A Placebo-Controlled Randomized Trial of Warfarin in Idiopathic Pulmonary Fibrosis

TLDR

Animal and human studies indicate that the coagulation cascade plays a key role in pulmonary fibrosis. The study tested whether therapeutic warfarin could lower mortality, hospitalization, and forced vital capacity decline in patients with progressive idiopathic pulmonary fibrosis. In a double‑blind, 48‑week, randomized trial, patients were assigned 1:1 to warfarin (INR 2–3) or placebo, with INR monitored via home point‑of‑care devices, and the primary endpoint was a composite of death, non‑bleeding hospitalization, or ≥10% FVC decline. Warfarin increased mortality (14 vs 3 deaths, P = 0.005), led to early study termination, and showed no benefit in reducing the composite outcome, indicating a higher risk of death in IPF patients without other anticoagulation indications.

Abstract

Animal and human studies support the importance of the coagulation cascade in pulmonary fibrosis.In a cohort of subjects with progressive idiopathic pulmonary fibrosis (IPF), we tested the hypothesis that treatment with warfarin at recognized therapeutic doses would reduce rates of mortality, hospitalization, and declines in FVC.This was a double-blind, randomized, placebo-controlled trial of warfarin targeting an international normalized ratio of 2.0 to 3.0 in patients with IPF. Subjects were randomized in a 1:1 ratio to warfarin or matching placebo for a planned treatment period of 48 weeks. International normalized ratios were monitored using encrypted home point-of-care devices that allowed blinding of study therapy.The primary outcome measure was the composite outcome of time to death, hospitalization (nonbleeding, nonelective), or a 10% or greater absolute decline in FVC. Due to a low probability of benefit and an increase in mortality observed in the subjects randomized to warfarin (14 warfarin versus 3 placebo deaths; P = 0.005) an independent Data and Safety Monitoring Board recommended stopping the study after 145 of the planned 256 subjects were enrolled (72 warfarin, 73 placebo). The mean follow-up was 28 weeks.This study did not show a benefit for warfarin in the treatment of patients with progressive IPF. Treatment with warfarin was associated with an increased risk of mortality in an IPF population who lacked other indications for anticoagulation.