Pulmonary Perspectives®

The rise and fall of treatment trials in group 3 pulmonary hypertension: Where do we go from here?


Treatment of fibrotic interstitial lung disease (ILD) is often dissatisfying to clinicians and patients. Despite significant advances in the field, particularly the validation of the efficacy of the antifibrotic drugs nintedanib (Richeldi L, et al. N Engl J Med. 2014;370[22]:2071) and pirfenidone (King TE Jr, et al. N Engl J Med. 2014;370[(22]:2083) in slowing the progression of idiopathic pulmonary fibrosis (IPF), we are still left with a paucity of therapeutic options to modulate the course of disease and improve functional outcomes. Given the difficulties in addressing the progression of parenchymal fibrosis, the pulmonary community has looked for alternative ways to approach treatment of ILD. One potential therapeutic inroad that has garnered substantial interest is the treatment of concurrent pulmonary hypertension (PH) or group 3 PH (Seeger W, et al. J Am Coll Cardiol. 2013;62 (25 Suppl):D109).

Group 3 PH – The rationale to treat

Group 3 PH has an indisputable association with adverse outcomes, including decreased functional status, increased need for supplemental oxygen, and decreased survival (King CS, Nathan SD. Pulmonary Hypertension and Interstitial Lung Disease. Ed 2. Ch 4.2017;67-84). In fact, PH is such a powerful predictor of survival in fibrotic ILD, the International Society of Heart and Lung Transplant (ISHLT) guidelines on candidate selection for lung transplantation cite development of PH as an indication for transplant listing (Weill D, et al. J Heart Lung Transplant. 2015;34:1). When one considers the strong association between group 3 PH and adverse outcomes, the numerous pulmonary vasodilator agents available to treat pulmonary arterial hypertension (PAH), and the success achieved in treating PAH, it is easy to see why group 3 PH is such a tempting therapeutic target.

Previous studies of pulmonary vasodilator therapy for group 3 PH

Dr. Christopher King
Over 20 studies assessing the effectiveness of pulmonary vasodilator therapy in ILD have been published (King CS, Nathan SD. Pulmonary Hypertension and Interstitial Lung Disease. Ed 2. Ch 4. 2017;67) The majority was small and unblinded with inherent limitations. To date, no randomized controlled trial (RCT) of therapy for group 3 PH has demonstrated efficacy. Several studies amongst the RCTs deserve highlighting. The most encouraging RCT of therapy for group 3 PH was STEP-IPF. This study compared sildenafil with placebo in 180 patients with advanced IPF. Though the study failed to demonstrate a difference in the primary endpoint of ≥ 20% increase in 6-minute walk test (6MWT) distance, it did show improvement in several secondary endpoints, including arterial oxygen saturation and quality of life measures (Zisman DA, et al. N Engl J Med. 2010;363[7]:620).

The BUILD-3 study compared bosentan with placebo in 617 patients with IPF. Enrolled patients were not required to have PH. While bosentan was well tolerated, it failed to improve the primary endpoint of time to disease progression or death or secondary endpoints regarding quality of life or dyspnea (King TE Jr, et al. Am J Respir Crit Care Med. 2011; 184[1]:92). A smaller study comparing bosentan with placebo in 60 patients with fibrotic ILD with right-sided heart catheterization (RHC) confirmed PH failed to demonstrate any difference in pulmonary vascular hemodynamics, functional status, or symptoms (Corte TJ, et al. Am J Respir Crit Care Med. 2014;190[2]:208). Studies of the newer endothelin receptor antagonists, macitentan (Raghu, et al. Eur Respir J. 2013;42[6]:1622) and ambrisentan (Raghu, et al. Ann Int Med. 2013;158[9]:641), were conducted and failed to demonstrate improvements in outcomes, as well. Overall, the results of the available RCTs of pulmonary vasodilator therapy in group 3 PH have been disappointing, failing to conclusively improve the primary outcome in any of the studies performed.

Hot off the presses – RISE-IIP

The latest letdown in group 3 PH is “Riociguat for the Treatment of Pulmonary Hypertension in Idiopathic Interstitial Pneumonia (RISE-IIP). The results of the study were recently presented at the European Respiratory Society meeting in Milan, Italy, by my colleague from Inova Fairfax Hospital (Falls Church, VA), Dr. Steven Nathan. Riociguat is a soluble guanylate cyclase stimulator approved for use in PAH and chronic thromboembolic pulmonary hypertension. The rationale for the study was that riociguat would improve pulmonary hemodynamics leading to improved functional status. Additionally, several preclinical models have demonstrated antifibrotic effects of the drug (Geschka S, et al. PLoS One. 2011;6:e21853). Justification for the study was also bolstered by promising results from a pilot study conducted in 22 patients with RHC-confirmed PH with a mean pulmonary artery pressure (mPAP) > 30 and fibrotic lung disease. In this study, patients treated with riociguat had improved pulmonary vascular resistance, cardiac output, and 6MWT distance.