Positive randomised controlled trials of PAH therapies
| Trial name | Treatment | Trial duration | Number/type of patients | Primary endpoint met | Secondary endpoint significant improvements | Adverse events |
|---|---|---|---|---|---|---|
| Treatment of primary PH with continuous intravenous prostacyclin (epoprostenol)19 | Continuous intravenous epoprostenol at doses determined during baseline catheterisation or conventional treatment (mean dose 7.9±2.7 ng/kg/min) | 8 weeks followed by non-randomised treatment for up to 18 months | 19 patients with primary PH. 10 patients received epoprostenol and 9 received only anticoagulants, oral vasodilators and diuretics | Total pulmonary resistance –7.9 units (95% CI −13.1 to −2.2) at 8 weeks, sustained for up to 18 months | Mean PAP | Complications attributable to administration method |
| Continuous subcutaneous infusion of treprostinil, a prostacyclin analogue, in patients with pulmonary arterial hypertension20 | Continuous, subcutaneously infused treprostinil up to 22.5 ng/kg/min | 12 weeks | 470 patients with PH, either primary or associated with CTD or congenital systemic-to-pulmonary shunts | Change from baseline in 6MWD at 12 weeks. Median treatment difference +16 m (95% CI 4.4 to 27.6) | Haemodynamics, symptoms score, QoL | Infusion-site pain, infusion-site reaction, infusion-site bleeding, headache, diarrhoea, nausea, jaw pain, flushing, lower limb oedema, gastrointestinal haemorrhage |
| Double-blind placebo-controlled clinical investigation into the efficacy and tolerability of inhaled treprostinil sodium in patients with severe pulmonary arterial hypertension (TRIUMPH I)21 | Inhaled treprostinil (up to 54 µg) four times daily | 12 weeks | 235 patients with PAH | Peak change from baseline in 6MWD at 12 weeks. Median treatment difference +20 m (95% CI 8.0 to 32.8) | QoL, NT-proBNP | Cough, headache, nausea, dizziness, flushing, throat irritation, pharyngolaryngeal pain, diarrhoea |
| Efficacy and safety of oral treprostinil monotherapy for the treatment of pulmonary arterial hypertension (FREEDOM-M)22 | Oral treprostinil 0.25–12 mg twice daily | 12 weeks | 349 treatment-naïve patients with PAH | Change from baseline in 6MWD at 12 weeks. Median treatment difference +23 m (95% CI 4 to 41) | Borg dyspnoea score | Headache, nausea, diarrhoea, jaw pain |
| The aerosolised iloprost randomised study (AIR)23 | Inhaled iloprost 2.5 µg or 5 µg six or nine times daily; median inhaled dose 30 μg per day | 12 weeks | 203 patients with mixed types of PH | An increase of at least 10% in 6MWD and 1 NYHA FC at 12 weeks. 16.8% of iloprost patients vs 4.9% of placebo patients achieved the primary endpoint | Haemodynamics, Borg dyspnoea score, QoL | Increased cough, flushing, jaw pain |
| Arterial PH and beraprost European trial (ALPHABET)24 | Beraprost sodium 20–120 µg four times daily | 12 weeks | 130 patients with PAH | Change from baseline in 6MWD at 12 weeks. Mean treatment difference +25.1 m (95% CI 1.8 to 48.3) | Borg dyspnoea score | Headache, flushing, jaw pain, diarrhoea |
| Bosentan randomised trial of endothelin antagonist therapy (BREATHE-1)25 | Bosentan 62.5 mg three times daily for 4 weeks, increased to 125 or 250 mg three times daily for 12 weeks | 16 weeks | 213 treatment-naïve patients with either IPAH or PAH-CTD | Change from baseline in 6MWD at 16 weeks. Mean treatment difference +44 m (95% CI 21 to 67) | WHO FC, Borg dyspnoea score, TTCW | Headache, dizziness, worsening PAH |
| Endothelin antagonist trial in mildly symptomatic pulmonary arterial hypertension patients (EARLY)26 | Bosentan 62.5 mg three times daily, increasing to 125 mg three times daily after 4 weeks | 6 months | 185 patients with WHO FC II PAH | PVR at rest at 6 months, expressed as a percentage of the baseline value and change from baseline in 6MWD at 6 months. Treatment difference –22.6% (95% CI –33.5 to –10.0) for PVR, and +19.1 m (95% CI 3.6 to 41.8) for 6MWD. 6MWD endpoint not significant | TTCW, NT-proBNP, QoL | Nasopharyngitis, abnormal liver function tests |
| Ambrisentan in pulmonary arterial hypertension, randomised, double-blind, placebo-controlled, multicentre, efficacy (ARIES-1 and ARIES-2)27 | Ambrisentan ARIES-1, 5 or 10 mg once daily; ARIES-2, 2.5 or 5 mg once daily | 12 weeks | 202 (ARIES-1) and 192 (ARIES-2) patients with PAH | Change from baseline in 6MWD at week 12. Mean treatment difference +45 m (95% CI 24 to 65) for 5 mg combined; +32 m (95% CI 2 to 63) for 2.5 mg and +51 m (95% CI 27 to 76) for 10 mg | ARIES-1: WHO FC, Borg dyspnoea score, BNP ARIES-2: TTCW, QoL, Borg dyspnoea score, BNP | Peripheral oedema, headache, nasal congestion |
| Study with an endothelin receptor antagonist in pulmonary arterial hypertension to improve clinical outcome (SERAPHIN)28 | Macitentan 3 mg or 10 mg once daily | Event-driven study, median duration 115 weeks | 742 treatment-naïve or pretreated patients with PAH | Time from initiation of treatment to first occurrence of a composite morbidity or mortality endpoint. HR vs placebo 0.7 (97.5% CI 0.52 to 0.96) for 3 mg; 0.55 (97.5% CI 0.39 to 0.76) for 10 mg | 6MWD, WHO FC, haemodynamics | Headache, nasopharyngitis, anaemia |
| Sildenafil use in pulmonary arterial hypertension (SUPER)29 | Sildenafil 20, 40 or 80 mg three times daily | 12 weeks | 278 treatment-naïve patients with IPAH, PAH-CTD or with repaired congenital systemic-to-pulmonary shunts | Change from baseline in 6MWD at week 12. Mean treatment difference +45 m (99% CI 21 to 70) for 20 mg; +46 m (99% CI 20 to 72) for 40 mg; +50 m (99% CI 23 to 77) for 80 mg | Mean PAP, WHO FC, haemodynamics | Headache, flushing, dyspepsia |
| Tadalafil in the treatment of pulmonary arterial hypertension (PHIRST-1)30 | Tadalafil 2.5, 10, 20 or 40 mg once daily | 16 weeks | 405 treatment-naïve or pretreated patients with PAH | Change from baseline in 6MWD at week 16. Mean treatment difference +33 m (95% CI 15 to 50). Endpoint not met in pretreated patients | Mean PAP, PVR, cardiac index, QoL | Headache, myalgia, flushing |
| Pulmonary arterial hypertension soluble guanylate cyclase–stimulator trial 1 (PATENT-1)31 | Riociguat 1.5 mg or 2.5 mg three times daily | 12 weeks | 443 treatment-naïve or pretreated patients with PAH | Change from baseline in 6MWD at week 12. Mean treatment difference +36 m (95% CI 20 to 52) | Haemodynamics, NT-proBNP, WHO FC, TTCW, Borg dyspnoea score | Headache, dizziness, dyspepsia, hypotension, peripheral oedema |
6MWD, 6 min walking distance; BNP, B-type natriuretic peptide; IPAH, idiopathic PAH; NT-proBNP, N-terminal prohormone of brain natriuretic peptide; NYHA FC, New York Heart Association functional class; PAH, pulmonary arterial hypertension; PAH-CTD, PAH associated with connective tissue disease; PAP, pulmonary arterial pressure; PH, pulmonary hypertension; PVR, pulmonary vascular resistance; QoL, quality of life; TTCW, time to clinical worsening; WHO FC, WHO functional class.