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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 other shortcomings; it included patients who were not naive to PDE5 inhibitor use, and the comparison of the two compounds was unfair, as tadalafil was given at its regular dose, whereas only the starting dose of sildenafil (50 mg) was given to patients, without the option of titrating to the maximum dose of 100 mg; moreover, the duration of treatment was too short (4 weeks). Thus, the two pivotal patient?preference studies are the double?blind studies by Keitz et al.

[ 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 factors, i.e. diabetes mellitus, hypertension and/or hyperlipidaemia [ 10 ], Particular populations were recruited also in the other studies by [ 6, 8, 9, 11 ], which are also important, notwithstanding the lack of blinding, for this very reason.

Their patient populations included: all patients naive to PDE5 best online ed meds inhibitor [ 8, 9 ], the general population including the elderly [ 6, 8, 9 ], patients in a non?interventional clinical practice setting [ 11 ], different cultural settings in terms of country (USA/Canada and various European countries, including UK, Sweden, Italy, Spain, Germany) and different healthcare settings (general hospitals, University teaching hospitals, private practice).

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

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

Such questionnaires were also used in the studies by Eardley et al.

All 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 finding.

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. [ 11 ] physicians rated that 72% of patients allocated to the sildenafil?tadalafil sequence and 61% allocated to the tadalafil?sildenafil sequence preferred tadalafil; 76% of partners of patients allocated to the sildenafil?tadalafil sequence and 65% allocated to the tadalafil?sildenafil sequence preferred tadalafil. This study is also unique in showing how 6–8% of patients refused both sildenafil and tadalafil, and wanted to try another medication, and 2% preferred to stop any ED medication in a setting resembling routine clinical practice.

[ 7 ] was not influenced by age, country, presence of comorbidities, aetiology and severity of ED, previous treatment with sildenafil, titration of sildenafil dose or treatment sequence. The same was observed in other studies [ 5, 6, 8 ], in which both the pre?study sildenafil dose [ 5, 6, 8 ] and the duration of ED [ 5 ] did not influence the preference rate.

[ 12 ] also conducted a post hoc analysis of the data in an attempt to identify patient characteristics associated with their preference.

The only baseline characteristic that was significantly associated with preference was hyperlipidaemia, which increased the preference for sildenafil from 27% to 49% ( P = 0.01); no explanation for this finding is given by the authors.

One possibility is that patients preferred tadalafil because of its more flexible instructions for use (drug to be taken 0.5–24 h before sexual activity, vs 0.5–4 h before, for sildenafil) and efficacy not influenced by food intake.

[ 7 ], who found that significantly more patients preferred the instructions for tadalafil (67% vs 33%, P = 0.04). Thus, the difference in instructions for use contributes to the preference for tadalafil. Another possibility is that tadalafil was preferred because it is better tolerated. [ 12 ] showed that the perception of side?effect severity was associated with preference ( P = 0.001).

However, the sildenafil online reddit safety profile of the two drugs is comparable according to the Summary of Product Characteristics (Available at: http://www.emea.europa.eu/humandocs/Humans/EPAR/vigra/vigra.htm; http://www.emea.europa.eu/humandocs/Human/EPAR/cialis/cialis.htm). The most common events (?2% of patients) are similar with both drugs: headache (the most frequent, occurring in 10.8% of patients with sildenafil and 14.5% with tadalafil), dyspepsia, flushing and nasal congestion, dyspepsia being more common with tadalafil (12.3% vs 3.0%) and flushing being more common with sildenafil (10.9% vs 4.1%); in addition, sildenafil is associated with visual alterations (3.6%), whereas tadalafil is associated with back pain (6.5% and myalgia (5.7%).

A third possibility is that tadalafil was preferred because of its efficacy. Two patient?preference studies also collected efficacy information via the International Index of Erectile Function (IIEF) questionnaire [ 8, 9 ]. In both studies there was a trend towards greater improvement in IIEF scores with tadalafil; in the study by Tolra et al. [ 9 ] the median IIEF score increased from 17 at baseline to 29 with sildenafil and to 30 with tadalafil ( P = 0.09), and in the study by Eardley et al. [ 8 ] the mean difference was 9.6 with sildenafil and 10.1 with tadalafil ( P = 0.08). An analysis of the difference in IIEF domain scores showed that the trend in favour of tadalafil was due to significantly greater improvement in orgasmic function (difference, +0.28 95% CI 0.02–0.53, P = 0.03) and sexual desire (+0.19 95% CI 0.02–0.35, P = 0.02). The analysis of the association between the change in IIEF domain scores vs baseline and patient preference showed that greater changes in erectile function, sexual desire, intercourse satisfaction and overall satisfaction were significantly associated with patient preference (all P 12 ]. However, such numeric differences might not be regarded as clinically relevant. The hypothesis that some patients preferred tadalafil to sildenafil because of greater efficacy is better discussed considering the three patient?preference trials in which the patients were asked the reasons for their preference.

[ 11 ] physicians provided reasons for patient preference.

According to them, the main reason for preferring tadalafil was either its longer duration of action (45%) or greater efficacy (better erections) (34–37%), but on the other side, greater efficacy (better erections in 64%) was also the main reason for preferring sildenafil.

[ 9 ] patients provided the reasons for their preferences directly: the main reason for preferring tadalafil was the awareness of the opportunity of being able to have a second intercourse the following day, with the same quality of erection (48.9%), or achieving a more intense and longer?lasting erection (23.4%). In the minority of patients who did not prefer tadalafil, the main reason for preferring sildenafil and vardenafil was the achievement of a more intense and longer?lasting erection (84% and 88.9%, respectively). [ 9 ] also showed that the median EDITS score was significantly higher after tadalafil than after sildenafil (41 vs 38, P = 0.01). The PAIRS questionnaire was administered in the studies by Eardley et al.

Tadalafil improved several PAIRS domains to a significantly greater extent vs baseline than did sildenafil: sexual self?confidence (+0.17 95% CI 0.09–0.25, P 13 ]; greater changes in these PAIRS domain scores were significantly associated with patient preference ( P 12 ]. [ 13 ] also evaluated the Drug Attribute Questionnaire, which asked what was the best and second?best reason for the patient’s preference.

The main reason for preferring tadalafil (67% of patients) was the ability to obtain an erection, with sexual stimulation, long after the drug was taken (e.g. 16 or 24 h later), followed by the firmness of the erection (35.4%) and the erections that occurred the following morning (30.1%), whereas the main reasons for preferring sildenafil were firmness of erection (60%), early onset of action (41%) and reliable efficacy after every stimulation (40%). The 150 patients who had justified their preference for tadalafil, and the 12 who had justified their preference for sildenafil by mentioning the possibility of having an erection the following day were then asked to choose a statement that explained why this was so important.

Nearly half (46%) of the patients chose the following statement: ‘There was less need to plan when my best online ed meds partner and I would have sex’ whereas nearly a third (33%) chose ‘I could take the pill and not worry about when my partner and I might have sex’, and a fifth (21%) ‘It made me feel that my sexual function was like it used to be before I got ED’.

None of the currently available patient?preference studies on

PDE5

Of the 7 trials conducted so far according to Mulhall criteria, five comparing tadalafil with sildenafil consistently reported that patients preferred tadalafil to sildenafil, mainly because of the longer duration of action that increases the patient’s freedom in sexual life. Interestingly, although efficacy measures failed to detect any clinically relevant difference, in patient perception the efficacy of the two drugs might differ, and this might contribute to explaining patient?preference results for either tadalafil or, in a minority of cases, sildenafil. These observations further outline the need to seriously consider patient’s and partner’s wishes and preferences, to achieve the best clinical results. Finally, one study indicated that patients have no particular preference between vardenafil and sildenafil, and another suggested that tadalafil might also be preferred to vardenafil. The authors thank Dr Jennifer Hartwig for her contribution to the writing and linguistic revisions of this paper and Filippo Aglietti (Eli Lilly Italy) for his invaluable help in articles selection and retrieval. Riccardo Sicuteri and Andrea Rossi are full?time employees of Eli Lilly Italy.

Francesco Montorsi is a speaker for Eli Lilly Italy and a paid consultant for Pfizer, Pierre Fabre Medicament, AMS, Mipharm and Bayer Schering.

Vardenafil is used to treat erectile dysfunction (impotence; inability to get or keep an erection) in men. Vardenafil is in a class of medications called phosphodiesterase (PDE) inhibitors.

It works by increasing blood flow to the penis during sexual stimulation.