Sildenafil for pulmonary hypertension complicating idiopathic pulmonary fibrosis: a rationale grounded in basic science

Sildenafil added to pirfenidone in patients with advanced idiopathic pulmonary fibrosis and risk of pulmonary hypertension: A Phase IIb, randomised, double-blind, placebo-controlled study – Rationale and study design

“…This study is designed to assess the treatment of patients with advanced disease who have evidence suggestive of PH most likely caused by IPF. PH is a major contributor to morbidity and mortality in patients with advanced IPF [11,15,16]. A higher mPAP at initial evaluation of patients with IPF may be an independent predictor of prognosis [40], and elevated pulmonary vascular resistance (PVR) may be a strong haemodynamic predictor of early mortality in patients with diffuse fibrotic lung disease, including IPF, regardless of the severity of fibrosis [41].…”

“…Sildenafil, a PDE-5 inhibitor that stabilises cGMP, enhances the vasodilatory effects and platelet anti-aggregatory activity of NO and inhibits thrombus formation; these pleiotropic properties may render it attractive as an add-on treatment for IPF [16,32,48]. Additionally, ex vivo experiments using pulmonary arteries from healthy donors and patients with IPF or PH associated with IPF revealed a direct relaxant/ anti-contractile and anti-remodelling role for sildenafil [48].…”

“…A concern with the use of vasodilatory drugs is the potential for worsening of ventilation-perfusion mismatching and, consequently, hypoxaemia [16]. However, evidence from preclinical studies showed that sildenafil did not modify the ventilation-perfusion ratio in a bleomycin model of pulmonary fibrosis associated with PH [48].…”

“…The incidence and prevalence of PH in patients with IPF remain unclear and estimates vary widely, from 8.1% to 84%, reflecting the heterogeneous subpopulations of patients studied, underlying disease severity, disease definition and different diagnostic measures used [10][11][12][13][14]. PH is a malignant prognostic determinant in patients with IPF, associated with a three-fold increase in mortality, especially when systolic pulmonary arterial pressure (sPAP) by echocardiogram (ECHO) exceeds 50 mm Hg [11,15,16]. The development of PH in patients with underlying IPF is also associated with a diminished exercise tolerance and QoL.…”

Pulmonary arterial hypertension in connective tissue disorders: Pathophysiology and treatment

“…Milara et al 76 demonstrated that in a model of bleomycin-induced pulmonary fibrosis, sildenafil given by infusion did not alter the V/Q matching, probably due to its preferential vasodilatory effect in areas that are well ventilated and where NO is available. 77 In a pilot trial evaluating riociguat in PH-ILD (including both IPF and SSc patients), hemodynamics improved with a small decrease in arterial oxygen saturation after 12 weeks of therapy. 78 However, the RISE-IIP RCT to evaluate the efficacy and safety of riociguat in patients with IPF was terminated early due to an increased mortality in patients treated with riociguat vs. placebo.…”