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Available treatments: PAH

Available treatments in PAH

The main goals of PAH treatment are to alleviate symptoms, improve functional capacity and quality of life, and reduce morbidity, mortality and hospitalisation. Here, the available treatments and key clinical trials are discussed

Naushad Hirani MD FRCPC Jason Weatherald MD FRCPC Division of Respiratory Medicine, University of Calgary, Canada

The main goals of pulmonary arterial hypertension (PAH) treatment are to alleviate symptoms, improve functional capacity and quality of life, and reduce morbidity, mortality and hospitalisation. General measures, such as psychosocial support and immunisation, rehabilitation/ exercise, supportive treatment with anticoagulants, diuretics, digitalis and oxygen, are important, but are not sufficient to treat patients presenting with symptomatic PAH. Agents targeting the endothelin-1 (ET-1), nitric oxide (NO) and prostacyclin (PGI2) pathways, known to play important roles in the pathophysiology of the disease, are the mainstay in management of patients with idiopathic non-vasoreactive PAH.1 Patients with acutely vasoreactive PAH must be distinguished from non- vasoreactive patients with right heart catheterisation. High-dose calcium channel blockers (CCBs) are reserved for these patients who clearly have a distinct pathobiology and prognosis, as CCBs can be dangerous in the majority of PAH patients with a fixed pulmonary vascular resistance.

Mechanisms of action

ET-1 is a vasoconstrictor and mitogenic peptide that binds to endothelin-A receptors (ETA), present in the vascular smooth muscle cells of the lung, and to endothelin-B receptors (ETB), also located in endothelial cells. The deleterious effects of ET-1 signalling, namely fibrosis and

observed in PAH. Similar to NO, PGI2 is a vasodilator whose expression is deficient in the endothelium in the lung of patients with PAH. A number of prostacyclin analogues are currently used to treat PAH and have been demonstrated to be very effective agents for this condition.2


Ambrisentan, a non-sulfonamide ERA specific for ETA, is available in North America and the EU for the treatment of patients with World Health Organization (WHO) Group 1 PAH.3–5

The agent has

hypertrophy of blood vessels, are thought to be mitigated with endothelin receptor antagonists (ERAs). NO induces vasodilation and inhibits proliferation of smooth muscle cells by increasing production of cyclic guanosine monophosphate (cGMP) via activation of soluble guanylate cyclase (sGC). Patients with PAH seem to produce insufficient NO, which affects downstream synthesis of cGMP. Therefore, inhibition of phosphodiesterase type 5 (PDE-5), a currently used therapeutic strategy, leads to the accumulation of intracellular cGMP. sGC stimulation, on the other hand, promotes cGMP production and also constitutes a therapeutic approach for attenuating the pathophysiologic effects

been evaluated as monotherapy in several randomised Phase III trials. In ARIES-1 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

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


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 19

ARIES-3 was an

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