Warfarin use tied to bleak outcomes in ILD patients

The use of anticoagulants, particularly warfarin, appears to convey an increased risk of death or transplant among patients with interstitial lung disease (ILD), including those with idiopathic pulmonary fibrosis (IPF), according to a study.

“The most provocative findings from our study are the comparison of the effects of warfarin vs direct oral anticoagulants (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,” the investigators pointed out.

“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,” they added.

The investigators acknowledged that they could not give a conclusive reason for inferior outcomes with warfarin compared with DOACs, given the observational nature of the study. “However, 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.” [Am J Respir Crit Care Med 2012;186:88-95]

ACE-IPF supports the notion that warfarin could exert adverse effects that accelerate progression of disease in fibrotic lung disease. Indeed, in the current study, treatment with the vitamin K antagonist led to increased mortality that was not attributable to bleeding complications of therapy.

Potential mechanisms underlying increased harm with warfarin, according to the investigators, include alveolar haemorrhage, detrimental effects of inhibition of vitamin K-dependent clotting factors, or loss of beneficial effects of protein C on inflammation and remodeling.

Need for anticoagulation common in ILD

The present study drew data from the Pulmonary Fibrosis Foundation Patient Registry and included a cohort of 1,911 well-characterized patients with ILD. Of these, 1,176 (61.5 percent) had IPF, 201 (10.5 percent) had an idiopathic interstitial pneumonia (IIP) other than IPF, 287 (15.0 percent) had connective tissue disease-associated ILD (CTD-ILD), 152 (8.0 percent) had chronic hypersensitivity pneumonitis, and 95 (5.0 percent) had other ILDs. [Chest 2021;159:1507-1516]

The investigators believe that this cohort reflected a more “real-world” population, as patients with advanced IPF and those with significant comorbidities, including severe cardiovascular, were excluded from clinical trials.

Overall, anticoagulant use was documented in 9.1 percent of patients (n=174), ranging from a low of approximately 5 percent in non-IPF IIP to a high of 13.7 percent in other ILDs. Of the patients with IPF, 9.0 percent were taking anticoagulants, whereas connective tissue disease-associated ILD also had a high prevalence of anticoagulant use at 11.5 percent.

In terms of anticoagulant type, 93 patients (4.9 percent) were prescribed a DOAC and 81 (4.2 percent) warfarin. Compared with nonusers, patients on anticoagulation tended to be older, male, have a history of cardiac issues or venous thromboembolism, use immunosuppressants, and had lower Dlco (diffusing capacity of the lung for carbon monoxide).  

Cox proportional hazards models showed a twofold increased risk of death or transplant for patients receiving DOACS, with the risk being more than two-and-half times greater with warfarin. In patients with IPF, the vitamin K antagonist contributed to a decline in transplant-free survival. DOACs were associated with neither outcome.

Despite the limitations, including the nature of the study design and small number of events, the investigators asserted that the study provides a meaningful contribution to the existing literature and advocates preferential use of DOACs in patients with fibrotic lung disease when feasible.

In an accompanying editorial, Drs Cathryn Lee and Ayodeji Adegunsoye of the University of Chicago, Chicago, Illinois, US, sounded their agreement with the investigators. [Chest 2021;159:1321-1323]

“Th[e] study highlights the potential implications of anticoagulation in clinical practice for the multimorbid patient with ILD and adds to the armamentarium of evidence for potential harm with warfarin in patients with pulmonary fibrosis. Where possible, patients may benefit from the use of a DOAC instead of warfarin, aligning with the growing number of professional societies recommending its use in all patients who require anticoagulation,” they wrote.

Lee and Adegunsoye called for additional research to establish the role of the coagulation cascade in patients with pulmonary fibrosis and identify other medical conditions and therapeutics that could have an unintended effect on clinical outcomes.

“This fusion of bench, bedside, and big data is the next frontier in advancing the care of the everyday patient with pulmonary fibrosis. For now, the idea that certain anticoagulants carry therapeutic value in pulmonary fibrosis is still a fleeting promise that remains unproved and hopefully will have ILD researchers resolutely searching for the truth in the years ahead,” the experts said.