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What's New in Pulmonary Hypertension?


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Veronica Franco, MD
The Ohio State University
Columbus, Ohio, US
veronica.franco@osumc.edu



Preparations for the 2015 ISHLT meeting are underway and it promises to be a great collection of symposia in the beautiful city of Nice. The world of pulmonary hypertension is also full of exciting news. Today, PH specialists have many more treatment options than they did a decade ago and three new medications have been approved as of 2013 [1,2]. Additional studies on these newer medications were presented at the American Thoracic Society (ATS) meeting in May 2014.

Data from the SERAPHIN trial was presented by Dr. Mehta; 10 mg daily of Macitentan, an endothelin receptor antagonist, significantly reduced all-cause hospitalizations in PAH patients compared to placebo. links imageSERAPHIN [1] was an event driven study where double-blinded therapy was continued until patients either experienced a primary endpoint (morbidity or mortality) event or until the end of study. Of the 250 patients in the placebo group, and the 242 patients in the macitentan 10 mg group, 117 (47%) and 90 (37%) were hospitalized at least once, experiencing 171 and 135 hospitalizations over a median treatment duration of 85 and 104 weeks, respectively. The risk of hospitalization for causes unrelated to PAH was similar between patients on placebo and those treated with macitentan 10 mg (HR 0.890; 95% CI 0.616-1.285; p=0.5347). Compared with the placebo, the risk of being hospitalized for any cause was significantly reduced by 32% with macitentan 10 mg (HR 0.677; 95% CI 0.514-0.891; p=0.0051) (Figure). The annual rate of all-cause hospitalization was reduced by 33% with macitentan 10 mg compared with placebo (27.7 vs 41.5 hospitalizations per 100 patient-years, respectively; p=0.0005).

There is a paradigm change in clinical trials in PAH, calling for newer and improved trial design in this orphan disease [3]. The PH community will continue to look for novel therapies that will not only improve functional capacity, but also morbidity and mortality. The SERAPHIN trial studied important aspects in the care of PAH patients, such as hospitalizations. Current developments in PAH therapeutics and better trial design with robust clinical outcomes will certainly continue to improve the state of the disease.

Another interesting study was presented at ATS by Dr. White. It discussed the safety and tolerability of transitioning from parental to oral treprostinil [2] in patients with PAH. This was a preliminary report of an ongoing, open-label, multi-center study for subjects with well-compensated PAH being managed with parental treprostinil (25-150 ng/kg/min) plus an oral PAH-specific therapy. Participants were included if they had WHO functional class I/II symptoms and cardiac index ≥ 2.2 L/m/m2. 27 subjects were enrolled. Baseline demographics included a median age of 50 years (18-80) and median 6MWD of 457 meters (279-641); most patients were idiopathic or heritable PAH (n=19). The median treprostinil dose at baseline was 54 ng/kg/min (25-124.5). Seven patients were receiving ERA & PDE5-I, seventeen PDE5-I, and three ERA therapy. The majority of patients were transitioned to oral trepostinil within 4 days as inpatients. 10 patients were transitioned to oral treprostinil BID and 17 patients to TID dosing. At the end of the transition phase, the median total daily dose of oral treprostinil was 24 mg. Only 9 patients have reached 6 months evaluations by the time this trial was presented. 17 are ongoing, and 1 patient with scleroderma did not tolerate oral treprostinil (after transition) and returned to parenteral treprostinil. Interim data were available on the first 9 patients to reach 6 month follow up. Median 6MWD was 453 meters (354-641) with no worsening of functional class. Pharmacokinetic analyses confirmed that 1 mg TID ~ 5 ng/kg/min in terms of treprostinil exposure (AUC) for a typical 70 kg patient.

This study was small and follow up at 6 months was only available in 9 patients;however, it provides important information to a question in everyone's mind: are we ready to change stable patients on IV or SQ treprostinil to oral therapy? Interestingly, this was a question many had ~ 10 years ago, when the only available therapy was IV epoprostenol and bosentan was approved. In the current era, we certainly have a significant number of patients only on oral specific PAH therapy. The adequate timing to start parental prostacyclins remains controversial, and many experts in the field advocate for "the earlier the better." Patients, on the other hand, are excited about not dealing with an intricate system and using a "much simpler pill." Interestingly, the oral therapeutic alternative is now another prostacyclin. This study shows that stable and very carefully-selected PAH patients can be safely transitioned to oral treprostinil without a significant decline in exercise capacity at least up to 6 months. Yet, the most important question remains: will the long-term efficacy be comparable to parental prostacyclins? Stay tuned!

Other important trials will also be presented at upcoming meetings, such as the European Respiratory Society and American College of Chest Physicians. 1) The AMBITION trial evaluated an upfront combination of Ambrisentan and Tadalafil for patients with PAH. There are several potential advantages of using combination treatment. Using combination therapy may provide additive, and in some cases synergistic, benefit by simultaneously addressing multiple disease pathways. Currently, physicians use a goal-directed approach to combine agents from different classes to target multiple pathologic pathways in an attempt to increase efficacy and optimize outcomes in PAH. If a patient has not reached the goal walk distance, functional class or hemodynamic ideal response, an additional medication is added after 3-6 months. Yet, supporting data for this approach are largely anecdotal and its use remains controversial. AMBITION has been designed to answer this important question; 2) The GRIPHON study evaluated the efficacy of oral selexipag, a prostacyclin IP receptor agonist that is highly selective for the human prostacyclin IP receptor. Prostacyclin analogs are not selective and activate other prostacyclin receptors. The very selective profile of selexipag causes greater vasodilatory effects than iloprost. Selexipag has a half-life of ~8 hours, making it an attractive candidate for clinical use. ■

Disclosure Statement: The author is a speaker bureau/consultant for Gilead and Bayer, and has received research support from Bayer, Actelion, Gilead and United Therapeutics.


References:

  1. Pulido T, Adzerikho I, Channick R, et al. Macitentan and morbidity and mortality in pulmonary arterial hypertension. N Engl J Med 2013; 369: 809-819.
  2. Jing ZA, Parikh K, Pulido T, et al. Efficacy and safety of oral treprostinil monotherapy for the treatment of pulmonary arterial hypertension: a randomized controlled trial. Circulation 2013; 127: 624-633.
  3. Gomberg-Maitland M, Bull TM, Saggar R, et al. New trial designs and potential therapies for pulmonary artery hypertension. J Am Coll Cardiol 2013; 62: D82-91.



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