance matrix to model across time, and (2) a completely general, unstructured covariance matrix. Treatment effects for all IIEF domain scores calculated using individual or multi-domain modeling were similar, reflecting the robust application of the integrated model to these data. In conclusion, modeling correlations simultaneously across domains and across time more rigorously address the natural interrelationship between domains and can provide a more accurate representation of treatment effects.

Erectile dysfunction diagnosis and treatment as a means to improve medication adherence and optimize comorbidity management.

INTRODUCTION: Optimal pharmacologic management of diseases comorbid with erectile dysfunction (ED), such as cardiovascular disease, depression, diabetes, dyslipidemia, hypertension, and benign prostatic hyperplasia/lower urinary tract symptoms (BPH/LUTS), is dependent upon long-term treatment compliance and may be complicated by poor adherence to medication use. ED may contribute to poor adherence to medication use because poor quality erectile function may be an unwanted adverse effect of antihypertensives, antidepressants, and 5-α reductase inhibitors for treatment of BPH/LUTS. Diminished erectile spontaneity, rigidity, and/or sustaining capability also negatively affects mood, self-esteem, and confidence, which compromise motivation to be compliant with medications that treat diseases comorbid with ED. AIM: Literature review was performed to explore the role of ED diagnosis and effective treatment in enhancing overall management of selected ED comorbidities, highlighting the role of medication adherence. METHODS: Several PubMed searches were performed. RESULTS: Diagnosis and successful treatment of concomitant ED may promote improved adherence and management of comorbid diseases. Concomitant ED management may improve treatment outcome, decrease healthcare costs, and possibly prevent or even improve deterioration in medical conditions comorbid with ED. Because ED is a silent marker and predictor of comorbidities, especially cardiovascular disease, earlier diagnosis of ED may provide an opportunity to prevent future cardiovascular events. In men presenting with complaints of ED, screening for, monitoring, and appropriately treating diseases that are comorbid with ED is essential. Screening for and appropriately treating ED is important for enhanced life quality and improved motivation in men with existing ED comorbidities or risk factors. CONCLUSIONS: Appropriate management of ED and its risk factors may have beneficial effects on diseases that are comorbid with ED, and vice versa, most likely via shared pathophysiological pathways. Clinicians may need to consider men's health overall, of which sexual health is a central component, in order to provide optimal disease management.