Novel Oral Agent Improves Pulmonary HTN
Published: Aug 28, 2013 | Updated: Aug 29, 2013
The novel dual endothelin-receptor antagonist macitentan (Opsumit) improved clinical outcomes in pulmonary arterial hypertension (PAH), the SERAPHIN trial showed.
Action Points
- The novel dual endothelin-receptor antagonist macitentan (Opsumit) improved clinical outcomes in pulmonary arterial hypertension (PAH).
- Point out that the beneficial effect was driven by fewer cases of worsening PAH but came with generally good tolerability.
The oral agent reduced the composite risk of death, atrial septostomy, lung transplantation, starting IV or subcutaneous prostanoids, or worsening PAH by 30% at the 3-mg dose and by 45% at the 10-mg dose compared with placebo, Tomás Pulido, MD, of the National Heart Institute in Mexico City, Mexico, and colleagues found.
The effect was driven by fewer cases of worsening PAH but came with generally good tolerability, the group reported in the Aug. 29 issue of the New England Journal of Medicine, mirroring results initially presented at a conference.
"We now have proof that oral medications do indeed reduce morbidity and mortality in PAH and we don't always have to rely on the more invasive IV medications to accomplish this endpoint," commentedRaymond L. Benza, MD, director of the pulmonary hypertension program at Pittsburgh's Allegheny General Hospital.
He called it a landmark trial as the first powered for a hard clinical endpoint instead of just change in functional class or 6 minute walk distance.
However, the 6 minute walk results were less impressive, noted Brett Fenster, MD, a cardiologist at National Jewish Health in Denver.
The gain over placebo was 17 m with the low macitentan dose and 22 m with the higher dose. While both met statistical significance, most studies with PAH treatments have shown changes of more than 30 m, Fenster explained in an interview with MedPage Today.
Also, the improvement in WHO functional class on either dose of the drug was modest compared with placebo (20% and 22% versus 13%), though again significant.
"So one concern is that this drug really isn't improving the functional capacity of patients the way we would normally see it," Fenster said. "However, one argument has been made that a lot of patients in this group were functional class 2; that is, relatively healthier patients. And in general it's hard to make a healthy patient healthier."
The more important limitation was that the study wasn't powered for and didn't show a significant reduction in all-cause or PAH-related mortality, he noted.
"However, designing a study to reach that endpoint is incredibly difficult, especially in a rare disease that's often progressive," Fenster acknowledged. "And probably this drug alone, even in combinations of drugs, is unlikely to ever achieve that."
The Study with an Endothelin Receptor Antagonist in Pulmonary Arterial Hypertension to Improve Clinical Outcome (SERAPHIN) trial did show areduction in PAH hospitalizations, with rates of 19% on the higher macitentan dose and 22% on the lower dose compared with 32% on placebo.
The combined endpoint of PAH-related hospitalization or death from PAH did come out significantly lower with the novel oral agent, with a 50% relative risk reduction on the 10-mg dose and 33% relative risk reduction on the lower dose compared with placebo (P=0.01 andP<0.001, respectively).
That's an important consideration in this era of focus on cost savings and efficiency, Benza added.
Also, the analysis counted only the first event, and clinical deterioration usually precedes death in this progressive disease, the researchers pointed out.
The 742-patient trial didn't show a difference in treatment effect by whether patients were on other therapies for PAH at baseline.
Overall, the primary composite endpoint occurred in 38% of patients randomized to once-daily 3-mg macitentan and 31% randomized to the higher drug dose compared with 46% on the placebo (P=0.01 and P<0.001, respectively).
Adverse events associated with macitentan more frequently than with placebo were headache, nasopharyngitis, and anemia. Liver enzyme elevations were uncommon across treatment groups. Peripheral edema on macitentan didn't differ from placebo.
Limitations included the lack of an active comparator control arm and that patients who discontinued treatment before a primary endpoint event weren't followed out to the end of the trial.
"Because pulmonary arterial hypertension is a chronic life-threatening disease, data from long-term outcome studies are required to assess the effect of therapy on disease progression," the researchers added.
CORRECTION: This article, which was originally published Aug. 28, 2013, at 6:55 p.m., has been corrected. There were 742 patients in the trial, not 250.
The study was funded by Actelion Pharmaceuticals, which provided study oversight and statistical support.
Pulido reported serving on a macitentan advisory board for which he received consulting fees or honoraria, travel support, and fees for serving as a member of a scientific board, all from Actelion.
He also reported consulting for Actelion, Pfizer, Eli Lilly, and Bayer; receiving grant funds from Actelion, Bayer, United Therapeutics, and Gilead; receiving payment for speaking from Actelion, Bayer, and Eli Lilly; and getting grant funds to his institution from the National Heart Institute.
Three co-authors were Actelion employees.
From the American Heart Association:
