Inhaled Treprostinil Shows Promise for ILD-Induced Pulmonary Hypertension


Patients receiving the drug experienced improvement in the 6-minute walk test and demonstrated a lower risk of clinical worsening.

Aaron Waxman, MD, PhD

Aaron Waxman, MD, PhD

Findings from a new study demonstrated that inhaled treprostinil improved exercise capacity in patients with pulmonary hypertension due to interstitial lung disease (ILD).

The drug was further associated with a lower risk of clinical worsening, a reduction in NT-proBNP levels, and fewer exacerbations of underlying lung disease when compared with placebo.

Previous research has shown treprostinil to improve exercise capacity after 12 weeks of therapy with group 1 pulmonary hypertension; however, no therapies are currently approved for treatment of pulmonary hypertension in patients with ILD.

Led by Aaron Waxman, MD, PhD, Brigham and Women’s Hospital, the team of investigators enrolled a total of 326 patients in a multicenter, randomized, double-blind, placebo-controlled INCREASE trial.

They sought to evaluate the efficacy and safety of the prostacyclin analogue over the course of 16 weeks.

Treprostinil for ILD-Related Pulmonary Hypertension

All enrolled patients were randomized 1:1 to receive inhaled treprostinil or placebo. The medication was administered through an ultrasonic, pulsed-delivery nebulizer in up to 12 breaths, 4 times daily.

Efficacy was thus evaluated using the 6-minute walk test, which was assessed at baseline, weeks 4, 8, 12, and 16. Tests were performed 10-60 minutes following the most recent dose of the drug or placebo.

The investigators then used the difference in this change from baseline to week 16 between the groups as their primary efficacy endpoint.

“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% CI, 16.85-45.39; P<0.001),” Waxman and colleagues wrote.

They also noted similar effects across subgroups, inclduing disease cause and severity. Such effects were likewise reported across baseline hemodynamic and dosing groups.

The team observed a 15% reduction in NT-proBNP levels from baseline with usage of inhaled treprostinial—on the contrary, placebo was associated with a 46% (treatment ratio, 0.58; 95% CI, 0.47-0.72; P<.001).

In the treprostinil group, clinical worsening occurred in 37 patients, while worsening in the placebo group occurred in 54 patients (HR, 0.61; 95% CI, 0.40-0.92; P = .04).

As for safety, 152 treprostinil-treated patients experienced ≥1 adverse events—compared with 149 placebo-treat patients.

The most frequently reported events were cough, headache, dyspnea, nausea, fatigue, and diarrhea.

Serious adverse events were reported in 38 patients treated with treprostinil and in 42 who received placebo.

And finally, 43 patients in the treprostinil group experienced exacerbations of underlying disease—versus 63 in the placebo group (P = .02).

Promise and Limitations

The investigators acknowledged that the trial has shown no evidence of worsened oxygenation, given general care concerns surrounding ventilation-perfusion mismatching for those with group 3 pulmonary hypertension.

“Inhaled agents have the advantage of preferentially redirecting blood flow to the best-ventilated lung units, thus reducing the risk of ventilation–perfusion mismatching,” Waxman and colleagues wrote.

As acknowledged by the team, certain limitations surrounding the trial were its overall short duration and the fact that 21% of the patients prematurely discontinued the study.

“Finally, the size of the favorable treatment effect on the 6-minute walk distance with inhaled treprostinil is similar to estimates of the minimum clinically important difference for this test in patients with pulmonary disease,” they noted.

Nevertheless, they expressed optimism of the efficacy and safety of treprostinal for patients with ILD-induced pulmonary hypertension.

The study, “Inhaled Treprostinil in Pulmonary Hypertension Due to Interstitial Lung Disease,” was published online in The New England Journal of Medicine.

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