Discussion. Sildenafil (Viagra): a meta-analysis of clinical trial reports

DiscussionThis review demonstrated that considerable amounts of useful information are available in clinical trial reports submitted for marketing authorisation (licensing). That information adequately describes research methods used, though could be improved, perhaps using the updated CONSORT criteria. If these guidelines are becoming necessary for publication of randomised trials in our major medical journals, then they should be minimum criteria for clinical trials reports required by licensing authorities. We did not check the reports against each CONSORT criterion because the reports were from 1997 soon after the publication of the original CONSORT statement.

Despite scores of 3 or 4 out of five on a commonly-used quality score, and acknowledging that scores like this are not associated with bias, the areas where the clinical trials reports were weak were important ones. Only two reports stated how the randomisation sequence was generated. No report adequately described allocation concealment, though several mentioned sealed envelopes. No report described the implementation of the allocation sequence. Only two reports described how double blinding was achieved.

In other areas, reporting was good. Participants, and inclusion and exclusion criteria were explicit, as was a description of the intervention. Patient flow (though without diagrams) was thoroughly described, together with reasons for withdrawal. Baseline information on participants, numbers analysed and methods used were all well described, both for efficacy and adverse events. One criticism, outside CONSORT, was the use of mean scores for results of IIEF questions. Mean scores are of little value, especially when there may not be a normal distribution when they can be misleading . Better would be the number or proportion of men achieving good or excellent outcomes.

Clinical trial reports were a good source of information, and with minor changes would become an excellent source of information for meta-analysis. For sildenafil in erectile dysfunction these reports allowed interesting conclusions to be drawn from a homogeneous population of men with similar aetiologies, but excluding those with erectile dysfunction following spinal cord trauma, with diabetes, or following treatment for prostate cancer. Although two small studies on spinal cord trauma and one on diabetes were available in the full review, much more information on men with erectile dysfunction of particular aetiology has become available since 1997.

Efficacy was available in a number of formats in addition to mean responses to IIEF scores 3 and 4. The number of men in whom sildenafil was successful (erections hard enough for penetration, and resulting in intercourse) more than 60% of the time, and more than 40% of the time was available, and chosen by us for evaluation. Cut points every 20% from 0% to 100% were also available. The number of men responding positively to the global question on improved erections was also available. Clearly there is a gradation here from outcomes that are less easy to achieve to those that are easier to fulfil. A greater proportion of men achieved the easier than harder outcome for all doses (Figure 5). Numbers needed to treat and the proportion of patients achieving the outcome could easily be calculated.

Figure 5
Figure 5. Mean percentage of men achieving the outcomes of more than 60% success (blue) more than 40% success (red) and improved erections on the global question (green) with placebo and different doses and dosing schedules of sildenafil

Adverse events were also well described, and presented in a number of formats, from the number of men with any treatment related adverse event, through the number with severe or serious adverse events, particular adverse events, and discontinuations. From these it was possible to calculate numbers needed to harm and the proportion of patients for each outcome.

The ability to perform these calculations with information pooled from 10 studies was informative. Firstly, it supported the optimised dosing regimen for sildenafil. Optimised dosing produced efficacy equivalent to the highest fixed dose, and harm equivalent to the lowest fixed dose. Figure Figure66 shows the effects on the two broadest efficacy and harm outcomes, global response about improved erections and treatment related adverse effects. Figure Figure77 shows the NNTs and NNHs for three efficacy outcomes, three harm outcomes and three discontinuation outcomes. Optimised dosing was better than fixed dosing.

Figure 6
Figure 6. Mean percentage of men with improved erections on a global scale (blue), and reporting treatment related adverse effects (red) with placebo and different doses and dosing schedules of canadian sildenafil

Figure 7
Figure 7. Number needed to treat for different efficacy outcomes (more than 60% success, more than 40% success and improvement on global question) and number needed to harm for different adverse event outcomes (treatment related adverse events, all cause discontinuations, discontinuations due to inefficacy and adverse events and serious and severe adverse events). For NNT low numbers are better and for NNH high or negative numbers are better. TR AE – treatment related adverse event, Disc – discontinuation

It is also germane to enquire whether results obtained from clinical trial reports of the earliest studies are borne out in later reviews. A review of 20 trials comparing generic sildenafil with placebo with about 4,000 men included both published and unpublished information, and supplemented by the manufacturer where appropriate, arrived at broadly similar results. Only seven of the references to trials in that review were dated 1997 or before (mostly as abstracts), and would have been available at the time of marketing approval. Though combining all doses of sildenafil from 5 mg to 200 mg and dose escalation together in a comparison with placebo, the result for global efficacy yielded an NNT of 2, the same as is found in this review for all doses higher than 25 mg.

This investigation of the evidential properties of clinical trial reports of sildenafil for treatment of erectile dysfunction indicates that, in this instance, reports could have been used for systematic review at the time of product launch. With little additional effort the clinical trial reports could have fulfilled CONSORT guidelines for the reporting of randomised controlled trials. Making clinical trial reports publicly available at the time of product launch, perhaps through the Internet, would make their introduction evidence-based, as well as allowing healthcare services to plan ahead more effectively. This would benefit commercial organisations by maximising the uptake of effective new technology, and may accelerate discontinuation of less effective, or less safe, older technology.

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