ItHome Hypertension Efficacy and safety of sildenafil added to pirfenidone in patients with advanced idiopathic pulmonary fibrosis and risk of pulmonary hypertension: a double-blind, randomised, placebo-controlled, phase 2b trial

Efficacy and safety of sildenafil added to pirfenidone in patients with advanced idiopathic pulmonary fibrosis and risk of pulmonary hypertension: a double-blind, randomised, placebo-controlled, phase 2b trial

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Efficacy and safety of sildenafil added to pirfenidone in patients with advanced idiopathic pulmonary fibrosis and risk of pulmonary hypertension: a double-blind, randomised, placebo-controlled, phase 2b trial

Background

The benefit of sildenafil in patients with advanced idiopathic pulmonary fibrosis
(IPF) at risk of poor outcomes from pulmonary hypertension, whether already present
or likely to develop, is uncertain. We aimed to assess the efficacy and safety of
sildenafil added to pirfenidone versus placebo added to pirfenidone for 52 weeks in
patients with advanced IPF and at risk of group 3 pulmonary hypertension.

Methods

We did a multicentre, international, double-blind, randomised, placebo-controlled,
phase 2b study at 56 university clinics, research hospitals, and tertiary sites in
Canada, Europe (Belgium, Czech Republic, Germany, Greece, Hungary, Italy, the Netherlands,
Spain, and Turkey), Israel, and Africa (Egypt and South Africa). Eligible patients
(aged 40–80 years) had advanced IPF (carbon monoxide diffusing capacity ≤40% predicted
at screening), and were at risk of group 3 pulmonary hypertension (mean pulmonary
artery pressure of ≥20 mm Hg with pulmonary artery wedge pressure of ≤15 mm Hg on
previous right-heart catheterisation, or intermediate or high probability of group
3 pulmonary hypertension on echocardiography as defined by the 2015 European Society
of Cardiology and European Respiratory Society guidelines). Patients were randomly
assigned 1:1 to oral sildenafil tablets (20 mg three times daily) or placebo, both
in addition to oral pirfenidone capsules (801 mg three times daily), using a validated
interactive voice-based or web-based response system with permuted block randomisation,
stratified by previous right-heart catheterisation (yes or no) and forced expiratory
volume in 1 s to forced vital capacity ratio (ClinicalTrials.gov,
NCT02951429, and is no longer recruiting. The 11-month safety follow-up is ongoing.

Findings

Between Jan 13, 2017, and Aug 30, 2018, 247 patients were screened for eligibility,
177 of whom were randomly assigned to a treatment group (n=88 sildenafil; n=89 placebo)
and were assessed for the primary outcome. There was no difference in the proportion
of patients with disease progression over 52 weeks between the sildenafil (64 [73%]
of 88 patients) and placebo groups (62 [70%] of 89 patients; between-group difference
3·06% [95% CI −11·30 to 17·97]; p=0·65). Serious treatment-emergent adverse events
were reported in 54 (61%) patients in the sildenafil group and 55 (62%) patients in
the placebo group. Treatment-emergent adverse events leading to mortality occurred
in 22 (25%) patients in the sildenafil group and 26 (29%) in the placebo group.

Interpretation

Addition of sildenafil to pirfenidone did not provide a treatment benefit versus pirfenidone
plus placebo up to 52 weeks in patients with advanced IPF and risk of pulmonary hypertension.
No new safety signals were identified with either treatment. Although the absence
of a beneficial treatment effect suggests that sildenafil is not an appropriate treatment
in the overall population, further research is required to establish if specific subgroups
of patients with IPF might benefit from sildenafil.

Funding

F Hoffmann-La Roche.

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