Development of Interstitial Lung Disease Among Patients With Atrial Fibrillation Receiving Oral Anticoagulants in Taiwan

Abstract

ImportanceThere are emerging concerns from case reports and pharmacovigilance analyses of a possible risk of interstitial lung disease (ILD) associated with the use of factor Xa (FXa) inhibitors.ObjectiveTo evaluate the risk of incident ILD associated with the use of oral anticoagulants (OACs) in patients with nonvalvular atrial fibrillation (NVAF).Design, Setting, and ParticipantsThis nationwide retrospective cohort study used data from the Taiwan National Health Insurance Research Database. Patients with NVAF without preexisting lung disease who received OACs from June 1, 2012, to December 31, 2017, were included. Propensity score stabilized weighting (PSSW) was used to balance covariates across the medication groups (FXa inhibitors, dabigatran, and warfarin, with warfarin as the reference). Patients were followed up from the drug index date until the onset of ILD, death, or end of the study (December 31, 2019), whichever occurred first. Data were analyzed from September 11, 2021, to August 3, 2022.ExposuresPatients with NVAF were treated with FXa inhibitors, dabigatran, or warfarin.Main Outcomes and MeasuresNew-onset idiopathic ILD.ResultsAmong the 106 044 patients (mean [SD] age, 73.4 [11.9] years; 59 995 men [56.6%]) included in the study, 64 555 (60.9%) received FXa inhibitors (apixban [n = 15 386], edoxaban [n = 12 413], and rivaroxaban [n = 36 756]), 22 501 (21.2%) received dabigatran, and 18 988 (17.9%) received warfarin at baseline. The FXa inhibitors were associated with a higher risk of incident ILD (0.29 vs 0.17 per 100 patient-years; hazard ratio, 1.54 [95% CI, 1.22-1.94]; P < .001), whereas dabigatran was associated with a nonsignificant difference in risk of incident ILD compared with warfarin (reference) after PSSW. The higher risk of incident ILD for FXa inhibitors vs warfarin was consistent with several high-risk subgroups.Conclusions and RelevanceResults of this study suggest that FXa inhibitors were associated with lung injury among patients with NVAF who were treated with OACs. Physicians should be vigilant in monitoring for any potential adverse lung outcomes associated with the use of these drugs.

Interstitial Lung Disease With Non–Vitamin K Oral Anticoagulants—A Clinical Concern?

“…Moreover, channeling bias (the propensity to preferentially prescribe NOACs in frail patients with risk factors for adverse events) is a real threat in pharmacovigilance. The study by Chan et al supported the existence of a genuine pharmacovigilance signal (ie, a real adverse drug reaction) and, for the first time, corroborated the association between FXa inhibitors and ILD.…”

“…The (small) absolute difference in rates of ILD between the FXa inhibitors and warfarin groups (0.12 per 100 patient-years each) was much lower than the corresponding absolute reduction in thromboembolism and major bleeding (0.78 per 100 patient-years each) and even lower than previous estimates on DILI (0.73 per 100 person-years). 5 Therefore, the welcome contribution by Chan et al 2 should not be viewed as an alarm but rather as an alert for clinicians, including general practitioners, hospitals, and specialized physicians.…”

“…In this context, the timely retrospective nationwide cohort study by Chan et al 2 tested the hypothesis that NOACs are associated with increased risk of incident interstitial lung disease (ILD) in patients with nonvalvular AF without a preexisting lung disease, an emerging safety issue, especially in the current COVID-19 era. Using the Taiwan National Health Insurance Research Database, a recognized claims archive covering 99% of the population in Taiwan, Chan et al 2 implemented an intention-to-treat design and applied a propensity score stabilized weighting method to balance more than 30 covariates across groups, including comorbidities and baseline medications. Several subgroup and sensitivity analyses were also performed to handle the measurable and unmeasurable confounders, including the use of falsification outcomes, use of a cause-specific hazard model, and restriction to new users or to a rigid idiopathic pulmonary fibrosis definition.…”

“…This population-based study by Chan et al has the key merit of assessing a previous pharmacovigilance signal to confirm (or refute) the drug-related hypothesis . When examining adverse reactions to NOACs from spontaneous reporting systems, an undeclared overlooked bias might exist, with potential implications for results: compared with the old-fashioned warfarin, drug-related complications associated with NOACs are likely to be more easily reported in the interest of postmarketing surveillance and detection of rare adverse effects.…”

“…Therefore, the welcome contribution by Chan et al should not be viewed as an alarm but rather as an alert for clinicians, including general practitioners, hospitals, and specialized physicians. Recommending the close monitoring of lung function in patients who were treated with NOACs is not justified, and any regulatory measure cannot be envisioned other than an update of the summaries of product characteristics.…”