Treatment Strategy for Non-Responders to Tadalafil and Vardenafil: A Real-Life Study

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1 european urology 50 (2006) available at journal homepage: Sexual Medicine Treatment Strategy for Non-Responders to Tadalafil and Vardenafil: A Real-Life Study Konstantinos Hatzimouratidis, Kyriakos Moysidis, Athanasios Bekos, Zoi Tsimtsiou, Evangelos Ioannidis, Dimitrios Hatzichristou * The 2nd Department of Urology, Papageorgiou General Hospital, and the Center for Sexual and Reproductive Health, Aristotle University of Thessaloniki, Greece Article info Article history: Accepted February 23, 2006 Published online ahead of print on March 10, 2006 Keywords: Erectile dysfunction Treatment failure Phosphodiesterase inhibitors Tadalafil Vardenafil Abstract Objectives: To develop and test step-wise treatment strategy for erectile dysfunction non-responders to tadalafil and vardenafil. Material and methods: Two groups [tadalafil-treated (TG); vardenafil-treated (VG)] of 100 consecutive patients complaining of non-response to treatments were enrolled in three-phase study. Phase 1: inadequate use was identified and patients were rechallenged, after receiving detailed usage information. Phase 2: true non-responders were given new instructions based on drugs pharmacologic profiles: TGs were dosed at least 2 h before intercourse; VGs were dosed only in fasted state. Remaining non-responders entered phase 3: continuous administration of 20 mg tadalafil every other day, or 20 mg vardenafil every day for 2 weeks. Efficacy was based on positive (yes) response to two questions: Were your erections rigid, and did they last long enough to have successful intercourse? and Do you want to repeat your prescription? Results: Tadalafil group: Inappropriate use was recognized in 32 patients; 14 (43.75%) responded after adequate instruction. Phase 2: 32 of 86 (37.2%) had intercourse at least 2 h after dose intake. Phase 3: 6 of 86 (11.1%) responded to continuous administration. Overall salvage rate was 52 of 100 (52%). Vardenafil group: Inappropriate use was recognized in 38 patients; 12 (31.58%) responded after adequate instruction. Phase 2, 22 of 88 (25%) responded to dosing in a fasted state. Phase 3: 12 of 66 (18.2%) responded to daily dosing. Overall salvage rate was 46 of 100 (46%). Conclusions: Following proposed treatment strategy may maximize response rate to phosphodiesterase 5 inhibitors; appropriate usage instructions may play significant role in response rate. # 2006 European Association of Urology. Published by Elsevier B.V. All rights reserved. This study was awarded the Prize of the Congress President for the best presentation on clinical urology at the XXth Congress of the European Association of Urology, Istanbul, Turkey, March * Corresponding author. 77 Mitropoleos Street, Thessaloniki, Greece. Tel ; Fax: address: hatzichr@med.auth.gr (D. Hatzichristou) /$ see back matter # 2006 European Association of Urology. Published by Elsevier B.V. All rights reserved. doi: /j.eururo

2 european urology 50 (2006) Introduction Phosphodiesterase type 5 (PDE5) inhibitors are today the first treatment option of erectile dysfunction (ED) among physicians and patients [1]. Efficacy of PDE5 inhibitors in most published clinical trials is about 70%, although it is significantly lower in difficult-to-treat subpopulations (e.g., diabetes mellitus, radical prostatectomy) [2]. The majority of patients with ED are treated in primary care settings on the basis of minimal patient work-up [3]. As a result, urologists are dealing mainly with treatment failures to oral pharmacotherapy, rather than treating naïve patients. Treatment failures may be due to severity of underlying pathophysiology, inappropriate use of medication, unrealistic patient expectations, difficult relationship dynamics, severe performance anxiety and other intrapsychic conflicts and problems of the man. Physicians need to address these issues to identify true treatment failures attributable to inefficacy of the drugs. Several studies showed that 50% 80% of patients treated with sildenafil are receiving inappropriate instructions and inadequate follow-up [4 6]. After adequate instructions on proper use of sildenafil, 30% 50% of the initial non-responders converted to responders. There are no data today regarding the use of tadalafil and vardenafil. Instructions for use provided by the industry are generalized and may be inadequate according to the pharmacokinetic properties of these drugs [7 10]. Everydaydosing with PDE5 inhibitors is now gaining attention, since it may be associated with several advantages for the patients in terms of efficacy and tolerability [11,12]. The purpose of this study was to identify real-life factors that may affect response rate to tadalafil and vardenafil, and to test the efficacy of a newly proposed step-wise management strategy that may maximize the overall efficacy of these new PDE5 inhibitors. 2. Material and methods The study comprised two groups of ED patients disappointed by the efficacy of tadalafil (TG) or vardenafil (VG), who were either self-admitted or referred by other physicians to an andrology outpatient clinic. All patients were self-reported as nonresponders to either tadalafil or vardenafil. Only naïve patients with ED were included in the study. Inclusion criteria were (1) previous medical diagnosis of ED, (2) reported use of prescription tadalafil or vardenafil, respectively and (3) selfreported inadequate efficacy of the drug, defined as an erection of inadequate rigidity or maintenance capability to permit completion of sexual intercourse. Exclusion criteria were (1) tolerance-associated discontinuation (including side effects and patient/partner reluctance to treatment) and (2) any contraindication for treatment with PDE5 inhibitors. All patients underwent the basic work-up (medical and sexual history, physical examination, lab tests and hormonal profile) and completed the erectile function (EF) domain of the International Index of Erectile Dysfunction (IIEF) and a questionnaire regarding the previous use of tadalafil or vardenafil. Questions referred to (1) the administered dose, (2) time of administration with regard to previous food consumption, (3) time between administration and sexual intercourse, (4) adequate sexual stimulation and (5) schedule of a follow-up appointment by their physician. Patients also were asked whether they felt they had been given adequate information on drug use and possible adverse events. The study design consisted of three phases, reflecting a three-step model for the newly proposed treatment strategy of self-reported non-responders to PDE5 inhibitors (Fig. 1). No diaries were used throughout the study. In phase 1, patients identified inappropriate use of these drugs and received written information on the appropriate use of either tadalafil or vardenafil according to labeling information, which included use of tadalafil at least 30 min before sexual intercourse and use of vardenafil at least 25 min before sexual intercourse. Instructions also included titration to the maximum recommended dose (20 mg for both drugs) without any food restrictions for tadalafil and avoidance of fatty meal for vardenafil. Patients were asked to retry sexual intercourse using at least four tablets/attempts at home. All patients were re-evaluated in a scheduled follow-up visit. Efficacy was based on a positive (yes) response to the two questions: Were your erections rigid, and did they last long enough to have successful intercourse? Moreover, patients were also asked, Do you want to refill your prescription? [with the PDE5 inhibitor already being used]. If the patients were true non-responders ( no response to both questions), they entered phase 2, together with those who had used the drugs appropriately and noticed no efficacy. In phase 2, new instructions were given, including use of tadalafil at least 2 h before sexual intercourse for the tadalafil group and use of vardenafil only in a fasted state for the vardenafil group. Re-evaluation and follow-up was based on the same questions asked in phase 2, after a new retrial with at least four tablets/attempts. Finally, at phase 3, patients who had not responded to the phase 2 trial were again rechallenged with continuous administration of tadalafil, 20 mg every other morning in the TG group, and vardenafil, 20 mg every day taken 3 h apart Fig. 1 Study design. IIEF = International Index of Erectile Dysfunction; max = maximum; OD = on demand.

3 128 european urology 50 (2006) from the last meal in the VG group, for 2 consecutive weeks with at least four attempts during the study period. Response definition was identical to that of the previous two phases. 3. Results One hundred consecutive non-responders to tadalafil and 100 consecutive non-responders to vardenafil ED patients were enrolled for the purpose of the present study in the TG and VG groups, respectively. Eighty-eight patients had been referred by other physicians (only seven from urologists), who felt unable to treat them further; the remaining 112 admitted themselves because they were disappointed by the results of the PDE5 inhibitor tested. In 62 of the 112 (55.36%) patients, their physicians (11 were urologists) informed them that there was no treatment for their problem, while 34 did not get a follow-up appointment with their physicians (eight were urologists) Tadalafil group Mean patient age was years (range, 23 65), and the mean duration of ED years (range, 0.3 7). Mean EF domain score of the IIEF was (range, 7 25). Risk factors for ED were recognized in 55 patients (Table 1). Sixty-eight patients had received adequate instructions for the use of tadalafil at home. In the remaining 32 patients, inappropriate use of tadalafil was recognized (Fig. 2). The most common problem was that most patients (29 of 32, 90.6%) had experienced fewer than four doses/attempts, while six of them had tried only a single dose. The highest recommended dose (20 mg) had not been used by 10 of 32 (31.3%) patients. In 28 patients, both reasons were identified. After Fig. 2 Reasons for inappropriate use of tadalafil and vardenafil. receiving appropriate dose titration to the maximum-tolerated dose and instructions on administration (use of at least four doses), 14 patients responded to tadalafil (Fig. 3), all of them using the 20 mg dose (phase 1). After phase 1, 86 patients were still non-responders and entered phase 2. Following new instructions to use tadalafil at least 2 h before intercourse, 32 of 86 (37.2%) patients converted to responders (Fig. 3); actually most patients (75 of 86) were taking the medication long before sexual attempts (e.g., in the morning or afternoon and having intercourse at evening or night). No patient tried a second sexual attempt after the 36-h efficacy of tadalafil. After phase 2, 54 of 86 (62.8%) patients were still non-responders and were asked to participate in phase 3 of the study. Twenty of 54 (37%) patients did not agree to participate, because of either the high cost of the treatment (17 patients) or disappointment with the results of phase 2 (3 patients). Table 1 Patient demographics Tadalafil group (n = 100) Vardenafil group (n = 100) Age (y; mean SD [range]) (23 65) (28 72) Duration of ED (y; mean SD [range]) (0.3 7) (0.3 11) IIEF erectile function domain score (mean SD [range]) (7 25) (5 24) Presence of risk factors for ED Medical history Smoking (current, ex-smokers) Hypertension Diabetes mellitus Hypercholesterolemia Cardiovascular disease 7 9 Renal failure 1 LUTS (under treatment) 12 5 Multiple sclerosis 2 1 Depression 2 ED = erectile dysfunction; IIEF = International Index of Erectile Dysfunction; LUTS = lower urinary tract symptoms.

4 european urology 50 (2006) ). Mean EF domain score of the IIEF was (range, 5 24). Risk factors for ED were recognized in 61 patients (Table 1). Hypertension was recorded in 21 patients, diabetes mellitus in 21, hypercholesterolemia in 22 and cardiovascular disease in nine, while 61 patients were current or ex-smokers. Other medical conditions included renal failure in one patient, multiple sclerosis in one patient and depression in two patients, while five patients were receiving treatment for lower urinary tract symptoms. Sixty-two patients had received adequate instructions for the use of vardenafil at home. In the remaining 38 patients, inappropriate use of vardenafil was recognized (Fig. 2). The most common problem was that all patients (38 of 38, 100%) had tried fewer than four doses/attempts, while 18 of them had tried only a single dose. The highest recommended dose (20 mg) has not been used by three of 38 (7.9%) patients. Following appropriate dose titration to maximum tolerated dose (20 mg) Fig. 3 Results of management strategy to initial nonresponders to tadalafil (all three phases of the study). Following continuous administration of tadalafil 20 mg every other day for 2 consecutive weeks, 6 patients converted to responders (Fig. 3). Finally, 48 of 54 (88.9%) patients remained non-responders (including patients who did not agree to participate in the continuous administration scheme). No adverse events associated with dropout was noticed in any of the phases, although 10 patients reported mild side effects: headache (one in phase 1, one in phase 3), dyspepsia (one in phase 1, one in phase 3), flushing (two in phase 1, one in phase 3), myalgia (both in phase 3), reflux (both in phase 3). Only one patient experienced two side effects in the same phase (flushing and headache in phase1, although mild and tolerable) Vardenafil group Mean patient age was years (range, 28 72) and mean duration of ED, years (range, Fig. 4 Results of management strategy to initial nonresponders to vardenafil (all three phases of the study).

5 130 european urology 50 (2006) and instructions on administration (use at least four doses), 12 patients responded to vardenafil (Fig. 4), four of them using the 10-mg dose and eight using the 20-mg dose (phase 1). After phase 1, 88 patients were still non-responders and entered phase 2. Following new instructions use of vardenafil in the fasted state only 22 of 88 (25%) patients converted to responders (Fig. 4). After phase 2, 66 of 88 (75%) patients were still non-responders and entered phase 3. Only 32 of 66 (48.5%) patients agreed to participate, mainly because they had to cover the drug expenses. Following continuous administration of vardenafil every day for 2 consecutive weeks, 12 patients converted to responders (Fig. 4). Finally, 54 of 66 (81.8%) patients remained non-responders (including patients who did not agree to participate in the continuous administration scheme). No side-effect associated dropout was noticed in any phase in the vardenafil group. However, 14 patients experienced mild and tolerable side effects: headache in six (three in phase 1, one in phase 2, two in phase 3); flushing in five (two in phase 2, two in phase 2, one in phase 3); reflux in one (in phase 3) and nasal congestion in three (one in each phase). 4. Discussion The first phase of the present study is similar to the one published previously on the inadequate use of sildenafil in a group of 100 sildenafil non-responders [4]. Using the same study design (phase 1), the authors recognized inappropriate use of tadalafil and vardenafil in 32% and 38% of patients, respectively. Two reasons for inappropriate use were identified. Most patients had experienced fewer than four doses/attempts (90.6% for tadalafil and 100% for vardenafil), while six patients in the tadalafil group and 18 patients in the vardenafil group had tried only a single dose. The highest recommended dose (20 mg) had not been used by 31.3% of patients in the tadalafil group and by 7.9% of patients in the vardenafil group. Both reasons were identified in 28 patients in the tadalafil group and in all 38 patients in the vardenafil group. Patients were defined as non-responders after four unsuccessful attempts using the highest tolerated drug dose in accordance with manufacturer s guidelines with respect to timing relative to meals, alcohol ingestion, use of concomitant medications and adequate sexual stimulation/arousal [13]. Following appropriate dose titration to maximum tolerated dose (20 mg) and instructions on administration (use at least four doses), 14 patients responded to tadalafil, all of them using the 20-mg dose, while 12 patients responded to vardenafil, four of them using the 10-mg dose and eight, the 20- mg dose. The impact of each single reason on the failure rate for tadalafil or vardenafil is not clear, as in most cases both factors affecting treatment efficacy were recognized. This is the first study demonstrating that patients treated with the two new PDE5 inhibitors tadalafil and vardenafil may receive inadequate instructions and follow-up, as has been shown previously with sildenafil. This finding maybeduetothefactthatthevastincreasein men seeking help for ED has resulted in widespread prescription of PDE5 inhibitors by physicians who do not have the background knowledge or time to educate and treat ED patients appropriately [14]. However, fewer patients received inappropriate instructions with tadalafil and vardenafil (32% and 38%, respectively), compared with data of several studies with sildenafil (56% in our previous study, up to 80% in the literature) a few years ago. Furthermore, previously recognized reasons for inadequate use of sildenafil, such as use without the presence of sexual stimulation, was not identified in the present study. This finding may be due to the fact that today 7 years after sildenafil came on the market physicians are better educated on proper use of PDE5 inhibitors and recognize the need for close follow-up. Nevertheless, there is still a long way to go. Critical aspects in management of ED patients, such those included in the acronym FAST (Follow-up, Adjustment of time of administration, Sexual stimulation and Titration to the maximum tolerated dose) [15], are still essential. Erectile dysfunction is a chronic disease; follow-up visits are mandatory, not only to improve physician-patient communication but also to identify and solve treatment problems that may have occurred, as well as to offer continuing education to both patients and their partners. Comparative studies that do not consider the importance of physicianpatient interaction, timing of administration and dose titration should not be considered valid [16]. In phase 2 of the study, new instructions were given to the patients. Tadalafil labeling instructs patients to use the drug at least 30 min before sexual intercourse. However, the time to maximum plasma concentration for tadalafil (Tmax) is about 2 h, and clinical data demonstrate that the percentage of patients with a successful erection within 30 min is 52%. These findings mean that almost half of the patients may not be given the option to respond

6 european urology 50 (2006) to tadalafil if they engage in sexual activity 30 min after administration, since the drug would not achieve its maximum plasma concentration. Vardenafil labeling denotes that the drug can be taken with or without food, although there is a precaution that a high-fat calorie meal (>57% of calories derived from fat) may delay onset of action. Such a high-fat diet may be common in everyday life. Therefore, response to vardenafil may be suboptimal if patients are not aware of this fact. The new set of instructions included use of tadalafil at least 2 h before sexual intercourse and use of vardenafil in the fasted state only. Following these new instructions, 32 of 86 (37.2%) patients using tadalafil and 22 of 88 (25%) patients using vardenafil converted to responders. Subgroup analysis based on ED severity did not show any difference between them. Furthermore, this study was not a head-tohead comparison between tadalafil and vardenafil. These patients would have been considered as true non-responders regardless. Physicians have to be aware of these facts and properly inform patients despite current labeling information. Daily dosing of PDE5 inhibitors recently has come to our attention. Continuous inhibition of PDE5 results in a permanent high concentration of cyclic guanosine monophosphate, offering ED patients and their partners not only a higher level of efficacy, as indicated in the present study, but also greater flexibility and spontaneity in sexual involvement. McMahon [11] previously treated non-responders with on-demand tadalafil with continuous use on a daily basis at flexible doses of tadalafil 10 and 20 mg for 12 weeks. Daily tadalafil significantly improved ( p < 0.001) the IIEF EF domain score and Sexual Encounter Profile question 3, compared with on-demand tadalafil. Mirone et al. [12] compared tadalafil 20-mg treatment on demand to continuous use of tadalafil 20 mg, 3 times/week for 5 6 weeks. On-demand tadalafil 20 mg was preferred by 57.8% of men, while 42.2% preferred the 3 times/week treatment. In both studies, there were no significant differences between treatment arms in terms of safety. In phase 3 of the present study, non-responders of phase 2 were rechallenged with continuous use of tadalafil 20 mg every other day or vardenafil 20 mg every day for 2 consecutive weeks. Only 34 of 54 (63%) patients in the tadalafil group and 32 of 66 (48.5%) patients in the vardenafil group agree to participate in this phase, mainly because they had to cover the drug expenses. Following continuous administration, six of 54 (11.1%) patients in the tadalafil group and 12 of 66 (18.2%) patients in the vardenafil group converted to responders. On the basis of these data, efficacy may be maximized with continuous administration. This treatment strategy resulted in an overall salvage of 52 of 100 (52%) patients in the tadalafil group and 46 of 100 (46%) patients in the vardenafil group. However, patients self-selecting continuous therapy may have achieved responses on the basis of various factors, and a true effective therapy alone cannot be ascertained. Although there are limited data on the systemic effects of the continuous inhibition of PDE5, chronic administration of tadalafil has been shown to improve endothelial function in patients with increased cardiovascular risk [17], while sildenafil administration is associated with vasodilation of epicardial coronary arteries, improvement of endothelial dysfunction and inhibition of platelet activation in patients with coronary artery disease [18]. Sildenafil also improves endothelium-dependent, flow-mediated vasodilatation in patients with diabetes mellitus and chronic heart failure, and in current smokers [19 21]. Further research is needed on the continuous administration of PDE5 inhibitors, as well as on possible benefits of everyday use on the cardiovascular system, especially in patients at risk, such as patients with metabolic syndrome. 5. Conclusion ED patients often receive insufficient information on appropriate use of tadalafil and vardenafil. Fewer than four doses/attempts is the most common factor leading to treatment failure, followed by insufficient dose titration to the maximum tolerated dose. Addressing such mistreatment factors must be the first step in identifying true nonresponders to tadalafil and vardenafil. Timing of intercourse and food instructions also may play a significant role in the response rate of ED patients under PDE5 inhibitors treatment. A continuous administration scheme also may be considered in future studies, as preliminary data presented in the present study showed that it may maximize efficacy in a certain subpopulation. Following the steps of the present real-life study, several of the so-called non-responders to PDE5 inhibitors may be salvaged. References [1] Lue TF, Giuliano F, Montorsi F, et al. Summary of the recommendations on sexual dysfunctions in men. J Sex Med 2004;1:6 23. [2] Hatzimouratidis K, Hatzichristou DG. A comparative review of the options for treatment of erectile dysfunc-

7 132 european urology 50 (2006) tion: which treatment for which patient? Drugs 2005;65: [3] Hatzichristou D, Hatzimouratidis K, Bekas M, Apostolidis A, Tzortzis V, Yannakoyorgos K. Diagnostic steps in the evaluation of patients with erectile dysfunction. J Urol 2002;168: [4] Hatzichristou D, Moysidis K, Apostolidis A, et al. Sildenafil failures may be due to inadequate patient instructions and follow-up: a study on 100 non-responders. Eur Urol 2005;47: [5] McCullough AR, Barada JH, Fawzy A, Guay AT, Hatzichristou DG. Achieving treatment optimization with sildenafil citrate (Viagra 1 ) in patients with erectile dysfunction. Urology 2002;60: [6] Atiemo HO, Szostak MJ, Sklar GN. Salvage of sildenafil failures referred from primary care physicians. J Urol 2003;170: [7] Hatzichristou D, Montorsi F, Buvat J, Laferriere N, Bandel TJ, Porst H. The efficacy and safety of flexible-dose vardenafil (levitra) in a broad population of European men. Eur Urol 2004;45: [8] Potempa AJ, Ulbrich E, Bernard I, Beneke M. Efficacy of vardenafil in men with erectile dysfunction: a flexibledose community practice study. Eur Urol 2004;46:73 9. [9] Montorsi F, Verheyden B, Meuleman E, et al. Long-term safety and tolerability of tadalafil in the treatment of erectile dysfunction. Eur Urol 2004;45: [10] Skoumal R, Chen J, Kula K, et al. Efficacy and treatment satisfaction with on-demand tadalafil (Cialis) in men with erectile dysfunction. Eur Urol 2004;46: [11] McMahon C. Efficacy and safety of daily tadalafil in men with erectile dysfunction previously unresponsive to ondemand tadalafil. J Sex Med 2004;1: [12] Mirone V, Costa P, Damber JE, et al. An evaluation of an alternative dosing regimen with tadalafil, 3 times/week, for men with erectile dysfunction: SURE study in 14 European countries. Eur Urol 2005;47: [13] Carson C, Giuliano F, Goldstein I, et al. The effectiveness scale therapeutic outcome of pharmacologic therapies for ED: an international consensus panel report. Int J Impot Res 2004;16: [14] Rutchik SD, Baudiere M, Wade M, Sullivan G, Rayford W, Goodman J. Practice patterns in the diagnosis and treatment of erectile dysfunction among family practice physicians. Urology 2001;57: [15] Hatzichristou DG. Sildenafil citrate: lessons learned from 3 years of clinical experience. Int J Impot Res 2002;14:S [16] von Keitz A, Rajfer J, Segal S, et al. A multicenter, randomized, double-blind, crossover study to evaluate patient preference between tadalafil and sildenafil. Eur Urol 2004;45: [17] Rosano GM, Aversa A, Vitale C, Fabbri A, Fini M, Spera G. Chronic treatment with tadalafil improves endothelial function in men with increased cardiovascular risk. Eur Urol 2005;47: [18] Halcox JP, Nour KR, Zalos G, et al. The effect of sildenafil on human vascular function, platelet activation, and myocardial ischemia. J Am Coll Cardiol 2002;40: [19] Desouza C, Parulkar A, Lumpkin D, Akers D, Fonseca VA. Acute and prolonged effects of sildenafil on brachial artery flow-mediated dilatation in type 2 diabetes. Diabetes Care 2002;25: [20] Katz SD, Balidemaj K, Homma S, Wu H, Wang J, Maybaum S. Acute type 5 phosphodiesterase inhibition with sildenafil enhances flow-mediated vasodilation in patients with chronic heart failure. J Am Coll Cardiol 2000;36: [21] Kimura M, Higashi Y, Hara K, et al. PDE5 inhibitor sildenafil citrate augments endothelium-dependent vasodilation in smokers. Hypertension 2003;41: Editorial Comment Rafael R. Badalyan, National Institute of Health, Yerevan, Armenia andrology@web.am PDE 5 inhibitors, being the first line therapy for erectile dysfunction, are largely prescribed not only by professionals in ED treatment but by GPs, cardiologists, and other specialists as well; in some countries, these drugs even can be freely obtained at pharmacies, without prescription. Thus, on one hand there is easy to treatment for men, who are more reluctant for seeking medical help, but on the other hand, treatment failure, due to inappropriate use of medications may be more detrimental for these patients. In previously published article [1], when dosed adequately, correctly executed treatment instructions and patient follow-up were considered, a 55% salvage rate was reported in sildenafil nonresponders. In current paper, the authors present a well designed 3 phase study which evaluates the efficacy of 2 new PDE5i, tadalafil and vardenafil in a group of patients with previous treatment failure by using the above mentioned drugs with a newly proposed management strategy. Results on appropriate information regarding medications and adequate dosing, 12% of non-responders in vardenafil group and 14% - in tadalafil group were converted to responders. The outcome of Phase II is of a particular interest as 37.2% of patients became treatment responders with administration of tadalafil at least 2 h before the intercourse; and in the other group of patients 25% converted to responders while taking vardenafil in a fasted state. Such administration scheme for new PDE5i is probably applied by some professionals in everyday practice; however, this study first has described and obviously confirmed the evident, which should be considered in ED patient management. With the treat-

8 european urology 50 (2006) ment administration for 2 consecutive weeks, a positive response was reported among 15% of previously failed men. It is disputable, whether the effect of continuous administration was influencing the phase II outcomes of the study as well as continuation of phase I in to phase II was done without washout period; although, as it mentioned by the authors, designed as a real life study, they were avoiding limitations. In ED treatment perspectives, chronic administration and the possible curative effect of PDE5i is becoming more and more challenging [2], but it needs further clarifications in basic and clinical trials. References [1] Hatzichristou D, Moysidis K, Apostolidis A, Bekos A, Tzortzis V, Hatzimouratidis K, et al. Sildenafil failures may be due to inadequate patient instructions and follow-up: A Study on 100 Non-Responders. Eur Urol 2005;47: [2] Montorsi F, Briganti A, Salonia A, Rigatti P, Burnett AL. Can phosphodiesterase type 5 inhibitors cure erectile dysfunction? Eur Urol 2006;49: