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Available treatments: PAH

Table 1: Phase III clinical trials of currently approved agents as monotherapy for PAH Drug

Mechanism of action

Ambrisentan (Galie, 2008)6


(Rubin, 2002; Galiè, 2008)8,9

Macitentan (Pulido, 2013)10


(Galiè, 2005; Rubin, 2011)11,12


(Galiè, 2009; Oudiz, 2012)13,14

Riociguat (Ghofrani, 2013)15 Beraprost

(Galie, 2002; Barst 2003)22,23


(Barst, 1996; Rubin, 1990)17,36


(Olschewski, 2002)21 Treprostinil

(Simmoneau, 2002; McLaughlin, 2010; Jing, 2013)18–20

Adapted from Galiè, 2013.1

ERA=endothelin receptor antagonist; NYHA=New York Heart Association Functional Class; PAH=pulmonary arterial hypertension; PC=prostacyclin; PDE-5i=phosphodiesterase type 5 inhibitor; sCGS=soluble guanylate cyclase stimulator; WHO=World Health Organization; WHO-FC=World Health Organization Functional Class

and -2, patients received a daily dose of ambrisentan, or placebo, for 12 weeks. Patients treated with the ERA at all the doses tested showed significant improvements in the placebo-corrected mean change from baseline in the six- minute walk distance (6MWD) test; time to clinical worsening also improved in these patients. Peripheral oedema and headache were the most frequently reported adverse events.6

ARIES-3 was an open-label study in a broader patient population. Increased 6MWD was observed at 24 weeks overall, but not for specific PAH aetiologies falling outside Group 1.7

In the same pharmacological class, bosentan exerts its antagonistic action on both ETA and ETB and is available in North America and the EU for the treatment of PAH.1,3,4

The BREATHE-1 study

demonstrated the efficacy and safety of bosentan in patients with poor functional capacity.8

Mildly symptomatic patients

were evaluated in the EARLY trial, which investigated whether early treatment could delay clinical deterioration. After six months of treatment with bosentan, patients performed significantly better in the 6MWD test.9

20 Treatment with macitentan, the most

recently developed ERA with improved receptor affinity and enhanced tissue penetration, resulted in reduced clinical worsening using a combined endpoint. The randomised, placebo-controlled SERAPHIN study enrolled 742 patients for a median duration of 115 weeks, the longest and largest pivotal study in PAH to date (Table 1).2,10


Oral sildenafil is marketed in North America and the EU for the treatment of PAH. The SUPER-1 and -2 studies showed that sildenafil as monotherapy increased exercise capacity and maintained or improved functional class in the short term and subsequently for up to three years. The safety and tolerability profile was consistent with that reported in studies of sildenafil for other indications.11,12 Taladafil, an oral selective PDE-5i, showed similar clinical outcomes in the 16-week PHIRST-1 and in the 52-week extension phase PHIRST-2 trials, with improvement in exercise capacity sustained for at least ten months (Table 1).13,14

sGC stimulation Riociguat is the only sGC stimulator

(sGCS) currently approved for the treatment of PAH. The PATENT-1 study and its long-term extension trial, PATENT-2, evaluated oral riociguat in patients who had not received treatment with a PDE-5i or IV prostanoids. While half of the patients enrolled in this trial were treatment naive, more than 40% were already treated with an ERA. The agent showed a favourable long-term safety and tolerability profile and induced sustained effects on exercise capacity and functional class at 16 weeks (Table 1).15


pilot, Phase IIIb trial (RESPITE) is being conducted in patients presenting with WHO-FC III PAH at screening who did not respond to treatment with a PDE-5i.


Epoprostenol is administered as a continuous iv infusion, and is a potent vasodilator that is the only agent that has been demonstrated to decrease mortality in idiopathic PAH (IPAH).16,17


administration of this agent is difficult as it requires an indwelling venous access and care of the line as well as technical competence from the patient to reconstitute the drug and safely operate the delivery device on a daily basis. Many



PC Barst et al. PC ALPHABET sGCS PATENT-1, -2

Improved exercise capacity, functional class, haemodynamics, and time to clinical worsening, improved health-related quality of life

Systemic hypotension

Short-term improved exercise capacity Headache, flushing, jaw pain and diarrhoea

Improved exercise capacity, symptoms, and haemodynamics Decreased mortality

Improved exercise capacity, symptoms, pulmonary vascular resistance Flushing, jaw pain

Improved exercise capacity, symptoms, haemodynamics, quality of life Infusion-site pain

PDE-5i PHIRST-1, -2 ERA PDE-5i ERA ERA Study name ARIES-1, -2


SERAPHIN SUPER-1, -2 Overall efficacy and safety

Improved exercise capacity, haemodynamics, and time to clinical worsening Increased incidence of peripheral oedema

Improved exercise capacity, functional class, haemodynamics and time to clinical worsening

Reversible increased hepatic aminotransferases

Delayed time to clinical worsening (primary endpoint), haemodynamics and quality of life Reduced blood haemoglobin (≤8g/dl)

Improved exercise capacity, and haemodynamics Mild headache, flushing

Improved exercise capacity, haemodynamics, and time to clinical worsening

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