People with idiopathic pulmonary fibrosis (IPF) and right heart dysfunction may benefit more from a therapy combining Ofev (nintedanib) with sildenafil than from Ofev alone in terms of cardiac health, according to data from a Phase 3 study.
The study, “Nintedanib and Sildenafil in Patients with Idiopathic Pulmonary Fibrosis and Right Heart Dysfunction (INSTAGE): a Pre-specified Sub-group Analysis of a Double-blind, Randomized Clinical Trial,” was published in the American Journal of Respiratory and Critical Care Medicine.
Results from a previous Phase 3 clinical trial (NCT00517933), named STEP-IPF, showed that 12 weeks of treatment with sildenafil eased some symptoms of IPF in patients with a severely reduced lung gas exchange capacity (less than 35% of the lungs’ normal capacity to diffuse carbon monoxide, called DLCO).
Treatment with sildenafil was not associated with significant improvements in exercise capacity (measured by the six-minute walk test) compared to placebo, but it significantly improved blood oxygenation, DLCO, and quality of life in these patients.
Based on these data, researchers hypothesized that IPF patients with very poor long function could benefit from the addition of sildenafil to Ofev — an approved IPF treatment marketed by Boehringer Ingelheim.
Results of the INSTAGE trial, a multicenter, double-blind and randomized Phase 3 study (NCT02802345), suggested no additional benefits regarding quality of life and lung function in IPF patients with a DLCO of 35% or less given the Ofev and sildenafil combination.
Further analysis of the STEP-IPF data, however, showed that sildenafil was associated with better exercise capacity and life quality in IPF patients with right heart dysfunction (when the right ventricle, or pumping chamber, is not working properly) compared to placebo.
Researchers now re-analyzed data from the INSTAGE trial, looking at whether the combo therapy showed greater benefits than Ofev alone in patients with right heart dysfunction.
They analyzed changes in health-related quality of life, assessed using the St. George’s Respiratory Questionnaire (SGRQ); lung function, assessed through forced vital capacity (FVC) or the volume of air in liters the lungs can sustain; and blood levels of B-type natriuretic peptide (BNP), a marker of right ventricular strain and pulmonary arterial hypertension that correlates with disease progression and mortality. All measures were taken after 12 and 24 weeks of combination treatment.
Of the trial’s 273 patients, 117 people (61 treated with Ofev plus sildenafil, 56 treated with Ofev alone) had clinical signs of right heart dysfunction at the beginning of the study; 156 people (76 treated with Ofev plus sildenafil, 80 treated with Ofev alone) did not.
Results showed that the combo therapy did not significantly improve life quality or lung function in patients with right heart dysfunction compared to Ofev alone. Effects of the two therapy regimens were also similar between patients with or without right heart dysfunction.
“In the INSTAGE trial, there were no significant differences in the effects of nintedanib [Ofev] plus sildenafil versus nintedanib alone on changes in SGRQ and FVC between patients with or without echocardiographic signs of RHD [right heart dysfunction] at baseline,” the researchers wrote.
However, the combination of Ofev and sildenafil led to a significantly greater decrease in BNP levels in patients with right heart dysfunction, who had higher BNP levels at the study’s beginning, than those without the dysfunction.
Overall, based on these results, the team concluded that “patients with IPF who have raised BNP levels may be more likely to benefit from a combination of [Ofev and sildenafil],” they wrote.
The researchers added that long-term studies comparing the two therapy regimens are needed to clarify the potential benefit of adding sildenafil to Ofev in this subgroup of IPF patients who are at a greater risk of heart failure.