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`Phosphodiesterase 5 inhibitors for pulmonary hypertension
`(Review)
`
`Kanthapillai P, Walters EH
`
`KanthapillaiP, WaltersEH.
`Phosphodiesterase 5 inhibitors for pulmonary hypertension.
`Cochrane Database of Systematic Reviews 2004, Issue 4. Art. No.: CD003562.
`DOI: 10.1002/14651858.CD003562.pub2.
`
`www.cochranelibrary.com
`
`Phosphodiesterase 5 inhibitors for pulmonary hypertension (Review)
`Copyright © 2019 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
`
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`UNITED THERAPEUTICS CORP., EX1016, page 1
`UNITED THERAPEUTICS CORP. v. ACTELION PHARMACEUTICALS
`U.S. PATENT 8,268,847
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`T A B L E O F C O N T E N T S
`ABSTRACT.....................................................................................................................................................................................................
`PLAIN LANGUAGE SUMMARY.......................................................................................................................................................................
`BACKGROUND..............................................................................................................................................................................................
`OBJECTIVES..................................................................................................................................................................................................
`METHODS.....................................................................................................................................................................................................
`RESULTS........................................................................................................................................................................................................
`DISCUSSION..................................................................................................................................................................................................
`AUTHORS' CONCLUSIONS...........................................................................................................................................................................
`ACKNOWLEDGEMENTS................................................................................................................................................................................
`REFERENCES................................................................................................................................................................................................
`CHARACTERISTICS OF STUDIES..................................................................................................................................................................
`DATA AND ANALYSES....................................................................................................................................................................................
`Analysis 1.1. Comparison 1 Oral sildenafil versus placebo, Outcome 1 Improvement in NYHA status - post treatment in crossover
`studies....................................................................................................................................................................................................
`Analysis 1.2. Comparison 1 Oral sildenafil versus placebo, Outcome 2 Exercise time on treadmill - crossover studies.................
`Analysis 1.3. Comparison 1 Oral sildenafil versus placebo, Outcome 3 Exercise time on treadmill - 1st arm/parallel studies........
`Analysis 1.4. Comparison 1 Oral sildenafil versus placebo, Outcome 4 Exercise capacity - 6 minute walk test - crossover studies....
`Analysis 1.5. Comparison 1 Oral sildenafil versus placebo, Outcome 5 Cardiac index - crossover studies......................................
`Analysis 1.6. Comparison 1 Oral sildenafil versus placebo, Outcome 6 Pulmonary artery systolic pressure - crossover studies......
`Analysis 1.7. Comparison 1 Oral sildenafil versus placebo, Outcome 7 Borg dyspnea score - crossover studies............................
`Analysis 1.8. Comparison 1 Oral sildenafil versus placebo, Outcome 8 Quality of life: dyspnoea - crossover studies....................
`Analysis 1.9. Comparison 1 Oral sildenafil versus placebo, Outcome 9 Quality of life: fatigue - crossover studies.........................
`Analysis 1.10. Comparison 1 Oral sildenafil versus placebo, Outcome 10 Quality of life - emotional function (crossover studies)....
`Analysis 2.1. Comparison 2 High dose oral sildenafil versus low dose oral sildenafil, Outcome 1 Change in pulmonary vascular
`resistance...............................................................................................................................................................................................
`Analysis 3.1. Comparison 3 Oral sildenafil versus prostacyclin, Outcome 1 Change in pulmonary vascular resistance.................
`ADDITIONAL TABLES....................................................................................................................................................................................
`APPENDICES.................................................................................................................................................................................................
`WHAT'S NEW.................................................................................................................................................................................................
`HISTORY........................................................................................................................................................................................................
`CONTRIBUTIONS OF AUTHORS...................................................................................................................................................................
`DECLARATIONS OF INTEREST.....................................................................................................................................................................
`SOURCES OF SUPPORT...............................................................................................................................................................................
`NOTES...........................................................................................................................................................................................................
`INDEX TERMS...............................................................................................................................................................................................
`
`Phosphodiesterase 5 inhibitors for pulmonary hypertension (Review)
`Copyright © 2019 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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`[Intervention Review]
`Phosphodiesterase 5 inhibitors for pulmonary hypertension
`
`Parthipan Kanthapillai1, E Haydn Walters2
`
`1Luton and Dunstable NHS Trust, Luton, UK. 2NHMRC Centre of Research Excellence for Chronic Respiratory Disease, School of Medicine,
`University of Tasmania, Hobart, Australia
`
`Contact: Parthipan Kanthapillai, Luton and Dunstable NHS Trust, Lewsey Road, Luton, Bedfordshire, LU4 0DZ, UK.
`Parthipan.Pillai@ldh.nhs.uk.
`
`Editorial group: Cochrane Airways Group.
`Publication status and date: Stable (no update expected for reasons given in 'What's new'), published in Issue 2, 2019.
`
`Citation: KanthapillaiP, WaltersEH. Phosphodiesterase 5 inhibitors for pulmonary hypertension. Cochrane Database of Systematic
`Reviews 2004, Issue 4. Art. No.: CD003562. DOI: 10.1002/14651858.CD003562.pub2.
`
`Copyright © 2019 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
`
`A B S T R A C T
`
`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 eIicacy 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 eIects 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 diIerence) or SMD (standardised mean diIerence) 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 eIects of sildenafil. Two
`small crossover study assessed the eIects of long term administration. The 'acute eIect' studies indicated that sildenafil has a pulmonary
`vasodilatory eIect. 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 eIects is undermined by small participant numbers and inadequate exploration of the diIerent disease
`etiologies. The eIects on long term outcome such as NYHA functional class, symptoms, mortality and exercise capacity require further
`
`Phosphodiesterase 5 inhibitors for pulmonary hypertension (Review)
`Copyright © 2019 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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`validation. More studies of adequate size are required before the long term eIects of sildenafil on clinically important outcomes can be
`established.
`
`P L A I N L A N G U A G E S U M M A R Y
`
`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 leL 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 eIects 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.
`
`Phosphodiesterase 5 inhibitors for pulmonary hypertension (Review)
`Copyright © 2019 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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`B A C K G R O U N D
`
`M E T H O D S
`
`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, leL sided valvular or myocardial disease, congenital heart
`disease and systemic connective tissue disease.
`
`Until now the eIicacy 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 eIicacy 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.
`
`O B J E C T I V E S
`
`To determine the eIicacy of sildenafil in the treatment of patients
`with pulmonary hypertension.
`
`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.
`
`if diagnosis was based on clinical
`included
`Studies were
`findings, pulmonary and cardiac imaging and ideally pulmonary
`angiograms.
`
`included subjects with severe current other
`Studies which
`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
`1. Haemodynamics including CO, PA pressure, others
`2. Gas exchange, ABG
`3. Exercise capacity
`4. Quality of life/ Health status
`5. Dyspnoea score
`6. Mortality
`7. Hospitalisation/intervention
`8. 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.
`
`Phosphodiesterase 5 inhibitors for pulmonary hypertension (Review)
`Copyright © 2019 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
`
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`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
`soLware.
`
`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 diIerence was calculated by pooling the data from diIerent
`studies together, where a common metric had been used. A
`standardised mean diIerence was calculated where studies had
`measured the same outcome but with diIerent metrics (e.g. L/min
`and % predicted). We pooled data using a Fixed EIect model.
`
`For dichotomous variables (e.g. side eIects), an Odds Ratio (OR)
`was calculated based on the event rate data in the studies. Data
`were pooled using a Fixed EIect 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 EIects 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 diIerences 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 eIect estimates
`will be combined using both Fixed and Random eIect models, and
`
`diIerences between the two types of modelling (if any) will be
`reported.
`
`Subgroup analysis and investigation of heterogeneity
`Possible subgroup analyses include:
`
`1. Primary versus secondary pulmonary hypertension (where data
`are reported separately) .
`2. Adults > 18 versus children < 18 years.
`3. Route of administration of sildenafil such as oral, IV and
`inhalation.
`4. Dosage of sildenafil (high versus low).
`
`R E S U L T S
`
`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 aLer 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 (see
`Table 1).
`
`Included studies
`Study design
`All included studies were randomised. Two studies had a parallel
`open label design (Ghofrani 2002; Ghofrani 2002a). Sastry 2004 and
`Bharani 2003 were double-blind crossover studies.
`
`Participants
`Participants suIered from a mixture of PPH and secondary PH in
`Ghofrani 2002, and suIered from PH secondary to lung fibrosis
`in Ghofrani 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. In Bharani 2003 and Sastry 2004,
`participants were classified as being in NYHA class II or above.
`Mean PAP in the short-term studies suggested that participants
`were suIering 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 eIects of treatment were
`assessed in the trials aLer an initial inhalation of NO. Ghofrani
`2002 compared oral sildenafil
`in four treatment regimens:
`12.5mg, 50mgs, 12.5mgs + inhaled iloprost and 50mgs + inhaled
`
`Phosphodiesterase 5 inhibitors for pulmonary hypertension (Review)
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`iloprost. Ghofrani 2002a compared oral sildenafil 50mgs versus
`IV epoprostenol. Sastry 2004 and Bharani 2003 assessed the
`eIects 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 and Bharani 2003 were
`conducted in an outpatient setting.
`
`Outcomes
`Bharani 2003 reported change in NYHA functional class status.
`Ghofrani 2002; Ghofrani 2002a assessed the acute eIects of
`sildenafil and focused on haemodynamic variables. Sastry 2004
`and Bharani 2003 measured exercise capacity. Sastry 2004
`assessed treatment eIects in terms of the 'Chronic Heart Failure
`Questionnaire'. Sastry 2004 and Bharani 2003 measured symptoms
`and adverse eIects.
`
`Risk of bias in included studies
`All studies with the exception of Bharani 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 eIects, where there is subjective
`assessment of treatment eIects, 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).
`
`E<ects 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
`diIerence reported).
`
`Quality of life
`Total scores were not reported, but the findings from three domains
`of the CHFQ reported by Sastry 2004 were:
`
`Dyspnoea: Significant diIerence in favour of sildenafil (21.95 (SD
`6.02)) versus placebo (17.62 (SD 5.68)), P = 0.009.
`Fatigue: Significant diIerence in favour of sildenafil (22.33 (4.82))
`versus placebo (20.67 (SD 5.19)), P = 0.04.
`Emotional function: No significant diIerence between sildenafil
`(37.33 (SD 9.32)) and placebo (34.71 (SD 10.91)), P = 0.06.
`
`Phosphodiesterase 5 inhibitors for pulmonary hypertension (Review)
`Copyright © 2019 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
`
`Borg scores
`in Borg
`reported a significant diIerence
`Bharani 2003
`breathlessness scores ) (Scale 0 10) aLer the 6 minute walk test of
`1.55 (P < 0.01)
`
`Exercise capacity
`This was measured by Sastry 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 by Bharani 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 from Bharani 2003 and Sastry 2004 were pooled with a
`subgroup analysis by etiology (PPH versus mixed population
`studies). With a Fixed EIect 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 EIects 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 diIerent
`baseline arterial pressures in addition to diIerent 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 diIerent responses to treatment.
`
`Sastry 2004 reported a significant diIerence 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 e"ects
`A table of adverse eIects is given in Table 2. No statistical analysis
`was undertaken on the diIerence in the side-eIects in the study.
`No participants withdrew due to side-eIects. One death occurred
`in the placebo group during the first arm of treatment.
`
`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-
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`intervention to give a WMD in favour of high dose sildenafil of
`-15.86% (-30.64 to -1.08). The significant eIect 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 diIerences reported).
`
`Treatment eIects 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-eIects 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 eIects 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 diIer
`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 diIered
`statistically between the groups in favour of sildenafil (p = 0.0005).
`However, no values were reported. Mean PaO2 diIered 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 eIects for sildenafil outlasted the observation period of
`120-150 minutes.
`
`Safety
`No adverse events were reported during combination therapy
`
`D I S C U S S I O N
`
`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 eIects of sildenafil on the course of PH are diIicult
`to draw. Additionally, the participants in all the studies had very
`high pulmonary artery pressures, and in the case of Ghofrani 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 the WHO
`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 eIects observed in the acute studies
`require replication in larger and more rigorously controlled trials,
`but would indicate that there is a vasodilatory eIect in PH when
`sildenafil is administered. Bharani 2003 and Sastry 2004 showed
`diIerences in terms of important outcomes such as symptoms
`and exercise capacity over two and six weeks. Nevertheless,
`these eIects require confirmation on a larger scale, as well as
`its correlation with long term benefits including hospitalisation,
`mortality, and functional class status. Although Sastry 2004
`reported mild side-eIects, the study design and duration means
`that we cannot exclude the possibility that sildenafil may have
`long term side eIects. Data from small non-randomised studies
`in people with PH have not found any systemic side-eIects, such
`as visual disturbance, flushing, headache and dyspepsia (Ghofra