REVIEW
`PULMONARY ARTERIAL HYPERTENSION
`
`Epoprostenol and pulmonary arterial
`hypertension: 20 years of clinical
`experience
`
`Olivier Sitbon1,2,3 and Anton Vonk Noordegraaf4
`
`Affiliations: 1Universite Paris-Sud, Faculté de Médecine, Université Paris-Saclay, Le Kremlin-Bicêtre, France.
`2AP-HP, Service de Pneumologie, Centre de Référence de l’Hypertension Pulmonaire Sévère, Hôpital Bicêtre,
`Le Kremlin-Bicêtre, France. 3INSERM UMR_S 999, Hôpital Marie-Lannelongue, Le Plessis-Robinson, France.
`4Dept of Pulmonology, Vrje Universiteit Medical Centre, Amsterdam, the Netherlands.
`
`Correspondence: Olivier Sitbon, Service de Pneumologie, Hôpital de Bicêtre, 78 rue Général Leclerc, 94270
`Le Kremlin-Bicêtre, France. E-mail: olivier.sitbon@aphp.fr
`
`@ERSpublications
`The evolution of the place of epoprostenol in the management of pulmonary arterial hypertension
`http://ow.ly/OkY3303N2CX
`
`Cite this article as: Sitbon O, Vonk Noordegraaf A. Epoprostenol and pulmonary arterial hypertension:
`20 years of clinical experience. Eur Respir Rev 2017; 26: 160055 [https://doi.org/10.1183/16000617.0055-
`2016].
`
`ABSTRACT Epoprostenol was the first therapy to be approved for the treatment of pulmonary arterial
`hypertension (PAH). In the 20 years since the introduction of this prostacyclin analogue, the outlook for
`patients with PAH has improved, with survival rates now double those from the era before the
`development of disease-specific treatments. Today, there are a large amount of data on the clinical role of
`prostacyclin treatments and a body of evidence attesting the efficacy of epoprostenol in improving exercise
`capacity, key haemodynamic parameters and PAH symptoms, as well as in reducing mortality. The place
`of epoprostenol in the therapeutic management of PAH continues to evolve, with the development of new
`formulations and use in combination with other drug classes. In this review, we provide a historical
`perspective on the first 20 years of epoprostenol, a therapy that led to evidence-based study of PAH-
`specific treatments and the subsequent expansion of treatment options for PAH.
`
`Introduction
`Pulmonary arterial hypertension (PAH) is a rare, progressive disease associated with significant morbidity
`[1–4]. The disease is characterised by elevated pulmonary artery pressure (PAP) and pulmonary vascular
`resistance (PVR). Left untreated, PAH leads to right-sided heart failure and premature death [1–4]. In the
`1980s, median survival was 2.8 years from diagnosis; the 5-year survival rate was 34% [5]. Although PAH
`remains
`incurable,
`insights
`into the underlying mechanisms have led to the development of
`disease-specific treatments that have approximately doubled survival rates [6–8]. Today there are 10
`approved PAH-specific therapies [9]. The first of these was the prostacyclin analogue epoprostenol, which
`was approved in 1995 in the USA before being licensed, a year later, in Europe. This treatment is still
`regarded as the gold standard to which other therapies should be compared [10–12].
`
`In this review, we take a historical perspective on epoprostenol and its place in PAH management over the
`past 20 years. We also consider the role of epoprostenol at a time when new formulations that are stable at
`room temperature are becoming more widely available. This review is based on our knowledge of the field,
`
`Received: June 02 2016 | Accepted after revision: Aug 28 2016
`
`Conflict of interest: Disclosures can be found alongside this article at err.ersjournals.com
`
`Provenance: Submitted article, peer reviewed.
`
`Copyright ©ERS 2017. ERR articles are open access and distributed under the terms of the Creative Commons
`Attribution Non-Commercial Licence 4.0.
`
`https://doi.org/10.1183/16000617.0055-2016
`
`Eur Respir Rev 2017; 26: 160055
`
`IPR2021-00406
`United Therapeutics EX2051
`
`

`

`PULMONARY ARTERIAL HYPERTENSION | O. SITBON AND A. VONK NOORDEGRAAF
`
`supplemented by a methodical literature search designed to provide a comprehensive historical overview of
`milestones since the approval of epoprostenol. The literature review comprised searches of a database of
`PAH pdf
`files, PubMed, Scopus and the abstract database Searchlight for relevant publications on
`in PAH using “epoprostenol” and “pulmonary arterial hypertension” as keywords. The
`epoprostenol
`period for the PubMed, Scopus and Searchlight searches was 1994 to December 2014 and all English
`language citations were captured. Titles and abstracts of original articles were manually searched and
`potentially relevant articles selected; the authors reviewed the resulting publication list and agreed papers
`of
`interest. Review articles that capture the historical narrative of
`the development and study of
`epoprostenol have been included.
`
`Background
`Impact of epoprostenol on PAH treatment
`Before the approval of epoprostenol, PAH was treated using a combination of non-specific treatments
`including warfarin, calcium-channel blockers, digoxin, diuretics and supplemental oxygen. These therapies
`targeted specific aspects of the disease, but demonstrated little short-term or long-term benefit on major
`haemodynamic parameters or clinical outcomes (reviewed in [3, 13]), with the exception of long-term
`calcium channel blockers that improved outcomes in a majority of patients classed using strong criteria
`such as acute pulmonary vasodilator responders [14]. The introduction of epoprostenol transformed the
`care of patients with PAH [15]: epoprostenol improved exercise capacity, key haemodynamic parameters
`and PAH symptoms [16, 17] and, importantly, was the first pharmacological therapy to reduce mortality
`[18]. Twenty years later, epoprostenol remains the only treatment to have reduced mortality in patients
`with idiopathic PAH (IPAH) in a randomised study [17].
`
`Early studies of epoprostenol improved our understanding of pulmonary hypertension from associated
`causes, and led to evidence-based studies of PAH-specific treatments and the subsequent expansion of
`treatment options for PAH [19, 20]. Lessons learned from studying epoprostenol have informed the
`development of other inhaled, oral and subcutaneously administered prostanoid therapies. More recently,
`epoprostenol and some other prostacylins have been shown to be effective and well tolerated when used in
`combination with other PAH drug classes [21–25]. Therapies previously reserved for patients with severe
`disease are now being considered for use in those with earlier stage disease, in an attempt to further
`prolong life and improve patient outcomes [11, 12, 26, 27].
`
`Current recommendations and evolving terminology
`The 2015 European Society of Cardiology and European Respiratory Society guidelines for the diagnosis and
`treatment of pulmonary hypertension outline the continued place of epoprostenol within treatment options for
`patients with PAH (World Health Organization (WHO) group 1 pulmonary hypertension) [11, 12]. Based on
`level A evidence of efficacy (data derived from multiple randomised clinical
`trials or meta-analyses),
`intravenous epoprostenol is recommended as a class I monotherapy in patients with PAH (WHO group 1)
`with WHO functional class (FC) III or IV. It should also be considered (class IIa) for use in upfront
`combination therapy in patients with WHO FC III or IV alongside bosentan, and alongside bosentan and
`sildenafil, based on level C efficacy evidence (consensus of opinion of experts and/or small studies, retrospective
`studies and registries) [11, 12]. Today, epoprostenol is approved in many countries including the USA where it
`is indicated to improve exercise capacity in patients with WHO group 1 pulmonary hypertension (specifically,
`patients with IPAH, heritable PAH and PAH associated with coexisting conditions such as connective tissue
`disease (PAH–CTD)) based on studies including predominantly patients with New York Heart Association
`(NYHA) FC III–IV symptoms [28]. The term IPAH had not been developed at the time of initial approval of
`epoprostenol; thus, early studies describe patients with primary pulmonary hypertension (PPH) which was the
`preferred term at this time. Current terminology will be used within this review wherever appropriate. WHO
`FC and NYHA FC are used interchangeably when characterising patients with PAH.
`
`Early research and discovery
`The development of epoprostenol stemmed from the discovery of endogenous prostacyclins in the
`vasculature by MONCADA et al. [29] in the 1970s. Soon after this, epoprostenol was synthesised and shown
`to have anti-platelet activity and vasodilatory effects in humans [30–32]. One of the first patients given
`epoprostenol was a young, cyanotic, hospitalised and bed-bound woman with IPAH. Intravenous
`epoprostenol improved haemodynamic parameters and clinical symptoms and the patient was discharged
`to continue long-term treatment [33]. Another early proof-of-concept study involving seven patients with
`IPAH showed that epoprostenol increased cardiac output and reduced PAP and PVR [34]. These and
`other early explorations preceded the innovative clinical studies that
`led to the first approval of
`epoprostenol for the treatment of patients with IPAH in 1995 [16, 17].
`
`https://doi.org/10.1183/16000617.0055-2016
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`PULMONARY ARTERIAL HYPERTENSION | O. SITBON AND A. VONK NOORDEGRAAF
`
`Epoprostenol in profile
`Pharmacology
`Epoprostenol is a synthetic analogue of the naturally occurring eicosanoid prostacyclin (prostaglandin I2
`or PGI2), which is the main metabolite of arachidonic acid [30, 35]. Endogenous prostacyclin is produced
`predominantly by endothelial cells and acts both on local vasculature and on blood cells that adhere to the
`endothelium [26]. In PAH, the normal release of endogenous prostacyclin is depressed and release of the
`vasoconstrictor thromboxane A2 is increased [36]. In addition, pulmonary endothelin-1 homeostasis is
`abnormal, and this may contribute to the progressive rise in PVR that typifies PAH [37].
`
`Prostacyclins (and related prostanoids) have direct and potent vasodilatory effects resulting from their
`action on vascular smooth muscle cells; they inhibit platelet aggregation and thrombus formation, and
`have antiproliferative and anti-inflammatory actions (figure 1) [26, 38]. These effects are mediated via
`G-protein-coupled prostanoid IP receptors
`in blood vessels,
`leukocytes and thrombocytes
`[26].
`Epoprostenol may also have indirect vasodilatory effects owing to inhibition of production of the potent
`vasoconstrictor endothelin-1 [39]. In patients with PAH, therapeutic use of prostanoids is associated with
`immediate vasodilatory action in the pulmonary and systemic circulation and resultant,
`longer-term
`haemodynamic changes that contribute to additional decreases in PVR [26]. It has been suggested that
`indirect positive inotropic effects of therapy may also ameliorate systemic hypotension [26]; however, such
`effects have not been established in any model of chronic pulmonary hypertension, and the effect of
`epoprostenol in chronic pressure overload on the right ventricle remains unknown.
`
`The pharmacokinetic properties of the original formulation of epoprostenol are dominated by the lability
`of the molecule in aqueous fluids at physiological temperature and pH. Epoprostenol has a short
`elimination half-life of approximately 3–6 min in human blood, which necessitates administration via
`continuous intravenous infusion [15]. Treatment has to be initiated by an experienced physician, and
`long-term use requires a permanent central venous catheter and portable infusion pump [11, 12].
`
`Clinical studies with epoprostenol in the treatment of PAH
`Today there is substantial evidence from randomised controlled trials (RCTs) supporting the use of
`prostacyclin treatments in PAH, while data from observational studies and registries provide real-world
`evidence and experiences of patient management (for reviews see [6, 40]). Table 1 provides an overview of
`key studies that have contributed to our understanding of the clinical profile of epoprostenol.
`
`RCTs with epoprostenol in PAH
`Epoprostenol was initially approved for use in patients with “PPH and moderate-to-severe functional
`status”, based on data from two RCTs [16, 17]. The first studied 24 patients with IPAH (NYHA FC II−IV),
`randomised to receive either intravenous epoprostenol or the conventional treatment of the time for
`8 weeks [16]. Epoprostenol was associated with a significant and sustained decrease in total pulmonary
`resistance (–7.9 units; p=0.022) but there was no change for patients on conventional treatment (–0.2
`units), and six out of 10 patients in the epoprostenol group compared with only one out of nine patients in
`the conventional treatment group had reductions in mean PAP (mPAP) of greater than 10 mmHg. This
`study also reported that continued epoprostenol treatment for up to 18 months was associated with
`
`Prostanoids
`
`Vessels
`
`Leukocytes
`
`SMC
`
`Fibroblasts
`
`EC
`
`Platelets
`
`Mono
`
`MA
`
`PMN
`
`T-cells
`
`Vaso-
`dilation
`
`Anti-
`proliferation
`
`Matrix
`secretion
`
`Anti-
`coagulation
`
`NF-κB
`TNF-α
`IL-1
`IL-10
`
`MAPK
`iNOS
`
`Burst
`Elastase/secretion
`Leukotrienes
`
`TNF-α
`IFN-α
`IL-2
`
`FIGURE 1 The effects of prostanoids on vasculature and blood cells; a variety of vascular cells, platelets and leukocytes have been identified as
`targets for the antiproliferative, anti-inflammatory and anti-aggregatory actions of prostaglandins. SMC: smooth muscle cells; EC: endothelial
`cells; Mono: mononuclear cells; NF: nuclear factor; TNF: transforming nuclear factor; IL: interleukin; MA: macrophages; MAPK: mitogen-
`activated protein kinase; iNOS: inducible nitric oxide synthase; PMN: polymorphonuclear neutrophils; Burst: generation of reactive oxygen
`species. Reproduced from [38] with permission from the publisher.
`
`https://doi.org/10.1183/16000617.0055-2016
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`

`

`TABLE 1 Overview of key studies that have contributed to our understanding of the clinical profile of epoprostenol
`
`Study, first author year [ref.]
`
`Aetiology of PAH
`
`Study design
`
`Treatments/intervention
`
`Patient characteristics
`
`Efficacy assessments/ primary
`endpoint and key outcomes
`
`PVR changes
`
`Safety data
`
`PULMONARY ARTERIAL HYPERTENSION | O. SITBON AND A. VONK NOORDEGRAAF
`
`Headache (n=6); nausea (n=4);
`vomiting (n=2); cutaneous
`flushing (n=5); diplopia (n=1,
`resolved on discontinuation);
`systemic hypertension
`during dose-ranging (n=2;
`resolved on discontinuation);
`temporary significant
`reduction in systemic blood
`pressure during continuous
`infusion (n=1)
`Sterile pleural effusion ascites
`(treated with diuretics);
`cannula-associated
`Staphylococcal bacteraemia
`(resolved by cannula
`change)
`
`Loose stools (100%), jaw pain
`(57%) and photosensitivity
`(36%) were common with
`epoprostenol. One patient
`discontinued owing to
`pulmonary oedema; most
`complications were linked
`with the drug-delivery
`system
`
`Continued
`
`Early studies in patients
`with PAH
`RUBIN 1982 [34]
`
`IPAH
`
`Exploratory study
`
`Seven patients
`
`Dose-ranging protocol
`(starting dose
`2 ng·kg−1·min−1 to
`maximum
`12 ng·kg−1·min−1) and
`continuous i.v.
`epoprostenol in three
`patients for up to 48 h
`
`mPAP decreased in six out of seven
`patients and total pulmonary
`resistance decreased by >20%
`in all patients; cardiac output
`and stroke volume increased
`by >40%
`
`Total pulmonary
`resistance 17.1±8.7
`units at baseline versus
`9.7±5.9 units following
`epoprostenol infusion
`(mean±SD)
`
`HIGENBOTTAM 1983 [33]
`
`IPAH
`
`Key RCTs in patients
`with PAH
`RUBIN 1990 [16]
`
`IPAH
`
`Case: first report of
`long-term i.v.
`epoprostenol therapy
`
`Continuous i.v.
`epoprostenol 4–
`20 ng·kg−1·min−1
`
`Woman with uncontrolled
`post-partum PH
`
`Decreased PVR, improved
`oxygenation and exercise
`tolerance allowed patient to live
`independently at home
`
`PVR fell from baseline 25–
`30 units to 15 units;
`values maintained over
`10 months
`
`8-week RCT with an
`18-month non-RCT
`extension
`
`Total pulmonary
`resistance significantly
`decreased on
`epoprostenol
`
`Continuous i.v.
`epoprostenol (starting
`dose 1–2 ng·kg−1·min−1)
`versus conventional
`treatment (optimum
`doses of oral
`vasodilators,
`anticoagulants,
`supplemental oxygen,
`cardiac glycosides and
`diuretics)
`
`24 patients (NYHA FC II–IV) Epoprostenol significantly
`decreased total pulmonary
`resistance after 8 weeks
`(decrease of 7.9 units from
`baseline of 21.6 units) (p=0.022)
`versus conventional therapy
`(decrease of 0.2 units from
`baseline of 20.6)
`(non-significant). Six out of 10
`patients receiving epoprostenol
`showed >10 mmHg reductions in
`mPAP versus one out of nine
`patients on conventional
`treatment (p=0.057).
`Haemodynamic improvements
`were maintained over 18 months
`in nine patients
`
`https://doi.org/10.1183/16000617.0055-2016
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`

`

`TABLE 1 Continued
`
`Study, first author year [ref.]
`
`Aetiology of PAH
`
`Study design
`
`Treatments/intervention
`
`Patient characteristics
`
`Efficacy assessments/ primary
`endpoint and key outcomes
`
`PVR changes
`
`Safety data
`
`PULMONARY ARTERIAL HYPERTENSION | O. SITBON AND A. VONK NOORDEGRAAF
`
`Exercise capacity by 6MWD
`(primary endpoint): patients on
`epoprostenol (n=41) showed
`improvements in median change
`in distance walked from baseline
`to week 12 (median increase,
`31 m; median distance of 315 m
`at baseline, 362 m at 12 weeks)
`versus conventional therapy
`(median decrease, 29 m; median
`distance of 270 m at baseline,
`204 m at 12 weeks) (p<0.002,
`nonparametric analysis). Mean
`distance walked increased by
`32 m in the epoprostenol group
`(316 m at baseline; 348 m at
`week 12) and decreased by 15 m
`in the conventional therapy
`group (272 m at baseline; 257 m
`at week 12) (p<0.003, parametric
`analysis). mPAP changes: –8%
`for epoprostenol versus +3% for
`conventional therapy (difference
`in mean change, −6.7 mmHg;
`95% CI, –10.7 to −2.6 mmHg;
`p<0.002). Indices of HRQoL
`improved in the epoprostenol
`group (p<0.01). Eight deaths in
`conventional therapy group
`versus no mortality in
`epoprostenol group (p=0.003)
`Exercise capacity by 6MWD
`(primary endpoint): patients on
`epoprostenol (n=56) showed
`improvements from baseline
`(median, 270 m) to week 12
`(316 m) versus conventional
`therapy (240 m at baseline;
`192 m at week 12) (difference in
`median distance walked, 108 m,
`95% CI, 55.2–180.0 m, p<0.001).
`Change from baseline in mPAP:
`epoprostenol, −5.03±1.09 mmHg
`versus conventional therapy,
`+0.94±1.10 mmHg (difference
`between groups, −5.97 mmHg;
`95% CI, −8.98 to −2.96). 21
`patients on epoprostenol versus
`zero patients on conventional
`therapy showed improvements in
`NYHA FC
`
`mPVR changes of −21%
`for epoprostenol versus
`+9% for conventional
`therapy (difference in
`mean change:
`−4.9 mmHg·L−1·min−1;
`95% CI: −7.6 to −2.3;
`p<0.001)
`
`Jaw pain, diarrhoea, flushing,
`headaches, nausea and
`vomiting were frequent.
`Four episodes of
`catheter-related sepsis; one
`thrombotic event. Delivery
`system-related issues
`included device malfunction
`(n=26) and irritation/
`infection (n=7), bleeding
`(n=4) and pain (n=4) at
`catheter site
`
`PVR change from baseline:
`epoprostenol −4.58
`±0.76 mmHg·L−1·min−1
`versus conventional
`therapy 0.92±0.56
`mmHg·L−1·min−1
`(mean±SE) (difference,
`−5.50 mmHg·L−1·min−1;
`95% CI, −7.33 to −3.67)
`
`Jaw pain (75% versus 0%),
`anorexia (66% versus 47%),
`nausea (41% versus 16%),
`diarrhoea (50% versus 5%)
`and depression (13% versus
`4%) more common in
`epoprostenol versus
`conventional therapy group,
`respectively. Drug-delivery
`system associated with eight
`catheter-related AEs,
`including sepsis, cellulitis,
`haemorrhage and
`pneumothorax (4% each)
`
`Continued
`
`BARST 1996 [17]
`
`IPAH
`
`12-week, prospective,
`multicentre, open-label
`RCT
`
`81 patients with
`severe disease
`(NYHA FC III–IV)
`
`Continuous i.v.
`epoprostenol (starting
`dose 2 ng·kg−1·min−1
`to maximum
`tolerated dose of
`9.2±0.5 ng·kg−1·min−1)
`plus conventional
`treatment
`(anticoagulants, oral
`vasodilators, diuretic
`agents, cardiac
`glycosides and
`supplemental oxygen)
`versus conventional
`treatment alone
`
`BADESCH 2000 [18]
`
`PAH secondary to
`scleroderma
`
`12-week, prospective,
`multicentre, open-label
`RCT
`
`111 patients with
`moderate-to-severe
`disease
`
`Continuous i.v.
`epoprostenol (starting
`dose ⩽2 ng·kg−1·min−1
`to mean dose
`11.2 ng·kg−1·min−1 at
`week 12) plus
`conventional treatment
`versus conventional
`treatment alone
`
`https://doi.org/10.1183/16000617.0055-2016
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`5
`
`

`

`TABLE 1 Continued
`
`Study, first author year [ref.]
`
`Aetiology of PAH
`
`Study design
`
`Treatments/intervention
`
`Patient characteristics
`
`Efficacy assessments/ primary
`endpoint and key outcomes
`
`PVR changes
`
`Safety data
`
`PULMONARY ARTERIAL HYPERTENSION | O. SITBON AND A. VONK NOORDEGRAAF
`
`Not reported in detail. One
`patient discontinued
`
`Local infections at catheter site
`(119 episodes; 0.24 per
`person-year), sepsis (70
`episodes; 0.14 per
`person-year), tunnel
`infections (10 episodes; 0.02
`per person-year), catheter
`replacement required (72
`instances; 0.15 per
`person-year)
`
`Jaw pain, headache, diarrhoea,
`flushing, leg pain and
`nausea/vomiting were
`common. Catheter-related
`sepsis (76 episodes in 53
`patients; 0.19 per
`patient-year); four deaths
`due to severe
`catheter-related infections
`(three were nosocomial
`infections acquired in
`intensive care); seven
`deaths due to severe
`pulmonary oedema
`N/A
`
`PVR at baseline (mean±SD):
`16.7±6.4 units versus
`10.2±5.4 units at first
`follow-up (p<0.0001)
`
`Total pulmonary
`resistance (mean±SD):
`37.3±10.5 units·m−2 at
`baseline; 25.4
`±6.6 units·m−2 at
`3 months; 25.0
`±6.9 units·m−2 at 1 year,
`(both p<0.0001 versus
`baseline)
`
`PVR decreased by
`700 dyn·s−1·cm–5
`(p<0.0001) and
`299 dyn·s−1·cm–5
`(p=0.009) in
`treatment-naïve and
`treatment-experienced
`patients, respectively
`
`Significant reduction in maximum
`systolic pressure gradient
`between right ventricle and right
`atrium (from mean±SD 84.1±24.1
`to 62.7±18.2 mmHg; p<0.01). 1-,
`2- and 3-year survival rates:
`80%, 76% and 49%, respectively
`Significant changes in mean right
`atrial pressure, mPAP, cardiac
`output, cardiac index and PVR
`between baseline and first
`follow-up (all p<0.0001). 1-, 2-
`and 3-year survival rates: 87.8%,
`76.3% and 62.8%, respectively
`versus expected survival of
`58.9%, 46.3% and 35.4%,
`respectively (p<0.001 at
`all time points)
`Baseline 6MWD (mean±SD): 251
`±144 m; 3 month 6MWD: 376
`±114 m (p<0.001), with 90% of
`patients achieving an
`improvement in 6MWD. Among
`patients on epoprostenol for
`1 year, mPAP, cardiac index,
`oxygen saturation and total
`pulmonary resistance
`significantly changed from
`baseline at 3 months and 1 year.
`1-, 2-, 3- and 5-year survival
`rates: 85%, 70%, 63% and 55%,
`respectively
`Improvements in haemodynamic
`parameters and clinical
`outcomes reported according to
`whether patients were
`treatment-naïve or
`treatment-experienced (previous
`PAH therapy). 4 months of
`epoprostenol increased 6MWD
`by 146 m (p<0.0001) and by 41 m
`(p=0.03) in treatment-naïve and
`treatment-experienced patients,
`respectively. 1-year and 3-year
`survival rates from treatment
`initiation were 84% and 69%,
`respectively. Greatest survival
`benefit was in treatment-naïve
`patients given upfront
`combination epoprostenol plus
`oral therapy (1-year survival,
`92%; 3-year survival, 88%)
`
`Continued
`
`Selected non-RCT studies in
`patients with PAH
`SHAPIRO 1997 [41]
`
`IPAH
`
`Observational,
`single-centre study
`
`Continuous i.v.
`epoprostenol increased
`to 1–2 ng·kg−1·min−1
`every 2 months
`
`69 patients (NYHA FC III–
`IV); 18 followed for
`>330 days
`
`MCLAUGHLIN 2002 [42]
`
`IPAH
`
`Observational,
`single-centre, registry
`database study
`
`Continuous i.v.
`epoprostenol
`
`162 patients (NYHA FC III–
`IV), followed for mean
`36.3 months
`
`SITBON 2002 [8]
`
`IPAH
`
`Observational,
`single-centre study
`
`Continuous i.v.
`epoprostenol (mean
`dose 14 ng·kg−1·min−1)
`
`178 patients (NYHA FC III–
`IV), followed for mean
`±SD 26±21 months
`
`BERGOT 2014 [43]
`
`IPAH, heritable or
`anorexigen-associated
`PAH
`
`Observational, French PH
`registry study (2006–
`2010)
`
`Continuous i.v.
`epoprostenol (dose not
`stated)
`
`209 patients (NYHA FC II–
`IV)
`
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`PULMONARY ARTERIAL HYPERTENSION | O. SITBON AND A. VONK NOORDEGRAAF
`
`TABLE 1 Continued
`
`Study, first author year [ref.]
`
`Aetiology of PAH
`
`Study design
`
`Treatments/intervention
`
`Patient characteristics
`
`Efficacy assessments/ primary
`endpoint and key outcomes
`
`PVR changes
`
`Safety data
`
`Selected clinical trials of
`reformulations
`TAMURA 2013 [81]
`
`IPAH or heritable PAH
`
`12-week, open-label,
`prospective,
`single-arm, two-centre
`exploratory study
`
`Switch to continuous i.v.
`epoprostenol AS
`(started on same dose;
`mean starting dose
`40.13 ng·kg−1·min−1)
`
`Eight patients (NYHA FC I–
`III) receiving stable
`epoprostenol dose
`
`SITBON 2014 [74]
`
`IPAH, heritable PAH,
`PAH-CTD or PAH
`associated with drugs/
`toxins
`
`3-month, open-label,
`prospective,
`multicentre, single-arm
`study
`
`41 patients (NYHA FC I–III)
`receiving stable
`epoprostenol dose
`
`Switch to continuous i.v.
`epoprostenol AS
`(starting dose±10% of
`previous epoprostenol
`dose; six patients
`required dose
`adjustment during
`study)
`
`PROVENCHER 2015 [80]
`
`IPAH, heritable PAH or
`PAH associated with
`concomitant conditions
`
`4-week, open-label,
`prospective,
`multicentre, single-arm
`study
`
`Switch to continuous i.v.
`pH-adjusted
`epoprostenol
`reformulation (started
`on same dose)
`
`16 patients (WHO FC II–III)
`receiving stable
`epoprostenol dose
`
`PVR was 448.3
`±158.1 dyn·s−1·cm−5 at
`baseline and 453.6
`±175.3 dyn·s−1·cm−5 at
`week 12 (mean±SD)
`
`No significant changes in
`haemodynamic factors or
`NT-proBNP concentrations from
`baseline to week 12; WHO FC
`also remained unchanged
`Patient-reported improvement in
`convenience on TSQM-9
`(p=0.0313). No unexpected safety
`or tolerability concerns after
`switching formulations
`
`PVR decreased by 8.0
`±116.8 dyn·s−1·cm–5 at
`month 3 (mean±SD)
`
`PVR was 8.4
`±5.5 mmHg·L−1·min−1
`at baseline and 6.9
`±3.6 mmHg·L−1·min−1
`2-h post transition
`(mean±SD)
`
`No clinically relevant changes in
`haemodynamics, exercise
`tolerance or NT-proBNP from
`baseline to month 3; NYHA FC
`improved in one patient and
`worsened in four patients.
`Patient-reported improvement in
`convenience on TSQM-9 (mean
`score change, +12.7±20.0 (95%
`CI, 6.1–19.3). Adverse events
`consistent with those described
`previously
`No significant changes in
`Short-Form 36 scores, 6MWD,
`Borg dyspnoea index,
`NT-proBNP or dose of
`epoprostenol after 4 weeks
`versus baseline; WHO FC
`improved in one patient. Small
`improvements in mean scores
`on most questions in 15-item
`study-specific HRQoL
`questionnaire; 14 out of 16
`patients preferred the
`reformulated product to the
`previous formulation. No
`significant changes in
`haemodynamic parameters in
`patient subgroup assessed 2 h
`post transition
`
`18 adverse events experienced
`in seven patients;
`gastrointestinal disorders
`(six events in five patients);
`infections/infestations (three
`events in three patients);
`skin/subcutaneous
`disorders (three events in
`two patients), ear-related
`(one event); musculoskeletal
`(one event); nervous system
`(one event); respiratory (one
`event); device-related (two
`events in two patients)
`Adverse events occurring in
`>5% of patients included:
`headache (n=12),
`nasopharyngitis (n=7), jaw
`pain (n=6), flushing/hot
`flush (n=6), dyspnoea (n=5),
`device connection issue
`(n=3), epistaxis (n=3),
`extremity pain (n=3) and
`palpitations (n=3)
`
`Three and nine patients
`experienced adverse events
`during run-in and treatment
`phases, respectively. Severe
`events reported were not
`considered related to study
`drug and included
`device-related infections
`(n=2) in run-in period and
`back pain (n=1) in treatment
`period; proportions with
`adverse events considered
`related to study drug were
`similar in run-in and
`treatment periods (one
`versus three subjects,
`respectively)
`
`This table does not represent a comprehensive list of all clinical studies on epoprostenol. PAH: pulmonary arterial hypertension; RCT; randomised clinical trial; IPAH: idiopathic PAH;
`mPAP: mean pulmonary arterial pressure; PH: pulmonary hypertension; PVR: pulmonary vascular resistance; NYHA FC: New York Heart Association Functional Class; 6MWD: 6-min
`walking distance; HRQoL: health-related quality of life; mPVR: mean PVR; AE: adverse event; N/A: not applicable; NT-proBNP: N-terminal prohormone of brain natriuretic peptide; PAH-
`CTD: PAH associated with connective tissue disease; TSQM-9: treatment satisfaction questionnaire for medication; WHO: World Health Organization.
`
`https://doi.org/10.1183/16000617.0055-2016
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`PULMONARY ARTERIAL HYPERTENSION | O. SITBON AND A. VONK NOORDEGRAAF
`
`persistent haemodynamic effects (table 1) [16]. The second, pivotal RCT was a study in 81 patients with
`IPAH (NYHA FC III or IV) that compared treatment with intravenous epoprostenol for 12 weeks in
`addition to conventional therapy with conventional therapy alone (table 1) [17]. This study demonstrated
`that epoprostenol treatment improved exercise capacity as shown by a median increase from baseline in
`6-min walking distance (6MWD) of 31 m for patients receiving epoprostenol compared with a decrease of
`29 m for those receiving conventional
`therapy alone (p<0.002). Key cardiopulmonary variables also
`improved significantly in the epoprostenol-treated group, with a change in mPAP of –8% compared with
`+3% in the conventional therapy group (p<0.002), and a significant mean change in PVR of –21% in those
`receiving epoprostenol versus +9% with conventional therapy alone (p<0.001). This study also reported that
`treatment with epoprostenol conferred a survival advantage over conventional therapy alone, with eight
`patients on conventional therapy dying during the study compared with none in the epoprostenol-treated
`group (p=0.003). This remains the only RCT in which a treatment approved for PAH reduced mortality.
`
`In 2000, another pivotal RCT in patients with moderate-to-severe PAH (patients with PAH due to scleroderma
`(PAH–CTD)), was published (table 1) [18]. This study involved 111 patients randomised to receive continuous
`epoprostenol plus conventional therapy or conventional therapy alone for 12 weeks. Epoprostenol treatment was
`associated with significant improvements in exercise capacity at 12 weeks as demonstrated by a median change
`from baseline in 6MWD of +63.5 m in the epoprostenol group compared with –36.0 m in the conventional
`treatment only group (p<0.001). Patients receiving epoprostenol experienced improvements in haemodynamic
`parameters compared with those on conventional therapy alone, achieving a change from baseline in mPAP of
`–5.03 mmHg compared with +0.94 mmHg in the conventional therapy only group, and a mean change from
`
`
`
`−1·min−1 compared with +0.92 mmHg·L−1·min−1 for the
`baseline in PVR at 12 weeks of –4.58 mmHg·L
`conventional treatment only group. Long-term outcome data showed improved survival in patients receiving
`epoprostenol during a 3-year extension period compared with historical controls [44].
`
`Non-RCTs and observational studies
`There is a strong body of evidence from non-RCTs showing that long-term treatment with continuous
`intravenous
`epoprostenol
`is
`associated with sustained improvements
`in exercise
`capacity and
`haemodynamic parameters. Some studies also reported improved survival in epoprostenol-treated patients
`compared with historical controls and have supported the role of epoprostenol as a bridge to lung
`transplantation or heart and lung transplantation [8, 41–43, 45–49]. One of the earliest non-RCTs to
`describe long-term outcomes of epoprostenol therapy was an open-label, multicentre, uncontrolled study
`in 18 patients with IPAH (NYHA FC II−IV) [45]. This study reported that improvements in the primary
`endpoint, change in 6MWD from baseline at 6 months, were sustained at 18 months, and demonstrated
`that haemodynamic improvements, such as an increase in cardiac index and reduction in total pulmonary
`resistance, were maintained over 12 months of treatment. Furthermore, in the 17 patients with NYHA FC
`III−IV followed for 37−69 months, survival was significantly improved compared with historical controls
`who had not received PAH-specific therapy (p=0.045) [45]. The literature also includes reports from
`small-scale studies of the short- and long-term benefits of continuous intravenous epoprostenol in patients
`with PAH–CTD associated with scleroderma and systemic lupus erythematosus [50–53].
`
`The survival benefits of long-term treatment with epoprostenol were also highlighted by an early US
`followed 69 patients with IPAH (NYHA FC III–IV)
`observational
`study that
`[41]. Continuous
`epoprostenol therapy decreased PAP and was associated with 1-, 2- and 3-year survival rates of 80%, 76%
`and 49%, respectively, compared with historical cohort survival rates of 56% at 20 months and 47% at
`30 months [41]. Subsequently, data from two other single-centre non-RCTs also reported improved
`survival in IPAH cohorts treated with long-term epoprostenol. One study that followed 162 consecutive
`patients with IPAH reported that continuous epoprostenol treatment for at least 1 year resulted in
`significantly greater survival rat