| Study characteristics | Patients | Outcome measures | Side effects | Comments | |||||||
| Rubin et al 1990115 P R OL De novo Epoprostenol vs supportive therapy Duration: 8 weeks 6–18 month extension Outcomes: 1. Haemodynamics 2. FC, 6MWD | n = 24 IPAH 24 Age FC II:III:IV 6MWD MPAP TPR Svo2 CO | Post 8 weeks: 1 withdrawal 4 deaths (3 placebo, 1 Epo) | Diarrhoea 100% Jaw pain 57% Photosensitivity 36% Thrombophlebitis 1 Pump malfunction 5 Catheter replacement 8 | Follow-up up to 18 months with sustained effect (dose increases required—doubled every 6 months) | |||||||
| Supp 35 1:6:5 205 62 1752 62% 3.2 | Epo 37 1:10:1 246 60 1736 60% 3.2 | Mean dose: 7.9 ng/kg/min | |||||||||
| 6MWD FC improved mPAP TPR CO | Supp 292 +2 0 −16 +0.4 | Epo 378 +10 −9 −616 +0.6 | Treatment effect +88 ** −9 −600 +0.2 | ||||||||
| Barst et al 199611 P R OL De novo Epoprostenol vs supportive therapy Duration: 12 weeks Outcomes: 1. 6MWD 2. Survival, QoL, haemodynamics | n = 81 (M 22, F 59) IPAH 81 Age FC III/IV 6MWD RAP MPAP PVR Svo2 CI | Post 12 weeks: 3 transplants during study (1 Epo, 2 Supp) 2 withdrawals from Epo group | Minor complications “frequent” 4 non-fatal sepsis 1 non-fatal thrombosis 7 site infections 4 catheter site pain 4 catheter site bleeding | Statistically significant survival benefit for Epo at 12 weeks. All components of Chronic Heart Failure questionnaire, Dyspnoea-Fatigue Score and 4/6 components of Nottingham Health Profile showed significant improvement in Epo group | |||||||
| Supp 40 29/11 272 12 59 1280 59 2.1 | Epo 40 31/10 316 13 61 1280 62 2.0 | Mean dose: 9.2 ng/kg/min | |||||||||
| 6MWD FC improved QOL RAP MPAP PVR Svo2 CI Survival | Supp 257 1 nc +0.1 +1.9 +120 −2.6% −0.2 Supp 80% | Epo 348 16 Improved −2.2 −4.8 −272 1.2% 0.3 | Treatment effect +91* * ** ns ns -4.9* ns 0.5* | ||||||||
| Epo 100%* | |||||||||||
| Badesch et al 2000112 P R OL Epoprostenol + supportive therapy vs supportive therapy alone for scleroderma Duration: 12 weeks Outcomes: 1. 6MWD 2. Haemodynamics, BORG score, FC, Raynaud’s score | n = 111 (M 15, F 96) SSc 111 (70% limited disease) Age FC II:III:IV 6MWD RAP MPAP PVR Svo2 CI | Post 12 weeks: 9 deaths (Supp 5, Epo 4) | Syncope | Supp 11 | Epo 4 | Patients who died tended to have a longer duration of scleroderma spectrum symptoms despite similar duration of pulmonary hypertension. Improvements in Dyspnoea-Fatigue score and BORG score were noted within 6 weeks of starting therapy. | |||||
| Supp 57 4:45:6 240 11 49 896 59 2.2 | Epo 53 1:42:13 271 13 51 1136 57 1.9 | Mean dose: NR | Ascites Anorexia Diarrhoea Jaw pain Depression | 33 25 3 0 4 | 23 37 28 42 7 | ||||||
| 6MWD FC improved BORG Score Raynaud’s score RAP MPAP PVR Svo2 CI | Supp 192 0 +1.0 43.1 +1 +1 +72 −1% −0.1 | Epo 316 21 −2.0 52.3 −1 −5 −366 +4% +0.5 | Treatment effect +108* * −3.0 ** ns ns −440* +5* +0.6* | ||||||||
| Pneumothorax 2 Sepsis 2 Exit site infection 2 | |||||||||||
| Higgenbottam et al 1998119 P R OL Cross over design IV epoprostenol vs IV iloprost Duration: 4 weeks Outcomes: 1–12MWD | n = 8 (M 4, F 4) IPAH 5, CTEPH 3 Age FC III: IV 12MWD RAP MPAP PVR Svo2 CI | Similar effects during acute testing Mean duration of cross over 7 weeks | Not reported. “Headaches, diarrhoea and abdominal pain may occur initially” | Limited sample size. Iloprost twice as potent at Epo as an acute vasodilator | |||||||
| 38 5:3 407 10 67 1360 59% 1.7 | Epo IV Ilo Dose 8.7 2.1(ng/kg/min)12MWD 591 602 | ||||||||||
| No deterioration in symptoms or exercise capacity after cross-over period All patients on calcium blockers (n = 5) improved on iloprost | |||||||||||
| Simonneau et al 2002116 (UT15 Study) P R DB SC treprostinil vs supportive Duration: 16 weeks Outcomes: 1. 6MWD 2. Haemodynamics, FC, MLHF QoL, composite symptom score | n = 470 (M 87, F 382) IPAH 270; CTD 90; CHD 109 Age FC II:III:IV 6MWD RAP MPAP PVRI Svo2 CI | After 16 weeks: 14 deaths, 7 in each group | Withdrawals | Pbo 1 | Tre 18 | Only 22% achieved target dose of 14 ng/kg/min in Tre group. Change in 6MWD strongly dose dependant—36 m for >13.8 ng/kg/min. Most severe patients (baseline 6MWD <150) had greatest treatment effect (+51m). Trend towards improved physical dimension and global MLHF QoL score for Tre group | |||||
| Pbo 44 28:192:16 327 10 60 2000 60% 2.3 | Tre 45 25:190:16 326 10 62 2080 62% 2.4 | Mean dose Tre 9.3 ng/kg/min | Infusion pain Site reaction Diarrhoea Jaw pain Vasodilation Oedema | 62 62 36 11 11 6 | 200 196 58 31 25 21 | ||||||
| 6MWD MLHF QOL score Composite symptom score RAP mPAP PVRI Svo2 CI | Pbo 0 +0.9 +1.4 +0.7 +96 −1.4% −0.1 | Tre 10 −0.1 −0.5 −2.3 −280 +2% +0.1 | Treatment effect +16* ns +1.0* −1.9* −3* −376* −3.4%* +0.2* | ||||||||
| Infusion system malfunction common (24 vs 33%) | |||||||||||
| Olschewski et al 2002114 (AIR Study) P R OL Nebulised iloprost vs placebo Duration: 12 weeks Outcomes: 1. 6MWD 2. Haemodynamics, composite endpoint | n = 203 (M 66, F 137) IPAH 102, CTD 37, anorex 9, CTEPH 57 Age FC III:IV 6MWD RAP MPAP PVR CO | Post 12 weeks: Mean frequency of inhalation 7.5×/day Median inhaled dose 30 μg/day | “Serous adverse effects similar” | Improvements most marked in IPAH group Combined end point comprising: • Improvement in FC • >10% improvement in 6MWD • Lack of clinical deterioration | |||||||
| Right heart failure Syncope Cough Headache Flushing Hypotension Jaw pain Diarrhoea Nausea Vertigo | Pbo 10% 0 26% 20% 9% 6% 3% 11% 8% 11% | Ilo 4% 5%** 39%** 30% 27%* 11% 12%** 9% 13% 7% | |||||||||
| Supp 53 59:43 315 8 54 1041 3.8 | Ilo 51 60:41 332 9 53 1029 3.8 | 5 deaths (4 Pbo, 1 Ilo) | |||||||||
| Improved FC 6MWD Combined endpoint EuroQoL RAP mPAP PVR Svo2 CO | Pbo 13% NR 5% +7 +1.4 −0.2 +96 −3% −0.2 | Ilo 24% NR 17% −1 +0.5 -0.1 −9* −1% +0.1** | Treatment effect +36* +8** ns ns −103 ns +0.3 | ||||||||
| Flushing and jaw pain usually transient | |||||||||||
Trial design: DB, double blind; E, extension; NR, not randomised; OL, open label; P, prospective; Pbo, placebo controlled; pt, patient; R, randomised; Re; retrospective.
Treatments: Bos (), bosentan (daily dose); Epo (), epoprostenol (ng/kg/min); IV Ilo (), intravenous iloprost (ng/kg/min); Neb Ilo (), nebulised iloprost (daily dose in μg); Sild (), sildenafil (daily dose in mg); Sitax (), sitaxsentan (daily dose in mg); Supp, supportive; Trep, trepostinil.
Conditions: APAH, associated pulmonary arterial hypertension (connective tissue disease, repaired congenital heart disease, HIV infection or anorexigen use); ASD, atrial septal defect; CHD, congenital heart disease; CTD, connective tissue disease; CTEPH, chronic thromboembolic pulmonary hypertension; IPAH, idiopathic pulmonary arterial hypertension; PoPH, porto-pulmonary hypertension; VSD, ventricular septal defect.
Parameters: 6MWD, 6 min walk distance (metres); AT, anaerobic threshold; BDI, Borg dyspnoea index; CI cardiac index (l/min/m2); CW, clinical worsening; F, female; FC, functional class; I/II/III/IV functional classes I/II/III/IV; m, male; mPAP, mean pulmonary arterial pressure (mm Hg); PFI, pulmonary flow index (l/min/m2); PVR, pulmonary vascular resistance (dyn.s/cm5); PVRI, pulmonary vascular resistance index (dyn.s/cm5/m2); Svo2, mixed venous oxygen saturation; QoL quality of life; RAP, right atrial pressure (mm Hg); SBP, systolic (systemic) blood pressure; SF-36, Medical Outcomes Study 36-item short-form health survey; SFI, systemic flow index (l/min/m2); Sp o2, peripheral oxygen saturations; TCW, time to clinical worsening; TPR, total pulmonary resistance; ‡ Trough haemodynamics – measurements taken before Iloprost nebulisation; Ve/Vco2 ventilatory efficiency; Vo2max, maximal oxygen uptake on cardiopulmonary exercise testing (ml/min/kg); BNP, B-type natriuretic peptide.
Statistics: NS non-significant (p>0.05); NR data not reported; *p<0.01; **p<0.05. Miscellaneous: HLTx, heart–lung transplantation; PEA, pulmonary endarterectomy; PT, patient; ULN, upper limit of normal.