Phosphodiesterase Type 5 Inhibitors: The Day After

european urology 51 (2007) 75–89

available at www.sciencedirect.com journal homepage: www.europeanurology.com

Review – Sexual Medicine

Phosphodiesterase Type 5 Inhibitors: The Day After Konstantinos Hatzimouratidis, Dimitrios Hatzichristou * 2nd Department of Urology, Papageorgiou General Hospital and Center for Sexual and Reproductive Health, Aristotle University of Thessaloniki, Greece

Article info

Abstract

Article history: Accepted July 14, 2006 Published online ahead of print on August 1, 2006

Objective: Review the literature on phosphodiesterase type 5 inhibitors (PDE5-Is), addressing critical issues in their current and future use, assessing unanswered questions, and identifying research needs. Methods: A MEDLINE search was conducted on PDE5-Is, with emphasis on clinical trials and experience, for interpretation and analysis of their present and future role. Results: Although approximately 40 million patients with erectile dysfunction have been treated successfully worldwide with the three available PDE5-Is, inappropriate instructions, lack of follow-up, and lack of patient-centered care models are the main reasons for ‘‘nonresponse,’’ leading to drop-out rates of >50%. Patients with severe neurologic damage, diabetes mellitus, or severe vascular disease may be resistant to PDE5-Is. Preservation of corporal smooth muscle with chronic administration of PDE5-Is has been reported and substantial evidence indicates that these drugs have beneficial effects on endothelium and cardiovascular function; sildenafil has been approved for the treatment of idiopathic pulmonary hypertension. Improvement of lower urinary tract symptoms in men with benign prostatic hyperplasia after PDE5-I administration has been also suggested. Conclusions: The data indicate the necessity for (1) exploration of the pharmacologic characteristics of the three PDE5-Is; (2) research on their pharmacologic differences because some actions seems to be drugspecific; (3) development of alternative management strategies, such as chronic, low, everyday doses of PDE5-Is, if the monthly cost is affordable; and (4) clinical trials on use of PDE5-Is to treat other chronic conditions. The door for innovative therapeutic approaches will open, specifically for cross-risk factor treatment with PDE5-Is or their use in combination treatments or new multimodal pills that take advantage of drugs that exert pleiotropic vascular actions.

Keywords: Endothelium Erectile dysfunction Phosphodiesterase inhibitors Treatment outcome

# 2006 European Association of Urology. Published by Elsevier B.V. All rights reserved. * Corresponding author. 77 Mitropoleos str, 54622 Thessaloniki, Greece. Tel. +30 2310 693256; Fax: +30 2310 263 939. E-mail address: [email protected] (D. Hatzichristou). 0302-2838/$ – see back matter # 2006 European Association of Urology. Published by Elsevier B.V. All rights reserved.

doi:10.1016/j.eururo.2006.07.020

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1.

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Introduction

Epidemiologic and help-seeking behaviour studies have shown that erectile dysfunction (ED) is highly prevalent, as well as being the major sexual concern of men [1–4]. Such a high percentage of men reporting and seeking help for ED may be attributable to the availability of phosphodiesterase type 5 inhibitors (PDE5-Is) as efficacious and safe oral therapy for ED and the accompanying publicity in the media. However, despite the fact that, worldwide, approximately 40 million men with ED have been treated successfully with PDE5-Is, several questions remain unanswered. A substantial body of evidence indicates that this new class of drugs has beneficial effects in several chronic conditions; sildenafil has been recently approved for the treatment of idiopathic pulmonary hypertension [5], and numerous articles have suggested that PDE5-Is may improve arterial function [6–17]. Additionally, improvement in patients with benign prostatic hyperplasia (BPH)-associated lower urinary tract symptoms (LUTS), as well as in patients with premature ejaculation, has been also reported [18–21]. As a consequence, PDE5-Is are gaining major attention and research focus by both basic researchers and clinicians. Although such research avenues are exciting and provocative, moving them into clinical practice requires caution and a careful eye on current data, as well as continuous monitoring of future data. The present article addresses critical issues in current and future use of PDE5-Is, assessing unanswered questions and identifying future research needs. To do so, a MEDLINE search was conducted on PDE5-Is between 1998 and 2006, for interpretation and critical analysis of the available clinical data.

2. Unanswered questions: what do we know and what do we have to learn about PDE5-Is? 2.1.

Efficacy of PDE5-Is

All available guidelines, including the recently published European Association of Urology (EAU) updated guidelines on ED, consider PDE5-Is as the reference class for ED treatment [22]; such wide acceptability is based on the published results of numerous clinical trials, where both the efficacy and safety profile of the three PDE5-Is in broad population, as well as in specific subpopulations, has been proven [23]. Several studies have been published exploring the efficacy and safety of PDE5-Is in patients with diabetes mellitus, hypertension,

cardiovascular disease (CVD), depression, multiple sclerosis, spinal cord injury, chronic renal insufficiency, renal transplants, liver disorders, and other conditions [23–25]. Although the overall efficacy rate is about 60–70%, efficacy rates are lower in the socalled difficult-to-treat populations. Patients with severe neurologic damage, diabetes mellitus, or severe vascular disease may be resistant to PDE5-Is; decreased expression or activity of neuronal or endothelial nitrous oxide synthase (NOS), impaired nitric oxide (NO) release, or NO destruction precludes sufficient cyclic guanosine monophosphate (cGMP) formation and eliminates PDE5-I efficacy [26]. In such subpopulations, specific response predictors have been identified; in diabetics, for example, major predictors for PDE5-I efficacy include glycemic control and diabetic complications [27]. ED in men with prostate cancer undergoing radical prostatectomy is another difficult-to-treat group of major interest to urologists. The main predictors of the postoperative erectile capacity and the response to pharmacologic treatment include surgical technique and skills (bilateral nerve-sparing, minimal use of coagulation, experience of the surgeon), the age and health status (existence of comorbidities associated with ED) of the patient, and the preoperative potency status [28–30]. However, several problems exist in the interpretation of the literature: (1) most of the data are coming from centres of excellence that are able to treat a small proportion of the total number of patients with prostate cancer worldwide; (2) taking into consideration the fact that information given to patients preoperatively is retrieved from the medical literature, it becomes clear that such data often give misinformation, leading to unrealistic expectations by the patients; and (3) major differences in potency rates after prostatectomy have been reported, ranging between 16% and 86% [31]. Several factors contribute to these discrepancies: (a) there are substantial differences in the surgical technique, and the learning curve for radical prostatectomy has not been well justified; (b) patient selection criteria differ substantially and affect the outcome, and the centres of excellence usually have the privilege of operating on younger patients without risk factors for ED, and therefore with excellent preoperative potency status; (c) there is lack of homogeneity in the assessment of potency status because most studies did not use validated tools to evaluate potency, whereas several others calculated postoperative potency rate including PDE5-I responders. To determine the impact of radical prostatectomy and get valid information on the postoperative

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potency status, a large-scale, independent clinical trial is necessary; such study ideally may be organised by a scientific society such as EAU, using strict inclusion criteria, validated research tools for preoperative and postoperative potency status, and an independent CRO. Furthermore, a European prostate cancer/radical prostatectomy registry, including centres with low and large volumes of patients will allow a precise description of the current clinical practice and outcome within Europe. 2.2. Comparing the pharmacologic characteristics of PDE5-Is

The onset of action of PDE5-Is has been defined in clinical trials and all three drugs may offer good response in some patients in about 15 min; sildenafil may be successful in 35% of men after 14 min, tadalafil in 32% after 16 min, and vardenafil in 23% after 11 min [32–34]. In the everyday clinical practice, however, such data may lead to misuse of the drugs and an increased number of non-responders. If patients are instructed that any of the three PDE5Is may work within 10–15 min, at least two of three patients will be ‘‘non-responders’’ with several and serious implications: (1) patients will not trust the drug and possibly their physician again, (2) they may interpret the result as the ‘‘end of their sexual life,’’ and (3) a trajectory period for their intimate relationship may follow. Pharmacokinetic data, therefore, must be considered when instructing patients. The time for maximum plasma concentration is about 1 h for sildenafil and vardenafil and 2 h for tadalafil. Furthermore, a fatty meal may decrease absorption and therefore prolong onset of action; this is clear for sildenafil, as well as for vardenafil in case of a meal with >57% of calories deriving from fat, but seems not to be the case for tadalafil. Moreover, the discrepancies between pharmacologic studies and real life are well documented; in a recent study, 37.2% of the tadalafil non-responders and 25% of the vardenafil non-responders converted to responders when tadalafil was used at least 2 h before sexual intercourse and vardenafil was administered only in the fasted state, justifying the need for further exploration in the clinical setting of the pharmacologic characteristics of the available PDE5-Is [35]. Another unanswered question remains the duration of action of the PDE5-Is. Initial reports characterised sildenafil and vardenafil as short-acting drugs for up to 4 h. On the other hand, the duration of action of tadalafil was initially reported to be 24 h. Consecutive trials, however, have shown a consistent efficacy of tadalafil for up to 36 h [36]. Clinical

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experience has shown that the duration of action of both sildenafil and vardenafil far exceeds the 4-h therapeutic window; initial reports on sildenafil and vardenafil have shown that both drugs may be efficacious for 8–12 h after dosing [37,38]. Until the availability of convincing data, however, the duration of sildenafil and vardenafil remains under question. Physicians have to be aware of these facts and properly inform their patients. 2.3. Adequate instructions on PDE5-I use increases efficacy

Several studies have identified inappropriate instructions and lack of follow-up as common causes for ‘‘non-response’’ to PDE5-Is. All published reports showed that 30–50% of the initial nonresponders to PDE5-Is may be converted to responders [35,39–41]. The main reasons for non-response included inappropriate timing of sexual intercourse, single-dose trial, and lack of titration to the highest recommended dose. Such data emphasise the need for regular follow-up and exploration of the self-reports of non-response; a patient should be considered as a true non-responder only after ‘‘4 sexual attempts with administration of 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’’ [42]. Furthermore, a recent study clearly demonstrated that counselling may also convert ‘‘non-responders’’ to responders [43]. To adequately treat our patients, critical aspects in ED management, such as those included in the acronym FAST (follow-up, adjustment of time of administration, sexual stimulation, and titration to the maximum tolerated dose), are essential [44]. 2.4.

Is there still a safety issue for PDE5-Is?

Despite the fact that PDE5-Is have limited contraindications (mainly organic nitrates and other nitrate preparations, patients with history of retinitis pigmentosa or diseases predisposing to priapism such as leukaemia or multiple myeloma), several cardiovascular safety issues have been addressed since the marketing of the first PDE5-I. Clinical trials and post-marketing pharmacologic surveillance data on sildenafil, tadalafil, and vardenafil have demonstrated no increase in myocardial infarction rates in patients who received these agents compared to expected rates in aged-matched populations [24,45,46]. Furthermore, numerous studies have proven not only the cardiovascular safety

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of PDE5-Is but have also described mechanisms and clinical results of possible cardiovascular benefits of PDE5-Is; for example, very recent data suggest that PDE-5 inhibition by sildenafil deactivates multiple heart hypertrophy signaling pathways suppressing cardiac hypertrophy and pathologic remodeling that frequently lead to heart failure [47,48]. Recently the Second Princeton Consensus Panel published a state-of-the-art document that summarises the existing knowledge on this issue [49]. In addition, the recent approval of sildenafil in doses of 20 and 40 mg, taken every 8 h life-long by patients with pulmonary hypertension, clearly indicates that the regulatory bodies have accepted PDE5-I safety, not only for ‘‘on-demand’’ use, but also as a chronic daily treatment [5]. However, there is still public awareness regarding the cardiovascular safety of PDE5-Is. This may be explained by the high prevalence of CVD among patients seeking treatment for sexual dysfunction because the potential cardiac risks associated with sexual activity are well established [50]. Moreover, an increasing body of evidence not only supports ED as the first sign of CVD in men with disease-free medical history, but also justifies prevention strategies, because ED may present well before CVD with a mean time interval of even 3 yr [51]. Recently, Montorsi et al. proposed a pathophysiologic mechanism to explain the link between ED and coronary artery disease (CAD), the ‘‘the artery size hypothesis.’’ According to this hypothesis, because penile arteries are smaller in diameter than coronary arteries, patients with ED will seldom have concomitant symptoms of CAD, whereas patients with CAD will frequently complain of ED [52]. Based on the above data, several investigators have proposed that vasculogenic ED may be considered as a marker of silent vascular disease or a risk factor for CVD and should accordingly alert the physician to the need for cardiovascular risk screening [50,53,54]. This new focus is incorporated in the management algorithm offered by the Second Princeton Consensus Conference [49], which clearly states that sex in some patients and not PDE5-Is may be dangerous for the heart. Furthermore, CVD and ED not only share common risk factors [55–57], but also there are two clinical scenarios in which the two conditions may coexist: the patient with ED who later develops CAD and the patient with overt CAD who is casually found to have ED [58]. Such data support adoption of a common prevention and treatment strategy, as has been recently recommended (Table 1) [59]. An important safety issue of major interest to urologists is the coadministration of PDE5-Is with

a-blockers in patients with BPH-related LUTS. Although the adverse event profile of the PDE5-I is not worsened by a background of antihypertensive medicines, even when the patient is taking multiple antihypertensive agents, all PDE5-Is appear to have some interaction with a-blockers, which under some conditions may result in clinically significant orthostatic hypotension [49]. This is most likely to occur in patients treated with doxazosin (a longacting a-blocker). Hemodynamic interactions of tadalafil with tamsulosin [60] or alfuzosin [61], as well as interactions of vardenafil with tamsulosin [62], are clinically insignificant. Today, a-blockers are no longer considered a contraindication for any of the three PDE5-Is, but precautions in the use of these drugs are listed. Patients who demonstrate hemodynamic instability on a-blocker therapy alone are at increased risk of symptomatic hypotension with concomitant use of PDE5-Is; therefore, patients should be stable on a-blocker therapy prior to initiating a PDE5-I and PDE5-I treatment must be initiated at the lowest recommended dose, whereas PDE5-I dosing should be 3–4 h apart from antihypertensive administration. Finally, the potential relationship between nonarteritic anterior ischemic optic neuropathy (NAION) and PDE5-I use has raised important questions and a strong reaction not only among regulatory agencies, but also within the scientific community and mass media as well [63]. NAION is characterised by acute ischemia of the anterior portion of the optic nerve in the absence of provable arteritis, which may result in visual field defect or vision loss. No effective treatment is available and prevention is limited to the treatment of risk factors mainly aimed at decreasing the risk of a similar event in the other eye. Numerous risk factors have been reported for NAION, mainly cardiovascular risk factors, including hypertension, diabetes, and hypercholesterolaemia. Post-marketing surveillance data have detected >50 cases of NAION among PDE5-I users. Because PDE5-I have been used by approximately 40 million men worldwide and the incidence of NAION has been reported as 2.3/100,000 persons, we would expect far more than the reported 50 cases associated with the use of PDE5Is. Although surveillance is based on voluntary reporting, and thus NAION may be underreported, there is no epidemiologic evidence that the incidence of NAION is higher in patients taking PDE5-Is than would be expected in an age-matched population with similar medical histories. According to the European Medicine Evaluation Association (EMEA) labelling, however, patients taking or considering taking PDE5-Is should inform their health care

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Table 1 – Reasons for inadequate use of PDE5-Is and treatment strategy Study

PDE5-I used

Reasons for inadequate use

Treatment strategy

McCullough [97]

Sildenafil

 Only 50 mg used and <5 attempts (55%)

Atiemo [40]

Sildenafil

   

Jiann [41]

Sildenafil

 No sexual stimulation (30%)  <4 attempts (60%)  Maximum dose <100 mg (45%)

Hatzichristou [39]

Sildenafil

   

Gruenwald [43]

Sildenafil

Hatzimouratidis [35]

Hatzimouratidis [35]

Results of treatment

 Re-education (proper administration and expectations)  Retrial with at least 8 attempts (100 mg if needed)

54% converted to responders

 Re-education (videotape, personal instructions, instruction sheets for patient and partner)  Retrial (100 mg if 50 mg after one attempt was inadequate)

41.5% converted to responders

 Adequate instructions  Retrial with 4 doses (100 mg)

58.5% converted to responders

 Adequate instructions  Retrial with 4 doses (100 mg if needed)

55.4% converted to responders

 Maximum dose <100 mg (76%)  2.5 attempts (average)

 Adequate instructions (oral and written, videotape in some cases)  Retrial with 8 doses (100 mg)

23.6% achieved normal erectile function

Tadalafil

 Maximum dose <20 mg (10%)  <4 attempts (29%)

 Adequate instructions  Retrial with 4 doses (100 mg if needed)

43.75% converted to responders

Vardenafil

 Maximum dose <20 mg (3%)  <4 attempts (38%)

 Adequate instructions  Retrial with 4 doses (100 mg if needed)

31.6% converted to responders

Use after meal (13.3%) No sexual stimulation (33.7%) Timing of sex (14.3%) Too few attempts (20.4%)

Maximum dose <100 mg (44%) Use after meal (32%) Use just before sex (22%) No sexual stimulation (12%)

PDE5-I = phosphodiesterase type 5 inhibitor.

professionals if they have ever had severe loss of vision, which might reflect a prior episode of NAION, because such patients are at an increased risk of developing NAION again and they should be referred to the ophthalmologist [22]. 2.5. Class-specific versus drug-specific actions of the PDE5-Is

A large volume of research has been published, investigating the cardiovascular actions of PDE5-Is, especially sildenafil. A question that rises is whether all these actions are identical for all three PDE5-Is or whether they are drug-specific actions. Recent publications suggest that there are drug-specific rather than class-specific actions. Gofrani et al. were the first to compare the short-term haemodynamic profiles of sildenafil, vardenafil, and tadalafil in a well-defined group of patients with chronic pulmonary arterial hypertension [64]. Although vardenafil showed the most rapid onset of effects, this substance lacked selectivity for the pulmonary circulation, which was demonstrated for sildenafil and tadalafil. Sildenafil, on the other hand, but not

vardenafil and tadalafil, did improve arterial oxygenation; the authors concluded that their findings strongly support careful evaluation of the pulmonary hemodynamic and gas exchange effects of each of the three drugs, despite their common classification as PDE5-Is. In another study, Teixeira et al. demonstrated that vardenafil, but not sildenafil or tadalafil, affects Ca2+ handling in the rat aorta, besides increasing cGMP levels through inhibition of PDE5 to cause relaxation [65]. In contrast, a recent publication compared the efficacy of the three PDE5Is in preventing acute hypoxic pulmonary vasoconstriction in isolated rat pulmonary arteries; the authors demonstrated that the three PDE5-Is were equally efficacious in causing pulmonary artery relaxation, but only tadalafil inhibited hypoxic pulmonary vasoconstriction and attenuated hypoxia-induced pulmonary artery tissue necrosis factor a and interleukin 1b expression (Table 2) [66]. The etiology of these differences among the three PDE5-Is is not known; it may be due to differences in selectivity with respect to other PDE isoforms or in their binding capacity to PDE5 during hypoxia [66]. Such data suggest that some of the PDE5-I properties

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Table 2 – Impact of PDE5-I on arterial function Study

Drug used

Target group

Method of assessment

Result in endothelial function

Single dose of sildenafil 12.5, 25, or 50 mg taken 1 h before assessment (double-blind, randomised, placebo-controlled study)

Patients with chronic heart failure

Flow-mediated dilation (FMD) 1, 3, and 5 min after release of transient brachial artery occlusion

Improvement (after 25 and 50 mg sildenafil)

Halcox [7]

Single dose of sildenafil 100 mg vs 10 mg isosorbide dinitrate (ISDN) or placebo taken 45 min before assessment (double-blind, randomised, placebo-controlled study)

CAD patients vs control group (healthy volunteers)

FMD of the brachial artery

Improvement

Desouza [8]

Sildenafil 25 mg daily for 2 wk (double-blind, placebo-controlled, crossover study)

Patients with type 2 diabetes and ED

FMD of the brachial artery

Improvement (sustained at least 24 h after last dose)

Kimura [9]

Single dose of sildenafil 100 mg taken 1 h before assessment

Chronic smokers vs nonsmokers

Forearm blood flow (FBF) responses to acetylcholine and to sodium nitroprusside

Improvement (similar to smokers and nonsmokers)

Vlachopoulos [16]

Single dose of sildenafil 50 mg (double-blind, placebo-controlled, crossover study) measurements for 3 h

Patients with CAD

Aortic stiffness, wave reflections from peripheral sites

Improvement

Vlachopoulos [10]

Single dose of sildenafil 50 mg taken 50 min before smoking (randomised, placebo controlled, crossover study)

Smokers

FMD of the brachial artery

Improvement

Dishy [98]

Single dose of sildenafil 25 mg taken 1 h before assessment (double-blind, placebo-controlled, crossover study)

Chronic smokers

FMD of the brachial artery and forearm postischemic reactive hyperemia

No improvement

Hirata [17]

Single dose of sildenafil 50 mg (double-blind, placebo-controlled, crossover study) measurements for 3 h

Patients with controlled left ventricular failure and ejection fractions <35%

Total systemic resistance, aortic stiffness, wave reflections from peripheral sites

Improvement

Caretta [12]

Tadalafil 20 mg/48 h vs controls for 3 mo

ED patients (60–70 yr old) vs control patients (aged 18–40 yr affected by psychogenic ED)

Ultrasound evaluation of common carotid artery intima-media thickness (IMT)

Improvement with spontaneous resumption of erections

Foresta [14]

Single dose of vardenafil

Healthy young men

Endothelial progenitor cells (EPCs), which add to the process of continuous repair of the endothelium

Significant increase in EPCs. The effect occurred early (4 h)

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Katz [6]

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may not be class-specific, but rather drug-specific or even species-specific. Further research is urgently needed for careful evaluation of the relative efficacy and selectivity for each one of the three PDE5-Is in different organs and functions.

Significant increase in FMD and EPCs

2.6.

PSE5-I = phosphodiesterase type 5 inhibitor; CAD = coronary artery disease; ED = erectile dysfunction; CVD = cardiovascular disease.

FMD of the brachial artery and EPCs Chronic treatment with tadalafil Foresta [15]

CAD patients vs control group (healthy volunteers)

Improvement FMD of the radial artery measured before and after 15 min of ischaemia at the level of the brachial artery followed by 15 min of reperfusion Single dose of sildenafil 50 mg taken 2 h before assessment (double-blind, placebo-controlled, crossover study) Gori [13]

Healthy volunteers (25–45 yr old)

Improvement (sustained at least 2 wk after discontinuation of treatment) FMD of the brachial artery ED patients with increased CVD risk Tadalafil 20 mg/48 h vs placebo for 4 wk (parallel, double-blind, placebo-controlled study) Rosano [11]

Study

Table 2 (Continued )

Drug used

Target group

Method of assessment

Result in endothelial function

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Are comparative preference trials conclusive?

From the clinical viewpoint, it is natural that comparisons be made among the three available PDE5-Is because such comparisons might allow patients and physicians to choose one drug over another. From the published comparative trials, none is without serious limitations and methodologic problems, explaining the wide range of results. The methodologic problems include biased drug instructions, comparison of nonequivalent doses, lack of standardised preference assessment, differences in patient demographics, and lack of robust statistics [67]. But are such trials helpful for the everyday clinical practice? Do they offer guidance to physicians on which drug they should prescribe? In a recently published study, for example, with minimal design limitations, tadalafil and sildenafil showed similar efficacy as assessed by International Index of Erectile Function (IIEF) and SEP questionnaires and similar side-effect profiles. Tadalafil showed better scores on the Psychological and Interpersonal Relationship Scales (PAIRS) questionnaire and much higher preference rates [68]. Among the factors that influence choice, the most common reasons included the ability to get an erection long after taking the drug, the hardness of erections, and the fast onset. The recognition of multiple predictors of preference, which go beyond simple efficacy and safety, is the only common conclusion of several publications [69]. Based on the controversial findings of the comparative trials, several experts express the opinion that patients may choose their favourite drug after exposure to all three PDE5-Is. Such practice allows patients to choose the compound that is perceived by them to have the best efficacy, as well as other features, such as time of onset, duration of action, window of opportunity, and their own individual experience with sideeffects. A patient may have to try up to 4 tablets of 2 doses of each drug before choosing the preferable one. Considering that a typical use of a PDE5-I is twice per week, the duration of the selection period may be 3 mo; in everyday clinical practice, such strategy seems unrealistic. On the other hand, if a clinician follows the results of any of the preference trials, which show a preference of 60–70% for a certain drug, at least 30% of patients may not be getting the

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highest benefit that PDE5-Is offer. Such observation clearly shows that comparative trials, although important from a marketing perspective, may have limited value from a clinical viewpoint and sometimes are confusing for the non-experts. The solution to this problem may be in adapting the principles of patient-centered and personalised medicine in our future management strategies for ED. 2.7. The need for a patient-centered care model for ED: a frontier to personalised medicine

Recent data on ED treatment outcomes have shown that many patients discontinue treatment, despite the availability of efficacious pharmacotherapies, because doctors fail to inform patients properly and to ensure continuity in care, as well as to be routinely involved in asking patients about their needs and expectations [70]. Disparities arise also when clinicians do not understand the unique health values and beliefs of individuals. Qualitative research has indicated that health professionals typically view their professional responsibilities in a disease-centered framework that may not include the patient’s perspective. Effective doctor–patient communication and patient-centered care is a fundamental task in medicine and seems to be at the heart of sexual medicine. According to the recent evidence-based guidelines and recommendations of the International Consultation on Sexual Dysfunction, physicians should adopt a holistic approach that would a recognise a patient’s psychosocial profile, focus on each patient’s special needs, and establish an effective partnership among the clinician, patient, and partner, empowering them to become active participants in their own health [71]. Physicians seem to recognise the need for adaptation of patient-centered care, as well as nonjudgemental attitudes towards a patient’s sexual practices and beliefs [72]. A more artful, patient-centered care, specifically tailored to each individual’s personal beliefs, cultural values, and priorities, seems mandatory [73]. Such observations augment the need for the development of care models in sexual medicine, as happens with every other chronic condition, such as diabetes mellitus and CVD. In addition, it becomes clear that we are heading towards an era in which personalised medicine will replace traditional schema; diagnosis is integrated with therapy for selection of the treatment as well for monitoring the outcome. Development and adaptation of a patient-centered care model in sexual medicine will increase efficacy and safety of current and future treatments, as well as patients’ adherence, with certain benefits not

only for our patients, but also for the health care systems, especially in terms of cost effectiveness.

3.

Future perspectives

3.1. Chronic administration of PDE5-Is: toward everyday, low-dose use

Continuous inhibition of PDE5 results in a permanent high concentration of cGMP, offering ED patients and their partners not only greater flexibility and spontaneity in sexual involvement, but possibly better tolerability and adherence to treatment [74,75]. Initially, chronic use was reported in non-responders to the on-demand use of PDE5-Is; McMahon treated a group of non-responders with on-demand tadalafil with continuous use on a daily basis, at flexible doses of 10 and 20 mg tadalafil for 12 wk [74]. Improved erections at the end point were reported by 69% of men compared with 42% of men with on-demand use. Hatzimouratidis et al. explored the efficacy of continuous use of 20 mg tadalafil every other day and 20 mg vardenafil every day, respectively, for 2 consecutive weeks in a well-defined group of non-responders; 11.1% in the tadalafil group and 18.2% in the vardenafil group converted to responders. Mirone et al., in the first comparative trial, investigated efficacy and patient preference between on-demand tadalafil, 20-mg treatment, versus continuous use of the same dose, 3 times/ wk for 6 wk [75]. On-demand tadalafil 20 mg was preferred by 57.8% of men, whereas 42.2% preferred the 3 times/wk treatment. Once-a-day dosing with 5 and 10 mg tadalafil also significantly improved erectile function versus placebo, and patients were highly compliant with this dosing regimen [76]. There were no side-effects or safety issues in any of the three studies. Such data show that chronic dosing may safely maximise efficacy, although data are limited on the systemic effects of the continuous inhibition of PDE5 in large studies; the existing data are mainly derived from the clinical trials of sildenafil approval for idiopathic pulmonary hypertension [5]. Despite the proven long-term efficacy of PDE5-Is, it has been suggested that tachyphylaxis to this therapy may develop. Long-term treatment with PDE5-Is and excessive cGMP accumulation may upregulate PDE5 [77]. Such an hypothesis, however, has not been proven in the existing clinical trials with chronic PDE5-I therapy [78–81]. Because for the vast majority of the patients ED is not a situational symptom but rather a chronic disease, daily dosing seems an essential management strategy, as occurs with all other chronic

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conditions, such as hypertension, arthritis, and diabetes mellitus. The major issue remains the cost of such dosing schema, which may prevent patients from accepting continuous administration of a PDE5-I. Currently, several studies are exploring efficacy and safety profiles of low, everyday dosing of PDE5-Is. Initial results are promising and the availability in the future of low doses of PDE5-I at an affordable monthly cost, which should not exceed the current cost of the typical 6–8 tablets/mo use, may become an attractive alternative for some patients. 3.2.

Potential prophylactic use of PDE5-Is

Basic and clinical studies suggest a possible role of PDE5-Is in the urogenital tract, including prophylaxis to preserve penile smooth muscle after radical prostatectomy and in patients with early-stage Peyronie’s disease, treatment of premature ejaculation, and ejaculatory delay secondary to serotonergic reuptake inhibitor therapy [25]. The most promising of the above is clearly the preservation of the smooth muscle of the corpora cavernosa. Early use of vasoactive agents has been shown to rehabilitate erectile function after nerve-sparing radical retropubic prostatectomy (RRP). The loss of intracorporeal smooth muscle and an increase in intracorporeal fibrosis have been demonstrated in vasculogenic impotence and implicated in permanent post-RRP erectile dysfunction. In a study of 40 potent volunteers with prostate cancer who underwent RRP, Schwartz et al. showed that sildenafil administration every other night for 6 mo increased substantially corporal smooth muscle content [82]. Convincing clinical data about potential mechanisms and outcome induced by long-term PDE5-I administration in men who are affected by ED are lacking. Animal studies indicate that chronic exposure to PDE5-Is could have a beneficial effect on endothelial dysfunction. Further well-designed, prospective, randomised, placebo-controlled trials are urgently needed to assess whether chronic administration of PDE5-Is may help restore erectile function in patients affected by ED [83]. 3.3.

Is there a role for PDE5-Is in patients with LUTS?

It has been well established not only that BPH is associated with ED, but also that the presence and severity of LUTS are independent risk factors for sexual dysfunction in older men [84]. The link between ED and LUTS is based on four theories: (1) NOS/NO levels decreased or altered in the prostate and penile smooth muscle; (2) autonomic

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hyperactivity effects on LUTS, prostate growth, and ED; (3) increased Rho-kinase activation/endothelin activity; and (4) prostate and penile ischemia [85]. Cyclic nucleotide second messengers cGMP and cyclic adenosine monophosphate (cAMP) are involved in the control of the normal function of the prostate; recent research indicated the presence of PDE isoenzymes 4, 5, and 11 in the transition zone of the human prostate [86]. The concept of PDE inhibition has, therefore, gained tremendous interest in the field of urology and the rationale for the use of PDE inhibition in the pharmacotherapy of BPH and LUTS is being explored. Sairam et al., in a proofof-concept study, showed that ED treatment with sildenafil improved both sexual function scores (based on IIEF) and LUTS, and urinary scores correlated strongly with sexual function scores at 3 mo [18]. There was a significant inverse relationship between the baseline IPSS and sexual function scores after treatment. A lower IPSS at baseline appeared to predict a better response to ED therapy with sildenafil. Mulhall et al., in a group of ED patients treated with sildenafil, similarly noticed that 60% of men improved their IPSS result, and 35% had at least a 4point improvement in their score [87]. Because of the increasing percentage of the world male population suffering from ED and BPH-associated LUTS, new and innovative therapeutic approaches are needed. PDE5-Is form a promising class of drugs for crossdisease treatment, if ongoing clinical research proves that these drugs are efficacious for treating the symptoms of both these conditions; if this is the case, it will open the door for innovative therapeutic approaches, and specifically for cross-risk factor treatment with PDE5-Is. 3.4. Are PDE5-Is efficacious in patients with premature ejaculation?

The pathophysiology of premature ejaculation is poorly understood, and no treatment with indications for the condition is available yet. PDE5-Is have been suggested to be beneficial for such patients, possibly due to a peripheral inhibition of contractile response of vas deferens, seminal vesicles, prostate, and urethra as well as a reduced central sympathetic output through a prolonged NO effect [88]. A limited number of clinical studies have shown controversial results. Combination of sildenafil with paroxetine significantly prolongs intravaginal ejaculation latency time (IELT) and is associated with better intercourse satisfaction compared with paroxetine alone [21]. In a group of non-responders to other treatments, sildenafil combined with paroxetine

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and psychological-behavioural counselling alleviated premature ejaculation [20]. However, sildenafil was not superior to placebo or combination treatment with topical lidocaine/prilocaine cream [19]. It remains uncertain whether PDE5-Is act on the physiologic process of ejaculation, or indirectly, improving erectile function and therefore, reducing performance anxiety in men with ED. They may also reset the erectile threshold to a lower level of arousal [89]. Further placebo-controlled, well-designed studies are needed to explore if there is any role for PDE5-Is in the treatment of premature ejaculation, although short-acting, selective serotonin reuptake inhibitors (SSRIs) seem to be the most promising drug category under development. 3.5.

Furthermore, reversal of endothelial dysfunction may cause erectile improvement and a return to spontaneous erections in patients treated with PDE5Is over the long term, which could represent a key factor in prophylactic administration of these compounds in selected patients, such as those with metabolic syndrome and no current ED [83]. These data clearly suggest not only the interplay among those conditions but also raise a critical question for the development of a common prevention strategy: Can chronic use of PDE5-Is prevent or reverse endothelial dysfunction and possibly inhibit the atherosclerotic process? If the answer is yes, a new era is opened in the management of CVD. Research is urgently needed to answer such a crucial question, especially for patients at risk.

Potentials for cross-risk factor treatment with PDE5-Is

The clinical success of PDE5-Is in ED treatment not only marginalised the importance of this class of compounds but also focused the research on potential use in other medical conditions. Researchers have explored the beneficial effects of PDE5-Is in treating patients with cardiovascular risk factors or disease. Such research becomes even more important because CVD and ED share common risk factors, such as diabetes mellitus, hypertension, hyperlipidaemia, smoking, and obesity. They also share a pathophysiologic mechanism of decreased vascular blood flow via endothelial dysfunction; the endothelium mediates vascular tone, structure, and function by the release and regulation of multiple vasoactive substances that promote or inhibit vasodilation, vasoconstriction, cell growth, and other mechanisms. Preclinical data and preliminary clinical reports suggest that PDE5-Is may improve endothelial function and decrease arterial stiffness, introducing this class of compounds as potential drugs for patients with metabolic syndrome and diabetes mellitus [6–13]. Sildenafil improves endothelium-dependent, flow-mediated vasodilatation in patients with diabetes mellitus and chronic heart failure and in current smokers, and provokes vasodilation of epicardial coronary arteries, improvement of endothelial dysfunction, and inhibition of platelet activation in patients with CAD [6,8,9]. Tadalafil has been also shown to improve endothelial function in patients with increased cardiovascular risk [11]. Because a substantial body of evidence indicates that endothelial dysfunction in men with ED can be detected well before overt manifestations of vascular damage, including atherosclerotic effects, it is assumed that improving CVD risk factors in midlife may decrease the risk of ED as well as CVD.

3.6. Potentials for the use of PDE5-Is in combination/ multimodal pills

As discussed previously, the prevalence of ED in patients with CVD is high and the conditions may have common risk factors, such as local decompensation of NO signaling underlying the pathogenesis of ED, endothelial dysfunction, atherogenesis, CAD, stroke, and peripheral vascular disease. A rational approach therefore in the management of such patients, especially those who also suffer from ED, includes improvement in endothelial function, through different classes of drugs that positively affect endothelial function. This strategy becomes even more important considering the evidence that multiple risk factors, including hypertension and hyperlipidaemia, lead to a synergistic effect on endothelial function. Certain agents, including antihypertensives, such as calcium channel blockers and angiotensin-converting enzyme inhibitors, apart from their classic mechanisms of action, exert pleiotropic endothelial actions, including their antiinflammatory, antithrombotic, and vascular protective actions [90]. Recent insights into cellular mechanisms, on the other hand, indicate that statins promote vasorelaxation by up-regulating the expression of endothelial NOS, activating the phosphatidylinositide 3-kinase/Akt pathway, and inhibiting superoxide anion generation and endothelin synthesis, and by anti-inflammatory effects. In this regard, statins preserve endothelial function through the improvement of NO bioavailability and the reduction of oxidative stress, thereby shifting the balance from vasoconstriction to vasodilation [91]. Considering the new trend to move towards treating the overall risk of developing CVD, numerous patients are treated for more than one of these conditions;

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Table 3 – What can we expect in the future for PDE5-Is? Potential indication

Rationale

Chronic administration of PDE5-Is (everyday, low-dose use)

Chronic dosing may safely maximise efficacy improving endothelial dysfunction, although there are limited data on the systemic effects of the continuous inhibition of PDE5

ED prevention/cure

Current evidence supports the potential of prevention/cure of ED mainly through improving endothelial dysfunction

Treatment of LUTS due to BPH

PDE5-Is may relieve obstruction, improve LUTS, potentiate NO-mediated relaxation in prostate

Cross-risk factor treatment

Beneficial effects of PDE5-Is in treating patients with cardiovascular risk factors or disease have been shown.

Combination multimodal pills

A single compound can target a number of risk factors to improve patient compliance.

PDE5-I = phosphodiesterase type 5 inhibitor; ED = erectile dysfunction; LUTS = lower urinary tract symptoms; BPH = benign prostatic hyperplasia; NO = nitric oxide.

such patients bear a heavy pill burden, which affects their compliance. One potential solution to this problem is the development of cross-risk factor fixed-dose combinations. The first cross-risk factor ‘‘polypill’’ for the prevention and treatment of cardiovascular disease has already reached the market (Pfizer’s Caduet, combining the long-acting calcium channel blocker amlodipine with the synthetic lipid-lowering agent atorvastatin) [92]. The portfolio potential and pipelines of leading cardiovascular pharmaceutical companies to develop fixed-dose combinations and multimodal drugs is currently high. However, do we have evidence for incorporating such strategies in patients with ED with risk for CVD. Which will be used in such combination treatment for ED management? In 1994, Kostis et al. first noticed that statins significantly increased the duration of nocturnal tumescence (NPT) after 2 wk of treatment [93]. In a small study of 9 men, atorvastatin was able to improve erectile function in 8 of 9 men with hypercholesterolaemia as the only risk factor for ED [94]. In a recent randomised, double-blind, placebo-controlled pilot study, the hypothesis for beneficial effect of administration of two drugs, atorvastatin and sildenafil, both known to improve endothelial function through different mechanisms of action, was tested in a small group of poor responders to 100 mg sildenafil. Mean low-density lipoprotein cholesterol decreased by 43%, and the IIEF ED domain score improved by 7.8 [95]. Although large-scale studies are necessary to prove the new concept, a new research area has clearly opened, where combination treatments, including PDE5-Is will be tested not only for

ED/CVD treatment, but also for prevention, because pharmacologic reversal of endothelial dysfunction may represent a new approach in preventing CVD and ED in concert. It should not be a surprise in the future if combination treatment or new multimodal pills are included in the development of cardiovascular pharmacology because such strategies may contribute to clinical benefits for cardiovascular and ED risk factor management strategies (Table 3) [96].

4.

Conclusions

PDE5-Is are not only considered as the reference class for ED treatment but are definitely among the most promising new classes of drugs. Their unique mechanism of actions and their pleiotropic pharmacologic properties have generated a focus for basic and clinical research, which may be translated in the future into novel therapeutic options and modern drug development, potentially targeting the management of several other chronic conditions. Adoption of PDE5-Is for new indications will require considerable evidence and a thorough assessment of benefit and risk. References [1] Feldman HA, Goldstein I, Hatzichristou DG, Krane RJ, McKinlay JB. Impotence and its medical and psychosocial correlates: results of the Massachusetts Male Aging Study. J Urol 1994;151:54–61. [2] Braun M, Wassmer G, Klotz T, Reifenrath B, Mathers M, Engelmann U. Epidemiology of erectile dysfunction: results of the ‘‘Cologne Male Survey’’. Int J Impot Res 2000;12: 305–11.

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Editorial Comment Juza Chen, Department of Urology, Tel-Aviv Sourasky Medical Center, 6 Weitzman Street, Tel-Aviv, 64239 Israel [email protected] With the introduction of the first phosphodiesterase type 5 inhibitor (PDE5-I) in 1998, treatment preference for erectile dysfunction (ED) has been changed dramatically and irreversibly, marking a new era of effective and safe treatment of ED and providing opportunities for the recovery of normal male sexual function. The authors of this article are to be congratulated for a well-written review that discusses current and future use of PDE5-Is and tries to answer questions on adequate instruction for medication use, safety, preferences among various PDE5-Is, effects of chronic administration of the medication, potential effects of PDE5-I use for several pathologic conditions (e.g., cardiovascular and lower urinary tract diseases), and possible advantage of using PDE5-Is in combination with other medications. Although several earlier review articles discussed the same issues [1,2], new updated information on PDE5-Is will add valuable knowledge for better patient management. Several independent studies have shown that daily use of a PDE5-I may play a role in curing ED [3]. This concept was based on previous experience showing a positive role of chronic use of PDE5-Is in the early rehabilitation of corpus cavernosum endothelial function following radical prostatectomy. According to some investigations, early rehabilitation may be achieved by preventing cavernosal tissue damage during the period of neurapraxia by providing adequate oxygenation to the cavernous tissue, leading to an increased production of intracavernous prostanoids, which are postulated to protect endothelium of the cavernosal smooth muscle [4]. This rationale and its mechanism have not, however, been fully elucidated nor have they been replicated in category 1 (double-blind, placebo-controlled) studies with large numbers of patients. Therefore, this promising initiative needs more scientific and clinical proof before considering its introduction as a therapeutic measure.

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Another relatively new concept briefly discussed in this article, and one that requires further confirmation, is the role of PDE5-Is alone or in combination with a-blockers in the treatment of benign prostatic hyperplasia (BPH) and lower urinary tract symptoms (LUTS). The effect of a PDE5-I on the lower urinary tract has been explained by its effect on the nitric oxide pathway. It has been suggested that nitric oxide is an important mediator of the relaxation of the isolated bladder and urethral smooth muscle and could modulate prostatic smooth muscle tone. Together with a-blockers, this action of the PDE5-I can be expected to have a positive effect on ED and LUTS. Although placebo-controlled studies are required to confirm the impact of these drugs alone or in combination on ED and LUTS, this area of research is promising and should be encouraged [5]. Finally, the new generation of PDE5-Is, such as Avenafil (VIVUS, USA) and, especially, DA-8159 (Dong-A Pharmaceutical Company, Korea) [6], promises to have beneficial effects on patients with ED secondary to hypercholesterolaemia. These belong to a new class of PDE5-Is that may be important in the treatment and cure of ED.

References [1] Burnett AL. Phosphodiesterase 5 mechanisms and therapeutic applications. Am J Cardiol 2005;96:29M–31M. [2] Carson CC, Lue TF. Phosphodiesterase type 5 inhibitors for erectile dysfunction. BJU Int 2005;96:257–80. [3] Hellstrom WJG, Kendirci M. Type 5 phosphodiesterase inhibitors: curing erectile dysfunction. Eur Urol 2006; 49:942–5. [4] Moreland RB, Albadawi H, Bratton C, et al. O2-dependent prostanoids synthesis activates functional PGE receptors on corpus cavernosum smooth muscle. Am J Physiol Heart Circ Physiol 2001;281:H552–8. [5] Carson CC. Combination of phosphodiesterase-5 inhibitors and alpha-blockers in patients with benign prostatic hyperplasia: treatments of lower urinary tract symptoms, erectile dysfunction, or both? BJU Int 2006; 97:39–43. [6] Kang KK, Yu JY, Yoo M, et al. The effect of DA-8159, a novel PDE5 inhibitor, on erectile function in the rat model of hypercholesterolemic erectile dysfunction. Int J Impot Res 2005;17:409–16.