TABLE 3.
Completed and ongoing trials of pulmonary arterial hypertension (PAH)-specific therapies in patients with suspected pulmonary hypertension associated with left heart disease (PH-LHD)
| Drug, year [ref.] | Study acronym/identifier# | Subjects n | Patient characteristics | Design | Primary end-point | Key results |
| Epoprostenol 1996 [51] | FIRST | 471 | Severe heart failure, WHO FC IIIb–IV | 1:1 randomisation Event-driven Mean dose 4 ng·kg−1·min−1 | Survival | Early termination (trend to decreased survival in treated group) |
| Bosentan 2002 [50] | ENABLE | 1613 | Severe heart failure, WHO FC IIIb–IV | 1:1 randomisation 18-month duration 125 mg twice daily | Mortality and hospital stays | No effect Early risk of worsening heart failure necessitating hospitalisation due to fluid retention with treatment |
| Bosentan 2005 [49] | REACH-1 | 370 | Severe heart failure, WHO FC IIIb–IV | 1:1:1 randomisation 26-week duration 500 mg twice daily via rapid or slow infusion | Change in clinical status | No effect Early termination (safety concerns) |
| Darusentan 2002 [56] | HEAT | 179 | Chronic heart failure, WHO FC III | 1:1:1:1 randomisation 3-week duration Doses of 30, 100 and 300 mg daily | Haemodynamics (change in PAWP/cardiac index) | Increased cardiac index No change in PAWP |
| Darusentan 2004 [52] | EARTH | 642 | Chronic heart failure, WHO FC II–IV | 1:1:1:1:1 randomisation 6-month duration Doses of 10, 25, 50, 100 and 300 mg daily | LVESV changes by MRI and clinical events | No effect |
| Sildenafil 2007 [53] | NCT00309816 | 13 | Heart failure, WHO FC III | Nonrandomised, open-label 50 mg single dose | Exercise capacity and haemodynamics after 60 min | Significant reduction in resting PAP, SVR and PVR, and increased resting and exercise cardiac index (p<0.05) |
| Sildenafil 2007 [55] | NCT00309790 | 34 | Heart failure, WHO FC II–IV | 1:1 randomisation 12-week duration 25–75 mg three times daily | Haemodynamics (change in peak V′O2) | Significantly greater increase in V′O2 (p=0.02) |
| Sildenafil 2007 [54] | NCT00407446 | 46 | Chronic heart failure, WHO FC II–III | 1:1 randomisation 6-month duration 50 mg twice daily | Exercise performance, ventilation efficiency, symptoms | Significant increases at 3 and 6 months (p<0.01) |
| Sildenafil 2013 [59] | RELAX | 216 | Heart failure, WHO FC II–IV | 1:1 randomisation 24-week duration 20 mg three times daily for 12 weeks, then 60 mg three times daily for 12 weeks | Haemodynamics (change in peak V′O2) | No effect |
| Riociguat 2013 [48] | LEPHT | 201 | Heart failure, WHO FC II–IV | 2:1:1:2 randomisation 16-week duration 0.5 mg, 1 mg or 2 mg three times daily | Change in mPAP | No effect |
| Riociguat 2014 [61] | DILATE-1 | 39 | HFpEF | 1:1:1:1 randomisation 0.5 mg, 1 mg or 2 mg single dose | Largest mPAP change from baseline ≤6 h after drug administration | No effect |
| Tadalafil 2015 [58] | PITCH-HF | 23 | Heart failure, NYHA FC II–IV | 2:1 randomisation ≤3-year duration 40 mg daily | Cardiovascular mortality or hospitalisation due to heart failure | Trial terminated early |
| Macitentan 2015 [57] | MELODY-1 | Estimated enrolment=60 | CpcPH due to left ventricular dysfunction | 1:1 randomisation 12-week duration 10 mg once daily | Safety and tolerability | Estimated completion quarter 4 2015 |
WHO FC: World Health Organization functional class; PAWP: pulmonary artery wedge pressure; LVESV: left ventricular end-systolic volume; MRI: magnetic resonance imaging; PAP: pulmonary arterial pressure; SVR: systolic vascular resistance; PVR: pulmonary vascular resistance; V′O2: oxygen uptake; mPAP: mean pulmonary arterial pressure; HFpEF: heart failure with preserved ejection fraction; NYHA FC: New York Heart Association functional class; CpcPH: post-capillary pulmonary hypertension with a pre-capillary component. #: identifier numbers listed are for the https://clinicaltrials.gov/ registry.