Skip navigation

Erectile Dysfunction


Bandolier 43 raised the issue of treatments for erectile dysfunction. At that time only one study in 12 men was available on the new oral treatment, sildenafil [1]. Two new studies in much larger populations are now available for assessment of sildenafil in more detail [2].

Measuring erectile dysfunction

The basic method used in the sildenafil study was that of a self-administered measure of erectile dysfunction, the international index of erectile dysfunction (IIEF) [3]. The importance of this instrument is that it has been developed to examine the main features of erectile dysfunction, is quick and simple to complete, and has the sensitivity and specificity to detect treatment-related changes in erectile dysfunction. It has 15 questions, easily scored, and is likely to be a useful diagnostic aid in erectile dysfunction.

The key features of the scale and its development were:

  • 15 questions dealing with erectile function, orgasmic function, sexual desire, intercourse satisfaction and overall satisfaction.
  • Based on literature search of existing questionnaires.
  • Developed from an initial questionnaire after trials with patients and review by an expert panel.
  • Validated in ten languages.
  • Examined for validity in a number of contexts.

The full questionnaire is a bit too long for the pages of Bandolier , but is given in an appendix in the paper [3].

Sildenafil efficacy 1

The first study was a double-blind dose-response design in which men were randomly assigned placebo (216 men), or 25 mg (96), 50 mg (105), or 100 mg (101) of sildenafil one hour before planned sexual activity (and not more than once daily). For inclusion, men had to be in a stable relationship of more than six months' duration. They had to have erectile dysfunction of organic, psychogenic, or mixed origin. Exclusions included men with penile anatomical defects, another sexual disorder, spinal cord injury, major psychiatric disorder, poorly controlled diabetes, or stroke, or myocardial infarction within six months, or use of organic nitrates.

Results

The mean age was 58 years, about 80% had organic causes of erectile dysfunction for an average of 3 years, and about 28% had hypertension, 18% hyperlipidaemia, 14% diabetes, 11% radical prostatectomy and 8% ischaemic heart disease. Results on efficacy were taken from questions 3 ("When you attempted sexual intercourse, how often were you able to penetrate your partner?") and question 4 ("During sexual intercourse, how often were you able to maintain an erection after you had penetrated your partner?") of the IEFF index.

There was a dose-response with sildenafil (Figures).

With doses of 50 and 100 mg there was a change from erections rarely adequate for penetration and rarely maintained to erections being both adequate and maintained much more than half the time. The effectiveness of sildenafil was broadly similar for men whose erectile dysfunction had an organic, psychogenic or mixed cause.

Sildenafil efficacy 2

A second study enrolled 329 different men who were randomly assigned to placebo (160 men) or 50 mg sildenafil (163 men) for 12 weeks. At follow up visits the dose could be doubled, or reduced by 50% on the basis of effectiveness and adverse effects.

Results

During the last four weeks of treatment the mean number of successful attempts at sexual intercourse was 5.9 with sildenafil, compared with 1.5 with placebo. Successful sexual intercourse occurred in 69% of attempts with sildenafil and 22% with placebo. Improved erections were reported by 101 of 136 men taking sildenafil and 23 of 118 taking placebo. This gives a number needed to treat of 1.8 (95% CI 1.5 to 2.3).

Adverse effects

Use of sildenafil was associated with some adverse effects. In the first Table adverse effects from both studies [2] and all doses are combined, though most showed a dose-response. The main adverse effects reported were flushing, headache, dyspepsia, visual disturbance (changes in perception of colour hue or brightness) and rhinitis. These were mild, and the number of discontinuations because of adverse effects was small at 5 of 479 patients (<1%).

 

Sildenafil adverse effects: combined studies and doses
  Placebo (N=382) Sildenafil (N=479) Number needed to harm (95%CI)
Adverse effect      
Flushing 4 93 5.4 (4.5 to 6.8)
Headache 20 99 6.5 (5.1 to 9.0)
Dyspepsia 7 41 15 (10 to 26)
Visual disturbance 2 22 24 (16 to 49)
Rhinitis 5 24 27 (17 to 69)
Discontinuations      
Inadequate response 14 6  
Treatment-related 2 5  

 

A more complete picture of adverse events comes from an analysis of all randomised and double blind placebo controlled studies, together with open label extensions [4]. The second Table extracts the information on the 1500 men given sildenafil or placebo in flexible dose studies, those most likely to reflect drug use in practice. The adverse effect incidence is only slightly different. Over 90% of these adverse effects were mild or moderate, and adverse effect discontinuations in these studies was just over 2% for both placebo and sildenafil. There were no cases of priapism in any of the studies.

 

Sildenafil adverse effects in PRN flexible-dosing studies
Adverse effect Placebo (N=725) Sildenafil (N=734) Number needed to harm (95%CI)
  Percent  
Headache 4 16 8.4 (6.7 to 11)
Flushing 1 10 11 (8.9 to 15)
Dyspepsia 2 7 20 (14 to 36)
Rhinitis 2 4 53 (28 to 753)
Visual disturbance 0 3 33 (23 to 56)
Diarrhoea 1 3 49 (29 to 165)
Adverse effects were mild or moderate in 92% of cases

 

Because the men who will be prescribed sildenafil will have cardiovascular risk factors, like hypertension, hyperlipidaemia and diabetes, the drugs's effect on cardiovascular events is very important. An analysis of all 18 placebo-controlled trials showed no difference in the incidence of myocardial infarction, angina or coronary artery disorders between sildenafil use and placebo (4274 men), nor was the incidence higher in the 2199 men taking part in open-label extensions (third Table). Blood pressure and heart rate were unaffected.

 

Incidence of serious cardiovascular events in Phase II/II studies
  Incidence (95% CI)
Studies Placebo Sildenafil
Phase II/III placebo-controlled    
Serious cardiovascular events 5.7 (3.3 to 8.2) 4.1 (2.7 to 5.5)
Myocardial infarction 1.4 (0.2 to 2.6) 1.7 (0.8 to 2.6)
Pase II/III open-label extensions    
Serious cardiovascular events   3.5 (2.3 to 4.7)
Myocardial infarction   1.0 (0.3 to 1.6)
Serious adverse events includes myocardial infarction, angina and coronary artery disorders

 

Comment

Here we have some well-conducted and large randomised trials which show good efficacy for important outcomes, together with a sensible portrayal of possible harm. The evidence so far is that sildenafil is effective, and safe. The men in the effectiveness study [2] had an average age of 58 years, and the majority had conditions associated with erectile dysfunction, and will represent a significant proportion of men with erectile dysfunction. The obvious missing group was men with spinal injuries, though abstracts of as-yet unpublished studies indicate that sildenafil is just as effective in them.

Treatment efficacy for oral sildenafil is about the same (NNT of about 2) as for intracavernosal injection or intraurethral application of alprostadil ( Bandolier 43 ). Adverse effects are different. Intraurethral alprostadil was associated with some mild pain (NNH 3.5), mild urethral trauma (NNH 25) and dizziness (NNH 50).

Because sildenafil's mode of action potentiation of hypotensive effects of nitrates is expected, and apparently was demonstrated in early studies. Use of sildenafil in men using organic nitrates is therefore contraindicated.

Clearly the advent of several new and effective treatments for male erectile dysfunction poses some difficult questions about who gets what treatment and when. And given that there is a large, and largely unmet, need, in an area that has caught the public (or at least the media) imagination, some thinking caps will be necessary to work out the most appropriate way to deal with what experience in the USA and elsewhere suggests might be an insatiable demand.

References:

  1. M Boolell, S Gepi-Attee, JC Gingell, MJ Allen. Sildenafil, a novel effective oral therapy for male erectile dysfunction. British Journal of Urology 1996 78: 257-61.
  2. I Goldstein, TF Lue, H Padma-Nathan et al. Oral sldenafil in the treatment of erectile dysfunction. New England Journal of Medicine 1998 338: 1397-1404.
  3. RC Rosen, A Riley, G Wagner et al. The international index of erectile dysfunction (IIEF): a multidimensional scale for assessment of erectile dysfunction. Urology 199749: 822-30.
  4. A Morales, C Gingell, M Collins et al. Clinical safety of oral sildenafil citrate (VIAGRA) in the treatment of erectile dysfunction. International Journal of Impotence Research 1998 10: 69-74.
previous or next story in this issue