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HONOLULU -- There was a signal of excess diffuse alveolar hemorrhage (DAH) among users of direct oral anticoagulants (DOACs), according to an analysis of the FDA Adverse Event Reporting System (FAERS) database.

Based on voluntary reports from 2013 to 2022, this class of antithrombotic, used for a wide variety of indications, carried a reporting odds ratio (ROR) of 12.84 for DAH (95% CI 11.65-14.20), reported Chengu Niu, MD, of Rochester General Hospital in New York.

FAERS patients with DOAC-associated DAH died in 0.4% of cases. Nearly 84% of this cohort had a life-threatening course and needed hospitalization -- a "pretty remarkable outcome," Niu said.

"The fact that DOACs present a nearly 13-fold increase associated with DAH is an important finding and cannot be ignored," Niu told the audience here at the CHEST annual meeting hosted by the American College of Chest Physicians.

His group identified 2,998 drug-induced DAH events in FAERS, of which 462 were DOAC-associated. DOAC-associated DAH appeared to be more frequent in people age 65-85 years (59.3%) and in men (61% vs 32% of women). DOAC use had most commonly been indicated by atrial fibrillation (51.9%) and venous thromboembolism (14.5%).

"The results of this study are interesting but further study would be needed to determine if they should influence clinical practice for patients treated with DOACs," Jordan Schaefer, MD, of the University of Michigan in Ann Arbor, told 番茄社区app via email.

"Factors including patient co-morbidities, medications, organ function, specific DOAC, DOAC dose, duration of anticoagulant use, test results, demographics, and more could be compared to patients with DAH on other anticoagulant drugs to determine if DOACs were associated with a higher risk of DAH," suggested Schaefer, who was not involved with the present study.

He noted that DOACs are extensively studied medications. As a class, the DOACs seem safer than warfarin in terms of some bleeding, especially intracranial bleeding, but have been linked to more gastrointestinal bleeds.

Niu's report "should remind DOAC prescribers of the importance of antithrombotic stewardship or the importance of evidence-based prescribing, providing appropriate follow-up care and monitoring, and the value of efforts to try to reduce patient bleeding risk," Schaefer said.

"When seeing patients, it is important to address potentially modifiable bleeding risk factors like blood pressure or to consider potentially changing anticoagulants in the setting of worsening organ function," he urged.

Niu and colleagues had performed an observational pharmacovigilance study analyzing adverse events reported from users of apixaban (Eliquis), betrixaban (Bevyxxa), dabigatran (Pradaxa), edoxaban (Savaysa), and rivaroxaban (Xarelto).

Rivaroxaban stood out for being the DOAC most represented among DOAC-DAH cases (47.8%), followed by apixaban (27.1%). Rivaroxaban had a ROR 5.80 for DAH (95% CI 5.06-6.66), and apixaban's ROR was 6.48 (95% CI 5.42-7.76).

However, since rivaroxaban and apixaban were the most frequently used DOACs to begin with, study authors found disproportionately more DAH reports for the less popular DOACs, dabigatran (ROR 13.47, 95% CI 11.01-16.48) and edoxaban ROR 21.44 (95% CI 14.21-32.33).

Niu said these extremely high figures were likely skewed by selective reporting on these less-used DOACs.

Schaefer also warned that "there may be biases in what events get reported, as reporting to FAERS is voluntary for healthcare providers and consumers; data are often incomplete, so it is challenging to draw firm conclusions."

There were no relevant adverse event reports related to betrixaban identified in FAERS in the end.

Ultimately, there is no definitive proof yet that reports of DOAC-associated DAH were necessarily caused by the DOAC.

CORRECTION: Study investigators previously reported an incorrect 95% CI for the ROR of all DOAC-associated DAH, which has since been corrected and updated in the article.

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