January 31st, 2014

A (Not So) New Drug Landscape for Pulmonary Arterial Hypertension

Just in the past several months, the FDA has approved three new medications for pulmonary arterial hypertension (PAH):

  • macitentan, an endothelin-receptor antagonist (ERA);
  • riociguat, the first-in-class soluble guanylate cyclase (sGC) stimulator; and
  • treprostinil, an oral prostacyclin.

As a clinician and researcher who works a lot in this area, I thought it might be time for a quick primer.

What Does the Research Show?

As the saying goes, “The more things change, the more they stay the same.” Yes, the new drugs for PAH are different from what we already have, but not dramatically so.

Macitentan joins bosentan and ambrisentan, two other ERAs on the market, as an oral therapeutic options for PAH. The SERAPHIN placebo-controlled trial of macitentan, the largest PAH trial to date, used a combined endpoint of morbidity and mortality as its primary outcome, unlike prior studies that relied on changes in 6-minute walk distance. In SERAPHIN, the primary endpoint was significantly lower among patients on 10 mg of macitentan than among placebo recipients (31% vs. 46%). However, from an outcomes perspective, the differences between macitentan and the other available ERAs appear to be minor. Macitentan is given once daily, which is an advantage over bosentan, and also has fewer hepatic side effects than have been documented with bosentan. Perhaps the biggest potential win is that, with the introduction of a third ERA to this market, prices might go down.

Riociguat is designed as an oral stimulator of soluble guanylate cyclase; it causes vasodilation of the pulmonary arterial vasculature. In the PATENT trial, the drug improved 6-minute walk distance by 30 meters at 12 weeks of therapy. However, riociguat’s mechanism is similar to that of phosphodiesterase 5 inhibitors (PDE5i), such as sildenafil and tadalafil, which are among the most commonly used agents for PAH. Therefore, riociguat is contraindicated in patients already on a PDE5i. It remains to be seen whether physicians will routinely use riociguat instead of a PDE5i or reserve it only for patients who do not tolerate PDE5i therapy. In addition, riociguat has a complex dosing protocol, designed to be initiated at 1 mg three times daily and then, by week 8, to be increased to a target dose of 2.5 mg three times daily. What may be most exciting about this drug is its indication for inoperable or persistent chronic thromboembolic pulmonary hypertension (CTEPH). Until now, no oral agent has been available for this disease process. But as Stephen Archer notes, the first-line therapy for CTEPH remains pulmonary endarterectomy (PEA), and riociguat should not replace that.

Oral treprostinil has been shown to improve 6-minute walk distance in patients with PAH who are naive to PAH medicines and are not already on background therapy. This differs a bit from common practice, which has been to add prostacyclin therapy in patients who are deteriorating on oral agents or to use intravenous, subcutaneous, or inhaled prostacyclins in patients who are in functional class III or IV. The side-effect profile of oral treprostinil is noteworthy: headaches in >70% of patients and diarrhea in >50%.

How Do the New Drugs Change Practice?

At my institution, our approach will probably remain a PDE5i or an ERA as a first-line agent, with the addition of a second oral agent if the patient deteriorates clinically. We will continue to use parenteral prostacyclin if patients are in functional class III or IV. What is new, though, is that we are likely to introduce riociguat in patients who do not tolerate PDE5i therapy. However, given that the annual mortality rate for patients with PAH is 15% to 30%, management must remain aggressive, with the timely introduction of advanced therapies.

What’s the Future of Therapy for PAH?

We need to develop better therapeutic options for the clinical finding of pulmonary hypertension that is secondary to heart and lung disease. Notably, 90% of clinical pulmonary hypertension is secondary to left-sided heart disease (valvular disease, systolic or diastolic dysfunction), chronic lung disease (COPD, idiopathic pulmonary fibrosis), or both. Pulmonary arterial hypertension remains incredibly rare, affecting 7 to 10 patients per million population. ERAs, PDE5i therapy, and prostacyclins have not been shown to be effective in pulmonary hypertension that is secondary to left-sided heart disease or chronic hypoxia, and they have even been harmful in some cases. Riociguat is currently being studied in clinical trials of group 2 pulmonary hypertension (LEPHT trial), as is tadalafil (PITCH-HF).

CTEPH is also very rare, even less common than PAH. Again, nearly all patients with CTEPH should first be offered PEA; only after being evaluated—and declining PEA or being deemed inoperable—should riociguat be introduced. An alternative circumstance would be to use riociguat if pulmonary hypertension persists after PEA, as in the CHEST trial. However, this is also an uncommon situation, as PEA often cures the associated pulmonary hypertension.


Share your thoughts on the new treatments for PAH.

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