Overview of key studies that have contributed to our understanding of the clinical profile of epoprostenol

Study, first author year [ref.]Aetiology of PAHStudy designTreatments/interventionPatient characteristicsEfficacy assessments/ primary endpoint and key outcomesPVR changesSafety data
Early studies in patients with PAH
 Rubin 1982 [34]IPAHExploratory studyDose-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 hSeven patientsmPAP 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)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)
 Higenbottam 1983 [33]IPAHCase: first report of long-term i.v. epoprostenol therapyContinuous i.v. epoprostenol 4–20 ng·kg−1·min−1Woman with uncontrolled post-partum PHDecreased PVR, improved oxygenation and exercise tolerance allowed patient to live independently at homePVR fell from baseline 25–30 units to 15 units; values maintained over 10 monthsSterile pleural effusion ascites (treated with diuretics); cannula-associated Staphylococcal bacteraemia (resolved by cannula change)
Key RCTs in patients with PAH
 Rubin 1990 [16]IPAH8-week RCT with an 18-month non-RCT extensionContinuous 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 patientsTotal pulmonary resistance significantly decreased on epoprostenolLoose 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
 Barst 1996 [17]IPAH12-week, prospective, multicentre, open-label RCTContinuous 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 alone81 patients with severe disease (NYHA FC III–IV)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)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
 Badesch 2000 [18]PAH secondary to scleroderma12-week, prospective, multicentre, open-label RCTContinuous 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 alone111 patients with moderate-to-severe diseaseExercise 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 FCPVR 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)
Selected non-RCT studies in patients with PAH
 Shapiro 1997 [41]IPAHObservational, single-centre studyContinuous i.v. epoprostenol increased to 1–2 ng·kg−1·min−1 every 2 months69 patients (NYHA FC III–IV); 18 followed for >330 daysSignificant 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%, respectivelyNot reported in detail. One patient discontinued
 McLaughlin 2002 [42]IPAHObservational, single-centre, registry database studyContinuous i.v. epoprostenol162 patients (NYHA FC III–IV), followed for mean 36.3 monthsSignificant 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)PVR at baseline (mean±sd): 16.7±6.4 units versus 10.2±5.4 units at first follow-up (p<0.0001)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)
 Sitbon 2002 [8]IPAHObservational, single-centre studyContinuous i.v. epoprostenol (mean dose 14 ng·kg−1·min−1)178 patients (NYHA FC III–IV), followed for mean±sd 26±21 monthsBaseline 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
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)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
 Bergot 2014 [43]IPAH, heritable or anorexigen-associated PAHObservational, French PH registry study (2006–2010)Continuous i.v. epoprostenol (dose not stated)209 patients (NYHA FC II–IV)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%)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, respectivelyN/A
Selected clinical trials of reformulations
 Tamura 2013 [81]IPAH or heritable PAH12-week, open-label, prospective, single-arm, two-centre exploratory studySwitch 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 doseNo 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 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)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)
 Sitbon 2014 [74]IPAH, heritable PAH, PAH-CTD or PAH associated with drugs/toxins3-month, open-label, prospective, multicentre, single-arm studySwitch to continuous i.v. epoprostenol AS (starting dose±10% of previous epoprostenol dose; six patients required dose adjustment during study)41 patients (NYHA FC I–III) receiving stable epoprostenol doseNo 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 previouslyPVR decreased by 8.0±116.8 dyn·s−1·cm–5 at month 3 (mean±sd)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)
 Provencher 2015 [80]IPAH, heritable PAH or PAH associated with concomitant conditions4-week, open-label, prospective, multicentre, single-arm studySwitch to continuous i.v. pH-adjusted epoprostenol reformulation (started on same dose)16 patients (WHO FC II–III) receiving stable epoprostenol doseNo 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 transitionPVR 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)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.