International Journal of Impotence Research (2007) 19, 281–295 & 2007 Nature Publishing Group All rights reserved 0955-9930/07 $30.00 www.nature.com/ijir

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

S Doggrell

School of Science, Charles Darwin University, Casuarina, Northern Territory, Australia

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 a1-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. International Journal of Impotence Research (2007) 19, 281–295. doi:10.1038/sj.ijir.3901525; published online 21 December 2006

Keywords: clinical trials; erectile dysfunction; quality-of-life; sildenafil; vardenafil; tadalafil

Introduction patients on dialysis, the incidence of ED is about 75%.6 ED is a side effect commonly associated with As many as 30 million men in the US have erectile use of the selective serotonin uptake inhibitors to dysfunction (ED),1 which is defined as the inability treat depression.7 ED is also common among a range to attain or maintain an erection sufficient for of other conditions (e.g. Parkinsonism, multiple satisfactory sexual performance. ED is estimated to sclerosis, spinal dysfunction). affect up to 50% of men between the ages of 40 and To induce penile erection, relaxation of the 70 years of age, and age is the variable most strongly smooth muscle cells of the corpus cavernosum and associated with ED.2,3 After adjustment for age, a associated arterioles is required. A major component higher probability of ED correlated with heart of this relaxation process is mediated by nitric oxide disease, hypertension, diabetes and associated med- stimulation of cGMP. In response to sexual stimula- ications.2 ED is frequently associated with depres- tion, the release of nitric oxide by nerve endings and sion, increased anxiety, poor self-esteem and endothelial cells increases the levels of cGMP to compromises interpersonal relationships.1 In dia- induce the erection. cGMP is readily hydrolyzed by betes mellitus, ED occurs at an earlier age and has a phosphodiesterase 5 (PDE5) resulting in restoration higher prevalence. In patients with localized pros- of quiescent muscle tone and detumescence. trate cancer treated with radiotherapy, ED estimates In the first part of this review, the pharmacology range from 15 to 60%.4,5 In end-stage renal disease 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. Correspondence: Dr S Doggrell, School of Science, Charles Consequently there is an emphasis on the safety of Darwin University, Darwin, Northern Territory 0909, Australia. the PDE5 inhibitors in patients with cardiovascular E-mail: [email protected] disease, and also whether this is linked to non- Received 5 June 2006; revised 12 September 2006; arteritic anterior ischaemic optic neuropathy accepted 17 September 2006; published online 21 December (NAION). The safety of the PDE5 inhibitors in men 2006 with benign prostatic hyperplasia is also considered. Vardenafil and tadalafil have advantages over sildenafil S Doggrell 282 This is followed by a description of the clinical trials 60 min with sildenafil and vardenafil, but later with with sildenafil in ED. The next sections consider the tadalafil (2 h). The half-life of tadalafil is 17.5 h, clinical trials with vardenafil and tadalafil, and compared to 3.8 h for sildenafil and 3.9 h for discuss the similarities and differences to sildenafil. vardenafil.19 Consequently, tadalafil would be ex- The development of sildenafil for the treatment of pected to have a longer duration of action than pulmonary hypertension and Raynaud’s disease are sildenafil and vardenafil. In accord with the half-life not discussed in this article. and directions given with tadalafil, many men do attempt intercourse in the 12–36 h window after administration.20 The chances of successful sexual Molecular pharmacology intercourse were increased 24 and 36 h after the administration of tadalafil. In a group of 327 Sildenafil, vardenafil and tadalafil are selective patients, 53% had successful intercourse at 24 h 8 21 inhibitors of PDE5 with IC50 values of 3.9 nM, (placebo, 29%) and 59% at 36 h (placebo, 28%). 9 10 0.7 nM and 5 nM, respectively. For sildenafil, the Another study showed that tadalafil 10 mg was IC50 values against PDE1-4 were 80–48500 times nearly as effective as tadalafil 20 mg after 24 and 22 greater than for PDE5 (3.5 nM), and ninefold greater 36 h. The successful intercourse attempts at 24 h than for PDE6.11 With vardenafil there is a 16-fold were 42, 56 and 67%, and at 36 h, 33, 56 and 62%, 22 selectivity for PDE5 (0.7 nM) over PDE6 (11 nM), and for placebo, tadalafil 10 and 20 mg, respectively. 200–41000 selectivity over PDE1, 3 and 4.12 For Sildenafil and vardenafil are also active for up to tadalafil, there is 1000 selectivity for PDE5 over 8–12 h. Thus, in a small study with 36 evaluable PDE1-4, and PDE6.10 To my knowledge, sildenafil, patients with ED, 97 and 74% of patients achieved vardenafil and tadalafil have not been reported to erections that resulted in successful intercourse with inhibit PDEs 7-10. completion (maintenance of erection) at 1 and 12 h PDE11 is the latest isoform of the PDE family to be postdose, respectively.23 Vardenafil has also been identified. PDE11 is highly expressed in the testis, shown to improve sexual activity 8 h postdose.24 prostate and spermatozoa, and may have a role in Vardenafil undergoes substantial first pass liver male reproduction.13 The PDE5A1/PDE11A4 selec- metabolism. As all three PDE5 inhibitors are tivities for sildenafil, vardenafil and tadalafil are metabolized by cytochrome P450 3A4, non-selective 1000-, 9300- and 40-fold, and this suggests that these inhibitors (cimetidine) or selective inhibitors of this PDE inhibitors are unlikely to inhibit PDE11A4 in enzyme (e.g. erythromycin, ketoconazole, ritonavir) patients with ED.14 increase plasma levels. In patients with moderate In addition to half-lives, dissociation rates from hepatic failure, the plasma levels of vardenafil may binding sites are determinants of the duration of be elevated, and a lower starting dose is recom- action of drugs with slow dissociation prolonging mended. Healthy elderly subjects (X65 years) have duration of action. The ability of the 3H-form of the a reduced clearance of sildenafil and tadalafil and PDE5 inhibitors to dissociate from the enzyme has an increased area under the curve, probably due to been measured. Vardenafil dissociates at a slower decreased hepatic clearance.25 Sildenafil, vardenafil rate than tadalafil or sildenafil.15 and tadalafil are excreted as metabolites mainly in the faeces. A high-fat meal delays the onset of action for Pharmacokinetics sildenafil and vardenafil,26 but not tadalafil.27 A sublingual preparation of sildenafil has been devel- Sildenafil, vardenafil and tadalafil are rapidly ab- oped, and this will not be affected by food. An initial sorbed after oral administration. The absolute bio- study with sublingual sildenafil (20 mg) has shown availability for sildenafil and vardenafil is about 40 that the mean onset of action was 15.5 min and and 15%, respectively, whereas the absolute bioavail- lasted for an average of 40 min with 13/20 of subjects ability of tadalafil has not been reported to date. All with ED achieving erections.28 Sublingual sildenafil three phosphodiesterase inhibitors have a rapid onset is not available by prescription, but non-propriety of action. In men who respond to sildenafil, within versions are available for purchase on the net. 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 Safety men with ED taking vardenafil 10/20 mg had at least one erection in the first four doses perceived to be The tolerability and side effects of PDE5 inhibitors sufficient for penetration (placebo, 26%).17 Also, in in clinical trials of men with ED is considered in the the home setting, 51% of men taking tadalafil 20 mg clinical trials sections: sildenafil, vardenafil and had at least one successful intercourse attempt tadalafil. The safety of the PDE5 inhibitors in within 30 min (placebo, 35%).18 patients with cardiac disease, and any possibly link The maximum plasma concentration with silde- to NAION is considered in this section, as is the nafil, vardenafil and tadalafil is obtained after safety in men with benign prostatic hyperplasia.

International Journal of Impotence Research Vardenafil and tadalafil have advantages over sildenafil S Doggrell 283 In patients with cardiac disease glyceryl trinitrate alone have little effect on blood Inhibiting PDE5 increases the levels of cGMP, pressure, but these effects were increased in the and this will occur at all sites where PDE5 is presence of sildenafil.35 One of the 15 patients had actively hydrolyzing cGMP. Thus, it is possible that a major drop in blood pressure with the combina- PDE5 inhibitors will potentiate the effect of tion, and it was suggested that the nitrates and endogenous vasodilators that cause vasodilation sildenafil should not be used in combination.35 via cGMP (nitric oxide, acetylcholine). Sildenafil Based on the pharmacokinetic profile of sildenafil, alone has modest effects on the cardiovascular the manufacturer suggests that nitrates should not system, although cerebral vasodilation probably be taken until at least 24 h after dosing with underlies the adverse effect of headache. In healthy sildenafil. men, sildenafil transiently decreased systolic Sildenafil will not alter the effects of drugs and diastolic blood pressure by under 10 mm Hg.29 that relax blood vessels by a mechanism not In 14 men with coronary artery disease and severe involving cGMP, but the effects may be additive. stenosis of at least one vessel, sildenafil 100 mg Thus, in hypertensive patients, the blood pressure produced only small decreases in systemic lowering effects of the calcium channel blocker and pulmonary arterial pressures and had no effect amlodipine and sildenafil were additive.36 Another on pulmonary-capillary wedge pressure, right study has shown that in 608 men with ED taking atrial pressure, heart rate or cardiac output.30 antihypertensive medication (diuretic, b-blockers, Coronary flow reserve increased by 13% in the a-adrenoceptor antagonists, ACE inhibitors or cal- normal coronary arteries but was unaffected in the cium channel blockers), sildenafil had a similar diseased arteries by sildenafil.30 These results ability to decrease blood pressure by a small extent suggest that sildenafil alone is safe to use in men (À3.6/À1.9 mm Hg) as in patients not taking with coronary artery disease. antihypertensives.36 The incidence of adverse There were some early indications that sildenafil effects, including adverse effects related to de- might increase the incidence of myocardial infarc- creases in blood pressure (hypotension, dizziness tion, ventricular tachycardia and death in ED and syncope) was similar in sildenafil patients with patients with coronary artery disease, but it has or without concomitant antihypertensive treat- been argued that these outcomes may just be ment.37 the normal complications or progression of coronary As with sildenafil, exercise testing in men with artery disease. To test this, the cardiovascular stable coronary artery disease, showed that varde- effects of sildenafil during exercise were determined nafil at 10 mg did not impair the ability of 41 in men with known or probably coronary artery patients to exercise at levels equivalent or greater disease.31 Before the study, nitrates were discon- than attained during sexual intercourse.38 At base- tinued.31 Although the 105 patients enrolled line (1 h after taking vardenafil or placebo), systolic had stable angina, their heart function was and diastolic blood pressure was 6 and 5 mm Hg quite good as the mean left ventricular ejection less, respectively, with vardenafil than placebo, fraction was 56%.31 Compared to placebo, sildenafil and heart rate was 3 beats/min higher.38 At peak had no additional effects on the symptoms, exercise exercise, vardenafil did not alter blood pressure or duration, or presence or extent of exercise-induced heart rate, relative to placebo.38 There are no peer- ischaemia (dyspnea or angina).31 This confirms reviewed published studies of the interaction that sildenafil is safe to use in ED patients with between vardenafil and the nitrates. The patient stable coronary artery disease and not taking information sheet for vardenafil states that in 18 nitrates. Exercise-testing in 23 ED patients with healthy subjects pretreated with vardenafil 20 mg, heart failure (left ventricular ejection fraction of there was an additional reduction in blood pressure 23%), also showed that sildenafil did not and increase in heart rate with nitroglycerin admin- have detrimental effects on the cardiovascular istration, and it is recommended that nitrates not system.32 Large-scale safety evaluations have also be used until at least 24 h after vardenafil.39 In confirmed that there is no increase in myocardial subjects with ED and hypertension, vardenafil did infarction or all-cause mortality rates in patients not alter the blood pressure of subjects taking anti- taking sildenafil.33 hypertensives.40 The nitrates are commonly used in the prevention In healthy subjects, tadalafil caused very small and treatment of angina, and the actions of these changes in blood pressure that were not considered drugs are terminated by cGMP hydrolysis in blood to be clinically relevant.38 Tadalafil reduced mean vessels. Thus, it seemed probably that sildenafil standing blood pressure by À4.6 mm Hg in patients would increase the effects of the nitrates, and this is with hypertension, but this unlikely to be of major in fact the case. In healthy male volunteers treated concern.41 Tadalafil has no effect on the time to with sildenafil, the ability of sublingual glyceryl exercise treadmill test-induced myocardial ischae- nitrate to decrease blood pressure was increased, mia in patients with stable coronary artery disease.42 precipitating symptomatic hypotension.34 In volun- Tadalafil has a similar interaction as sildenafil with teers with angina, isosorbide mononitrate and nitrates in patients with coronary artery disease that

International Journal of Impotence Research Vardenafil and tadalafil have advantages over sildenafil S Doggrell 284 is it increases the blood pressure lowering normally with 38 age-matched controls without a history of observed with nitroglycerin and isosorbide mono- NAOIN, showed that males with NAION were no nitrate.41,42 Tadalafil has a longer half-life and more likely to have a history of sildenafil or tadalafil duration of action than sildenafil or vardenafil. use than the age-matched controls.51 The same Thus, the interaction of tadalafil with the nitrates study showed that men with a history of myocardial lasts longer than with sildenafil and vardenafil. The infarction of hypertension were at risk of NAION.51 lowering of blood pressure in response to nitro- Similarly, pooled safety data from global clinical glycerin after tadalafil was greater than in the trials and European observational studies, with placebo group after 4, 8 and 24 h, but similar at 13 000 men and 35 000 patient years, showed an 48 h.43 Thus, nitrates should not be administered incidence of 2.8 cases of NAION per 10 000 patients- until 48 h after tadalafil.43 years of sildenafil exposures, which is similar to the Tadalafil is safe in patients receiving antihyper- incidence in the general population.52 tensives.42 Across the studies where tadalafil has been used for ED, there is no evidence for increased myocardial infarction or cardiac death In subjects with benign prostatic hyperplasia with tadalafil.44 Although not commonly used as antihypertensives As none of these PDE5 inhibitors inhibit the any longer, the a1-adrenoceptors antagonists are HERG (Human Ether-a-go-go-Related Gene) potas- used in the treatment of benign prostatic hyper- sium current at therapeutically relevant concentra- plasia, and their use is often associated with a small tions, they are unlikely to induce arrhythmias by decrease in blood pressure. As benign prostatic interacting with the HERG channel.45 Consistent hyperplasia and ED can coexist, it is possible for with this, sildenafil and tadalafil do not cause subject to be prescribed both a1-adrenoceptors clinically significant prolongation of QTc (a measure antagonists and sildenafil. Two of 20 patients of ventricular repolarization) in healthy volunteers. receiving the a1-adrenoceptors antagonist doxazosin Vardenafil does cause a small increase in QTc in and sildenafil 50 mg developed symptomatic hypo- healthy men, and has a warning for patients at risk tension.53 As a result of this finding, it is now for QTc prolongation.46 suggested that sildenafil should not be taken within a 4-h window of an a1-adrenoceptors antagonist. These include the a1-adrenoceptors antagonists Non-arteritic anterior ischaemic optic neuropathy (terazosin, alfuzosin and tamsulosin) for which the NAION is a sudden loss of eyesight because blood interaction with sildenafil has not been specifically flow is blocked to the optic nerve. NAOIN is studied. probably associated with vascular insufficiency at Vardenafil should be used with extreme caution the optic nerve head, leading to ischaemia, and has in patients taking a1-adrenoceptors antagonists, as it an annual incidence of 2.3–10.2 per 100 000 persons has been shown to cause a major reduction in blood over 50 years of age.47 Some patients have reported pressure when administered with terazosin, an developing NAION after ingestion of sildenafil, and a1-adrenoceptors antagonist used in the treatment the details of five such cases were reported in of benign prostatic hyperplasia.53 The selective 48 2002. Subsequently, in a set of seven patients who a1a-adrenoceptors (prostatic) antagonist tamsulosin developed NAION with sildenafil, it was shown that is generally considered to have a lesser effect on all the affected individuals had pre-existing hyper- blood pressure that the non-selective agents. Never- tension, diabetes, elevated cholesterol or hyper- theless, standing hypotension has also been re- lipidemia.49 ported with the combination of tamsulosin and By July 2005, the FDA reported visual loss in 38 vardenafil, and thus the combination of a1-adreno- patients after use of sildenafil and one after ceptors antagonists and vardenafil are not recom- vardenafil, and issued an alert for all the PDE5 mended.53 inhbitors.50 The alert says that it is unknown Similarly, tadalafil and doxazosin are associated whether sildenafil, vardenafil or tadalafil cause with hypotension, whereas tadalafil and tamsulosin NAION, and that NAION also happens in men are not, in healthy normotensive men.54 Recently, who do not take these medicine.50 They suggest that in 18 healthy, middle-aged men, tadalafil 20 mg people have a higher chance of NAOIN if they have showed no clinically relevant hemodynamic inter- heart disease, are over 50 years old, have diabetes, actions with alfuzosin 10 mg daily, although one have high blood pressure, have high cholesterol, subject did have an asymptomatic standing pressure smoke or have certain eye problems.50 The PDE5 of o85 mm Hg.55 Patients are advised to use tadalafil inhibitors are not contraindicated in any of these and a1-adrenoceptors antagonists with caution. For conditions, but patients are advised to stop taking those patients taking tadalafil, treatment with a1- the inhibitors if they have eye sight loss.50 adrenoceptors antagonists should start with the There is no clear evidence linking PDE inhibitor lowest dose. Similarly for patients using a1-adreno- use to NAION. A retrospective matched case– ceptors antagonists, treatment with tadalafil should control study of 38 cases of NAOIN were matched start with the lowest dose.

International Journal of Impotence Research Vardenafil and tadalafil have advantages over sildenafil S Doggrell 285 Clinical trials with sildenafil Table 1 Outcome of clinical trials of sildenafil in patients with ED of varying etiologies Trials combining men with ED of varying etiologies Reference Number Outcomea with sildenafil 100 mg In 1996, it was reported that in 12 patients with ED, of sildenafil (Viagra) enhanced the erectile response patients (duration and rigidity of erection) to visual sexual 56 stimulation. This first small controlled crossover 57 532 Improved erections in 84% (placebo, 25%) trial of sildenafil in 12 men with ED showed that 57 329 Improved erections in 74% (placebo, 19%) sildenafil increased the duration of rigidity, and the 58 254 Improved erections in 83% (placebo, 52%) 56 59 315 Improved erections in 82% (placebo, 24%) total number of erections. 60 133 Improved erections in 83% (placebo, 60%) These initial observations were followed by major 61 514 Improved erections in 86% (placebo, 24%) studies of 861 men with a clinical diagnosis of ED 57 of 6 months duration or longer. Most of the men Abbreviation: ED, erectile dysfunction. a studied (70%) had organic ED, but 11% had Measured on question 3 of the International Index of Erectile psychogenic ED and 18% had mixed ED.57 Men Function. 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 tion, it remained effective in most of the patients for before planned sexual activity.57 Outcomes were the year.63 questions three (frequency of penetration) and four In the real clinical setting, sildenafil has been (maintenance of erections after penetration) of the shown to be less effective in elderly men (mean International Index of Erectile Function, completed age ¼ 64 years) with ED than reported in the large at 0, 12 and 24 weeks.57 After 24 weeks, improved clinical trials.64 Thus, sildenafil was only effica- erections were reported by 56, 77 and 84% of men cious in 47% (76/162) of men with ED, and of these taking 25, 50 and 100 mg of sildenafil, respec- 58% were using the 100 mg dose, and 41% the 50 mg tively.57 dose.64 Uncontrolled diabetes, current smoking, In the other part of the study, the flexible hypogonadism and low pre-treatment erectile func- dose-escalation study, 329 men received either tion were predictors of a poor response.64 placebo or 50 mg of sildenafil, 1 h before sexual When the safety of sildenafil was evaluated in 3700 activity for 12 weeks, and during following visits patients, the most commonly reported adverse effects during this time, they doubled or reduced the remained headache (16 and 4% placebo), flushing (10 dose on the basis of the therapeutic response.57 At and 1% placebo), and dyspepsia (7 and 2% placebo), the end of the 12 weeks, most men (74%) were which were all transient and mild or moderate in taking 100 mg of sildenafil, and the scores for nature.65 These adverse effects did not lead to frequency and maintenance were higher for the last discontinuation as the discontinuation rates were 4 weeks than earlier.57 After 12 weeks, 74% of men similar in the sildenafil and placebo groups.65 Long- reported improved erections, compared to 19% term, open-label studies have demonstrated that in the control group.57 The most common side sildenafil continues to be well tolerated for 44years effects were transient headache, flushing, dyspepsia with no increase in the incidence or severity of and rhinitis.56 Transient visual disturbances (i.e. adverse effects.28 The higher doses of sildenafil can changes in the perception of colour hue or bright- cause slight changes in colour vision (‘blue haze’) and ness) were reported by some men.57 This initial increased sensitivity to light, probably by inhibiting flexible dose-escalation study was performed in PDE6, but these effects are transient, fully reversible, the US, but similar studies with similar outcomes and rarely lead to treatment discontinuation.28 have been performed elsewhere (e.g. Malaysian, In a quality of partnership study of 105 patients Singaporean and Filipino,58 European,59 Korean60) and their female partners, the tenderness and (Table 1). togetherness subscales were improved in appropri- The effectiveness of sildenafil in patients with ately treated ED patients, compared to untreated various etiologies was confirmed in another large controls.66 When sildenafil in ED was compared to fixed-dose study where the 514 men had ED that age-matched healthy control subjects, it was sug- was organic in 32%, psychogenic in 25% and mixed gested that sildenafil gave a near normalization of in 43%.61 In a follow-up of 267 patients, there was erectile function.67 On the International Index of a correlation between baseline sexual function and Erectile Function, sildenafil has been shown to response to sildenafil, but even in patients with improve general mental healthy (well-being, self- severe ED there is a 41% satisfaction rate.62 There control, satisfaction with relationship, health are also lower rates of satisfaction with sildenafil relative to 1 year ago, and mental health).68 The in patients with neurogenic causes of ED (diabetes, Self-Esteem And Relationship (SEAR) questionnaire prostate surgery) than psychogenic or vasculogenic is a validated psychometric test for men with ED. ED.62 A 1-year extension study showed that in Compared to the placebo group, the group treated patients where sildenafil improved erectile func- with sildenafil (n ¼ 128) had greater improvements

International Journal of Impotence Research Vardenafil and tadalafil have advantages over sildenafil S Doggrell 286 in all SEAR components.69 Another study has not respond to sildenafil, a double-blind trial of the shown that sildenafil is associated with the normal- long acting dopamine agonist cabergoline and ization of relationships, confidence and self-esteem placebo, showed only a moderate response to in the SEAR questionnaire in men with ED.70 cabergoline (placebo, 7.1%; cabergoline, 31.2%).79 In patients who do not respond to sildenafil at After the initial studies with sildenafil in ED in 100 mg, increasing the dose increases the responders otherwise relatively healthy men or large groups of but also increases the adverse effects. Most of the men with ED of varying etiologies, subsequent non-responders in the trial showing this had studies have been in men with specific health vascular disease.71 Only 13 of 54 patients, who problems. had previously not responded to sildenafil at 100 mg, had improved erectile function with 200 mg sildenafil, whereas 34 of the 54 reported Diabetes and cardiovascular adverse effects.71 A preliminary study showing that sildenafil im- Vardenafil has been shown to be effective in men proved penile rigidity and vaginal penetration in 21 with ED unresponsive to sildenafil (discussed in men with diabetes and ED was published in 1998.80 Clinical trials with vardenafil section), and it has Subsequently, a more substantial study was under- been inferred that this shows that vardenafil had taken with 252 men with ED and diabetes (pre- advantages over sildenafil. However, it may be that dominantly type II), using the same protocol as in the sildenafil was just being used inappropriately. the flexible dose-escalation study (see previously).81 A recent study has shown that of 100 consecutive At 12 weeks, most men (93%) in the sildenafil group sildenafil non-responders, 56 had been using the were taking the 100 mg dose, and 61% reported a drug inappropriately; 45 had never used the highest successful attempt at intercourse compared to 22% recommended dose (100 mg), 32 had taken the pill in the placebo group.81 Adverse effects were similar with a full stomach after a meal, 22 had taken the as in the non-diabetics and there was no excess of drug just before initiation of sexual activity and 12 cardiovascular events.81 Sildenafil was similarly were not aware that sexual stimulation was required effective in a trial that included only patients with to achieve an erection.72 Another study recruited (by type I diabetes.82 newspaper advertisement) 220 subjects with ED Sildenafil is not effective in diabetic patients with who had failed sildenafil treatment, and found that severe ED, where injections of PGE and/or papa- the majority had received limited or no instruction 1 verine may be preferred. Thus, when 81 ED patients on sildenafil use when it was prescribed.73 With with diabetes (29 with type I, 52 with type II), who counselling and dose adjustment to sildenafil had been successfully treated with injections, were 100 mg, if necessary, most subjects had an improve- changed to sildenafil 100 mg, 23 discontinued ment in erectile function.73 because of insufficiency.83 Men with insulin-depen- Before the introduction of oral treatments for ED, dent diabetes or requiring both PGE and/or papa- intracavernous prostaglandin E (PGE ) was used in 1 1 1 verine were more likely not to respond to the treatment of ED. Of 176 patients, 69% success- sildenafil.83 fully changed from PGE to oral sildenafil and 1 Sildenafil improved erectile function to a similar elected to continue oral treatment.74 Men with ED extent in ED patients taking antihypertensives as in who were switched from PGE to sildenafil were 1 patients not taking antihypertensives.32 Sildenafil equally satisfied with the onset of action, duration of also improved erectile function in patients with action and confidence in ability to engage in sexual stable coronary artery disease.84 Decreased sexual activity.75 The men expressed greater overall treat- activity and ED are commonly in men with chronic ment satisfaction with sildenafil, better ease of use, heart failure. Sildenafil was compared to placebo in and naturalness of erectile process.75 Partners were 322 men with heart failure, but not at high cardiac overall more satisfied with sildenafil.75 risk or taking nitrates.85 In ED in these patients, The dopamine receptor agonist apomorphine is an flexible dosing with sildenafil improved erections alternative to PDE5 inhibitors for the treatment of (18 vs 74%) and intercourse (68 vs 16%).85 It is ED. Most of the studies comparing apomorphine important to remember that these results should not with placebo have shown lower rates of success in be generalized to all patients with heart failure. overcoming ED than generally reported with silde- nafil.76 In a study comparing sublingual apomor- phine 3 mg with oral sildenafil (50 mg) for ED, sildenafil was more effective than apomorphine in Urogenital causing erection firm enough for intercourse (85 Treatment for either prostate cancer or benign vs 44%).77 In a crossover study of sildenafil and prostatic hyperplasia may lead to ED. Treatment of apomorphine, the successful intercourse rates were ED with sildenafil in patients who had had radio- 75 and 35%, respectively.78 Importantly, at the end therapy for prostate cancer was initially shown to be of the study, 96% of the men expressed a preference effective in non-controlled trials and then confirmed for sildenafil.78 In a study of 370 subjects who did in a controlled trial. When 50 patients with ED after

International Journal of Impotence Research Vardenafil and tadalafil have advantages over sildenafil S Doggrell 287 radiotherapy for localized prostate cancer, were for the ED, compared to placebo.95 Associated with treated with 50 mg sildenafil, firmness and durabil- this improvement in erectile function, there was ity of the erection improved in most (66–74%) of the a marked improvement in depressive symptoms patients.86 Patients with less severe dysfunction (Hamilton depression score decreases; sildenafil were most likely to benefit.86 In the 11 patients who 10.3, placebo, 2.3).95 had no improvement in erectile firmness, no Estimates of the ED associated with the use improvement was obtained with the higher 100 mg of selective serotonin reuptake inhibitors (SSRIs) dose of sildenafil.86 Another study found that 50 of to treat depression range from 3 to 80%.7 A retro- 62 patients with ED, either before or after prostate spective sub-analysis of trials with sildenafil brachytherapy for adenocarcinoma, responded to showed that sildenafil improved the ability to sildenafil, with only diabetes predicting failure.87 achieve and maintain an erection in ED patients The ability of sildenafil to improve erectile function taking SSRIs.96 These results have been confirmed in men who have had radiotherapy for prostate in double-blind studies of males with major depres- cancer has been confirmed in a double-blind study sion in remission and sexual dysfunction associated of 60 patients.88 with SSRIs.97,98 Erectile function, arousal, ejacula- Analysis of patients in a large study with patients tion, orgasm and overall satisfaction improved with of mixed aetiology showed that sildenafil was less sildenafil, compared to placebo, and depression effective in neurogenic causes of ED.57 In patients remained in remission.97,98 ED is also associated with ED after a radical prostatectomy for prostate with the use of the antipsychotic drugs olanzapine cancer, sildenafil was effective in 12 of 15 who had and risperidone, and sildenafil is also effective in had a bilateral nerve-sparing procedure, but not in this (olanzapine,99 resperidone100). Sildenafil was those who had undergone a unilateral nerve sparing also safe and effective in the treatment of another procedure or a non-nerve-sparing procedure.89 31 subjects with antipsychotic-induced ED (risper- Another study of 84 men with radical retropubic idone, n ¼ 15: olanzapine, 12).101 prostatectomy found that 45 had improved erections Parkinsonism is a common feature of multiple with sildenafil.90 A survey in 170 men after radical system atrophy along with autonomic and urinary prostatectomy, showed that in men under 55 years dysfunction. In ED patients with Parkinson’s disease in who both neurovascular bundles had been or multiple system atrophy and a standing preserved, had a response rate to sildenafil of blood pressure of at least 90/50 mm Hg, sildenafil 80%.91 In contrast, older patients with one pre- improved erectile function.102 In Parkinson’s dis- served neurovascular bundles, and those patients ease, sildenafil had its usual minimal effect on with no preserved neurovascular bundles did not blood pressure, whereas in multiple system atro- have a response to sildenafil.91 A recent systematic phy, sildenafil caused orthostatic hypotension.102 review of sildenafil in men with ED following This suggests that sildenafil should not be used in radical prostatectomy has shown a lower response multiple system atrophy, and when parkinsonism is rate after non-nerve-sparing (0–15%) than nerve- present, a definite diagnosis of Parkinson’s disease sparing surgery (35–75%).92 However, probably is needed before the use of sildenafil.102 because of the wide range of values, the review ED is common in men with multiple sclerosis, and could not distinguish between the effectiveness of sildenafil is effective in this population. Thus, in sildenafil in unilateral (10–80%) and bilateral nerve 217 men with multiple sclerosis and ED, flexible sparing therapy (35–75%).92 dose sildenafil improved erections compared to ED is a common sequel of pelvic fracture urethral placebo (89 vs 24%), and also improved quality dysfunction. After urethroplasty in 15 such patients, of life.103 47% overcame their ED with sildenafil 100 mg.93 ED is a common complication of spinal cord Sildenafil was much more effective in those subjects injury and in spina bifida. Small studies initially with neurogenic ED (60%) than those with arterial showed that sildenafil was effective in men with ED damage induced ED (20%).93 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 Central nervous system including spinal dysfunction When sildenafil was specifically studied in 44 men with psychogenic ED and no established organic Rectal excision and renal failure cause, sildenafil increased the erections adequate Rectal excision is associated with ED, probably for sexual intercourse and level of sexual satisfac- by damaging the pelvic parasympathetic nerve.107 tion.94 Depressed men commonly have ED and men Sildenafil was effective in 79% of patients with ED with ED are commonly depressed. In 152 ED after rectal excision for cancer or inflammatory patients with a mean score of 16.9 on the Hamilton bowel disease.107 In 41 patients with end-stage Depression Rating Score, sildenafil was efficacious kidney failure and ED, but no diabetes, sildenafil

International Journal of Impotence Research Vardenafil and tadalafil have advantages over sildenafil S Doggrell 288 improved erectile function in 85% of patients (10%, Vardenafil has not been tested in individual trials placebo).108 Sildenafil also improves erectile func- in such a broad range of conditions associated with tion in men who have ED following a kidney ED as sildenafil. Although it has been shown to transplant.109 be effective in ED after radical retropubic prosta- tectomy for adenocarcinoma,123 and spinal cord injury.124 Vardenafil has been tested in mild untreated depression and ED, as ED and depression Clinical trials with vardenafil are highly associated. Subjects received either placebo or vardenafil 10 mg, with the option of Smaller doses of vardenafil than sildenafil are used titration to 5 or 20 mg, and vardenafil was shown to to treat ED, as vardenafil is more potent than improve both erectile function and the Hamilton sildenafil in inhibiting PDE5. Single 10, 20110 and score for depression.125 40 mg111 doses of vardenafil (Levitra) were first Vardenafil has only been compared to sildenafil reported to increase penile rigidity and tumescence indirectly by systematically reviewing the trials to visual sexual stimulation in patients with ED in with sildenafil, vardenafil and tadalafil, and this 2001. These were followed by larger trials including review (discussed in more detail in the clinical a comparison of 5, 10 and 20 mg vardenafil to trials with tadalafil section) has shown that all three placebo in 580 men with mild to severe ED of mixed PDE5 inhibitors have had similarly efficacy and aetiology (organic B30%, psychogenic B30%, tolerability.126 mixed B40%).112 As with the sildenafil clinical Vardenafil has been tested in men with ED trials, patients taking nitrates were excluded, and unresponsive to sildenafil, and shown to be more patients were required to take the medication about effective than placebo treatment. The study enrolled 1 h before intended intercourse.112 With vardenafil 463 men with ED unresponsive to sildenafil (no at 12 weeks, there was a dose-related improvement response in at least four of six attempts with in erectile function, with 80% of the patients in the sildenafil) to vardenafil 10 mg (that could be titrated 20 mg group having improved erections (placebo, to 5 or 20 mg) or placebo.127 Compared to placebo, 30%).112 These outcomes are in the same range as the percentage of penetrations (30 vs 62%) and with sildenafil 100 mg. Also similarly to clinical successful intercourse (11 vs 46%) was higher with trials with sildenafil, the most frequent adverse vardenafil.127 Also, this study shown that vardenafil effects with vardenafil were headache (7–15%), was more effective than placebo from after 0.25 h flushing (10–11%) and up to 7% for dyspepsia or until beyond 6 h.128 rhinitis.112 No abnormal colour vision perception In order to replace sildenafil in the treatment (associated with inhibiting PDE6) was reported.112 of ED, vardenafil will have to be shown to Further analysis showed the effects of vardenafil be superior to sildenafil. To date, there are no were similar in the organic, psychogenic and mixed obvious major differences between sildenafil groups, and regardless of baseline severity.113,114 and vardenafil. One point of difference is that Similar results were obtained in a 6 month trials no alterations of colour vision were reported in the of 5, 10 or 20 mg vardenafil or placebo in 805 ED early studies with vardenafil.112,113,116,117 whereas 115 patients, mostly of organic aetiology, a 6 month transient visual disturbances were reported in the trial of 5, 10 or 20 mg vardenafil in 1650 men in early studies with sildenafil. There are no clinical 116 a broad of men with ED, and in flexible-dose trials directly comparing sildenafil and vardenafil, 117,118 studies starting with 10 mg vardenafil. A 12- and such trials should be undertaken to determine if month extension to a 12-month trial of 566 men with there are any differences between the drugs. ED of 10 and 20 mg vardenafil, showed that vardenafil had long-term efficacy, reliability and tolerability.119 Vardenafil has been shown to im- Clinical trials with tadalafil prove both the male with ED114,120,121 and female partner’s sexual quality-of-life.121 The first major trial of the effects of tadalafil (Cialis) In 452 ED patients with diabetes (predominantly in ED was published in 2001, and compared type II), 54% of those taking 20 mg vardenafil were tadalafil at 2, 5, 10 or 20 mg with placebo in 179 able to maintain an erection until the completion men over 3 weeks, excluding patients taking of intercourse (placebo, 23%).122 The overall re- nitrates.129 Patients were instructed to take a max- sponder rate for improved erections (measured as imum of one dose daily as needed over 21 days, the global assessment question ‘Has the treatment but not to exceed 14 doses.129 A maximum effect you have been taking over the past 4 weeks seemed to be apparent with 10 mg tadalafil, which improved your erections’) at 12 weeks, was 54 and was about 70% of successful attempts, compared to 72% in the vardenafil 10 and 20 mg, respectively 27% with placebo.129 Headache and dyspepsia were (placebo, 23%).122 Lower rates of successful inter- the most common adverse effects reported with course were achieved when the ED was severe at tadalafil.129 No alterations of colour vision were baseline (vardenafil 20 mg, 40%; placebo, 11%).122 reported.129

International Journal of Impotence Research Vardenafil and tadalafil have advantages over sildenafil S Doggrell 289 When the data from five clinical trials were that tadalafil (10 or 20 mg) was effective in all sub- combined, it was shown that in 1112 men with ED populations.139 The sub-populations were race (Cau- (B60% organic, B30% mixed) there was greater casion, African descent, Hispanic, Asian), age, body benefit with tadalafil at 25 mg than at 10 mg on mass index, ED aetiology, ED severity, ED duration, erectile function over 12 weeks.130 With the self- smoking, prior sildenafil use, presence of co-morbid administration prior to sexual intercourse, there conditions (diabetes, hypertension, cardiovascular were no timing restrictions or restrictions on food disease, hyperlipidemia, depression, benign pro- and alcohol intake.130 The successful intercourse static hyperplasia) and treatment with antihyper- attempts were 61 and 75% with 10 and 25 mg tensives or antidepressants.139 tadalafil, respectively, compared with 32% in the The efficacy of on demand tadalafil 20 mg and control group.130 Patients most severely affected daily dosed tadalafil 10 mg for the treatment of ED with ED tended to have greater improvements in has been compared.140 The rates for sexual inter- erectile function.130 The efficacy of tadalafil was course completion (Sexual Encounter Profile 3) were similar for patients older than 65 and their younger higher with daily tadalafil (84%) than with on- counterparts.130 About 20% of patients in this trial demand tadalafil (69%).140 In 112 men who were had diabetes, and in this population up to previously unresponsive to on-demand tadalafil for 76% reported improved erections.130 The most ED, better results were obtained with tadalafil daily common adverse effects reported were headache at flexible 10 or 20 mg doses.141 Thus, improved (14%; placebo, 6%) and dyspepsia (10%; placebo erections were reported by 69% of men on daily 2%), and there were no effects on vision.130 tadalafil, compared to 42% previously when they In a trial of 220 Western European men with ED, were taking on demand tadalafil.141 This findings tadalafil 20 mg provided successful sexual inter- need to be verified in a parallel trial comparing on- course to 74%, compared to 30% of those treated demand and daily tadalafil, as it is possible that with placebo.131 The most common adverse effects some of the response seen in this trial may have were headache, dyspepsia, flushing, back pain, pain been a placebo response. in limb and myalgia.131 In a trial of 207 US and In comparison with sildenafil, the major differ- Puerto Rican men, it was shown that the most ences, which are evident from comparing trials with successful intercourse attempts occurred between 4 either sildenafil or tadalafil, are that there is no and 36 h after taking tadalafil with 83% of men requirement to take tadalafil 1 h before sexual taking tadalafil reporting improved erections vs 20% intercourse, and tadalafil does not affect vision. A placebo.132 Another study confirmed the efficacy most interesting development, which has not and adverse effect profile with tadalafil, and also occurred with vardenafil, is comparison trials showed that patients and their sexual partners were between tadalafil and sildenafil. more satisfied than those given placebo.133 Im- proved sexual satisfaction with tadalafil 10 and 20 mg has also been reported in men with mild, Comparative trials moderate and severe ED.134 The long-term safety and tolerability of tadalafil A fixed dose, 2-period crossover trial of 213 men was studied in a 24-month open-label extension with ED, compared 20 mg tadalafil with 50 mg of previous studies, and the good safety and sildenafil, either in tadalafil-sildenafil or sildena- tolerability of tadalafil was confirmed.135 Headache fil-tadalafil sequence.142 Subjects had never re- (15.8%), dyspepsia (11.8%), nasopharyngitis ceived tadalafil, most had never received sildenafil (11.4%) and back pain (8.2%) were the most (85%), and some had undergone a previously common adverse effects.135 The rate of discontinua- inadequate trial of sildenafil (15%).142 Most cases tion due to adverse events for the 18–24 month of ED were mixed (42%) or organic (39%).142 Of the study was 6.3%.135 190 evaluable patients, 66% preferred tadalafil In separate trials, the ability of tadalafil to compared with 34% who preferred sildenafil.142 enhance erectile function in men with diabetes Headache (tadalafil, 11.2%; sildenafil, 8.8%), dys- (predominantly type II) and ED was con- pepsia (6.0 and 4.2%), nasopharyngitis (4.7 and firmed.136,137 Despite the 637 men with diabetes 2.8%) and flushing (2.8 and 4.7%) were the most having more severe ED than a group of 1681 men common adverse effects.142 The findings of this trial without diabetes, in the diabetic group, 53% of their only apply to the doses tested, 20 mg tadalafil and attempts at intercourse were successful in the 50 mg sildenafil. As most trials of sildenafil alone, tadalafil group, compared with 22% in the placebo show that most men with ED prefer 100 over 50 mg group.137 sildenafil, it may have been more appropriate to Tadalafil, taken on demand, is also effective in the have compared 20 mg tadalafil to 100 mg sildenafil. ED following bilateral nerve sparing radical retro- In a second trial of sildenafil and tadalafil, ED pubic prostatectomy.138 In combining 2102 men from patients who were taking sildenafil were switched 11 trials, with a broad spectrum of ED aetiology and to tadalafil and then asked which they preferred, various comorbid medical conditions, it was shown and most preferred tadalafil.143 The 147 evaluable

International Journal of Impotence Research Vardenafil and tadalafil have advantages over sildenafil S Doggrell 290 men in this study had been taking sildenafil at stable In order to achieve a definite answer to the fixed doses of 25, 50 or 100 mg as needed for at least preference question, studies need to be performed 6 weeks and up to 24 weeks.143 After a 3-week that are double-blind, have no bias in the drug prestudy sildenafil dose, there was a 9 week administration instructions, use the standard cross- tadalafil initiation/assessment phase at the end of over/washout design, and compare equivalent which the ED subjects could select either sildenafil doses.149,150 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, Comments and conclusions severity of ED, aetiology of ED, and sildenafil dose at 143 study entry. The obvious limitation to this study Sildenafil vs vardenafil was that it was not blinded, and another limitation The point of difference between sildenafil and was that it did not determine the effect on erectile vardenafil is relatively small. Vardenafil is a less function. potent inhibitor of PDE6 that sildenafil, and is less When a blinded trial was undertaken to evaluate likely to give the side effect associated with patient preference between 20 mg tadalafil and this inhibition, namely, abnormal colour perception. 50–100 mg sildenafil, most ED patients preferred As abnormal colour perception is a relatively rare tadalafil.144 Thus, 73% of 181 ED patients chose 144 and not particularly disturbing side effect with to receive tadalafil during the extension period. sildenafil, this point of difference has not been These studies have the same limitation as the first sufficient for vardenafil to be preferred to sildenafil crossover study, namely, that the comparison should as the first choice in ED. Obviously, in cases where have been between 20 mg tadalafil and 100 mg abnormal colour perception is observed with silde- sildenafil. For instance, in the blinded trial, only nafil, vardenafil could be substituted. 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 Sildenafil and vardenafil vs tadalafil spinal cord injury, a crossover study between There is a major point of difference between the tadalafil 10 mg and sildenafil 50 mg showed that short-acting agents, sildenafil and vardenafil, and tadalafil had a longer lasting efficacy than sildena- 145 the longer acting tadalafil. This probably allows fil. Similarly, this study would be more mean- more choice about the onset of sexual intercourse ingful if the doses of the PDE5 inhibitors had been with tadalafil than with sildenafil or vardenafil. The optimized. dosing instructions for sildenafil are that patients A more recent study has reduced the bias towards take sildenafil one hour before sexual activity, tadalafil by allowing the men with ED to titrate to whereas those for tadalafil suggest that sexual find their optimum dose (for sildenafil 25, 50 or 146 activity can be initiated between 30 min and 24 h 100 mg; for tadalafil 10 or 20 mg). After the after dosing. 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 Epilepsy a similar response for penetration (sildenafil, Two cases where it is possible that sildenafil has 151 82%; tadalafil, 85%), and only a slight difference induced tonic-clonic seizures have been reported, 152 in successful intercourse (sildenafil, 72%; tadalafil, and one case with vardenafil. Further studies are 77%).146 needed to determine whether this is a rare adverse When a population of 186 subjects with ED, of effect with sildenafil and vardenafil, and also to whom 64 had not been treated previously, were determine whether seizures occur with tadalafil. given eight tablets of a shorter acting PDEV inhibitor (four tablets sildenafil 100 mg, four tablets vardena- fil 20 mg) and eight tablets of the longer-acting Conclusions tadalafil 20 mg, overall there was no preference, although two-thirds of the naive patients preferred Sildenafil, vardenafil and tadalafil have all been the shorter acting PDEV inhibitor.147 One-fifth of shown to be similarly effective in the treatment of subjects requested both a shorter- and a long-acting men with ED of vary etiologies, to have similar medication to accommodate his needs.147 There are adverse effects profiles, and to improve quality of several flaws in this crossover trial including a lack life by similar amounts. All increase the hypoten- of treatment sequence randomization, the limitation sive effects of nitrates, making them unsuitable for of sildenafil and vardenafil exposure to four as use in patients taking nitrates. In patients taking opposed to eight tablets with tadalafil, and the lack a1-adrenoceptors antagonists for benign prostatic of a washout period between different treatment hyperplasia, the PDE5 inhibitors can be used with phases.148 caution. Tadalafil has a longer half-life than silde-

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