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 |
Early studies in patients with PAH | |||||||
Rubin 1982 [34] | IPAH | Exploratory study | 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 | Seven patients | 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) | 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] | 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 | Sterile pleural effusion ascites (treated with diuretics); cannula-associated Staphylococcal bacteraemia (resolved by cannula change) |
Key RCTs in patients with PAH | |||||||
Rubin 1990 [16] | IPAH | 8-week RCT with an 18-month non-RCT extension | 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 | Total pulmonary resistance significantly decreased on epoprostenol | 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 |
Barst 1996 [17] | IPAH | 12-week, prospective, multicentre, open-label RCT | 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 | 81 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 scleroderma | 12-week, prospective, multicentre, open-label RCT | 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 | 111 patients with moderate-to-severe disease | 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 | 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) |
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 | 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 | Not reported in detail. One patient discontinued | |
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 | 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) | 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] | 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 | 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 | 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 PAH | Observational, 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, respectively | N/A |
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 | 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 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/toxins | 3-month, open-label, prospective, multicentre, single-arm study | Switch 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 dose | 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 | PVR 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 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 | 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 | 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) | 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.