Archivio Italiano di Urologia e Andrologia 2016; 88, 2128 ORIGINAL PAPER A survey on the experience of 136 Italian urologists in the treatment of erectile dysfunction with PDE5 inhibitors and recommendations for the use of Avanafil in the clinical practice Vincenzo Mirone 1, Ferdinando Fusco 1, Fabio Parazzini 2, Alessandro Zucchi 3 1 Dipartimento Ostetricia, Ginecologia, Urologia - Clinica Urologica Università di Napoli Federico II, Italy; 2 I Clinica Ginecologica, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Università di Milano, Italy; 3 Clinica Urologica ed Andrologica, Università di Perugia, Italy. Introduction: PDE5 inhibitors are the first- line treatment for erectile dysfunction. Although all these drugs share the same mechanism of action, each agent could have different characteristics in terms of selectivity, pharmacokinetics and tolerability profile. Materials and Methods: This manuscript illustrates a project, undertaken by the Italian Society of Urology in order to obtain a “snapshot” of the experience of Italian urologists with the use of PDE5 inhibitors in the clinical practice. This project included a survey, targeting a sample of 136 Italian urologists experienced in the treatment of ED, and the organization of a conference of experts who, based on the findings of the survey, the scientific literature and the clinical experience, would define some recommendations for the use of PDE5 inhibitors in clinical practice with a particular focus on Avanafil, the most recent drug in this class. Results: The following recommendations on the use of Avanafil were issued: 1) In patients who are candidates for the use of Avanafil, it is advisable to use the 200-mg dose from the first administration; 2) When used at the highest dose (200 mg), Avanafil shows a favourable tolerability pro- file with an efficacy similar to that of other agents; 3) The patient should be instructed to take Avanafil on an empty stomach, i.e., 30-45 minutes before or 2 hours after a meal; 4) The efficacy window of Avanafil is between 30 min- utes and 6 hours after dosing, which qualifies this molecule as a new drug with an intermediate duration of action; 5) Avanafil at a dose of 50-100 mg/day may be a therapeutic option in chronic rehabilitation. Conclusions: Among PDE5 inhibitors, Avanafil is a new agent with an intermediate duration of action, characterized by high efficacy and good tolerability even at the highest dose (200 mg). KEY WORDS: Erectile dysfunction; PDE5 inhibitors; Avanafil; Italian survey; Recommendations; Dosage. Submitted 1 June 2016; Accepted 10 June 2016 Summary No conflict of interest declared. tion with a high prevalence worldwide; it has been esti- mated that 5-20% of men are affected by moderate-to- severe ED at some time during their sexual life (1). The introduction in the clinical practice of phosphodi- esterase type 5 inhibitors (PDE5is), in the early 1990s, represented a milestone in the treatment of ED. Penile erection is a complex neurovascular event that occurs due to relaxation of cavernosal helicine arteries and smooth muscle of corpora cavernosa in combination with a coincident veno-occlusion, leading to blood dis- tension of the corporal sinusoid and resultant penile rigidity (2). The primary mediator of this process is the nitric oxide (NO)/cyclic guanosin-monophosphate (cGMP) pathway. Phosphodiesterase type 5 (PDE5), the enzyme which breakdowns cGMP in the corpus caver- nosum, regulates the NO-mediated relaxation of smooth muscle cells. The mechanism of action of PDE5is con- sists precisely in the inhibition of PDE5, which results in increased cGMP concentrations with continued activa- tion of the NO/cGMP pathway and subsequent increase in blood flow into the corpora cavernosa (3). The efficacy of PDE5 inhibitors is independent of patient age, etiology of ED (organic, psychogenic, mixed), and baseline severity of the condition (4). Four PDE5is (Sildenafil, Tadalafil, Vardenafil, and Avanafil) have so far been approved for clinical use in Italy. Avanafil, the most recently marketed molecule, differs pharmacologically from the other agents of the same class due to its higher selectivity for the PDE5 isoen- zyme. Indeed, PDE5 inhibitors have different selectivi- ties for this isoenzyme, as they may exert inhibitory effects on other PDE isoforms resulting in potential side effects, sometimes serious enough to require treatment discontinuation. On the other end, the greater the selec- tivity for the PDE5 isoenzyme, the less likely is the occurrence of adverse events potentially related to the inhibition of other PDE isoforms (5). Experimental stud- ies have shown that Avanafil has higher selectivity for PDE5 than for other isoenzymes. It is generally believed that the high selectivity of Avanafil results in better toler- ability compared with other less selective agents (5, 6). DOI: 10.4081/aiua.2016.2.128 INTRODUCTION Erectile dysfunction (ED), defined as the consistent or recurrent inability to attain and maintain an erection sufficient for satisfactory sexual performance, is a condi- Mirone_Stesura Seveso 01/07/16 11:08 Pagina 128 129Archivio Italiano di Urologia e Andrologia 2016; 88, 2 Avanafil and ED: A survey on Italian urologists The efficacy of Avanafil in the treatment of ED is con- firmed by a number of double-blind, placebo-controlled, randomized clinical trials, conducted both in the gener- al population (7) and in “difficult” patient subgroups, such as those with diabetes mellitus (8) or those who have undergone nerve-sparing radical prostatectomy (9). In these clinical trials, Avanafil demonstrated a rapid onset of action, often as early as 15 minutes after dosing, a prolonged therapeutic effect (in some cases up to 6 hours after administration), and a good tolerability (10). After approximately two years from the Avanafil launch in Italy, urologists have now developed a specific clinical experience with the use of this drug. However, there are still some “uncertainties” about the best use of Avanafil, particularly with regard to dosage, efficacy, and safety profile compared with older PDE5is. In order to obtain a “snapshot” of the use of Avanafil in the clinical practice, and to make recommendations for its “best” use, the Italian Society of Urology (SIU, Società Italiana di Urologia) started a project involving: 1) a survey, targeting a sample of Italian urologists experi- enced in the treatment of ED, with a particular focus on their clinical experience with the use of Avanafil; and 2) the organization of a conference of experts who, based on the findings of the survey and the scientific litera- ture, would define some recommendations for the use of Avanafil in clinical practice. This paper describes, in its first part, the preliminary results of the survey, and subsequently presents the rec- ommendations made by the conference of experts. MATERIAL AND METHODS This research was conducted from February to April 2016 through an online survey. SIU members were invited to answer anonymously a number of questions included in a questionnaire. In particular, SIU local chairpersons and physicians experienced in the treatment of ED were invit- ed to participate. The questionnaire investigated the number of ED patients treated over the past 12 months, and the proportion of them treated with Avanafil. Physicians were also asked to indicate, based on their clinical experience, the character- istics of the patients (expressed in percentage) who had been treated with Avanafil 100 mg and 200 mg. The aim of this survey was to collect information on physicians' experience in this context; therefore, detailed information on individual patients was not collected. A total of 136 urologists responded to the survey (88.2% male; mean age 47 years, range 26-71 years; 48.5% of the respondents stated they worked mainly in a hospital setting). Overall, urologists who participated in this survey stated that they had treated 17.856 patients during the 12 months prior to the completion of the questionnaire. Of these, 13% were treated with Avanafil 100 mg, and 26% with Avanafil 200 mg (the same patient could have been treated, at different times, with both doses of Avanafil). Table 1 shows the characteristics of the patients treated with Avanafil 100 mg and 200 mg, the patient satisfac- tion, and the frequency of side effects. Patients treated with Avanafil 200 mg were on average older and were more likely to report comorbid diabetes mellitus. The use of Avanafil 100 mg was more com- mon in treatment-naïve patients. Patient satisfaction was greater in those treated with Avanafil 200 mg. Likewise, the frequency of side effects was slightly higher in individuals treated with the higher dose of Avanafil: overall, the observed difference in the fre- quency of side effects was essentially due to a higher frequency of headaches. The methodology chosen for the production of recom- mendations was that of the “consensus conference”, which involves the drafting of recommendations by a “jury” at the end of a presentation and consultation of experts summa- Patient characteristics Patients treated with Avanafil 100 mg (%) Patients treated with Avanafil 200 mg (%) Age (years) > 50/< 50 61.6/38.4 65.7/34.3 Organic-based ED 56.6 51.1 Comorbid diabetes mellitus 28.6 36.2 First treatment (treatment-naïve pts) 45.7 40.4 On-demand use 65.4 63 Patient satisfaction (yes/no) 54.2/45.8 58.4/41.6 Frequency of side effects Any side effects 15.9 22.4 Headache* 12.6 16.5 Hot flushes 5.5 4.1 Back ache 2.5 1.1 Rash/itching 2.6 2 * Only the side effects reported in more than 2% of the patients in at least one of the two groups are listed. The percentages shown are mean percentages, weighted by the number of patients treated by each physician. Table 1. Characteristics of patients receiving Avanafil 100 mg and 200 mg as reported by physicians participating in the SIU survey. Mirone_Stesura Seveso 01/07/16 11:08 Pagina 129 Archivio Italiano di Urologia e Andrologia 2016; 88, 2 V. Mirone, F. Fusco, F. Parazzini, A. Zucchi 130 rizing scientific knowledge on a given topic. The critical analysis of the literature enables the “jury” to compare the available evidence with expert opinions or reports. This method implies the following steps: 1. the definition of the themes of the recommendations; 2. the search for relevant literature; 3. the preparation of the first draft of the consensus statement by a drafting group; 4. the discussion by a “jury” of experts, and the prepara- tion of the final document. In March 2016, the drafting group identified the themes of the recommendations, searched PubMed using the key words “avanafil, erectile dysfunction, treatment”, and then prepared a first draft of the recommendations. The experts invited to take part in the production of the recommendations participated in a workshop that was held on April 21-22, 2016. During this workshop, the results of the literature review and the findings of the SIU survey, reported in the introduction of this paper, were presented. Subsequently, the recommendations prepared by the drafting group were also presented. The expert panel was composed of 16 SIU local chair- persons and 32 experts (2 per local area) in the treatment of ED, identified among the SIU members by the local chairpersons of the association. RESULTS All the experts discussed, amended, and approved in plenary session the recommendations that are presented herein, with comments illustrating their rationale and relevance for the clinical practice. 1. In patients who are candidates for the use of Avanafil, it is advisable to use the 200-mg dose from the first administration. The data of this survey indicate that the 200-mg dose of Avanafil is the most commonly used in clinical practice. This practice is supported at least partly by scientific liter- ature. Corona et al. (11) have recently published a system- atic review of the literature on randomized controlled tri- als (RCTs), evaluating Avanafil versus placebo in the treat- ment of erectile dysfunction. This systematic review included five placebo-controlled RCTs, showing that Avanafil was superior to placebo in improving vaginal penetration and achieving a successful sexual intercourse. This review of the literature concluded that both the 100- and 200-mg doses of Avanafil were effective and well tolerated. Actually, the single most commonly reported adverse effect with Avanafil 200 mg was an increased frequency of headache com- pared to Avanafil 100 mg, although this difference was not statistically sig- nificant (this finding has also been reported in the present survey on the clinical practice in Italy). No differ- ences were observed between the two groups in the rate of treatment contin- uation. With regard to efficacy, the analysis of published studies indicates a greater efficacy (although not statistically significant) of the treatment with the 200-mg dose. The effect of Avanafil 100 mg was also lower in elderly subjects, while no differences were observed with Avanafil 200 mg. The observation that the 200-mg dose of Avanafil shows greater efficacy in all patient categories, while having a substantially similar tolerability profile, clearly supports the recommendations of our working group. 2. When used at the highest dose (200 mg), Avanafil shows a favourable tolerability profile with an efficacy similar to that of other agents. Chen et al. (12) have recently published a “network meta- analysis” that included RCTs evaluating the efficacy of Sildenafil, Tadalafil, Vardenafil, and Avanafil, usually in comparison with placebo. Overall, the authors included 82 RCTs (for a total of 47626 patients) for the efficacy analysis, and 72 RCTs (20325 patients) for the tolerability analysis. The authors concluded that there were no significant dif- ferences between Avanafil, Sildenafil, Tadalafil, and Vardenafil, when the maximum recommended doses of these drugs (200, 100, 20 and 20 mg, respectively) were administered. With regard to tolerability, Avanafil was sig- nificantly associated with a lower incidence of adverse effects when drugs were given at the maximum recom- mended dosage patients were treated with the maximum recommended doses of these drugs (200, 100, 20, and 20 mg, respectively). 3. The patient should be instructed to take Avanafil on an empty stomach, i.e., 30-45 minutes before or 2 hours after a meal. It is important to adequately educate the patient about the fact that Avanafil should be taken on an empty stom- ach. In fact, the median Time to Maximum Plasma Concentration (Tmax) is obtained within 30-45 minutes after dosing, and the concomitant intake with food caus- es a delay in median Tmax of 1 hour and 25 minutes , as reported in the Summary of Product Characteristics (SPC) of Avanafil (13). 4. The efficacy window of Avanafil is between 30 minutes and 6 hours after dosing, which qualifies this molecule as a new drug with an intermediate duration of action. Table 2 shows the median Tmax and the plasma half-life (in hours) of the four PDE5 inhibitors available today in Italy for the treatment of ED (13-17). With regard to Avanafil, discordant data about half-life have been pre- sented in the literature. Its terminal half-life is 6-17 h, as reported in the SPC, while the apparent T1/2 is 1.20 to Parameter Avanafil Sildenafil Vardenafil Tadalafil Tmax (median) 30-45 min 1 h 1 h 2 h Plasmatic half-life 1.20-5 h 3–5 h 4–5 h 17.5 h (mean) Table 2. Tmax and plasmatic half-life of PDE5-inhibitors (13-17). Mirone_Stesura Seveso 01/07/16 11:08 Pagina 130 131Archivio Italiano di Urologia e Andrologia 2016; 88, 2 Avanafil and ED: A survey on Italian urologists 5 hours (17), in line with the duration of the therapeutic effect observed in clinical trials. It is quite clear from above that Avanafil can be qualified as a new agent with an intermediate duration of action, as compared with other active substances. 5. Avanafil at a dose of 50-100 mg/day may be a thera- peutic option in chronic rehabilitation. There is scientific evidence supporting the use of PDE5 inhibitors as on-demand or chronic (daily) treatment for penile rehabilitation following radical prostatectomy. The fibrosis of cavernous bodies has been associated with reduced penile length: experimental studies have demonstrated that, following bilateral cavernous nerve injury, there is a significant reduction in the cavernosal smooth muscle/collagen ratio. Chronic use of PDE5is has been specifically studied with the aim to improve this clinical problem. Avanafil has been shown to be effective in the treatment of patients with ED following radical prostatectomy. When prescribed for chronic use, these agents are usually given at the lowest dose available (18), and increasing their dose does not seem to improve their efficacy (19). DISCUSSION As emphasized by the recent guidelines of the European Association of Urology (EAU), PDE5is are the first-line therapeutic option for most men with ED. Currently available PDE5is (Sildenafil, Tadalafil, Vardenafil, and Avanafil) have the same mechanism of action; therefore, their efficacy is substantially similar at comparable doses. There are, however, relevant differences in the pharma- cokinetic profile and degree of selectivity between differ- ent agents, and this should be taken in account in the therapeutic decision-making process. The high selectivity of Avanafil, in particular, gives this agent a very satisfactory tolerability profile, as pointed out also by one of the recommendations in this paper, which suggests that good tolerability is one of the main “strengths” of Avanafil compared to other molecules. The prevailing opinion among the participants in this survey is that, in patients who are candidates for the use of Avanafil, the 200-mg dose should be used from the start of the treatment; in fact, this dose provides an appropriate balance between the efficacy and tolerability of PDE5is, in combination with satisfactory response and compliance rates. According to the findings of this sur- vey, there seem to be no significant differences in terms of efficacy between Avanafil, Sildenafil, Tadalafil, and Vardenafil when the maximum recommended doses of these drugs are used (200, 100, 20, and 20 mg, respec- tively); moreover, Avanafil shows a favourable tolerabili- ty profile when used at the highest dose (200 mg), with an efficacy similar to that of other agents. A crucial point for the successful treatment of ED with PDE5is is the effectiveness of Doctor-Patient communi- cation in relation to the proper administration of pre- scribed medications and the outcomes to be expected, both in terms of efficacy and response times. In fact, if these issues are not adequately explained to the patients, they may mistakenly believe that the treatment pre- scribed is ineffective and/or may inappropriately stop or change their medications on their own initiative. In particular, the patient should be instructed to take Avanafil on an empty stomach, i.e., 30-45 minutes before or 2 hours after a meal, in order to obtain an optimal therapeutic effect; it is also necessary to explain that the efficacy window of Avanafil is between 30 minutes and 6 hours after dosing, which qualifies this new PDE5i as an agent with intermediate duration of action. 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J Sex Med. 2012; 9:1448. 19. Bannowsky A, Schulze H, van der Horst C, et al. Recovery of erectile function after nerve-sparing radical prostatectomy: improvement with nightly low-dose sildenafil. BJU Int. 2008; 101:1279. 20. Cui YS, Li N, Zong HT, et al. Avanafil for male erectile dys- function: a systematic review and meta-analysis. Asian Journal of Andrology. 2014; 16:472. Correspondence Vincenzo Mirone, MD mirone@unina.it Ferdinando Fusco, MD (Corresponding Author) ferdinando-fusco@libero.it Dipartimento Ostetricia, Ginecologia, Urologia Clinica Urologica Università di Napoli Federico II, Italy Fabio Parazzini, MD fabio.parazzini@unimi.it I Clinica Ginecologica, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Università di Milano, Italy Alessandro Zucchi, MD zucchi.urologia@gmail.com Clinica Urologica ed Andrologica, Università di Perugia, Italy Mirone_Stesura Seveso 01/07/16 11:08 Pagina 132