Sildenafil citrate efficacy 8 h postdose in men with mild to moderate erectile dysfunction

Abstract

In two randomized, double-blind, placebo-controlled trials of 100 mg sildenafil citrate, men (N=601) with mild to moderate erectile dysfunction (ED) attempted intercourse 8 h (range, 7–9 h) postdose. The baseline to end-of-treatment improvement in the sildenafil groups vs placebo was greater (P<0.001) for the per-patient proportion (PPP) of ‘yes’ responses to the Sexual Encounter Profile question 3 (SEP3: successful intercourse (primary outcome)) (odds ratio (OR)=3.2 (trial 1), 7.6 (trial 2) and 5.6 (pooled data)); PPP of erection hardness score 4 (EHS 4, completely hard and fully rigid) (OR=6.2 (trial 1) and 10.9 (trial 2)); scores on the International Index of Erectile Function; and other EHS and SEP outcomes. Two to three times as many men were satisfied with sildenafil vs placebo treatment (Erectile Dysfunction Inventory of Treatment Satisfaction Index >50). Thus, responsiveness to 100 mg sildenafil may persist for 8 h postdose in men with mild to moderate ED.

Introduction

The incidence and prevalence of erectile dysfunction (ED)1 are expected to increase with the aging of the US population.2 ED may be an early symptom of underlying cardiovascular disease,3 and it can also diminish a man's quality of life by affecting his self-esteem,4 making it important to diagnose and treat this condition. The treatment of ED was revolutionized by the advent of oral phosphodiesterase type 5 inhibitors, the first of which was sildenafil citrate (VIAGRA; Pfizer Inc, New York, NY, USA). Sildenafil is rapidly absorbed after ingestion and is a competitive inhibitor of phosphodiesterase type 5.5 The main treatment-related adverse events reported in clinical studies are headache, facial flushing and dyspepsia.6 These are usually transient and mild to moderate in severity. The recommended starting dose of sildenafil is 50 mg. Although a few men cannot tolerate sildenafil 50 mg and have their dose reduced to 25 mg, the majority of men are titrated to a 100 mg dose for optimal efficacy.6

In men with ED, empirical observations and the results of clinical trials suggest that the duration of sildenafil activity may be much longer than the 4–5 h currently described in the manufacturer's prescribing information.7, 8 The 4–5 h duration of activity for sildenafil on erectile response was inferred from its pharmacokinetic characteristics (that is, the achievement of maximum plasma concentrations within 1 h and a terminal elimination half-life of between 3 and 6 h).9 However, previously published clinical trial results support a longer duration of activity.8, 10 A better definition of the period of responsiveness to sildenafil would assist in its optimal use. Recently, a randomized, double-blind, placebo-controlled trial of sildenafil 100 mg in men with mild to moderate ED prospectively assessed sexual intercourse attempted at 8 h postdose and (after crossover to the alternative treatment) 12 h postdose during sequential, 4-week treatment periods.11 In addition, a second, similarly designed trial of sildenafil 100 mg also prospectively assessed sexual intercourse attempted 8 h postdose. In this report, we present individual and combined results of these trials to further demonstrate the efficacy of sildenafil at 8 h postdose.

Materials and methods

Trial designs

Results of sexual intercourse attempts at 8 h (range, 7–9 h) postdose came from two multicenter, parallel-group, randomized (1:1), double-blind, placebo-controlled trials of sildenafil 100 mg administered on demand over a 4-week treatment period. Trial 2 had one double-blind, placebo-controlled treatment period, whereas trial 1 also had crossover to the alternative treatment after the first 4 weeks of double-blind, placebo-controlled treatment. In the second 4-week period in trial 1, intercourse was to occur 12 h (range, 11–13 h) postdose in patients who had crossed over to the alternate treatment. For each trial, the sildenafil dose was 100 mg, and intercourse was to occur on at least four occasions, at least 1 day apart, during each trial period. The trials were conducted in compliance with the ethical principles of the Declaration of Helsinki, all patients gave written informed consent and the institutional review boards of all the participating centers approved the trials.

Treatment administration

Sildenafil 100 mg or matching placebo was taken as needed 7–9 h before intercourse.

Patients

To meet the inclusion criteria of either trial, men were required to be 18–70 years of age with a clinical diagnosis of mild to moderate ED12 (score of 11–25 out of 30 on the Erectile Function domain of the International Index of Erectile Function (IIEF))13 of 3 months duration. Participants were either known responders (2 months of previous successful treatment with 50 mg sildenafil and no severe or serious treatment-related adverse events) or their responder status was unknown (6 doses of any phosphodiesterase type 5 inhibitor within the past 3 months (each center was to enroll 2 such men)). They had to have a stable sexual partner for the duration of the trial.

Key exclusion criteria included systolic hypotension (<90/50 mm Hg) or hypertension (>160/110), orthostatic hypotension, significant cardiovascular disease within 3 months of enrollment, uncontrolled diabetes or a history of prostate cancer or retinitis pigmentosa. Men taking nitrates or nitric oxide donors in any form, either regularly or intermittently, who were currently taking any other commercially available drug or nondrug treatment for ED or who were taking potent cytochrome P450 3A4 inhibitors (for example, ritonavir) were excluded.

Measurements

An event log that included the Sexual Encounter Profile (SEP)14 and the validated Erection Hardness Score (EHS)15 was completed after each sexual encounter. SEP questions are SEP1 (‘Were you able to achieve at least some erection (some enlargement of the penis)?’), SEP2 (‘Were you able to insert your penis into your partner's vagina?’), SEP3 (‘Did your erection last long enough for you to have successful intercourse?’), SEP4 (‘Were you satisfied with the hardness of your erection?’) and SEP5 (‘Were you satisfied overall with this sexual encounter?’). EHS categories are 1 (increase in size but not hard), 2 (hard but not hard enough for penetration), 3 (hard enough for penetration but not completely hard) and 4 (completely hard and fully rigid).15

The IIEF16 and the Erectile Dysfunction Inventory of Treatment Satisfaction (EDITS)17 were completed at study visits. The EDITS assesses satisfaction with ED treatment and is scored as the EDITS Index (25 times the average EDITS item score (range, 0–100)).17 The percentage of patients satisfied with treatment (EDITS Index >50) was determined for each treatment group.

Efficacy outcomes

The primary outcome was the mean per-patient proportion (PPP) of successful intercourse attempts (‘yes’ responses to SEP3) at 8 h postdose. The secondary outcomes included the mean PPP of ‘yes’ responses to SEP2 (able to insert penis into partner's vagina), SEP4 (satisfaction with erection hardness) and SEP5 (satisfaction overall with the sexual encounter); the mean PPP of EHS 3 or 4 erections and of EHS 4 erections; the IIEF domain and item scores; and the proportion of men who were satisfied with treatment 8 h postdose based on EDITS Index scores.

Efficacy analyses

The efficacy analyses were based on the intent-to-treat population (that is, men who took 1 dose of study drug and contributed data to 1 efficacy analysis). Several statistical tests (all of which were two-sided and performed at the 5% significance level) were used to analyze the data.

The PPP was calculated as clustered binomial data using the PROC LOGISTIC procedure with a scale adjustment for overdispersion (estimated via Williams method).18 The use of logistic regression produced estimates of the percentage of ‘yes’ responses weighted by each patient's number of attempts within the allotted period after dosing. Model terms included treatment group, age, ED duration and ED etiology. For the pooled trial data, ‘trial’ was added as an additional random effect. Treatment effects were estimated using predicted percentages from the model.

The change from baseline in mean PPP of ‘yes’ responses to SEP questions, mean PPP of erections of a given EHS and mean IIEF item scores was estimated using analysis of covariance, including terms of baseline value, center, treatment group, age, ED etiology and ED duration. For the pooled trial data, ‘trial’ was added as an additional random effect. The dichotomized treatment satisfaction was derived from the EDITS Index, which was analyzed using a multiple logistic regression model with terms for treatment group, age, duration of ED and ED etiology. Treatment effects were estimated using predicted percentages from the model.

Results

Patient population

In trial 1, the 351 men randomized to sildenafil (N=174) or placebo (N=177) were well-matched (Table 1); 172 and 174, respectively, were included in the intent-to-treat population analysis. Only two discontinuations, occurring during the double-blind, placebo-controlled periods, were related to sildenafil (both because of adverse events of headache).

Table 1 Baseline characteristics

In trial 2, the 250 men randomized to sildenafil (N=126) or placebo (N=124) were also well-matched (Table 1); 125 and 121, respectively, were included in the intent-to-treat population analysis. Only four discontinuations during the double-blind, placebo-controlled period were related to sildenafil. One man who discontinued experienced altered color vision, nausea, headache, nasal congestion and flushing, which were severe. Another experienced chest discomfort, pain in an extremity and headache, which were moderate in severity. The other two men experienced mild nasal congestion and moderate headache, respectively.

In both trials, the most prevalent concomitant medical conditions were hypertension (30–41%), hypercholesterolemia (20–27%) and benign prostatic hyperplasia (18–31%) (Table 1). All except one of the 25 men stabilized on α-blocker treatment before randomization to sildenafil continued α-blocker treatment during the trial.

Successful intercourse attempts (Sexual Encounter Profile question 3)

At the end of the double-blind, placebo-controlled treatment, the least squares (LS) mean±s.e. change (improvement) in PPP of SEP3 was greater for sildenafil (31.9±4.3%) than for placebo (7.5±4.3%; P<0.001) in trial 1, such that the rate of successful intercourse attempts was approximately 50% higher in the sildenafil group compared with the placebo group (odds ratio (OR)=3.2; P<0.001) (Figure 1). The improvement in PPP of SEP3 showed an even greater difference between sildenafil and placebo in trial 2 (47.5±3.9% vs 1.3±4.0%, respectively; P<0.001) and in the pooled data (37.9±3.0% vs 3.5±3.0%; P<0.001), with a correspondingly greater disparity in the rate of successful intercourse (OR=7.6 (P<0.001) and 5.6 (P=0.04), respectively) (Figure 1). Although the OR is numerically larger in trial 2 than in trial 1, the difference is not statistically different because the lower bound of the 95% confidence interval (CI) of the trial 2 OR overlaps with the upper bound of the 95% CI of the trial 1 OR (Figure 1).

Figure 1
figure1

Change in per-patient proportion (PPP) of successful intercourse attempts of men attempting intercourse 8 h postdose. EOT, end of treatment; OR, odds ratio.

Secondary outcomes

Erection Hardness Score

At baseline in trial 1, the mean PPP of erections that were hard enough for penetration but not completely hard (EHS 3) or that were completely hard and fully rigid (EHS 4) was 71.4% for sildenafil and 65.1% for placebo. At the completion of the double-blind, placebo-controlled treatment period, the LS mean±s.e. PPP change (improvement) was greater for sildenafil (20.1±3.8%) vs placebo (–1.3±3.8%; P<0.001), such that the estimated percentage of EHS 3 or EHS 4 was 87.9% (95% CI, 82.4–91.9) vs 66.0% (58.9–72.4) (OR=3.8, P<0.001). For EHS 4 erections alone, the improvement with sildenafil was four times greater than that with placebo (41.0±4.2% and 10.6±4.1%, respectively; P<0.001), as was the overall estimated percentage (OR=6.2, P<0.001; Figure 2).

Figure 2
figure2

Change in per-patient proportion (PPP) of Erection Hardness Score (EHS) 4 erections of men attempting intercourse 8 h postdose. EOT, end of treatment; OR, odds ratio.

Similar results were seen in trial 2, with the PPP of EHS 3 or EHS 4 at baseline being 65.4% for sildenafil vs 64.9% for placebo (mean values), improvement of 25.8±3.9% vs –4.8±3.9% (LS mean±s.e.; P<0.001) and end-of-treatment estimated percentages (95% CIs) of 92.3% (88.2–95.0%) vs 60.8% (53.8–67.3%) (OR=7.7; P<0.001). For EHS 4 erections alone, the improvement with sildenafil was more than five times greater than that with placebo (47.1±4.5 vs 8.4±4.5%; P<0.001), and the overall estimated percentage was more than five times greater (OR=10.9, P<0.001; Figure 2). Although the EHS 4 OR is numerically larger in trial 2 than in trial 1, the difference is not statistically different because the lower bound of the 95% CI of the trial 2 OR overlaps with the upper bound of the 95% CI of the trial 1 OR (Figure 2).

Sexual function and satisfaction (disease related and treatment related)

In each trial, men taking sildenafil achieved statistically greater improvement in scores for all IIEF domains (Figure 3) and items (data not shown) compared with men taking placebo (P<0.001).

Figure 3
figure3

Change from baseline in IIEF domain scores of men attempting intercourse 8 h postdose. IIEF, International Index of Erectile Function; LS, least squares. *P<0.0001; P<0.001.

In each trial, the OR for a ‘yes’ response (improvement) to other SEP questions 8 h postdose was significantly larger in the sildenafil group relative to the placebo group (P<0.001 for each). In trial 1, the OR=3.5 for SEP2 (penetration); OR=6.1 for SEP4 (satisfaction with erection hardness); and OR=4.6 for SEP5 (satisfaction overall with the sexual encounter). In trial 2, the OR=6.6 for SEP2; OR=12.8 for SEP4; and OR=10.0 for SEP5.

More men taking sildenafil vs placebo were satisfied with treatment (EDITS Index >50). In trial 1, satisfaction (EDITS Index >50) was 84% (95% CI, 77–89%) in the sildenafil arm vs 37% (95% CI, 30–45%; OR=8.7, P<0.001) in the placebo arm. In trial 2, satisfaction (EDITS Index >50) was 86% (95% CI, 78–91%) in the sildenafil arm vs 29% (95% CI, 21–38%; OR=14.4, P<0.001) in the placebo arm.

Safety

In both trials, the most commonly reported adverse events related to sildenafil were headache, flushing, nasal congestion/nasopharyngitis and visual color disturbances (Table 2). Most of these adverse events were mild to moderate in severity. Only one man experienced a serious adverse event related to sildenafil treatment (severe headache). As described above, two men discontinued from trial 1 and four men discontinued from trial 2 because of adverse events attributed to sildenafil.

Table 2 Adverse events during double-blind treatment

Discussion

In addition to safety and tolerability, the optimal ED treatment would offer the convenience of rapid onset and a sufficiently long duration of activity to accommodate a patient's perceived need for a flexible time frame for sexual activity. Some men achieve an erection suitable for intercourse in as few as 14 min after taking sildenafil,19 and, based on the currently reported results of two trials designed to prospectively assess erectile function 8 h postdose, treatment with sildenafil 100 mg is associated with at least an 8-h duration of activity in men with mild to moderate ED. As expected from previous trials, most adverse events were mild or moderate in severity, and there were few discontinuations because of treatment-related adverse events.

A prolonged duration of sildenafil activity is also supported by previously published trials. In a randomized, double-blind, placebo-controlled, four-way, crossover trial of single doses in 16 men with ED, efficacy was documented by penile plethysmography (RigiScan; Dacomed Corporation, Minneapolis, MN, USA) and self-assessment after taking sildenafil 100 mg or placebo and receiving visual sexual stimulation.7 On the basis of intra-patient comparisons of responses at each time point, the duration of erections suitable for intercourse was significantly longer 8 and 12 h postdose with sildenafil than with placebo.7 Of the men who responded to sildenafil 1 h after administration (defined as erections of 60% rigidity for 4 min and 50% improvement over erections achieved when on placebo), 82% responded at 8 h and 45% responded at 12 h. In another trial, conducted in 40 sildenafil responders under open-label conditions, 97% and 74% of 34 evaluable men treated with sildenafil 100 mg achieved erections that resulted in successful intercourse at 1 and 12 h postdose, respectively.8

The 4-h time frame estimated previously for sildenafil activity was deduced from the drug's terminal elimination half-life (t1/2) and the time to maximum plasma concentration. The sildenafil t1/2 (3–6 h9) is similar to that of vardenail (Levitra; Bayer Pharmaceuticals Corporation, West Haven, CT, USA; t1/2=4–5 h)20 and shorter than that of tadalafil (Cialis; Lilly ICOS LLC, Indianapolis, IN, USA; t1/2=17.5 h).21 In men treated with flexible-dose vardenafil, approximately two-thirds of whom had mild to moderate ED and 75% of whom were using the maximum recommended dose (20 mg), the LS mean±s.e. PPP of successful intercourse (SEP3) at 8 h postdose was 65% over 10 weeks of treatment (P<0.001 vs placebo).22 Tadalafil 20 mg (the maximum recommended dosage) improved the ability of men with ED to complete successful sexual intercourse up to 36 h postdose (P<0.001 vs placebo).23 The mean PPP of successful intercourse at the end of 4–6 weeks of double-blind, placebo-controlled treatment with tadalafil 20 mg was 77.4% (mild ED) and 85.9% (moderate ED) at 24 h postdose and was 75.7% (mild ED) and 57.8% (moderate ED) at 36 h postdose.24 Thus, all phosphodiesterase type 5 inhibitors currently marketed for the treatment of ED enable successful intercourse for at least twice as long as the t1/2.

The prolonged duration of activity demonstrated for sildenafil in the current report and previous trials suggests that other pharmacologic factors than the t1/2 and the time to maximum plasma concentration may be involved. The volume of distribution of sildenafil is approximately 105 l, which substantially supersedes the 42 l estimated volume of total body water.25 The large volume of distribution suggests that sildenafil is distributed to tissues and that tissue binding may contribute to its sustained clinical effects. As the drug is not degraded intracellularly by phosphodiesterase type 5 or other enzymes, it is possible that sildenafil may be retained by and remains active in smooth muscle cells despite its disappearance from the plasma,26 thereby explaining its extended activity. Further pharmacologic support for a prolonged duration of activity comes from the association between the minimum time to onset of an erection that led to successful intercourse after taking a 100 mg dose (35% of men within 14 min, P<0.05 vs placebo) and known plasma concentrations at comparable times (20 ng ml−1 (7% of the maximum plasma concentration of 286 ng ml−1) at 15 min after a 100 mg dose).19, 27, 28 This comparison suggests that an erectile response sufficient for successful intercourse can occur in a substantial proportion of men at plasma concentrations that are lower than those observed at 8 h (approximately 50 ng ml−1) and similar to those observed at 12 h (approximately 20 ng ml−1) after a 100 mg dose.29

The combined analysis presented here has some limitations. It is unknown if similar results would be achieved in men with more severe ED or in those who are administered a lower dose of sildenafil. The results are generalizable for men with an ED that is mild to moderate in severity.

Conclusions

Sildenafil demonstrated significant efficacy over placebo at 8 h postdose. These data illustrate that the period of responsiveness in some men with mild to moderate ED after a single dose of sildenafil 100 mg may be at least 8 h, allowing flexibility in the timing of sexual activity.

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Acknowledgements

Study investigators included Connie Abarikwu, Stephen Auerbach, James Bailen, Martin Bastuba, David Bilhartz, Orpheus Bizzozero Jr, Joseph Camps Jr, Michael Collins, Lawrence Feldman, Robert Feldman, Sheldon Freedman, Evan Goldfischer, Gerard Henry, Adrian James, Jed Kaminetsky, Joel Kaufman, Edward Loizides, Andrew McCullough, James McMurray, Marcia Miller, Simon Mirelman, William Monnig, William Moseley Jr, Patrick Ogilvie, Terri Oskin, Juan Otheguy, Harin Padma-Nathan, Walter Pittman, Steven Rosenberg, Randolph Ross, Jose Sotolongo Jr, Christopher Steidle, Mark Swierzewski and David Talley. The studies were funded by Pfizer Inc. Editorial assistance was provided by Deborah M Campoli-Richards, BSPHA, RPh, and Nancy E Price, PhD, of Complete Healthcare Communications Inc., and was funded by Pfizer Inc.

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Correspondence to A R McCullough.

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Andrew McCullough has been a consultant, investigator, lecturer and/or Advisory Board member for Auxillium Pharmaceuticals, Bayer-GSK, Guilford Pharmaceuticals, Ion Channel, Johnson & Johnson, Lilly-ICOS, Pfizer and Schering Plough; Christopher P Steidle has been a lecturer for Astellas Pharma, Auxillium Pharmaceuticals Pfizer and Solvay Pharmaceuticals. Joel Kaufman has been a consultant, lecturer, trial investigator and/or on the Speakers’ Bureau for Amgen, Astellas Pharma, Coloplast, Indevus Pharmaceuticals, Lilly, Novartis Pharmaceuticals, Pfizer and Solvay Pharmaceuticals. Evan R Goldfischer has been a consultant, investigator and/or lecturer for Amgen, Astellis Pharma, Auxillium Pharmaceuticals, Bayer-GSK, Indevus Pharmaceuticals, Johnson & Johnson, Lilly, Merck & Co., Novartis Pharmaceuticals, Ortho McNeil Pharmaceutical, Pfizer, Sanofi-Aventis, Schering Plough and Schwartz. Brian Klee and Martin Carlsson are employees of Pfizer lnc.

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McCullough, A., Steidle, C., Kaufman, J. et al. Sildenafil citrate efficacy 8 h postdose in men with mild to moderate erectile dysfunction. Int J Impot Res 20, 388–395 (2008). https://doi.org/10.1038/ijir.2008.21

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Keywords

  • erectile dysfunction
  • sildenafil citrate
  • duration of activity

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