Introduction

PH is a progressive pulmonary vascular disorder characterized by increased pulmonary arterial pressures and pulmonary vascular resistance, eventually associated with right heart failure.¹ PH is a frequent complication in patients with ILD.^2-4 PH with ILD is associated with decreased survival, impaired exercise capacity, decreased quality of life, and higher need for supplemental oxygen.^3,5

Although there has been a significant progress in pharmacotherapy and drug development for patients with pulmonary arterial hypertension,⁶ the use of selective pulmonary vasodilators has not been shown to be beneficial in patients with other forms of PH, including PH with ILD.⁷ Furthermore, safety concerns were identified in some of the largest clinical trials,^8-10 which had to be stopped prematurely.

It has been postulated that systemic vasodilators could worsen ventilation-perfusion mismatch in patients with PH with ILD, which could partially explain the reported adverse outcomes. As such, inhaled agents could offer more selective and effective vasodilatory effect.¹¹ A case series in patients with chronic lung disease and PH revealed a signal toward improvements in functional class and exercise capacity after treatment with inhaled treprostinil.¹² The INCREASE trial assessed the safety and efficacy of inhaled treprostinil in patients with PH with ILD.

The INCREASE Trial

Methods

The INCREASE trial was a 16-week, phase III, multicenter, randomized, double-blind, placebo-controlled, parallel group study of inhaled treprostinil in patients with PH with ILD.¹³ The study population consisted of patients with PH with ILD aged 18 years of age and older. ILD was diagnosed as evidence of diffuse parenchymal lung disease on computed tomography of the chest, and PH was confirmed by right heart catheterization with evidence of pre-capillary PH (using a mean pulmonary artery pressure of ≥25 mmHg, which was the hemodynamic definition at the time of study design). Patients were assigned in a 1:1 ratio to receive either inhaled treprostinil or placebo. The primary efficacy endpoint was the difference between the 2 groups in the change in peak 6MW distance from baseline to week 16. Secondary efficacy endpoints included the change in NT-proBNP levels at week 16 and the time to clinical worsening (composite endpoint including hospitalization for a cardiopulmonary indication, decrease in 6MW distance greater than 15%, death from any cause, or lung transplantation).

Results

A total of 326 patients underwent randomization, with 163 patients assigned to receive inhaled treprostinil and 163 patients assigned to placebo. The rate of study discontinuation was similar in both groups (20.2% and 21.5% of patients in the treprostinil and placebo arms, respectively). Baseline characteristics were similar between both groups. The mean age of participants was 66.5 years, 46.9% were female, and idiopathic interstitial pneumonia was the most common diagnosis.

There was a statistically significant difference in the change from baseline in peak 6MW distance. The 6MW distance increased by a mean of 21.08 m in the treprostinil group, and it decreased by 10.04 m in the placebo group. The least-squares mean difference between the treprostinil group and the placebo group was 31.12 m (95% confidence interval [CI], 16.85-45.39; p < 0.001). This effect was observed across different subgroups, being more pronounced in individuals with a baseline diffusing capacity for carbon monoxide <40% predicted (least-squares mean difference 33.0; 95% CI, 17.7-48.3) and a pulmonary vascular resistance ≥4 Wood units (least-squares mean difference 40.8; 95% CI, 24.1-57.6). For the secondary outcomes, NT-proBNP levels decreased by 15% from baseline in the treprostinil group and increased 46% from baseline in the placebo group (treatment ratio 0.58; 95% CI, 0.47-0.72; p < 0.001). The treprostinil group had fewer clinical worsening events (hazard ratio 0.61; 95% CI, 0.4-0.92; p = 0.04), although this difference was due principally to the effect on 6MW distance. The incidence of serious adverse events was similar between groups (23.3% and 25.8% in the treprostinil and placebo groups, respectively). Cough, throat irritation, and oropharyngeal pain were more common in the treprostinil group.

Discussion

The INCREASE trial is the first randomized clinical trial to show improvements in exercise capacity and other clinical outcomes in patients with PH with ILD treated with inhaled treprostinil. Patients treated with inhaled treprostinil had statistically significant improvements in exercise capacity, as evidenced by changes in 6MW distance, compared with placebo. Patients also had significant improvements in NT-proBNP levels, as a marker of right ventricular dysfunction, as well as fewer clinical worsening events.

Previous studies using pulmonary vasodilators in PH with ILD have not shown major clinical improvements but have instead shown harm and impaired outcomes. In ARTEMIS-PH (Study of Ambrisentan in Subjects With Pulmonary Hypertension Associated With Idiopathic Pulmonary Fibrosis), patients with IPF were randomized to ambrisentan or placebo. The study had to be prematurely terminated due to observed higher rates of disease progression and increased hospitalization for respiratory events in patients receiving ambrisentan.^8,9 More recently, the RISE-IIP (Efficacy and Safety of Riociguat in Patients With Symptomatic Pulmonary Hypertension Associated With Idiopathic Interstitial Pneumonias) trial randomized patients with PH with ILD to riociguat or placebo.¹⁰ There was no significant improvement in the primary outcome of change in 6MW distance, but the study was terminated early due to an increased number of deaths and adverse events in the riociguat group. The reported adverse outcomes have been thought to be linked to non-selective vasodilation with the use of pulmonary vasodilators, which could lead to ventilation-perfusion mismatch.

The INCREASE trial has several limitations. The study was of short duration (16 weeks), and it is unclear if the improvement in exercise capacity could be maintained over a longer period. In addition, 21% patients discontinued the trial prematurely. The large amount of missing outcome data and the analytic models used could also affect the magnitude of the treatment benefit reported.

The significance of the changes in 6MW distance requires further discussion. The minimal clinically important difference is the smallest difference in a measure that can be perceived to be important. The minimal clinically important difference reported in patients with ILD is in the range of 21.7-45 m.^14,15 The size of the favorable treatment effect with inhaled treprostinil certainly falls within the minimal clinically important difference range. Regardless of whether this significant but small improvement is clinically meaningful, the 6MW-distance improvement in the INCREASE trial is of similar magnitude as the one reported in the TRIUMPH (Clinical Investigation Into Inhaled Treprostinil Sodium in Patients With Severe Pulmonary Arterial Hypertension) trial, in which patients with pulmonary arterial hypertension on background oral therapy were randomized to inhaled treprostinil or placebo, and the treprostinil arm had an improvement of 20 m at week 1.¹⁶ Furthermore, and perhaps more important, it should also be noted that the placebo group actually had a decline in exercise capacity, and it is known that declines in exercise capacity could predict clinical worsening both in PH and ILD.^17,18 We believe the improvement in clinical outcomes reported in the INCREASE trial are promising in this complex group of patients.

Conclusion

The INCREASE trial is the first randomized clinical trial to show clinical improvements in patients with PH with ILD treated with pulmonary vasodilators. The use of inhaled treprostinil was associated with improvement in exercise capacity, decrease in NT-proBNP levels, and lower incidence of clinical worsening events. Longer-term data are needed for further assessment of the magnitude of clinical improvement.

References

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Clinical Topics: Diabetes and Cardiometabolic Disease, Heart Failure and Cardiomyopathies, Noninvasive Imaging, Prevention, Pulmonary Hypertension and Venous Thromboembolism, Vascular Medicine, Acute Heart Failure, Pulmonary Hypertension, Hypertension

Keywords: Hypertension, Pulmonary, Quality of Life, Vasodilator Agents, Double-Blind Method, Ventricular Dysfunction, Right, Vasodilation, Exercise Tolerance, Arterial Pressure, Pharynx, Pulmonary Artery, Idiopathic Interstitial Pneumonias, Vascular Resistance, Lung Diseases, Interstitial, Idiopathic Pulmonary Fibrosis, Lung Transplantation, Perfusion, Heart Failure, Cardiac Catheterization, Disease Progression, Hospitalization, Tomography, Oxygen

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