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PH Council Year in Review

Amresh Raina, MD
PH Council Links Newsletter Liaison

Mardi Gomberg-Maitland, MD
PH Council Chair

The past year since the Annual 2014 meeting for the Pulmonary Hypertension (PH) Council has been a productive one. We completed our first PH monograph, our first Core Academy, and awarded our first PH grant (Bayer sponsored). The council continues to grow and promote its members.

The past year has also been one of continued rapid advancement in the field of PH. With the approval of oral treprostinil by the US Food and Drug Administration (FDA) in December 2013, we now have 12 approved therapeutic options for the treatment of patients with pulmonary arterial hypertension (PAH) which contrasts starkly with the landscape in 1996 when the first therapy for PAH, intravenous epoprostenol, was approved. And a 13th therapy may not be far away from the pharmacy shelves…

Results of 3 major clinical trials of novel therapies and therapeutic strategies in PAH were reported in the past year and have dominated dialogue in the field. Clinical trials in PAH have also moved towards much larger, multicenter and international studies using morbidity and mortality primary endpoints rather than changes in 6-minute walk distance, and this was the case for the trials whose results were reported in 2014-2015.

GRIPHON was a large randomized, placebo-controlled trial of a novel oral selective IP prostacyclin receptor agonist, selexipag, in PAH either as monotherapy or, more commonly, in combination with other background oral PAH therapies such as PDE-5 inhibitors or endothelin receptor antagonists.

Results of the GRIPHON study were first reported at the American College of Cardiology meeting in March 2015 followed by our annual ISHLT meeting. The active treatment group showed a significant reduction in the composite morbidity/mortality endpoint, mainly driven by a reduction in hospitalization.

Surprisingly, although there were only a small number of all cause-deaths in total, more were in the active group plus there was no significant change in 6MWD which was unexpected. Unfortunately, despite the selective prostacyclin receptor agonism, the side effect profile of selexipag was largely similar to other prostacyclin agents. Selexipag is presently under evaluation at the US FDA based on GRIPHON results.

The other major clinical trials reported in 2014-2015 are unique in that they did not study unique therapeutic agents but rather sought to evaluate the optimal treatment strategy for using combinations of currently approved agents either, up-front or as sequential add-on therapy.

Many experts in the field have long been using combinations of PAH therapeutic agents which target different pathophysiologic pathways, with the assumption that these therapies would be synergistic in terms of improvements in hemodynamics and symptoms in patients with PAH, though evidence for this strategy had been limited to relatively small sequential add-on studies.

COMPASS-2 was a large, randomized placebo-controlled study of the addition of bosentan vs. placebo to patients already receiving sildenafil for at least 12 weeks with primary composite endpoint of reduction in first morbidity/mortality event. The study failed in terms of its primary endpoint (relative risk reduction of only 17% vs. placebo, p=0.25).

In contrast, AMBITION, a large multicenter trial of up-front combination therapy with ambrisentan and tadalafil vs. monotherapy with either drug in treatment naïve PAH patients showed a significant reduction in time to first clinical failure event, driven mainly by a reduction in hospitalizations.

As a result of the impressive results of AMBITION, the strategy of up-front combination therapy vs. sequential add-on therapy has been a major talking point in the field and the question remains as to whether this trial will ultimately change guidelines for the initial management of patients with newly diagnosed PAH and WHO functional class II or III symptoms ... stay tuned!

Finally, chronic thromboembolic pulmonary hypertension (CTEPH) has been a major focus in the pulmonary hypertension community in 2014-2015. The number of centers in the United States performing pulmonary thromboendarterectomy has increased, as has awareness of this elusive disease, which is often under-diagnosed. November 18th 2014 was the first annual CTEPH awareness day, and a new US CTEPH registry is in the early stages of development.

Overall the past year has been filled with major advances in the field of pulmonary hypertension many of which are beyond the scope of this recap to fully describe, but with the current rate of development, we are getting closer to the ultimate goal of a cure for this deadly disease. ■

Disclosure Statement: the authors have no conflicts of interest to report.

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