ERECTION HARDNESS: A UNIFYING FACTOR FOR DEFINING RESPONSE IN THE TREATMENT OF ERECTILE DYSFUNCTION

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1 ERECTION HARDNESS: A UNIFYING FACTOR FOR DEFINING RESPONSE IN THE TREATMENT OF ERECTILE DYSFUNCTION JOHN P. MULHALL, LAURENCE A. LEVINE, and KLAUS-PETER JÜNEMANN ABSTRACT The extensive sildenafil citrate erectile dysfunction (ED) database of double-blind, placebo-controlled clinical trials was examined to determine the relation between erection hardness graded on the Erectile Hardness Grading Scale (EHGS) and (1) erectile function (EF), as assessed by the EF domain of the International Index of Erectile Function (IIEF); (2) frequency of erections hard enough for penetration, as assessed by IIEF Q2; and (3) the percentage of successful sexual intercourse attempts according to patient event logs. Pooled data from 6549 men with ED provided strong proof and improved characterization of the response to sildenafil. Almost half of men with ED and a baseline IIEF EF domain score classified as severe ED ( 10) shifted to a score classified as no ED ( 26). Sildenafil recipients showed greater mean improvement from baseline to end point in IIEF Q2 scores versus placebo, regardless of baseline ED severity, and a higher mean percentage of successful sexual intercourse attempts occurred during the last 4 weeks of treatment versus placebo (5.4-fold vs 2.0-fold increase from baseline). At end point, 95% of men who scored no ED on the IIEF EF domain and 92% of men who reported almost always/always achieving an erection hard enough for penetration (IIEF Q2) had graded their erections hard (rigid) enough for penetration (grade 3) or completely hard and fully rigid (grade 4) during the last 4 weeks of treatment, suggesting that the IIEF EF domain and IIEF Q2 may be good surrogate end points for erection hardness. Furthermore, during the last 4 weeks of treatment, the percentage of grade 3 and/or 4 erections correlated positively with the percentage of successful sexual intercourse attempts. Hence, hard erections may be considered a unifying factor that defines response to ED treatment. Completely hard and fully rigid erections (grade 4) should be recognized as the optimal goal of an ED therapy. Evidence presented here demonstrates that sildenafil significantly improved EF as assessed by the IIEF EF domain and assessments of erection hardness in patients with ED; a dose response relation was observed in the proportions of men with ED who graded their erections hard (rigid) enough for sexual penetration or completely hard and fully rigid. UROLOGY 68 (Suppl 3A): 17 25, Elsevier Inc. The prevalence of erectile dysfunction (ED) has been estimated at 13% to 28% of men aged 40 to 80 years worldwide, 1 and 52% of men aged 40 to From the Department of Urology, Weill Medical College of Cornell University, New York Presbyterian Hospital, New York, New York, USA, and Department of Urology, Memorial Sloan-Kettering Cancer Center, New York, New York, USA (JPM); Rush University Medical Center, Chicago, Illinois, USA (LAL); and Klinikum der Christian-Albrechts-Universität, Kiel, Germany (K-PJ). John P. Mulhall receives research support from Pfizer Inc. Laurence A. Levine is a paid consultant to, member of the Speakers Bureau for, and member of the medical advisory board for, Pfizer Inc. Reprint requests: John P. Mulhall, MD, Department of Urology, Weill Medical College of Cornell University, New York Presbyterian Hospital and Memorial Sloan-Kettering Cancer Center, 525 East 68th Street, New York, NY jpm2005@med.cornell.edu 70 years in the Massachusetts Male Aging Study. 2 A cross-sectional survey of 820 men aged 40 years in the United States revealed that 22% of men reported sometimes or never being able to achieve and maintain an erection satisfactory for sexual intercourse. 3 Sildenafil citrate (Viagra ; Pfizer Inc, New York, NY), an oral phosphodiesterase-5 inhibitor that was generally well tolerated in most men from diverse populations of patients with ED, has proved effective in the treatment of ED according to subjective patient self-assessments such as the International Index of Erectile Function (IIEF), patient event logs, and global efficacy questions. 4 The IIEF is a validated patient-reported questionnaire in the domains of Erectile Function (EF), Orgasmic Function, Sexual Desire, Intercourse Satisfaction, 2006 ELSEVIER INC /06/$32.00 ALL RIGHTS RESERVED doi: /j.urology

2 and Overall Satisfaction. 5 The EF domain of the IIEF elicits patient responses to questions regarding (1) the frequency, during sexual activity, of erections (IIEF Q1), erections hard enough for penetration (IIEF Q2), penetration (IIEF Q3), and maintenance of erection after penetration (IIEF Q4); (2) the difficulty of maintaining an erection to completion of intercourse (IIEF Q5); and (3) confidence to achieve and maintain an erection (IIEF Q15). Patient event logs are used to record, at the occasion of sexual activity, the number of attempts at sexual intercourse and outcomes such as penetration, erection maintenance, and orgasm. Global efficacy questions, which address improvement in erection and in the ability to have sexual intercourse by eliciting a dichotomous (yes/no) response, provide a general overview of treatment. These subjective assessment tools are described by Rosen et al. 6 in this supplement, and the advantages and limitations have been reviewed in detail. 7 Erection hardness is a physiologic response that is measured objectively with the use of penile tumescence monitoring (RigiScan; Dacomed, Minneapolis, MN) and is graded subjectively on the Erection Hardness Grading Scale (EHGS). In double-blind trials of men with ED who were given sildenafil, penile tumescence monitoring and the EHGS have shown increases relative to placebo in measures of erection hardness To determine the relationship between erection hardness graded subjectively by the patient and other measures of response, we analyzed a large database of randomized, double-blind, placebocontrolled trials of sildenafil in men with ED, conducted from 1996 to METHODS ASSESSMENTS Although designed for the assessment of EF, the EF domain of the IIEF has also been used to categorize ED severity. 12 IIEF EF domain scores 26 define no ED, scores of 22 to 25 are categorized as mild ED, scores of 17 to 21 as mild-to-moderate ED, scores of 11 to 16 as moderate ED, and scores 10 as severe ED. However, in many ED studies, only a very small number of men are categorized with mild ED at baseline. Small sample size negatively influences the generalization of statistical inference because the sample is not large enough to be representative of the population of men with mild ED. Consequently, for analyses presented in this article, we combined data from men categorized with mild ED at baseline with data from men categorized with mild-to-moderate ED at baseline, defined this group of men as having mild-to-moderate ED (IIEF EF domain scores of 17 to 25), and referred to them as such. The erection hardness component of EF is addressed specifically by IIEF Q2, which is included in the IIEF EF domain: Over the past 4 weeks, when you had erections with sexual stimulation, how often were your erections hard enough for penetration? The percentage of successful sexual intercourse attempts during the last 4 weeks of treatment was calculated from patient event logs. Erection hardness was graded according to the EHGS, on which grade 1 represents increase in size but not hardness, grade 2 represents hard but not hard enough for penetration, grade 3 represents hard enough for penetration but not completely hard, and grade 4 represents completely hard and fully rigid. 9 POOLED EFFICACY ANALYSES To more clearly characterize the response to sildenafil treatment in patients with ED, we analyzed pooled data from randomized, double-blind, placebo-controlled trials that assessed safety and efficacy. Data were pooled separately from 5 flexible-dose trials of 12 to 36 weeks duration and from 26 flexible-dose phase 2, 3, and 4 multicenter trials of sildenafil (25, 50, or 100 mg PRN) that were conducted in populations of patients with ED who were defined by race/ethnicity, by geographic location (eg, North, South, and Central America, Europe, Asia, Africa, and Australia), or by concomitant diseases or treatments Four of the trials in the 5-trial pooled analysis were also included in the 26-trial pool. The minimum age for inclusion was 18 years in most trials. Exclusion criteria included hypotension ( 90/50 mm Hg) or hypertension ( 170/110 or 180/110 mm Hg), significant cardiovascular disease, and the use of nitrates, nitric oxide donors, or ritonavir. Trials were approved by appropriate local independent review boards and were conducted in accordance with the Declaration of Helsinki; all patients provided written informed consent. The most common duration of therapy was 12 weeks (range, 6 36 weeks). In all pooled analyses, differences between treatment groups were calculated through analysis of covariance, with terms defined for treatment group, study, and baseline values of efficacy outcomes. The 5-trial pool was used to calculate the proportions of men who shifted from having severe ED at baseline to having moderate, mild-to-moderate, or no ED at the end of treatment, according to IIEF EF domain scores. The 26-trial pool was used to assess changes in specific aspects of EF, including the frequency of erections hard enough for penetration (IIEF Q2); end-of-treatment scores on the 6 individual questions of the IIEF EF domain were stratified by baseline ED severity. In 18 of 26 pooled double-blind, placebo-controlled trials, patients maintained an event log of sexual activity. We analyzed the pooled data from these 18 trials to calculate changes in the percentage of successful sexual intercourse attempts. RELATION BETWEEN ERECTION HARDNESS AND EFFICACY, AND BETWEEN ERECTION HARDNESS AND SILDENAFIL DOSE We conducted new analyses on results from a 24-week, double-blind, placebo-controlled trial of fixed-dose sildenafil (25, 50, or 100 mg PRN) in 532 men with ED, which was completed in the United States and for which other results were reported previously. 20,34 The first analysis evaluated concordance of erection hardness grade 3 (hard enough for penetration but not completely hard) or grade 4 (completely hard and fully rigid) with EF as assessed by the IIEF EF domain and by IIEF Q2 (erection hard enough for penetration). In addition, the Pearson product moment analysis was used to calculate correlations between the percentage of erections of a specific hardness grade and the percentage of successful sexual intercourse attempts during the last 4 weeks of treatment, as recorded in event logs. Descriptive statistics are presented for the percentage of men with ED who had a modal (eg, most frequently occurring) erection hardness grade of 3 or 4 during the last 4 weeks of treatment. Because fixed doses of sildenafil were administered, it was possible to determine the relation between erection hardness grade and sildenafil dose. 18 UROLOGY 68 (Supplement 3A), September 2006

3 FIGURE 1. Shift in severity of erectile dysfunction (ED) in men who had severe ED at baseline as measured by the Erectile Function (EF) domain of the International Index of Erectile Function (IIEF). A pooled analysis of 5 randomized, double-blind, placebo-controlled trials of sildenafil in men with ED revealed that, compared with placebo, a greater proportion who had severe ED at baseline and received sildenafil improved to mild-to-moderate ED or no ED by the end of treatment. No ED IIEF EF domain score of 26 to 30; mild-to-moderate ED IIEF EF domain score of 17 to 25; moderate ED IIEF EF domain score of 11 to 16; severe ED IIEF EF domain score 10. *P vs baseline IIEF EF domain scores. RESULTS POOLED EFFICACY ANALYSES Among 1128 men with ED (placebo 550, sildenafil 578) in the 5-trial pooled analysis, improvement of EF by 1 IIEF EF domain severity category was seen in 405 individuals (70%) who received sildenafil compared with 115 individuals (21%) who were given placebo. Of the 405 men with ED who received sildenafil and improved by 1 ED severity category, the 211 (52%) who had severe ED at baseline shifted to moderate ED (38 of 211, 18%), mild-to-moderate ED (73 of 211, 35%), or no ED (100 of 211, 47%) by the end of treatment (Figure 1). Of the 115 men with ED who received placebo and improved by 1 ED severity category, the 52 (45%) who had severe ED at baseline shifted to moderate ED (31 of 52, 60%), mild-to-moderate ED (13 of 52, 25%), or no ED (8 of 52, 15%) by the end of treatment. These data reveal that, compared with men with ED who were given placebo, a substantially higher proportion of men with ED who received sildenafil shifted from having IIEF EF domain scores that indicated severe ED to having scores that indicated no ED. Data from the 26-trial pool, which represents a multinational and multicultural population of patients with ED, further support the beneficial effects of sildenafil on EF. The 3095 patients who were randomized to placebo and the 3454 patients who were randomized to sildenafil were well balanced for age and for cause and duration of ED (Table I). Regardless of baseline ED severity, the change in scores from baseline to end of treatment on all questions of the IIEF EF domain (Q1 to Q5 and Q15), including frequency of erections hard enough for penetration (IIEF Q2), was significantly greater for patients who received sildenafil compared with those given placebo (P ) (Table II and Figure 2). Because patients with more severe ED had lower baseline IIEF EF domain scores, they achieved numerically greater improvements in function by the end of treatment. In the 18-trial subset of the 26-trial pool, in which data on intercourse success were collected through patient event logs, 1601 patients were randomized to placebo and 1969 were randomized to sildenafil. Compared with men with ED who were given placebo, those who received sildenafil had a significantly higher mean percentage of successful sexual intercourse attempts during the last 4 weeks of treatment (P ) (Figure 3). Because men with moderate or severe ED had lower sexual intercourse success rates at baseline, they achieved greater improvement in success rates with sildenafil treatment. However, for all patients who took sildenafil, the mean percentage of successful sexual intercourse attempts was 5.4 times higher during the last 4 weeks of treatment than at baseline, compared with a 2.0-fold increase for patients who took placebo. RELATION BETWEEN ERECTION HARDNESS GRADE AND OTHER RESPONSE OUTCOMES Results from the randomized, double-blind, placebo-controlled trial of fixed-dose sildenafil UROLOGY 68 (Supplement 3A), September

4 TABLE I. Characteristics of patients with erectile dysfunction (ED) in the pooled analysis of 26 randomized double-blind, placebo-controlled trials Characteristic Placebo (n 3095) Sildenafil (n 3454) Age (yr) Mean SD Range By age group, n (%) (17) 636 (18) (61) 2105 (61) (21) 699 (20) Unspecified 8 (0.3) 14 (0.4) Race, n (%) White 1894 (61) 1933 (56) Black 287 (9) 291 (8) Asian 581 (19) 893 (26) Hispanic 175 (6) 167 (5) Other 158 (5) 170 (5) Causes of ED, n (%) Mixed 934 (30) 1102 (32) Organic 1632 (53) 1732 (50) Psychogenic 450 (14) 546 (16) Unknown 79 (3) 74 (2) Duration of ED in all patients, yr (range) 4.5 ( ) 4.4 ( ) in 532 men with ED revealed the relation between erection hardness graded by the EHGS and other response outcomes. EF as assessed by the IIEF EF domain and the frequency of erections hard enough for penetration as assessed by the IIEF Q2 showed very high concordance with erection hardness grade. A total of 95% of patients with IIEF EF domain scores that indicated no ED (score 26) by the end of treatment had most frequently graded their erections 3 (hard enough for penetration) (42%) or 4 (completely hard) (53%) in their event logs during the last 4 weeks of treatment (Figure 4). Consistent with this, 92% of patients who responded to IIEF Q2 that they almost always or always achieved an erection hard enough for penetration had most frequently graded their erections 3 (46%) or 4 (46%). Correlations between the percentage of erections graded 3 or 4 and the percentage of successful sexual intercourse attempts based on event log responses during the last 4 weeks of treatment were positive and ranged from 0.65 to 0.76 (P ) (Figure 5). Data show that, in men with ED treated with sildenafil, achievement of erections graded hard enough for penetration or completely hard was associated with a higher percentage of successful sexual intercourse attempts. RELATION BETWEEN ERECTION HARDNESS GRADE AND SILDENAFIL DOSAGE Results of the double-blind, placebo-controlled trial of fixed-dose sildenafil in 532 patients with ED indicated a dose-response relation in the erection hardness grade achieved with sildenafil. As reported in an earlier publication, 72%, 80%, and 85% of men with ED who took sildenafil (25, 50, or 100 mg, respectively) achieved erections of grades 3 or 4 according to the EHGS, compared with 50% of men with ED who were given placebo (P ). 20 The current analysis determined that the percentage of men with ED taking sildenafil who improved from a modal (eg, most frequently occurring) erection grade of 1 at baseline to modal grades 3 or 4 hardness during the last 4 weeks of treatment was also positively related to sildenafil dose, increasing from 41% for 25 mg, to 45% for 50 mg, to 78% for 100 mg, compared with only 12% for placebo (Figure 5). A positive dose-response relation was also evident in the improvement to grade 4 erection hardness during the last 4 weeks of treatment (Figure 6). DISCUSSION These analyses, derived from the extensive randomized, double-blind, placebo-controlled clinical trials database, demonstrated the response to sildenafil in the treatment of men with ED as as- 20 UROLOGY 68 (Supplement 3A), September 2006

5 TABLE II. Changes in scores from baseline to the end of treatment on questions from the Erectile Function (EF) domain of the International Index of Erectile Function (IIEF) in the pooled analysis of 26 randomized double-blind, placebo-controlled trials Questions* Q15: Confidence in Ability to Achieve and Maintain Erection Q5: Difficulty of Maintaining Erection to Intercourse Completion Q4: Frequency of Maintenance of Erections After Penetration Q3: Frequency of Penetration Q2: Frequency of Erections Hard Enough for Penetration Q1: Frequency of Erections Placebo Sildenafil Placebo Sildenafil Placebo Sildenafil Placebo Sildenafil Placebo Sildenafil Placebo Sildenafil Baseline ED Severity Mild-to-moderate ED Moderate ED Severe ED All patients ED erectile dysfunction. *For all IIEF EF domain questions, increased score indicates improvement. Mild-to-moderate ED score of 17 25; moderate ED score of 11 16; severe ED score 10. Significantly (P ) greater improvement from baseline to the end of treatment compared with placebo. sessed by the IIEF EF domain, the IIEF Q2 (frequency of erections hard enough for penetration), and the percentage of successful sexual intercourse attempts calculated from patient event logs. These analyses confirmed and strengthened the results of smaller studies, case reports, and anecdotal stories, and further defined the level of improvement achieved across varying levels of ED severity. Subsequently, positive associations were demonstrated between these response outcomes and erection hardness graded with the EHGS. Lastly, a positive association was shown between erection hardness graded with the EHGS and sildenafil dose. The ability to achieve a hard erection is intuitively one of the most essential components of erectile function. Recently, an International Consensus Advisory Panel of urology, psychology, and reproductive health specialists with experience in assessing and treating ED was convened to develop guidelines, definitions, and an evaluation algorithm. This panel defined ED treatment efficacy as...the ability of a pharmacologic agent to promote achievement and maintenance of firm or adequate erections and described a complete response as...consistent achievement and maintenance of full erection [italics added] Moreover, the advisory panel noted that efficacy is generally based on patient self-report of surrogate end points for objective, physiologic changes in penile firmness or rigidity. 35 Our demonstration of an association between erection hardness graded with the EHGS and other response outcomes (ie, IIEF EF domain scores and frequency of erections hard enough for penetration [IIEF Q2]) in men with ED who took sildenafil suggests that the IIEF EF domain and the IIEF Q2 may be good surrogate end points for subjective assessment of erection hardness. Sildenafil treatment improves EF in men with ED, and penile tumescence monitoring and the EHGS have been used to describe the effects of sildenafil on erection hardness in men with ED Early efficacy trials showed that sildenafil was superior to placebo in improving the duration of hard erections. For example, in a randomized, doubleblind, placebo-controlled, 2-way crossover trial of 12 sildenafil-naive men (mean age, 48 years; range, 36 to 63 years) with ED for a mean duration of 3.4 years (range, 1.5 to 10 years), mean erection rigidity, measured by penile tumescence monitoring, was 80% 11 minutes after a 50-mg dose of sildenafil was taken compared with 1 minute after placebo was taken 9 and was 60% after 32 minutes and 3 minutes, respectively. 8 In a double-blind, placebo-controlled, 4-way crossover trial of sildenafil 100 mg in 16 men with ED (mean age, 55 years; range, 36 to 68 years), erections were UROLOGY 68 (Supplement 3A), September

6 FIGURE 2. Changes in International Index of Erectile Function (IIEF) Erectile Function (EF) domain scores from baseline to the end of treatment. A pooled analysis of 26 randomized, double-blind, placebo-controlled trials showed that, compared with placebo, men with erectile dysfunction (ED) randomized to receive sildenafil reported significantly greater mean score increases on all questions of the EF domain of the IIEF, independent of ED severity at baseline. Mild-to-moderate ED IIEF EF domain score of 17 to 25; moderate ED IIEF EF domain score of 11 to 16; severe ED IIEF EF domain score 10. For all IIEF EF domain questions, increased score indicates improvement: Q1 frequency of erections; Q2 frequency of erections hard enough for penetration; Q3 frequency of penetration; Q4 frequency of maintenance of erection after penetration; Q5 difficulty of maintaining erection to completion of intercourse; and Q15 confidence in ability to achieve and maintain an erection. *P vs corresponding placebo value at the end of treatment, by baseline ED severity. FIGURE 3. Percentage of successful sexual intercourse attempts at baseline and during the last 4 weeks of treatment as measured by the Erectile Function (EF) domain of the International Index of Erectile Function (IIEF). A pooled analysis of 18 randomized, double-blind, placebo-controlled trials showed that, compared with placebo, men with erectile dysfunction (ED) randomized to receive sildenafil had significantly more successful sexual intercourse attempts during the last 4 weeks of treatment, independent of ED severity at baseline. No ED IIEF EF domain score of 26 to 30; mild-to-moderate ED IIEF EF domain score of 17 to 25; moderate ED IIEF EF domain score of 11 to 16; severe ED IIEF EF domain score 10. *P vs corresponding placebo value at the end of treatment, by baseline ED severity. achieved through visual sexual stimulation 1 hour after sildenafil or placebo was taken. 11 In this study, the mean duration of erections with 60% rigidity was 26 minutes after sildenafil was taken, compared with only 3 minutes after placebo was taken (P 0.05), and the mean duration of erections graded by the patient as 3 or 4 on the EHGS was 33 and 7 minutes, respectively. 11 The onset of erection hardness with sildenafil was rapid. A randomized, double-blind, placebo-controlled, 2-way crossover trial, which included 17 sildenafil-naive men with ED (mean age, 52 years; range, 37 to UROLOGY 68 (Supplement 3A), September 2006

7 FIGURE 4. Concordance between erection hardness assessed with the Erection Hardness Grading Scale (EHGS) and erectile function (EF) assessed with the EF domain of the International Index of Erectile Function (IIEF) and the IIEF Q2 (frequency of erections hard enough for penetration). In a 24-week double-blind, placebo-controlled trial of sildenafil in 524 patients with erectile dysfunction (ED), modal hardness grade during the last 4 weeks of treatment and end-of-treatment ED severity categories based on scores for the IIEF EF domain and the IIEF Q2 were analyzed, and concordance between outcomes was determined. EF assessed with the IIEF EF domain and frequency of erection hard enough for penetration assessed with the IIEF Q2 showed high concordance with erection hardness graded with the EHGS. No ED IIEF EF domain score 26; mild ED IIEF EF domain score of 22 to 25; mild-to-moderate ED IIEF EF domain score of 17 to 21; moderate ED IIEF EF domain score of 11 to 16; and severe ED IIEF EF domain score 10. FIGURE 5. Percentage of men with erectile dysfunction (ED) who shifted from erections of grade 1 hardness at baseline to erections of grades 3 or 4 hardness during the last 4 weeks of treatment, and correlations between the percentage with grades 3 or 4 erections and the percentage of successful sexual intercourse attempts during the last 4 weeks of treatment. After 24 weeks of double-blind treatment, the proportion of men with ED who reported a best erection of grade 1 at baseline and then reported a best erection of grade 3 or grade 4 during the last 4 weeks of treatment was significantly greater in those randomized to sildenafil (25, 50, or 100 mg) compared with placebo. The correlations between the percentage who achieved grade 3 or grade 4 erections during the last 4 weeks of treatment and the percentages of successful sexual intercourse attempts during the last 4 weeks of treatment were positive and ranged from 0.65 to 0.76 (95% confidence interval). years; mean duration of ED, 3.1 years; range, 0.5 to 19 years) determined that some achieved erections as soon as 12 minutes after taking sildenafil. 10 In this trial, erections were graded 3 or 4 on the EHGS by 71% of men with ED (12 of 17) after taking sildenafil compared with 35% of men (6 of 17) after taking placebo. The rapid speed of onset of sildenafil was further supported by results of a doubleblind trial in which men with ED who had been successfully treated with sildenafil for 2 months were randomized to sildenafil 100 mg (n 115; mean age, 61 years; mean duration of ED, 6.8 years) or placebo (n 113; mean age, 59 years; mean duration of ED, 7.2 years). 36 An erection that enabled successful sexual intercourse was achieved by significantly more sildenafil recipients UROLOGY 68 (Supplement 3A), September

8 FIGURE 6. Percentage of men with erectile dysfunction (ED) who shifted from erections of grades 1, 2, or 3 hardness at baseline to erections of grade 4 hardness during the last 4 weeks of treatment. After 24 weeks of double-blind treatment, the percentage of men with ED who reported a best erection of grades 1, 2, or 3 at baseline and then reported a best erection of grade 4 during the last 4 weeks of treatment was greater in those randomized to sildenafil (25, 50, or 100 mg) compared with placebo. For the placebo group, percentages are zero, except for the men who reported a best erection of grade 3 at baseline. compared with placebo recipients within 14 minutes (P 0.05), and by most sildenafil recipients within 20 minutes. Sildenafil recipients were 3 times as likely as placebo recipients to obtain an erection that resulted in a successful sexual intercourse attempt. These previously reported trials established that most men with ED rapidly achieved increased erection hardness, achieved an erection that was hard enough for penetration (eg, grade 3) or completely hard and fully rigid (eg, grade 4), and had erection hardness that persisted severalfold longer than did men with ED who took placebo. The current analysis expands on these previous results by demonstrating positive correlations between erection hardness grade and successful sexual intercourse during the last 4 weeks of treatment, thereby addressing the National Institutes of Health (NIH) Consensus Statement definition of ED:...the inability to attain and/or maintain penile erection sufficient for satisfactory sexual performance [italics added]. 37 Moreover, the current analysis demonstrates a sildenafil dose-response relation in the proportion of men with ED who improved from achieving grade 1 erections (increase in size but not hard) to achieving erections hard enough for penetration or completely hard and fully rigid. CONCLUSIONS We have demonstrated that the IIEF EF domain and the frequency of erections hard enough for penetration (IIEF Q2) were good surrogate end points for erection hardness, which correlated positively with successful sexual intercourse during the last 4 weeks of treatment. Hence, achievement of hard erections may be considered a unifying factor that defines response in ED treatment. Completely hard and fully rigid erections should be recognized as the optimal goal of an ED therapy. Sildenafil treatment can improve erectile function and erection hardness in men with ED, and a doseresponse relation was noted in the proportion who achieved erections that were hard enough for penetration or were completely hard and fully rigid. REFERENCES 1. Laumann EO, Nicolosi A, Glasser DB, et al: Sexual problems among women and men aged y: prevalence and correlates identified in the Global Study of Sexual Attitudes and Behaviors. Int J Impot Res 17: 39 57, Feldman HA, Goldstein I, Hatzichristou DG, et al: Impotence and its medical and psychosocial correlates: results of the Massachusetts Male Aging Study. J Urol 151: 54 61, Carson CC, West SL, Glasser DB, et al: Prevalence and correlates of erectile dysfunction in a United States nationwide population-based sample: phase I results [abstract]. J Urol 167(suppl): 29 30, Carson CC, Burnett AL, Levine LA, et al: The efficacy of sildenafil citrate (Viagra) in clinical populations: an update. Urology 60(suppl 2B): 12 27, Rosen RC, Riley A, Wagner G, et al: The International Index of Erectile Function (IIEF): a multidimensional scale for assessment of erectile dysfunction. Urology 49: , Rosen RC, Althof SE, Giuliano F: Research instruments for the diagnosis and treatment of patients with erectile dysfunction. Urology 68(suppl 3A): 6 16, Rosen RC, Cappelleri JC, Gendrano N III: The International Index of Erectile Function (IIEF): a state-of-the-science review. Int J Impot Res 14: , Boolell M, Allen MJ, Ballard SA, et al: Sildenafil: an orally active type 5 cyclic GMP-specific phosphodiesterase inhibitor for the treatment of penile erectile dysfunction. Int J Impot Res 8: 47 52, UROLOGY 68 (Supplement 3A), September 2006

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