High-Dose Treprostinil Helps Pulmonary Hypertension in Interstitial Lung Disease

Early initiation and uptitration of inhaled treprostinil — to a dose of at least 9 breaths 4 times daily — offers patients with pulmonary hypertension (PH) due to fibrotic interstitial lung disease (ILD) the greatest benefit with respect to clinical improvement and prevention of clinical worsening. These were among post-hoc clinical trial findings published in Chest.

In the INCREASE study, (ClinicalTrials.gov Identifier: NCT02630316), a 16-week, randomized, placebo-controlled, double-blind trial in 326 patients with PH due to ILD, investigators found that higher doses of inhaled treprostinil were associated with greater improvements in 6-minute walking distance. In that trial, patients were uptitrated from 3 inhalations to 9 to 12 inhalations of treprostinil, 4 times daily, over the 16-week study period. The current study, a post hoc analysis of the INCREASE trial, further examined the association between dosage level of inhaled treprostinil and rates of clinical worsening/clinical improvement in patients with PH-ILD. 

For the post hoc analysis, investigators kept patients in the following cohorts for an initial 4-week period: a high-dose treprostinil cohort (n=70 patients receiving at least 9 inhalations of treprostinil per treatment session), a high dose placebo cohort (n=86), a low-dose treprostinil cohort (n=79 patients receiving less than 9 inhalations per session), and a low-dose placebo cohort (n=67). Baseline demographics and clinical variables were well-balanced between the 4 groups.

Between weeks 4 and 16, a total of 40 patients in the low-dose treprostinil group were uptitrated to the high-dose treprostinil group and 4 patients in the high-dose treprostinil group were downtitrated to the low-dose treprostinil group. Correspondingly, in the placebo groups, 45 patients were uptitrated and 3 patients were downtitrated during that same time period. The trial was completed at week 16 with 97 patients on high-dose treprostinil, 26 patients on low-dose treprostinil, 114 in the high-dose placebo cohort, and 11 in the low-dose placebo cohort.

Patients were assessed for clinical improvement (defined as a 15% increase in the 6-minute walk distance, with 30% reduction in N-terminal pro b-type natriuretic peptide, without any clinical worsening event) or clinical worsening (defined as lung transplantation, cardiopulmonary hospitalization, death, or a 15% decrease in the 6-minute walk distance). Researchers found that between weeks 4 and 16, the rate of clinical worsening in the high-dose treprostinil group was 17.1% vs 22.8% in the low-dose treprostinil group and 33.7% and 34.3% in the high- and low-dose placebo groups, respectively (P =.006). By week 16, the researchers found clinical improvement among 15.7% of patients in the high dose treprostinil group, 12.7% of those in the low-dose treprostinil group, and 7% and 1.5% of those in the high- and low-dose placebo groups, respectively (P =.003).

Sensitivity analysis showed fewer patients with clinical worsening in the high-dose treprostinil group (16.4%) vs the low dose treprostinil group (30.8%), high-dose placebo group (32.3%), low-dose placebo group (42.35%). This analysis also showed greater clinical improvement among patients in the high-dose treprostinil group (17.3%) vs the low dose treprostinil group (5.1%), high-dose placebo group (4.7%), and low-dose placebo group (3.8%).

Study limitations include changes in patient cohort placement mid-study; short study duration; the use of patient tolerance of higher dosage levels as a surrogate for disease severity; and lack of central adjudication of clinical worsening events.

Overall, in the post hoc analysis of INCREASE, approximately 75% of patients were able to achieve a dose of at least 9 inhalations 4 times a day, suggesting that uptitrating the dosage of treprostinil “is feasible in most patients over a relatively short period of time with appropriate adverse event management,” said study authors. These results underscore “the importance of early initiation and uptitration of inhaled treprostinil therapy to at least 9 breaths or more 4 times a day,” they added.

Disclosure: This research was supported by United Therapeutics Corporation. Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.

Reference

Nathan SD, Deng C, King CS, et al. Inhaled treprostinil dose in pulmonary hypertension associated with interstitial lung disease and its effects on clinical outcomes. Chest. Published online September 14, 2022. doi:10.1016/j.chest.2022.09.007