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Comparing PDE-5 inhibitors: 2005 update

Clinical bottom line

Despite enriched enrolment in tadalafil and vardenafil trials, the greater clinical and geographical variation for sildenafil than tadalafil and vardenafil, results for the three PDE-5 inhibitors were generally similar for efficacy and particular adverse events. Discontinuation rates were somewhat lower for sildenafil.


Reference

RA Moore et al. Indirect comparison of interventions using published randomised trials: Systematic review of PDE-5 inhibitors for erectile dysfunction. BMC Urology 2005 2005, 5:18.

Systematic review

Randomised trials were sought of three PDE-5 inhibitors (sildenafil, tadalafil, vardenafil), with placebo or active comparator, in men with erectile dysfunction of any causation, with drugs used at home. Previous systematic reviews were used to source trials or trial data, supplemented by electronic searches of PubMed (to June 2005, and supplemented by searches to November 2005 for this update) and the Cochrane Library (issue 1, 2005) using drug names and randomis(z)ed trial.

Information extracted was of efficacy, using a number of different efficacy outcomes, discontinuations, and specific adverse events. Almost all information was available for the 10 and 20 mg dose, and a dose optimised regimen; information was combined for 10 and 20 mg fixed dose, and for the dose optimised regimen.

Results

There were more men in sildenafil trials (7,135) than tadalafil (2,071) or vardenafil (3,374). Trials were of generally high reporting quality, and all of them were at a minimum both randomised and double blind.

Compared with tadalafil and vardenafil, sildenafil was studied in more clinical conditions, though with erectile dysfunction of mixed aetiology or diabetes comprised about 85% of all men in the studies. There was a wider geographical spread with sildenafil, but most studies were in Europe, North America, or Australia. Although various doses were used in the trials, and some dose-optimised regimens for sildenafil and vardenafil, results from the top two doses or dose-optimised regimens were similar for each drug, and pooled.

The analysis therefore aggregates the most information for the three PDE-5 inhibitors. This report shows the results, without any attempt to demonstrate statistical differences between the three PDE-5 inhibitors.

Outcomes reported

Table 1 at the bottom of the page shows the outcomes reported, in terms of percentage of men in the trials reporting that outcome. Improved erections and success rates were reported commonly, together with the final score and mean change in the erectile function domain.

Discontinuations, for any reason, or because of adverse events or lack of efficacy, were also commonly reported. Adverse event reporting was less consistent, with some adverse events being reported consistently, and others not. The reason was that adverse events with incidence below 2%-5% were often not reported.

Efficacy

The erectile function domain score at the end of treatment, and the change in the erectile function domain score for the top doses of all three PDE-5 inhibitors are shown in Figure 1. The percentage of men with improved erections, and percentage of successful attempts at intercourse, are shown in Figure 2. There is similarity between the three treatments, though with a tendency for slightly better results with sildenafil.

Figure 1: Mean erectile function scores at end of treatment, and mean domain change

Figure 2: Mean percent with improved erections, and percentage of successful attempts at intercourse

Discontinuations

Figure 3 shows discontinuation rates for any cause, for lack of efficacy, and for adverse events for all three PDE-5 inhibitors. Rates were generally lower with sildenafil, though this was also the case with placebo, and the differences may reflect differing expectations over time. Tadalafil and vardenafil were studied in men in whom PDE-5 inhibitors were known to work, and it might have led to less tolerance of adverse events in them.

Figure 3: Discontinuation rates for any cause, lack of efficacy, and adverse events

Particular adverse events

None of the three PDE-5 inhibitors had any difference between them and placebo for serious adverse events. Particular adverse events, headache, flushing, dyspepsia and rhinitis were commonly reported, and Figure 4 shows the average incidence for each PDE-5 inhibitor. There were generally similar.

Figure 4: Event rates for headache, flushing, dyspepsia and rhinitis

Comment

Perhaps the most obvious difference between trials of different drugs was the use of different exclusion criteria in individual studies. Five of eight tadalafil studies, and six of seven vardenafil studies excluded men previously unresponsive to PDE-5 inhibitors, thus permitting enrolment to be enriched by responders compared with sildenafil studies, in which such an exclusion would not have been used because it was the first available PDE-5 inhibitor. It is not clear how this major difference might have affected the measured performance of the drugs. Exclusion of non-responders to other PDE-5 inhibitors might be expected to enhance the measured performance of any other PDE-5 inhibitor under test, making it look better in indirect comparisons.

Despite this, and despite the greater clinical and geographical variation in sildenafil trials than tadalafil and vardenafil trials, results for the three PDE-5 inhibitors were generally similar for efficacy and particular adverse events. Discontinuation rates were somewhat lower for sildenafil.

Another systematic review [1] compared top fixed-dose schedules of the PDE-5 inhibitors (sildenafil 100 mg, tadalafil 20-25 mg; vardenafil 20 mg). It came to similar conclusions, with better results for sildenafil than tadalafil than vardenafil, despite having many fewer studies.

Reference:

  1. MM Berner et al. Efficacy of PDE-5 inhibitors for erectile dysfunction. A comparative meta-analysis of fixed-dose regimen randomized controlled trials administering the International Index of Erectile Fuinction in broad-spectrum populations. International Journal of Impotence Research 2005 (published online 20 October)

Table 1: Percentage of men in all trials for whom an outcome is reported

Outcome
Sildenafil
n=6860
Tadalafil
n=2036
Vardenafil
n=3274
Efficacy

Improved erections

83

83

100

Mean # erections/week

21

0

0

Successful attempts at SI

49

72

100

More than 60/75% successful

10

0

18

More than 40% successful

0

0

0

Final score IIEF Q3

94

27

26

Mean change IIEF Q3

91

27

26

Final score IIEF Q4

94

27

26

Mean change IIEF Q4

91

27

26

Final score EF Domain

58

72

100

Mean change EF Domain

55

83

77

Normal EF at endpoint

8

56

14

Discontinuations
All-cause
82
65
69
Lack of efficacy
81
72
82
Adverse event
89
83
100
Adverse events
Men with any adverse event
40
40
18
Severe
25
25
35
Serious
36
83
78
Treatment related
54
3
43
Headache
99
90
86
Dyspepsia
78
71
73
Flushing
99
73
73
Nasal congestion/Rhinitis
62
35
73
Visual disturbances
89
46
55
Back pain
13
73
9
Myalgia/Increased CPK
16
60
18
Flu syndrome
18
30
34
CV events
25
27
33
Limb pain
10
11
0
Fatigue
0
15
0
Priapism
30
0
0
Nausea
14
0
0