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

Adv Ther. 2019 Oct;36(10):2910-2926. doi: 10.1007/s12325-019-01052-y. Epub 2019 Aug 10.


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.

Publication types

  • Clinical Trial, Phase III
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Anti-Inflammatory Agents, Non-Steroidal / adverse effects*
  • Anti-Inflammatory Agents, Non-Steroidal / therapeutic use*
  • Atrial Fibrillation / drug therapy
  • Cardiovascular Agents / therapeutic use
  • Cardiovascular Diseases / chemically induced*
  • Cardiovascular Diseases / prevention & control*
  • Coronary Artery Disease / drug therapy
  • Female
  • Hemorrhage / chemically induced
  • Hemorrhage / prevention & control
  • Humans
  • Idiopathic Pulmonary Fibrosis / drug therapy*
  • Male
  • Middle Aged
  • Pyridones / adverse effects*
  • Pyridones / therapeutic use*
  • Retrospective Studies
  • Risk Factors
  • Treatment Outcome
  • Warfarin / therapeutic use


  • Anti-Inflammatory Agents, Non-Steroidal
  • Cardiovascular Agents
  • Pyridones
  • Warfarin
  • pirfenidone

Associated data

  • figshare/10.6084/m9.figshare.9205154