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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



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

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

deterioration. After six months of treatment with bosentan, patients performed significantly better in the 6MWD test.9

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

PDE-5i 20

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 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

A 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.

Prostacyclins 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.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 patients also find prostanoids difficult to tolerate due to many potentially limiting adverse effects that can include flushing, diarrhoea, and jaw pain. Because of its effectiveness, epoprostenol is used in the most severe cases (WHO Class IV) or for patients who have an insufficient response to oral agents. In many situations it can be used as a bridge to lung transplantation. Treprostinil has a longer half-life than epoprostenol and can be administered via continuous subcutaneous or intravenous infusion.18

Subcutaneous delivery avoids

the complications of intravenous infusions, but also is associated with site pain and local complications that can be limiting. Oral treprostinil potentially circumvents the limitations associated with injectable and inhaled PGI2 agents.

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