| Humbert et al 2004145 | | Pbo/Epo | Bos/Epo | | Pbo/Epo | Bos/Epo | Bos/Epo vs Pbo/Epo (%)Elevated liver enzymes 9 vs 18NSCardiopulmonary failure 14 vs 18NSLower limb oedema 27 vs 9NSDeaths 2 vs 0NS | The bosentan group included more women, patients with scleroderma and patients with signs of heart failure. Underpowered study and many non-significant trends in favour of combination therapy, but no end points reached |
| n | 11 | 22 | Improvement in FC | 45% | 59% |
| BREATHE-2 | M/F | 5/6 | 5/17 | 6MWD (median) | +74 | +68NS |
| R DB PC | Age | 47 | 45 | RAP | +0.3 | −1.9NS |
| Addition of Bos(250) to Epo | IPA H | 10 | 17 | mPAP | −1.7 | −6.7NS |
| at start of therapy | CTD | 1 | 5 | CI | +0.6 | +0.8NS |
| Duration: 16 weeks | II/III/IV | 0/8/3 | 0/17/5 | PVR | −376 | −564NS |
| 6M WD | NR | NR | TPR | −386 | −681NS |
| Outcomes: | RAP | 11.9 | 11.9 | Dyspnoea-fatigue index | +1.0 | 0NS |
| 1. TPR | mPAP | 61 | 59 | p vs Pbo/Epo | | |
| 2. Haemodynamics, | CI | 1.7 | 1.7 | | | |
| Δ6MWD, FC, dyspnoea-fatigue index | PVRTPR | 14261628 | 15111697 | | | |
| Target Epo dose 12–16 ng/kg/min | | | |
| McLaughlin et al 2006146 | | Pbo | Ilo | | Pbo | Ilo | p |
| n | 33 | 34 | Inhalations | 5.7 | 5.6 | | No significant elevations in transaminases. Most commonly reported side-effects in the Ilo group were known side effects of prostanoids (headache, flushing and jaw pain). Serious adverse events: Ilo 5 pts (14%), 5 events: 2 drug-related1 discontinuation0 hospitalisationsPbo 7 pts (32%), 12 events1 drug-related1 discontinuation4 hospitalisations | In Ilo group, MPAP, PVR and Svo2 measured post-nebulisation of Ilo were significantly improved compared with baseline pre-nebulisation (p<0.01). Some patients contributed haemodynamic data but no 12 week data, but baseline data included in analysis. Although no difference between Ilo and Pbo in pre-neb 6MW, Ilo resulted in significant increase in 6MW cf. baseline, unlike Pbo. Post-neb there was a significant difference in 6MW between groups. Post-neb there was a significant fall in SVR (−2% vs +5%) |
| M/F | 7/26 | 7/27 | Improved by 1 FC | 2 | 11 | * |
| Age | 49 | 51 | Worsened by 1 FC | 1 | 0 | NR |
| STEP | IPAH | 20 | 17 | Clinical worsening | 5 | 0 | ** |
| R DB PC | APAH | 13 | 17 | Pre-neb data | | | |
| | | | 6MWD | 358NS | 365NS | NS |
| Addition of Neb Ilo(30-45) | II/III/IV | 1/30/2 | 0/34/1 | mPAPPVR | +2+15 | −2−8 | NSNS |
| to Bos(250) | 6MWD | 340 | 331 | Post-neb data | | | |
| Duration: 12 weeks | mPAP | 52 | 51 | 6MWD | 343NS | 367* | NS |
| | | | mPAP | +2 | −6 | * |
| CO | 4.6 | 4.7 | PVR | +81 | −164 | * |
| PVR | 783 | 815 | CO | +0.1 | +0.1 | NS |
| Mean study drug inhalations (5 μg): Ilo 5.6: Pbo 5.7 | BDI | 0.0NS | −0.5** | NS |
| | | | | |
| | | | | |
| | p values vs baseline in same columnp values Ilo vs Pbo (4th column) Missing FC data—1 (Ilo) |
| |
| Hoeper et al 2006144 | | Bos | Ilo/Bos | | Bos | Ilo/Bos | p | One discontinuation of Ilo due to intractable coughIn Ilo group: Diarrhoea 2Headache and flushing 2Haemoptysis 1 | QoL measured using EuroQoL questionnaire After 40 pts enrolled, study was stopped after a futility analysis predicted failure with respect to predetermined sample size |
| n | 21 | 19 | 6MWD | 297 | 309 | NS |
| COMBI | M/F | 5/16 | 4/15 | FC | +0.1 | −0.1 | NS |
| R OL PC | Age | 56 | 48 | Vo2max | 0 | −1 | NS |
| Addition of Ilo(30) to | 6MWD | 296 | 317 | Ve/Vco2 | +1 | −1 | NS |
| Bos(250)in IPAHWHO FC | RAP | 9 | 9 | Peak SBPQoL | −6−3 | −3+7 | NSNS |
| III | mPAP | 59 | 54 | CW | 4 | 3 | NS |
| Duration 12 weeks | CI | 2.1 | 2.1 | | | | |
| PVR | 1032 | 1080 | | | | |
| Outcomes: | Vo2max | 10.7 | 11.8 | | | | |
| 1. 6MWD | Ve/Vco2 | 49 | 55 | | | | |
| 2. FC, Vo2max, peak SBP | Peak SBP | 155 | 144 | | | | |
| during exercise, Ve/Vco2 at AT, QoL, CW | QoL | 48 | 40 | | | | |