Cardiovascular Risks, Bleeding Risks, and Clinical Events from 3 Phase III Trials of Pirfenidone in Patients with Idiopathic Pulmonary Fibrosis

Abstract

Introduction: This study assessed baseline cardiovascular (CV) risk factors, concomitant CV medication use, risk of major adverse cardiac events-plus (MACE-plus), and bleeding adverse events (AEs) in patients with idiopathic pulmonary fibrosis (IPF) in three randomized, placebo-controlled phase III trials of pirfenidone.

Methods: Patients in the pirfenidone phase III trials were included. Patients with unstable or deteriorating cardiac disease within 6 months before enrollment were ineligible. Medical history at baseline and concomitant CV medication use during treatment were reported. A retrospective, blinded review of AE preferred terms was conducted to identify MACE-plus and bleeding events. Subgroup analyses examined the impact of concomitant CV medication use on how pirfenidone treatment affected clinical outcomes.

Results: In total, 1247 patients were included [n = 623 pirfenidone (2403 mg/day) and n = 624 placebo]. The median age was 68 years, 74% were male, and 65% were current/former smokers. Commonly reported CV risk factors included hypertension (52%), obesity (44%), hypercholesterolemia (23%), and hyperlipidemia (23%). Pre-existing cardiac disorders included coronary artery disease (16%), myocardial infarction (5%), and atrial fibrillation (5%). Lipid-modifying agents (60%), antithrombotic agents (54%), and renin-angiotensin inhibitors (39%) were commonly used concomitant CV medications. The incidences of MACE-plus and bleeding events were similar between the pirfenidone and placebo groups (1.8% and 2.9% for MACE-plus events and 3.7% and 4.3% for bleeding events, respectively). Except for patients receiving heparin, pirfenidone had a beneficial effect compared with placebo on efficacy outcomes regardless of concomitant CV medications.

Conclusions: CV risk factors and comorbidities and use of concomitant CV medications are common in patients with IPF. Pirfenidone did not appear to increase the risk of CV or bleeding events. Use of several concomitant CV medications, including warfarin, did not appear to adversely impact pirfenidone's beneficial effect on efficacy outcomes.

Trial registration: NCT00287716, NCT00287729, and NCT01366209.

Funding: F. Hoffmann-La Roche Ltd. and Genentech, Inc.

Keywords: Bleeding; Cardiovascular; Idiopathic pulmonary fibrosis; Pirfenidone; Respiratory.

Figures

Fig. 1

Treatment-emergent major adverse cardiovascular events–plus (a) and treatment-emergent bleeding events (b)

Fig. 2

Time to first major adverse cardiac event–plus (a) and time to first bleeding event (b)

Fig. 3

Hazard ratios for death (a), respiratory-related hospitalization (b), ≥ 10% absolute decline in % predicted FVC or death (c), and ≥ 10% absolute decline in % predicted FVC, respiratory-related hospitalization, or death (d) among users and non-users of concomitant CV medications over 12 months*. CV cardiovascular, FVC forced vital capacity, HR hazard ratio. *Only medications with a start date on or before day 365 were included in this analysis, which evaluated outcomes for 12 months. Heparin includes low-molecular-weight heparins. Subgroup n and HR values can be found in S1 Table