Phosphodiesterase 5 inhibitors for pulmonary hypertension
Parthipan Kanthapillai
E Haydn Walters
Corresponding author.
Collection date 2004 Oct.
Abstract
Background
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.
Objectives
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.
Search methods
MEDLINE, EMBASE and CENTRAL were searched with pre‐defined search terms. Searches were current as of October 2006.
Selection criteria
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.
Main results
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.
Authors' conclusions
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.
Plain language summary
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.
Background
Pulmonary artery hypertension is characterised by resting mean pulmonary artery pressure of greater than 25 mm Hg. This can be divided into primary where there is no demonstrable cause identified and secondary where there are underlying causes.
Primary pulmonary hypertension (PPH) is a disease of unclear aetiology. It is sporadic and a familial predisposition has been observed in 10% of the cases. Observation suggests that pulmonary arteriolar vasoconstriction plays an important role in the pathogenesis of PPH, characterised by pathologic demonstration of medial hypertrophy, impaired pulmonary vascular endothelial production of the vasodilator prostacyclin and nitric oxide and increased pulmonary vascular endothelial production of the vasoconstrictor endothelin.
The main symptoms of PPH are exertional dyspnoea, exertional chest pain, syncope, and oedema. Mean age upon diagnosis of PPH is 36 years.
Secondary pulmonary hypertension is mainly due to chronic hypoxaemia, parenchymal lung disease, chronic thromboembolic disease, left sided valvular or myocardial disease, congenital heart disease and systemic connective tissue disease.
Until now the efficacy of pulmonary vasodilator therapy has been limited due to the lack of potency and lack of selectivity, as almost all pulmonary vasodilators are also systemic vasodilators. Thus apparent benefits on the pulmonary circulation may be merely due to decreased venous blood return and decreasing right ventricular stroke output. Currently available proven therapeutic interventions for PPH include anticoagulation, vasodilators such as calcium channel blockers, epoprostenol infusion (prostacyclin analogue), nitric oxide, and lung transplantation. A Cochrane review examining the efficacy of prostacyclin has shown it to confer at least a short‐term benefit (Paramothayan 2004).
Nitric oxide (NO) is a potent, short acting vasodilator. Within the vascular smooth muscle it activates soluble guanylate cyclase, which generate cGMP, which in turn relaxes smooth muscle. cGMP is degraded by phosphodiesterase (PDE). Sildenafil is a potent and selective inhibitor of PDE‐5, best known for its use as a treatment for male erectile dysfunction (Viagra). In addition to its high concentration in the corpora cavernosa, PDE‐5 is abundant in the vascular, tracheal and visceral smooth muscle and in platelets. The work so far with PDE‐5 inhibitors have shown improved haemodynamics in pulmonary hypertension.
The reviewers intend to summarise the evidence currently published concerning the use of sildenafil in pulmonary hypertension.
Objectives
To determine the efficacy of sildenafil in the treatment of patients with pulmonary hypertension.
Methods
Criteria for considering studies for this review
Types of studies
Randomised, double blind or single blind, placebo controlled studies were included.
Types of participants
Adult and paediatric subjects with a diagnosis of pulmonary hypertension who require medical treatment for their condition. All patients had to be anticoagulated. We included studies where mean PAP was 25> mm Hg.
Studies were included if diagnosis was based on clinical findings, pulmonary and cardiac imaging and ideally pulmonary angiograms.
Studies which included subjects with severe current other diagnoses were excluded.
Types of interventions
The following interventions have been included.
Sildenafil versus placebo
Sildenafil versus prostacyclin
Sildenafil + prostacyclin versus prostacyclin alone
Sildenafil + inhaled NO (nitric oxide) versus inhaled NO alone
High dose versus low dose sildenafil
Any route of administration of sildenafil was considered, such as oral, IV and inhalation. Any co‐intervention was acceptable. Studies of any duration were considered.
Types of outcome measures
Primary outcomes
Improvement in NYHA functional class status
Secondary outcomes
Haemodynamics including CO, PA pressure, others
Gas exchange, ABG
Exercise capacity
Quality of life/ Health status
Dyspnoea score
Mortality
Hospitalisation/intervention
Adverse events
Search methods for identification of studies
Electronic searches
Searches with pre‐defined terms were conducted on MEDLINE (1966‐Sept 2005,Appendix 1); EMBASE (1980‐ Sept 2005,Appendix 2), and the Cochrane Central Register of Controlled Trials (CENTRAL Issue 3,2005,Appendix 3) for relevant trials.
Searching other resources
Hand searches of abstracts from meetings of ATS, BTS and ERS were conducted. Drug companies were contacted for relevant trial data where appropriate.
Data collection and analysis
Selection of studies
All trials which appeared to fit the criteria for inclusion were identified for full review by two reviewers (PK and TL).Two reviewers (PK and TL) independently selected trials for inclusion in the review. Disagreement was resolved by discussion between the two reviewers.
Selection of studies
All trials which appeared to fit the criteria for inclusion were identified for full review by two reviewers (PK and TL).Two reviewers (PK and TL) independently selected trials for inclusion in the review. Disagreement was resolved by discussion between the two reviewers.
Data extraction and management
Two authors independently assessed studies for inclusion in the review. Data were extracted and entered into Review Manager software.
Assessment of risk of bias in included studies
We assessed the risk of bias for each study in terms of allocation, blinding and other sources of bias relating to treatment or population recruited. The domains we used as the basis for this assessment (allocation generation, allocation concealment, and blinding) were judged to be at low, high or unclear risk of bias.
Data synthesis
For continuous data variables (e.g. blood pressure) a weighted mean difference was calculated by pooling the data from different studies together, where a common metric had been used. A standardised mean difference was calculated where studies had measured the same outcome but with different metrics (e.g. L/min and % predicted). We pooled data using a Fixed Effect model.
For dichotomous variables (e.g. side effects), an Odds Ratio (OR) was calculated based on the event rate data in the studies. Data were pooled using a Fixed Effect model.
Heterogeneity was tested using the I2 statistic, which measures the extent of heterogeneity not attributable to the play of chance. Where the statistic exceeds 20% Random Effects modelling was applied to see if the results altered.
Limited meta‐analysis prevented the investigation of heterogeneity when the trials were combined. In anticipation of future studies meeting the inclusion criteria of this review, heterogeneity will be explored where the I2 statistic reaches 20%. Attempts will be made explore the differences based on the clinical characteristics of the included studies. Clinically dissimilar studies will not be statistically combined. However, when a group of studies with heterogeneous results appear to be clinically similar, the pooled effect estimates will be combined using both Fixed and Random effect models, and differences between the two types of modelling (if any) will be reported.
Subgroup analysis and investigation of heterogeneity
Possible subgroup analyses include:
Primary versus secondary pulmonary hypertension (where data are reported separately) .
Adults > 18 versus children < 18 years.
Route of administration of sildenafil such as oral, IV and inhalation.
Dosage of sildenafil (high versus low).
Results
Description of studies
Results of the search
Electronic searches yielded a total of 193 references. Of these we retrieved 19 studies that were potentially relevant. One study was identified from a search of PubMed in May 2004. Four studies met the inclusion criteria (Bharani 2003;Ghofrani 2002;Ghofrani 2002a;Sastry 2004). Sixteen studies failed to meet the inclusion criteria (review articles: N = four; before and after studies: N = six; RCTs not assessing sildenafil: N = two; retrospective analysis: N = one; animal studies: N = one; observational studies: N = one; correspondence: N = one). For details of these studies, please see "Characteristics of Excluded Studies". An update search was conducted in October 2005, in which 286 references were retrieved. Of these eight were obtained for full scrutiny but none met the inclusion criteria (seeTable 1).
1. Seach update detail.
| Search date | Articles retrieved | N assessed | Unique studies | Included | Excluded |
| October 2004‐5 | 285 | 8 | 8 | 0 | 8 (observational study/before and after study: 3; Healthy volunteers: 3; RCT of wrong comparison: 1; study of ERAs: 1) |
| October 2005‐6 | 396 | 19 | 17 |
Included studies
Study design
All included studies were randomised. Two studies had a parallel open label design (Ghofrani 2002;Ghofrani 2002a).Sastry 2004 andBharani 2003 were double‐blind crossover studies.
Participants
Participants suffered from a mixture of PPH and secondary PH inGhofrani 2002, and suffered from PH secondary to lung fibrosis inGhofrani 2002a.Sastry 2004 recruited participants with PPH.Bharani 2003 recruited participants with PH of varied etiologies. In the two parallel studies, participants were classified as being in either NYHA class III or IV. InBharani 2003 andSastry 2004, participants were classified as being in NYHA class II or above. Mean PAP in the short‐term studies suggested that participants were suffering from particularly severe forms of PH (Ghofrani 2002: treatment group mean PAPs were 53 to 59mmHg;Ghofrani 2002a: 40mmHg).Bharani 2003 reported very high baseline mean PAP (80.78 (SD 21.3).Sastry 2004, reported particularly high baseline mean PAP of 107.36 (SD 24.98), and included only participants with a baseline mean PAP in excess of 30mm Hg.
Interventions
Two studies were short term (< 3 hours,Ghofrani 2002;Ghofrani 2002a). In these studies, the acute effects of treatment were assessed in the trials after an initial inhalation of NO.Ghofrani 2002 compared oral sildenafil in four treatment regimens: 12.5mg, 50mgs, 12.5mgs + inhaled iloprost and 50mgs + inhaled iloprost.Ghofrani 2002a compared oral sildenafil 50mgs versus IV epoprostenol.Sastry 2004 andBharani 2003 assessed the effects of oral sildenafil compared with a placebo, for six and two week periods respectively, in addition to concomitant therapies such as digoxin and diuretics.Sastry 2004 also reported that oral anticoagulants were used at the physician's discretion. Co‐interventions did not include other vasodilators in either study.
Setting
Ghofrani 2002 conducted the study in an ITU,Ghofrani 2002a did not report the setting of the trial.Sastry 2004 andBharani 2003 were conducted in an outpatient setting.
Outcomes
Bharani 2003 reported change in NYHA functional class status.Ghofrani 2002;Ghofrani 2002a assessed the acute effects of sildenafil and focused on haemodynamic variables.Sastry 2004 andBharani 2003 measured exercise capacity.Sastry 2004 assessed treatment effects in terms of the 'Chronic Heart Failure Questionnaire'.Sastry 2004 andBharani 2003 measured symptoms and adverse effects.
Risk of bias in included studies
All studies with the exception ofBharani 2003 were well reported, and adequately randomised by computer generated randomisation schedules. However, in the two short term studies, blinding was not attempted. In clinical trials this may contribute to an overestimation of treatment effects, where there is subjective assessment of treatment effects, e.g. physician or patient rated clinical and/symptom scores. However, due to the short‐term duration of the studies, this aspect may not have threatened internal validity. Due to the design of the two acute studies they have not measured longer term clinical symptoms, such as NYHA functional class status. The primary outcome of the review (change in NYHA functional class status), was measured in one study (Bharani 2003).
Effects of interventions
Oral sildenafil versus placebo (plus usual care) ‐ crossover studies
Bharani 2003 (n=9, treatment period 2 weeks);Sastry 2004 (n=22, treatment period 6 weeks)
NYHA
Following treatment with sildenafil,Bharani 2003 reported that two participants improved their NYHA status by one class (no significant difference reported).
Quality of life
Total scores were not reported, but the findings from three domains of the CHFQ reported bySastry 2004 were:
Dyspnoea: Significant difference in favour of sildenafil (21.95 (SD 6.02)) versus placebo (17.62 (SD 5.68)), P = 0.009. Fatigue: Significant difference in favour of sildenafil (22.33 (4.82)) versus placebo (20.67 (SD 5.19)), P = 0.04. Emotional function: No significant difference between sildenafil (37.33 (SD 9.32)) and placebo (34.71 (SD 10.91)), P = 0.06.
Borg scores
Bharani 2003 reported a significant difference in Borg breathlessness scores ) (Scale 0 10) after the 6 minute walk test of 1.55 (P < 0.01)
Exercise capacity
This was measured bySastry 2004 as time on treadmill. Participants were able to spend longer on the treadmill compared with placebo treatment (686.82 seconds (SD 224.02) versus 475.05 seconds (SD 168.02), P < 0.0001.
This was measured byBharani 2003 as distance covered in a 6 minute walk test. Participants treated with sildenafil were able to walk further than those treated with placebo by 93.37metres (P < 0.005).
Haemodynamic variables
Data fromBharani 2003 andSastry 2004 were pooled with a subgroup analysis by etiology (PPH versus mixed population studies). With a Fixed Effect model there was a significant reduction in mean PAP in favour of sildenafil of ‐11.14mmHg [‐17.56, ‐4.72]. However, there was a significant level of heterogeneity (I2 72.5%), and a Random Effects model gave a non‐significant result (‐12.76 [‐25.7, 0.19]). The etiology of disease may not be the only variable to distinguish between these two studies. There were also different baseline arterial pressures in addition to different study duration and dosing regimens. In the absence of other studies, and the small sample sizes involved, the subgroup analysis is under‐powered to provide useful insights into different responses to treatment.
Sastry 2004 reported a significant difference in cardiac index in favour of sildenafil (Sildenafil: 3.45 l/m2 (SD 1.16) versus placebo: 2.80 (SD 0.90), P < 0.0001).
Adverse effects
A table of adverse effects is given inTable 2. No statistical analysis was undertaken on the difference in the side‐effects in the study. No participants withdrew due to side‐effects. One death occurred in the placebo group during the first arm of treatment.
2. Adverse effects in Sastry 2004.
| Effect | Sildenafil (N/22) | Placebo (N/22) |
| Body aches | 1 | 2 |
| Backache | 3 | 1 |
| Headache | 3 | 1 |
| Insomnia | 2 | 3 |
| Leg pains | 3 | 6 |
| Numbness of hands & feet | 4 | 1 |
| Anorexia | 3 | 3 |
| Nausea & vomiting | 1 | 5 |
| Abdominal discomfort | 3 | 6 |
| Constipation | 3 | 0 |
| Giddiness | 1 | 4 |
| Syncope | 0 | 1 |
| Death | 0 | 1 |
High dose oral sildenafil versus low dose sildenafil with and without iloprost ‐ parallel studies
Ghofrani 2002 (n=30, treatment duration single dose)
NYHA functional class status
No data on functional class status were reported
Haemodynamic variables
Data were presented on change from baseline scores for PVR, mean PAP, Cardiac Index and PVR/SVR. We have extracted data only for PVR as these were presented at equivalent time points (120 minutes). Data for all other variables were presented at 120 mins for sildenafil only treatment, and at 180 minutes for sildenafil plus additional iloprost inhalation. We entered data for the two sets of comparisons and stratified them on the basis of co‐intervention. The trialists reported that combination therapy led to significant decrease in PVR compared with sildenafil alone (p < 0.001), and also to significant increase in cardiac index (p < 0.001). Data for all four treatment groups were presented in the original paper in graph format. These were extracted, entered and pooled by co‐intervention to give a WMD in favour of high dose sildenafil of ‐15.86% (‐30.64 to ‐1.08). The significant effect we observed in meta‐analysis should be interpreted with caution due to the wide distribution of change scores in the study as a result of the small numbers.
Data on arterial oxygen saturation were not presented (non‐significant differences reported).
Treatment effects for both single administration of sildenafil and combination therapy outlasted the observation periods of 120 minutes and 180 minutes respectively.
Safety
No adverse events were reported during combination therapy. No comment was made on the side‐effects of single administration of sildenafil.
Oral sildenafil versus IV epoprostenol ‐ parallel studies
Ghofrani 2002a (n=16, treatment duration‐ single dose)
NYHA
No data were reported on the effects of treatment on functional class status.
Haemodynamic variables
Epoprostenol (a prostaglandin analogue) caused a 42% median increase in cardiac index , compared with 9.1% in sildenafil treated patients (p = 0.002). Change in mean PAP and PVR did not differ significantly between the two groups (p = 0.054 and p = 0.197 respectively, no values are reported). Mean systematic arterial blood pressure was reduced by both treatments, but differed statistically between the groups in favour of sildenafil (p = 0.0005). However, no values were reported. Mean PaO2 differed significantly and was higher with sildenafil (p = 0.005, no values presented). Sildenafil also led to a higher, more favourable PVR/SVR ratio compared with prostacyclin (p = 0.02, no values were presented).
Treatment effects for sildenafil outlasted the observation period of 120‐150 minutes.
Safety
No adverse events were reported during combination therapy
Discussion
Four small studies have been included in this review. Due to the acute nature of two studies, and the limited assessment of functional class status in the remaining studies, firm conclusions regarding the effects of sildenafil on the course of PH are difficult to draw. Additionally, the participants in all the studies had very high pulmonary artery pressures, and in the case ofGhofrani 2002, were recruited in an ITU setting. Therefore they were representative of patients from the more severe end of the spectrum. Only one study explicitly recruited participants who conformed to theWHO 2001 classification of PH (Ghofrani 2002a). Whilst this classification may become more commonly used in clinical trials in PH, there is currently limited evidence in our review to draw a distinction between this diagnostic model and others such as functional status (NYHA), threshold blood pressure levels or even disease etiology.
The positive physiological effects observed in the acute studies require replication in larger and more rigorously controlled trials, but would indicate that there is a vasodilatory effect in PH when sildenafil is administered.Bharani 2003 andSastry 2004 showed differences in terms of important outcomes such as symptoms and exercise capacity over two and six weeks. Nevertheless, these effects require confirmation on a larger scale, as well as its correlation with long term benefits including hospitalisation, mortality, and functional class status. AlthoughSastry 2004 reported mild side‐effects, the study design and duration means that we cannot exclude the possibility that sildenafil may have long term side effects. Data from small non‐randomised studies in people with PH have not found any systemic side‐effects, such as visual disturbance, flushing, headache and dyspepsia (Ghofrani 2003;Kothari 2002) which have been reported in one large study of sildenafil for erectile dysfunction (Rosen 2003).
In an uncontrolled trialGhofrani 2003 measured the effects of long term sildenafil treatment in addition to inhaled iloprost in severe pulmonary hypertension. The participants in the study were adults with mixed PH (PPH: N = 9, PH secondary to collagen vascular disease: N = 5), and were already deemed to have failed treatment with iloprost. After 12 months of additional sildenafil treatment improvements were noted in functional class status, exercise capacity and haemodynamic variables.Kothari 2002 also assessed long‐term effects of sildenafil in paediatric and adult populations with mixed PH (PPH: N = 9, PH secondary to surgical correction of heart defect: N = 5). After a follow‐up period of 7.3 months (SEM 2.4), improvements were observed in terms of NYHA status, exercise capacity and right ventricular systolic pressure. Findings from these studies indicate that randomised studies measuring similar outcomes are warranted. In such studies the etiology of the disease should be considered as a potential explanation for different responses to treatment, and ideally studies should be limited to specific diagnostic groups e.g. solely PPH.
Authors' conclusions
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.
What's new
| Date | Event | Description |
|---|---|---|
| 26 February 2019 | Review declared as stable | This review has been superseded by http://dx.doi.org/10.1002/14651858.CD012621.pub2 |
History
Protocol first published: Issue 3, 2001 Review first published: Issue 4, 2004
| Date | Event | Description |
|---|---|---|
| 5 June 2014 | Amended | Title and PLS title amended |
| 15 August 2008 | Amended | Converted to new review format. |
| 2 October 2006 | New search has been performed | Literature search re‐run, no new studies found |
| 1 August 2004 | New citation required and conclusions have changed | Substantive amendment |
Notes
This review has been superseded by http://dx.doi.org/10.1002/14651858.CD012621.pub2
Acknowledgements
We would like to thank the staff of the Cochrane Airways Group, namely Karen Blackhall, Liz Arnold and Sarah Tracy for logistical and technical support. We would also like to thank Dr Sastry for communicating additional data (Sastry 2004).
Appendices
Appendix 1. MEDLINE search strategy
(combined with RCT filter outlined in Group Module)
1 exp Hypertension, Pulmonary/ 2 (pulmonary adj5 hypertens$).mp. [mp=title, original title, abstract, name of substance, mesh subject heading] 3 1 or 2 4 exp Vasodilator Agents/ 5 [exp VASODILATION/de [Drug Effects]] 6 (viagra or sildenafil).mp. [mp=title, original title, abstract, name of substance, mesh subject heading] 7 exp Phosphodiesterase Inhibitors/ 8 PDE5.mp. 9 4 or 5 or 6 or 7 or 8 10 3 and 9
Appendix 2. EMBASE search strategy
(combined with RCT filter outlined in Group Module)
1. exp Pulmonary Hypertension/ 2. (pulmonary adj5 hypertens$).mp. [mp=title, abstract, subject headings, drug trade name, original title, device manufacturer, drug manufacturer name] 3. 1 or 2 4. exp Vasodilator Agent/ 5. exp Vasodilatation/ 6. exp Sildenafil/ 7. sildenafil.mp. 8. viagra.mp. 9. exp Phosphodiesterase Inhibitor/ 10. PDE5.mp. [mp=title, abstract, subject headings, drug trade name, original title, device manufacturer, drug manufacturer name] 11. 4 or 5 or 6 or 7 or 8 or 9 or 10 12. 3 and 11
Appendix 3. CENTRAL search strategy
#1. HYPERTENSION PULMONARY explode tree 1 (MeSH) #2. (pulmonary near hypertens*) #3. (#1 or #2) #4. VASODILATOR AGENTS explode tree 1 (MeSH) #5. VASODILATION [de] single term (MeSH) #6. PHOSPHODIESTERASE INHIBITORS single term (MeSH) #7. pde5 #8. (viagra or sildenafil) #9. (#4 or #5 or #6 or #7 or #8) #10. (#9 and #3)
Data and analyses
Comparison 1. Oral sildenafil versus placebo.
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 1 Improvement in NYHA status ‐ post treatment in crossover studies | 1 | Odds Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 2 Exercise time on treadmill ‐ crossover studies | 1 | Seconds (Fixed, 95% CI) | Totals not selected | |
| 3 Exercise time on treadmill ‐ 1st arm/parallel studies | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 4 Exercise capacity ‐ 6 minute walk test ‐ crossover studies | 1 | Metres (Fixed, 95% CI) | Totals not selected | |
| 5 Cardiac index ‐ crossover studies | 1 | L/m2 (Fixed, 95% CI) | Totals not selected | |
| 6 Pulmonary artery systolic pressure ‐ crossover studies | 2 | 58 | mmHg (Fixed, 95% CI) | ‐11.14 [‐17.56, ‐4.72] |
| 6.1 Primary pulmonary hypertension | 1 | 40 | mmHg (Fixed, 95% CI) | ‐6.73 [‐14.59, 1.13] |
| 6.2 Mixed population studies | 1 | 18 | mmHg (Fixed, 95% CI) | ‐20.0 [‐31.13, ‐8.87] |
| 7 Borg dyspnea score ‐ crossover studies | 1 | Borg (Fixed, 95% CI) | Totals not selected | |
| 8 Quality of life: dyspnoea ‐ crossover studies | 1 | CHFQ score (Fixed, 95% CI) | Totals not selected | |
| 9 Quality of life: fatigue ‐ crossover studies | 1 | CHFQ score (Fixed, 95% CI) | Totals not selected | |
| 10 Quality of life ‐ emotional function (crossover studies) | 1 | CHFQ score (Fixed, 95% CI) | Totals not selected |
1.1. Analysis.
Comparison 1 Oral sildenafil versus placebo, Outcome 1 Improvement in NYHA status ‐ post treatment in crossover studies.
1.2. Analysis.
Comparison 1 Oral sildenafil versus placebo, Outcome 2 Exercise time on treadmill ‐ crossover studies.
1.3. Analysis.
Comparison 1 Oral sildenafil versus placebo, Outcome 3 Exercise time on treadmill ‐ 1st arm/parallel studies.
1.4. Analysis.
Comparison 1 Oral sildenafil versus placebo, Outcome 4 Exercise capacity ‐ 6 minute walk test ‐ crossover studies.
1.5. Analysis.
Comparison 1 Oral sildenafil versus placebo, Outcome 5 Cardiac index ‐ crossover studies.
1.6. Analysis.
Comparison 1 Oral sildenafil versus placebo, Outcome 6 Pulmonary artery systolic pressure ‐ crossover studies.
1.7. Analysis.
Comparison 1 Oral sildenafil versus placebo, Outcome 7 Borg dyspnea score ‐ crossover studies.
1.8. Analysis.
Comparison 1 Oral sildenafil versus placebo, Outcome 8 Quality of life: dyspnoea ‐ crossover studies.
1.9. Analysis.
Comparison 1 Oral sildenafil versus placebo, Outcome 9 Quality of life: fatigue ‐ crossover studies.
1.10. Analysis.
Comparison 1 Oral sildenafil versus placebo, Outcome 10 Quality of life ‐ emotional function (crossover studies).
Comparison 2. High dose oral sildenafil versus low dose oral sildenafil.
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 1 Change in pulmonary vascular resistance | 1 | 30 | Mean Difference (IV, Fixed, 95% CI) | ‐15.86 [‐30.64, ‐1.08] |
| 1.1 Sildenafil plus iloprost | 1 | 15 | Mean Difference (IV, Fixed, 95% CI) | ‐17.0 [‐40.38, 6.38] |
| 1.2 Sildenafil alone | 1 | 15 | Mean Difference (IV, Fixed, 95% CI) | ‐15.1 [‐34.17, 3.97] |
2.1. Analysis.
Comparison 2 High dose oral sildenafil versus low dose oral sildenafil, Outcome 1 Change in pulmonary vascular resistance.
Comparison 3. Oral sildenafil versus prostacyclin.
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 1 Change in pulmonary vascular resistance | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 1.1 Low dose sildenafil | 0 | Mean Difference (IV, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 1.2 High dose sildenafil | 1 | Mean Difference (IV, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
3.1. Analysis.
Comparison 3 Oral sildenafil versus prostacyclin, Outcome 1 Change in pulmonary vascular resistance.
Characteristics of studies
Characteristics of included studies [ordered by study ID]
Bharani 2003.
| Methods | Randomised, double‐blind, crossover study. Methods of randomisation: Not reported. Method of blinding: unclear. Withdrawals: N = 1. Jadad score: 3 (R: 1; B: 1; W: 1) Statistical analysis: Paired t test. | |
| Participants | N = 9 (5F). PPH: N = 3; PH secondary to ILD: N = 2; Thromboembolism: 1; Eisenmeger syndrome: Ventricular septal defect: N = 2; Patent ducus arteriosis: N = 1. NYHA status: II: N = 3; III: N = 5; IV: N = 1. Mean age: 32.11 (SD 15.06). Diagnosis established by clinical examination; routine lab evaluation; chest x‐ray; ECG Inclusion criteria: NYHA >/= II; Doppler‐estimated pulmonary systolic pressure: >/=35 mmHg; normal left ventricular function. Exclusion criteria: Reversible cause for PAH; contraindications for sildenafil therapy. | |
| Interventions | Sildenafil 25mg 3 times per day versus placebo. Previous vasodilator therapy was withheld from 1 week to study entry. All other conventional therapy was maintained (warfarin; nifedipine; diuretics (N = 2); digoxin (N = 2). Study duration: 2 x 2 week treatment periods | |
| Outcomes | 6 minute walk test; change in symptoms; change in NYHA functional class; change in Borg; change in resting pulmonary artery systolic pressure. | |
| Notes | ||
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Described as randomised, no other information available |
| Allocation concealment (selection bias) | Unclear risk | Information not available |
| Blinding (performance bias and detection bias) All outcomes | Unclear risk | Placebo‐controlled; uncertain of similarity between treatments. |
Ghofrani 2002.
| Methods | Randomised, parallel group open label study. Methods of randomisation: Computer generated randomisation (blocks of 4). Blinding not undertaken. No withdrawals. Jadad score: 3 (R: 2; B: 0; W: 1) | |
| Participants | N = 30 (23F). PPH: N = 10; Calcinosis: N = 6; chronic thromboembolic PH: N = 13; PH due to aplasia of left pulmonary artery: N = 1. NYHA: III or IV. Sildenafil 12.5: N = 7; Sildenafil 50: N = 8; Sildenafil 12.5 + iloprost: N = 7; Sildenafil 50 + iloprost: N = 8 Inclusion criteria: Mean PAP: >40 mm Hg; PH as defined by WHO World Symposium in PPH Exclusion criteria: PH secondary to COPD; pulmonary venous congestion; congenital heart disease; acute or chronic inflammatory lung disease; pregnancy or insufficient contraceptive methods; previous treatment with PDE inhibitors (including theophylline). Response to NO was recorded, but was not an inclusion nor an exclusion criterion. | |
| Interventions | All participants had inhaled NO. Subsequently they were randomised to one of the following treatment groups: Sildenafil 12.5 mg Sildenafil 50 mg Sildenafil 12.5 mg + iloprost Sildenafil 50 mg plus iloprost. Study duration: 120 minutes for participants receiving sildenafil alone; 180 minutes for participants receiving sildenafil plus iloprost | |
| Outcomes | Arterial pressure; cardiac output; central venous pressure; peripheral oxygen saturation; blood gases; | |
| Notes | No blinding undertaken. Short term study assessing the acute effects of sildenafil alone or in combination with iloprost. No assessment of safety undertaken/possible due to the short term nature of the study. Mixed population. Trialists undertook subgroup analysis ‐ no significant difference in response to treatment determined by type of PH. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Computer generated randomisation (blocks of 4) |
| Allocation concealment (selection bias) | Unclear risk | Information not available |
| Blinding (performance bias and detection bias) All outcomes | High risk | Open label trial |
Ghofrani 2002a.
| Methods | Randomised, open label parallel group trial. Patients were randomised by computer in blocks of four. Blinding not possible. No participants withdrew. Jadad score: 3 (R: 2; B: 0; W: 1) | |
| Participants | Eligible: 25; N = 16. Mean age: 56.5 years (27 to 79); mean PAP: 40 mm Hg (25 to 62); Cardiac Index: 2.3 L/min/m2 (1.2 to 4.3); PVR: 1108.7 dyne/s/cm‐5/m2 (448 to 3296); PaO2: 73.5 mm Hg (52 to 104); NYHA status: III (N = 10); IV: (N = 6) Inclusion criteria: Lung fibrosis defined by ATS and ERS guidelines; severe PH (mean PAP >35 mm Hg) Exclusion criteria: Pulmonary venous PH (pulmonary arterial wedge pressure >15 mm Hg); underlying lung disease other than fibrosis (COPD; recurrent PE); prior treatment with theophyllines | |
| Interventions | All participants inhaled NO prior to randomisation. Participants were randomised to IV iloprost (epoprostenol given in doses increased by 2 ng/kg/min) or oral sildenafil 50 mg Study duration: 60 minutes | |
| Outcomes | PVR; mean PAP; pulmonary shunt flow; PaO2; cardiac output; adverse effects (short term) | |
| Notes | Short term study assessing the acute effects of sildenafil versus epoprostenol in terms of haemodynamic variables. No blinding undertaken. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Computer generated randomisation |
| Allocation concealment (selection bias) | Unclear risk | Information not available |
| Blinding (performance bias and detection bias) All outcomes | High risk | Open label trial |
Sastry 2004.
| Methods | Randomised, double‐blind, crossover study. Method of randomisation: computer generated random numbers. Blinding: unclear. Withdrawals: N = 2. ITT analysis. Jadad score: 4 (R: 2, B: 1, W:1). Statistical analysis: Paired t test. | |
| Participants | N = 22. Age range: 16‐55 years; mean PAP: > 30 mmHg (mean not reported); Cardiac Index (L/m2): 2.83 (SD 1.06); Pulmonary artery systolic pressure (mmHg) 107.36 (SD 24.98); NYHA status: II (N = 18); III (N = 4); Quality of Life (CHFQ): Dyspnoea: 21.86 (SD 6.47); Fatigue: 20.38 (SD 5.12); Emotional function: 34.14 (SD 10.38) Inclusion criteria: 12‐65 years of age; NYHA II & III; estimated PAP >30mmHg; able to walk on a treadmill Exclusion criteria: NYHA I or IV; significant r‐to‐l shunt; valvular heart disease; left ventricular systolic dysfunction; systemic hypertension; secondary pulmonary hypertension; severe co‐morbid conditions | |
| Interventions | Oral sildenafil versus placebo. Participants could not use other vasodilators. Digoxin, diuretics and oral anticoagulants were used at clinician's discretion. Dosage varied according to body weight (0‐25kg, 3x25mg per day; 26‐50kg, 3x50mg per day; >51kg, 100mg 3x100 per day) Study duration: 6 weeks. No washout phase was undertaken | |
| Outcomes | Exercise capacity; Quality of life (dyspnoea, emotion, fatigue); change in pulmonary artery systolic pressure; cardiac output; adverse events | |
| Notes | ||
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Computer generated random numbers |
| Allocation concealment (selection bias) | Unclear risk | Information not available |
| Blinding (performance bias and detection bias) All outcomes | Unclear risk | Placebo‐controlled; uncertain of similarity between treatments. |
CHFQ: Chronic heart failure questionnaire; COPD: chronic obstructive pulmonary disease; Jadad scores: R: Randomisation; B: Blinding: W: Withdrawals; NO: Nitric oxide; NYHA: New York Heart Association Funcional Class Status; PAP: pulmonary arterial pressure; PVR: Pulmonary vascular resistance; PH: Pulmonary hypertension; PPH: Primary pulmonary hypertension; ILD: Interstitial Lung Disease
Characteristics of excluded studies [ordered by study ID]
| Study | Reason for exclusion |
|---|---|
| Anonymous 2001 | Before and after study in healthy volunteers who had breathed in low levels of oxygen to induce 'pulmonary hypertension'. |
| Anonymous 2001a | Review article on pulmonary hypertension in neonates |
| Channick 2001 | Review article |
| Chockalingam 2005 | Before and after study |
| Deeb 1989 | Retrospective analysis of amrinone therapy in patients with pulmonary hypertension |
| Dweik 2002 | Review article |
| Ewert 2003 | Correspondence in response to a non‐randomised study. |
| Frost 2005 | Study of endothelin |
| Ghofrani 2003 | Before and after study. |
| Ghofrani 2004 | Healthy volunteers |
| Hoeper 2003 | Review article |
| Humpl 2005 | Before and after study |
| Ikeda 2005 | Observational study |
| Kothari 2002 | Before and after study of sildenafil administered to 14 people with PAH. |
| Kulkarni 1996 | Randomised controlled trial comparing the effects of oxygen, sublingual isosorbide dinitrate, IV aminophylline, and sublingual nifedipine. Sildenafil was not administered. |
| Lepore 2002 | Non‐randomised prospective observational study. |
| Machado 2005 | Before and after study |
| McKay 1989 | Before and after study in 10 patients with pulmonary hypertension. |
| Michelakis 2002 | Before and after study |
| Richalet 2004 | Healthy volunteers |
| Richalet 2005 | Healthy volunteers |
| Schmid 1999 | Randomised controlled trial examining the effects of iNO (inhaled nitric oxide) in post‐operative with severe PH post‐operative in comparison with IV vasodilators. Excluded as neither of the two vasodilators used as comparators were sildenafil. |
| Wilkens 2001 | Before and after study |
| Wilkins 2005 | Comparison of sildenafil and endothelin |
| Zhao 2001 | Animal study. |
IV: Intravenous
Contributions of authors
PK: Initiation of the review, study assessment, data extraction and entry, interpretation TJL: Study assessment, data extraction and entry, analysis, interpretation EHW: Content supervision, interpretation and editorial support
Sources of support
Internal sources
Division of Community Health Sciences, St George's, University of London, UK.
External sources
No sources of support supplied
Declarations of interest
None known.
Stable (no update expected for reasons given in 'What's new')
References
References to studies included in this review
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