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The immediate objective of PDE5 inhibitor treatment is to restore the ability of a man to achieve and/or maintain an erection adequate for sexual intercourse.

As erectile dysfunction (ED) generally develops in the second half of life, the ultimate objective generally is not procreation, but quality of sexual life.

Indeed, ED is known to impair quality of life considerably: two?thirds of men report that ED has impaired their self?esteem and nearly a third claim that it has damaged the relationship with their partner [ 1 ].

It follows that the therapeutic success of PDE5 inhibition has an important subjective component, which is compounded by the subjective nature and complexity of sexual life in humans. This makes it very difficult for physicians to be certain that they have selected the optimum therapy for a couple, even after a thorough evaluation [ 1 ].

The 2007 European Association of Urology Guidelines [ 2 ] stress the importance of educating the patient and claim that ‘the patient will choose the final drug after his own experience’. However, Hatzimouratidis and Hatzichristou [ 3 ] point out that PDE5 inhibitors are typically used twice a week, so a patient would have to spend ?3 months trying the various compounds and dosages to achieve adequate exposure to all three PDE5 inhibitors; this would seem an unrealistic strategy in normal clinical practice. The acknowledgement that the patient has an important role in therapeutic decisions for ED has fuelled interest in the concept of patient preference. It has been established that patient preference depends on three factors, i.e.

personal characteristics, such as age, duration of ED, frequency and dynamics of sexual relations, and the characteristics of their partners, such as age, menopausal status and level of interest in sexual activity and medication profile.

Medication features of interest include efficacy in terms of quality of erection, consistency of effects, rapid onset of action, long duration of action, side?effect profile and route of administration; drug costs have to be considered, too, if the medicinal product is not reimbursed [ 1 ]. Three PDE5 inhibitors are currently commercially available; each one is characterized by particular pharmacokinetic features. In the attempt to evaluate which is the most favoured drug, several preference studies have been conducted in the last few years.

Unfortunately, several of them have proved to be severely flawed because of methodological pitfalls. Mulhall [ 4 ] made the point that patient preference studies are not the same as the classical efficacy and safety studies, and set forth detailed recommendations for their conduct. The ideal study for preference evaluation should: (i) be randomized, double?blind, crossover; (ii) not include bias by pre?selection of patients (e.g.

only nonresponders to previous treatment); (iii) make fair comparisons, adopting equivalent doses of each drug and giving each drug for

equal

He also indicated several pitfalls: drug instructions might differ considerably, e.g.

because of differences in duration of action, and invalidate the blinding, or might even condition patient preference; period effects might produce improvements over time that bias results in studies with medications that require an adaptation period or training; carry?over effects might produce an overlap in the effects of medications, jeopardizing their comparison, when the wash?out interval between periods is too short. He also raised the issue of how

patient

Several published studies are available that evaluated patient preference for tadalafil or vardenafil vs sildenafil and that meet some, but not all, the requirements listed above.

The aim of this review is to establish whether current knowledge enables any conclusive judgement.

We electronically searched Medline (from 1966 to 2007 week 18) and EMBASE (from 1988 to 2007 week 18) using the search string ‘(tadalafil or vardenafil) AND Sildenafil AND clinical trial AND erectile dysfunction’ combined with ‘drug preference OR drug

choice

We identified seven patient?preference studies (Table 1) [ 5-12 ], comprising six interventional trials [ 5-10, 12 ] and one observational trial [ 11 ].

All of them compared tadalafil with sildenafil, except two, i.e.

a large double?blind study by Rubio?Aurioles et al.

[ 10 ] that compared vardenafil with sildenafil, and a small open?label study by Tolra et al. [ 9 ] that compared sildenafil with vardenafil and tadalafil. Three of the studies were declared as sponsored by Lilly ICOS LLC [ 7, 8, 11 ] and one jointly by Bayer and Glaxo?SmithKline [ 10 ].

Ref Design Population, n inclusion criteria Treatment Questionnaires [ 5 ] Randomized, double?blind Crossover Fixed dose 1–2 week washout SIL vs TAD 191 completers 18–65 years ?3 months ED Heterosexual TAD naive SIL naive/insufficient therapy SIL 50 mg 30 min up to 4 h before sex TAD 20 mg 30 min up to 24 h before sex ?4 weeks TP question SEP diary TEAE [ 6 ] Open?label, fixed dose, 1?way cross over, 1?week screening3?week SIL assess 1 week treatment?free washout 6?week TAD initiation 3?week TAD assess 6?month extension 147 completers ?18 years ?3?month history of ED on SIL treatment at stable dose for 6–24 weeks Stable heterosexual relationship SIL continue 25–100 mg as before (100 mg max 35%) TAD 20 mg % choosing TAD for extension SEP diary TEAE [ 7 ] Randomized, Double?blind, crossover 4?armed study drug preference TAD – SIL or SIL – TAD DIP TAD – SIL (drug was always TAD) Drug comparison, 219 Instructions comparison, 46 18–65 years Heterosexual ?3?month history of ED SIL 50 mg (up to 35% 100 mg) TAD 20 mg ? 12 weeks + 12?week extension Instructions SIL take 30 min up to 4 h before sex; TAD take 30 min up to 24 h before sex TP question DIP question Time from dosing to sex TEAE [ 8 ] Randomized 291 completers SIL 25–100 mg TP question [ 12 ] Open?label Crossover SIL vs TAD 4?week run?in 7–10 day washout 8?week titration 8?week extension ?18 years Steady relationship PDE5I?naive 30 min to 4 h before sex TAD 10–20 mg 30 min to 12 h before sex ? 12 weeks IIEF SEP diary PAIRS Correlate baseline, IIEF, SEP and PAIRS with PP TEAE [ 9 ] Randomized, Open?label Crossover Fixed dose 7?day washout SIL vs TAD vs VAR 90 completers ?18 years Heterosexual ?6 months ED Mild viagra sale without prescription to moderate according to IIEF PDE5 naive SIL 100 mg TAD 20 mg VAR 20 mg ?6 times over 45–60 days IIEF EDITS TP questions TEAE [ 10 ] Pooled data from two randomized, double?blind, crossover with 1 week wash?out SIL vs VAR 931 patients (ITT population) ?18 years 4?week treatment periods Stable heterosexual relationship ?6 months ED History/diagnosis of diabetes mellitus, hypertension and/or hyperlipidaemia SIL, 100 mg VAR 20 mg TP questions IIEF SEP GAQ TSS [ 11 ] Non?interventional observational previous 8 weeks 2425 Use of SIL or TAD within the Need to change to other medication data collected on SIL, TAD PPPQ TP question 4, to patient 5, to partner 6, GAQ N (%) patients Accompanied by partner Who informed partner about PDE5I treatment, EDITS.

GAQ, global assessment question; PDE5I, PDE5 inhibitor; PP, patient preference; PPPQ, physician?rated patient?treatment preference questionnaire; SEP, Sexual Encounter Profile; SIL, sildenafil TAD, tadalafil; TEAE, treatment emergent adverse events; TP, treatment preference; TSS, Treatment Satisfaction Scale; VAR, vardenafil; ITT, intent?to?treat.

In the light of the considerations above, the six interventional trials are good, but not ideal, studies, as all of them meet most, but not all of Mulhall’s criteria.

Three of the five interventional studies [ 6, 8, 9 ] were open?label studies because of the difficulty in conducting a blind study with these compounds, as there are major differences in their instructions on use. [ 5 ] is reduced by

several

[ 7 ], which compared tadalafil and sildenafil, and by Rubio?Aurioles et al. In these two studies elaborate measures were taken that put patients in conditions that differed considerably from usual clinical practice. [ 5 ] had an elaborate crossover design; patients were randomized to one of 4 arms (i) tadalafil + tadalafil instructions vs sildenafil + sildenafil instructions; (ii) sildenafil + sildenafil instructions vs tadalafil + tadalafil instructions; (iii) tadalafil + tadalafil instructions vs tadalafil + sildenafil instructions; (iv) tadalafil + sildenafil instructions vs tadalafil + tadalafil instructions. The comparison between arm 1 and 2 was between drugs, whereas the comparison between arm 3 and 4 was between instructions.

This design enabled the study to also address the key issue of the difference in instruction sets by comparing these while always giving the same drug, tadalafil.

The only pitfall of this study is that 66% of the patients were not naive to PDE5 inhibitor. Double?blind conditions were achieved in the study by Rubio?Aurioles et al. [ 10 ] by encapsulating sildenafil tablets, creating a formulation that does not exist on the market.

This obliged them to carry out another trial to show the bioequivalence of the encapsulated formulation with the marketed one. This appears to be the only flaw of the study, which met all the main Mulhall criteria for patient?preference studies. However, the patient population only included a particular subgroup of PDE5 inhibitor users, those with cardiovascular

risk

A non?interventional setting that closely resembled routine clinical practice is the main strength of the large observational study by

Lee

This study enrolled 2425 patients in Canada, and assessed some of the partners, using more detailed questionnaires, which provide more extensive information related to the reasons for preference: the Erectile Dysfunction Inventory of Treatment Satisfaction (EDITS), the Psychological and Interpersonal Relationship Scale (PAIRS), the Drug Attribute Questionnaire, and preference questions put not only to the patient but also to the partner.

Such questionnaires were also used in the studies by Eardley et al. All womens viagra buy the studies comparing tadalafil and sildenafil showed a significant preference for tadalafil than sildenafil (Table 2). [ 7 ] was clear; 73% of patients preferred tadalafil to sildenafil ( P 9 ] to 90.5% in the study by Stroberg et al. However, the latter trial was conducted in patients who had taken sildenafil for 5, 8, 9, 11 ] was much more similar to the study of von Keitz et al. [ 7 ], as the proportion of patients who preferred tadalafil was 66–71%.

[ 9 ] vardenafil was the least popular PDE5 inhibitor, as only 20% of patients preferred this drug.

However, the sample was too small to provide adequate power, so this preference rate should be considered as a

preliminary

Its results were contradicted by the large, adequately powered, non?inferiority, double?blind study by Rubio?Aurioles et al. [ 10 ], which documented a 38.9% preference rate for vardenafil vs 34.5% for sildenafil (26.6% of patients had no preference). Some studies also addressed secondary preference objectives.

[ 8 ], in which patients were asked to specify whether they preferred one drug to the other ‘strongly’ or ‘moderately’, 73% of the patients who preferred tadalafil had a strong preference, vs only 45% amongst those who preferred sildenafil.