Do vardenafil and tadalafil have advantages over sildenafil in the treatment of erectile dysfunction?

Abstract

Erectile dysfunction (ED) affects up to 50% of men between the ages of 40 and 70 years of age. Sildenafil, vardenafil and tadalafil have all been shown to be similarly effective in the treatment of men with ED of vary etiologies, to have similar adverse effects profiles, and to improve quality-of-life by similar amounts. As these phosphodiesterase 5 (PDE5) inhibitors all increase the hypotensive effects of nitrates, they are not suitable for use in patients taking nitrates for the treatment of ischaemic heart disease. All three inhibitors must be used with caution in patients taking α1-adrenoceptors antagonists for benign prostatic hyperplasia. Although nonarteritic anterior ischaemic neuropathy has been reported in some users of the PDE5 inhibitors, there is no conclusive evidence that PDE5 inhibitors cause this rare effect. Tadalafil has a longer half-life than sildenafil or vardenafil, and a longer duration of action than sildenafil and vardenafil. Most preference studies have shown tadalafil to be preferred, but there are serious limitations to some of these studies. One approach to treatment is to give each patient a short- and long-acting agent, and for individuals to decide their preference.

Introduction

As many as 30 million men in the US have erectile dysfunction (ED),1 which is defined as the inability to attain or maintain an erection sufficient for satisfactory sexual performance. ED is estimated to affect up to 50% of men between the ages of 40 and 70 years of age, and age is the variable most strongly associated with ED.2, 3 After adjustment for age, a higher probability of ED correlated with heart disease, hypertension, diabetes and associated medications.2 ED is frequently associated with depression, increased anxiety, poor self-esteem and compromises interpersonal relationships.1 In diabetes mellitus, ED occurs at an earlier age and has a higher prevalence. In patients with localized prostrate cancer treated with radiotherapy, ED estimates range from 15 to 60%.4, 5 In end-stage renal disease patients on dialysis, the incidence of ED is about 75%.6 ED is a side effect commonly associated with use of the selective serotonin uptake inhibitors to treat depression.7 ED is also common among a range of other conditions (e.g. Parkinsonism, multiple sclerosis, spinal dysfunction).

To induce penile erection, relaxation of the smooth muscle cells of the corpus cavernosum and associated arterioles is required. A major component of this relaxation process is mediated by nitric oxide stimulation of cGMP. In response to sexual stimulation, the release of nitric oxide by nerve endings and endothelial cells increases the levels of cGMP to induce the erection. cGMP is readily hydrolyzed by phosphodiesterase 5 (PDE5) resulting in restoration of quiescent muscle tone and detumescence.

In the first part of this review, the pharmacology of the PDE5 inhibitors sildenafil, vardenafil and tadalafil are briefly considered. When sildenafil was introduced there was some controversy concerning its effects in men with cardiovascular problems. Consequently there is an emphasis on the safety of the PDE5 inhibitors in patients with cardiovascular disease, and also whether this is linked to non-arteritic anterior ischaemic optic neuropathy (NAION). The safety of the PDE5 inhibitors in men with benign prostatic hyperplasia is also considered. This is followed by a description of the clinical trials with sildenafil in ED. The next sections consider the clinical trials with vardenafil and tadalafil, and discuss the similarities and differences to sildenafil. The development of sildenafil for the treatment of pulmonary hypertension and Raynaud's disease are not discussed in this article.

Molecular pharmacology

Sildenafil, vardenafil and tadalafil are selective inhibitors of PDE5 with IC50 values of 3.9 nM,8 0.7 nM9 and 5 nM,10 respectively. For sildenafil, the IC50 values against PDE1-4 were 80–>8500 times greater than for PDE5 (3.5 nM), and ninefold greater than for PDE6.11 With vardenafil there is a 16-fold selectivity for PDE5 (0.7 nM) over PDE6 (11 nM), and 200–>1000 selectivity over PDE1, 3 and 4.12 For tadalafil, there is 1000 selectivity for PDE5 over PDE1-4, and PDE6.10 To my knowledge, sildenafil, vardenafil and tadalafil have not been reported to inhibit PDEs 7-10.

PDE11 is the latest isoform of the PDE family to be identified. PDE11 is highly expressed in the testis, prostate and spermatozoa, and may have a role in male reproduction.13 The PDE5A1/PDE11A4 selectivities for sildenafil, vardenafil and tadalafil are 1000-, 9300- and 40-fold, and this suggests that these PDE inhibitors are unlikely to inhibit PDE11A4 in patients with ED.14

In addition to half-lives, dissociation rates from binding sites are determinants of the duration of action of drugs with slow dissociation prolonging duration of action. The ability of the 3H-form of the PDE5 inhibitors to dissociate from the enzyme has been measured. Vardenafil dissociates at a slower rate than tadalafil or sildenafil.15

Pharmacokinetics

Sildenafil, vardenafil and tadalafil are rapidly absorbed after oral administration. The absolute bioavailability for sildenafil and vardenafil is about 40 and 15%, respectively, whereas the absolute bioavailability of tadalafil has not been reported to date. All three phosphodiesterase inhibitors have a rapid onset of action. In men who respond to sildenafil, within 20 min of sildenafil dosing, 51% had an erection that led to successful intercourse (placebo, 30%).16 In the home setting, within 25 min of dosing, 50/53% of men with ED taking vardenafil 10/20 mg had at least one erection in the first four doses perceived to be sufficient for penetration (placebo, 26%).17 Also, in the home setting, 51% of men taking tadalafil 20 mg had at least one successful intercourse attempt within 30 min (placebo, 35%).18

The maximum plasma concentration with sildenafil, vardenafil and tadalafil is obtained after 60 min with sildenafil and vardenafil, but later with tadalafil (2 h). The half-life of tadalafil is 17.5 h, compared to 3.8 h for sildenafil and 3.9 h for vardenafil.19 Consequently, tadalafil would be expected to have a longer duration of action than sildenafil and vardenafil. In accord with the half-life and directions given with tadalafil, many men do attempt intercourse in the 12–36 h window after administration.20 The chances of successful sexual intercourse were increased 24 and 36 h after the administration of tadalafil. In a group of 327 patients, 53% had successful intercourse at 24 h (placebo, 29%) and 59% at 36 h (placebo, 28%).21 Another study showed that tadalafil 10 mg was nearly as effective as tadalafil 20 mg after 24 and 36 h.22 The successful intercourse attempts at 24 h were 42, 56 and 67%, and at 36 h, 33, 56 and 62%, for placebo, tadalafil 10 and 20 mg, respectively.22

Sildenafil and vardenafil are also active for up to 8–12 h. Thus, in a small study with 36 evaluable patients with ED, 97 and 74% of patients achieved erections that resulted in successful intercourse with completion (maintenance of erection) at 1 and 12 h postdose, respectively.23 Vardenafil has also been shown to improve sexual activity 8 h postdose.24

Vardenafil undergoes substantial first pass liver metabolism. As all three PDE5 inhibitors are metabolized by cytochrome P450 3A4, non-selective inhibitors (cimetidine) or selective inhibitors of this enzyme (e.g. erythromycin, ketoconazole, ritonavir) increase plasma levels. In patients with moderate hepatic failure, the plasma levels of vardenafil may be elevated, and a lower starting dose is recommended. Healthy elderly subjects (65 years) have a reduced clearance of sildenafil and tadalafil and an increased area under the curve, probably due to decreased hepatic clearance.25 Sildenafil, vardenafil and tadalafil are excreted as metabolites mainly in the faeces.

A high-fat meal delays the onset of action for sildenafil and vardenafil,26 but not tadalafil.27 A sublingual preparation of sildenafil has been developed, and this will not be affected by food. An initial study with sublingual sildenafil (20 mg) has shown that the mean onset of action was 15.5 min and lasted for an average of 40 min with 13/20 of subjects with ED achieving erections.28 Sublingual sildenafil is not available by prescription, but non-propriety versions are available for purchase on the net.

Safety

The tolerability and side effects of PDE5 inhibitors in clinical trials of men with ED is considered in the clinical trials sections: sildenafil, vardenafil and tadalafil. The safety of the PDE5 inhibitors in patients with cardiac disease, and any possibly link to NAION is considered in this section, as is the safety in men with benign prostatic hyperplasia.

In patients with cardiac disease

Inhibiting PDE5 increases the levels of cGMP, and this will occur at all sites where PDE5 is actively hydrolyzing cGMP. Thus, it is possible that PDE5 inhibitors will potentiate the effect of endogenous vasodilators that cause vasodilation via cGMP (nitric oxide, acetylcholine). Sildenafil alone has modest effects on the cardiovascular system, although cerebral vasodilation probably underlies the adverse effect of headache. In healthy men, sildenafil transiently decreased systolic and diastolic blood pressure by under 10 mm Hg.29 In 14 men with coronary artery disease and severe stenosis of at least one vessel, sildenafil 100 mg produced only small decreases in systemic and pulmonary arterial pressures and had no effect on pulmonary-capillary wedge pressure, right atrial pressure, heart rate or cardiac output.30 Coronary flow reserve increased by 13% in the normal coronary arteries but was unaffected in the diseased arteries by sildenafil.30 These results suggest that sildenafil alone is safe to use in men with coronary artery disease.

There were some early indications that sildenafil might increase the incidence of myocardial infarction, ventricular tachycardia and death in ED patients with coronary artery disease, but it has been argued that these outcomes may just be the normal complications or progression of coronary artery disease. To test this, the cardiovascular effects of sildenafil during exercise were determined in men with known or probably coronary artery disease.31 Before the study, nitrates were discontinued.31 Although the 105 patients enrolled had stable angina, their heart function was quite good as the mean left ventricular ejection fraction was 56%.31 Compared to placebo, sildenafil had no additional effects on the symptoms, exercise duration, or presence or extent of exercise-induced ischaemia (dyspnea or angina).31 This confirms that sildenafil is safe to use in ED patients with stable coronary artery disease and not taking nitrates. Exercise-testing in 23 ED patients with heart failure (left ventricular ejection fraction of 23%), also showed that sildenafil did not have detrimental effects on the cardiovascular system.32 Large-scale safety evaluations have also confirmed that there is no increase in myocardial infarction or all-cause mortality rates in patients taking sildenafil.33

The nitrates are commonly used in the prevention and treatment of angina, and the actions of these drugs are terminated by cGMP hydrolysis in blood vessels. Thus, it seemed probably that sildenafil would increase the effects of the nitrates, and this is in fact the case. In healthy male volunteers treated with sildenafil, the ability of sublingual glyceryl nitrate to decrease blood pressure was increased, precipitating symptomatic hypotension.34 In volunteers with angina, isosorbide mononitrate and glyceryl trinitrate alone have little effect on blood pressure, but these effects were increased in the presence of sildenafil.35 One of the 15 patients had a major drop in blood pressure with the combination, and it was suggested that the nitrates and sildenafil should not be used in combination.35 Based on the pharmacokinetic profile of sildenafil, the manufacturer suggests that nitrates should not be taken until at least 24 h after dosing with sildenafil.

Sildenafil will not alter the effects of drugs that relax blood vessels by a mechanism not involving cGMP, but the effects may be additive. Thus, in hypertensive patients, the blood pressure lowering effects of the calcium channel blocker amlodipine and sildenafil were additive.36 Another study has shown that in 608 men with ED taking antihypertensive medication (diuretic, β-blockers, α-adrenoceptor antagonists, ACE inhibitors or calcium channel blockers), sildenafil had a similar ability to decrease blood pressure by a small extent (−3.6/−1.9 mm Hg) as in patients not taking antihypertensives.36 The incidence of adverse effects, including adverse effects related to decreases in blood pressure (hypotension, dizziness and syncope) was similar in sildenafil patients with or without concomitant antihypertensive treatment.37

As with sildenafil, exercise testing in men with stable coronary artery disease, showed that vardenafil at 10 mg did not impair the ability of 41 patients to exercise at levels equivalent or greater than attained during sexual intercourse.38 At baseline (1 h after taking vardenafil or placebo), systolic and diastolic blood pressure was 6 and 5 mm Hg less, respectively, with vardenafil than placebo, and heart rate was 3 beats/min higher.38 At peak exercise, vardenafil did not alter blood pressure or heart rate, relative to placebo.38 There are no peer-reviewed published studies of the interaction between vardenafil and the nitrates. The patient information sheet for vardenafil states that in 18 healthy subjects pretreated with vardenafil 20 mg, there was an additional reduction in blood pressure and increase in heart rate with nitroglycerin administration, and it is recommended that nitrates not be used until at least 24 h after vardenafil.39 In subjects with ED and hypertension, vardenafil did not alter the blood pressure of subjects taking antihypertensives.40

In healthy subjects, tadalafil caused very small changes in blood pressure that were not considered to be clinically relevant.38 Tadalafil reduced mean standing blood pressure by −4.6 mm Hg in patients with hypertension, but this unlikely to be of major concern.41 Tadalafil has no effect on the time to exercise treadmill test-induced myocardial ischaemia in patients with stable coronary artery disease.42 Tadalafil has a similar interaction as sildenafil with nitrates in patients with coronary artery disease that is it increases the blood pressure lowering normally observed with nitroglycerin and isosorbide mononitrate.41, 42 Tadalafil has a longer half-life and duration of action than sildenafil or vardenafil. Thus, the interaction of tadalafil with the nitrates lasts longer than with sildenafil and vardenafil. The lowering of blood pressure in response to nitroglycerin after tadalafil was greater than in the placebo group after 4, 8 and 24 h, but similar at 48 h.43 Thus, nitrates should not be administered until 48 h after tadalafil.43

Tadalafil is safe in patients receiving antihypertensives.42 Across the studies where tadalafil has been used for ED, there is no evidence for increased myocardial infarction or cardiac death with tadalafil.44

As none of these PDE5 inhibitors inhibit the HERG (Human Ether-a-go-go-Related Gene) potassium current at therapeutically relevant concentrations, they are unlikely to induce arrhythmias by interacting with the HERG channel.45 Consistent with this, sildenafil and tadalafil do not cause clinically significant prolongation of QTc (a measure of ventricular repolarization) in healthy volunteers. Vardenafil does cause a small increase in QTc in healthy men, and has a warning for patients at risk for QTc prolongation.46

Non-arteritic anterior ischaemic optic neuropathy

NAION is a sudden loss of eyesight because blood flow is blocked to the optic nerve. NAOIN is probably associated with vascular insufficiency at the optic nerve head, leading to ischaemia, and has an annual incidence of 2.3–10.2 per 100 000 persons over 50 years of age.47 Some patients have reported developing NAION after ingestion of sildenafil, and the details of five such cases were reported in 2002.48 Subsequently, in a set of seven patients who developed NAION with sildenafil, it was shown that all the affected individuals had pre-existing hypertension, diabetes, elevated cholesterol or hyperlipidemia.49

By July 2005, the FDA reported visual loss in 38 patients after use of sildenafil and one after vardenafil, and issued an alert for all the PDE5 inhbitors.50 The alert says that it is unknown whether sildenafil, vardenafil or tadalafil cause NAION, and that NAION also happens in men who do not take these medicine.50 They suggest that people have a higher chance of NAOIN if they have heart disease, are over 50 years old, have diabetes, have high blood pressure, have high cholesterol, smoke or have certain eye problems.50 The PDE5 inhibitors are not contraindicated in any of these conditions, but patients are advised to stop taking the inhibitors if they have eye sight loss.50

There is no clear evidence linking PDE inhibitor use to NAION. A retrospective matched case–control study of 38 cases of NAOIN were matched with 38 age-matched controls without a history of NAOIN, showed that males with NAION were no more likely to have a history of sildenafil or tadalafil use than the age-matched controls.51 The same study showed that men with a history of myocardial infarction of hypertension were at risk of NAION.51 Similarly, pooled safety data from global clinical trials and European observational studies, with 13 000 men and 35 000 patient years, showed an incidence of 2.8 cases of NAION per 10 000 patients-years of sildenafil exposures, which is similar to the incidence in the general population.52

In subjects with benign prostatic hyperplasia

Although not commonly used as antihypertensives any longer, the α1-adrenoceptors antagonists are used in the treatment of benign prostatic hyperplasia, and their use is often associated with a small decrease in blood pressure. As benign prostatic hyperplasia and ED can coexist, it is possible for subject to be prescribed both α1-adrenoceptors antagonists and sildenafil. Two of 20 patients receiving the α1-adrenoceptors antagonist doxazosin and sildenafil 50 mg developed symptomatic hypotension.53 As a result of this finding, it is now suggested that sildenafil should not be taken within a 4-h window of an α1-adrenoceptors antagonist. These include the α1-adrenoceptors antagonists (terazosin, alfuzosin and tamsulosin) for which the interaction with sildenafil has not been specifically studied.

Vardenafil should be used with extreme caution in patients taking α1-adrenoceptors antagonists, as it has been shown to cause a major reduction in blood pressure when administered with terazosin, an α1-adrenoceptors antagonist used in the treatment of benign prostatic hyperplasia.53 The selective α1a-adrenoceptors (prostatic) antagonist tamsulosin is generally considered to have a lesser effect on blood pressure that the non-selective agents. Nevertheless, standing hypotension has also been reported with the combination of tamsulosin and vardenafil, and thus the combination of α1-adrenoceptors antagonists and vardenafil are not recommended.53

Similarly, tadalafil and doxazosin are associated with hypotension, whereas tadalafil and tamsulosin are not, in healthy normotensive men.54 Recently, in 18 healthy, middle-aged men, tadalafil 20 mg showed no clinically relevant hemodynamic interactions with alfuzosin 10 mg daily, although one subject did have an asymptomatic standing pressure of <85 mm Hg.55 Patients are advised to use tadalafil and α1-adrenoceptors antagonists with caution. For those patients taking tadalafil, treatment with α1-adrenoceptors antagonists should start with the lowest dose. Similarly for patients using α1-adrenoceptors antagonists, treatment with tadalafil should start with the lowest dose.

Clinical trials with sildenafil

Trials combining men with ED of varying etiologies

In 1996, it was reported that in 12 patients with ED, sildenafil (Viagra) enhanced the erectile response (duration and rigidity of erection) to visual sexual stimulation.56 This first small controlled crossover trial of sildenafil in 12 men with ED showed that sildenafil increased the duration of rigidity, and the total number of erections.56

These initial observations were followed by major studies of 861 men with a clinical diagnosis of ED of 6 months duration or longer.57 Most of the men studied (70%) had organic ED, but 11% had psychogenic ED and 18% had mixed ED.57 Men taking nitrates were excluded from these studies.57 In the first study, 532 men received either placebo, or 25, 50 or 100 mg sildenafil approximately 1 h before planned sexual activity.57 Outcomes were questions three (frequency of penetration) and four (maintenance of erections after penetration) of the International Index of Erectile Function, completed at 0, 12 and 24 weeks.57 After 24 weeks, improved erections were reported by 56, 77 and 84% of men taking 25, 50 and 100 mg of sildenafil, respectively.57

In the other part of the study, the flexible dose-escalation study, 329 men received either placebo or 50 mg of sildenafil, 1 h before sexual activity for 12 weeks, and during following visits during this time, they doubled or reduced the dose on the basis of the therapeutic response.57 At the end of the 12 weeks, most men (74%) were taking 100 mg of sildenafil, and the scores for frequency and maintenance were higher for the last 4 weeks than earlier.57 After 12 weeks, 74% of men reported improved erections, compared to 19% in the control group.57 The most common side effects were transient headache, flushing, dyspepsia and rhinitis.56 Transient visual disturbances (i.e. changes in the perception of colour hue or brightness) were reported by some men.57 This initial flexible dose-escalation study was performed in the US, but similar studies with similar outcomes have been performed elsewhere (e.g. Malaysian, Singaporean and Filipino,58 European,59 Korean60) (Table 1).

Table 1 Outcome of clinical trials of sildenafil in patients with ED of varying etiologies

The effectiveness of sildenafil in patients with various etiologies was confirmed in another large fixed-dose study where the 514 men had ED that was organic in 32%, psychogenic in 25% and mixed in 43%.61 In a follow-up of 267 patients, there was a correlation between baseline sexual function and response to sildenafil, but even in patients with severe ED there is a 41% satisfaction rate.62 There are also lower rates of satisfaction with sildenafil in patients with neurogenic causes of ED (diabetes, prostate surgery) than psychogenic or vasculogenic ED.62 A 1-year extension study showed that in patients where sildenafil improved erectile function, it remained effective in most of the patients for the year.63

In the real clinical setting, sildenafil has been shown to be less effective in elderly men (mean age=64 years) with ED than reported in the large clinical trials.64 Thus, sildenafil was only efficacious in 47% (76/162) of men with ED, and of these 58% were using the 100 mg dose, and 41% the 50 mg dose.64 Uncontrolled diabetes, current smoking, hypogonadism and low pre-treatment erectile function were predictors of a poor response.64

When the safety of sildenafil was evaluated in 3700 patients, the most commonly reported adverse effects remained headache (16 and 4% placebo), flushing (10 and 1% placebo), and dyspepsia (7 and 2% placebo), which were all transient and mild or moderate in nature.65 These adverse effects did not lead to discontinuation as the discontinuation rates were similar in the sildenafil and placebo groups.65 Long-term, open-label studies have demonstrated that sildenafil continues to be well tolerated for >4 years with no increase in the incidence or severity of adverse effects.28 The higher doses of sildenafil can cause slight changes in colour vision (‘blue haze’) and increased sensitivity to light, probably by inhibiting PDE6, but these effects are transient, fully reversible, and rarely lead to treatment discontinuation.28

In a quality of partnership study of 105 patients and their female partners, the tenderness and togetherness subscales were improved in appropriately treated ED patients, compared to untreated controls.66 When sildenafil in ED was compared to age-matched healthy control subjects, it was suggested that sildenafil gave a near normalization of erectile function.67 On the International Index of Erectile Function, sildenafil has been shown to improve general mental healthy (well-being, self-control, satisfaction with relationship, health relative to 1 year ago, and mental health).68 The Self-Esteem And Relationship (SEAR) questionnaire is a validated psychometric test for men with ED. Compared to the placebo group, the group treated with sildenafil (n=128) had greater improvements in all SEAR components.69 Another study has shown that sildenafil is associated with the normalization of relationships, confidence and self-esteem in the SEAR questionnaire in men with ED.70

In patients who do not respond to sildenafil at 100 mg, increasing the dose increases the responders but also increases the adverse effects. Most of the non-responders in the trial showing this had vascular disease.71 Only 13 of 54 patients, who had previously not responded to sildenafil at 100 mg, had improved erectile function with 200 mg sildenafil, whereas 34 of the 54 reported adverse effects.71

Vardenafil has been shown to be effective in men with ED unresponsive to sildenafil (discussed in Clinical trials with vardenafil section), and it has been inferred that this shows that vardenafil had advantages over sildenafil. However, it may be that the sildenafil was just being used inappropriately. A recent study has shown that of 100 consecutive sildenafil non-responders, 56 had been using the drug inappropriately; 45 had never used the highest recommended dose (100 mg), 32 had taken the pill with a full stomach after a meal, 22 had taken the drug just before initiation of sexual activity and 12 were not aware that sexual stimulation was required to achieve an erection.72 Another study recruited (by newspaper advertisement) 220 subjects with ED who had failed sildenafil treatment, and found that the majority had received limited or no instruction on sildenafil use when it was prescribed.73 With counselling and dose adjustment to sildenafil 100 mg, if necessary, most subjects had an improvement in erectile function.73

Before the introduction of oral treatments for ED, intracavernous prostaglandin E1 (PGE1) was used in the treatment of ED. Of 176 patients, 69% successfully changed from PGE1 to oral sildenafil and elected to continue oral treatment.74 Men with ED who were switched from PGE1 to sildenafil were equally satisfied with the onset of action, duration of action and confidence in ability to engage in sexual activity.75 The men expressed greater overall treatment satisfaction with sildenafil, better ease of use, and naturalness of erectile process.75 Partners were overall more satisfied with sildenafil.75

The dopamine receptor agonist apomorphine is an alternative to PDE5 inhibitors for the treatment of ED. Most of the studies comparing apomorphine with placebo have shown lower rates of success in overcoming ED than generally reported with sildenafil.76 In a study comparing sublingual apomorphine 3 mg with oral sildenafil (50 mg) for ED, sildenafil was more effective than apomorphine in causing erection firm enough for intercourse (85 vs 44%).77 In a crossover study of sildenafil and apomorphine, the successful intercourse rates were 75 and 35%, respectively.78 Importantly, at the end of the study, 96% of the men expressed a preference for sildenafil.78 In a study of 370 subjects who did not respond to sildenafil, a double-blind trial of the long acting dopamine agonist cabergoline and placebo, showed only a moderate response to cabergoline (placebo, 7.1%; cabergoline, 31.2%).79

After the initial studies with sildenafil in ED in otherwise relatively healthy men or large groups of men with ED of varying etiologies, subsequent studies have been in men with specific health problems.

Diabetes and cardiovascular

A preliminary study showing that sildenafil improved penile rigidity and vaginal penetration in 21 men with diabetes and ED was published in 1998.80 Subsequently, a more substantial study was undertaken with 252 men with ED and diabetes (predominantly type II), using the same protocol as in the flexible dose-escalation study (see previously).81 At 12 weeks, most men (93%) in the sildenafil group were taking the 100 mg dose, and 61% reported a successful attempt at intercourse compared to 22% in the placebo group.81 Adverse effects were similar as in the non-diabetics and there was no excess of cardiovascular events.81 Sildenafil was similarly effective in a trial that included only patients with type I diabetes.82

Sildenafil is not effective in diabetic patients with severe ED, where injections of PGE1 and/or papaverine may be preferred. Thus, when 81 ED patients with diabetes (29 with type I, 52 with type II), who had been successfully treated with injections, were changed to sildenafil 100 mg, 23 discontinued because of insufficiency.83 Men with insulin-dependent diabetes or requiring both PGE1 and/or papaverine were more likely not to respond to sildenafil.83

Sildenafil improved erectile function to a similar extent in ED patients taking antihypertensives as in patients not taking antihypertensives.32 Sildenafil also improved erectile function in patients with stable coronary artery disease.84 Decreased sexual activity and ED are commonly in men with chronic heart failure. Sildenafil was compared to placebo in 322 men with heart failure, but not at high cardiac risk or taking nitrates.85 In ED in these patients, flexible dosing with sildenafil improved erections (18 vs 74%) and intercourse (68 vs 16%).85 It is important to remember that these results should not be generalized to all patients with heart failure.

Urogenital

Treatment for either prostate cancer or benign prostatic hyperplasia may lead to ED. Treatment of ED with sildenafil in patients who had had radiotherapy for prostate cancer was initially shown to be effective in non-controlled trials and then confirmed in a controlled trial. When 50 patients with ED after radiotherapy for localized prostate cancer, were treated with 50 mg sildenafil, firmness and durability of the erection improved in most (66–74%) of the patients.86 Patients with less severe dysfunction were most likely to benefit.86 In the 11 patients who had no improvement in erectile firmness, no improvement was obtained with the higher 100 mg dose of sildenafil.86 Another study found that 50 of 62 patients with ED, either before or after prostate brachytherapy for adenocarcinoma, responded to sildenafil, with only diabetes predicting failure.87 The ability of sildenafil to improve erectile function in men who have had radiotherapy for prostate cancer has been confirmed in a double-blind study of 60 patients.88

Analysis of patients in a large study with patients of mixed aetiology showed that sildenafil was less effective in neurogenic causes of ED.57 In patients with ED after a radical prostatectomy for prostate cancer, sildenafil was effective in 12 of 15 who had had a bilateral nerve-sparing procedure, but not in those who had undergone a unilateral nerve sparing procedure or a non-nerve-sparing procedure.89 Another study of 84 men with radical retropubic prostatectomy found that 45 had improved erections with sildenafil.90 A survey in 170 men after radical prostatectomy, showed that in men under 55 years in who both neurovascular bundles had been preserved, had a response rate to sildenafil of 80%.91 In contrast, older patients with one preserved neurovascular bundles, and those patients with no preserved neurovascular bundles did not have a response to sildenafil.91 A recent systematic review of sildenafil in men with ED following radical prostatectomy has shown a lower response rate after non-nerve-sparing (0–15%) than nerve-sparing surgery (35–75%).92 However, probably because of the wide range of values, the review could not distinguish between the effectiveness of sildenafil in unilateral (10–80%) and bilateral nerve sparing therapy (35–75%).92

ED is a common sequel of pelvic fracture urethral dysfunction. After urethroplasty in 15 such patients, 47% overcame their ED with sildenafil 100 mg.93 Sildenafil was much more effective in those subjects with neurogenic ED (60%) than those with arterial damage induced ED (20%).93

Central nervous system including spinal dysfunction

When sildenafil was specifically studied in 44 men with psychogenic ED and no established organic cause, sildenafil increased the erections adequate for sexual intercourse and level of sexual satisfaction.94 Depressed men commonly have ED and men with ED are commonly depressed. In 152 ED patients with a mean score of 16.9 on the Hamilton Depression Rating Score, sildenafil was efficacious for the ED, compared to placebo.95 Associated with this improvement in erectile function, there was a marked improvement in depressive symptoms (Hamilton depression score decreases; sildenafil 10.3, placebo, 2.3).95

Estimates of the ED associated with the use of selective serotonin reuptake inhibitors (SSRIs) to treat depression range from 3 to 80%.7 A retrospective sub-analysis of trials with sildenafil showed that sildenafil improved the ability to achieve and maintain an erection in ED patients taking SSRIs.96 These results have been confirmed in double-blind studies of males with major depression in remission and sexual dysfunction associated with SSRIs.97, 98 Erectile function, arousal, ejaculation, orgasm and overall satisfaction improved with sildenafil, compared to placebo, and depression remained in remission.97, 98 ED is also associated with the use of the antipsychotic drugs olanzapine and risperidone, and sildenafil is also effective in this (olanzapine,99 resperidone100). Sildenafil was also safe and effective in the treatment of another 31 subjects with antipsychotic-induced ED (risperidone, n=15: olanzapine, 12).101

Parkinsonism is a common feature of multiple system atrophy along with autonomic and urinary dysfunction. In ED patients with Parkinson's disease or multiple system atrophy and a standing blood pressure of at least 90/50 mm Hg, sildenafil improved erectile function.102 In Parkinson's disease, sildenafil had its usual minimal effect on blood pressure, whereas in multiple system atrophy, sildenafil caused orthostatic hypotension.102 This suggests that sildenafil should not be used in multiple system atrophy, and when parkinsonism is present, a definite diagnosis of Parkinson's disease is needed before the use of sildenafil.102

ED is common in men with multiple sclerosis, and sildenafil is effective in this population. Thus, in 217 men with multiple sclerosis and ED, flexible dose sildenafil improved erections compared to placebo (89 vs 24%), and also improved quality of life.103

ED is a common complication of spinal cord injury and in spina bifida. Small studies initially showed that sildenafil was effective in men with ED and spina bifida,104 and spinal cord injury in the region T6–L5.105 In 178 men with spinal injury, sildenafil improved erections in about 75% of men with and without residual erectile function.106

Rectal excision and renal failure

Rectal excision is associated with ED, probably by damaging the pelvic parasympathetic nerve.107 Sildenafil was effective in 79% of patients with ED after rectal excision for cancer or inflammatory bowel disease.107 In 41 patients with end-stage kidney failure and ED, but no diabetes, sildenafil improved erectile function in 85% of patients (10%, placebo).108 Sildenafil also improves erectile function in men who have ED following a kidney transplant.109

Clinical trials with vardenafil

Smaller doses of vardenafil than sildenafil are used to treat ED, as vardenafil is more potent than sildenafil in inhibiting PDE5. Single 10, 20110 and 40 mg111 doses of vardenafil (Levitra) were first reported to increase penile rigidity and tumescence to visual sexual stimulation in patients with ED in 2001. These were followed by larger trials including a comparison of 5, 10 and 20 mg vardenafil to placebo in 580 men with mild to severe ED of mixed aetiology (organic 30%, psychogenic 30%, mixed 40%).112 As with the sildenafil clinical trials, patients taking nitrates were excluded, and patients were required to take the medication about 1 h before intended intercourse.112 With vardenafil at 12 weeks, there was a dose-related improvement in erectile function, with 80% of the patients in the 20 mg group having improved erections (placebo, 30%).112 These outcomes are in the same range as with sildenafil 100 mg. Also similarly to clinical trials with sildenafil, the most frequent adverse effects with vardenafil were headache (7–15%), flushing (10–11%) and up to 7% for dyspepsia or rhinitis.112 No abnormal colour vision perception (associated with inhibiting PDE6) was reported.112 Further analysis showed the effects of vardenafil were similar in the organic, psychogenic and mixed groups, and regardless of baseline severity.113, 114 Similar results were obtained in a 6 month trials of 5, 10 or 20 mg vardenafil or placebo in 805 ED patients, mostly of organic aetiology,115 a 6 month trial of 5, 10 or 20 mg vardenafil in 1650 men in a broad of men with ED,116 and in flexible-dose studies starting with 10 mg vardenafil.117, 118 A 12-month extension to a 12-month trial of 566 men with ED of 10 and 20 mg vardenafil, showed that vardenafil had long-term efficacy, reliability and tolerability.119 Vardenafil has been shown to improve both the male with ED114, 120, 121 and female partner's sexual quality-of-life.121

In 452 ED patients with diabetes (predominantly type II), 54% of those taking 20 mg vardenafil were able to maintain an erection until the completion of intercourse (placebo, 23%).122 The overall responder rate for improved erections (measured as the global assessment question ‘Has the treatment you have been taking over the past 4 weeks improved your erections’) at 12 weeks, was 54 and 72% in the vardenafil 10 and 20 mg, respectively (placebo, 23%).122 Lower rates of successful intercourse were achieved when the ED was severe at baseline (vardenafil 20 mg, 40%; placebo, 11%).122

Vardenafil has not been tested in individual trials in such a broad range of conditions associated with ED as sildenafil. Although it has been shown to be effective in ED after radical retropubic prostatectomy for adenocarcinoma,123 and spinal cord injury.124 Vardenafil has been tested in mild untreated depression and ED, as ED and depression are highly associated. Subjects received either placebo or vardenafil 10 mg, with the option of titration to 5 or 20 mg, and vardenafil was shown to improve both erectile function and the Hamilton score for depression.125

Vardenafil has only been compared to sildenafil indirectly by systematically reviewing the trials with sildenafil, vardenafil and tadalafil, and this review (discussed in more detail in the clinical trials with tadalafil section) has shown that all three PDE5 inhibitors have had similarly efficacy and tolerability.126

Vardenafil has been tested in men with ED unresponsive to sildenafil, and shown to be more effective than placebo treatment. The study enrolled 463 men with ED unresponsive to sildenafil (no response in at least four of six attempts with sildenafil) to vardenafil 10 mg (that could be titrated to 5 or 20 mg) or placebo.127 Compared to placebo, the percentage of penetrations (30 vs 62%) and successful intercourse (11 vs 46%) was higher with vardenafil.127 Also, this study shown that vardenafil was more effective than placebo from after 0.25 h until beyond 6 h.128

In order to replace sildenafil in the treatment of ED, vardenafil will have to be shown to be superior to sildenafil. To date, there are no obvious major differences between sildenafil and vardenafil. One point of difference is that no alterations of colour vision were reported in the early studies with vardenafil.112, 113, 116, 117 whereas transient visual disturbances were reported in the early studies with sildenafil. There are no clinical trials directly comparing sildenafil and vardenafil, and such trials should be undertaken to determine if there are any differences between the drugs.

Clinical trials with tadalafil

The first major trial of the effects of tadalafil (Cialis) in ED was published in 2001, and compared tadalafil at 2, 5, 10 or 20 mg with placebo in 179 men over 3 weeks, excluding patients taking nitrates.129 Patients were instructed to take a maximum of one dose daily as needed over 21 days, but not to exceed 14 doses.129 A maximum effect seemed to be apparent with 10 mg tadalafil, which was about 70% of successful attempts, compared to 27% with placebo.129 Headache and dyspepsia were the most common adverse effects reported with tadalafil.129 No alterations of colour vision were reported.129

When the data from five clinical trials were combined, it was shown that in 1112 men with ED (60% organic, 30% mixed) there was greater benefit with tadalafil at 25 mg than at 10 mg on erectile function over 12 weeks.130 With the self-administration prior to sexual intercourse, there were no timing restrictions or restrictions on food and alcohol intake.130 The successful intercourse attempts were 61 and 75% with 10 and 25 mg tadalafil, respectively, compared with 32% in the control group.130 Patients most severely affected with ED tended to have greater improvements in erectile function.130 The efficacy of tadalafil was similar for patients older than 65 and their younger counterparts.130 About 20% of patients in this trial had diabetes, and in this population up to 76% reported improved erections.130 The most common adverse effects reported were headache (14%; placebo, 6%) and dyspepsia (10%; placebo 2%), and there were no effects on vision.130

In a trial of 220 Western European men with ED, tadalafil 20 mg provided successful sexual intercourse to 74%, compared to 30% of those treated with placebo.131 The most common adverse effects were headache, dyspepsia, flushing, back pain, pain in limb and myalgia.131 In a trial of 207 US and Puerto Rican men, it was shown that the most successful intercourse attempts occurred between 4 and 36 h after taking tadalafil with 83% of men taking tadalafil reporting improved erections vs 20% placebo.132 Another study confirmed the efficacy and adverse effect profile with tadalafil, and also showed that patients and their sexual partners were more satisfied than those given placebo.133 Improved sexual satisfaction with tadalafil 10 and 20 mg has also been reported in men with mild, moderate and severe ED.134

The long-term safety and tolerability of tadalafil was studied in a 24-month open-label extension of previous studies, and the good safety and tolerability of tadalafil was confirmed.135 Headache (15.8%), dyspepsia (11.8%), nasopharyngitis (11.4%) and back pain (8.2%) were the most common adverse effects.135 The rate of discontinuation due to adverse events for the 18–24 month study was 6.3%.135

In separate trials, the ability of tadalafil to enhance erectile function in men with diabetes (predominantly type II) and ED was confirmed.136, 137 Despite the 637 men with diabetes having more severe ED than a group of 1681 men without diabetes, in the diabetic group, 53% of their attempts at intercourse were successful in the tadalafil group, compared with 22% in the placebo group.137

Tadalafil, taken on demand, is also effective in the ED following bilateral nerve sparing radical retropubic prostatectomy.138 In combining 2102 men from 11 trials, with a broad spectrum of ED aetiology and various comorbid medical conditions, it was shown that tadalafil (10 or 20 mg) was effective in all sub-populations.139 The sub-populations were race (Caucasion, African descent, Hispanic, Asian), age, body mass index, ED aetiology, ED severity, ED duration, smoking, prior sildenafil use, presence of co-morbid conditions (diabetes, hypertension, cardiovascular disease, hyperlipidemia, depression, benign prostatic hyperplasia) and treatment with antihypertensives or antidepressants.139

The efficacy of on demand tadalafil 20 mg and daily dosed tadalafil 10 mg for the treatment of ED has been compared.140 The rates for sexual intercourse completion (Sexual Encounter Profile 3) were higher with daily tadalafil (84%) than with on-demand tadalafil (69%).140 In 112 men who were previously unresponsive to on-demand tadalafil for ED, better results were obtained with tadalafil daily at flexible 10 or 20 mg doses.141 Thus, improved erections were reported by 69% of men on daily tadalafil, compared to 42% previously when they were taking on demand tadalafil.141 This findings need to be verified in a parallel trial comparing on-demand and daily tadalafil, as it is possible that some of the response seen in this trial may have been a placebo response.

In comparison with sildenafil, the major differences, which are evident from comparing trials with either sildenafil or tadalafil, are that there is no requirement to take tadalafil 1 h before sexual intercourse, and tadalafil does not affect vision. A most interesting development, which has not occurred with vardenafil, is comparison trials between tadalafil and sildenafil.

Comparative trials

A fixed dose, 2-period crossover trial of 213 men with ED, compared 20 mg tadalafil with 50 mg sildenafil, either in tadalafil-sildenafil or sildenafil-tadalafil sequence.142 Subjects had never received tadalafil, most had never received sildenafil (85%), and some had undergone a previously inadequate trial of sildenafil (15%).142 Most cases of ED were mixed (42%) or organic (39%).142 Of the 190 evaluable patients, 66% preferred tadalafil compared with 34% who preferred sildenafil.142 Headache (tadalafil, 11.2%; sildenafil, 8.8%), dyspepsia (6.0 and 4.2%), nasopharyngitis (4.7 and 2.8%) and flushing (2.8 and 4.7%) were the most common adverse effects.142 The findings of this trial only apply to the doses tested, 20 mg tadalafil and 50 mg sildenafil. As most trials of sildenafil alone, show that most men with ED prefer 100 over 50 mg sildenafil, it may have been more appropriate to have compared 20 mg tadalafil to 100 mg sildenafil.

In a second trial of sildenafil and tadalafil, ED patients who were taking sildenafil were switched to tadalafil and then asked which they preferred, and most preferred tadalafil.143 The 147 evaluable men in this study had been taking sildenafil at stable fixed doses of 25, 50 or 100 mg as needed for at least 6 weeks and up to 24 weeks.143 After a 3-week prestudy sildenafil dose, there was a 9 week tadalafil initiation/assessment phase at the end of which the ED subjects could select either sildenafil or tadalafil for a 6-month extension.143 Most of the men selected tadalafil (90%), and the proportions preferring tadalafil were similar irrespective of age, severity of ED, aetiology of ED, and sildenafil dose at study entry.143 The obvious limitation to this study was that it was not blinded, and another limitation was that it did not determine the effect on erectile function.

When a blinded trial was undertaken to evaluate patient preference between 20 mg tadalafil and 50–100 mg sildenafil, most ED patients preferred tadalafil.144 Thus, 73% of 181 ED patients chose to receive tadalafil during the extension period.144 These studies have the same limitation as the first crossover study, namely, that the comparison should have been between 20 mg tadalafil and 100 mg sildenafil. For instance, in the blinded trial, only 35% of the men had the ability to titrate to 100 mg sildenafil and this may have biased the preference towards tadalafil. In 28 men with ED associated with spinal cord injury, a crossover study between tadalafil 10 mg and sildenafil 50 mg showed that tadalafil had a longer lasting efficacy than sildenafil.145 Similarly, this study would be more meaningful if the doses of the PDE5 inhibitors had been optimized.

A more recent study has reduced the bias towards tadalafil by allowing the men with ED to titrate to find their optimum dose (for sildenafil 25, 50 or 100 mg; for tadalafil 10 or 20 mg).146 After the crossover between the drugs, the 367 men with ED were given the choice of sildenafil or tadalafil and 29% chose sildenafil and 71% chose tadalafil.146 This preference occurred despite both drugs giving a similar response for penetration (sildenafil, 82%; tadalafil, 85%), and only a slight difference in successful intercourse (sildenafil, 72%; tadalafil, 77%).146

When a population of 186 subjects with ED, of whom 64 had not been treated previously, were given eight tablets of a shorter acting PDEV inhibitor (four tablets sildenafil 100 mg, four tablets vardenafil 20 mg) and eight tablets of the longer-acting tadalafil 20 mg, overall there was no preference, although two-thirds of the naive patients preferred the shorter acting PDEV inhibitor.147 One-fifth of subjects requested both a shorter- and a long-acting medication to accommodate his needs.147 There are several flaws in this crossover trial including a lack of treatment sequence randomization, the limitation of sildenafil and vardenafil exposure to four as opposed to eight tablets with tadalafil, and the lack of a washout period between different treatment phases.148

In order to achieve a definite answer to the preference question, studies need to be performed that are double-blind, have no bias in the drug administration instructions, use the standard crossover/washout design, and compare equivalent doses.149, 150

Comments and conclusions

Sildenafil vs vardenafil

The point of difference between sildenafil and vardenafil is relatively small. Vardenafil is a less potent inhibitor of PDE6 that sildenafil, and is less likely to give the side effect associated with this inhibition, namely, abnormal colour perception. As abnormal colour perception is a relatively rare and not particularly disturbing side effect with sildenafil, this point of difference has not been sufficient for vardenafil to be preferred to sildenafil as the first choice in ED. Obviously, in cases where abnormal colour perception is observed with sildenafil, vardenafil could be substituted.

Sildenafil and vardenafil vs tadalafil

There is a major point of difference between the short-acting agents, sildenafil and vardenafil, and the longer acting tadalafil. This probably allows more choice about the onset of sexual intercourse with tadalafil than with sildenafil or vardenafil. The dosing instructions for sildenafil are that patients take sildenafil one hour before sexual activity, whereas those for tadalafil suggest that sexual activity can be initiated between 30 min and 24 h after dosing.

Epilepsy

Two cases where it is possible that sildenafil has induced tonic-clonic seizures have been reported,151 and one case with vardenafil.152 Further studies are needed to determine whether this is a rare adverse effect with sildenafil and vardenafil, and also to determine whether seizures occur with tadalafil.

Conclusions

Sildenafil, vardenafil and tadalafil have all been shown to be similarly effective in the treatment of men with ED of vary etiologies, to have similar adverse effects profiles, and to improve quality of life by similar amounts. All increase the hypotensive effects of nitrates, making them unsuitable for use in patients taking nitrates. In patients taking α1-adrenoceptors antagonists for benign prostatic hyperplasia, the PDE5 inhibitors can be used with caution. Tadalafil has a longer half-life than sildenafil or vardenafil. Most preference studies have shown tadalafil to be preferred, but there are serious limitations to some of these studies. One approach to treatment is to give each patient a short and long acting agent, and for individuals to decide their preference.

References

  1. 1

    NIH consensus development panel on impotence. Impotence. JAMA 1993; 270: 83–90.

  2. 2

    Feldman HA, Goldstein I, Hatzichristou DG, Krane RJ, Mckinlay JB . Impotence and its medical and psychological correlates: results of the Massachusetts Male Aging Study. J Urol 1994; 151: 54–61.

  3. 3

    Johannes CB, Araujo AB, Felman HA, Derby CA, Kleinman KP, McKinlay JB . Incidence of erectile dysfunction in men 40–69 years old: longitudinal results from the Massachusetts Male Aging Study. J Urol 2000; 163: 460–463.

  4. 4

    Banker FL . The preservation of potency after external beam irradiation for prostate cancer. Int J Radiat Oncol Biol Phys 1988; 15: 219–220.

  5. 5

    Stock RG, Stone NN, Iannuzzi C . Sexual potency following interactive ultrasound-guided brachytherapy for prostate cancer. Int J Radiat Oncol Biol Phys 1996; 35: 267–272.

  6. 6

    Rosas SE, Joffe M, Franklin E, Strom BL, Kotzker W, Brensinger C et al. Prevalence and determinants of erectile dysfunction in hemodialysis patients. Kidney Int 2001; 59: 2259–2266.

  7. 7

    Rosen RC, Lane RM, Menza M . Effects of SSRIs on sexual function: a critical review. J Clin Psychopharmacol 1999; 19: 67–85.

  8. 8

    Boolell M, Allen MJ, Ballard SA . Sildenafil: an orally active type 5 cyclic GMP-specific phosphodiesterase inhibitor for the treatment of penile erection dysfunction. Int J Impot Res 1996; 8: 47–52.

  9. 9

    Bischoff E, Niewoehner U, Haning H . Vardenafil a potent and selective inhibitor of phosphodiesterase type 5 increases cGMP in rabbit corpus cavernosum. Int J Impot Res 2000; 12 (Suppl 3): 65.

  10. 10

    Daugan A, Grondin P, Ruault C, Le Monnier de Gouville AC, Coste H et al. The discovery of tadalafil: a novel and highly selective PDE5 inhibitor. 2: 2,3,6,7,12,12a-hexahydropyrazino[1′,2′:1,6]pyrido[3,4-b]indole-1,4-dione analogues. J Med Chem 2003; 46: 4533–4542.

  11. 11

    Ballard SA, Gingell CJ, Tang K, Turner LA, Price ME, Naylor AM . Effects of sildenafil on the relaxation of human corpus cavernosum tissue in vitro and the activities of cyclic nucleotide phosphodiesterase isozymes. J Urol 1998; 159: 2164–2171.

  12. 12

    Saenz De Tejada I, Angulo J, Cuevas P, Fernandez A, Moncada I, Allona A et al. The phosphodiesterase inhibitory selectivity and the in vitro and in vivo potency of the new PDE5 inhibitor vardenafil. Int J Impot Res 2001; 13: 282–290.

  13. 13

    Wayman C, Phillips S, Lunny C, Webb T, Fawcett L, Baxendale R et al. Phosphodiesterase 11 (PDE11) regulation of spermatozoa physiology. Int J Impot Res 2005; 17: 216–223.

  14. 14

    Weeks JL, Zoraghi R, Beasley A, Sekhar KR, Francis SH, Corbin JD . High biochemical selectivity of tadalafil, sildenafil and vardenafil for human phosphodiesterase 5A1 (PDE5) over PDE11A4 suggests the absence of PDE11A4 cross-reaction in patients. Int J Impot Res 2005; 17: 5–9.

  15. 15

    Blount MA, Beasley A, Zoraghi R, Sekhar KR, Bessay EP, Francis SH et al. Binding of tritiated sildenafil, tadalafil, or vardenafil to the phosphodiesterase-5 catalytic site displays potency, specificity, heterogeneity, and cGMP stimulation. Mol Pharmacol 2004; 66: 144–152.

  16. 16

    Padma-Nathan H, Stecher VJ, Sweeney M, Orazem J, Tseng LJ, Deriesthal H . Minimal time to successful; intercourse after sildenafil citrate: results of a randomized, double-blind, placebo-controlled trial. Urology 2003; 62: 400–403.

  17. 17

    Montorsi F, Padman-Nathan H, Buvat J, Schwaibold H, Beneke M, Ulbrich E et al. Earliest time to onset of action leading to successful intercourse with vardenafil determined in an at-home setting: a randomized, double-blind, placebo-controlled trial. J Sex Med 2004; 1: 168–178.

  18. 18

    Rosen RC, Padma-Nathan H, Shabish R, Saikali K, Watkins V, Pullman W . Determining the earliest time within 30 min to erectogenic effect after tadalafil 10 and 20 mg: a multicenter, randomized, double-blind, placebo-controlled, at-home study. J Sex Med 2004; 1: 193–200.

  19. 19

    Porst H . IC351 (tadalafil, Cialis): update on clinical experience. Int J Impot Res 2002; 14 (Suppl 1): S57–S64.

  20. 20

    Shabsigh R, Burnett AL, Eardley I, Sharlip ID, Ellsworth PI, Garcia CS et al. Time from dosing to sexual intercourse attempts in men taking tadalafil in clinical trials. BJU Int 2005; 96: 857–863.

  21. 21

    Porst H, Padma-Nathan H, Giuliano F, Anglin G, Varanese L, Rosen R . Efficacy of tadalafil for the treatment of erectile dysfunction at 24 and 36 h after dosing: a randomized controlled trial. Urology 2003; 62: 121–125.

  22. 22

    Young JM, Feldman RA, Auerback SM, Kaufman JM, Garcia CS, Shen W et al. Tadalafil improved erectile function at twenty-four and thirty-six hours after dosing in men with erectile dysfunction: US Trial. J Androl 2005; 26: 310–318.

  23. 23

    Moncada I, Jara J, Subira D, Castano I, Hernandez C . Efficacy of sildenafil citrate at 12 h after dosing: re-exploring the therapeutic window. Eur Urol 2004; 46: 357–360.

  24. 24

    Porst H, Sharlip ID, Hatzichristou D, Rubio-Aurioles E, Gittelman M, Stancil BN et al. Extended duration of efficacy of vardenafil when taken 8 h before intercourse: a randomized, double-blind, placebo-controlled study. Eur Urol 2006 (E-pub ahead of print).

  25. 25

    Gupta M, Kovar A, Meibohm B . The clinical pharmacokinetics of phosphodiesterase-5 inhibitors for erectile function. J Clin Pharmacol 2005; 45: 987–1003.

  26. 26

    Rajagopalan P, Mazzu A, Xia C, Dawkins R, Sundaresan P . Effect of high-fat breakfast and moderate-fat evening meal on pharmacokinetics of vardenafil, an oral phosphodiesterase-5 inhibitor for the treatment of erectile dysfunction. J Clin Pharmacol 2003; 43: 260–267.

  27. 27

    Forgue ST, Patterson BE, Bedding AW, Payne CD, Phillips DL, Wrishko RE et al. Tadalafil pharmacokinetics in healthy subjects. Br J Clin Pharmacol 2006; 61: 280–288.

  28. 28

    Deveci S, Peskircioglu L, Aygun C, Tekin MI, Dirim A, Ozkardes H . Sublingual sildenafil in the treatment of erectile dysfunction: faster onset of action with less dose. Int J Urol 2004; 11: 989–992.

  29. 29

    Jackson G, Benjamin N, Jackson N, Allen AJ . Effects of sildenafil citrate on human hemodynamics. Am J Cardiol 1999; 83: 13C–20C.

  30. 30

    Hermann HC, Chang G, Klugherz BD, Mahoney PD . Hemodynamic effects of sildenafil in men with severe coronary artery disease. N Engl J Med 2000; 342: 1622–1626.

  31. 31

    Arruda-Olson AM, Mahoney DW, Nehra A, Leckel M, Pellikka PA . Cardiovascular effects of sildenafil during exercise in men with known or probably coronary artery disease: a randomized crossover trial. JAMA 2002; 287: 719–725.

  32. 32

    Bocchi EA, Guimaraes G, Mocelin A, Bacal F, Bellotti G, Ramires JF et al. Sildenafil effects on exercise, neurohormonal activation, and erectile dysfunction in congestive heart failure: a double-blind, placebo-controlled, randomized study followed by a prospective treatment for erectile dysfunction. Circulation 2002; 106: 1097–1103.

  33. 33

    Padma-Nathan H, Eardley L, Kloner RA, Laties AM, Montorsi F . A 4-year update on the safety of sildenafil citrate (Viagra). Urology 2002; 60 (2Suppl2): 67–90.

  34. 34

    Webb DJ, Freestone S, Allen MJ, Muirhead GJ . Sildenafil citrate and blood-pressure-lowering drugs: results of drug interaction studies with an organic nitrate and a calcium antagonist. Am J Cardiol 1999; 83: 21C–28C.

  35. 35

    Webb DJ, Muirhead GJ, Wulff M, Sutton JA, Levi R, Dinsmore WW . Sildenafil citrate potentiates the hypotensive effects of nitric oxide donor drugs in male patients with stable angina. J Am Coll Cardiol 2000; 36: 25–31.

  36. 36

    Zusman RM, Prisant LM, Brown MJ . Effect of sildenafil citrate on blood pressure and heart rate in men with erectile dysfunction taking concomitant antihypertensive medication. Sildenafil Study Group. J Hypertension 2000; 18: 1865–1869.

  37. 37

    Kloner RA, Brown M, Prisant LM, Collins M . Effect of sildenafil in patients with erectile dysfunction taking antihypertensive therapy. Sildenafil Study Group. Am J Hypertension 2001; 14: 70–73.

  38. 38

    Thadani U, Smith W, Nash S, Bittar N, Glasser S, Narayan P et al. The effects of vardenafil, a potent and highly selective phosphodiesterase-5 inhibitor for the treatment of erectile dysfunction, on the cardiovascular response to exercise in patients with coronary artery disease. J Am Coll Cardiol 2002; 40: 2006–2012.

  39. 39

    Patient Information Sheet for Vardenafil. Available at http://www.fda.gov/cder/drug/infopage/vardenafil/default.htm.

  40. 40

    Van Ahlen H, Wahle K, Kupper W, Yassin A, Reblin T, Neureither M . Safety and efficacy of vardenafil, a selective phosphodiesterase 5 inhibitor, in patients with erectile dysfunction and arterial hypertension treated with multiple antihypertensives. J Sex Med 2005; 2: 856–864.

  41. 41

    Kloner RA, Mitchell M, Emmick JT . Cardiovascular effects of tadalafil. Am J Cardiol 2003; 92 (9A): 37M–346M.

  42. 42

    Kloner RA, Mitchell M, Emmick JT . Cardiovascular effects of tadalafil in patients on common antihypertensive therapies. Am J Cardiol 2003; 92 (9A): 47M–457M.

  43. 43

    Kloner RA, Hunter AM, Emmick JT, Mitchell MI, Denne J, Jackson G . Time course of the interaction between tadalafil and nitrates. J Am Coll Cardiol 2003; 42: 1855–1860.

  44. 44

    Patterson D, Kloner R, Effron M, Emmick J, Bedding A, Warner M et al. The effect of tadalafil on the time to exercise-induced myocardial ischaemia in subjects with coronary artery disease. Br J Clin Pharmacol 2005; 60: 459–468.

  45. 45

    Dustan Sarazan R, Crumb Jr WJ, Beasley Jr CM, Emmick JT, Ferguson KM, Strnat CA et al. Absence of clinically important HERG channel blockade by three compounds that inhibit phosphodiesterase 5 – sildenafil, tadalafil, and vardenafil. Eur J Pharmacol 2004; 502: 163–167.

  46. 46

    Carson III C . Cardiac safety in clinical trials with phosphodiesterase 5 inhibitors. Am J Cardiol 2005; 96: 37M–341M.

  47. 47

    Hattenhauer MG, Leavitt JA, Hodge DO, Grill R, Gray DT . Incidence on nonarteritic anterior ischemic optic neuropathy. Am J Ophthalmol 1997; 123: 103–107.

  48. 48

    Pomeranz HD, Smith KH, Hart WM, Egan RA . Sildenafil-associated nonarteritic anterior ischemic optic neuropathy. Ophthalmology 2002; 109: 584–587.

  49. 49

    Pomeranz HD, Bhavsar AR . Nonarteritic ischemic optic neuropathy developing soon after use of sildenafil (Viagra): a report of seven new cases. J Neuroophthalmol 2005; 25: 9–13.

  50. 50

    FDA Alert at http://www.fda.gov/cder/drug/infopage/cialis/default.htm.

  51. 51

    McGwin G, Vaphiades MS, Hall TA, Owsley C . Non-arteritic anterior ischaemic optic neuropathy and the treatment of erectile dysfunction. Br J Ophthalmol 2006; 90: 154–157.

  52. 52

    Gorkin L, Hvidsten K, Sobel RE, Siegel R . Sildenafil citrate use and the incidence of nonarteritic anterior ischemic optic neurophathy. Int J Clin Pract 2006; 60: 500–503.

  53. 53

    Kloner RA . Cardiovascular effects of the 3 phosphodiesterase-5 inhibitors approved for the treatment of erectile dysfunction. Circulation 2004; 110: 3149–3155.

  54. 54

    Kloner RA, Jackson G, Emmick JT, Mitchell MI, Bedding A, Warmer MR et al. Interaction between the phosphodiesterase 5 inhibitor, tadalafil and 2 alpha-blockers, doxazosin and tamsulosin in healthy normotensive men. J Urol 2004; 172: 1935–1940.

  55. 55

    Giuliano F, Kaplan SA, Cabanis MJ, Astruc B . Hemodynamic interaction study between the alpha1-blocker alfuzosin and phosphodiesterase-5 inhibitor tadalafil in healthy male subjects. Urology 2006; 67: 1199–1204.

  56. 56

    Boolell M, Gepi-Atee S, Gingell JC, Allen MJ . Sildenafil, a novel effective oral therapy for male erectile dysfunction. Br J Urol 1996; 78: 257–261.

  57. 57

    Goldstein I, Lue TF, Padma-Nathan H, Rosen RC, Steers WD, Wicker PA . Oral sildenafil in the treatment of erectile dysfunction. Sildenafil Study Group. N Eng J Med 1998; 338: 1397–1404.

  58. 58

    Tan HM, Moh CL, Mendoza JB, Gana T, Albana GJ, de la Cruz R et al. Asian sildenafil efficacy and safety study (ASSESS-1): a double-blind, placebo-controlled, flexible-dose study of oral sildenafil in Malaysian, Singaporean, and Filipino men with erectile dysfunction. The Assess-1 Study Group. Urology 2000; 56: 635–640.

  59. 59

    Meuleman E, Cuzin B, Opsomer RJ, Hartmann U, Bailey MJ, Maytom MC et al. A dose-escalation study to assess the efficacy and safety of sildenafil citrate in men with erectile dysfunction. BJU Int 2001; 87: 75–81.

  60. 60

    Choi HK, Ahn TY, Kim JJ, Kim SC, Paick JS, Suh JK et al. A double-blind, randomised- placebo, controlled, parallel group, multicentre, flexible-dose escalation study to assess the efficacy and safety of sildenafil administered as required to male outpatients with erectile dysfunction in Korea. Int J Impot Res 2003; 15: 80–86.

  61. 61

    Montorsi F, McDermott TE, Morgan R, Olsson A, Schultz A, Kirkeby HJ et al. Efficacy and safety of fixed-dose oral sildenafil in the treatment of erectile dysfunction of various etiologies. Urology 1999; 53: 1011–1018.

  62. 62

    Jarow JP, Burnett AL, Geringer AM . Clinical efficacy of sildenafil citrate based on etiology and response to prior treatment. J Urol 1999; 162: 722–725.

  63. 63

    Christiansen E, Guirguis WR, Cox D, Osterloh IH . Long-term efficacy and safety of oral Viagra (sildenafil citrate) in men with erectile dysfunction and effect of randomised treatment withdrawal. Int J Impot Res 2000; 12: 177–182.

  64. 64

    Park K, Ku JH, Kim SW, Paick JS . Risk factors in predicting a poor response to sildenafil citrate in elderly men with erectile dysfunction. BMJ Int 2005; 95: 366–370.

  65. 65

    Morales A, Gingell C, Collins M, Wicker PA, Osterloh IH . Clinical safely of oral sildenafil citrate (VIAGRA) in the treatment of erectile dysfunction. Int J Impot Res 1998; 10: 69–73.

  66. 66

    Muller MJ, Ruof J, Graf-Morgenstern M, Porst H, Benkert O . Quality of partnership in patients with erectile dysfunction after sildenafil treatment. Pharmacopsychiatry 2001; 34: 91–95.

  67. 67

    Dinsmore WW, Hodges M, Hargreaves C, Osterloh IH, Smith MD, Rosen RC et al. Sildenafil citrate (Viagra) in erectile dysfunction in men with broad-spectrum erectile dysfunction compared with age-matched healthy controls subjects. Urology 1999; 53: 800–805.

  68. 68

    Giuliano F, Pena BM, Mishra A, Smith MD . Efficacy results and quality-of-life measures in men receiving sildenafil citrate for the treatment of erectile dysfunction. Qual Life Res 2001; 10: 359–369.

  69. 69

    O’Leary MP, Althof SE, Cappelleri JC, Crowley A, Sherman N, Duttagupta S . Self-esteem, confidence and relationship satisfaction of men with erectile dysfunction treated with sildenafil citrate: a multicentre, randomized, parallel group, double-blind, placebo controlled study in the United Sates. J Urol 2006; 175: 1058–1062.

  70. 70

    Cappelleri JC, Bell SS, Althof SE, Siegel RL, Stecher VJ . Comparison between sildenafil-treated subjects with erectile dysfunction and control subjects on the Self-Esteem And Relationship questionnaire. J Sex Med 2006; 3: 274–282.

  71. 71

    McMahon CG . High dose sildenafil citrate as a salvage therapy for severe erectile dysfunction. Int J Impot Res 2002; 14: 533–538.

  72. 72

    Hatzichristou D, Moysidis K, Apostolidis A, Bekos A, Tzortzis V, Hatzimouratidis K et al. Sildenafil failures may be due to inadequate patients instructions and follow-up: a study on 100 non-responders. Eur Urol 2005; 47: 518–522.

  73. 73

    Gruenwald T, Shenfeld O, Chen J, Raviv G, Richter S, Cohen A et al. Positive effect of counselling and dose adjustment in patients with erectile dysfunction who failed treatment with sildenafil. Eur Urol 2006 (E-pub ahead of print).

  74. 74

    Giuliano F, Montorsi F, Mirone V, Rossi D, Sweeney M . Switching from intracavernous prostaglandin E1 injections to oral sildenafil citrate in patients with erectile dysfunction: results of a multicenter European Study. The Sildenafil Multicentre Study Group. J Urol 2000; 164: 708–711.

  75. 75

    Montorsi F, Althof SE, Sweeney M, Menchini-Fabris F, Sasso F, Giuliano F . Treatment satisfaction in patients with erectile dysfunction switching from prostaglandin E(1) intracavernosal injection therapy to oral sildenafil citrate. Int J Impot Res 2003; 15: 444–449.

  76. 76

    Hatzimouratidis K, Hatzichristou DG . A comparative review of the options for treatment of erectile dysfunction: which treatment for which patient? Drugs 2005; 65: 1621–1650.

  77. 77

    Pavone C, Curto F, Anello G, Serretta V, Almasio PL, Pavone-Macaluso M . Prospective, randomized, crossover comparison of sublingual apomorphine (3 mg) with oral sildenafil (50 mg) for male erectile dysfunction. J Urol 2004; 172: 2347–2349.

  78. 78

    Eardley I, Wright P, MacDonagh R, Hole J, Edwards A . An open-label, randomized, flexible-dose, crossover study to assess the comparative efficacy and safety of sildenafil citrate and apomorphine hydrochloride in men with erectile dysfunction. BJU Int 2004; 93: 1271–1275.

  79. 79

    Safarinejad MR . Salvage of sildenafil failures with cabergoline: a randomized, double-blind, placebo-controlled study. Int J Impot Res 2006 (E-pub aheadof print).

  80. 80

    Price DE, Gingell JC, Gepi-Attee S, Wareham K, Yates P, Boolell M . Sildenafil: study of a novel oral treatment for erectile dysfunction in diabetic men. Diabet Med 1998; 15: 821–825.

  81. 81

    Rendell MS, Raifer J, Wicker PA, Smith MD . Sildenafil for treatment of erectile dysfunction in men with diabetes: a randomized controlled trial. Sildenafil Diabetes Study Group. JAMA 1999; 281: 421–426.

  82. 82

    Stuckey BG, Jadzinsky MN, Murphy LJ, Montorsi F, Kadioglu A, Fraige F et al. Sildenafil citrate for treatment of erectile dysfunction in men with type 1 diabetes: results of a randomized controlled trial. Diabet Care 2003; 26: 279–284.

  83. 83

    Perimenis S, Markou S, Gyftopoulos K, Athanasopoulos A, Giannitsas K, Barbalias G . Switching from long-term treatment with self-injections to oral sildenafil in diabetic patients with severe erectile dysfunction. Eur Urol 2002; 41: 387–391.

  84. 84

    Debusk RF, Pepine CJ, Glasser DB, Shpilsky A, DeRiesthal H, Sweeney M . Efficacy and safety of sildenafil citrate in men with erectile dysfunction and stable coronary artery disease. Am J Cardiol 2004; 93: 147–153.

  85. 85

    Katz SD, Parker JD, Glasser DB, Bank AJ, Sherman N, Wang H et al. Efficacy and safety of sildenafil citrate in men with erectile dysfunction and chronic heart failure. Am J Cardiol 2005; 95: 36–42.

  86. 86

    Zelefsky MJ, Mckee AB, Lee H, Leibel SA . Efficacy of oral sildenafil in patients with erectile dysfunction after radiotherapy for carcinoma of the prostate. Urology 1999; 53: 775–778.

  87. 87

    Merrick GS, Butler WM, Lief JH, Stipetich RL, Abel LJ, Dorsey AT . Efficacy of sildenafil citrate in prostate brachytherapy patients with erectile dysfunction. Urology 1999; 53: 1112–1116.

  88. 88

    Incrocci L, Koper PC, Hop WC, Slob AK . Sildenafil citrate (Viagra) and erectile dysfunction following external beam radiotherapy for prostate cancer: a randomized double-blind, placebo-controlled, cross-over study. Int J Radiat Oncol Biol Phys 2001; 51: 1190–1195.

  89. 89

    Zippe CD, Kedia AW, Kedia K, Nelson DR, Agarwal A . Treatment of erectile dysfunction after radical prostatectomy with sildenafil citrate (Viagra). Urology 1998; 52: 963–966.

  90. 90

    Lowentritt BH, Scardino PT, Miles BJ, Orejuela FJ, Schatte EC, Slawin KM et al. Sildenafil citrate after radical retropubic prostatectomy. J Urol 1999; 162: 1614–1617.

  91. 91

    Zagaja GP, Mhoon DA, Aikens JE, Brendler CB . Sildenafil in the treatment of erectile dysfunction after radical prostatectomy. Urology 2000; 56: 631–634.

  92. 92

    Montorsi F, McCullough A . Efficacy of sildenafil citrate in men with erectile dysfunction following radical prostatectomy: a systematic review of clinical data. J Sex Med 2005; 2: 658–667.

  93. 93

    Shenfield OZ, Gofrit OD, Gdor Y, Landau I, Katz R, Pode D . The role of sildenafil in the treatment of erectile dysfunction with pelvic fracture urethral disruption. J Urol 2004; 172: 2350–2352.

  94. 94

    Eardley I, Morgan R, Dinsmore W, Yates P, Boolell M . Efficacy and safety of sildenafil citrate in the treatment of men with mild to moderate erectile dysfunction. Br J Psychiatry 2001; 178: 325–330.

  95. 95

    Seidman SN, Roose SP, Menza MA, Shabsigh R, Rosen RC . Treatment of erectile dysfunction in men with depressive symptoms: results of a placebo-controlled trial with sildenafil citrate. Am J Psychiatry 2001; 158: 1623–1630.

  96. 96

    Nurnberg HG, Gelenberg A, Hargreave TB, Harrison WM, Siegel RL, Smith MD . Efficacy of sildenafil citrate for the treatment of erectile dysfunction in men taking serotonin reuptake inhibitors. Am J Psychiatry 2001; 158: 1926–1928.

  97. 97

    Nurnberg HG, Hensley PL, Gelenberg AJ, Fava M, Lauriello J, Paine S . Treatment of antidepressant-associated sexual dysfunction with sildenafil: a randomized controlled trial. JAMA 2003; 289: 56–64.

  98. 98

    Fava M, Nurnberg HG, Seidman SN, Holloway W, Nicholas S, Tseng L-J et al. Efficacy and safety of sildenafil in men with serotonergic antidressant-associated erectile dysfunction: results from a randomized, double-blind, placebo-controlled trial. J Clin Psychiatry 2006; 67: 240–246.

  99. 99

    Atmaca M, Kuloglu M, Tezcan E . Sildenafil use in patients with olanzapine-induced erectile dysfunction. Int J Impot Res 2002; 14: 547–549.

  100. 100

    Aviv A, Shelef A, Weizman A . An open-label trial of sildenafil addition in risperidone-treated male schizophrenia patients with erectile dysfunction. J Clin Psychiatry 2004; 65: 97–103.

  101. 101

    Gopalakrishnan R, Jacob KS, Kuruvilla A, Vasantharaj B, Johm JK . Sildenafil in the treatment of antipsychotic-induced erectile dysfunction: a randomized, double-blind, placebo-controlled, flexible-dose, two-way crossover trial. Am J Psychiatry 2006; 163: 494–499.

  102. 102

    Hussain IF, Brady CM, Swinn MJ, Mathias CJ, Fowler CJ . Treatment of erectile dysfunction with sildenafil citrate (Viagra) in parkinsonism due to Parkinson's disease or multiple system atrophy with observations on orthostatic hypotension. J Neurol Neurosurg Psychiatry 2001; 71: 371–374.

  103. 103

    Fowler CJ, Miller JR, Sharief MK, Hussain IF, Stecher VJ, Sweeney M . A double blind, randomised study of sildenafil citrate for erectile dysfunction in men with multiple sclerosis. J Neurol Neurosurg Psychiatry 2005; 76: 700–705.

  104. 104

    Palmer JS, Kaplan WW, Firlit CF . Erectile dysfunction in spina bifida is treatable. Lancet 1999; 354: 125–126.

  105. 105

    Maytom MC, Derry FA, Dinsmore WW . A two-part pilot study of sildenafil (VIAGRA) in men with erectile dysfunction caused by spinal cord injury. Spinal Cord 1999; 37: 110–116.

  106. 106

    Guiliano F, Hulting C, El Masry WS, Smith MD, Osterloh IH, Orr M et al. Randomized trial of sildenafil for the treatment of erectile dysfunction in spinal cord injury. Sildenafil Study Group. Ann Neurol 1999; 46: 15–21.

  107. 107

    Lindsey I, George B, Kettlewell M, Mortensen N . Randomized, double-blind, placebo-controlled trial of sildenafil (Viagra) for erectile dysfunction after rectal excision for cancer and inflammatory bowel disease. Dis Colon Rectum 2002; 45: 727–732.

  108. 108

    Seibel I, Poli De Figueiredo CE, Teloken C, Moraes JF . Efficacy of oral sildenafil in hemodialysis with erectile dysfunction. J Am Soc Nephrol 2002; 13: 2770–2775.

  109. 109

    Barrou B, Cuzin B, Malavaud B, Petit J, Pariente JL, Bucher M et al. Early experience with sildenafil for the treatment of erectile dysfunction in renal transplant recipients. Nephrol Dial Transplant 2003; 18: 411–417.

  110. 110

    Klotz T, Sachse R, Heidrich A, Jockenhovel F, Rohde G, Wensing G et al. Vardenafil increases penile rigidity and tumescence in erectile dysfunction patients: a RigiScan and pharmacokinetic study. World J Urol 2001; 19: 32–39.

  111. 111

    Stark S, Sachse R, Liedl T, Hensen J, Rohde G, Wensing G et al. Vardenafil increases penile rigidity and tumescence in men with erectile dysfunction after a single oral dose. Eur Urol 2001; 40: 181–190.

  112. 112

    Porst H, Rosen R, Padma-Nathan H, Goldstein I, Giuliano F, Ulbrich E et al. The efficacy and tolerability of vardenafil, a new, oral, selective phosphodiesterase type 5 inhibitor, in patients with erectile dysfunction: the first at-home clinical trial. Int J Impot Res 2001; 13: 192–199.

  113. 113

    Porst H, Young JM, Schmidt AC, Buvat J, International Vardenafil Study Group. Efficacy and tolerability of vardenafil for treatment of erectile dysfunction in patient subgroups. Urology 2003; 62: 519–523.

  114. 114

    Donatucci C, Taylor T, Thibonnier M, Bangerter K, Gittelman M, Casey R, Vardenafil Study Group. Vardenafil improves patient satisfaction with erection hardness, orgasmic function, and overall sexual experience, while improving quality of life in men with erectile dysfunction. J Sex Med 2004; 1: 185–192.

  115. 115

    Montorsi F, Hellstrom WJG, Valiquette L, Bastuba M, Collins O, Taylor T et al. Vardenafil provides reliable efficaby over time in men with erectile dysfunction. Urology 2004; 64: 1187–1195.

  116. 116

    Hellstrom WJ, Gittelman M, Karlin G, Segerson T, Thibonnier M, Taylor T et al. Sustained efficacy and tolerability of vardenafil, a highly potent selective phosphodiesterase type 5 inhibitor, in men with erection dysfunction: results of a randomized, double-blind, 26-week placebo-controlled pivotal trial. Urology 2003; 61 (4Suppl 1): 8–14.

  117. 117

    Hatzichristou D, Montorsi F, Buvat J . The efficacy and safety of flexible-dose vardenafil (levitra) in a broad population of European men. Eur Urol 2004; 45: 634–641.

  118. 118

    Mirone V, Palmieri A, Cucinotta D, Parazzini F, Morelli P, Bettocchi C et al. Flexible-dose vardenafil in a community-based population of men affected by erectile dysfunction: a 12-week open-label, multicenter trial. J Sex Med 2005; 2: 842–847.

  119. 119

    Stief C, Porst H, Saenz De Tejada I, Ulbrich E, Beneke M et al. Sustained efficacy and tolerability with vardenafil over 2 years treatment in men with erectile dysfunction. Int J Clin Pract 2004; 58: 230–239.

  120. 120

    Hatzichristou D, Curzin B, Martin-Morales A, Buvat J, Porst H, Laferriere N et al. Vardenafil improves satisfaction rates, depressive symptomatology, and self-confidence in a broad population in men with erectile dysfunction. J Sex Med 2005; 2: 109–116.

  121. 121

    Fisher WA, Rosen RC, Mollen M, Brock G, Karlin G, Pommerville P et al. Improving the sexual quality of life of couples affect by erectile dysfunction: a double-bline, randomized, placebo-controlled trial of vardenafil. J Sex Med 2005; 2: 699–708.

  122. 122

    Goldstein I, Young JM, Fischer J, Bangerter K, Segerson T, Taylor T . Vardenafil, a new phosphodiesterase type 5 inhibitor, in the treatment of erectile dysfunction in men with diabetes: a multicenter double-blind placebo-controlled fixed-dose study. Diabet Care 2003; 26: 777–783.

  123. 123

    Brock G, Nehra A, Lipshultz LI, Karlin GS, Gleave M, Seger M et al. Safety and efficacy of vardenafil for the treatment of men with erectile dysfunction after radial retropubic prostatectomy. J Urol 2003; 70: 1278–1283.

  124. 124

    Giuliano E, Rubio-Aurioles E, Kennelly M, Montorsi F, Kim ED, Finkbeiner AE et al. Efficacy and safety of vardenafil in men with erectile dysfunction caused by spinal cord injury. Neurology 2006; 66: 210–216.

  125. 125

    Rosen R, Shabsigh R, Berber M, Assalian P, Menza M, Rodriguez-Vela L et al. Efficacy and tolerability of vardenafil in men with mild depression and erectile dysfunction: the depression-related improvement with vardenafil for erectile response study. Am J Psychiatry 2006; 163: 79–87.

  126. 126

    Moore RA, Derry S, MCQuay HJ . Indirect comparison of interventions using published randomised trials: systematic review of PDE-5 inhibits for erectile dysfunction. BMC Urol 2005; 5: 18.

  127. 127

    Carson CC, Hatzichristou DG, Carrier S, Lording D, Lyngdorf P, Aliotta P et al. Erectile response with vardenafil in sildenafil nonresponders: a multicentre, double-blind, 12-week, flexible-dose, placebo-controlled erectile dysfunction clinical trial. BJU 2004; 94: 1301–1309.

  128. 128

    Hatzichristou DG, Aliotta P, Auerback S, Barkin J, Lording D, Murdock M et al. Erectile response to vardenafil in men with a history of nonresponse to sildenafil: a time-from-dosing descriptive analysis. Clin Ther 2005; 27: 1452–1461.

  129. 129

    Padma-Nathan H, McMurray JG, Pullman WE, Whitaker JS, Saoud JB, Ferguson KM et al. On demand IC351 (Cialis) enhances erectile function in patients with erectile dysfunction. Int J Impot Res 2001; 13: 2–9.

  130. 130

    Brock GB, Mcmahon CG, Chen KK, Costigan T, Shen W, Watkins V et al. Efficacy and safety of tadalafil for the treatment of erectile dysfunction: results of integrated analyses. J Urol 2002; 168: 1332–1336.

  131. 131

    Eardley I, Gentle V, Austoni E, Hackett G, Lembo D, Wang C, Beardsworth A . Efficacy and safety of tadalafil in a Western European population of men with erectile dysfunction. BJU Int 2004; 94: 871–877.

  132. 132

    Seftel AD, Wilson SK, Knapp PM, Shin J, Wang WC, Ahuja S . The efficacy and safety of tadalafil in United States and Puerto Rican men with erectile dysfunction. J Urol 2004; 172: 652–657.

  133. 133

    Carson C, Shabsigh R, Segal S, Murphy A, Fredlund P, Kuepfer C . Efficacy, safety, and treatment satisfaction of tadalafil versus placebo in patients with erectile dysfunction evaluated at tertiary-care academic centers. Urology 2005; 65: 353–359.

  134. 134

    Rosen RC, Shabsigh R, Kuritzky L, Wang WC, Sides GD . The efficacy of tadalafil in improving sexual satisfaction and overall satisfaction in men with mild, moderate, and sever erectile dysfunction: a retrospective pooled analysis of data from randomized, placebo-controlled clinical trials. Curr Med Res Opin 2005; 21: 1701–1709.

  135. 135

    Montorsi F, Verheyden B, Meuleman E, Junemann KP, Moncada I, Valiquette L et al. Long-term safety and tolerability of tadalafil in the treatment of erectile dysfunction. Eur Urol 2004; 45: 339–344.

  136. 136

    Saenz De Tejada I, Anglin G, Knoght JR, Emmick JT . Effects of tadalafil on erectile dysfunction in men with diabetes. Diabet Care 2002; 25: 2159–2164.

  137. 137

    Forseca V, Seftel A, Denne J, Fredlund P . Impact of diabetes mellitus on the severity of erectile dysfunction and response to treatment: analysis of data from tadalafil clinical trials. Diabetologia 2004; 47: 1914–1923.

  138. 138

    Montorsi F, Nathan HP, McCullough A, Brock GB, Broderick G, Ahuja S et al. Tadalafil in the treatment of erectile dysfunction following bilateral nerve sparing radical retropubic prostatectomy: a randomized, double-blind, placebo controlled trial. J Urol 2004; 172: 1036–1041.

  139. 139

    Lewis RW, Sadovsky R, Eardley I, O'Leary M, Seftel A, Wang WC et al. The efficacy of tadalafil in clinical populations. J Sex Med 2005; 2: 517–531.

  140. 140

    McMahon C . Comparison of efficacy, safety, and tolerability of on-demand tadalafil and daily dosed tadalafil for the treatment of erectile dysfunction. J Sex Med 2005; 2: 415–425.

  141. 141

    McMahon C . Efficacy and safety of daily tadalafil in men with erectile dysfunction previously unresponsive to on-demand tadalafil. J Sex Med 2004; 1: 292–300.

  142. 142

    Govier F, Potempa AJ, Kaufman J, Denne J, Kovalenko P, Ahuja S . A multicenter, randomized, double-blind, crossover study of patient preference for tadalafil 20 mg or sildenafil citrate 50 mg during initiation of treatment for erectile dysfunction. Clin Ther 2003; 25: 2709–2723.

  143. 143

    Stroberg P, Murphy A, Costigan T . Switching patients with erectile dysfunction from sildenafil citrate to tadalafil: results of European multicenter, open-label study of patient preference. Clin Ther 2003; 25: 2724–2737.

  144. 144

    Von Keitz A, Rajfer J, Segal S, Murphy A, Denne J, Costigan T et al. A multicenter, randomized, double-blind, crossover study to evaluate patient preference between tadalafil and sildenafil. Eur Urol 2004; 45: 499–507.

  145. 145

    Del Popolo G, Li Marzi V, Mondaini N, Lombardi G . Time/duration effectiveness of sildenafil versus tadalafil in the treatment of erectile dysfunction in male spinal cord-injured patients. Spinal Cord 2004; 42: 643–648.

  146. 146

    Eardley I, Mirone V, Montorsi F, Ralph D, Kell P, Warner MR et al. An open-label, multicentre, randomized, crossover study comparing sildenafil citrate and tadalafil for treating erectile dysfunction in men naïve to phosphodiesterase 5 inhibitor therapy. BJU Int 2005; 96: 1323–1332.

  147. 147

    Stoberg P, Hedelin H, Ljunggren C . Prescribing all phosphodiesterase 5 inhibitors to a patient with erectile dysfunction – arealistic and feasible option in everyday clinical practice – outcomes of a simple treatment regime. Eur Urol 2006; 49: 900–907.

  148. 148

    McMahon M . Editorial comment. Eur Urol 2006; 49: 907.

  149. 149

    Mulhall JP . Understanding erectile dysfunction medication preference studies. Curr Opin Urol 2004; 14: 367–373.

  150. 150

    Mulhall JP, Montorsi F . Evaluating preference trials of oral phosphodiesterase 5 inhibitors for erectile dysfunction. Eur Urol 2006; 49: 30–37.

  151. 151

    Gilad R, Lampl Y, Eshel Y, Sadeh M . Tonic-clonic seizures in patients taking sildenafil. BMJ 2002; 325: 869.

  152. 152

    Koussa S, Hage CS, Togme A, Riachi M . Epileptic seizures and vardenafil. Rev Neurol (Paris) 2006; 162: 651–652.

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Doggrell, S. Do vardenafil and tadalafil have advantages over sildenafil in the treatment of erectile dysfunction?. Int J Impot Res 19, 281–295 (2007). https://doi.org/10.1038/sj.ijir.3901525

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Keywords

  • clinical trials
  • erectile dysfunction
  • quality-of-life
  • sildenafil
  • vardenafil
  • tadalafil

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