Inhaled treprostinil in pulmonary hypertension due to interstitial lung disease

Aaron Waxman, Ricardo Restrepo-Jaramillo, Thenappan Thenappan, Ashwin Ravichandran, Peter Engel, Abubakr Bajwa, Roblee Allen, Jeremy Feldman, Rahul Argula, Peter Smith, Kristan Rollins, Chunqin Deng, Leigh Peterson, Heidi Bell, Victor Tapson, Steven D. Nathan

Research output: Contribution to journalArticlepeer-review

277 Scopus citations


BACKGROUND: No therapies are currently approved for the treatment of pulmonary hypertension in patients with interstitial lung disease. The safety and efficacy of inhaled treprostinil for patients with this condition are unclear.

METHODS: We enrolled patients with interstitial lung disease and pulmonary hypertension (documented by right heart catheterization) in a multicenter, randomized, double-blind, placebo-controlled, 16-week trial. Patients were assigned in a 1:1 ratio to receive inhaled treprostinil, administered by means of an ultrasonic, pulsed-delivery nebulizer in up to 12 breaths (total, 72 μg) four times daily, or placebo. The primary efficacy end point was the difference between the two groups in the change in peak 6-minute walk distance from baseline to week 16. Secondary end points included the change in N-terminal pro-B-type natriuretic peptide (NT-proBNP) level at week 16 and the time to clinical worsening.

RESULTS: A total of 326 patients underwent randomization, with 163 assigned to inhaled treprostinil and 163 to placebo. Baseline characteristics were similar in the two groups. At week 16, the least-squares mean difference between the treprostinil group and the placebo group in the change from baseline in the 6-minute walk distance was 31.12 m (95% confidence interval [CI], 16.85 to 45.39; P<0.001). There was a reduction of 15% in NT-proBNP levels from baseline with inhaled treprostinil as compared with an increase of 46% with placebo (treatment ratio, 0.58; 95% CI, 0.47 to 0.72; P<0.001). Clinical worsening occurred in 37 patients (22.7%) in the treprostinil group as compared with 54 patients (33.1%) in the placebo group (hazard ratio, 0.61; 95% CI, 0.40 to 0.92; P = 0.04 by the log-rank test). The most frequently reported adverse events were cough, headache, dyspnea, dizziness, nausea, fatigue, and diarrhea.

CONCLUSIONS: In patients with pulmonary hypertension due to interstitial lung disease, inhaled treprostinil improved exercise capacity from baseline, assessed with the use of a 6-minute walk test, as compared with placebo. (Funded by United Therapeutics; INCREASE number, NCT02630316.).

Original languageEnglish (US)
Pages (from-to)325-334
Number of pages10
JournalNew England Journal of Medicine
Issue number4
StatePublished - Jan 28 2021

Bibliographical note

Funding Information:
Supported by United Therapeutics.

Publisher Copyright:
Copyright © 2021 Massachusetts Medical Society.


  • Administration, Inhalation
  • Adult
  • Aged
  • Aged, 80 and over
  • Antihypertensive Agents/adverse effects
  • Double-Blind Method
  • Epoprostenol/adverse effects
  • Exercise Tolerance/drug effects
  • Female
  • Humans
  • Hypertension, Pulmonary/drug therapy
  • Least-Squares Analysis
  • Lung Diseases, Interstitial/complications
  • Male
  • Middle Aged
  • Quality of Life
  • Walk Test

PubMed: MeSH publication types

  • Research Support, Non-U.S. Gov't
  • Randomized Controlled Trial
  • Multicenter Study
  • Journal Article


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