12 April 2021

Will the INCREASE study levitate group 3 PH awareness and interest?

Steven D. Nathan, MD; Aaron Waxman, MD, PhD.


Word count: 800

Reports documenting the presence and impact of pulmonary hypertension (PH) complicating lung disease date back to the early 1980s.  Ever since effective therapies for group 1 pulmonary arterial hypertension started to emerge in the 1990s with IV epoprostenol, through the early 2000s with the endothelin receptor antagonists and PDE-5 inhibitors, there has been increasing interest in the potential role of these therapies for PH beyond group 1 disease (1).  The only successful foray thus far has been for group 4 chronic thromboembolic PH with riociguat being the only drug specifically approved for this indication.  There have been multiple prior attempts addressing the role of pulmonary vasoactive therapies for group 3 PH, primarily in patients with interstitial lung disease and chronic obstructive pulmonary disease.  Many of these have been small case series, and retrospective analyses with very few randomised controlled studies (1).  While there have been suggestions and signals suggesting potential efficacy, there have not previously been any definitive double blind placebo controlled randomised controlled studies to demonstrate efficacy in group 3 PH.  In fact, the prior largest study of riociguat in patients with pulmonary hypertension related to idiopathic interstitial pneumonia (RISE-IIP) was a negative study that was halted early at the behest of the data safety monitoring committee for increased harm in the treatment arm (2).  After the failure of the RISE-IIP study, there was some despair in the community that perhaps PH related to lung disease should not be treated, and that this may be a reactive or compensatory phenomenon rather than a maladaptive process.  In an attempt to identify causation, a post-hoc analysis of RISE-IIP was undertaken which suggested that the high parenchymal lung disease burden and the presence of more emphysema than fibrosis might have predisposed patients to poor outcomes. Therefore, studies of therapy for group 3 pulmonary hypertension should include centrally adjudicated imaging for morphologic phenotyping and disease burden evaluation during screening (3).  In any event, it was with great excitement, and a measure of relief, when the positive results of the INCREASE study results were released in February 2020. The INCREASE study was subsequently presented virtually at ATS 2020 and published in the New England Journal of Medicine in January 2021 (4).

INCREASE is the largest double-blind placebo controlled randomised study in group 3 pulmonary hypertension to date.  It included 326 patients with various forms of interstitial lung disease who were randomised to receive inhaled treprostinil versus inhaled placebo over a period of 16 weeks.  The main inclusion criteria required having interstitial lung disease with right heart catheterisation documented pulmonary hypertension (PVR>3WU, PCWP<15mmHg, mPA>25mmHg).  The primary endpoint of the study was the placebo corrected difference in 6 minute walk distance at 16 weeks.  There were also a number of secondary and safety endpoints evaluated.  The 2 groups were generally well matched with the predominant underlying interstitial lung diseases constituted by idiopathic interstitial pneumonia (45 percent), combined pulmonary fibrosis and emphysema (25 percent), connective tissue disease-related interstitial lung disease (22 percent), and chronic hypersensitivity pneumonitis (6 percent).  This was a sick group of patients with the majority (71.5 percent) on supplemental oxygen and a baseline 6 minute walk distance of 254 meters for the Inhaled treprostinil group and 265 meters for the placebo arm.  The study met its primary endpoint with a 31 meter difference in the (drug) peak 6 minute walk distance at 16 weeks favoring the treatment arm (Mixed-model repeated-measures analysis). Most of the secondary endpoints were met, including clinical worsening (22.7% in the treatment arm versus 33.1% in the placebo arm, p=0.04), change in the NT-proBNP (15% decrease in the treatment arm versus a 46% increase in the placebo group), difference in the peak 6 minute walk distance at 12 weeks (31.29 m), and the trough 6 minute walk distance at 15 weeks (21.99 m). The secondary endpoints that were not met included change in the Saint Georges Respiratory Questionnaire and change in the distance-saturation product. Adverse event rates were similar in both groups as were the number of drop-outs. There were no unfavorable safety signals, most notably there was no evidence of increased oxygen requirements in the treatment arm. Interestingly, two prespecified safety outcomes pointed to additional benefits from inhaled treprostinil; specifically, there were fewer acute exacerbations of the underlying lung disease in the treatment arm, and there was a notable favorable difference in the placebo-corrected change in FVC at 16 weeks. The latter finding is especially intriguing as it suggests that inhaled treprostinil may have clinically relevant antifibrotic properties.

The INCREASE study results herald a new era in the management of patients with ILD complicated by PH. Previously physicians could be nihilistic about PH complicating ILD, because “there was nothing to do”. Now there is something that can potentially be done to modify the course of these sick patients who invariably have limited options (short of transplant) by the time they develop PH. Heightened awareness, more aggressive screening, and ultimately a lower threshold to perform right heart catheterisations in these patients can be anticipated.  While there is biologic plausibility and a clinical signal of an antifibrotic effect (5,6,7), this will be definitively addressed through a randomized controlled study that is now underway (NCT04708782).


  1. Nathan SD, Barbera JA, Gaine SP, Harari S, Martinez FJ, Olschewski H, Olsson KM, Peacock AJ, Pepke-Zaba J, Provencher S, Weissmann N, Seeger W. Pulmonary Hypertension in Chronic Lung Disease. Eur Respir J 2019; 53: 1801914 doi: 10.1183/13993003.01914-2018
  2. Nathan SD, Behr J, Collard HR, Cottin V, Hoeper MM, Martinez F, Corte T, Keogh A, Leuchte H, Mogulkoc N, Ulrich S, Wuyts W, Shah S, Yao M, Boateng F, Wells A. Riociguat for Idiopathic Interstitial Pneumonia-Associated Pulmonary Hypertension: The Randomized RISE-IIP Study. Lancet Res Med 20197:780-790
  3. Steven D. Nathan, Vincent Cottin, Juergen Behr, Marius M. Hoeper, Fernando J. Martinez, Tamera J. Corte, Anne M. Keogh, Hanno Leuchte, Nesrin Mogulkoc, Silvia Ulrich, Wim A. Wuyts, Zhen Yao, Julia Ley-Zaporozhan, Ullrich G. Mueller-Lisse, Frank-Detlef Scholle, Guenther Brueggenwerth, Dennis Busse, Sylvia Nikkho, Athol U. Wells. Impact of lung morphology on clinical outcomes with riociguat in patients with pulmonary hypertension and idiopathic interstitial pneumonia: A post hoc subgroup analysis of the RISE-IIP study. J Heart Lung Transplant 2021 Feb 19; S1053-2498(21)02178-1. doi: 10.1016/j.healun.2021.02.006
  4. Aaron Waxman, MD, PhD, Ricardo Restrepo, MD, Thenappan Thenappan, MD, Ashwin Ravichandran, MD, Peter Engel, MD, Abubakr Bajwa, MD, Roblee Allen, MD, Jeremy Feldman, MD, Rahul Argula, MD, Peter Smith, PharmD, Kristan Rollins, PharmD, CQ Deng, MD, PhD, Leigh Peterson, PhD, Heidi Bell, MD, Victor Tapson, MD, and Steven D. Nathan, MD. Inhaled Treprostinil in Patients with Pulmonary Hypertension due to Interstitial Lung Disease. N Engl J Med 2021; 384:325-334 DOI: 10.1056/NEJMoa2008470
  5. Lambers C, Roth M, Jaksch P, Muraközy G, Tamm M, Klepetko W, Ghanim B, Zhao F. Treprostinil inhibits proliferation and extracellular matrix deposition by fibroblasts through cAMP activation. Sci Rep 2018 Jan 18;8(1):1087.  doi: 10.1038/s41598-018-19294-1.
  6.  Nikitopoulou I, Manitsopoulos N, Kotanidou A, Tian X, Petrovic A, Magkou C, Ninou I, Aidinis V, Schermuly RT, Kosanovic D, Orfanos SE. Orotracheal treprostinil administration attenuates bleomycin-induced lung injury, vascular remodeling, and fibrosis in mice. Pulm Circ. 2019 Nov 15;9(4):2045894019881954.
  7. Steven D. Nathan, Aaron Waxman, MD, Sudarshan Rajagopal, Amy Case, Shilpa Johri, Hilary DuBrock, David De La Zerda, Sandeep Sahay, Christopher King,  Lana Melendres-Groves, Peter Smith, Eric Shen, Lisa Edwards, Andrew Nelsen, Victor Tapson. Inhaled Treprostinil and FVC change in Patients with Interstitial Lung Disease and associated Pulmonary Hypertension. Revision in submission.


Comments (0)

Our research platform is the world.

Through worldwide collaboration, we can begin to answer the question of a global disease.

Join the PVRI