Idiopathic interstitial pneumonias are heterogeneous fibrotic lung disorders frequently complicated by pulmonary hypertension.1, 2 In the revised American Thoracic Society (ATS)/European Respiratory Society (ERS) classification of idiopathic interstitial pneumonia, major subtypes include idiopathic pulmonary fibrosis, idiopathic nonspecific interstitial pneumonia, respiratory bronchiolitis-interstitial lung disease, desquamative interstitial pneumonia, cryptogenic organising pneumonia, and acute interstitial pneumonia.3 Of these, idiopathic pulmonary fibrosis is the most common and well studied.3, 4 At the time of idiopathic pulmonary fibrosis diagnosis, pulmonary hypertension is present in 8–15% of patients;5 however, this value increases to about 50% during follow-up or at the time of lung transplantation,6, 7, 8, 9 and its presence is associated with substantially increased morbidity and mortality.5, 6, 10, 11, 12, 13, 14, 15, 16, 17, 18
Research in context
Evidence before this study
We searched PubMed for papers published between Jan 2, and Feb 28, 2014, using the search terms “pulmonary hypertension” AND “idiopathic interstitial pneumonias” AND “interstitial lung disease” AND “idiopathic pulmonary fibrosis”. Pulmonary hypertension complicating idiopathic interstitial pneumonias (PH-IIPs), specifically idiopathic pulmonary fibrosis, is associated with worse functional status and increased mortality. Several studies have addressed the potential benefit of pulmonary vasodilatory medications in patients with PH-IIP, but most of these have been retrospective or small case series. One prospective study of bosentan in PH-IIP was negative; however, a small phase 2 randomised controlled study of riociguat suggested a beneficial response. The endothelin receptor antagonist ambrisentan has been contraindicated in PH-IIP and there is no evidence of benefit for other endothelin receptor antagonists in PH-IIP. Additionally, there are scarce data regarding the use of prostanoids as a therapeutic option, whereas data on the use of sildenafil are conflicting. Therefore, it remains unknown if treating PH-IIP is beneficial, but this is an area that warrants further study given the very poor prognosis associated with PH-IIP.
Added value of this study
This randomised, placebo-controlled, phase 2b study investigated riociguat for the treatment PH-IIP in a cohort of 147 patients. To our knowledge, it is the largest prospective randomised controlled study to date evaluating the treatment of pulmonary hypertension complicating any form of idiopathic pulmonary pneumonitis (mostly idiopathic pulmonary fibrosis). Patients experienced a greater number of serious adverse events in the riociguat group than in the placebo group, and there were more deaths in the riociguat group than in the placebo group, with no evidence of clinical benefit. As a result of this unfavourable risk–benefit profile, the study was terminated early. This study documents harm and is an important message for those who are inclined to treat pulmonary hypertension complicating idiopathic pulmonary fibrosis and other forms of lung disease with off-label pulmonary arterial hypertension therapies.
Implications of all the available evidence
Our data suggest that riociguat should not be used in patients with PH-IIP due to the absence of benefit and potential presence of harm. Studies in this patient population are, however, feasible, and there remains an urgent unmet medical need to address this challenging condition.
Although there are approved treatments for idiopathic pulmonary fibrosis (eg, pirfenidone and nintedanib), there are none for pulmonary hypertension associated with idiopathic interstitial pneumonia (PH-IIP). Drugs approved for the treatment of pulmonary arterial hypertension have been evaluated in idiopathic pulmonary fibrosis,19, 20, 21, 22, 23, 24, 25 but these studies have been invariably accompanied by limitations. These studies have either focused on fibrotic processes alone, included only small numbers of patients or did not adequately evaluate the presence of pulmonary hypertension. Overall, the clinical benefit of drugs approved for pulmonary arterial hypertension has not been shown in patients with pulmonary hypertension and idiopathic pulmonary fibrosis,19, 20, 21, 22, 23, 24, 25 and guidelines recommend against their use for this indication outside of clinical trials.26, 27 Thus, the management of pulmonary hypertension in idiopathic interstitial pneumonias represents an urgent unmet medical need, including the identification of which (if any) specific phenotype is appropriate for treatment with medication approved for pulmonary arterial hypertension.
Riociguat is a soluble guanylate cyclase stimulator approved for treatment of pulmonary hypertension in WHO group 1 (pulmonary arterial hypertension) and group 4 (inoperable, persistent, or recurrent chronic thromboembolic pulmonary hypertension [CTEPH]). In a 12-week, open-label, phase 2, pilot study28 in 22 patients with pulmonary hypertension and interstitial lung disease, riociguat improved 6-min walking distance (6MWD), cardiac output, and pulmonary vascular resistance, but not mean pulmonary arterial pressure. Adverse events were consistent with those observed in previous studies.29, 30, 31 Four patients discontinued riociguat during the 12-week trial period owing to adverse events, and another six did so during the 12-month extension period.
Soluble guanylate cyclase stimulators inhibit experimental fibrosis by blocking transforming growth factor β signalling, which plays an important role in the development of fibrosis.32 Furthermore, anti-fibrotic effects of riociguat have consistently been shown in several animal models.33, 34, 35, 36 Based on these findings, together with the positive risk–benefit profile of riociguat in patients with pulmonary arterial hypertension or CTEPH, and the data from the open-label pilot study in patients with pulmonary hypertension associated with interstitial lung disease, we hypothesised that patients with PH-IIP might benefit from riociguat treatment. Here, we report the findings from the riociguat in patients with symptomatic pulmonary hypertension associated with idiopathic interstitial pneumonias (RISE-IIP) study and its long-term extension.