| Barst et al 1994117 P NR OL De novo epoprostenol Long term follow-up (up to 69 months) | n = 18 (M 6, F 12) IPAH 18 | Post 1 year: 2 deaths Mean dose: 17.6 ng/kg/min | “Minor complications common” 7 non-fatal sepsis 2 deaths due to pump failure Clotting of line 5 Catheter replacement 3 | Survival includes patients who were transplanted (8/18 patients) Survival strongly associated with NYHA class at baseline. |
| Age FC II:III:IV 6MWD RAP MPAP TPR SvO2 CI | Epo 36 1:13:4 264m 11 61 1760 59% 1.9 |
| 6MWD RAP mPAP TPR SvO2 CI | 6 months 370 −4 −6 −560 +8% +0.4 | 12 months 348 −3 −7 −640 +5% +0.6 |
| Long term follow-up (mean duration Epo 17 months) 4 deaths, 8 transplanted |
| Survival 1 year 2 year 3 year | NIH predicted 77% 41% 27% | Epo 87% 72% 63% |
| Higgenbottam et al 1998113 R NR OL Epoprostenol 61 Iloprost 13 Supportive 24 No therapy 48 Duration: up to 3 years | n = 146 (M 54, F 92) IPAH 98; CTD 9; CTEPH 39 | 72 died 22 transplanted, 2 pulmonary endarterectomy Median survival 695 days Predictors of death: Svo2, PVR, FC III or IV, supportive therapy For patients with Svo2 <60%, median survival: Prostanoid group: 585 days Supportive group: 239 days | NR | Only 9% of patients with FC II were given prostanoids vs 64% of FC III or IV No difference in survival when stratified for acute responder status |
| Age FC I/II:III/IV RAP MPAP PVR CI Svo2 | Supp 43 32:39 8 58 14.6 2.1 63% | Prost 34 3:69 12 67 18.7 1.7 57 |
| Rozenweig et al 1999125 P NR OL IV epoprostenol (failed supportive therapy) in congenital heart disease Duration: 12 months | n = 20 (M 8, F 12) CHD 20 | Post 1 year: 1 patient died during follow up FC improved in 14, unchanged in 5 Mean dose: 82 ng/kg/min | No change in mean systolic pressure with chronic use Jaw pain 8 Rash 8 Arthralgia 6 Nausea 2 Dislodged catheter 7 Local line infection 4 Sepsis 0 Pump malfunction 2 | A mixed group of patients including 11 patients who had undergone surgical repair of defects; 4 had had surgery within the previous year |
| Age FC II:III:IV 6MWD RAP MPAP PVRI Svo2 CI | Epo 15 3:10:7 408 m 6 77 25 64% 3.5 |
| 6MWD RAP MPAP PVRI Svo2 CI | Epo 460m +2 −16 −12 +6% +2.4 | p Value ns * * * * |
| Long term outcome (16 months to 5.5 years) 3 transplanted, 1 death |
| McLaughlin et al 199911 P NR OL Epoprostenol for secondary pulmonary hypertension Duration: 12 months | n = 33 (M 7; F 26) CHD 7; CVD 14; CTEPH 3; PoPH 7 | Post 12 months: 3 patients died | 1 death due to pump failure Side-effects “common”: diarrhoea, jaw pain, headaches, flushing 7 patients had local exit site infections 3 patients had sepsis Incidence of infection: Exit site: 0.38 per patient year Sepsis: 0.09 per patient year | Walk distance not reported No patients transplanted |
| Age FC III:V RAP MPAP PVR Svo2 CO | Epo 43 13:20 13 60 1143 54% 3.9 | FC II:III:IV RAP MPAP PVR Svo2 CO | Epo 3:16:1 −3 −14 −568 +10% +2.4 | p value ns * * * * |
| Long term outcome: 6 deaths within 18 month period |
| Sitbon et al 200215 P NR OL E Long term IV Epoprostenol Duration: up to 98 months | n = 178 (M 43, F 135) IPAH 178 | Mean follow up 26 months (range 0.5 to 98) Mean dose Epo 14.4 ng/kg/min After 1 year: | Minor complications frequent 76 episodes of catheter related sepsis (0.19 events per patient- year) 4 deaths due to sepsis 7 patients developed severe pulmonary oedema, confirmed as PVOD/PCH in 3 | Majority of deaths occurred within 2 years of commencing therapy. Those who improved to FC I or II during first 3 months had highest probability of survival Mortality independent of age or gender. Predictors of death at baseline: • FC IV at baseline • 6MWD <250 m at baseline • RAP ⩾12 mm Hg • mPAP <65 mm Hg |
| Age FC III:IV 6MWD RAP MPAP TPR Svo2 CI | Epo 43 120:58 240 12 67 2936 54 2.0 | 26 deaths, 13 transplanted |
| FC I:II:III:IV RAP MPAP TPR Svo2 CI Survival 1 year 2 year 3 year | Epo 5:77:42:6 0 −8 −984 +8% +0.6 NIH predicted 76% 60% 47% | p Value ns * * * * Epo 85% 70% 63% |
| McLaughlin et al 2002107 P NR OL Long term IV epoprostenol Duration: up to 122 months | n = 162 (M:F 1:3) IPAH 162 | Mean follow up 36 months (median 31, range 1 to 122) Mean dose Epo 52 ng/kg/min After 18 months: | Minor side-effects not reported 119 local infections at exit site (0.24 per person-year) 70 episodes of sepsis (0.14 per person year) 4 deaths due to sepsis 72 episodes requiring catheter replacement 1 death due to interruption of Epo | No relationship between dose and survival noted Those patients who remained FC III or IV at 18 months at worst survival Improved haemodynamics also predicted long term survival Predictors of death at baseline: • Baseline exercise time • Lack of vasodilator response • FC IV at baseline • RAP |
| Age FC III:IV Exercise time RAP MPAP PVR Svo2 CI | Epo 42 91:71 192 s 14 61 1400 53% 1.8 | FC improved Exercise time RAP MPAP PVR Svo2 CI Survival 1 year 2 year 3 year | Epo 79% +215 −3 −8 −520 +8% +0.6 NIH predicted 59% 46% 35% | p Value * * * * * * Epo 88% 76% 63% |
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| Tapson et al 2005126 P NR OL IV treprostinil Duration: 12 weeks | n = 16 (F 16) IPAH 8, CTD 6, CHD 2 | Post 12 wks 1 patient died, 1 unavailable for follow-u p Mean dose Tre 41 ng/kg/min | No serious adverse effects attributable to Tre Extremity pain 11 (severe 1) Jaw pain 11 Diarrhoea 8 Headache 7 Nausea/vomiting 7 Flushing 3 | |
| Age FC III : IV 6MWD RAP MPAP PVR CI | Tre 45 14:2 307 12 58 2320 1.7 | FC I:II:III:IV RAP MPAP PVR CI | Epo 1:4:9:0 −1 −4 −752 +0.5 | p Value ns * * * |
| Lang et al 2006121 P NR OL E Long term SC Treprostinil Duration up to 57 months | n = 122 (male 34, female 88) IPAH 50, CTD 10, CHD 23, PoPH 3, HIV 3, CTEPH 23, Other 10 | Mean follow up 26 months (range 3 to 57) 31 deaths, 5 transplanted | 82% site pain Only 6 patients (4.9%) withdrew due to pain Complication rate 0.23 per patient-year: • Cellulitis 8% • Abscesses 13% • Bleeding 7% | No clear difference in survival between treatment groups, including CTEPH Survival similar to that of IV epoprostenol studies, and superior to NIH prediction Low withdrawal rate due to site pain |
| Dose (ng/kg/min) 6MWD Mean FC | 12 months 26 409* | 24 months 32 444* 2.5 |
| Age FC II:III:IV Mean FC 6MWD RAP MPAP PVR CI | Tre 49 8:81:3 3 3.2 305 10 60 1228 2.1 |
| 22 patients received combination therapy after 1 year |
| Survival 1 year 3 year | All cause 89% 71% |
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| Barst et al 2006118 P NR OL Long term SC treprostinil Duration up to 4 years | n = 860 IPAH 412, CTD 166, CHD 177, HIV 13, PoPH 43, CTEPH 49 | Of 860 reviewed: Mean time since diagnosis 42 months 506 prematurely discontinued 136 patients died, 11 transplanted 117 deteriorated requiring alternative therapy | 199 (23%) withdrew due to adverse effects Site pain 792 (92%) Bleeding/bruising 170 (20%) Site infection 35 (4%) 538 (63%) remained on Tre at 1 year, mean dose 26 ng/kg/min | Study population taken from extension of RCT and de novo patients No difference in survival noted between sub- groups Predictors of survival: Functional class Smo2 PVR |
| Survival 1 year 2 year 3 year | Tre 87% 78% 71% |
| Age FC II:III:IV | Tre 46 128:654:78 |
| Of 332 IPAH patients: |
| 332 IPAH patients analysed (male 74, female 258) | Mean time since diagnosis 28 months |
| Survival 1 year 2 year 3 year | NIH predicted 69% 56% 46% | Tre 91% 82% 76% |
| Age FC II:III:IV RAP MPAP CI | Tre 45 128:654:78 10 59 2.2 |
| Olschewski et al 2000123 P NR OL Nebulised Iloprost Duration: 3 months | n = 19 (male 5, female 14 ) IPAH 12, CTD 3, CTEPH 2, ILD 2 | Post 3 months Mean dose 120 μg/day 4 patients died 4 remained bed bound | 2 patients had dose reductions due to nausea Cough common Nausea, oedema, thoracic pain, headache, jaw pain transient Others: tongue sensitivity, gum swelling, retrosternal burning | Severe population as baseline (9/19 bed bound or syncopal at rest) |
| Age FC III:IV 6MWD RAP MPAP PVR CI | Neb Ilo 39 4:15 15 66 1854 1.6 | 6MWD FC III:IV RAP mPAP PVR CI Svo2 | Neb Ilo 362 5:4 −5.5 −7.5 −295 +0.2 +4.5% | p Value ** ** ** ** ** ** |
| 7 remained on Ilo long term (mean duration 536 days) |
| Hoeper et al 2000120 P NR OL Nebulised iloprost Duration: 1 year | n = 24 (male 9, female 15) IPAH 24 |
Post 12 months:
| Cough common during first few days of treatment Lung function stable 5 flushing, headache or jaw ache No discontinuations No symptomatic hypotension Exercise capacity fluctuated in relation to timing of dose | Persisting short term vasodilation post dose noted throughout 12 months Those with greatest short term result had most marked long term improvement in PVR |
| Age FC III:IV 6MWD RAP MPAP PVR Svo2 CO | Neb Ilo 38 20:4 278 8 59 1205 62% 3.8 | 6MWD RAP mPAP PVR Svo2 CO | 3 months 353** −3** −6** −204** +3%** +0.2 | 12 months 363** −3** −6** −280** +5%** +0.6** |
| Opitz et al 2005124 P NR OL Long term nebulised iloprost Duration: up to 5 years | n = 76 (male 22, female 54) IPAH 76 | After 3 months: 5 died Median dose 100 μg/day | NR | Predictors of event-free survival at baseline: • Svo2 • RAP • CI • PVR • Peak V o2 • Exercise duration |
| Age FC II:III:IV Peak V o2 RAP MPAP PVR Svo2 CI | Neb Ilo 43 18:51: 7 11.2 8 61 1639 58% 1.8 | FC RAP mPAP PVR Svo2 CI | Neb Ilo NR +1 +1 +130 −3 −1 | p Value ns ns ns ** ** |
| After 1 year: 32 patients remained on Iloprost monotherapy 9 deaths, 2 transplanted 33 required alternative therapy |
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| Survival 1 year 2 year 3 year | NIH expected 68% 55% 46% | Ilo 79% 70% 59% |