Phosphodiesterase 5 inhibitors for pulmonary hypertension: Cochrane systematic review
Pulmonary Hypertension (PH) can be either of unknown aetiology (primary pulmonary hypertension (PPH)) or due to a known underlying cause (secondary pulmonary hypertension (SPH). Pulmonary arteriolar vasoconstriction is considered to be an important characteristic of PH. Therapies which aim to vasodilate are used to treat pulmonary hypertension.
To determine the clinical efficacy of sildenafil, a vasodilator which works through inhibition of the enzyme phosphodiesterase type V (PDE5I), administered via any route to people with pulmonary hypertension in primary or secondary forms.
MEDLINE, EMBASE and CENTRAL were searched with pre-defined search terms. Searches were current as of October 2006.
Randomised controlled trials were considered for inclusion in the review. We included studies which assessed the effects of sildenafil in participants with PPH and SPH.
Data collection and analysis
Two reviewers independently assessed and extracted data from clinical trials. Data were entered in RevMan Analyses 1.0.2. Continuous data were pooled with an estimate on either WMD (weighted mean difference) or SMD (standardised mean difference) scales. Dichotomous data were pooled and a RR (relative risk) was calculated.
Four studies recruiting 77 participants met the inclusion criteria of the review. Two studies assessed the acute effects of sildenafil. Two small crossover study assessed the effects of long term administration. The 'acute effect' studies indicated that sildenafil has a pulmonary vasodilatory effect. The two crossover studies showed improvement in symptoms. One study showed improvement in fatigue domains from a validated health status questionnaire. Both crossover studies reported that the drug was well tolerated.
The validity of the observed effects is undermined by small participant numbers and inadequate exploration of the different disease etiologies. The effects on long term outcome such as NYHA functional class, symptoms, mortality and exercise capacity require further validation. More studies of adequate size are required before the long term effects of sildenafil on clinically important outcomes can be established.
Kanthapillai Parthipan, Walters E Haydn
Phosphodiesterase 5 (sildenafil) inhibitors for pulmonary hypertension
Pulmonary hypertension (PH) is high blood pressure in the lung circulation. It can occur without a known cause, or it can be caused by another lung disease or be secondary to abnormalities in the left side of the heart. The review sought to determine whether there was evidence that sildenafil (also known as Viagra), a drug which opens up the arteries and increases the flow of blood, could decrease pulmonary artery blood pressure and alleviate symptoms of PH. A limited number of studies of short term i duration indicated that the drug can open up the arteries. One small longer-term study found some favourable effects in terms of symptoms, but in the absence of longer term outcomes, we could not establish whether this meant that the people given the drug felt that their levels of daily activity were better. Future studies should be longer in duration, and should measure the impact of treatment on daily activities, mortality, quality of life and exercise capacity.
Implications for practice
Current evidence from randomised studies does not indicate whether long term administration of sildenafil in PH is justified. The studies have shown that there may be a vasodilatory effect either in combination or in comparison with inhaled iloprost in selected patients. Two small studies reported differences on exercise capacity and symptoms over two to six weeks, which require validation in larger studies. Further work is urgently required to establish that the short term effects observed in these patients can be replicated in larger, more representative and better defined patient samples, and that short term improvements in haemodynamic variables correlate with long term outcomes. A more adequate side-effect profile is also required.
Implications for research
Further studies are required and should take account of the following methodological and clinical considerations:
- Adequate blinding of both study participant and trialist.
- Trials should measure outcomes which are clinically relevant (e.g. mortality, NYHA functional class, hospitalisation) and which have been collected from adequate follow-up periods, so that long term effects can be established. Assessment of side-effects in larger samples of patients with PH would also be appropriate.
- Disease etiology should be clearly described in future studies, and if possible data on participants with PPH and secondary PH should be analysed separately, to facilitate better identification of effects within these two subgroups.
- Future studies should also assess the effects of treatment in less severe forms of PH.
- To date the studies have recruited predominantly adult populations. The effects of sildenafil in children with PH needs also to be established.
- Confirmatory studies are required to establish whether there is a dose response to sildenafil.
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