- CONDITION CENTERS
Multiple surveys have shown that erectile dysfunction (ED) affects a growing number of older men.1-3 In most instances, the disorder is mild, but about a quarter of the men report severe disturbance of erectile function.2 Men who have certain chronic health problems, particularly cardiovascular disease or diabetes, have an even higher risk of ED.2,4-6
Until recently, first-line therapy for ED had consisted of lifestyle modification, drug treatment aimed at anxiety reduction or desensitization, psychosocial counseling, or androgen replacement therapy. In the United States, oral testosterone was contraindicated because of the risk of hepatotoxicity. Introduction of selective phosphodiesterase enzyme 5 (PDE5) inhibitors offered patients and their physicians a new alternative for first-line treatment of ED.7,8
The introduction of sildenafil, the first of the PDE5 inhibitors, provided encouragement for men to acknowledge and seek treatment for ED. In the United States, diagnosis of ED has increased 250% since sildenafil became available.6
Currently, 3 PDE5 inhibitors are available in the United States? tadalafil, vardenafil, and sildenafil. Collectively, these agents have increased the options for treatment of ED. Equally important, development of PDE5 inhibitors has provided much needed knowledge about the physiology of penile erection.
Erectile Physiology and the Role of PDE5
Penile erection involves interaction between the peripheral and central nervous systems. The end result is smooth muscle relaxation and vasodilation in the corpus cavernosum.9,10 In the late 1980s, Saenz de Tejada et al reported that neural- and endothelium-dependent factors that induce relaxation in corporal smooth muscle were impaired in men with diabetes and erectile dysfunction. 11 Subsequently, nitric oxide was shown to be the principal mediator of smooth muscle relaxation in the corpus cavernosum.12 Released in response to sexual stimulation, nitric oxide activates guanylate cyclase in smooth muscle cells, leading to increased production of cyclic guanosine monophosphate (cGMP), followed by activation of protein kinase G. The nitric oxide?driven process eventually results in decreased cytosolic calcium levels and relaxation of smooth muscle (Figures 1 and 2).13,14
Discovery and characterization of the nitric oxide?cGMP pathway led to identification of PDE5, which is the predominant isoenzyme that degrades cGMP in the corpus cavernosum.15 Elucidation of the functional role of PDE5 led to the hypothesis that inhibition of PDE5 would increase cGMP concentration in the corpus cavernosum and thereby enhance and prolong smooth-muscle relaxation and ultimately potentiate penile erection.10,16,17
Sildenafil citrate, the first of the selective PDE5 inhibitors, became available in the United States in 1998.18
The newest members of the PDE5 inhibitor class, vardenafil and tadalafil, received Food and Drug Administration approval in 2003.19,20 All 3 drugs have a similar mechanism of action and have demonstrated efficacy in a variety of populations and subpopulations of men with ED.
The discussion that follows provides an overview of clinical efficacy for the 3 PDE5 inhibitors that are currently available. The data come from a variety of placebo-controlled trials and provide a basis for assessing the efficacy of the individual drugs. However, caution should be exercised when comparing results obtained with different agents or when attempting to extrapolate results from one PDE5 inhibitor to another. Data from head-to-head comparative trials are lacking, and varying characteristics of the patient populations studied can affect treatment outcomes.
As the oldest of the members of the PDE5 inhibitor class, sildenafil has been studied most extensively. Two sequential, placebo-controlled trials were representative of the clinical investigation of sildenafil.21 Collectively, the trials involved a total of 831 men with ED of at least 6 months' duration. In a 24-week, dose-response study involving 532 men, patients were randomized to placebo or to sildenafil 25, 50, or 100 mg. Treatment with sildenafil demonstrated dose-dependent improvement in erectile function.
The second of the sequential trials was a 12-week, dose-escalation (on demand) study of sildenafil in 329 men. At the end of the study, 74% of patients who received sildenafil gave positive responses to the question: "Did this drug improve your erections?"(P < .001) compared with a 20% positive response rate among placebo-treated patients. During the final 4 weeks of the evaluation, significantly more sildenafil patients (65% vs 20% with placebo, P < .001) said their erections lasted long enough to permit successful intercourse (Figure 3).22
Erectile dysfunction is particularly common in men with diabetes.23,24 A placebo-controlled trial evaluated the effect of sildenafil on the proportion of diabetic men with ED who said the drug improved their erections. The study involved 268 men whose duration of ED averaged 5.8 years. After 12 weeks of treatment, 56% of the sildenafil group and 10% of the placebo group reported improvement in erectile function (P < .001). Treatment in both groups was on an as-needed basis and was taken 1 hour before anticipated sexual activity. The starting sildenafil dose was 50 mg, which could be adjusted up or down within the range of 25 to 100 mg.25
The postprostatectomy population poses another challenge to treatment of ED. One representative study involved 91 patients who presented for evaluation of ED after unilateral or bilateral nerve-sparing prostatectomy and were treated with sildenafil.26 During follow-up that ranged from less than 6 months to more than 12 months, the men were asked whether they could achieve erections that were satisfactory for intercourse. In the bilateral nerve-sparing group, 72% said they could achieve satisfactory erections, as did 50% of patients who had unilateral nerve-sparing prostatectomy.26
Ischemic heart disease
Vascular disorders are widely considered to be the most common organic cause of ED.27 Sildenafil efficacy in patients with ischemic heart disease (IHD) was evaluated in a subanalysis of 357 men enrolled in 11 randomized, placebo-controlled trials. All the men included in the subanalysis had stable IHD, and treatment for ED lasted between 4 and 24 weeks in the different trials.
End-of-treatment scores for various outcome parameters favored sildenafil over placebo. Sildenafil demonstrated statistically significant advantages for ability to achieve and maintain erection (P < .001), mean scores on all 5 domains of the International Index of Erectile Function (IIEF) (P < .05), and overall improvement in erections (P < .0001).28
A 12-week, placebo-controlled trial evaluated the effectiveness of 3 doses of vardenafil (5, 10, or 20 mg) in 580 men who had ED for an average of 2.8 years. The primary end points were change from baseline in ability to penetrate a partner (IIEFQ3) and the ability to maintain erection during intercourse (IIEF-Q4). Patients receiving any of the 3 doses of vardenafil had significantly more improvement in IIEF-Q4 scores compared with placebo (P < .001). Responses to all 5 IIEF domains (a secondary end point) also improved significantly at all vardenafil doses compared with placebo (P < .001). In general, efficacy was dose related, and the greatest improvement occurred in patients taking the 20-mg dose. Self-reported rates of successful sexual intercourse was 67% at the end of the trial. Analysis of the data stratified by age indicated that vardenafil improved erectile function to a similar degree in men younger than 45 years of age and those older than 65 (Figure 4).29
Vardenafil use by men with diabetes was evaluated in a 12-week, randomized, placebo-controlled multicenter phase 3 trial. The study involved 452 men who had type 1 or type 2 diabetes and took vardenafil 10 or 20 mg as needed. At the end of follow-up, men treated with 20 mg of vardenafil had a 72% response rate for improved erections, and the 10-mg dose was associated with a response rate of 57%, compared with 13% in the placebo group (P < .0001). Treatment with either dose of vardenafil significantly improved IIEF domain scores, rates of successful penetration, and erection maintenance compared with placebo (P < .0001).30
A randomized study involving 411 postprostatectomy patients compared vardenafil 10 or 20 mg with placebo for treatment of ED. The study population included men who had either bilateral or unilateral nerve-sparing radical prostatectomy. After 12 weeks of treatment, 59% of men who received 10-mg vardenafil and 65% of those treated with 20-mg vardenafil reported improved erections, as compared with 13% of placebo patients (P < .0001). Additionally, 37% of the vardenafil 10-mg group and 34% of the 20-mg group said they had erections sufficient for successful intercourse. Those rates were compared with a 10% rate of successful intercourse in the placebo group (P < .001).31
The newest entry into the PDE5 class of therapy for ED has been evaluated in a variety of populations and subgroups. The investigations have demonstrated efficacy across a spectrum of severity and comorbid conditions.32 An integrated analysis of 5 randomized, placebo-controlled trials involved a total of 1112 men treated for 12 weeks with tadalafil at doses ranging between 2.5 and 20 mg. The analysis had 3 coprimary outcomes: change from baseline in the erectile function domain of the IIEF and the proportion of positive responses to questions 2 and 3 of the Sexual Encounter Profile (SEP). Efficacy was also evaluated by means of the Global Assessment Questionnaire (GAQ).33
As compared with placebo, tadalafil significantly improved all outcome measures at all doses, and improvement tended to be dose dependent. Patients treated with 20-mg tadalafil improved by an average of 7.9 in the erectile function domain of the IIEF (P < .001 compared with placebo), and 75% of intercourse attempts were completed successfully (P < .001 compared with placebo) (Figure 5). GAQ results showed that 81% of patients treated with tadalafil 20 mg had improved erections at study conclusion, compared with 35% in the placebo group (P < .001). Tadalafil was effective across all severities and etiologies of ED and in patients of all ages.33
A multicenter, placebo-controlled trial assessed the efficacy of tadalafil in 216 men who were randomized to placebo or to tadalafil 10 or 20 mg and followed for 12 weeks. At the end of the study, 64% of patients treated with tadalafil 20 mg and 56% of those treated with the lower dose reported improved erections, compared with 25% of the placebo group (P < .001). IIEF erectile function domain scores improved significantly more with tadalafil than with placebo (P < .001), as did the proportion of positive responses to the SEP diary questions relating to ability to penetrate and to consummate intercourse (P < .001 for both).34
The 20-mg tadalafil dose tended to produce better results with respect to improvement in erectile function. More patients on the higher dose achieved >5-point improvement in IIEF domain scores, as compared with patients treated with 10-mg tadalafil. The 20-mg dose also produced a trend toward higher rates of successful penetration and intercourse, as compared with 10 mg.
Overall, tadalafil improved erectile function regardless of diabetes type, current diabetes therapy, baseline glycemic control, or presence of microvascular complications.
Tadalafil 20 mg was evaluated in a randomized, placebo-controlled trial involving 303 patients who had ED following prostatectomy. All the patients had undergone bilateral nerve-sparing surgery, and 201 had some residual function. After 12 weeks of treatment, 62% of the entire cohort said tadalafil had improved erections, compared with 23% of placebo-treated patients. Among the subgroup with residual function, 71% of the tadalafil group and 24% of the placebo group said their erections had improved during treatment (P < .001 for both comparisons). Assessment of successful intercourse attempts during the last 4 weeks of the study showed success rates of 41% and 52% with tadalafil, respectively, in all patients and those who had residual function. Corresponding rates in the placebo group were 19% and 26% (P < .001 for both comparisons).35
A recent summary of tadalafil clinical experience demonstrated efficacy in the treatment of ED function regardless of the severity of the disorder or the presence or severity of common comorbidities, including diabetes, hypertension, and cardiovascular disease.36
Clinical Practice Implications
In concert with appropriate sexual stimulation, selective PDE5 inhibitors enhance vasodilation and relaxation of penile vascular smooth muscle to promote penile erection. Each of the currently available agents has demonstrated efficacy in a variety of patient populations affected by ED. However, as previously stated, the relative efficacy of the agents remains unclear, as no head-to-head clinical trials have been conducted recently. The lack of data complicates any attempt to make distinctions among the drugs.
In the absence of comparative trials, each physician's decision as to which agent should be prescribed must rely on clinical practice experience related to efficacy, observed differences in tolerability and side effects, and patient preference. As clinical experience with PDE5 inhibitors increases, differences among the agents might be clarified and provide guidance to physicians and their patients about the management of ED.
The advent of selective PDE5 inhibitors has heralded the beginning of a revolutionary era in the treatment of ED.37 PDE5 inhibitors have demonstrated efficacy across a wide spectrum of patient populations affected by ED. The agents' ability to enhance erectile function and sexual performance has improved quality of life for millions of men worldwide. Whether clinically important efficacy differences exist among the available agents has yet to be determined. Continued clinical investigation of selective PDE5 inhibitors should bring greater definition to the role of these agents in the management of ED and might reveal important distinctions among the agents with respect to pharmacokinetics/pharmacodynamics, efficacy, and tolerability.
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37. Padma-Nathan H. Anew era in the treatment of erectile dysfunction. Am J Cardiol. 1999;84(suppl):18N-23N.