Higher Tyvaso Doses Better at Preventing PH-ILD Worsening
Post hoc analysis shows benefit of starting Tyvaso early, increasing dosage
A high dose of Tyvaso (inhaled treprostinil) — at least nine breaths four times per day — is more effective at preventing clinical worsening than lower doses for people with pulmonary hypertension associated with interstitial lung disease (PH-ILD), a new study indicates.
“This analysis further reinforces that [Tyvaso] prevents clinical worsening, and in addition demonstrates that [Tyvaso] is associated with significantly more patients experiencing clinical improvement when compared to placebo. In addition, our analysis suggests that higher dose [Tyvaso] is more effective than lower dose in achieving these outcomes,” the researchers wrote.
The study, “Inhaled Treprostinil Dose in Pulmonary Hypertension Associated with Interstitial Lung Disease and Its Effects on Clinical Outcomes,” was published in Chest. The work was funded by United Therapeutics, which markets Tyvaso in the U.S.
Tyvaso was approved by the U.S. Food and Drug Administration (FDA) in 2021 to treat PH-ILD. The approval was supported by data from the Phase 2/3 INCREASE trial (NCT02630316) that compared it against a placebo in 326 adults with PH-ILD.
INCREASE met its main goal: after 16 weeks, participants given Tyvaso showed improvements in exercise capacity, measured by a six-minute walk distance (6MWD), compared to those on a placebo.
At the start of INCREASE, participants were given Tyvaso or a placebo at a dose of three breaths per session, four times daily. Under the direction of a study investigator and based on tolerability, participants would gradually increase the dose up to a maximum of 12 breaths per session. Based on the titration schedule, the earliest a patient could increase to a dose of nine breaths per session would be on study day 21 (three weeks).
In this post hoc analysis, researchers divided the patients into two groups based on the dosage they had been on at week four. A post hoc analysis is one carried out after the study is already over and data have been collected.
Of 149 patients in the Tyvaso group, 70 were on a dose of at least nine breaths per session at week four, as were 86 of 153 patients in the placebo group. The rest were on lower doses. From week four through the end of the study, the scientists compared rates of clinical worsening — defined as 15% decrease in 6MWD, hospitalization, lung transplant, or death — in the dosage groups.
Rates of clinical worsening in the high- and low-dose Tyvaso groups were 17.1% and 22.8%, respectively. In the high- and low-dose placebo groups, the respective rates were significantly higher at 33.7% and 34.3%.
Clinical improvement — a 15% increase in 6MWD and 30% decrease in levels of a marker of heart damage called NT-proBNP by study week 16, in the absence of any worsening events — was reported in 15.7% of patients in the high-dose Tyvaso group and 12.7% in the low-dose Tyvaso group. In the high- and low-dose placebo groups, improvement was reported in 7% and 1.5% of patients.
“This post hoc analysis demonstrates that a higher dose of [Tyvaso] is associated with an overall greater benefit in patients with PH-ILD, not only in comparison to placebo but also in comparison to lower dose of [Tyvaso],” the scientists wrote.
The researchers said they limited their analysis to weeks four through 16 in order to avoid biased data during the early dose-adjusting period. Still, they noted a number of clinical worsening events occurred during the first few weeks of the study, even though those were not included in the dose analysis.
“The fact that there were a sizable group of patients who did have clinical worsening during this early phase of the study does however underscore the need for the early implementation of therapy,” the scientists wrote, noting a limitation of the study was that participants were allowed to continue adjusting doses throughout the study, so the dosage at week four was not necessarily the one through week 16. However, sensitivity analyses based on the last dose received, rather than at week four, yielded very similar results to the primary analysis.
“These results support the importance of early initiation and uptitration of inhaled [Tyvaso] therapy to at least 9 breaths or more four times a day,” the researchers concluded.