The Efficacy and Safety of Flexible-Dose Vardenafil (Levitra W )inabroadpopulationofeuropeanmen

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1 European Urology European Urology 45 (4) The Efficacy and Safety of Flexible-Dose (Levitra W )inabroadpopulationofeuropeanmen Dimitrios Hatzichristou a,*, Francesco Montorsi b, Jacques Buvat c, Nicole Laferriere d, Tiemo-Joerg Bandel e, Hartmut Porst f for the European Study Group 1 a Department of Urology and Center for Sexual and Reproductive Health, Aristotle University of Thessaloniki, 77 Mitropoleos str., Thessaloniki, Greece b Instituto San Raffaele, Milan, Italy c Centre ETPARP, Lille, France d Bayer AG, Leverkusen, Germany e Bayer AG, Wuppertal, Germany f Praxisklinik am Rothenbaum, Hamburg, Germany Accepted 26 January 4 Published online 19 February 4 Abstract Background: In fixed-dose studies, vardenafil 5,, and mg improves erectile function in men with erectile dysfunction (ED). Here, the efficacy and tolerability of vardenafil when used in a flexible-dose regimen was assessed. Methods: In this multicenter trial, 323 patients randomly received vardenafil mg or placebo. After 4 weeks, patients could switch to 5 or mg (or corresponding placebo), or remain on mg for an additional 4 weeks; doseswitching was optional for the last 4 weeks. Efficacy variables included the IIEF-EF domain score, GAQ, and percentage of positive responses to SEP2/SEP3 questions. Results: The IIEF-EF domain score significantly improved from a baseline of moderate ED ( ) to mild ED in men on vardenafil ( ) compared with placebo ( ) at weeks 4, 8, 12, and last observation carried forward (LOCF) ( p < :5 vs. placebo). A significantly greater proportion of men receiving vardenafil at weeks 4, 8, 12, and LOCF reported improved erections (8 86% vs % for placebo, p < :5). Successful SEP2 rates increased after vardenafil, reaching 84% at weeks 8 and 12 vs % receiving placebo ( p < :5 vs. placebo). improved successful SEP3 rates ranging from 58% to 74% compared to 22 34% for placebo. The most common adverse events, flushing and headache, were generally mild and transient. Conclusion: In this flexible dose study, vardenafil was well-tolerated, and produced clinically relevant improvements in erectile function in men with ED. # 4 Published by Elsevier B.V. Keywords: Erectile dysfunction; ; Phosphodiesterase type 5 inhibitors; Clinical trials 1. Introduction The availability of orally administered phosphodiesterase 5 (PDE5) inhibitors has significantly * Corresponding author. Tel. þ ; Fax: þ address: hatzichr@med.auth.gr (D. Hatzichristou). 1 Supported by: Bayer Corporation, Bayer AG, GlaxoSmithKline. improved the effectiveness and acceptability of treatment for ED compared to local, more invasive therapies [1,2]. A clear benefit of oral PDE5 inhibitor therapy is the patient s ability to consult with their physician in order to optimize dosing to obtain a favorable response based on efficacy and tolerability. This dosing flexibility offers the opportunity for patients with ED to play an active role in their disease management /$ see front matter # 4 Published by Elsevier B.V. doi:.16/j.eururo

2 D. Hatzichristou et al. / European Urology 45 (4) , a potent, selective PDE5 inhibitor, is efficacious in improving erectile function in men with ED, as demonstrated in phase III, multicenter, fixeddose, placebo-controlled clinical trials [3 6]. While mg vardenafil is the recommended starting dose, patients also benefit from the mg dose [7,8]. Since fixed-dose studies do not fully represent utilization of PDE5 inhibitors in general clinical practice, this study was designed to evaluate efficacy of vardenafil using a flexible-dose regimen in which patients initially received mg of vardenafil (or placebo) and, after consultation with their physician, could remain on that dose or titrate to 5 mg or mg vardenafil dosages (or matching placebo). 2. Methods 2.1. Study design This was a prospective, randomized, placebo-controlled, flexible-dose study involving 26 centers in 9 European countries and conducted between October 1 and May 2. The study protocol received approval from institutional review boards at the clinical centers; all patients provided signed written consent. Once enrolled, patients underwent a 4-week run-in phase with no ED treatment. Patients received study medication at the baseline visit (end of run-in) and at week-4 and week-8 visits. During the first 4-week double-blind treatment period, patients received either mg vardenafil or corresponding placebo. After 4 weeks, the patient and investigator assessed the patient s response and tolerance of the initial dose; the patient could continue taking mg (or corresponding placebo) or switch to 5 or mg dosage (or corresponding placebo) for a second 4-week treatment period. At week 8, after another patient physician discussion regarding the patient s response and tolerance of the current dose, adjustment of the dose (or matching placebo) could occur by one level if necessary for use during the third 4-week treatment period. was supplied as 5,, or mg tablets. Randomization codes were generated by Bayer. Patients were instructed to take the study medication about 1 hour before intended sexual intercourse with a maximum of 1 dose per calendar day. No specific instructions were given with regard to alcohol use or food Inclusion and exclusion criteria Males 18 years of age and older were eligible if they had ED (the inability to achieve or maintain a penile erection sufficient for satisfactory sexual intercourse [9]) and had been in a stable, heterosexual relationship for 6 months. Men were required to make 4 or more attempts at sexual intercourse on 4 separate days during the 4-week baseline period, at least 5% of which must have been considered unsuccessful based on a no answer to at least 1 of the following questions in the patient diary: (1) Were you able to achieve at least some erection? (2) Were you able to insert your penis into your partner s vagina? and (3) Did your erection last long enough for you to have successful intercourse? Exclusion criteria included penile anatomical abnormalities, primary hypoactive sexual desire, spinal cord injury resulting in ED, radical prostatectomy, unstable angina, poorly controlled diabetes (HbA 1C >12%), clinically significant hypertension, and clinically significant liver or hematologic disease. Use of organic nitrates, other nitric oxide donors, or potent CYP3A4 inhibitors were not permitted. Prior sildenafil use was permitted except in case of unresponsiveness or side effects leading to discontinuation; sildenafil had to be discontinued within 7 days of screening Efficacy variables The primary efficacy variables were the EF domain score of the International Index of Erectile Function (IIEF) questionnaire [], and the Global Assessment Question (GAQ): Has the treatment you have been taking over the past 4 weeks improved your erections?. Scores were recorded at the baseline visit and at week 4, 8, and 12 visits. Secondary efficacy variables included the SEP2, Were you able to insert your penis into your partner s vagina? and SEP3, Did your erection last long enough for you to have successful intercourse? The per-patient overall success rate for each 4-week time period was compiled from individual diary entries. The intent-to-treat (ITT) population was used for determining efficacy and included those patients who had a baseline and a postbaseline assessment and who took at least 1 dose of study medication Safety A physical examination including vital signs, hematology, blood chemistry, urinalysis, and medical history were recorded at screening. Laboratory tests, heart rate and blood pressure were performed at baseline, and weeks 4, 8, and 12. A 12-lead electrocardiogram was recorded at screening, baseline, and weeks 4 and 12 (or at early discontinuation). Patients were asked to report all treatment-emergent adverse events, which were assessed by the investigators using standard criteria for intensity and relationship to study medication. Patients who had received at least 1 dose of study medication and had postbaseline safety assessments were included in the safety analysis Statistical analysis The number of patients recruited in this study was based on the IIEF-EF domain score and the GAQ. Intending to demonstrate a difference between placebo and vardenafil of 23% in GAQ, expecting an improvement rate of % under placebo, 1 patients were needed to detect this difference with a a risk of 5% and a power of 95%. Simultaneously, with 1 patients, a 5-point difference on the IIEF-EF domain score can be detected with a power of more than 99% assuming a standard deviation of 7.6. For this sample size, the overall power for both primary endpoints was 94%. Taking into account 25% of screening failure and % of lost to follow-up it was planned to screen 4 patients. The primary IIEF data were tabulated and analyzed by analysisof-covariance (ANCOVA) testing with baseline values used as the covariate, and treatment and investigational center as main-effect terms. To account for patient dropouts, the main analysis was applied at last observation carried forward (LOCF) and at each time point. Responses to the GAQ were analyzed using logistic regression with the same terms used in the ANCOVA. Data for diary questions (SEP2 and SEP3) were reported as mean perpatient success rate and were analyzed by ANCOVA with baseline response used as the covariate and investigational center and treatment as main effect terms. All reported results were least squares means (LS means) except for the analysis by sequence of doses which remained only descriptive. All statistical tests were two-sided.

3 636 D. Hatzichristou et al. / European Urology 45 (4) Results 3.1. Patient characteristics A total of 157 and 166 patients were randomized to receive vardenafil or placebo. Premature discontinuation occurred in 17% of the vardenafil group and 29% of the placebo group. Reasons for premature discontinuation included adverse events (vardenafil, n ¼ 4 [3%], placebo, n ¼ 3 [2%]), non-compliance (vardenafil, n ¼ 9 [6%], placebo, n ¼ [%]), withdrawal of consent (vardenafil, n ¼ 6 [4%], placebo, n ¼ [12%]), insufficient therapeutic effect (vardenafil, n ¼ 2 [1%], placebo, n ¼ [12%]), loss to followup (vardenafil, n ¼ 4 [3%], placebo, n ¼ 5 [3%]), and protocol violations (vardenafil, n ¼ 1 [1%], placebo, n ¼ [%]). The treatment groups were well balanced with regard to baseline demographic characteristics and medical history. A total of 54% of patients who received vardenafil and 5% of patients who received placebo reported prior sildenafil use (Table 1) Dose variation At the start of the first flexible-dose period (week 4), 95/154 vardenafil patients and 136/155 placebo patients in consultation with their physicians chose Table 1 Demographic and erectile dysfunction characteristics of patients (ITT population) Placebo (n ¼ 154) (n ¼ 155) Age at enrollment, mean year Weight, mean kg BMI, mean kg/m ED duration since first diagnosis mean year Etiology Organic 42% 37% Psychogenic 22% 21% Mixed 36% 43% Alcohol Abstinent 36% 32% Light 47% 52% Moderate 14% 15% Heavy 3% 1% Smoking Non 38% 39% Past/present 61% 61% Prior sildenafil use 5% 54% Medical history Hypertension 24% 34% Diabetes mellitus (incl. subtypes) % 16% Hyperlipidemia 5% 2% Cardiac disease 6% 9% Respiratory, thoracic, mediastinal disorders % 5% BMI: body mass index; ED: erectile dysfunction. Table 2 Doses per patient in the ITT population Placebo doses/patient doses/patient Mean Median Mean Median BL to week Week 4 to week Week 8 to week Overall BL: baseline; ITT: intent to treat. to increase the dosage to mg or matching placebo. An additional vardenafil and 4 placebo patients switched to mg (or matching placebo) at week 8. A smaller number of men in consultation with their physicians had dosage reduced at weeks 4 or 8 (6 patients, all receiving vardenafil, at week 4; 8 patients, including 1 in the placebo group, at week 8). These included both reductions from to 5 mg, and reductions from to mg. Adverse events were the commonly stated reasons for dose reduction. Dose frequency was greater in the vardenafil group than in the placebo group at all time points (Table 2) Efficacy IIEF-EF domain promoted significant ( p < :5) improvements in mean IIEF-EF domain scores. At week 4, the EF domain score was 21. in the vardenafil group and 13.7 in the placebo group. These scores increased to 23.5 and 24.2 at weeks 8 and 12, respectively, in the vardenafil group compared to 15.3 and 15.6, respectively, in the placebo group (Fig. 1A). Subset descriptive analysis was performed according to dose-sequence. All groups receiving vardenafil, but not placebo, showed significant clinical improvement over the baseline EF domain score (Fig. 1B). Men in the // and // (vardenafil mg for 4 weeks, followed by vardenafil mg for 4 weeks, and vardenafil mg or mg for the final 4 weeks) reported an increase in IIEF-EF domain score from 13 and 15, respectively, at baseline to 27 (normal EF) at week 4; this efficacy was sustained over the 12 weeks. The // group was the largest subset of patients; these patients (baseline IIEF-EF of 12) reached scores of 18, 23, and 22 at weeks 4, 8, and 12, respectively. The // group appeared to show less efficacy compared with the 4-week time point, but the number of patients was very small in this group (n ¼ 6). Relatively few men in the study (7 vardenafil-treated patients) decreased the dosage to vardenafil 5 mg (data not shown). Two patients who chose /5/5

4 D. Hatzichristou et al. / European Urology 45 (4) LS Mean EF Score (A) Mean EF Score (B) n 13.7 Placebe Baseline 21. * 23.5 * * 23.3 * n Week 4 Week 8 Week 12 LOCF p <.5 vs. placebo Normal Mild to Moderate Moderate Severe had near-maximum scores on the IIEF-EF (mean ). Another 2 patients chose /5/ and had relatively low scores in spite of resuming the higher dosage GAQ At week 4, 8% of men receiving vardenafil ( mg) and 21% receiving placebo had improved erections (Fig. 2A). Efficacy was sustained through weeks 8 (83% vardenafil vs. 36% placebo) and 12 (86% vardenafil vs. 36% placebo) and was significantly superior to placebo ( p < :5) at all time points. Subgroup analysis of affirmative response rates according to the dosage sequence chosen showed that vardenafil had a very high percentage of affirmative responses to the GAQ in the // (96%/%/ 92%) and // subgroups (%/85%/%) at weeks 4, 8, and 12, respectively, compared to placebo (21%/36%/36%) over the 4, 8, and 12 week intervals, respectively. The vardenafil // subgroup had a response rate (7% 83%), that was also greater than that in the placebo group (21 36%) (Fig. 2B). The vardenafil /5/5 and /5/ subgroups had a % affirmative response rate to the GAQ (data not shown due to the small number of patients, n 2) Baseline Week 4 Week 8 Week Placebo // // // // Mild Normal Mild Mild to Moderate Moderate Severe Fig. 1. IIEF-EF domain scores (questions 1 5, 15; possible total score 1 ) for men receiving flexible-dose vardenafil ( mg with choice of modification to 5 or mg) or placebo. (A) Least square mean IIEF-EF scores for all patients at weeks 4, 8, and 12, and at LOCF. (B) Mean IIEF- EF scores at baseline, at weeks 4, 8, and 12 for patients categorized by the dosage chosen for the three 4-week study periods. Normal erectile function is defined as EF domain scores 26. Intent-to-treat population; last observation carried forward (LOCF). p < :5 vs. placebo. % Yes (A) % Yes (B) * n Week Placebo 36 83* Week 8 86* 84* SEP2 During the screening period (i.e., the 4-week unmedicated baseline period), mean per-patient rates of positive responses to the SEP2 question ranged from 38 to 39% in the vardenafil group and 44 to 48% in the placebo group. During flexible dose study periods ending at week 12, the mean per patient SEP2 success rate increased to 73% at week 4 and 84% at weeks 8 and 12 in the vardenafil group and remained nearly unchanged in the placebo group at 41% to 53% ( p < :5) (Fig. 3A). In the subgroup analysis, comparing the SEP2 responses according to the sequence of dosages taken, vardenafil led to improvements without regard to the sequence of dosages (Fig. 3B). In men who followed the sequence of dosages // mg at 4, 8, and 12 weeks, respectively, the mean per patient penetration success rate was greater than 95% at all time points compared to the placebo rate (41% to 54%). The // subgroup had a very similar outcome at weeks 4 and 12 (95% and 93%, respectively) Week 12 LOCF p <.5 vs. placebo n Placebo Week 4 Week 8 Week // // // // Fig. 2. Percentage of patients answering Yes to the Global Assessment Question (GAQ): Has the treatment you have taken over the past 4 weeks improved your erections? for men receiving flexible-dose vardenafil ( mg with choice of modification to 5 or mg) or placebo. (A) Percent answering Yes to the GAQ for all patients at weeks 4, 8, and 12, and at LOCF. (B) Percent answering Yes to the GAQ at weeks 4, 8, and 12, for patients categorized by the dosage chosen for the three 4-week study periods. Intent-to-treat population.

5 638 D. Hatzichristou et al. / European Urology 45 (4) LS mean per patient success rate (%) (A) * n Week 4 Placebo Baseline Week 8 84* 84* Week * LOCF p <.1 vs. placebo LS mean per patient success rate (%) (A) n Week 4 Placebo Baseline 71 * 74 * 69 * 58 * Week Week LOCF p <.1 vs. placebo Mean per patient success rate (%) (B) n Baseline Week 4 Week 8 Week Placebo // // // // Fig. 3. Mean per-patient success rates for the SEP2 diary question Were you able to insert your penis into your partner s vagina? for men receiving flexible-dose vardenafil ( mg with choice of modification to 5 or mg) or placebo. (A) Mean per-patient success rates for all patients at weeks 4, 8, and 12, and at LOCF. (B) Mean per-patient success rates at baseline, weeks 4, 8, and 12, with patients categorized by the dosage chosen for the three 4-week study periods. Intent-to-treat population. Mean per patient success rate (%) (B) Baseline Week 4 Week 8 Week n Placebo // // // // Fig. 4. Mean per-patient success rates for the SEP3 diary question Did your erection last long enough for you to have successful intercourse? for men receiving flexible-dose vardenafil ( mg with choice of modification to 5 or mg) or placebo. (A) Mean per-patient success rates for all patients at weeks 4, 8, and 12, and at LOCF. (B) Mean per-patient success rates at baseline, weeks 4, 8, and 12, with patients categorized by the dosage chosen for the three 4-week study periods. Intent-to-treat population. and a slightly lower success rate at week 8 (81%). For the largest subgroup in this study following the dosage sequence //, the mean success rate was % at week 4 and increased to 77% and 74% at weeks 8 and 12, respectively. The baseline for this subset of patients was lower (34%) than the majority of the larger groups (44% 52%). The small number of patients (n ¼ 6) following the dosage sequence // experienced an increase to 85% at week 8 followed by a decrease to % at week 12 when treated with mg SEP3 significantly improved mean per-patient success rates for SEP3 versus placebo (Fig. 4A) ( p < :5). The mean per-patient success rates in the vardenafil group were 14% at baseline, 58% at week 4, 71% at week 8, and 74% at week 12 compared to placebo with a baseline ranging from 18 % with slight increases to 22%, 31%, and 34%, at week 4, 8 and 12, respectively. In the subgroup analysis (Fig. 4B), success rates to SEP3 showed similar patterns among dosage subgroups to those with SEP2. Men in the vardenafil // group achieved successful intercourse rates of 93%, 97%, and 87% at weeks 4, 8, and 12, respectively, compared to placebo (22%, %, and 33%, respectively). Men in the // group initially responded at week 4 with an 89% successful intercourse rate, this efficacy decreased to 65% at week 8; titration to mg vardenafil improved success rates to 85% at week 12. In the // subgroup, the mean success rate was 39% at week 4 with an increase to 62% and 64% at weeks 8 and 12 after up-titration. Interestingly, the baseline successful intercourse rate for this group was 11%, which was less than other groups (17 %). Patients in the // subgroup (n ¼ 6) had successful intercourse rates ranging from 49% to 51% Adverse events was generally well tolerated and treatment-emergent adverse events were mostly mild and

6 D. Hatzichristou et al. / European Urology 45 (4) Table 3 Treatment-emergent adverse events in 2% of patients (n ¼ 157) Placebo (n ¼ 164) Flushing 19 (12%) (%) Headache 18 (11%) 3 (2%) Rhinitis (6%) 4 (2%) Flu syndrome 8 (5%) 7 (4%) Dyspepsia 6 (4%) 1 (1%) Back pain 4 (3%) 1 (1%) CPK increased 5 (3%) 3 (2%) Dizziness 3 (2%) 2 (1%) Accidental injury 3 (2%) 2 (1%) Hypertension 3 (2%) 1 (1%) QT interval prolonged 1 (1%) 5 (3%) transient. Forty-five percent of vardenafil patients and 27% of placebo patients experienced at least 1 treatment-emergent adverse event, however, a small proportion of these patients withdrew (3% vs. 2%). Adverse events occurring in 2% or more of either group are shown in Table 3. Adverse events considered to be related to study drug and occurring in 2% or more of either treatment group are shown in Table 4. Adverse events were consistent with the pharmacological action of PDE5 inhibitors. Adverse events reported for vardenafil- and placebo-treated patients (>5%) included headache (11%/2%), flushing (12%/ %), rhinitis (6%/2%), and flu syndrome (5%/4%) and were usually mild. Twenty-nine percent of patients receiving vardenafil experienced at least 1 drugrelated adverse event compared with 5% in the placebo group. Five men receiving placebo and 4 receiving vardenafil experienced serious adverse events, none of which were considered by the investigator to be drug-related. Five patients (3%) withdrew because of treatment-emergent adverse events in the vardenafil group (1 for abdominal pain, 2 for headache, 1 for dysphagia, and 1 for pneumonia (not drug-related) and 3 patients (2%) in the placebo group (1 for accidental injury, 1 for vascular anomaly, 1 for increase of creatine phosphokinase). The incidence of adverse events occurring on 5 mg was 14%, 32% on mg, 26% on mg, and 27% on placebo. The percentages for adverse events judged Table 4 Drug-related adverse events in 2% of patients (n ¼ 157) Placebo (n ¼ 164) Flushing 18 (11%) (%) Headache 15 (%) 3 (2%) Rhinitis 8 (5%) 1 (1%) Dyspepsia 4 (3%) (%) Dizziness 3 (2%) 1 (1%) by the investigator to be drug-related were 14%, 22%, 11%, and 5%. 4. Discussion Flexible dosing in the context of oral pharmacotherapy for ED provides the freedom and flexibility of the patient, in collaboration with his physician, to optimize the therapeutic approach to meet individual patient needs. Each patient may ultimately modify his initial therapy to maximize the efficacy provided by PDE5 inhibitors without significantly compromising tolerability. The results of this study demonstrate that vardenafil, when used in a flexible-dose regimen initiated at mg with option to titrate to 5 or mg, lead to clinically (DIIEF-EF scores >5) and statistically ( p < :5) significant improvements in erectile function. The IIEF-EF domain scores in patients receiving vardenafil significantly increased from a baseline of moderate ED to mild ED at weeks 4, 8, 12, and at LOCF (21., 23.5, 24.2, and 23.3, respectively) compared with placebo (13.7, 15.3, 15.6, and 14.5, respectively) ( p < :5 vs. placebo). The significant improvement in erectile function following vardenafil treatment was most likely a manifestation of the mechanism of action of the drug (i.e., prolonging the synthesis of nitric oxide through inhibition of cgmp). The generally stable response rates of the placebo group provides compelling evidence to demonstrate that the ability of vardenafil to improve erectile function was not due to an improvement of the psychogenic component of ED. Rather, these results suggest that flexible dosing of vardenafil, coupled with counseling, allowed for optimization of the therapeutic response. Since effective patient instruction and counseling may be of benefit in effective ED management [11,12], the results of this study demonstrate that patient physician collaboration may allow for optimal therapeutic oral PDE5 inhibitor therapy, as exemplified in this study. In each of the three 4-week phases of the study, 8 to 86% of men taking vardenafil reported erection improvement (GAQ). In addition, penetration (SEP2) and intercourse success (SEP3) rates were significantly improved by vardenafil treatment compared to placebo at all time points ( p < :5). was efficacious regardless of the sequence of dosages chosen. The majority of patients increased their dosage from mg to mg during the course of the study. Patients who remained at the mg dose throughout the course of the study (n ¼ 25) obtained mean IIEF-EF domain scores of 26 ( normal IIEF-EF

7 64 D. Hatzichristou et al. / European Urology 45 (4) score 26), reported strong responses to the GAQ (92%), experienced high penetration rates (95%), and successful intercourse rates (87%). Since the baseline IIEF-EF domain scores were generally similar between treatment groups (IIEF-EF domain scores between 11 and 13), these results suggest that those who remained at mg were highly responsive to the therapeutic action of the drug. Additional improvement was observed after each up-titration to mg in the majority of men who chose to exercise their option to titrate. The largest subgroup consisted of men receiving the // dose, whose IIEF-EF score improved to mild ED, with commensurate improvement in the other efficacy variables. A small number of patients who reduced their dosage to 5 mg also had very high response rates. Overall, the improvement in SEP2, SEP3, and GAQ rates observed in this study are consistent with those previously reported in studies employing vardenafil using a fixed dose regimen in men with ED [3,13]. was generally well tolerated with very few withdrawals caused by adverse events and few dosage reductions. The incidence of serious adverse events was similar in the vardenafil and placebo groups, and no serious adverse event was considered related to treatment. There were no drug-related clinically significant hemodynamic adverse events or laboratory abnormalities. 5. Conclusion This study to assess flexible doses of vardenafil in which physicians and patients in consultation select the dosage to achieve significant improvements in measures of erectile function compared to placebo is conclusive. The trial was designed to allow patients to reflect on their initial experience with vardenafil to sildenafil-naïve and experienced men with ED, to discuss their response in consultation with their urologist, and subsequently modify their therapy on two successive occasions to optimize their ED treatment by allowing for flexible dosing. The findings of this study demonstrate that in this clinical setting, vardenafil, when used in a flexible dose regimen, is highly efficacious and generally well tolerated, and can be doseadjusted to achieve an optimal response. Appendix A. The European Study Group Austria: Hr. Doz. Dr. Andreas Jungwirth (Landeskrankenhaus Salzburg), Hr. Dr. Harald Trummer (Universitäts Kliniken Graz) France: Docteur Jacques Buvat (CETPARP, Lille), Docteur Marie-Hélène Colson (CM-Labadie, Marseille), Docteur Béatrice Cuzin (Herriot, Lyon), Docteur Jean-Louis Davin (Clinique, Rhone- Avignon), Docteur Olivier Lan (Clinique St Gerard, Carpentras) Germany: Hr. Dr. Anastasios Kollias (Ammerland- Klinik, Westerstede), Hr. Prof. Dr. Hartmut Porst (Hamburg) Greece: Ass. Prof. Dimitrios Hatzichristou (Aristotle University of Thessaloniki), Prof. Michael Melekos (University Hospital of Larissa, Mezourlo) Italy: Prof. Fabrizio Menchini Fabris (Ospedale S. Chiara, Univ. di Pisa), Prof. Gaetano Frajese (Ospedale Fatebenefratelli, Rome), Prof. Vincenzo Mirone (Policlinico, Napoli), Prof. Francesco Montorsi (H. San Raffaele, Milan), Prof. Edoardo Pescatori (Ospedale Hesperia, Modena) Netherlands: Mr. Paul van Meurs (Utrecht) Spain: Dr. José Fernando Jiménez Cruz (Hospital La Fe, Valencia), Dr. Antonio Martín Morales (Hospital Carlos Haya, Málaga), Dr. José María Pomerol (Hospital Fundació Puigvert, Barcelona), Dr. Luís Rodríguez Vela (Hospital Miguel Servet Zaragoza) Switzerland: Hr. Dr. Räto Strebel (Universitätsspital Zürich) United Kingdom: Mr. Paul Abel (Ealing Hospital, Southall), Professor Pierre-Marc Bouloux (Royal Free Hospital, London), Mr. Davinder Sandhu (Leicester General Hospital, Leicester), Dr. Kevan Wyley (Royal Hallamshire Hospital, Sheffield) References [1] Levy A, Crowley T, Gingell C. Non-surgical management of erectile dysfunction. Clin Endocrinol (Oxf) ;52:253. [2] Levine LA. Diagnosis and treatment of erectile dysfunction. Am J Med ;9:3 12. [3] Hellstrom W, Gittelman M, Karlin G, Thibonnier M, Padma-Nathan H. for Treatment of Men With Erectile Dysfunction: Efficacy and Safety in a Randomized, Double-Blind, Placebo- Controlled Trial. J Androl 2;23: [4] Pryor J. : update on clinical experience. Int J Impot Res 2;14:S65 9. [5] 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 radical retropubic prostatectomy. J Urol 3;17: [6] Goldstein I, Young JM, Fischer J, Bangerter K, Segerson T, Taylor T., a new phosphodiesterase type 5 inhibitor, in the treatment

8 D. Hatzichristou et al. / European Urology 45 (4) of erectile dysfunction in men with diabetes: a multicenter doubleblind placebo-controlled fixed-dose study. Diabetes Care 3;26: [7] Donatucci C, I.E, Thibonnier M, and the EU and NA Study Groups. improves erectile function of etiology or baseline severity in men with erectile dysfunction. J Urol 2;167: 178 [Abstract 715]. [8] Donatucci C, Karlin G, Goldfischer E, Cohen S, Thibonnier M. Influence of age on the efficacy and safety of vardenafil, a novel phosphodiesterase-5 inhibitor, for the treatment of erectile dysfunction. J Amer Geriatic Soc 2;5:S7. [9] NIH Consensus Conference. Impotence. NIH Consensus Development Panel on Impotence. JAMA 1993;27:83 9. [] Rosen RC, Riley A, Wagner G, Osterloh IH, Kirkpatrick J, Mishra A. The international index of erectile function (IIEF): a multidimensional scale for assessment of erectile dysfunction. Urology 1997;49: 822. [11] McCullough AR, Barada JH, Fawzy A, Guay AT, Hatzichristou D. Achieving treatment optimization with sildenafil citrate (Viagra(R)) in patients with erectile dysfunction. Urology 2; : [12] Sadovsky R, Mulhall JP. The potential value of erectile dysfunction inquiry and management. Int J Clin Pract 3;57:1 8. [13] Hellstrom W, Gittelman M, Karlin G, Segerson T, Thibonnier M, Taylor T, Padma-Nathan H, on behalf of the Study Group. Sustained efficacy and tolerability of vardenafil (Levitra 1 ), a highly potent, selective phosphodiesterase-5 inhibitor, in men with erectile dysfunction: results of a randomized, double-blind, 26-week placebo-controlled pivotal trial. Urology 3;61(4 Suppl): Editorial Comment E. Meuleman, Nijmegen, Netherlands Six years after the arrival of the first PDE5 inhibitor, sildenafil (Viagra 1 ) in the marketplace, two competitors in the form of tadalafil (Cialis 1 ) and vardenafil (Levitra 1 ) have now been approved in several countries by the regulatory authorities. Although it would appear, at least in the test tube, that vardenafil is the most potent PDE5 inhibitor available there are no direct comparative studies nor clinical data to suggest that vardenafil will provide superior efficacy to sildenafil or tadalafil. So what does vardenafil offer over sildenafil and tadalafil? Certainly, not an advantage in terms of knowledge and safety data obtained in over million sildenafil users in over 1 countries (Pfizer Inc., data on file) or an absence of contraindications in nitrate users [1,2]. As a consequence of the primary action on PDE5, all selective or non-selective inhibitors will potentiate the effects of exogenous nitrates. This only leaves a differential in effectiveness, selectivity, onset or spontaneity of action and price. Although profitability on all three agents is at least 85%, we can probably rule out a price war. Much is made of its higher selectivity and potency in a wide range of patients even in difficult-to-treat cases. With the advent of vardenafil as another choice of effective and safe erection-enhancing therapy, it seems relatively straightforward to give any man with ED firm erections again. However, to make him come forward for treatment and getting him to make use of it regularly in lovemaking appears to be much more complicated [3]. Souverein et al. showed that during a follow-up period of 18 months 45% of all patients discontinued treatment. Age > years, diabetes medication, and disease/surgery in the pelvic region were associated with an increased likelihood of discontinuation [4]. Urologists claim that up to 65% of patients may never be seen again. In the UK, discontinuation rates range from 36% when ED is managed in a specialist clinic to 78% when care is initiated by a primary-care physician (data on file, Abbott, UK) [5]. In addition, discontinuation rates for ED treatment with sildenafil range from 29% at 5 months in sildenafil responders to as high as 72% after 1 year [6]. Therefore, it seems that in clinical practise it is not so much the drug but the guidance of a competent and caring physician that will make the difference. References [1] Gresser U, Gleiter CH. Erectile dysfunction: comparison of efficacy and side effects of the PDE-5 inhibitors sildenafil, vardenafil and tadalafil. Review of the literature. Eur J Med Res 2;7: [2] Juenemann KP. Wie wirksam sind die PDE-5 Hemmstoffe. Urologe [A] 3;42: [3] Althof SE. When an erection alone is not enough: biopsychosocial obstacles to lovemaking. Int Impot Res 2;14(Suppl 1):99 4. [4] Souverein PC, Egberts AC, Meuleman EJ, Urquhart J, Leufkens HG. Incidence and determinants of sildenafil (dis)continuation: the Dutch cohort of sildenafil users. Int J Impot Res 2;14(4): [5] Hackett GI, Milledge D. A 12-month follow up of 2 patients taking sildenafil. NHS clinical experience. In: Fourth Congress of the European Society for Sexual and Impotence Research (ESSIR), Rome, September 3 October 1 [Poster 171]. [6] Casabe A, Cobreros C, Bechara A, Roletto L, Cheliz G, Hochman S. Drop out reason in responders to sildenafil. Int J Impot Res 1; 13(Suppl 2):S5 [Moderated Poster 9].