Phosphodiesterase Type 5 (PDE5) Inhibitors in Erectile Dysfunction: The Proper Drug for the Proper Patient

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ORIGINAL RESEARCH—ED PHARMACOTHERAPY Phosphodiesterase Type 5 (PDE5) Inhibitors in Erectile Dysfunction: The Proper Drug for the Proper Patient jsm_2473

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Giovanni Corona, MD, PhD,*† Nicola Mondaini, MD,‡ Andrea Ungar, MD,§ Elisa Razzoli, MD,¶ Andrea Rossi, MoS,¶ and Ferdinando Fusco, MD, PhD** *Andrology and Sexual Medicine Unit, Department of Clinical Physiopathology, University of Florence, Florence, Italy; † Endocrinology Unit, Azienda Usl di Bologna, Maggiore-Bellaria Hospital, Bologna, Italy; ‡Urology Unit, Santa Maria Annunziata Hospital, University of Florence, Florence, Italy; §Unit of Geriatric Cardiology and Medicine, Department of Critical Care Medicine and Surgery, University of Florence, Florence, Italy; ¶Medical Department, Eli Lilly Italy, Sesto fiorentino (FI), Italy; **Urologic Clinic, University Federico II, Naples, Italy DOI: 10.1111/j.1743-6109.2011.02473.x

ABSTRACT

Introduction. Erectile dysfunction (ED) is a very common multidimensional disorder affecting men worldwide. Physical illness, reaction to life stresses, or an unhappy couple relationship influence clinical outcome. Phosphodiesterase type 5 (PDE5) inhibitors are recognized as efficacious and well tolerated, and are the first-line treatment for ED. Sildenafil, tadalafil, and vardenafil are the most widely used and studied PDE5 inhibitors. Data acquired during a routine diagnostic workup for ED should be taken into account when choosing the best PDE5 inhibitor for the individual patient, creating an individualized treatment plan, and going beyond “experience-based” subjective opinion and unfounded ideas and prejudice regarding currently available drugs. Aim. As the process of matching a given patient’s profile to any selected PDE5 inhibitor often relies more on physician’s personal convictions than on solid evidence, the aim of this review is to identify the main clinical, demographic, and relational factors influencing the choice of the PDE5 inhibitor to be used for the treatment of ED. Methods. A systematic literature search and current treatment guidelines were evaluated in a systematic manner. Main Outcome Measures. The main clinical, cultural, and demographical factors to be considered for the treatment of ED have been identified. Results. Main factors influencing the choice of the treatment for ED have been described. A short list of items that may help in choosing the right PDE5 inhibitor for the treatment of different patients in daily clinical practice has been prepared. Conclusions. The simple algorithms prepared should be a useful tool to be used in daily practice, which may help in choosing the right treatment for each subject affected by ED. Corona G, Mondaini N, Ungar A, Razzoli E, Rossi A, and Fusco F. Phosphodiesterase type 5 (PDE5) inhibitors in erectile dysfunction: The proper drug for the proper patient. J Sex Med 2011;8:3418–3432. Key Words. Erectile Dysfunction; PDE5 Inhibitors; Tailored Treatment

Introduction

E

rectile dysfunction (ED) is a very common multidimensional disorder, affecting many people worldwide, that includes a spectrum of clinical situations including physical illness (organic component of ED), reaction to life stresses (intra-

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psychic component of ED), or an unhappy couple relationship (relational component of ED). The evaluation of all these aspects is the cornerstone for a correct diagnosis and an essential step for the right ED treatment prescription [1–3]. The structured interview on erectile dysfunction, SIEDY, is a 13-item case history tool which simultaneously and © 2011 International Society for Sexual Medicine

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The Proper PDE5 Inhibitor for the Proper Patient quantitatively evaluates the underlying components of ED, predicting with 70% sensitivity and specificity the presence of an organic ED. SIEDY is therefore a unique, validated anamnestic and diagnostic instrument available to physicians dealing with ED [2]. The basic diagnostic workup for ED is clinical, and includes [4]: • a detailed medical history, in order to reveal the presence of ED risk factors, etiological factors, and comorbidities; • the assessment of sexual history, to determine ED presence and severity (preferably using validated questionnaires such as International Index of Erectile Function), and describe ED characteristics, sexual habits, and couple relationship; • a physical examination; and • a few laboratory tests. Besides correcting lifestyle changes and risk factors whenever possible, and providing sexual education and counseling, a first-line treatment strategy usually includes a phosphodiesterase type 5 (PDE5) inhibitor, either administered on-demand or on a daily basis. In the clinical setting, the choice of the best PDE5 inhibitor for each patient should be shared by the physician and patient after discussing the different characteristics of the drugs and individual sexual habits, preferences, and expectations of the patient [5]. Unfortunately, it is still a matter of debate if and how any information on the patient and any characteristic of his disease should lead to the selection of one treatment rather than another, and the process of matching a given patient’s profile to a particular PDE5 inhibitor often relies more on personal beliefs than on solid evidence. The poor adherence to treatment reported for the class of PDE5 inhibitors can be partially explained by the inability of physicians to better tailor the treatment to the patient’s needs, and highlights the inaccuracy of the drug selection process as it is currently conducted [6]. The purpose of the present article is to evaluate if any data acquired during a routine diagnostic workup for ED should be taken into account when choosing the best PDE5 inhibitor for the individual patient, creating an individualized treatment plan, and going beyond “experience-based” subjective ideas and unmotivated prejudice regarding the currently available drugs. Materials and Methods

A literature search in Medline (dating back to 1966) and Embase (dating back to 1988) databases

was conducted using the OVID interface in August 2010, restricted to any article or abstract in English, reporting any information on the epidemiology and treatment of ED. Abstracts and citations of reviews and clinical trials were screened and chosen by the authors depending on their relevance to this review, and the full texts of such publications were retrieved. Reference lists of retrieved articles and reviews were also searched and served as a source of relevant publications. When more than one article reported information about a certain topic, only articles reporting the most recent information were used. Article retrieval and selection is summarized in Figure 1. Pharmacological Characteristics of PDE5 Inhibitors

So far, three potent PDE5 inhibitors have been approved worldwide, and one has been approved in some Asian countries only (Table 1) [7]. All PDE5 inhibitors are rapidly absorbed after oral administration, and are reported as effective within 30 minutes from administration. Sildenafil and vardenafil have only a limited oral bioactivity (about 40% and 15%, respectively) because of extensive presystemic metabolism in the gut wall and liver via CYP3A4 and/or CYP3A5 pathways [7]. Tadalafil has the greatest mean half-life (17.5 hours) when compared with udenafil (12 hours), sildenafil (3.8 hours), and vardenafil (3.9 hours) [8,11–13]. A high-fat meal (about 910 Kcal, 57% of which from fat) had no significant effect on the rate and extent of absorption of tadalafil, but decreased the rate of absorption for sildenafil, vardenafil, and udenafil, possibly affecting the onset of effectiveness [8,11,12]. As only sildenafil, tadalafil, and vardenafil are widely available, udenafil will not be considered in this review. All products are available in tablet formulation, but vardenafil is also available in orodispersible formulation [14]. Although PDE5 inhibitors were initially approved as on-demand therapy, in 2008, tadalafil was also approved for everyday use in 2.5-mg or 5-mg doses [11,15]. How to Choose the Correct Treatment for ED

The goal for a specific tailored therapy should take into account two different main perspectives, deriving from the physician and the patient. First of all, the physician should carefully evaluate the presence of concomitant morbidities and, in particular, carJ Sex Med 2011;8:3418–3432

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Figure 1 Methods in the selection of articles. *SPCs = Summary of Product Characteristics, ^CTR = Clinical Trial Registry, °EAU = European Association of Urology.

diovascular (CV) risk factors. In fact, ED shares common risk factors with CV diseases including obesity, smoking, alcohol abuse, lack of exercise, and metabolic syndrome (MetS). The modification of these factors may improve the sexual problem [16]. In addition, the choice of treatment should be tailored to the individual patient’s characteristics, needs, and preferences. If available, the presence of the partner should be encouraged in order to better evaluate the couple’s situation, expectations, and preferences. All these points will be further discussed in the following sections. ED Concomitant Morbidities and Risk Factors

Diabetes Mellitus Prevalence of ED in men with diabetes mellitus is about three times higher when compared to the general population, and is strictly related to glycometabolic control, complications, and duration

Table 1

of the disease [17–19]. Several studies have shown that better glycemic control, in terms of lower levels of glycated haemoglobin (HbA1c), reduces the prevalence of ED and its severity in younger men (age <60 years) with type 2 diabetes [1,20]. PDE5 inhibitors improve ED in diabetic men [21]. PDE5 inhibitors have been shown to have no adverse effect on CV morbidity or mortality or on glycemic control in men with diabetes [22], while a trend toward reduction of mortality was observed when PDE5 inhibitors were used together with statins in diabetic patients with concomitant ED and asymptomatic coronary artery disease [23]. In diabetic patients, tadalafil once daily was efficacious and well tolerated [7,24], and its effect seemed to persist in a significant percentage of patients after cessation of a 12-month continuous treatment [25]. Interactions in the administration of PDE5 inhibitors with concomitant oral hypoglycemic drugs or insulin are not described [7,15].

Pharmacological characteristics of marketed PDE5 inhibitors

Sildenafil [11] Udenafil Tadalafil [13] Vardenafil [12]

Available

Dosages (mg)

Tmax

Half-life

Duration of response

On-demand 25, 50, 100 100, 200 [9] 10, 20 5, 10*, 20

Daily N/A N/A 2.5, 5 N/A

30–120 minutes 1–1.5 hours [9] 120 minutes 30–120 minutes

3–5 hours 11–13 hours [9] 17.5 hours 4–5 hours

4–5 hours Study ongoing [10] 36 hours* 4–5 hours

*Orodispersable formulation available [14]. Tmax = time after administration of a drug when the maximum plasma concentration is reached, N/A = not available.

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The Proper PDE5 Inhibitor for the Proper Patient

Hypertension In patients treated for hypertension, the prevalence of ED ranges from 15% to 25% [18,26]. Indeed, ED is reported more than twice as often in men with systolic blood pressure (SBP) >140 mm Hg than in men with SBP <140 mm Hg. In addition, pulse pressure (i.e., the arithmetic difference between SBP and diastolic blood pressure) has been recently demonstrated to predict incident major CV events in patients with ED [27]. Older antihypertensive drugs (diuretics, betablockers, centrally acting drugs) have been more frequently associated with negative effects on sexual function when compared to newer drugs, the latter having neutral or beneficial effects (calcium antagonists, angiotensin-converting enzyme inhibitors, angiotensin receptor antagonists, nebivolol) [28]. However, this point has not been completely clarified as the few placebo- or active comparatorcontrolled studies published so far did not report a negative effect of beta-blockers and thiazide diuretics [28]. Conversely, the treatment with spironolactone, due to its antiandrogen actions, results in indubitable sexual complaints [29]. A frequent clinical issue is the possible interaction between PDE5 inhibitors and antihypertensive drugs. When PDE5 inhibitors are prescribed to patients using antihypertensive drugs, they are usually well tolerated. However, alpha-blockers, and also beta-blockers interacting with alphaadrenergic receptors, should be used with caution in patients on PDE5 inhibitors. In particular, in patients already taking an optimal dose of PDE5 inhibitor, alpha-blockers should be initiated at the

lowest dose. Conversely, PDE5 inhibitors should be initiated at the lowest recommended dose in patients using alpha-blockers [7,17]. As no specific trials have been conducted in patients taking any antihypertensive drug starting daily treatment with tadalafil 5 mg, blood pressure should be monitored and an adjustment in the antihypertensive dose may be necessary [13,15].

CV Diseases According to the Second Princeton Consensus Panel recommendations [30], patients with CV disease can be separated in three clusters of low, intermediate, and high risk (Table 2). ED is a very important harbinger for CV events from 2 to 5 years earlier. These two conditions are strictly connected as they have the same pathogenetic mechanism: endothelial dysfunction [17,18,27]. The treatment of ED in patients with cardiac heart failure (CHF) must begin with optimization of CHF management. Sexual function improves as CHF symptoms are reduced and exercise capacity increases. If this approach does not work, PDE5 inhibitors are the first-line therapy [30]. They are safe and effective in treating ED in CHF patients in the New York Heart Association (NYHA) Class II and III, and an improvement in erectile function (EF) by PDE5 inhibitors is associated with an improvement of depressive symptoms and quality of life [30]. Sexual activity continues to be a contraindication in NYHA IV as it is considered as dangerous as doing easy housework or climbing a flight of stairs in these patients [2].

Table 2 Use of PDE5 inhibitors in patients with cardiovascular disease, stratified by risk profile (from Princeton Consensus Panel [30]) Risk profile

Description

Low

Less than three risk factors for coronary artery disease (CAD) (excluding gender) Initiate or resume sexual activity or Controlled hypertension treatment for sexual dysfunction Mild, stable angina pectoris Successful coronary revascularization History of uncomplicated acute myocardial infarct (AMI), mild valvular disease Congestive heart failure (CHF) without left ventricular dysfunction (NYHA Class I)

Sexual activities and PDE5 inhibitor use

Intermediate or indeterminate risk

At least three risk factors for CAD (excluding gender) Moderate, stable angina pectoris Recent AMI (from 2 to 6 weeks) Left ventricular dysfunction/CHF (NYHA Class II) Noncardiac atherosclerotic sequelae (stroke and/or peripheral arterial disease)

PDE5 inhibitors are not contraindicated, but a cardiac evaluation is necessary to reclassify as high or low risk

High

Unstable or refractory angina Uncontrolled hypertension NYHA Class III-IV CHF Recent AMI (<2 weeks) High-risk arrhythmias Severe cardiomyopathies Moderate to severe valvular disease

Sexual activity must be delayed until stabilization of cardiac condition

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3422 Among patients with coronary artery disease, the prevalence of ED ranges from 42% to 75%. Also in these patients, PDE5 inhibitors are safe and effective [7,22]. Concomitant use of PDE5 inhibitors and nitrates (nitroglycerin, isosorbide dinitrate, isosorbide mononitrate, amyl nitrate) is the most important contraindication reported in the literature because of the risk of hypotension. Past use of nitrates (>2 weeks) does not represent a contraindication. A period of >24 hours for short-acting PDE5 inhibitor (sildenafil, vardenafil), up to 48 hours for long-acting tadalafil, is recommended before taking nitrates. Due to this possible interaction, short-acting PDE5 inhibitors should be preferred in patients with concomitant CV disease [7,15,30]. Particular precaution is suggested in the use of labetalol and carvedilol (mixed alpha- and beta-blocker). Due to its effect on Q-T interval, vardenafil is not recommended in patients who take Type 1A antiarrhythmics (such as quinidine or procainamide) or Type 3 antiarrhythmics (such as sotalol or amiodarone) or in patients with congenitally prolonged Q-T syndrome [12]. No specific precaution has been reported for either sildenafil or tadalafil. Finally, for the high-risk CV patient, commonly on multiple antithrombotic treatments or on warfarin for systemic anticoagulation, potential effects of reduced platelet aggregation under the influence of PDE5 inhibitors should be considered, especially for sildenafil [7].

Obesity and MetS Although preliminary cross-sectional data failed to find any association between ED and obesity, longitudinal studies have clearly demonstrated a direct association between obesity at baseline and the subsequent development of ED [16,19]. The impact of body weight on PDE5 inhibitor efficacy has been evaluated for daily dosing with sildenafil as well as for single and multiple doses of tadalafil. In all cases, the drug’s efficacy was independent from baseline body mass index [31–33]. Data on vardenafil are not available. Central obesity is a key element of MetS, a cluster of metabolic abnormalities related to a state of insulin resistance and an increased risk of developing CV and metabolic diseases. Several epidemiological data have identified MetS as a potential risk factor for ED [19] and is related to low circulating androgen levels, which can clearly worsen EF [34,35]. PDE5 inhibitors are safe and effective in patients with ED and concomitant MetS [36]. In J Sex Med 2011;8:3418–3432

Corona et al. addition, tadalafil has been shown to have positive effects on beta-cell functions in such patients [37].

Dyslipidemia Association between ED and hyperlipidemia was found in several clinical studies. High concentrations of low-density lipoprotein cholesterol (LDL-C) seem to be related to ED [38]. Hypercholesterolemia at baseline was also shown as a predictor of ED 25 years later [39]. Accordingly, different studies have demonstrated that lipid-lowering therapy can lead to an improvement of EF in both clinical and experimental studies [40]. Furthermore, statin therapy may improve EF and PDE5 inhibitors outcomes [40]. All three PDE5 inhibitors have demonstrated their efficacy and safety in patients with dyslipidemia. Specific data on vardenafil showed that it was effective in men with dyslipidemia regardless of LDL-C levels, total cholesterol/high-density lipoprotein cholesterol ratio [40]. Smoking Cigarette smoking is clearly related to ED. Some studies suggest that smoking is associated with ED independently from any concomitant CV disease [41,42]. This hypothesis is supported by the dose response shown in several studies [43,44] and the fact that EF is improved after smoking cessation [45]. Cigarette smoking may be related to a downregulation of the nitric oxide/cyclic guanosine monophosphate pathway in penile tissue, probably related to increased oxidative stress [46]. Furthermore, acute nicotine administration caused a significant reduction of physiological erectile responses to erotic films in healthy nonsmoker men [47]. Prostatic Diseases Several epidemiological studies have indicated that the association between lower urinary tract symptoms (LUTS) and ED is more than a coincidence of age, with a possible cause-and-effect relationship [48]. Studies of all three available PDE5 inhibitors have shown improvements in both LUTS and ED in men with significant problems in both areas, without any substantial increase in side effect profile [49]. Radical prostatectomy (RP) remains the standard treatment for men with clinically localized prostate cancer, but postoperative ED is a common complication. This is mainly attributed to temporary cavernous nerve damage (neuropraxia) resulting in penile hypoxia, smooth muscle apoptosis, fibrosis, and veno-occlusive dysfunction [48].

The Proper PDE5 Inhibitor for the Proper Patient One of the most promising new approaches is the concept of early penile rehabilitation, which is thought to prevent ED after RP by countering post-RP pathophysiological changes during the period of neural recovery. Penile erections can be improved by using PDE5 inhibitors on demand [50]. The results of daily use of short-acting PDE5 inhibitors are conflicting, while data with tadalafil 5 mg daily administration are not yet available [51].

Spinal Cord Injury and ED The small numbers of publications with large and diverse outcome measures did not agree on a meta-analysis of treatment results [52,53]. Literature suggests that all oral PDE5 inhibitors represent a safe and effective treatment option for ED caused by spinal cord injury (SCI). Further research is needed on head-to-head comparative trials and SCI patient preference for these drugs; their impact on ejaculation and orgasm function, their early use after SCI to increase the recovery rate of spontaneous erections, and their effectiveness and tolerability in the long term are still to be investigated [53]. Relational Component Although less considered than organic and intrapsychic factors, the quality of the relationship represents another important determinant of a successful sexual functioning [1,34,54]. Corona et al. [54] demonstrated that the impairment of relational factors independently predicted ED severity. Interestingly, the same group also recently reported that moderate to severe perceived partner’s hypoactive sexual desire was independently associated with an increased risk of incident major adverse cardiovascular events (MACEs) [27]. Hence, perceived sexual interest (Eros) on the part of the woman can be seen for men not only as a fun and enjoyable behavior but also a safe strategy for improving a man’s overall health and life expectancy. Furthermore, women’s preference regarding the use of PDE5 inhibitors has to be considered when choosing therapy [55]. The majority of women prefer that their partners use tadalafil, emphasizing relaxed, satisfying, longer-lasting sexual experiences [55]. Intrapsychic Component The traditional dichotomized distinction of ED etiology in either organic or psychogenic forms reflects the historical division between body and mind, in contrast to the modern physiological

3423 research based on the concept that all psychological processes have a somatic basis [1,20,56]. Conversely, all sexual dysfunctions are stressful per se and can result in psychological disturbances [1,20]. Performance anxiety is the most common psychological disturbance in male patients with sexual dysfunction [20]. Over the long run, performance anxiety may lead to an avoidance of sex, loss of self-esteem, and, finally, a depressed mood. Psychiatric symptoms are often comorbid in patients with ED. Interestingly, Corona et al. [57] reported that in ED patients suffering from various psychopathological distresses, different psychiatric symptoms show specific associations with sexual, relational, and family functioning, depicting a rather specific profile for depressive, anxious, phobic, obsessive, and somatizing traits [2].

Depression Depression, antidepressants, and male sexual dysfunction are closely correlated. When patients complain of sexual dysfunction, it is important that the clinician take a careful history concerning psychopharmacologic agents [58]. It is possible that simple interventions may maintain the desired effect of the psychiatric drugs while also eliminating sexual side effects caused by these agents. Data derived from the European Male Aging Study, a large cross-sectional multicenter survey performed on a sample of 3,369 community-dwelling men aged 40–79 years across Europe, demonstrated that depressive symptoms represented an independent risk factor for ED [26]. Results obtained in a longitudinal population study suggested a bidirectional interaction between ED and depressive symptoms: moderate or severe depression may cause ED, and ED per se may cause or exacerbate depressive mood [59]. Finally, severe depressive symptoms in ED patients independently predicted incident MACE, emphasizing the evaluation of this aspect [60]. Treatment with PDE5 inhibitors demonstrated an improvement of depressive symptoms and ED in depressed men using sildenafil [61] or vardenafil [62]. Several studies showed that men with ED with comorbid depression improved ED when using tadalafil [9] while its effect on depressive symptoms needs to be confirmed [63]. The possible effect of these drugs on brain function needs to be investigated further. Ejaculatory Disorders The disorders of orgasm/ejaculation consist of a heterogeneous group of dysfunctions including premature ejaculation (PE), delayed ejaculation, J Sex Med 2011;8:3418–3432

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and reduced ejaculatory volume [64–66]. Reduced time to ejaculation is common as an early manifestation of ED. In fact, the subject may ejaculate early to hide the weakness of erection [67]. Conversely, ED may be superimposed on lifelong PE by efforts to minimize sexual excitement [67]. A distinguishing characteristic of men with delayed ejaculation is that they usually have little or no difficulty attaining or keeping their erection. In fact, they are often able to maintain erection for prolonged periods [65,67]. Only a few reports have evaluated the relationship between the perceived reduced ejaculatory volume (PREV) and ED. Recently, Corona et al. [68] demonstrated a negative association between PREV and ED severity.

Endocrine Disorders ED may be secondary to hormonal imbalance [35,69]. Hypogonadism is a frequent condition, whereas hyperprolactinemia and thyroid disorders are usually rarely present in patients with ED. Hyperprolactinemia mainly affects sexual desire, and more studies are needed to clarify the role of thyroid hormones on male sexual response [69]. Since testosterone (T) positively controls both the enzymatic steps necessary for initiation (positive effect on nitric oxide synthase [NOS] and negative on RhoA/ROCK) and termination (positive on PDE5) of the erectile process, its net effect on erection ends up as modest overall. The main physiological action of T is therefore to timely adjust the erectile process as a function of sexual desire, therefore finalizing erections with sex. Accordingly, sexual thoughts and motivations are

universally accepted as the most T-dependent aspects of male sexual behavior [35,70,71]. For all the aforementioned reasons, treating hypogonadism restores impaired penile erections in experimental animal models, as well as in a clinical setting. Conversely, T administration to otherwise eugonadal individuals is rather ineffective. In line with this evidence, a meta-analysis of placebocontrolled clinical trials indicated that, in comparison to placebo, a significant but moderate improvement of all aspects of sexual function was found in the studies of middle-age and elderly men with low T (T concentration <12 nmol/L, 346 ng/ dL) [72]. Interestingly, the meta-regression analysis demonstrated that the effect of T on EF was inversely related to the baseline T concentration. Hence, the more severe the hypogonadism, the more significant or impressive are the results obtained by treatment with T. Conversely, no effect was observed for baseline T levels higher than 12 nmol/L. Since androgens modulate the expression of both NOS and PDE5, several studies have suggested a reduced PDE5 inhibitor outcome in hypogonadal ED patients [35]. Several uncontrolled and four randomized placebo-controlled studies confirmed that hypogonadism hinders the effects of PDE5 inhibitors on EF (Table 3). Taken together, the results of these studies suggest that the combination of T and PDE5 inhibitors is able to improve the overall efficacy from 33% to 100%. All these observations emphasize the concept that hypogonadism must be ruled out and, if present, adequately treated before the prescription of any PDE5 inhibitor.

Table 3 Trials assessing the effect of combined therapy with testosterone (T) and sildenafil or tadalafil in men with erectile dysfunction unresponsive to PDE5 inhibitors or directly the combination of the two treatments

Reference

N

Baseline T-levels (ng/dL)

Aversa et al.* [73] Kalinchenko et al. [74] Shabsigh et al.* [75] Chatterjee et al. [76] Foresta et al. [77] Shamloul et al. [78] Greenstein et al. [79] Tas et al. [80] Rochira et al.* [81] Hwang et al. [82] Rosenthal et al. [83] Yassin et al. [84] Buvat et al.* [69]

20 120 75 12 15 40 31 23 24 32 90 69 173

<400 <340 <400 <400 <200 <340 <400 <400 <200 <300 <350 <340 <300

Therapy

Overall efficacy

T-patch/sildenafil 100 mg Oral-TU/sildenafil 100 mg T-gel/sildenafil 100 mg T-im/sildenafil 50–100 mg T-patch/sildenafil 50 mg Oral-TU/sildenafil 50–100 mg T-gel/sildenafil 100 mg T-im/sildenafil 50–100 mg T-im/sildenafil 50 mg T-os/sildenafil 100 mg T-gel/sildenafil 100 mg T-gel/tadalafil 20 mg T-gel/tadalafil 10 mg daily

80% 70% 70% 100% Normal NPT-par Improvement 63% 34% Impr. NPT-par 57% 92% 65% 33%

*Placebo-controlled studies. Impr = Improvement; NPT = nocturnal penile tumescence; par = parameters; TU = testosterone undecanoate.

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The Proper PDE5 Inhibitor for the Proper Patient Patient’s Perspective and ED Characteristics

Patient’s Age The normal aging process and age-related accumulation of ED risk factors contribute to the increased prevalence and severity of ED in the elderly, in most cases with an organic etiology [85,86]. Moreover, aging is associated with a substantial modification of sexual habits: the decreased frequency of sexual attempts is controversial, while the increased percentage of morning attempts (7:00–9:59 am), possibly due to the increased number of retired men, seems well recognized [86]. Age-related variations of PDE5 inhibitors pharmacokinetic properties have been also described. Men aged ⱖ65 years have higher plasma concentrations and mean area under the curve of sildenafil and vardenafil compared with younger men (18–45 years) [3,87]. For tadalafil, aging is associated with a negligible effect on the maximum plasma concentration of the drug (Cmax) and a slight decrease in apparent clearance and prolongation of t1/2 [88,89]. Similarly, vardenafil 5 mg, 10 mg, and 20 mg have been reported to improve EF compared with placebo in nondiabetic men across age groups [90]. No differences in the safety of any dose of sildenafil have been observed in older patients compared with younger men [3]. As a consequence, dosage adjustments of sildenafil are not required in elderly patients [87]. Vardenafil has been proven to be generally well tolerated in all age groups. The rates and identity of severe adverse events showed no age or dose preference. However, since the Cmax of vardenafil in men without ED is 50% higher in men aged >65 years than in men aged <65 years, judicious dosing should be considered. Several studies have shown that tadalafil at maximum dosage (20 mg) was well tolerated across all age groups and regardless of treatment regimen (on-demand vs. three times a week) [86]. ED Etiology Clinical studies demonstrate that the three PDE5 inhibitors are similarly effective at improving the EF domain scores of patients with organic, psychogenic, and mixed etiology ED [90–92]. Vardenafil has been proven to be similarly effective at improving EF without significant difference in response among doses (5 mg, 10 mg, 20 mg) [90]. The improvement was similar, despite ED etiology, with 20 mg tadalafil [91]. Notably, the improvement with the 10 mg dose was not significant in the psychogenic group when compared to placebo, although there were relatively few patients with ED

3425 of psychogenic origin treated with 10 mg [91]. The efficacy measures for sildenafil have not been analyzed by drug dose in clinical studies [92].

Reproductive Plans PDE5 inhibitors may increase the prostatic secretory function that results in an improvement in sperm motility in several cases. Some studies additionally demonstrate a role of PDE5 inhibitors in the regulation of sperm capacitation process [93,94]. In normal men, acute sildenafil administration does not modify semen characteristics [95]. In a small study on young infertile men, few differences between sildenafil and tadalafil in sperm motility were observed [96]. Wider studies demonstrated no deleterious effects of 9 months of daily tadalafil 20 mg on spermatogenesis or hormones related to testicular function in men aged >45 years [97]. Vardenafil daily at the maximum recommended dose for 6 months had no adverse effects on sperm concentration, total sperm count per ejaculate, sperm morphology, and motility compared with sildenafil and placebo [98]. Duration of ED Clinical studies suggest that men often wait years before they seek treatment for their ED [99]. Men with a longer duration of ED are more likely to perceive that their ED is more severe and is likely to be permanent, have a lower current frequency of sexual activity, are more willing to seek help for their problem, and try various forms of treatment [99]. Sildenafil has been proven to be effective across all efficacy measures, regardless of ED duration [92]. No similar data have been published for tadalafil or vardenafil. In a study by Matic et al. [99], men who had experienced ED for different lengths of time did not differ in their preference for or satisfaction with PDE5 inhibitors with longer or shorter duration of action [99]. Previous Treatment Used for ED and Patient’s Expectations PDE5 inhibitor therapy failure is frequent in patients with ED, and it may be often due to inadequate patient education, incorrect PDE5 inhibitor usage, and psychosocial factors [100]. Currently, 30–35% of patients fail to respond to or are dissatisfied with treatment. PDE5 inhibitor dose adjustment or PDE5 inhibitor switching are valid strategies [101]. As lack of spontaneity and “naturalness” with on-demand regimens are reported to be mainly responsible for reduced treatment compliance, the use of a PDE5 inhibitor J Sex Med 2011;8:3418–3432

3426 with a longer duration of action may provide a treatment option with greater flexibility and potentially less anxiety surrounding sexual activity [102]. Higher levels of satisfaction in patients taking tadalafil were reported in an observational study, mainly because of changes in time concerns [103].

Partner ED has significant adverse impact on the female partner’s sexual experience [104]. Women with partners who were currently using PDE5 inhibitor had a more satisfying sexual experience than others [105]. This has been demonstrated for all PDE5 inhibitors. Less than 40% of the patients suffering from moderate or mild ED and using a PDE5 inhibitor shared this information with their partners [106]. Frequency of Sexual Activities The three PDE5 inhibitors differ in terms of pharmacokinetic properties, mainly half-life (17.5 hours for tadalafil and approximately 4 hours for sildenafil and vardenafil). This aspect should be carefully considered when planning an ED treatment as it influences the window of opportunity available for sexual activity. Patients receiving sildenafil and vardenafil have a short time interval from dosing to intercourse, whereas patients receiving tadalafil have a significantly longer time interval. As reported by the erectile dysfunction observational study, 30% of the patients receiving sildenafil and 39% of patients receiving vardenafil treatment reported they had intercourse >4 hours after dosing compared with 68% of the patients who received tadalafil treatment [103]. The longer-lasting efficacy of tadalafil may reduce the anxiety of planning an intercourse and completing it before the drug’s time of action is over. The fact sheets of the three available PDE5 inhibitors clearly state that the maximum frequency of PDE5 inhibitor dosing is once a day. As a consequence, patients with a high frequency of sexual attempts may benefit from a PDE5 inhibitor with a wider window of efficacy or tadalafil 5 mg once daily [107]. Sexual Orientation Almost all clinical studies on PDE5 inhibitors have been performed on heterosexual men. Available data about men who have sex with men demonstrate that PDE5 inhibitor use is common and is associated with behaviors that may place their and others’ health at risk: greater numbers of male sexual partners, higher levels of unprotected anal sex, illegal provision of drugs, and higher levels of illicit recreJ Sex Med 2011;8:3418–3432

Corona et al. ational drug use with consequent increased risk pattern for HIV/sexually transmitted diseases transmission [108,109]. Interventions to reduce risk among this group should be considered [110,111].

Food and Alcohol Intake There is a close relationship between sexual activity and meals or alcohol consumption. It is useful for clinicians to understand the effects of food and alcohol on the pharmacokinetics of PDE5 inhibitors to give correct instructions to patients. The rate and extent of absorption of tadalafil is not influenced by alcohol consumption or food ingestion [33,112]. On the contrary, the administration of a high-fat meal decreases the rate of absorption for sildenafil and vardenafil [113]. For this reason, sildenafil and vardenafil package inserts state that efficacy may be delayed after a high-fat meal, independently from the type of formulation [11,12], while tadalafil can be taken independently of food intake [13,113]. Use of Recreational Drugs Few studies on populations using ED medications together with recreational drugs have been conducted [114]. A study of club drug use among 450 gay and bisexual men indicates that at least one PDE5 inhibitor is used frequently in combination with club drugs such as methamphetamine, ecstasy, ketamine, cocaine, and gamma-hydroxybutyrate [115]. Recreational use and misuse of all PDE5 inhibitors has been reported concomitantly with club drugs, leading to potentially harmful or fatal drug interactions [116]. Accordingly, it should be emphasized that amyl nitrate is contained in “poppers,” a recreational substance often used by young people. This emphasizes the importance of correct information concerning the use of PDE5 inhibitors, which always require a physician’s prescription and should be obtained through legitimate providers. Patient’s Preference Allowing the patient with more than one drug to determine his individual preference can be useful to better tailor the treatment, increase satisfaction, and lower the dropout rate [117]. Most preference studies available in the literature report preference rates favorable to tadalafil—although there are many possible sources of bias in preference studies [6]. It is very difficult to assess an individual patient’s preference in an objective way in daily clinical practice because it would require a time-consuming process of testing all

3427

The Proper PDE5 Inhibitor for the Proper Patient available drugs and dosing schedules. However, the results of preference studies, together with a patient’s and his partner’s needs and expectations could be used to determine the best “tailored” therapy.

Cost of Treatment The influence of PDE5 inhibitors costs is well recognized, negatively influencing patient’s compliance mainly in households with lower income [118] or in those under rehabilitation [119]. As the costs of PDE5 inhibitors vary between different countries, a standardized comparison is practically impossible.

Conclusion

Factors that should be collected during the visit of the patient affected by ED and their relevance to PDE5 inhibitor choice are summarized in Figure 2. All PDE5 inhibitors currently available are potentially suitable to treat any patient affected with ED, unless clear contraindications are present. Nevertheless, differences exist among the three widely available PDE5 inhibitors: sildenafil, tadalafil, and vardenafil that can potentially affect the therapeutic success, the satisfaction with the prescribed drug, and the long-term adherence to treatment.

Figure 2 Factors influencing phosphodiesterase type 5 (PDE5) inhibitor choice during patient’s assessment (right side) vs. anamnestic factors to be collected during patient’s assessment not influencing PDE5 inhibitor choice (left side). ED = erectile dysfunction; PDE5I = phosphodiesterase type 5 inhibitor.

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3428 Table 4

Corona et al. PDE5 inhibitor choice from clinical characteristics

Item

Leads to choose

Motivation

Reference

Age >65 years

Long-acting PDE5 inhibitor Elderly men have frequently sex in the morning after waking up, possibly due to retirement. No titration needed in elderly Usually have food Long-acting PDE5 inhibitor Efficacy independent on food and alcohol and alcohol before assumption sex Relational Evaluate case by case The majority of women prefer their partner’s use component of tadalafil. Women’s preference on the use of the PDE5 inhibitor has to be considered while choosing therapy. Previous treatment Evaluate case by case. Long-acting, short-acting, and daily treatments used for ED and E.g., spontaneity need may differently correspond to individual patient’s may particularly benefit preferences. expectations from daily dosing. Different PDEIs from that Effectiveness, side effects, and satisfaction are high in the PDE5 inhibitors class, but already tried, but first check for “false individuals may respond differently to different nonresponders”. molecules. Frequency of sexual Evaluate case by case Once-daily administration of tadalafil may be activities Long-acting PDE5 inhibitor preferred in patients who anticipate to have frequent sex. Evaluate case by case In patients treated with alpha-blockers, labetalol, Cardiovascular diseases— or carvedilol start with lowest dose; in patients concomitant treated with Class I antiarrhythmics, vardenafil should be administrated with caution. therapies

Most data retrieved during a formal evaluation, comprising medical history, questionnaires, physical examination, and first-line laboratory analyses, although very important in assessing the patient’s characteristics and ED etiology, do not help the physician to select the best PDE5 inhibitor for a given patient. In clinical practice, only a few points related to patient’s age, lifestyle, sexual habits, previous and concomitant diseases, and therapies can guide the choice of PDE5 inhibitor treatment for an individual patient (Table 4). Approaching together with the patient the important decision of treatment choice, physicians and caregivers involved in the clinical management of ED who aim to personalize the treatment of ED may wish to focus their attention on these selected items.

Wespes et al., 2007 [86]

Trocóniz et al., 2007 [33]; Patterson et al., 2001 [112] Conaglen et al., 2008 [55]; [104]

Mirone et al., 2009 [6]; Hackett, 2005 [102]

Hatzichristou et al., 2005 [107]

Jackson et al., 2006 [30]; McPartlin et al., 2008 [15]; Corona, Razzoli et al., 2008 [7]

Corresponding Author: Ferdinando Fusco, MD, PhD, Urologic Clinic, University Federico II, Naples 80132, Italy. Tel: +39 081-7462611; Fax: +39 081-5452959; E-mail: [email protected] Conflict of Interest: G. Corona, N. Mondaini, A. Ungar, and F. Fusco are occasionally involved as speakers in symposia sponsored by Eli Lilly, Pfizer, and Bayer. A. Rossi and E. Razzoli are employees of Eli Lilly Italy. Statement of Authorship

Category 1 (a) Conception and Design Giovanni Corona; Ferdinando Fusco (b) Acquisition of Data Andrea Rossi; Andrea Ungar (c) Analysis and Interpretation of Data Elisa Razzoli; Nicola Mondaini

Acknowledgments

Category 2

Eli Lilly Italia SpA has provided funding for literature search, editorial support, and provided secretarial support to the authors. The authors thank Dr. Jennifer Hartwig (professional medical writer) for her support in drafting this manuscript (funded by Eli Lilly), Eva Delgado (PRIMO Scientific Corporation), Luca Cantini (professional medical writer) and Frank Boess (Eli Lilly) for their manuscript revisions, and Giulia Calamai (Eli Lilly Italia) for her secretarial support.

(a) Drafting the Article Giovanni Corona; Ferdinando Fusco; Andrea Ungar; Andrea Rossi (b) Revising It for Intellectual Content Elisa Razzoli

J Sex Med 2011;8:3418–3432

Category 3 (a) Final Approval of the Completed Article Andrea Rossi; Giovanni Corona; Nicola Mondaini; Ferdinando Fusco; Elisa Razzoli

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