Slight Risk of Interstitial Lung Disease Seen With Certain DOACs

Among patients with atrial fibrillation (AF), use of factor Xa inhibitors for stroke prevention is associated with a greater risk of interstitial lung disease (ILD) than use of warfarin, although the absolute difference is small, according to retrospective data out of Taiwan.

The rate of incident idiopathic ILD was 0.29 per 100 patient-years with the direct oral anticoagulants (DOACs) and 0.17 per 100 patient-years with warfarin (HR 1.54; 95% CI 1.22-1.94), researchers led by Yi-Hsin Chan, MD (Chang Gung Memorial Hospital, Taoyuan City, Taiwan), report in a study published online this week in JAMA Network Open.

The finding was consistent across several high-risk subgroups and across individual factor Xa inhibitors.

Senior author Gregory Lip, MD (Liverpool Heart & Chest Hospital, England), underscored to TCTMD that due to the study’s observational nature, it cannot establish causal relationships, adding that additional research is needed to explore potential mechanisms.

For now, he said via email, “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.”

Geoffrey Barnes, MD (University of Michigan, Ann Arbor), commenting via email, also didn’t advise any major changes to current practice based on these findings.

“There has been some discussion about potential side effect risks for factor Xa inhibitor medications, including lung disease,” Barnes said, noting the limitations associated with an observational study and calling the difference in ILD risk between the factor Xa inhibitors and warfarin observed here “quite small.”

He pointed out, too, that several large RCTs and observational analyses have demonstrated significant benefits with factor Xa inhibitors compared with vitamin K antagonists, including lower bleeding risks and similar or better efficacy in preventing stroke, in the setting of AF.

“While this study is important to highlight a potential side effect of these medications, this finding should not deter patients or clinicians from using factor Xa inhibitors as first-line therapy for stroke prevention in AF,” Barnes said.

Risk Small Compared With DOAC Benefits

Over the past decade or so, the DOACs—including dabigatran (Pradaxa; Boehringer Ingelheim), a direct thrombin inhibitor, and the factor Xa inhibitors—have been steadily displacing warfarin as the preferred anticoagulant for stroke prevention in AF based on the results of their respective pivotal trials. Though the initial trials included reports of dyspnea, respiratory distress, and pneumonia as adverse events associated with the agents, rarer lung-related events only became evident in larger postmarketing studies. Of note, previous case reports and pharmacovigilance analyses have indicated a potential link between use of factor Xa inhibitors and ILD.

To explore that relationship further, Chan et al turned to the Taiwan National Health Insurance Research Database, examining data on 106,044 patients (mean age 73.4; 56.6% men) with AF and no preexisting chronic lung disease who received oral anticoagulation between June 2012 and December 2017. Most patients (60.9%) received one of the factor Xa inhibitors—rivaroxaban (Xarelto; Bayer/Janssen), apixaban (Eliquis; Bristol Myers Squibb), or edoxaban (Savaysa; Daiichi Sankyo). The rest were prescribed either dabigatran (21.2%) or warfarin (17.9%).

This finding should not deter patients or clinicians from using factor Xa inhibitors as first-line therapy for stroke prevention in AF. Geoffrey Barnes

The factor Xa inhibitors as a group, and individually, were associated with a slightly greater risk of ILD compared with warfarin after propensity score stabilized weighting was used to adjust for baseline differences. Dabigatran was not associated with a greater risk in the main analysis (P = 0.09), although the small difference compared with warfarin became significant in an analysis with death as a competing risk (P = 0.03).

The investigators put these risks into the context of the safety and efficacy of the DOACs. The absolute increases in ILD seen with the factor Xa inhibitors and dabigatran—0.12 and 0.05 per 100 patient-years, respectively—were much smaller than the absolute reductions in ischemic stroke/systemic embolism (0.78 and 0.64 per 100 patient-years, respectively) and major bleeding (0.78 and 1.01 per 100 patient-years, respectively).

Concomitant use of amiodarone was frequent in the study (24.7% to 42.5%), and it was associated with a higher risk of incident ILD regardless of type of oral anticoagulant—factor Xa inhibitors (HR 1.41; 95% CI 1.15-1.73), dabigatran (HR 1.62; 95% CI 1.12-2.35), and warfarin (HR 1.97; 95% CI 1.32-2.95).

The highest rate of incident ILD was observed in patients receiving both amiodarone and a factor Xa inhibitor (0.38 per 100 patient-years) and the lowest was seen in those prescribed warfarin without amiodarone (0.13 per 100 patient-years).

An Alert, Not an Alarm

The potential mechanism linking factor Xa inhibition to incident ILD is unclear, according to the researchers, who note that the study “did not mean to suggest that patients who were already being treated with NOACs (especially factor Xa inhibitors) change back to warfarin.”

How the risks and benefits of factor Xa inhibitors balance out when taking the risk of ILD into consideration requires further studies in different patient populations, Lip said. “We would initially look to see if the observations could be observed in other large cohorts, including non-Asian studies.”

Pointing to the limitations of this type of study, Emanuel Raschi, MD, PhD (University of Bologna, Italy), states in an accompanying editorial that these findings cannot be used when choosing an oral anticoagulant, adding that “the overall risk-benefit profile of NOACs remains unaffected.”

The study “should not be viewed as an alarm but rather as an alert for clinicians, including general practitioners, hospitals, and specialized physicians,” he says. “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.”

Patients and physicians should remain alert to the potential risk, Raschi says, adding that it’s important to report suspected cases. He calls for additional research to explore mechanisms, reversibility of ILD after drug discontinuation, population susceptibility, and other issues.