Higher Doses of Inhaled Treprostinil Reduce Clinical Worsening in Patients with Pulmonary Hypertension Associated with Interstitial Lung Disease
Presenter: Aaron Waxman, MD, Director, Pulmonary Vascular Disease Program, Brigham and Women's Hospital, Boston, MA, and Associate Professor of Medicine, Harvard Medical School, Boston, MA.
A summary of the oral abstract, Dose response analysis of inhaled treprostinil in pulmonary hypertension associated with interstitial lung disease and its effects on clinical worsening, October 17, 2021, Chest 2021.
Higher doses of inhaled treprostinil can reduce rates of clinical worsening in patients with interstitial lung disease and associated pulmonary hypertension (PH-ILD), according to results from a recent post-hoc analysis of the INCEASE study, according to Aaron Waxman, presenter and lead author of several reports from the study (Waxman N Engl J Med 2021; Waxman Chest 2021). The INCREASE study is a multicenter, randomized, double-blind, placebo-controlled, 16-week, parallel-group study that evaluated inhaled treprostinil in patients with PH-ILD.
According to Waxman, “The study met its primary endpoint of change in 6-minute walk distance at week 16. In the INCREASE study, higher doses of inhaled treprostinil were associated with greater improvements in 6-minute walk distance. However, it is unknown whether higher doses of inhaled treprostinil are associated with other benefits, such as decreased rates of clinical worsening.”
“In this post-hoc analysis (Waxman Chest 2021), patients in the inhaled treprostinil arm were divided based on maximum dose achieved into 2 groups, less than 9 and 9 or more breaths per session (bps),” he said. “Kaplan-Meier estimates were used to evaluate time to clinical worsening. We also compared overall rates of clinical worsening between groups using a log ranked test.”
“Among the 163 patients in the inhaled treprostinil arm, 41 patients were in the less than 9 bps group and 122 patients were in the group of 9 or more bps. The groups were similar in demographics, hemodynamics, and lung function at baseline. The median dose in the less than 9 and 9 or more bps group was 6 and 12 bps, respectively.”
“A total of 16 patients (39%) in the less than 9 bps and 21 patients (17%) in the 9 or more bps groups experienced a clinical worsening event,” Waxman said. “This was a statistically significant difference. Patients in the group of 9 or more bps group had a significantly lower rate of clinical worsening. Significantly fewer patients died in the higher dose group (3%) compared to the lower dose group (15%). There were similar incidences of 6-minute walking distance decline, cardiopulmonary hospitalization, lung disease exacerbation, and lung transplantation in both dose groups.”
In summary, Waxman said: “Higher doses of inhaled treprostinil were associated with a lower risk of clinical worsening. Kaplan-Meier curves separate early on after patients had up-titrated dose, demonstrating that the dose-response on clinical worsening occurs early in the treatment course. The majority of patients (75%) were able to achieve a dose of 9 or more bps 4 times daily, suggesting that titrating to efficacious doses of inhaled treprostinil is feasible in this patient population in the context of appropriate event management. These findings are similar to group 1 pulmonary arterial hypertension patients, suggesting that higher doses of inhaled treprostinil have beneficial effects on survival and delayed time to parenteral therapy.”
“Limitations of this analysis include a small sample size in the less than 9 bps group and the relatively short duration of the study,” he noted. “Additionally, the study separated patients based on maximum dose achieved and did not include the time spent (number of weeks) at the actual dose.”
“This post-hoc analysis suggests that a higher dose of inhaled treprostinil has beneficial effects on clinical worsening in patients with PH-ILD,” Waxman concluded. “Our results underscore the importance and benefits of titrating inhaled treprostinil dose to the maximum tolerated dose for those patients with PH-ILD.”
Disclosures
Aaron Waxman, MD: Acceleron (Grant/Research Support), ARIA CV (Consulting fee, Grant/Research Support), Gossamer (Grant/Research Support), United Therapeutics (Consulting fee, Grant/Research Support).
References
Waxman A, Restrepo-Jaramillo R, Thenappan T, et al. Inhaled treprostinil in pulmonary hypertension due to interstitial lung disease. N Engl J Med 2021; 384(4):325–334. doi: 10.1056/NEJMoa2008470
Waxman A, Nathan S, Fisher M, et al. Dose response analysis of inhaled treprostinil in pulmonary hypertension associated with interstitial lung disease and its effects on clinical worsening. Chest 2021; 160(4)(suppl): A2279–A2280. doi: 10.1016/j.chest.2021.07.1995