In the 7 years since sildenafil citrate (VIAGRA) was introduced as the first oral phosphodiesterase type 5 inhibitor therapy for erectile dysfunction, it has been used to treat nearly 27 million men with erectile dysfunction worldwide. Patient populations with erectile dysfunction of varying etiologies and with diverse comorbidities have benefited from sildenafil treatment. This update focuses on relatively recent research that further defines the response and effectiveness profiles of sildenafil and provides additional insight into optimizing treatment. In addition to providing recent data on sildenafil efficacy and safety/tolerability, the update provides data on assessments of erection hardness, measures of psychosocial outcomes (e.g., emotional well-being and treatment satisfaction), and treatment approaches to maximize response and effectiveness (e.g., by titrating to the maximum tolerated dose). Increased understanding of the sildenafil response and effectiveness profiles and optimal sildenafil treatment are central to the appropriate management of erectile dysfunction using sildenafil.
Erectile dysfunction (ED) is estimated to affect more than 150 million men globally, with this number expected to double by 2025.1 Sildenafil citrate (VIAGRA) was approved by the US Food and Drug Administration on 27 March 1998, as the first oral phosphodiesterase type 5 inhibitor to be used for the treatment for ED. In the 7 years following its approval, more than 700 000 physicians have written more than 150 million prescriptions for sildenafil for nearly 27 million men with ED, and sildenafil has been approved for marketing in more than 120 countries around the world.2
Initial clinical trials of sildenafil were conducted in the US,3 the UK4 and Europe, and were followed by trials performed in Central and South America,5, 6, 7 Africa,8, 9 Asia10, 11 and Australia.12 This initial database of double-blind trials and open-label trials conducted over a 10-year period (1993–2003) represents more than 13 000 patient-years of experience with sildenafil as a treatment for ED2 and established that sildenafil was generally well tolerated and efficacious in patients with ED of organic, psychogenic and mixed etiology3 and with various comorbidities.13, 14 Comprehensive reviews examining the efficacy and safety profile of sildenafil were published in 2002.13, 14
The focus of this update is on subsequent research that further defines the profile of sildenafil and provides additional insight into treating the patient with ED. It provides recent data on the response to sildenafil (e.g., its efficacy and safety/tolerability profile). In addition, the update provides data on assessments of erection hardness and measures of psychosocial outcomes (i.e., emotional well-being and treatment satisfaction). Psychosocial outcomes are important to the overall quality of the sexual experience and, as such, are central to the effectiveness of ED treatment. A specific focus of the update is on optimizing treatment outcomes to maximize response and effectiveness.
Assessments of erection hardness
In numerous clinical trials in men with ED, it was shown that sildenafil treatment can improve erectile function, allowing successful intercourse.15 Recently, attention has turned to improved understanding of the onset, magnitude and sustainability of erection hardness and rigidity in men treated with sildenafil for ED. In several clinical trials of sildenafil, patient diaries included self-assessments of erection hardness graded at the time of erection on a scale from 1 to 4: grade 1=increase in size, but not hard; grade 2=hard, but not hard enough for penetration; grade 3=hard enough for penetration, but not completely hard; grade 4=completely hard and fully rigid. Other outcome measures ask patients to retrospectively self-assess erection hardness over the previous 4 weeks, such as question 2 of the International Index of Erectile Function (IIEF Q2, ‘Over the past 4 weeks, when you had erections with sexual stimulation, how often were your erections hard enough for penetration?’).16
Early double-blind trials in men with ED showed that significantly more men achieved grade 3 and grade 4 erections after administration of sildenafil compared with placebo.3, 17 For example, Goldstein et al.3 reported that, during the last 4 weeks of a 24-week double-blind treatment period, men who took sildenafil (n=316) for their ED had significantly (P<0.001) more grade 3 and grade 4 erections compared with men who took placebo for their ED (n=216), more than 80% who took sildenafil 50 or 100 mg achieved grade 3 or 4 erections, and grade 4 erections were achieved five to six times more frequently in those who took sildenafil 50 or 100 mg than in those who took placebo. Successful intercourse was achieved with 80% of the grade 3 erections and 94% of the grade 4 erections.3
To further define the physiologic response to sildenafil, the findings from this double-blind trial were recently expanded in a new analysis.2, 18 In men with ED in whom the modal (most commonly experienced) erection was grade 1 at baseline, 45% who took sildenafil 50 mg and 78% who took sildenafil 100 mg compared with only 12% who took placebo improved to a modal erection grade of 3 or 4 during the last 4 weeks of treatment, and 35% who took sildenafil 50 or 100 mg compared with none who took placebo improved to a modal erection grade of 4 during the last 4 weeks of treatment.2 In a parallel analysis that assessed the best erection hardness rather than the modal erection hardness, improvement from grade 1 at baseline to grade 3 or 4 during the last 4 weeks of treatment was achieved by 47% who took sildenafil 50 mg and 67% who took sildenafil 100 mg compared with only 12% who took placebo, and improvement to grade 4 erections was achieved by 29, 40 and 4%, respectively.2 It is noteworthy that improvement was seen even in those men with ED whose best erection hardness at baseline was already grade 3 (hard enough for penetration but not completely hard), and in whom the best erection hardness during the last 4 weeks of treatment improved to grade 4 in 76% of those who took sildenafil 100 mg compared with only 17% of those who took placebo.2 Thus, improvement to completely hard and fully rigid erections was achieved by a substantial proportion of men with ED who took sildenafil 100 mg, including 40% of those whose best baseline erections were not hard (grade 1) and 76% of those whose best baseline erections were hard enough for penetration but not completely hard (grade 3). The percentage of men taking sildenafil 25, 50 or 100 mg, or placebo who reported grade 4 erections during the last 4 weeks of treatment correlated positively with the percentage of successful intercourse attempts during the last 4 weeks of treatment (r=0.45, 0.53, 0.55 and 0.29, respectively; P<0.001), as did the percentage who reported grade 3 or 4 erections during the last 4 weeks of treatment (r=0.76, 0.75, 0.66 and 0.65, respectively; P<0.0001).18
The physiologic response to sildenafil can be rapid in onset and sustained. Among 228 men who had responded to sildenafil treatment for their ED previously, significantly more who were randomized to sildenafil 100 mg than to placebo achieved an erection within 14 min of dosing that led to successful intercourse (35 vs 22%; P<0.05); the majority of sildenafil-recipients (51%) responded within 20 min.19 In a double-blind, placebo-controlled, 4-way crossover trial in 17 men with ED, in which visual sexual stimulation was provided 1 h after dosing, grade 3 or 4 erections lasted nearly five times longer after administration of sildenafil 100 mg compared with placebo (33 vs 7 min, P<0.05).20
A pooled analysis of 26 double-blind, placebo-controlled sildenafil trials conducted from 1996 to 2003, which included data from 3251 men with ED randomized to sildenafil and 2875 randomized to placebo, demonstrated significant (P<0.0001) improvements from baseline to the end of treatment in scores for the frequency of erections hard enough for penetration (IIEF Q2), the frequency of satisfactory sexual intercourse (IIEF Q7), the degree of enjoyment of sexual intercourse (IIEF Q8), and satisfaction with overall sex life (IIEF Q13) and sexual relationship (IIEF Q14).21 Moreover, the improvement in frequency of erections hard enough for penetration (IIEF Q2) correlated positively and significantly (P<0.0001) with the improvements in these IIIEF measures of sexual satisfaction and enjoyment (range of r=0.51–0.68).2
Diverse patient populations
Sildenafil has shown efficacy in clinical trials of men with ED, regardless of age, race, and body mass index; or ED severity, duration, and etiology; and in those with various comorbidities, including diabetes, ischemic heart disease, peripheral vascular disease, hypertension, depression, renal disease and post-radical prostatectomy.13, 14 In recent years, the efficacy of sildenafil for the treatment of ED has been further demonstrated in a number of trials of men with ED and common comorbid conditions. A double-blind trial conducted in men with ED and type 1 diabetes,12 and another in men with ED and type 2 diabetes,22 reported similar improvements in erectile function with sildenafil, even though those with type 1 diabetes tended to have a longer diabetes duration and developed ED at a younger age. The role of sildenafil in the treatment of ED in men with cardiovascular disease was further supported by its demonstrated efficacy in placebo-controlled trials of men with ED and coronary artery disease,23, 24 hypertension (and taking two or more antihypertensives),25 or congestive heart failure,26 and by its demonstrated effectiveness in an open-label, observational, epidemiological study of men with ED and hypertension.27 Earlier findings of sildenafil efficacy in trials of men with ED and depressive symptoms28 have been confirmed by two new double-blind, placebo-controlled trials: one of men with major depression in remission and antidepressant-associated ED29 and one of men whose ED was diagnosed when major depression was diagnosed but remained after depression was treated to remission.30 Depression remained in remission during sildenafil treatment.29
Several recent trials have assessed the response of men with renal disease to treatment with sildenafil for ED. More than 70% of men with ED and renal failure requiring dialysis reported improved erectile function in a single-dose trial of sildenafil 50 mg (75%, 38/51)31 and in a 4-week, open-label trial of sildenafil 25 mg increased to 50 mg if needed (71%, 20/30 on hemodialysis and 9/11 on peritoneal dialysis).32 This favorable response was confirmed in a double-blind, placebo-controlled trial of men with ED and chronic renal failure requiring hemodialysis, in which scores for the Erectile Function domain of the IIEF increased significantly after 1 month of sildenafil use in 17 of 20 (85%) who took sildenafil 50 mg compared with two of 21 (10%) who took placebo.33 Response to sildenafil treatment has also been reported in three open-label trials of men with ED that persisted after receipt of a renal transplant or that developed post-transplant, including statistically significant improvement in mean scores on the IIEF domains of Erectile Function, Sexual Desire, Intercourse Satisfaction, and Overall Satisfaction, but not Orgasmic Function, in 20 men with ED who used sildenafil 50 mg as needed for 4 weeks;34 on the abbreviated 5-question IIEF (IIEF-5) in 28 men with ED who received 4 weekly administrations of sildenafil 50 mg35; and on IIEF Q3 (ability to penetrate) and IIEF Q4 (ability to maintain erection after penetration) in 50 men with ED who used flexible-dose sildenafil (25, 50 and 100 mg based on efficacy and tolerability) for 3 months.36 Sildenafil coadministration in men who had received a renal transplant did not negatively affect mean concentrations of cyclosporine34, 36 or tacrolimus.36, 37
Sildenafil also previously showed efficacy in trials of men who developed ED after treatment for prostate cancer,13 with two open-label trials showing a better postprostatectomy response to sildenafil treatment (higher IIEF question scores and greater treatment satisfaction,38 and erection adequate for intercourse in at least half of attempts39) in men who developed ED after nerve-sparing surgery, particularly bilateral nerve-sparing surgery, compared with nonnerve-sparing surgery. A 3-year follow-up to 1 of these trials showed that this association was preserved during long-term sildenafil therapy (50 or 100 mg), with the highest mean IIEF-5 scores at follow-up in those who had undergone bilateral nerve-sparing surgery (19.97±1.12) compared with unilateral nerve-sparing (15.89±3.38) or nonnerve-sparing surgery (10.06±2.0).40 Overall 31 of 43 (72%) men with ED who responded to sildenafil at 1 year and participated in the 3-year follow-up survey were continuing to use sildenafil. The discontinuations were attributed to return of natural erections sufficient for vaginal intercourse (n=6), lack of efficacy (n=5), and the spouse's death (n=1).
In addition to these trials, which assessed the response of men with postprostatectomy ED to sildenafil administered as needed in anticipation of sexual intercourse, a randomized, double-blind, placebo-controlled trial assessed sildenafil 50 or 100 mg administered nightly for 36 weeks to prevent long-term ED following bilateral nerve-sparing prostatectomy.41 Fourteen of 51 men (27%) who completed sildenafil treatment were classified as responders (defined as return of normal, spontaneous (drug-free) erectile function) compared with 1 of 25 men (4%) in the placebo group (P=0.02). Sildenafil was generally well tolerated in this regimen.
The efficacy of sildenafil has also recently been demonstrated in open-label trials of men who developed ED subsequent to brachytherapy for prostate cancer. At a median of 41 (range 19–75) months post-brachytherapy, 53 of 62 (85%) men using sildenafil for brachytherapy-induced ED reported a positive response.42 Among 43 other men with brachytherapy-induced ED, 32 (74%) who used sildenafil for a median of 50 (range 36–66) months reported a positive response.43
In previously reviewed open-label trials of men with ED induced by external beam radiotherapy of their prostate cancer,13 37 of 50 (74%) who initiated sildenafil a median of 19 (range 6–75) months after radiotherapy reported improved firmness of erections,44 and 15 of 21 (71%) who initiated sildenafil a mean of 24.6±5.8 months after radiotherapy reported the ability to achieve firm erections.45 This favorable response to sildenafil was confirmed in a double-blind, crossover trial of 60 men with prolonged (⩾6 months) radiotherapy-induced ED.46 In this trial, sildenafil (50 mg increasing to 100 mg if necessary) for 4 weeks resulted in improved mean scores on IIEF questions compared with placebo, a higher percentage of patients reporting improved erections (45 vs 8%), and a higher rate of successful sexual intercourse (55 vs 18%).46 The 46 men with improved IIEF scores chose to proceed to 6 weeks of open-label follow-up, during which the efficacy demonstrated during double-blind treatment was maintained; 61% (n=28) reported improved erections. After 2 years, recontact was successful with 50 of the original double-blind participants.46 Twelve were continuing sildenafil treatment and 38 discontinued, including 23 who reported sildenafil was ineffective.
Safety and tolerability
Clinical trials have established that sildenafil is a generally well-tolerated treatment for ED. In the most recent combined analysis, which included 37 sildenafil flexible-dose, double-blind, placebo-controlled trials, the most common adverse events reported in men treated with sildenafil (n=4405) compared with placebo (n=3945) for ED were headache (13.5 vs 4.8%), facial flushing (vasodilatation) (11.3 vs 1.5%), dyspepsia (4.7 vs 1.3%), respiratory tract infection (4.4 vs 5.0%), rhinitis (3.4 vs 1.1%), dizziness (3.0 vs 1.5%), and abnormal vision (2.7 vs 0.7%).2 In general, adverse events have been transient and mild to moderate in severity. Interestingly, although the number of men treated with sildenafil for ED in clinical trials has increased several-fold, the rate and profile of adverse events has remained quite consistent with that originally reported from the six double-blind, flexible-dose (25, 50 and 100 mg) trials that supported marketing approval, in which the most common events in sildenafil-treated (n=734) compared with placebo-treated (n=725) men with ED were headache (16 vs 4%), flushing (10 vs 1%), dyspepsia (7 vs 2%), nasal congestion (4 vs 2%), urinary tract infection (3 vs 2%), abnormal vision (3 vs 0%), diarrhea (3 vs 1%), dizziness (2 vs 1%) and rash (2 vs 1%).47
The duration of adverse events in men with ED treated with sildenafil (n=2362) compared with placebo (n=1986) was assessed in a combined analysis of 17 randomized, double-blind, placebo-controlled, flexible-dose (25, 50 and 100 mg) trials of up to 16 weeks’ duration.15 During the first 4–6 weeks of treatment, the rate of adverse events was higher among men treated with sildenafil for ED than that among men treated with placebo for ED. However, at 8 weeks of treatment and thereafter, there were no differences in the rate of adverse events between sildenafil- and placebo-treated men with ED, suggesting that the occurrence of adverse events with sildenafil treatment tended to decline over time.
Analysis of data pooled from more than 120 sildenafil clinical trials showed that sildenafil use by men with ED was not associated with increase in the risk of myocardial infarction or cardiovascular death within the first 6 or 24 h after intercourse48 or overall.49 The overall incidence of myocardial infarction was 0.84/100 person-years for placebo treatment (n=5753) compared with 0.80/100 person-years for sildenafil treatment (n=7462) among men with ED participating in double-blind trials (P=0.88), and was 0.53/100 person-years among men treated with sildenafil for ED in open-label trials.49 The incidence of death attributed to a cardiovascular cause was 0.19/100 person-years for placebo-treated and 0.23/100 person-years for sildenafil-treated men with ED in double-blind trials (P=0.86), and was 0.16/100 person-years for sildenafil-treated men with ED in open-label trials. Compared with those who received placebo, the estimated relative risk of myocardial infarction or cardiovascular death was determined to be 1.08 (95% confidence interval (CI), 0.45–2.77) for men treated with sildenafil for ED.
The efficacy and tolerability of sildenafil in 150 men with ED and stable coronary artery disease24 was recently assessed in a double-blind, placebo-controlled, flexible-dose (25, 50 and 100 mg) trial. Sildenafil significantly improved erectile function and was generally well tolerated, with a low incidence of cardiovascular adverse events (e.g., hypertension, hypotension, chest pain and flushing). In a double-blind, placebo-controlled single-dose trial of men with ED and chronic stable angina limited by exercise, sildenafil 100 mg did not adversely affect any exercise parameter, including times to onset of angina and limiting angina, and total exercise duration, compared with placebo.50
Sildenafil was also shown to be efficacious and generally well tolerated in a double-blind, placebo-controlled trial of 559 men with ED taking 2 (n=324) or 3 or more (n=235) classes of antihypertensive medications.25 Compared with placebo-treated men with ED, mean scores on IIEF questions 3 (ability to attain an erection) and 4 (ability to maintain an erection) improved significantly in sildenafil-treated men with ED (P<0.0003). Although reports of headache and facial flushing occurred more frequently with sildenafil, <1% of men experienced serious adverse events and none of these events were considered treatment-related. Four men with ED in each treatment group discontinued because of adverse events, including three whose adverse events (mild headaches, moderate blurred vision, chromatopsia) were attributed to sildenafil treatment. The frequency and type of adverse events did not differ between men with ED taking 2 classes of antihypertensives and those taking three or more classes of antihypertensives.
Sildenafil was also shown to be efficacious and generally well tolerated in a trial of 35 men who had ED and New York Heart Association class II or III congestive heart failure, but who did not have active ischemia and were not taking nitrates.26 All 35 enrollees successfully completed the initial single-dose (sildenafil 50 mg) safety study – none reported any adverse effect and 4 h of monitoring showed no significant decrease in mean heart rate or blood pressure, and no decrease of more than 10% from baseline in mean arterial pressure – after which they were randomized to double-blind sildenafil 50 mg or placebo for 6 weeks, followed by crossover. Erectile function improved only during sildenafil administration, regardless of the treatment order (P<0.001) and with no difference between the groups (sildenafil first vs placebo first; P=0.98), and returned to baseline in the group that crossed over to placebo in the second period. During the placebo period, two men developed asymptomatic atrial fibrillation and a third developed worsening symptoms of congestive heart failure, but there were no significant hemodynamic effects during the trial, no hospitalizations within 30 days of trial completion, no deaths within 3 months of trial completion, and no reports of blurred or altered vision, flushing, headaches, or nausea.
In combination, these results demonstrate that sildenafil did not precipitate further cardiovascular events and was generally well tolerated in men with ED and cardiovascular disease. Similar results were reported in patients treated with sildenafil citrate (Revatio) 20, 40 or 80 mg for pulmonary hypertension in a large (n=278) randomized, double-blind, placebo-controlled trial, in which exercise tolerance (P<0.001) and the World Health Organization functional class (P<0.01) improved and the mean pulmonary-artery pressure decreased (P<0.05).51 There were only two serious treatment-related adverse events: left ventricular dysfunction in a patient receiving sildenafil 20 mg and postural hypotension in a patient receiving an initial dose of sildenafil 40 mg.
Before treating ED, physicians should consider the impact of resuming sexual activity and the impact of the mild and transient vasodilatory effects of sildenafil on blood pressure. Physicians should carefully consider whether men with ED and underlying cardiovascular disease or other more unusual conditions could be adversely affected by vasodilatory effects, especially in combination with sexual activity. Several sets of guidelines have been created based on expert consensus to provide a basis for decision-making for clinicians who are treating patients with ED and concomitant cardiovascular conditions.52, 53, 54, 55, 56
Nonarteritic anterior ischemic optic neuropathy
Nonarteritic anterior ischemic optic neuropathy (NAION) produces a sudden unilateral decrease in vision presumably due to a decrease in blood flow to the anterior portion of the optic nerve. Although the etiology of NAION is unknown, risk is believed to be increased in persons who have an anatomic variant of the optic nerve head often termed a ‘disc at risk.’ Many other NAION risk factors are similar to those for ED, including increased age, ischemic heart disease, hypertension, diabetes and smoking.57 The annual event rate of NAION has been estimated to be between 2.5 and 11.8 per 100 000 US men aged ⩾50 years.58, 59
There have been 17 published case reports of NAION among patients using sildenafil and three among patients using tadalafil (Cialis),57 prompting the US Food and Drug Administration and several other regulatory agencies to request that the prescribing information for all three marketed phosphodiesterase type 5 inhibitors be updated. These added label statements include information on NAION and its rare occurrence in association with phosphodiesterase type 5 inhibitor use, noting that it is not possible to determine whether these events are related directly to the use of phosphodiesterase type 5 inhibitors, to the patient's underlying vascular risk factors or anatomical defects, to a combination of these factors, or to other factors. Analyses of clinical trial and observational study data revealed no increased incidence of NAION in men treated with sildenafil for ED.57 The sildenafil ED clinical trial database (103 trials) included no cases of NAION in 13 400 men studied for more than 13 300 patient-years of observation. Additionally, the International Men's Health Study (IMHS), a prospective cohort study of 3813 men (mean age, 57 years; range, 18–100 years) receiving a sildenafil prescription in Germany, France, Spain or Sweden identified no cases of NAION during 2935 patient-years of follow-up. In the sildenafil Prescription Event Monitoring (PEM) postmarketing study, conducted by the Drug Safety Research Unit at the University of Southampton, a single case of NAION was identified during 35 500 patient-years of observation in more than 28 000 patients who received a UK National Health Service prescription for the drug. This represents an unadjusted incidence rate of NAION of 2.8 per 100 000 patient-years of sildenafil exposure. Thus, the incidence of NAION among carefully monitored patients receiving sildenafil was very similar to that reported to occur spontaneously in the general population of US men aged ⩾50 years.
Because sildenafil potentiates the hypotensive effects of organic nitrates,60, 61 concomitant use of sildenafil with nitrates or nitric oxide donors is contraindicated.62 Sildenafil 50 or 100 mg should not be taken within 4 h of taking an alpha blocker because coadministration may lead to symptomatic hypotension in some men with ED.62 Also, in the absence of information specific to mixed alpha/beta-blockers, such as carvedilol and labetalol, similar care should be taken as for alpha blockers.56
ED has been shown to be associated with depression, anxiety and loss of self-esteem.63, 64 The validated ED-specific Self-Esteem And Relationship (SEAR) questionnaire was developed to assess the benefits of therapies for ED on patient-reported outcomes of self-esteem, confidence, and sexual relationship satisfaction.65, 66 Two 12-week, placebo-controlled, flexible-dose (25, 50 and 100 mg) sildenafil trials assessed improvement from baseline to end point in erectile function using the IIEF and in self-esteem, confidence and relationship satisfaction using the SEAR questionnaire in a total of 512 men with ED.67, 68 In both trials, those randomized to sildenafil had significantly greater improvement in scores on all domains of the IIEF and on all components of the SEAR (Sexual Relationship domain, Confidence domain, the Self-Esteem and Overall Relationship subscales of the Confidence domain, and the overall score) compared with those randomized to placebo. Baseline to end point changes in IIEF Erectile Function domain scores showed positive correlations with baseline to end point changes in SEAR scores (P<0.0001), indicating that sildenafil enabled improvements in erectile function that were associated with improvement in measures of self-esteem, confidence and sexual relationship satisfaction.
Erectile dysfunction treatment satisfaction
The validated Erectile Dysfunction Inventory of Treatment Satisfaction (EDITS) was developed to assess patient satisfaction with medical treatments for ED.69 Double-blind, placebo-controlled, flexible-dose trials of sildenafil (25, 50, and 100 mg) showed that significantly more men treated with sildenafil compared with placebo for ED were satisfied with their ED treatment (defined as an EDITS Index score >50 out of 100), including 75% (93/124) compared with 30% (36/121) in the 12-week trial that initially used the EDITS (P<0.0001).70 In a pooled analysis of six trials of 6 or 12 weeks’ duration, treatment satisfaction rates were significantly higher with sildenafil compared with placebo regardless of patient age, with 70% (101/144) vs 28% (34/121) aged <65 years and 66% (45/68) versus 21% (16/77) aged ⩾65 years satisfied with their ED treatment (P⩽0.0001).71
An open-label, prospective trial of 2816 men with ED who received sildenafil for at least 10 weeks included an optional assessment of female partner treatment satisfaction using the 5-item partner EDITS at the final visit.72 Of the 677 female partners who completed the inventory, 92% reported that they were satisfied or very satisfied with sildenafil treatment for their partner's erection problem.
Optimizing sildenafil treatment to maximize effectiveness
Most men diagnosed with ED will continue to require treatment to achieve satisfactory erectile function. Several reports have described long-term effectiveness and treatment satisfaction with flexible-dose sildenafil (25, 50 and 100 mg). For example, in men who received sildenafil treatment for ED in a double-blind trial followed by 1 or more initial extension studies and then an open-label, 4-year extension study (for a total of up to 5.5 years’ treatment), results of the 4-year extension study showed that more than 94% of men at each yearly assessment were satisfied with the effect of sildenafil treatment on erections and had improved ability to engage in sexual activity.73 The discontinuation rate was only 6.3% (⩽2% per year) because of insufficient response and 1.2% because of adverse events. In a 52-week, prospective, observational study of 113 men initiating sildenafil therapy for a primary complaint of ED, 84 of the 92 (91%) who completed at least 12 weeks of treatment described sildenafil therapy as successful, and 59 of 74 (80%) who completed 52 weeks indicated that they would continue to use sildenafil.74 Retrospective assessment of effectiveness in 1290 men, 0.2–45 months after receiving a sildenafil prescription for ED at a multispecialty medical center, showed that 72% of those who took sildenafil were responders, defined as reporting successful intercourse.75 In this study, most (67%) who did not respond to sildenafil treatment did not try the maximum sildenafil dose (100 mg).75
Titrating to the maximum tolerated dose is among the management tips suggested by McCullough et al.76 to optimize sildenafil treatment effectiveness. Another is to try sildenafil on up to eight occasions when initiating therapy. Combined analysis of six double-blind, placebo-controlled trials showed that the cumulative probability of achieving successful sexual intercourse in the 654 men who took sildenafil for ED increased from 54% at the first occasion to 64% at the second occasion, and plateaued at 86%.76 Other management tips suggested by McCullough et al.76 include using sexual stimulation, avoiding excessive use of alcohol, and achieving proper timing for sildenafil administration. Sildenafil is typically taken 30–60 min before sexual activity, can be taken with or without food or alcohol, and (as discussed in the Efficacy section of this review) has a rapid onset of action in most men with ED – among those who had responded previously to sildenafil and were administered sildenafil 100 mg, an erection that led to successful intercourse was achieved within 14 min in some and within 20 min in the majority.19
When these guidelines were followed, 74% of 111 consecutive men with ED who visited a urology clinic and were enrolled in a goal-oriented disease management program reported successful intercourse with sildenafil 50 or 100 mg, and 54% of 76 previous sildenafil nonresponders identified by retrospective chart review became responders.76 The impact of reeducation and of titration to the maximum tolerated sildenafil dose is also supported by the results of Atiemo et al.,77 who reported a 42% (98/236) success rate in former sildenafil nonresponders, and by Jiann et al.,78 who reported a 59% (24/41) success rate in former sildenafil nonresponders. In these studies, incorrect administration (after heavy meals, lack of sexual stimulation, improper timing, too few attempts, and maximal dose <100 mg) was the most frequent cause for nonresponse to sildenafil. Further support for customized dose titration and instructions for use was provided by an open-label trial in which men with ED used sildenafil as needed for 4 weeks (phase 1) at a dose of 50 mg and according to the instructions in the sample pack, followed by use for 4 weeks (phase 2) after dose titration (to optimize efficacy and tolerability) and according to customized instructions (to facilitate success).79 Phase 1 was entered by 1109 men and phase 2 by 925, of whom 494 (53%) increased to 100 mg, 416 (45%) remained on 50 mg, and 15 (2%) decreased to 25 mg. For phases 1 vs 2, the mean number of attempts at sexual intercourse per week was 1.4 vs 1.7, 17 vs 18% of initial attempts were followed by a second attempt within 24 h of taking sildenafil, and 80 vs 91% of second attempts were successful. In both phases, nearly one quarter of second attempts occurred as long as 9–24 h after taking sildenafil, demonstrating a long therapeutic window.
As clinical experience with sildenafil continues to grow, so too does our understanding of its response and effectiveness profiles in the treatment of ED. A number of trials have increased understanding of the efficacy profile of sildenafil in men with ED and common comorbid conditions, including type 1 and type 2 diabetes, coronary heart disease, congestive heart failures, hypertension (including men taking multiple antihypertensive medications), depression (including antidepressant-associated ED), renal disease (including posttransplant), and following treatment for prostate cancer (i.e., radical prostatectomy, brachytherapy and external-beam radiotherapy). Continued monitoring of safety and completion of a number of studies in patients with cardiovascular disease provide reassuring evidence of the strong overall safety profile of sildenafil.
Compared with placebo, more men treated with sildenafil for ED more frequently achieved erections graded hard enough for penetration or completely hard and fully rigid; the physiologic response can be rapid and sustained. Whether their best baseline erections were graded not hard or were graded hard enough for penetration but not completely hard, improvement to erections graded completely hard and fully rigid was achieved by a substantial proportion of men who took sildenafil 100 mg for ED. Sildenafil enabled improvements in assessments of erection hardness (e.g., hardness grade and retrospective patient self-assessment of the frequency of erections hard enough for penetration (IIEF Q2)). The percentage of erections graded hard enough for penetration or completely hard and fully rigid was associated with the percentage of successful intercourse attempts, and improvement in the frequency of erections hard enough for penetration was associated with improvement in measures of sexual satisfaction (e.g., satisfaction and enjoyment of sexual intercourse, and satisfaction with sex life and sexual relationship). Also, sildenafil enabled improvements in erectile function that were associated with improvement in measures of emotional well-being (i.e., self-esteem, confidence, and relationship satisfaction). Psychosocial outcomes such as sexual satisfaction and emotional well-being are important to the overall quality of the sexual experience and, as such, are central to the effectiveness of ED treatment.
Optimal sildenafil treatment, such as titrating to the maximum tolerated dose, improved response and effectiveness rates. Increased understanding of the sildenafil response and effectiveness profiles, and optimal sildenafil treatment, are central to the appropriate management of ED using sildenafil.
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Padma-Nathan, H. Sildenafil citrate (Viagra) treatment for erectile dysfunction: an updated profile of response and effectiveness. Int J Impot Res 18, 423–431 (2006). https://doi.org/10.1038/sj.ijir.3901492
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