Factor Xa Inhibitors Tied to Interstitial Lung Disease in AF

Marilynn Larkin

November 23, 2022

In patients with nonvalvular atrial fibrillation (NVAF), treatment with factor Xa (FXa) inhibitors was associated with a greater risk of interstitial lung disease (ILD) than other oral anticoagulants (OACs), a medical records analysis shows.

Emerging concerns from case reports and pharmacovigilance analyses of a possible risk of ILD associated with the use of FXa inhibitors prompted the analysis, said Gregory Lip, MD, of the University of Liverpool and Liverpool Heart & Chest Hospital, UK.

"This is an observational study which describes associations, not causality," Lip told theheart.org | Medscape Cardiology. "Thus, this requires further studies in different populations and additional prospective work or clinical trials."

The researchers plan to initially look to see if the findings can be replicated in studies of other large cohorts, including non-Asian studies, he said. Meanwhile, "vigilance in monitoring for any potential adverse lung outcomes associated with the use of these drugs is recommended as part of the holistic approach to AF care and management," he said.

And they are not advocating that patients change back to warfarin, the authors note. The absolute difference in rates of ILD between the FXa inhibitors and warfarin was small (0.12 per 100 patient-years) and much lower than the absolute reduction in the incidence of thromboembolism (0.78 per 100 patient-years) and major bleeding (0.78 per 100 patient-years) between the FXa inhibitor and warfarin groups, they point out.

The cohort study of more than 100,000 patients in Taiwan was published online November 22 in JAMA Network Open.

Don't Change Back

The analysis of data from the Taiwan National Health Insurance Research Database included 106,044 patients with NVAF (mean age, 73.4 years; 56.6% men) without pre-existing lung disease who were treated with OACs from 2012 to 2017. The authors used propensity score stabilized weighting (PSSW) to balance covariates across the medication groups (FXa inhibitors, dabigatran, and warfarin, with warfarin as the reference).

Patients were followed from the drug index date until the onset of ILD, death, or study end (December 31, 2019).

Among the 60.9% of patients treated with FXa inhibitors, 24% received apixaban; 19%, edoxaban; and 57%, rivaroxaban. In addition, 21.2% received dabigatran and 17.9% received warfarin at baseline.

After PSSW, FXa inhibitors were associated with a higher risk of incident ILD (0.29 vs 0.17 per 100 patient-years; hazard ratio [HR], 1.54) and dabigatran was associated with a nonsignificant risk difference.

Furthermore, patients who were diagnosed with ILD during follow-up and treated with FXa inhibitors had a higher risk of ILD requiring consequent antifibrotic agents than those treated with warfarin (odds ratio, 3.01).

The higher risk of incident ILD for FXa inhibitors versus warfarin was consistent within several high-risk subgroups, such as those taking amiodarone (0.38 vs 0.26 per 100 patient-years; HR, 1.41). The risk also was higher with dabigatran (0.31 vs 0.18 per 100 patient-years; HR, 1.62), and warfarin (0.28 vs 0.13 per 100 patient-years; HR, 1.97). The lowest risk of ILD was in patients treated with warfarin without amiodarone.

Study limitations included the reliance on claims instead of clinical data on ILD; an older patient population with AF who may already have had a higher overall risk of incident ILD; lack of laboratory data on patient liver and kidney function, which may have affected treatment decisions; and enrollment of only Asian patients.

"Very Small, But Real"

Jonathan Paul Piccini, MD, associate professor of medicine at Duke University Medical Center and director of the cardiac electrophysiology section at the Duke Heart Center in Durham, North Carolina, commented on the study for theheart.org | Medscape Cardiology.

"The data from this study do suggest a very small but real incremental association with ILD in individuals treated with FXa inhibitors," he said. However, he added, "This incremental risk is very, very small relative to the degree of stroke protection with these drugs."

"For clinicians in North America, it is important to realize that this was an Asian cohort, and so, we really don't know what the risk might be in more diverse, US-based populations," he said. "Second, we need more studies to confirm if this association is real."

"At this point, I think it is important to be aware of this potential association, particularly when caring for individuals who may develop signs of ILD or those at high-risk for ILD, like those receiving amiodarone," he said. "Certainly, FXa therapy should not be stopped based upon concern for this complication. Clinicians should keep in mind that the guidelines recommend DOACs over warfarin for the prevention of stroke in persons with AF." 

Like Piccini and the authors, Emanuel Raschi, MD, PhD, of the University of Bologna, Italy, writes in a related editorial that "the overall risk–benefit profile of NOACs remains unaffected," as the "small" absolute difference in ILD rates was much lower than the absolute reduction in thromboembolism and major bleeding.

"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," Raschi writes. "However, patients should be instructed to timely communicate early respiratory signs and symptoms to their clinicians, who should remain vigilant for adverse lung effects, especially in patients receiving anti-FXa agents and concomitant amiodarone."

No commercial funding or conflicts of interest were disclosed for the study. Piccini has reported receiving research funding from Bayer and serving as a consultant for Boston Scientific and Abbott.

JAMA Netw Open. Published online November 22, 2022. Abstract, Editorial

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