warfarin and Idiopathic-Pulmonary-Fibrosis

Idiopathic pulmonary fibrosis (IPF) is a form of chronic progressive fibrosing interstitial lung disease of unknown origin. Recently, nintedanib and pirfenidone demonstrated efficacy in slowing disease progression and were approved by the US Food and Drug Administration. Although numerous treatments have been evaluated in IPF, none have shown significant decreases in mortality. The objective of this study was to identify all pharmacologic treatments evaluated for IPF and analyze their efficacy via Bayesian network meta-analysis and pairwise indirect treatment comparisons. This review did not evaluate the effect of steroid therapy.. We searched MEDLINE, Embase, and the Cochrane Library for studies published on or before August 2014. Studies were required to contain a randomized evaluation of nonsteroidal drug therapy for treatment of IPF and be published in English. Key outcomes of interest for this analysis were pulmonary function as measured by FVC as well as all-cause and respiratory-specific death. All outcomes were analyzed via a Bayesian framework.. Our review identified 30 eligible studies that evaluated 16 unique treatments. Under both the fixed-effect and random-effect models for respiratory-specific mortality, no treatments performed better than placebo. For all-cause mortality, pirfenidone and nintedanib had effects approaching significance with credible intervals slightly crossing the null under a fixed-effect model. Notably, for respiratory-specific mortality, all-cause mortality, and decline in percent predicted FVC, nintedanib and pirfenidone were virtually indistinguishable and no clear advantage was detected.. Although two treatments have been approved for IPF on the basis of reduced decline in pulmonary function, neither one has a clear advantage on mortality outcomes.

Topics: Acetylcysteine; Anti-Inflammatory Agents, Non-Steroidal; Anticoagulants; Azathioprine; Bayes Theorem; Bosentan; Endothelin Receptor Antagonists; Enzyme Inhibitors; Etanercept; Free Radical Scavengers; Humans; Idiopathic Pulmonary Fibrosis; Imatinib Mesylate; Immunosuppressive Agents; Indoles; Interferon-gamma; Phenylpropionates; Pyridazines; Pyridones; Pyrimidines; Recombinant Proteins; Sulfonamides; Vital Capacity; Warfarin

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.. 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.. 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.. 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.. NCT00287716, NCT00287729, and NCT01366209.. F. Hoffmann-La Roche Ltd. and Genentech, Inc.

Topics: Aged; Aged, 80 and over; Anti-Inflammatory Agents, Non-Steroidal; Atrial Fibrillation; Cardiovascular Agents; Cardiovascular Diseases; Coronary Artery Disease; Female; Hemorrhage; Humans; Idiopathic Pulmonary Fibrosis; Male; Middle Aged; Pyridones; Retrospective Studies; Risk Factors; Treatment Outcome; Warfarin

Procoagulant and antifibrinolytic activity has been associated with idiopathic pulmonary fibrosis (IPF); however, investigation of anticoagulant therapy in IPF has suggested deleterious effects. This post hoc analysis evaluated the effect of medically indicated anticoagulation on mortality and other clinical outcomes in IPF.Patients randomised to placebo (n=624) from three controlled trials in IPF were analysed by oral anticoagulant use. End-points included all-cause and IPF-related mortality, disease progression, hospitalisation, and adverse events, over 1 year.At baseline, 32 (5.1%) patients randomised to placebo were prescribed anticoagulants for non-IPF indications, 29 (90.6%) of whom received warfarin. Unadjusted analyses demonstrated significantly higher all-cause and IPF-related mortality at 1 year in baseline anticoagulant users versus nonusers (15.6% versus 6.3%, p=0.039 and 15.6% versus 3.9%, p=0.002, respectively). In multivariate analyses, baseline use of anticoagulants was an independent predictor of IPF-related mortality (hazard ratio 4.7, p=0.034), but not other end-points. Rates of bleeding and cardiac events did not differ significantly between groups. In an exploratory analysis, anticoagulant use at any time during the study was an independent predictor of all end-points.This post hoc analysis suggests that anticoagulants used for non-IPF indications may have unfavourable effects in IPF patients. Future studies are needed to explore this relationship further.

Topics: Administration, Oral; Aged; Anticoagulants; Blood Coagulation; Disease Progression; Female; Hemorrhage; Hospitalization; Humans; Idiopathic Pulmonary Fibrosis; Male; Middle Aged; Mortality; Proportional Hazards Models; Risk Factors; Time Factors; Treatment Outcome; Warfarin

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.

Topics: Adult; Aged; Aged, 80 and over; Anticoagulants; Double-Blind Method; Female; Hospitalization; Humans; Idiopathic Pulmonary Fibrosis; International Normalized Ratio; Male; Middle Aged; Treatment Failure; Warfarin

Topics: Anticoagulants; Heparin; Humans; Idiopathic Pulmonary Fibrosis; Warfarin

Topics: Atrial Fibrillation; Humans; Idiopathic Pulmonary Fibrosis; Male; Thrombophlebitis; Warfarin

Topics: Aged; Anticoagulants; Atrial Fibrillation; Fatal Outcome; Humans; Idiopathic Pulmonary Fibrosis; Male; Middle Aged; Thrombophlebitis; Warfarin

Topics: Atrial Fibrillation; Humans; Idiopathic Pulmonary Fibrosis; Male; Thrombophlebitis; Warfarin

Topics: Atrial Fibrillation; Humans; Idiopathic Pulmonary Fibrosis; Male; Thrombophlebitis; Warfarin

Topics: Anticoagulants; Female; Humans; Idiopathic Pulmonary Fibrosis; Male; Warfarin

Topics: Anticoagulants; Female; Humans; Idiopathic Pulmonary Fibrosis; Male; Warfarin

Topics: Aged; Aged, 80 and over; Anticoagulants; Comorbidity; Female; Humans; Idiopathic Pulmonary Fibrosis; Incidence; Logistic Models; Male; Middle Aged; Proportional Hazards Models; Pulmonary Embolism; Smoking; Venous Thrombosis; Warfarin

Topics: Anticoagulants; Female; Humans; Idiopathic Pulmonary Fibrosis; Male; Warfarin

Topics: Anticoagulants; Female; Humans; Idiopathic Pulmonary Fibrosis; Male; Warfarin

Topics: Anticoagulants; Female; Humans; Idiopathic Pulmonary Fibrosis; Male; Warfarin

IPF is a common form of interstitial lung disease for which there is no effective therapy and usually results in death. Two previous contradictory studies showed anticoagulant therapy  to be associated with both improved and worsened survival, respectively.. The objective of this retrospective cohort study was to evaluate the effect of anticoagulant therapy on the survival and disease progression of patients with idiopathic pulmonary fibrosis (IPF) in real clinical practice.. We compared the clinical characteristics, time to disease progression, incidence of acute exacerbation, and survival of 25 (20%) IPF patients receiving anticoagulant therapy to the remaining 97 IPF patients not receiving anticoagulant therapy. In addition we conducted a sensitivity analysis using as comparator a group of 25 patients matched by age, sex, functional impairment, cardiac comorbidities and pulmonary hypertension.. Patients on anticoagulant therapy had a worse 1- and 3-year survival (84% and 53% versus 89% and 64% in the non-anticoagulant group, respectively), a difference that persisted after adjusting for age and comorbidities (hazard ratio 3.1 - 95% confidence interval, 1.4 to 7.0; p=0.006) and after comparison with the matched group (adjusted HR=4.8, 95% CI: 1.8-12.8; p=0.002). IPF patients on anticoagulant therapy had a shorter interval to disease progression ( 0.7 years versus 1.6 years, adjusted HR 2.2 -95% CI, 0.96 to 5.1; p=0.063) confirmed also in the analysis with matched subgroups (HR=2.7 (95% CI: 1.2-6.5); p=0.023). The incidence of acute exacerbations did not differ in the two groups (22% versus 23%). Two patients (8%) experienced anticoagulant treatment related complications and included an episode of hemorrhagic shock.. In this retrospective study patients treated with anticoagulants had a worse survival and a shorter interval to disease progression. This support the recent finding that warfarin worsen the respiratory status and survival of IPF patients.

Topics: Anticoagulants; Cohort Studies; Humans; Idiopathic Pulmonary Fibrosis; Retrospective Studies; Warfarin

Topics: Anticoagulants; Female; Humans; Idiopathic Pulmonary Fibrosis; Male; Warfarin

Topics: Anticoagulants; Female; Humans; Idiopathic Pulmonary Fibrosis; Male; Warfarin

Topics: Anticoagulants; Female; Humans; Idiopathic Pulmonary Fibrosis; Male; Warfarin