Direct Oral Anticoagulant Consumption and the Risk of Acute Interstitial Lung Diseases: A Case‐Crossover Study Using Japanese Administrative Data

BACKGROUND: Direct oral anticoagulants (DOACs) offer advantages over warfarin; however, concerns exist regarding their association with acute interstitial lung diseases (ILDs). This study investigated the risk of acute-onset ILDs associated with DOAC use. METHODS: We conducted a case-crossover study to assess the risk of hospitalization for acute-onset ILDs following DOAC initiation using the JMDC database, a Japanese administrative claims database. Patients aged ≥ 18 years hospitalized for acute-onset ILDs (April 2011-February 2023) were included. DOAC exposure was defined as ≥ 14 days within predefined 30-day windows: 1-30 days before admission (exposure period) and 60-90 and 120-150 days before admission (reference periods). The primary outcome was hospitalizations for acute-onset ILD, identified using a validated algorithm. Conditional logistic regression estimated odds ratios (ORs). Sensitivity analyses included a bidirectional case-crossover design, a case-crossover analysis with warfarin as an active comparator, weighted case-crossover analysis, and a case-case-time-control design. A descriptive cohort analysis of new DOAC and warfarin users examined ILD frequency and prognosis. RESULTS: The main case-crossover analysis included 178 patients, showing an association between DOAC use and acute-onset ILDs (adjusted OR, 4.44 [95% CI, 1.58-12.5]). Sensitivity analyses demonstrated a consistent direction of association (adjusted ORs: 3.37-6.85). In descriptive cohort analysis (52 021 DOAC and 12 026 warfarin initiators), ILD incidence was low (0.24% vs. 0.20%), but 90-day mortality was higher in the DOAC group (21% vs. 0%). CONCLUSIONS: DOAC use was associated with an increased risk of hospitalization for acute-onset ILDs. Clinicians should monitor patients on DOACs for ILD symptoms.