Review Highlights Three Therapies on the Market for PAH Management

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A recent review, entitled “Medical treatment update on pulmonary arterial hypertension,” presents the latest research for three new drugs that have been approved by the US FDA to treat PAH. The review, which is published in Therapeutic Advances in Chronic Disease, highlights the mechanisms of action for the therapies, as well as the clinical trials that led to their approvals.

The three new drugs currently on the market include:

  • Macitentan: An oral endothelin receptor antagonist.
  • Riociguat: An oral soluble guanylate cyclase stimulator.
  • Treprostinil diolamine: An oral prostacyclin analogue or prostanoid.

According to the review authors, each of these drugs is prescribed differently from one another, require unique monitoring recommendations, and cause specific side effects that physicians and patients must carefully consider.


Macitentan is an endothelin receptor antagonist (ERA) that binds to and deactivates the endothelin receptor. When activated, the endothelin receptor causes vasoconstriction and worsening of PH. By antagonizing the receptor, Macitentan causes vasodilatation and reduction in arterial pressures in the lungs.  A recent trial called SERAPHIN demonstrated a reduction in PAH-related events in participants with the disease as measured by the study’s composite primary endpoint of time to first PAH-related event, which included worsening of PAH, infusion prostanoid initiation, lung transplantation, atrial septostomy, or death when patients took 10 mg per day. The major side effects of the drug observed in the study included nasopharyngitis, anemia, UTIs, bronchitis, influenza and headache.  The participants in the SERAPHIN study included patients that were taking macitentan as a monotherapy, as well as patients who were prescribed background therapy. Both groups of patients experienced benefit in the SERAPHIN trial, and as a result, macitentan is approved as both a monotherapy and in combination with PDE5 inhibitors or inhaled prostanoids.


More than one study was conducted on Riociguat for the management of PAH. Riociguat has been found to act on soluble guanylate cyclase, binding it to nitric oxide and causing vasodilatation.  In the PATIENT-1 study, participants were found to have significantly longer six minute walking distances. The maximum recommended dose is 2.5 mg three times daily.  Half of the participants were not taking treatment for PAH prior to taking Riociguat, while the other half were on at least one other medication for PAH at the time of the study.

In the CHEST-1 study on Riociguat, the participants were those who had pulmonary hypertension following a pulmonary endarterectomy. Most of the patients were taking the highest recommended dose of Riociguat by the end of the study and those who received the drug had a significantly longer six minute walking distance when compared to those who took the placebo.

Both studies had extension studies lasting up to two years.  The survival rate of those who took Riociguat over a longer period of time was 93 percent after two years with improving 6 minute walking distances.

Oral Treprostinil

Prior to the studies on oral treprostinil, prostanoids were only available by intravenous or inhaled means. As a class, prostanoids like Treprostinil reduce PAH by dilating the lung and systemic arterial vascular systems. They also inhibit the aggregation of platelets and suppress the proliferation of smooth muscle cells, resulting in lower blood pressures. More than one study was conducted on oral Treprostinil — one that included participants that were on other forms of therapy as well as one that involved participants on no previous therapy. In both studies, participants taking Treprostinil reported a reduction in their dyspnea fatigue score and on the combined 6 minute walking distance and Borg dyspnea score when compared to placebo. In the end, the recommended dosage of Treprostinil was 0.25 mg twice daily or 0.125 mg three times daily.

These three medications represent a new frontier for the treatment of pulmonary artery hypertension. Prior to the approval of these drugs, patients with PAH had limited treatment options and a high rate of morbidity and mortality. Now, however, these FDA-approved therapies for PAH are increasing quality of life and lifespan for those with the disease, while more experimental PAH therapies are currently in the drug development pipeline.

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