| Barst et al 2003136 BREATHE-3 P OL Bos (dose ranging) in PAH in paediatric pts Duration: 12 weeks | Weight (kg) n M/F Age II/III IPAH CHD Epo | 10–20 7 4/3 6 7/0 3 4 4 | 20–40 6 2/4 10 5/1 4 2 3 | >40 6 3/3 14 3/3 3 3 3 | Haemodynamics in pts >8 years (n = 17) | Minor: Flushing 4 Elevated transaminases 3 Peripheral oedema 3 Anaemia 0 Major: Tachycardia, hypotension, dizziness—1 Marked elevation in transaminases—1 (in association with sclerosing cholangitis) | Target dose by week 5: 10–20 kg: 31.25 twice daily 20–40 kg: 62.5 twice daily >40 kg: 125 twice daily Pharmacokinetics similar to adults |
| CI mPAP PVR SVR | Baseline 4.0 60 1209 1674 | 12 weeks 4.5 52** 910** 1248** |
| No significant changes in 6MWD or Vo2max Five children improved by one FC and one deteriorated |
| Langleben et al 2004142 P OL E Sitax(100) in PAH—continuation of STRIDE-1 Duration: 1 year | n M/F Age II/III/IV IPAH CTD CHD 6MWD mPAP CO PVR | 11 2/9 48 (n = 10) 1/9/0 (n = 10) 3 3 4 386 (n = 10) 44 (n = 10) 4.3 (n = 10) 742 (n = 10) | 1 pt died in the study and has not been included in the data. | Adverse effects attributable to Sitax: headache, peripheral oedema, nasal congestion, nausea. No elevated transaminases | |
| II/III/IV 6MWD mPAP CO PVR | 10/0/0* 436** +1NS +1.1* −157** |
| Arm of STRIDE-1: Pbo 4; 100 mg 3; 300 mg 3 |
| Sitbon et al 2004140 P OL Bos(250) in HIV PAH Duration 12 weeks | n M/F Age I/II/III/IV 6MWD RAP mPAP CI PVR BDI EQ-5D VAS EQ-5D SF-36 | 16 9/7 39 0/15/1 333 11 52 2.6 781 3.4 44 0.37 3.8 | I/II/III/IV 6MWD RAP mPAP CI PVR BDI EQ-5D VAS EQ-5D SF-36 | 12 weeks 3/10/3 424* 8 −11* +0.8* −339* 1.5** 63* 0.63** 1.8* | Most common adverse events: Peripheral oedema 5 Headache 3 Muscle cramps 2 Fluid retention 2 Vomiting 2 Transaminases >3×ULN 2 (1 reduced dose). 1 PAH related admission | No impact on CD4 count or viral load. No clear interaction with antiretroviral therapy |
| McLaughlin et al 2005138 P OL E IPAH patients from extension studies of BREATHE-125 and Channick et al.24 (see previous table) (Bos(250 and 500)) Duration: 3 years | n M/F (5) I/II(%) III/IV(%) Age 6MWD RAP mPAP CI PVR Bos(62.5) 1% | Study group 169 21/79 1/8 82/9 46 345 10 57 2.4 1032 Bos(125) 11.3% | NIH registry 187 0/29 71 36 NR 10 60 2.3 NR | Mean follow-up 2.1 years | Observation period for adverse events was 78 weeks. Incidence of elevated transaminases>3×ULN was 14.9%, 5-8×ULN 3.0%, >8×ULN 4.2%. | Does not include pts in whom prostanoid therapy was started during PC study (who were withdrawn from the study). No Pbo or historical matched control group. Patients were derived from PC studies, perhaps not reflecting normal IPAH population |
| 1 year survival 2 year survival | Study group 96%* 89%* | NIH registry 69% 57% |
| 20 deaths (including one pt lost to follow-up); 3 lung transplants. 39 pts received alternative therapy (including 1 pt lost to follow-up and 3 pts for whom treatment was unknown). Remaining on Bos monotherapy: 1 year 85%; 2 years 70% 6MWD NR |
| Bos(250) 77.4% | Bos(500) 10.1% |
| Hughes et al 2006137 Re Bos(250) in inoperable CTEPH Duration: 1 year Outcomes: 1. 6MWD, FC 2. Haemodynamics | n M/F Age Previous PEA II/III/IV 6MWD mPAP CI TPR | 47 20/27 60 13 10/32/5 291 51 2.1 1122 | Improvement in FC 6MWD (n = 45) mPAP (n = 28) CI (n = 28) TPR (n = 28) | 1 year 11 (24%) 321→364* 50→49NS 2.1→2.3* 1107→969* | Bos discontinued in 1 pt due to elevated transaminases (>2.5 years after starting Bos). No other serious adverse events | 18 pts had been followed up for 2 years. 3 pts commenced on alternative therapy. Over total period of follow-up (range 7–41 months), total of 5 pt deaths (all non-operated pts). Compared with historical data,35 including all forms of CTEPH, the likely survival of this cohort was 40% cf observed survival of 96%. |
| 2 pts dead at 1 year—date not included in comparison Improvement in 6MWD most marked for those who had undergone PEA 102 vs non-operated 40* 2 pts commenced on alternative therapy (1 Epo, 1 sc Trep); 3 pts increased to Bos (500) |
| Apostolopoulou et al 2007143 P OL E Bos(125 (pts 20–40 kg) and 250 (>40 kg)) in PAH related to CHD Duration: 2 years | n M/F Age Eisenmenger syn II/III/IV 6MWD Vo2max Spo2 mPAP PFI SFI PVRI SVRI BDI | 19 10/9 22 13 5/12/2 417 17.3 87 86 4.1 2.6 1946 2775 2.8 | Mean follow-up 2.4 years | No data reported on Spo2 after 2 years (which was primary end point in BREATHE-5), but reported no significant change. No incidence of elevated transaminases >3×ULN | 2 pts who died in the first phase of the study, reported earlier, not included in this analysis. Although the more subjective FC status remained preserved from 16 weeks to 2 years, 6MWD and Vo2max returned to or just below baseline, suggesting this effect is not prolonged |
| II/III/IV 6MWD Vo2max BDI | 16 weeks 13/6/0 463* 18.8** 2.0* | 2 years 13/6/0 402NS 17.3NS 3.0NS |
| p vs baseline |
| Williams et al 2006141 Re & P OL Survival before and after introduction of Bos in SSc | n M/F Limited/diffuse Age Time from diagnosis to starting treatment III/IV 6MWD RAP mPAP CI PVR | Historical controls 45 7/38 43/2 60 36 days 26/19 207 8 40 2.6 613 | Current era 47 7/40 34/13* 58 72 days* 36/11 179 7 40 2.7 597 | 1 year survival 2 year survival | Historical controls 68% 47% | Current era 81% 71% | | Exclusions: WHO FC I and II Significant pulmonary fibrosis Those meeting 2001 criteria for starting IV prostacyclin therapy (RAP >10, CI <2.3, Svo2 <63) |
| Provencher et al 2006139 Re Bos(250) in IPAH Duration 2yrs | n M/F Age III/IV 6MWD RAP mPAP CI PVRI | 103 28/75 54 91/12 319 9 58 2.4 1707 | Mean follow-up 24 months | Bos stopped in 3 pts and halved in 1 pt due to elevated transaminases, which resolved in 12 weeks | 6MWD and FC status only presented for those remaining on Bos monotherapy, therefore removing the negative impact of death or need to switch/add in therapy. At 1 year those still on monotherapy had had baseline 6MWD of 349 cf 319 for whole group |
| 1 year survival 2 year survival 3 year survival 1 year event-free survival 2 year event-free survival 3 year event-free survival | Study group 92% 89% 79%* | NIH registry 71% 61% 51% 63% 45% 40% |
| Events defined as need for prostanoid therapy, IV diuretic or IV dobutamine FC data and 6MWD only given for those evaluated on Bos monotherapy |
| II/III/IV 6MWD | 4 months (n = 99) 40/51/8 322→364 | 1 year (n = 59) 24/33/2 349→390 |