Association Between Anticoagulation and Survival in Interstitial Lung Disease

BackgroundAberrations in the coagulation system have been implicated in the pathogenesis of interstitial lung disease (ILD). Anticoagulants have been proposed as a potential therapy in ILD; however, a randomized controlled trial examining warfarin as a treatment for IPF was terminated early due to increased death rates. This has led some to speculate that warfarin specifically may be harmful in ILD, and use of direct oral anticoagulants (DOACs) could result in superior outcomes.Research QuestionThe goal of this study was to delineate the relationship between anticoagulation and outcomes in patients with ILD through an analysis of the Pulmonary Fibrosis Foundation Patient Registry.Study Design and MethodsAn analysis of all patients in the Pulmonary Fibrosis Foundation Patient Registry was performed. Patients were stratified into three groups: no anticoagulation, DOAC use, or warfarin use. Survival was analyzed by using both Kaplan-Meier curves and Cox proportional hazards models.ResultsOf 1,911 patients included in the analysis, 174 (9.1%) were given anticoagulants; 93 (4.9%) received DOACs, and 81 (4.2%) received warfarin. There was a twofold increased risk of death or transplant for patients receiving DOACS; for warfarin, the risk was over two and half times greater. DOACs were not associated with an increased risk of mortality following adjustment for confounding variables. However, even after adjustment, patients given the anticoagulant warfarin remained at increased risk of mortality. In patients with IPF, warfarin was associated with reduced transplant-free survival, but DOACs were not. There was no statistically significant difference in survival between those receiving warfarin and those receiving a DOAC.InterpretationThe need for anticoagulation is associated with an increased risk for death or transplant in patients with ILD, in both the IPF and non-IPF population. Further research is required to determine if warfarin and DOACs present varying safety profiles in patients with ILD. Aberrations in the coagulation system have been implicated in the pathogenesis of interstitial lung disease (ILD). Anticoagulants have been proposed as a potential therapy in ILD; however, a randomized controlled trial examining warfarin as a treatment for IPF was terminated early due to increased death rates. This has led some to speculate that warfarin specifically may be harmful in ILD, and use of direct oral anticoagulants (DOACs) could result in superior outcomes. The goal of this study was to delineate the relationship between anticoagulation and outcomes in patients with ILD through an analysis of the Pulmonary Fibrosis Foundation Patient Registry. An analysis of all patients in the Pulmonary Fibrosis Foundation Patient Registry was performed. Patients were stratified into three groups: no anticoagulation, DOAC use, or warfarin use. Survival was analyzed by using both Kaplan-Meier curves and Cox proportional hazards models. Of 1,911 patients included in the analysis, 174 (9.1%) were given anticoagulants; 93 (4.9%) received DOACs, and 81 (4.2%) received warfarin. There was a twofold increased risk of death or transplant for patients receiving DOACS; for warfarin, the risk was over two and half times greater. DOACs were not associated with an increased risk of mortality following adjustment for confounding variables. However, even after adjustment, patients given the anticoagulant warfarin remained at increased risk of mortality. In patients with IPF, warfarin was associated with reduced transplant-free survival, but DOACs were not. There was no statistically significant difference in survival between those receiving warfarin and those receiving a DOAC. The need for anticoagulation is associated with an increased risk for death or transplant in patients with ILD, in both the IPF and non-IPF population. Further research is required to determine if warfarin and DOACs present varying safety profiles in patients with ILD. FOR EDITORIAL COMMENT, SEE PAGE 1321Take-home PointsWe sought to better elucidate the relationship between interstitial lung disease and outcomes in patients on anticoagulation by analyzing the PFF-PR.The need for anticoagulation is common in ILDs and is associated with reduced transplant-free survival.Further research is required to determine if DOACs are associated with superior outcomes to warfarin in patients with ILD. FOR EDITORIAL COMMENT, SEE PAGE 1321 We sought to better elucidate the relationship between interstitial lung disease and outcomes in patients on anticoagulation by analyzing the PFF-PR. The need for anticoagulation is common in ILDs and is associated with reduced transplant-free survival. Further research is required to determine if DOACs are associated with superior outcomes to warfarin in patients with ILD. Idiopathic pulmonary fibrosis (IPF) is a deadly disease characterized by progressive parenchymal fibrosis leading to disability and eventual death in most patients. The pathogenesis of IPF remains incompletely understood. The prevailing hypothesis is that of an epigenetic phenomenon that manifests mostly in the context of aged, genetically predisposed individuals who might have been subjected to various inhalational injuries leading to an overly exuberant or prolonged healing response with resultant fibrosis. Dysregulation of coagulation is also suspected to play a role in the pathogenesis of IPF, as procoagulant enzymes may directly stimulate fibrosis.1Chambers R.C. Procoagulant signaling mechanisms in lung inflammation and fibrosis: novel opportunities for pharmacological intervention?.Br J Pharmacol. 2008; 153: S367-S378Crossref PubMed Scopus (149) Google Scholar Epidemiologic studies have shown that there is a higher prevalence of VTE and acute coronary syndromes in patients with IPF than in matched control subjects.2Hubbard R.B. Smith C. Le Jeune I. Gribbin J. Fogarty A.W. The association between idiopathic pulmonary fibrosis and vascular disease: a population-based study.Am J Respir Crit Care Med. 2008; 178: 1257-1261Crossref PubMed Scopus (171) Google Scholar, 3Sode B.F. Dahl M. Nielsen S.F. Nordestgaard B.G. Venous thromboembolism and risk of idiopathic interstitial pneumonia: a nationwide study.Am J Respir Crit Care Med. 2010; 181: 1085-1092Crossref PubMed Scopus (73) Google Scholar, 4Sprunger D.B. Olson A.L. Huie T.J. et al.Pulmonary fibrosis is associated with an elevated risk of thromboembolic disease.Eur Respir J. 2012; 39: 125-132Crossref PubMed Scopus (79) Google Scholar Given the association between IPF and VTE, as well as conjecture that dysregulation of coagulation may be a pathogenic mechanism for the development of pulmonary fibrosis, there has been interest in anticoagulation as a possible therapeutic strategy for IPF. This interest intensified following the publication of a prospective Japanese study of 56 patients with IPF admitted to the hospital with acute exacerbations.5Kubo H. Kakayama K. Yanai M. et al.Anticoagulant therapy for idiopathic pulmonary fibrosis.Chest. 2005; 128: 1475-1482Abstract Full Text Full Text PDF PubMed Scopus (392) Google Scholar These patients were randomized to receive either receive steroids plus anticoagulation (warfarin or heparin) or steroids alone. Mortality was markedly lower in the group receiving anticoagulants (18% vs 71%; P = .008). Based on the favorable results of this small trial, the Anticoagulant Effectiveness in Idiopathic Pulmonary Fibrosis (ACE-IPF) trial of warfarin for IPF was launched.6Noth I. Anstrom K.J. Calvert S.B. et al.Idiopathic Pulmonary Fibrosis Clinical Research Network (IPFNet)A placebo-controlled randomized trial of warfarin in idiopathic pulmonary fibrosis.Am J Respir Crit Care Med. 2012; 186: 88-95Crossref PubMed Scopus (355) Google Scholar Patients with IPF without a prior indication for anticoagulation were randomized to receive warfarin with an international normalized ratio goal of 2.0 to 3.0 vs placebo. The study was terminated following enrollment of 145 subjects due to increased death rates in the warfarin arm. In addition, two retrospective studies have found decreased survival in patients with IPF who were taking anticoagulants, a difference that persisted after controlling for age and co-morbidities.7Tomassetti S. Ruy J.H. Gurioli C. et al.The effect of anticoagulant therapy for idiopathic pulmonary fibrosis in real life practice.Sarcoidosis Vasc Diffuse Lung Dis. 2013; 30: 121-127PubMed Google Scholar,8Kreuter M. Wijsenbeek M.S. Vasakova M. et al.Unfavourable effects of medically indicated oral anticoagulants on survival in idiopathic pulmonary fibrosis.Eur Respir J. 2016; 47: 1776-1784Crossref PubMed Scopus (46) Google Scholar It has been hypothesized that the discrepant results emanating from these studies are due to the type of anticoagulant used.9Crooks M.G. Hart S. Coagulation and anticoagulation in idiopathic pulmonary fibrosis.Eur Respir Rev. 2015; 24: 392-399Crossref PubMed Scopus (30) Google Scholar Warfarin antagonizes vitamin K-dependent clotting factors and protein C. It is speculated that interference with the cytoprotective properties of protein C could lead to the increased release of inflammatory mediators, potentially worsening IPF outcomes. The direct oral anticoagulants (DOACs) have the potential for beneficial effects on the coagulation cascade without detrimental effects on protein C. Furthermore, both direct thrombin inhibition and factor Xa inhibition, the respective mechanism of action of the two classes of DOACs, has been shown to attenuate the development of fibrosis in the bleomycin mouse model. Evidence from the major trials in atrial fibrillation and VTE support that these agents are also associated with superior safety.10King C.S. Holley A.B. Moores L.K. Moving toward a more ideal anticoagulant: the oral direct thrombin and factor Xa inhibitors.Chest. 2013; 143: 1106-1116Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar The Pulmonary Fibrosis Foundation Patient Registry (PFF-PR) has collected data on a mixed population of > 2,000 patients with interstitial lung disease (ILD) enrolled at PFF care centers across the United States.11Pulmonary Fibrosis FoundationPFF Registry. The first step to a cure.https://www.pulmonaryfibrosis.org/medical-community/pff-patient-registryDate accessed: August 30, 2019Google Scholar We performed an analysis of the PFF-PR to characterize the prevalence and type of anticoagulant agents prescribed for patients with ILD, as well as the association of anticoagulant use with survival in ILD, specifically IPF. Data from the PFF-PR, a cohort of well-characterized patients with ILD, were analyzed to identify any association between anticoagulant use at baseline and time to death or transplant. Time zero from which outcomes were evaluated was at the time of consent for enrollment in the registry. Ongoing anticoagulant use was assessed at that time. Data were analyzed for patients who had enrolled between March 2016 and June 2018 with data lock on August 31, 2018. We analyzed all patients with ILD and then performed a subgroup analysis of those subjects with IPF. Patients were stratified into three groups: DOAC users, warfarin users, and anticoagulant-naive patients or nonusers. Patients on heparin (n = 26) at the time of baseline data collection were excluded from the study. The three groups were compared, after which an analysis of the combined anticoagulant vs nonuser group was performed. Proportions are reported for categorical variables and means for continuous variables. A χ2 or Fisher exact test was used to compare proportions, and F-tests were used to compare continuous variables. Kaplan-Meier curves were generated to display the difference in time to mortality between DOAC users, warfarin users, and nonusers. Log-rank tests were used to compare the groups. Those undergoing transplant were considered censored at the time of transplant. Cox proportional hazards models (adjusted and unadjusted) were used to compare the risk of death between groups. Hazard ratios (HRs) and their confidence limits were reported. Adjusted models included age, diffusing capacity of the lung for carbon monoxide (Dlco) percent predicted, FVC percent predicted, 6-min walk test (6MWT) distance, and the following dichotomous covariates: sex, arrhythmia, cancer, congestive heart failure, COPD, coronary artery disease, diabetes, pulmonary hypertension, and pulmonary embolism. All models complied with the assumptions of proportional hazards. Because a 6MWT was not available at time of consent in 26% of participants, and Dlco was unavailable in 13% of participants, multiple imputation was used to take advantage of all the data in the multivariable analyses. Analyses were performed by using SAS version 9.4 (SAS Institute, Inc.). The study was exempt from requirement of institutional review board approval given its retrospective design and the use of blinded registry data, although all participants provided informed consent to participate in the registry. A total of 1,911 patients were included in the analysis, 174 (9.1%) of whom were given anticoagulants (93 [4.9%] prescribed a DOAC and 81 [4.2%] prescribed warfarin). Of the 93 patients taking DOACs at baseline, 84 (49 IPF, 35 non-IPF) were taking factor Xa inhibitors, and 9 (8 IPF, 1 non-IPF) were taking direct thrombin inhibitors. Patients on anticoagulation were significantly more likely to be older, male, have a history of cardiac issues or VTE, use immunosuppressants, and had lower Dlco. Table 1 summarizes the demographic data of the entire patient population. The composition of the cohort according to ILD type is as follows: 1,176 (61.5%) had IPF, 201 (10.5%) had an idiopathic interstitial pneumonia (IIP) other than IPF, 287 (15.0%) had connective tissue disease-associated ILD (CTD-ILD), 152 (8.0%) had chronic hypersensitivity pneumonitis, and 95 (5.0%) had "other" ILDs. Table 2 presents a breakdown of the patient population according to disease type and anticoagulant use. The percentage of patients on anticoagulation according to disease type was as follows: 9.0% for IPF, 5.0% for IIP other than IPF, 11.5% for CTD-ILD, 7.9% for chronic hypersensitivity pneumonitis, and 13.7% for "other" ILDs. Although not statistically significant, there was a trend toward differences in anticoagulation use among patients of various disease categories (P = .066 based on χ2 test).Table 1Demographic Characteristics of the Entire Study Cohort Stratified According to Anticoagulant UseBaseline CharacteristicDOAC (n = 93)Warfarin (n = 81)None (n = 1,737)PaP values are based on F-test for continuous variables and χ2 test for categorical variables.Age, mean ± SD, y70.45 ± 9.8771.40 ± 9.6067.37 ± 10.19<.0001Male sex68 (73.1)58 (71.6)1,081 (62.2).0289BMI, mean ± SD, kg/m229.48 ± 5.5030.22 ± 5.7529.35 ± 5.85.4444Race White84 (90.3)74 (91.4)1,531 (88.1).8667bFisher exact test was used instead of χ2 test because of low cell counts. Black3 (3.2)2 (2.5)89 (5.1) Other6 (6.5)5 (6.2)117 (6.7)Gastroesophageal reflux disease12 (12.9)11 (13.6)281 (16.2).5898OSA27 (29.0)27 (33.3)429 (24.7).1518Cardiac arrhythmia40 (43.0)28 (35.0)101 (5.8)< .0001Cancer18 (19.4)14 (17.5)284 (16.4).7466Congestive heart failure11 (11.8)10 (12.5)48 (2.8)< .0001COPD6 (6.5)8 (10.0)134 (7.8).6777Coronary artery disease26 (28.0)20 (25.0)336 (19.5).0737Diabetes19 (20.4)13 (16.3)323 (18.7).7782Obesity19 (20.4)15 (18.8)278 (16.1).4637DVT15 (16.1)9 (11.3)27 (1.6)< .0001bFisher exact test was used instead of χ2 test because of low cell counts.Pulmonary embolism18 (19.4)11 (13.8)17 (1.0)< .0001bFisher exact test was used instead of χ2 test because of low cell counts.Pulmonary arterial hypertension16 (17.2)17 (21.3)104 (6.0)< .0001Peripheral vascular disease1 (1.1)1 (1.3)23 (1.3).1392bFisher exact test was used instead of χ2 test because of low cell counts.Nintedanib use15 (16.1)9 (11.1)331 (19.0).1639Pirfenidone use30 (32.3)29 (35.8)382 (21.9).0015Immunosuppressant use44 (47.3)36 (44.4)702 (40.4).3377Corticosteroid use35 (37.6)28 (34.6)530 (30.5).2744Oxygen45 (48.4)41 (50.6)706 (40.5).0776Walk distance, mean ± SD, m357.96 ± 192.13336.88 ± 167.59322.90 ± 179.05.2359Baseline Dlco predicted (Crapo-Morris), mean ± SD0.39 ± 0.150.37 ± 0.150.44 ± 0.18.0011Baseline FEV1 predicted (NHANES III), mean ± SD0.75 ± 0.200.73 ± 0.180.73 ± 0.20.5817Baseline FVC predicted (NHANES III), mean ± SD0.70 ± 0.180.68 ± 0.170.68 ± 0.18.7485All numbers in parentheses indicate frequency in percentage unless otherwise indicated. Statistically significant findings shown in bold. Dlco = diffusing capacity of the lung for carbon monoxide; DOAC = direct oral anticoagulant; NHANES = National Health and Nutrition Evaluation Survey.a P values are based on F-test for continuous variables and χ2 test for categorical variables.b Fisher exact test was used instead of χ2 test because of low cell counts. Open table in a new tab Table 2Disease Type and Anticoagulant UseAnticoagulantIPFIIP Non-IPFCTD-ILDCHPOther ILDTotalNone1,070191254140821,737 (90.9%)Warfarin494137881 (4.2%)DOAC576205593 (4.9%)Total1,176 (61.5%)201 (10.5%)287 (15.0%)152 (8.0%)95 (5.0%)1,911CHP = chronic hypersensitivity pneumonitis; CTD-ILD = connective tissue disease related interstitial lung disease; DOAC = direct oral anticoagulant; IIP = idiopathic interstitial pneumonia; IPF = idiopathic pulmonary fibrosis. Open table in a new tab All numbers in parentheses indicate frequency in percentage unless otherwise indicated. Statistically significant findings shown in bold. Dlco = diffusing capacity of the lung for carbon monoxide; DOAC = direct oral anticoagulant; NHANES = National Health and Nutrition Evaluation Survey. CHP = chronic hypersensitivity pneumonitis; CTD-ILD = connective tissue disease related interstitial lung disease; DOAC = direct oral anticoagulant; IIP = idiopathic interstitial pneumonia; IPF = idiopathic pulmonary fibrosis. Demographic data for the patients with IPF are provided in Table 3. Patients with IPF given anticoagulants were significantly more likely to be on pirfenidone (50%) than nintedanib (23%), compared vs patients with IPF not prescribed anticoagulants (33% vs 30%; χ2 test P = .007). A high proportion of patients (43 of 57 [75.4%]) taking DOACs and 34 of 49 (69.4%) taking warfarin were on antifibrotic therapy, whereas 677 of 1,070 (63%) patients with IPF not prescribed anticoagulants were on antifibrotics.Table 3Demographic Characteristics of Patients With IPF in the Study Cohort Stratified According to Anticoagulant UseBaseline CharacteristicDOAC (n = 57)Warfarin (n = 49)None (n = 1,070)PaP values are based on F-test for continuous variables and χ2 test for categorical variables.Age, mean ± SD, y72.8 ± 7.374.8 ± 7.570.2 ± 8.0<.0001Male sex41 (83.7)43 (75.4)807 (75.4).4186BMI, mean ± SD, kg/m229.13 ± 5.6829.41 ± 4.2329.04 ± 5.27.8957Race White54 (94.7)45 (91.8)989 (92,4).8115bFisher exact test was used instead of the χ2 test because of low cell counts. Black1 (1.75)1 (2.04)16 (1.5) Other65 (6.0)3 (6.1)65 (6.1)Gastroesophageal reflux disease6 (10.5)9 (18.4)185 (17.3).4012OSA15 (26.3)17 (34.7)280 (26.2).4171Cardiac arrhythmia26 (45.6)19 (38.8)67 (6.3)< .0001Cancer7 (12.3)9 (18.4)197 (18.6).4900Congestive heart failure5 (8.8)6 (12.2)30 (2.8).0002Coronary artery disease16 (28.1)18 (36.7)258 (24.3).1245COPD2 (3.5)5 (10.2)84 (7.9).3920Diabetes13 (22.8)12 (24.5)208 (19.6).6029Obesity11 (19.3)8 (16.3)162 (15.3).7038DVT13 (22.1)7 (14.3)16 (1.5)< .0001bFisher exact test was used instead of the χ2 test because of low cell counts.Pulmonary embolism12 (21.1)6 (12.2)10 (0.9)< .0001bFisher exact test was used instead of the χ2 test because of low cell counts.Pulmonary arterial hypertension8 (14.0)8 (16.3)52 (4.9)< .0001Peripheral vascular disease0 (0)1 (2.0)16 (1.5).6222bFisher exact test was used instead of the χ2 test because of low cell counts.Nintedanib use15 (26.3)9 (18.4)318 (29.7).2070Pirfenidone use28 (49.1)25 (51.0)359 (33.6).0032Immunosuppressant use15 (26.3)12 (24.5)227 (21.7).5816Corticosteroid use15 (26.3)10 (20.4)207 (19.4).4328Oxygen24 (42.1)24 (49.0)458 (42.8).6874Walk distance, mean ± SD, m379.89 ± 215.03342.14 ± 178.85327.66 ± 182.55.1628Baseline Dlco % predicted, mean ± SD0.39 ± 0.130.36 ± 0.140.42 ± 0.17.0456Baseline FEV % predicted, mean ± SD0.77 ± 0.190.75 ± 0.190.75 ± 0.19.7773Baseline FVC % predicted, mean ± SD0.71 ± 0.170.69 ± 0.170.68 ± 0.17.5152All numbers in parentheses indicate frequency in percentage unless otherwise indicated. Statistically significant findings shown in bold. Dlco = diffusing capacity of the lung for carbon monoxide; DOAC = direct oral anticoagulant; NHANES = National Health and Nutrition Evaluation Survey.a P values are based on F-test for continuous variables and χ2 test for categorical variables.b Fisher exact test was used instead of the χ2 test because of low cell counts. Open table in a new tab All numbers in parentheses indicate frequency in percentage unless otherwise indicated. Statistically significant findings shown in bold. Dlco = diffusing capacity of the lung for carbon monoxide; DOAC = direct oral anticoagulant; NHANES = National Health and Nutrition Evaluation Survey. At the time of data analysis, 9.96% of patients had died, had a transplant, or withdrawn: 110 deaths (5.8%), 45 transplants (2.4%), and 29 withdrawals (1.5%). Among the 1,176 patients with IPF, there were 80 deaths (6.8%), 36 transplants (3.1%), and 20 withdrawals (1.7%). Censoring was primarily due to a short period of follow-up at the time of the data lock, or due to transplant. Because follow-up data were collected through an electronic record review, the low number of withdrawals is considered noninformative. Transplant-free survival was significantly reduced in patients given anticoagulants for the entire cohort when analyzed according to Kaplan-Meier estimates (P = .0003) (Fig 1). Unadjusted Cox proportional hazards analysis also found a significant decrease in transplant-free survival in patients given anticoagulants (HR, 2.390; 95% CI, 1.472-3.881). After adjustment for covariates (described earlier), the use of anticoagulation was suggestive of an association with mortality but no longer statistically significant at an alpha level of 0.05 (HR, 1.78; 95% CI, 0.998-3.163). When stratified according to type of anticoagulant, Kaplan-Meier estimates still found a significant decrease in transplant-free survival (P = .009) (Fig 2). On unadjusted Cox proportional hazards analysis, both warfarin (HR, 2.752; 95% CI, 1.471-5.147) and DOACs (HR, 2.058; 95% CI, 1.037-4.084) were associated with reduced transplant-free survival. However, adjusted Cox proportional hazards analysis found that only warfarin (HR, 2.101; 95% CI, 1.025-4.307), and not DOACs (HR, 1.510; 95% CI, 0.709-3.215), were associated with a reduction in transplant-free survival. A direct comparison of warfarin to DOAC survival was not statistically significant (HR of 1.338, P = .5177 unadjusted; HR of 1.392, P = .4784 adjusted). A subgroup analysis of the IPF cohort revealed similar findings, with Kaplan-Meier estimates again showing an association between anticoagulation and reduced transplant-free survival (P = .0129) (Fig 3). A reduced likelihood of transplant-free survival in patients prescribed anticoagulants persisted after stratifying Kaplan-Meier estimates according to type of anticoagulant (P = .014) (Fig 4). On unadjusted Cox proportional hazards analysis, only warfarin (HR, 2.781; 95% CI, 1.336-5.791), and not DOACs (HR, 1.495, 95% CI, 0.602-3.710), was found to be associated with a significant increase in risk of death or transplant in patients with IPF. This relationship persisted for warfarin, even following adjustment for age, sex, Dlco, FVC, 6MWT, and comorbidities as described earlier (HR, 2.566; 95% CI, 1.095-6.0165). However, the association of DOACs with increased risk of death or transplant in patients with IPF was not maintained after a similar adjustment (HR, 1.368; 95% CI, 0.500-3.737).Figure 4Kaplan-Meier analysis of transplant-free survival in patients with idiopathic pulmonary fibrosis stratified according to type of anticoagulant. DOAC = direct oral anticoagulant.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Unadjusted Cox proportional hazards analysis of the non-IPF patients revealed that anticoagulation is associated with an increased risk of transplant or death (HR, 3.246; 95% CI, 1.392-7.568). This relationship failed to reach statistical significance following adjustment for confounding variables (HR, 2.16; 95% CI, 0.750-6.245). The detailed results of all survival analyses are provided in e-Appendix 1. In this analysis of the PFF-PR, we show that the use of anticoagulation in patients with fibrotic ILD is associated with increased mortality. Our subgroup analysis based on type of anticoagulation confirms that warfarin is associated with worse outcomes but that the DOACs are not, following adjustment for confounding variables. This analysis, derived from the largest cohort of its kind to be analyzed, provides the most comprehensive evaluation, to our knowledge, of the relationship between anticoagulation and fibrotic ILD to date. It is also the first report of anticoagulation usage in fibrotic ILDs other than IPF, as well as the first comparing the effects of DOACs and warfarin on outcomes in ILD. The overall need for anticoagulation for the cohort as a whole was 9.1% and ranged from a low of approximately 5% for non-IPF IIPs to a high of 13.7% in "other" ILDs. Of the patients with IPF, 9.0% were taking anticoagulants, whereas CTD-ILD also had a high prevalence of anticoagulant use at 11.5%. There was a trend toward increased need for anticoagulation in CTD-ILD and "other" ILD (P = .065), but this failed to meet statistical significance. Cardiac arrhythmias were reported in 169 patients (8.8%) and prior VTE events in 98 patients (5.1%), although the exact indication for the patients who were on anticoagulation was not known. The need for anticoagulation in patients with IPF from the study cohort (8.96%) is higher than the prevalence reported in the 624 patients (5.1%) constituting the placebo arms of the three major trials of antifibrotic drugs reported by Kreuter et al.8Kreuter M. Wijsenbeek M.S. Vasakova M. et al.Unfavourable effects of medically indicated oral anticoagulants on survival in idiopathic pulmonary fibrosis.Eur Respir J. 2016; 47: 1776-1784Crossref PubMed Scopus (46) Google Scholar It is likely that the current population reflects a more "real-world" population, as patients with advanced IPF, and those with significant comorbidities including severe cardiovascular or VTE disease, were excluded from clinical trials. However, our observed prevalence of anticoagulation use was markedly less than the rate of 20.5% reported by Behr et al12Behr J. Kreuter M. Hoeper M.M. et al.Management of patients with idiopathic pulmonary fibrosis in clinical practice: the INSIGHTS-IPF registry.Eur Respir J. 2015; 46: 186-196Crossref PubMed Scopus (150) Google Scholar from the Investigating Significant Health Trends in Idiopathic Pulmonary Fibrosis (INSIGHTS-IPF) registry. This increased prevalence may reflect a greater severity of illness in the INSIGHTS-IPF registry, as the reported mean 6MWT distance was lower (267 m) compared with that of the current cohort (336 m). Our study was consistent with other studies in terms of demographic characteristics of patients requiring anticoagulation.8Kreuter M. Wijsenbeek M.S. Vasakova M. et al.Unfavourable effects of medically indicated oral anticoagulants on survival in idiopathic pulmonary fibrosis.Eur Respir J. 2016; 47: 1776-1784Crossref PubMed Scopus (46) Google Scholar Specifically, patients requiring anticoagulation were older, had a lower Dlco, and had a higher incidence of cardiac and VTE disease. However, the 6MWT distance, baseline FVC, and need for oxygen were not statistically different from patients who did not require anticoagulation. It was gratifying to note that 64.1% (n = 754) of the 1,176 patients with IPF were on antifibrotic therapy. The need for anticoagulation did not alter use of antifibrotic therapy, as 72.6% of patients with IPF on anticoagulation were taking antifibrotics. However, the choice of antifibrotic was affected, with pirfenidone favored over nintedanib (50% vs 23.6%; P = .0073) in those taking anticoagulants, compared with those not taking anticoagulants (about 32% for both pirfenidone and nintedanib), presumably due to concerns for increased bleeding risk with nintedanib.13King C.S. Nathan S.D. Practical considerations in the pharmacologic treatment of idiopathic pulmonary fibrosis.Curr Opin Pulm Med. 2015; 21: 479-489Crossref PubMed Scopus (30) Google Scholar The need for anticoagulation in the current study was associated with an increased risk of death or transplant in both the general ILD population and in IPF patients specifically. This is consistent with the findings of previous studies.7Tomassetti S. Ruy J.H. Gurioli C. et al.The effect of anticoagulant therapy for idiopathic pulmonary fibrosis in real life practice.Sarcoidosis Vasc Diffuse Lung Dis. 2013; 30: 121-127PubMed Google Scholar,8Kreuter M. Wijsenbeek M.S. Vasakova M. et al.Unfavourable effects of medically indicated oral anticoagulants on survival in idiopathic pulmonary fibrosis.Eur Respir J. 2016; 47: 1776-1784Crossref PubMed Scopus (46) Google Scholar The exact reason for these inferior outcomes cannot be determined given the study methodology. Patients with ILD requiring anticoagulation were older and had a higher incidence of VTE and cardiac co-morbidities. They also had a higher rate of immunosuppressant use, including steroids. Although their pulmonary disease was not more severe based on lung volumes, they did have a lower Dlco, which could reflect either more severe ILD or concurrent pulmonary hypertension. Given the increased incidence of co-morbidities in the anticoagulation cohorts, it is likely that their outcomes were driven, at least in part, by factors other than their lung disease. Interestingly, when these confounders were adjusted for, the need for anticoagulation was still associated with a nearly twofold increased risk of death or transplant. The most provocative findings from our study are the comparison of the effects of warfarin vs DOACs on survival. Warfarin was associated with an increased risk of death in the study cohort as a whole, even after adjusted analysis for confounding variables. Anticoagulation with DOACs, however, did not adversely affect transplant-free survival in the general ILD population on adjusted analysis and were also not associated with inferior transplant-free survival in the IPF population on either adjusted or unadjusted analysis. The reason for inferior outcomes with warfarin compared with DOACs cannot be conclusively determined given the observational nature of the current study. It is noteworthy, however, that our findings are consistent with the results of the ACE-IPF study, which reported increased harm in the warfarin arm in the context of a double-blind randomized trial of patients with IPF.6Noth I. Anstrom K.J. Calvert S.B. et al.Idiopathic Pulmonary Fibrosis Clinical Research Network (IPFNet)A placebo-controlled randomized trial of warfarin in idiopathic pulmonary fibrosis.Am J Respir Crit Care Med. 2012; 186: 88-95Crossref PubMed Scopus (355) Google Scholar One could speculate that confounding variables which led to the choice of warfarin rather than DOACs are responsible for the worse outcomes noted. However, there were no clear demographic differences noted between the DOAC and warfarin cohorts. One important comorbidity we were unable to account for, which might have prompted the use of warfarin, was the presence of renal insufficiency. Unfortunately, this variable was not captured in the PFF-PR. Another possibility considered was that warfarin might be used more commonly in patients who are referred for transplant as it is more readily reversible, leading to an increased rate of transplant and thus worse transplant-free survival. However, a review of specific events in the IPF population shows that this is not the case. In fact, the death rate among warfarin-treated patients with IPF (16.3%) is higher than in patients taking DOACs (8.8%) or receiving no anticoagulation (6.1%). Another possibility is that warfarin may have deleterious effects that drive worse outcomes. Because specific data regarding cause of death in the PFF-PR are unavailable, it is difficult to know if this outcome was due to an increased propensity of bleeding. Indeed, DOACs consistently exhibited a superior safety profile to warfarin regarding bleeding in the clinical trials leading to their approval.10King C.S. Holley A.B. Moores L.K. Moving toward a more ideal anticoagulant: the oral direct thrombin and factor Xa inhibitors.Chest. 2013; 143: 1106-1116Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar Alternatively and perhaps more likely, warfarin might have adverse effects that accelerate progression of disease in fibrotic lung disease. The ACE-IPF study of warfarin in IPF seems to support this notion, as warfarin led to increased mortality that was not attributable to bleeding complications of therapy.6Noth I. Anstrom K.J. Calvert S.B. et al.Idiopathic Pulmonary Fibrosis Clinical Research Network (IPFNet)A placebo-controlled randomized trial of warfarin in idiopathic pulmonary fibrosis.Am J Respir Crit Care Med. 2012; 186: 88-95Crossref PubMed Scopus (355) Google Scholar Suggested potential mechanisms for increased harm with warfarin include alveolar hemorrhage, detrimental effects of inhibition of vitamin K-dependent clotting factors, or loss of beneficial effects of protein C on inflammation and remodeling. Although our data show no evidence of this, a rationale exists that other anticoagulants, including DOACs, might exert some beneficial effect in fibrotic lung disease. Both direct thrombin inhibitors and factor Xa inhibition have shown antifibrotic properties in a murine model of ILD.9Crooks M.G. Hart S. Coagulation and anticoagulation in idiopathic pulmonary fibrosis.Eur Respir Rev. 2015; 24: 392-399Crossref PubMed Scopus (30) Google Scholar,14Bogatkevich G.S. Ludwicka-Bradley A. Nietert P.J. Akter T. van Ryn J. Silver R.M. Antiinflammatory and antifibrotic effects of the oral direct thrombin inhibitor dabigatran etexilate in a murine model of interstitial lung disease.Arthritis Rheum. 2011; 63: 1416-1425Crossref PubMed Scopus (79) Google Scholar In addition, the study that prompted the inception of the ACE-IPF study did show benefit to anticoagulation therapy that was likely driven by the use of IV heparin when patients were admitted to the hospital.5Kubo H. Kakayama K. Yanai M. et al.Anticoagulant therapy for idiopathic pulmonary fibrosis.Chest. 2005; 128: 1475-1482Abstract Full Text Full Text PDF PubMed Scopus (392) Google Scholar The current study has a number of limitations. As previously mentioned, the nature of the study design precludes conclusions of causality regarding the adverse effects of warfarin. Also, although our study represents the largest cohort to date to report on the impact of these different forms of anticoagulation in ILD, the number of events was small and the follow-up time limited. It is possible that the small number of patients managed with DOACs limited the power of the study to detect an association with decreased transplant-free survival. Finally, we were unable to provide data on the specific DOACs used or the duration of use and compliance with anticoagulation. Advantages of this study are the large number of patients comprising a well-vetted cohort. All patients were evaluated at accredited PFF centers, which likely increases the accuracy of diagnosis for the various types of fibrotic lung disease. Despite the limitations, we feel this study provides a meaningful contribution to the existing literature regarding the use of anticoagulation in fibrotic lung disease and strengthens the argument to use DOACs preferentially in patients with fibrotic lung disease when feasible. In the future, we hope to re-analyze the data with additional follow-up time to capture more events and a larger patient cohort. We also hope to analyze the effects of the various anticoagulants on the rate of decline in FVC to determine if warfarin is in fact associated with an accelerated rate of decline in pulmonary function. We also believe that a pilot trial examining DOACs as a potential therapy for IPF should be considered. The need for anticoagulation is common in patients with ILD and is associated with inferior outcomes. Anticoagulation with warfarin specifically seems to be associated with reduced transplant-free survival. Further study comparing use of DOACs vs warfarin in patients with ILD is warranted. While we await these data, it may be prudent to use DOACs preferentially over warfarin in patients without a contraindication in accordance with current guidelines on atrial fibrillation and VTE.15Kearon C. Akl E.A. Ornelas J. et al.Antithrombotic therapy for VTE disease: Chest Guideline and Expert Panel Report.Chest. 2016; 149: 315-352Abstract Full Text Full Text PDF PubMed Scopus (2941) Google Scholar,16Lip G.Y.H. Banerjee A. Boriani G. et al.Antiothrombotic therapy for atrial fibrillation: CHEST Guideline and Expert Panel Report.Chest. 2020; 154: 1121-1201Abstract Full Text Full Text PDF Scopus (469) Google Scholar Author contributions: C. S. K. is the guarantor and is responsible for the content of the manuscript. C. S. K. contributed to study design, data analysis, and manuscript preparation; E. F. contributed to statistical analysis, study design, and manuscript preparation; A. W. B., O. A. S., S. A., K. A., V. K., K. R. F., and D. V. were responsible for study design and manuscript editing; and S. D. N. contributed to study design, data analysis, and manuscript editing. Financial/nonfinancial disclosures: The authors have reported to CHEST the following: C. S. K. is on the speakers bureau for Genentech and Actelion; and on advisory boards for United Therapeutics, Boehringer Ingelheim, and Actelion. A. W. B. has served on an advisory board for Promedior, Theravance, and Genentech; and serves on the speakers bureau for Genentech. O. A. S. has served as a consultant and on the speakers bureau for Lung Rx/United Therapeutics, Actelion, and Bayer. K. R. F. reports personal fees from Veracyte and Sanofi Genzyme; and grants and personal fees from Roche/Genentech and Boehringer Ingelheim. S. D. N. is a consultant for Actelion, Bellerophon, Roche-Genentech, Boehringer Ingelheim, Pliant, Merck, United Therapeutics, and Bayer Pharmaceuticals; and is on the speakers bureau for Roche-Genentech, Boehringer Ingelheim, and Bayer Pharmaceuticals. None declared (E. F., S. A., K. A., V. K., D. V.). Additional information: The e-Appendix can be found in the Supplemental Materials section of the online article. Download .pdf (.26 MB) Help with pdf files e-Online Data