Erectile dysfunction (ED) is a complex condition involving psychosocial and biological factors. It is defined as the persistent inability to achieve or maintain penile erection sufficient for satisfactory sexual performance. ED is a common disorder of male sexual function, affecting all age groups with a considerable impact on quality of life.
Oral phosphodiesterase type 5 (PDE–5) inhibitors are the first-line treatment options offered to patients with ED. This systematic review of the recent evidence on clinical benefits and harms associated with different pharmaceutical treatments used in the management of male ED is to clarify uncertainties in the field, as well as to identify existing knowledge gaps and directions for future research.
The University of Ottawa Evidence-based Practice Center (UO–EPC) reviewed and synthesized the published literature on the pharmaceutical treatment of male ED. This review addressed the following key questions (KQ): KQ 1: What is the clinical utility of routine blood tests—testosterone, prolactin, luteinizing hormone (LH), follicle stimulating hormone (FSH)—in identifying and affecting therapeutic outcomes for treatable causes of ED? KQ 2: What are the benefits of pharmaceutical treatments for patients with ED? How do patient-specific characteristics (e.g. specific symptoms, age, comorbid conditions) affect prognosis and treatment success for ED patients? Does likelihood of treatment success vary by underlying cause of ED? KQ 3: What are the harms of pharmaceutical treatments for ED? What is the evidence on specific harms such as nonarteritic ischemic optic neuropathy (NAION) and penile fibrosis of pharmaceutical treatments for ED?
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Results
KQ 1: What is the clinical utility of routine blood tests (testosterone, prolactin, LH, FSH) in identifying and affecting therapeutic outcomes for treatable causes of ED? The prevalence of hypogonadism varied widely across the studies (12.5 to 25.32 percent). This variation reflected differences in diagnostic criteria for hypogonadism, testosterone measurement methods (e.g. serum total, bioavailable or free levels) and concurrent conditions present across the studies. The prevalence of hypogonadism was higher in men ≥ 50 years versus men < 50 years of age. The results of several studies indicated that ED patients with decreased libido, testicular damage/abnormality, arterial disease, obesity, hyperlipidemia, diabetes, or hypothalamic abnormalities were more likely to have hypogonadism than those presenting without these factors.
The prevalence of hyperprolactinemia varied from 1.42 to 14.3 percent. One Egyptian study in elderly and obese men reported a prevalence of 32 percent. In one of the 9 studies reporting abnormal levels of LH/FSH, about 44 percent of the hypogonadal men had low LH/FSH levels (<13 IU/mL). The prevalence of high LH/FSH levels across three studies varied from 1.03 to 5.79 percent.
KQ 2: What are the benefits of pharmaceutical treatments for patients with ED? How do patient-specific characteristics (e.g. specific symptoms, comorbid conditions) affect prognosis/treatment success for ED patients? Does likelihood of treatment success vary by underlying cause of ED?
In total, 126 RCTs evaluating clinical benefits and harms of oral PDE–5 inhibitors (i.e., sildenafil, tadalafil, and vardenafil) in ED patients were included in the review. Patients receiving PDE–5 inhibitors (regardless of dose/dosing regimen) experienced statistically significant and clinically relevant improvements in erectile functioning (mean total IIEF–"EF domain" and IIEF–Q3/Q4 scores, mean SEP–Q2/Q3 scores, improved erection measured by GAQ–Q1) and satisfaction (mean total IIEF-"Intercourse Satisfaction" and "Overall Satisfaction" domains, Erectile Dysfunction Index of Treatment Satisfaction scores) compared with those receiving placebo. The meta-analyses indicated that the use of sildenafil was associated with statistically significant improvements in penile penetration (IIEF-Q3 mean difference: 1.46, 95 percent CI: 1.26–1.65) and improved erection (RR = 2.61, 95 percent CI: 2.34–2.91) compared with placebo. The clinical benefit associated with the use of PDE–5 inhibitors relative to placebo was also observed in clinically distinct subgroups of patients (e.g. diabetes, depression, prostate cancer).
Patients with mild or moderate ED at baseline (IIEF score 11–25) achieved higher mean IIEF–"EF domain" or IIEF–Q3/Q4 scores compared with those with severe ED. The mean scores for IIEF and SEP, improvement in erection, and mean duration of penile rigidity (>60 percent) tended to increase with higher doses of sildenafil (25 mg versus 50 mg versus 100 mg) and vardenafil (5 mg versus 10 mg versus 20 mg).
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Results from four head-to-head trials comparing sildenafil, vardenafil, and tadalafil for improvements in erectile function were inconclusive. The between-arm differences in the mean IIEF-EF scores were either statistically non-significant or significant but of small magnitude. In all 4 trials, higher proportion of patients preferred tadalafil to sildenafil or vardenafil. The mean time (in hours) between dosing and sexual attempt was longer for tadalafil compared with sildenafil (5.6 versus 2.7, p < 0.001) and a greater proportion of tadalafil-treated men had one or more successful intercourse attempt 12 or more hours post-dose versus sildenafil-treated men (55 versus 29 percent, p < 0.001).
The administration of intracavernosal injections (ICI) of alprostadil improved erections more often than no treatment, placebo, papaverine, or phentolamine alone, and at least as often as trimix (prostaglandin E1 plus papaverine plus phentolamine). In three trials, the use of intraurethral suppositories containing alprostadil was shown to be more effective than placebo.
There were 18 RCTs evaluating the efficacy of hormonal treatment with testosterone (in oral, injection, gel, patch, and cream forms) predominantly in hypogonadal patients with or without
ED as a main complaint. In only one of four small trials, the intramuscular injection of testosterone improved erectile function compared with placebo. Gel testosterone (50 mg and 100 mg doses) was found to have increased sexual intercourse frequency compared with placebo or patch testosterone.
Two RCTs compared testosterone treatment (alone or combined) with PDE–5 inhibitors in hypogonadal patients with ED that was refractory to prior sildenafil therapy (this was also relevant to Question 1). In both trials, patients treated with the combination of testosterone (either patch 5 mg/d or gel 1 percent) and 100 mg sildenafil had statistically significantly greater IIEF scores compared with those treated with sildenafil alone (endpoint: 21.8 versus 14.4, p<0.05 and mean change: 4.4 versus 2.1, p = 0.029).
KQ 3. What are the harms of pharmaceutical treatments for patients with ED? What is the evidence on specific harms such as nonarteritic ischemic optic neuropathy (NAION) and penile fibrosis related to pharmaceutical treatments in patients with ED?
All-cause adverse events were more frequent in patients treated with PDE–5 inhibitors compared with those treated with placebo. In particular, meta-analyses demonstrated that patients receiving sildenafil (any dose) were at higher risk of any adverse (RR = 1.51, 95 percent
CI: 1.32–1.72). The 12-week use of 20 mg tadalafil was also associated with an increased risk of any adverse events (RR = 1.61, 95 percent CI: 1.37–1.89). The most common adverse events in PDE–5 inhibitor-treated patients were headache, flushing, dyspepsia, and rhinitis. The use of both sildenafil and vardenafil was associated with an increased risk of headache, dyspepsia, or flushing compared with placebo. Patients treated with sildenafil had an increased risk of visual disturbances (RR = 3.66, 95 percent CI: 2.27–5.92).
Serious adverse events were not statistically different between PDE–5 inhibitor and placebo groups. For example, patients treated with vardenafil experienced a statistically non-significant 34 percent increase in risk of serious adverse events (RR = 1.34, 95 percent CI: 0.76–2.36). Although the rate of withdrawals due to adverse events was slightly increased in patients receiving vardenafil versus those on placebo, the pooled RR estimate did not reach the level of statistical significance (RR = 1.29, 95 percent CI: 0.78–2.13).
The incidence of adverse events increased with the dose of PDE–5 inhibitors. Meta-analyses demonstrated a statistically significant increase in the risk of any adverse events between patients receiving 20 mg versus 10 mg of either tadalafil (RR = 1.21, 95 percent CI: 1.05–1.38) or vardenafil (RR = 1.15, 95 percent CI: 1.06–1.25). The pooled RR estimates for specific events in sildenafil treated patients were: flushing (50 mg versus 25 mg; RR = 1.65, 95 percent CI: 1.132.42), headache (100 mg versus 50 mg; RR = 1.31, 95 percent CI: 0.93-1.84), and visual disturbances (100 mg versus 50 mg; RR = 4.18, 95 percent CI: 0.44-39.54). The differences in the incidence of any adverse events between treatment and placebo groups did not vary significantly among four head-to-head trials with patients treated with sildenafil, tadalafil, or vardenafil.
Penile pain or priapism was more frequent in patients treated with alprostadil injections compared with those who received placebo. Patients who received a testosterone patch had a higher rate of skin reactions at the application site compared with those who received the placebo. One trial reported prostate cancer in two patients treated with a testosterone patch. The use of gel testosterone did not show a dose-related increase in adverse events.
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To ascertain the incidence of NAION in subjects using PDE-5 inhibitors, this review identified 19 case reports and one large retrospective cohort study of U.S. veterans aged 50 years or older. In almost all case reports, the minimum dose of sildenafil was 50 mg. The risk of NAION in veterans prescribed PDE-5 inhibitors for 2 years was not increased compared with those who were not prescribed PDE-5 inhibitors (RR = 1.02, 95 percent CI: 0.92–1.12). The long-term data on fibrosis amongst penile injection users (e.g. PGE1, papaverine, and/or phentolamine) was obtained from 13 reports of non-randomized controlled trials and 7 retrospective cohort studies. In these studies, the proportion of patients with fibrosis amongst those receiving PGE1 injections for at least one year, ranged from 4.4 to 23.3 percent. Clinical diversity (i.e., populations, intervention dose/duration/frequency, injection type, duration of followup), scarce data, confounding, and lack of appropriate comparator precluded a meaningful between-group comparison of the incidence of fibrosis.
Conclusions
The evidence comparing cause-specific therapies with symptomatic treatments (e.g. PDE–5 inhibitors, injections, and hormonal treatments) for management of ED is lacking. Due to the complexity of causative and comorbid factors, more studies are needed to clarify the best treatment management options for various subgroups of patients with ED (e.g. endocrinopathies,
concurrent clinical conditions). There is also a need for trials comparing PDE–5 inhibitors with other treatments for ED (e.g. oral, injected and topical). Long-term effects of ED treatments in RCTs have not been adequately explored. To clarify and determine the clinical utility of routine hormonal blood tests in ED patients, studies are needed in representative populations, with comparable diagnostic criteria and types of tests for hormonal disorders. source: http://www.ahrq.gov/sites/default/files/wysiwyg/research/findings/evidence-based-reports/erecdys-evidence-report.pdf
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