Understanding the Effects of Sildenafil Treatment on Erection Maintenance and Erection Hardness

doi:10.1111/j.1743-6109.2010.01791.x

The Journal of Sexual Medicine

Volume 7, Issue 6, June 2010, Pages 2184-2191

https://doi.org/10.1111/j.1743-6109.2010.01791.x Get rights and content

ABSTRACT

Introduction

Erectile dysfunction (ED) is defined as the inability to attain and/or maintain penile erection sufficient for satisfactory sexual performance. Although intuitively related, the link between erection hardness and erection maintenance has not been formally established and quantified.

Aim

To understand the components of erection maintenance through statistical modeling.

Methods

Data from a double-blind placebo-controlled trial of fixed-dose sildenafil (100 or 50 mg, 8 weeks) with open-label extension of flexible-dose sildenafil (100 and 50 mg, 4 weeks) were analyzed. Erection maintenance was assessed with item 4 (how often erection was maintained) or item 5 (difficulty in maintaining erection) of the International Index of Erectile Function (IIEF). Erection hardness was assessed with the Erection Hardness Score.

Main Outcome Measures

Longitudinal modeling estimated mean treatment differences averaged over the double-blind phase for sildenafil 100 mg vs. placebo and 50 mg vs. placebo. Statistical mediation analysis was applied to partition the effect of sildenafil (pooled into one treatment group) on erection maintenance directly and indirectly through erection hardness.

Results

Longitudinal mean differences for sildenafil 100 and 50 mg vs. placebo were high (P < 0.0001 for each), with large standardized effect sizes (>0.8). Mediation modeling showed that sildenafil treatment affected maintenance directly as well as indirectly via erection hardness, when measured by IIEF item 4 (direct effect, 44.6%; indirect effect, 55.4%) or IIEF item 5 (direct effect, 56.9%; indirect effect, 43.1%).

Conclusions

Sildenafil treatment significantly improved erection maintenance, a physiologic requirement for satisfactory sexual performance. According to our model, only approximately half of the effect of sildenafil on erection maintenance was estimated to be driven through direct effects. Rather, the effect of sildenafil on erection maintenance seems to be substantially driven by erection hardness. Therefore, achievement of optimal initial erection hardness appears to be an important treatment goal for enhancing erection maintenance and achieving successful ED treatment. Claes HIM, Goldstein I, Althof SE, Berner MM, Cappelleri JC, Bushmakin AG, Symonds T, and Schnetzler G. Understanding the effects of sildenafil treatment on erection maintenance and erection hardness.

Introduction

Erectile dysfunction (ED) is defined as “. . . the inability to attain and/or maintain penile erection sufficient for satisfactory sexual performance.”[1] Erection maintenance depends in part on the integrity of the veno-occlusive mechanism, and erection hardness depends in part on the cavernosal artery perfusion pressure. Therefore, in men with ED, the effect of treatment on erection maintenance should be closely related to the effect of treatment on erection hardness.

In the treatment of ED, erection hardness is a well-established clinical outcome 2, 3. The Erection Hardness Score (EHS) is a validated single-item patient-reported outcome (PRO) for assessing erection hardness (Table 1) [4]. It became and remains an integral part of the clinical trials program for sildenafil citrate (VIAGRA®, Pfizer Inc., New York, NY, USA). The degree of penile rigidity assessed with the EHS can be mapped to other PROs such as the International Index of Erectile Function (IIEF), the Quality of Erection Questionnaire, the Sexual Experience Questionnaire, and the Self-Esteem and Relationship Questionnaire [5]. However, the extent to which ED treatment affects erection maintenance directly vs. indirectly (via erection hardness), when both maintenance and hardness are determined by patient questionnaire data, has not been established. Thus, the main objective of this report is to explore, by means of statistical modeling, the interrelationships among effective treatment of ED (as the factor), erection hardness (as the mediator), and erection maintenance (as the outcome) in men with ED, to guide treatment goals toward optimizing erection maintenance and achieving successful sexual intercourse.

Section snippets

Dataset

The dataset, which was described previously [6], was derived from a multinational (Republic of Korea, Russian Federation, Spain, and Sweden), parallel-group, randomized (1:1:1), double-blind placebo-controlled (DBPC) trial of fixed-dose sildenafil (100 or 50 mg, 8 weeks) with open-label (OL) extension of flexible-dose sildenafil (50 and 100 mg, 4 weeks). Medication was taken as needed for sexual activity but not more than once daily. Institutional review board approval was obtained from all study

Results

The 288 men randomized to sildenafil 50 mg (N = 94), sildenafil 100 mg (N = 99), or placebo (N = 95) were similar in age (mean, 51 years; range, 20–65 years) and ethnicity (approximately two-thirds white and one-third Asian).

Discussion

Using IIEF items 4 or 5 as a proxy for erection maintenance, we estimated that roughly half of the total effect of sildenafil treatment on erection maintenance was direct and the other half was mediated via erection hardness, which shows that erection hardness plays a substantial and crucial role in improving erection maintenance. Mapping showed a strong, positive, linear relationship of the EHS with IIEF items 4 and 5, which allowed us to approximate the path from hardness to maintenance as

Category 1

(a)
Conception and Design
Hubert I.M. Claes; Irwin Goldstein; Stanley E. Althof; Michael M. Berner; Joseph C. Cappelleri; Andrew G. Bushmakin; Tara Symonds; Gabriel Schnetzler
(b)
Acquisition of Data
Joseph C. Cappelleri; Andrew G. Bushmakin; Tara Symonds; Gabriel Schnetzler
(c)
Analysis and Interpretation of Data
Joseph C. Cappelleri; Andrew G. Bushmakin; Tara Symonds; Gabriel Schnetzler

Category 2

(a)
Drafting the Article
Hubert I.M. Claes; Irwin Goldstein; Stanley E. Althof; Michael M. Berner; Joseph C. Cappelleri; Andrew G.

Acknowledgments

This study was sponsored by Pfizer Inc. Editorial support was provided by Deborah M. Compoli-Richards, BSPHA, RPh, of Complete Healthcare Communications, Inc., and was funded by Pfizer, Inc. ClinicalTrials.gov Identifier: NCT00245258.

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Erection hardness score for the evaluation of erectile dysfunction: Further psychometric assessment in patients treated by intracavernous prostaglandins injections after radical prostatectomy
2014, Journal of Sexual Medicine
Citation Excerpt :
It has been formally validated in patients reporting all causes of ED and treated by phosphodiesterase type 5 inhibitors (PDE5), demonstrating satisfying psychometric properties and a good treatment responsiveness [17]. However, despite the apparent valuable properties provided by single‐items scales, concern has been raised with respect to the less comprehensive evaluation of ED severity in its various facets when compared with multidimensional tools such as the IIEF [9-18]. Second, because establishing the reliability and validity of a measurement instrument is of paramount importance, robustness of these psychometric properties should be confirmed when used in diversified contexts as well, so as to ensure the appropriateness and actual usefulness of a tool to clinical decision making in the field.
Erectile dysfunction (ED) affects quality of life in patients treated by radical prostatectomy (RP). The Erection Hardness Score (EHS) is a single‐item scale that has demonstrated good psychometric properties for assessing erectile function (EF) in patients treated by sildenafil, but its applicability to other treatment contexts has not yet been tested.
This study aims to test the validity and time and treatment responsiveness of the EHS to assess ED in men with post‐RP ED treated with alprostadil injections.
This is a 1‐year follow‐up cohort study of 75 patients treated by RP for localized prostate cancer in a urology department setting between January 2007 and December 2008. Data were prospectively collected at 6 and 12 months post‐RP.
The EHS, the International Index of Erectile Function (IIEF) reference questionnaire, the Global Assessment Questionnaire (GAQ), and Numeric Pain Scale (NPS) were collected. Convergent validity (Spearman correlation coefficients with IIEF domains), known‐groups validity (comparing EHS scores across ED severity groups), time and treatment responsiveness (effect size with/without treatment and over the follow‐up period), and predictive ability (area under the receiver operating characteristics curve [AUC‐ROC]) were analyzed for this study.
The EHS showed good convergent validity (all Spearman coefficients significant at the P < 0.05 level), adequate known‐groups validity (global differentiation between IIEF‐EF severity groups; P < 0.001), and treatment responsiveness (effect size: +1.8 [6 months], +2.1 [12 months]), but limited time responsiveness and predictive ability of the EHS for a normal EF at 12 months follow‐up when compared with the IIEF‐EF domain (AUC‐ROC: 0.72 vs. 0.85; P < 0.01).
Our findings support the overall good psychometric properties of the EHS in patients with post‐RP ED treated with alprostadil injections. However, evidence for limited predictive validity and responsiveness to change over time should be considered for its use in clinical follow‐up in this population. Parisot J, Yiou R, Salomon L, de la Taille A, Lingombet O, and Audureau E. Erection hardness score for the evaluation of erectile dysfunction: Further psychometric assessment in patients treated by intracavernous prostaglandins injections after radical prostatectomy. J Sex Med 2014;11:2109–2118.
How to evaluate the efficacy of the phosphodiesterase type 5 inhibitors
2012, Journal of Sexual Medicine
Several methods have been so far proposed to compare the effectiveness of the three available phosphodiesterase type 5 inhibitors (PDE5Is).
Two urologists (E.C. and G.B.B.), together with the Controversy's Editor (E.A.J.), with expertise in the area of medical treatment of erectile dysfunction (ED) present the various perspectives on the evaluation of PDE5Is in ED. The use of the most popular psychometric tool, the International Index of Erectile Function, is presented by an expert psychologist (L.R.D.).
Expert opinion supported by the critical review of the currently available literature.
Trials have demonstrated that the PDE5Is are excellent drugs with a great specificity of action and an almost perfect tolerance profile. Some instruments for comparison of clinical efficacy have to be considered subjective (psychometry, patient's preference, changes in quality of general, or sexual life). Some others are more objective (hardness, hormonal levels, and local circulation). An evidence‐based comparison of the three PDE5Is should in the future be rooted in both subjective and objective methods. This will be of paramount importance in the drug trial design of new, forthcoming PDE5Is.
Comparison between PDE5Is using both subjective and objective parameters will permit to individuate, on the basis of the evidence, the subset of couples where one drug, or one dose, or dose regimen, is to be considered of first choice. Jannini EA, DeRogatis LR, Chung E, and Brock GB. How to evaluate the efficacy of the phosphodiesterase type 5 inhibitors. J Sex Med 2012;9:26–33.
Men with mild erectile dysfunction benefit from sildenafil treatment
2010, Journal of Sexual Medicine
Citation Excerpt :
Mean scores on all domains of the IIEF, on the QEQ, and on analog scales assessing erection firmness, ability to maintain erections, reliability of erection, and general sexual performance were >80% of the maximum possible; responses to event log questions on hardness sufficient for penetration, duration long enough for successful intercourse, and ejaculation/orgasm were positive on >80% of occasions; 77% of men had IIEF-EF scores indicating no ED; approximately 90% of men reported improved erections and improved ability to have sexual intercourse on the GEQs; and erections were completely hard and fully rigid on 60% of occasions. Achieving completely hard and fully rigid erections is an important clinical target in men with ED [31–33]. Sildenafil was well tolerated.
Sildenafil treatment has not been evaluated in a double-blind, placebo-controlled (DBPC) trial specific to men with mild erectile dysfunction (ED), defined by a 22–25 score on the International Index of Erectile Function-erectile function domain (IIEF-EF).
To assess sildenafil efficacy in sexually dissatisfied men with mild ED.
Erectile Dysfunction Inventory of Treatment Satisfaction (EDITS), IIEF, Quality of Erection Questionnaire (QEQ), Erection Hardness Score (EHS 4 = completely hard/fully rigid), general efficacy questions (GEQs), event log questions (hardness sufficient for penetration, duration sufficient for successful intercourse, ejaculation/orgasm, and second erection within 24 hours), and analog scales (erection firmness, reliability, and maintenance, and general sexual performance).
Eight-week DBPC flexible-dose (25, 50, or 100 mg) trial with 6-week, open-label (OL) extension.
One hundred and seventy-six men were randomized (mean ± standard deviation: age, 50 ± 12 year; ED duration, 3.5 ± 3.2 year). Most had organic or mixed ED. For sildenafil vs. placebo, 66% vs. 89% titrated to 100 mg and efficacy at DBPC end was better, including the EDITS Index score (least squares mean [standard error], 80.3 [2.3] vs. 62.1 [2.5]; P < 0.0001); treatment satisfaction (EDITS Index score >50 in 89% vs. 63%; P = 0.0001); no ED (IIEF-EF ≥26 in 58% vs. 39%; P < 0.05); GEQs (≥4.9-fold greater odds of improved erections and ability to have sexual intercourse); and EHS 4 (47.2% vs. 25.2% of occasions; P < 0.0001). At OL end, 93% of men were satisfied (EDITS Index score > 50), 77% had no ED, and ≥89% were GEQ responders; mean scores on IIEF domains, the QEQ, and analog scales were >80% of the maximum; 60% of occasions had EHS 4; and event log responses were positive on >80% of occasions, except for second erections (41.9%). Headache, nasal congestion, and flushing, mostly mild to moderate, were the most common adverse events.
Men with mild ED derive substantial benefit from sildenafil treatment. Bénard F, Carrier S, Lee JC, Talwar V, and Defoy I. Men with mild erectile dysfunction benefit from sildenafil treatment.
Interrelationship of Sildenafil Treatment Effects on the Physiological and Psychosocial Aspects of Erectile Dysfunction of Mixed or Organic Etiology
2010, Journal of Sexual Medicine
Citation Excerpt :
The impact of sildenafil on erectile function and erection hardness, and the resulting improvement in confidence, sexual relationship satisfaction, and the level of anxiety about the next intercourse attempt, were assessed in men with ED in a double-blind placebo-controlled (DBPC) trial of sildenafil at a fixed dose of 50 mg or 100 mg [4]. The effect of sildenafil on erection maintenance, indirectly (mediated through erection hardness) and directly, was previously estimated [5]. In follow up to the previous modeling of the relationships between the physiological aspects of the treatment of ED (i.e., hardness and maintenance), the main objective of the current report is to test the historical psychosocial paradigm of ED, which focuses on performance anxiety, by using mediation modeling to define the relationship of the physiological aspects (hardness and maintenance) and the associated psychosocial aspects (confidence, sexual relationship satisfaction, and performance anxiety) of ED.
In a previous paper using mediation modeling, the direct and indirect effects of sildenafil on erection maintenance were demonstrated.
In an extension of this previous work, the historical psychosocial paradigm of ED, which focuses on performance anxiety, is tested by using mediation modeling to define the relationship of the physiological aspects (hardness and maintenance) and the associated psychosocial aspects (confidence, sexual relationship satisfaction, and performance anxiety) of ED.
Statistical mediation analysis using the following outcomes from a double-blind placebo-controlled trial of fixed-dose sildenafil 100 mg or 50 mg: Erection Hardness Score; the 15-item International Index of Erectile Function (IIEF), including item 4 (frequency of erection maintenance after penetration) and item 5 (difficulty of erection maintenance to intercourse completion); the Self-Esteem And Relationship questionnaire; and the question, “Do you feel anxious about your next attempt at sexual intercourse?”
Estimated percentages of direct and indirect effects of sildenafil on psychosocial aspects of ED (95% confidence intervals).
The model estimated that erection hardness mediated 43.7% (29.3%, 62.4%) of the effect of treatment onto confidence and 45.9% (32.2%, 61.8%) of the effect of treatment onto sexual relationship satisfaction, and that erection maintenance (using IIEF item 4 as a proxy) mediated 23.0% (10.1%, 39.1%) and 22.4% (10.1%, 36.5%), respectively. Similar results were obtained when IIEF item 5 was used as the proxy for measurement of maintenance. Of all possible paths to performance anxiety, only that from treatment via confidence was statistically significant, mediating an estimated 88.6% (55.5%, 146.2%; item 4 model) or 74.9% (47.0%, 121.0%; item 5 model) of the effect of treatment onto anxiety. The direct path to anxiety from treatment was not statistically significant.
In men treated with sildenafil for ED, performance anxiety might be ameliorated by improved confidence. Improved confidence might be mainly mediated via increased erection hardness. Althof SE, Berner MM, Goldstein I, Claes HIM, Cappelleri JC, Bushmakin AG, Symonds T, and Schnetzler G. Interrelationship of sildenafil treatment effects on the physiological and psychosocial aspects of erectile dysfunction of mixed or organic etiology.
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ORIGINAL RESEARCH—ED PHARMACOTHERAPYUnderstanding the Effects of Sildenafil Treatment on Erection Maintenance and Erection Hardness

ABSTRACT

Introduction

Aim

Methods

Main Outcome Measures

Results

Conclusions

Introduction

Section snippets

Dataset

Results

Discussion

Category 1

Category 2

Acknowledgments

J Sex Med

Urology

J Sex Med

J Sex Med

J Sex Med

Urology

Urology

J Urol

J Sex Med

Eur Urol

J Sex Med

J Sex Med

J Sex Med

J Sex Med

ORIGINAL RESEARCH—ED PHARMACOTHERAPY
Understanding the Effects of Sildenafil Treatment on Erection Maintenance and Erection Hardness