Which Anticoagulant Is Safest for Afib Patients With Cirrhosis?

— National cohort study finds up to 47% fewer serious hemorrhagic events with one agent

Last Updated July 9, 2024
A close up photo of bottles of Eliquis tablets.

Apixaban (Eliquis) was associated with lower serious bleeding rates than rivaroxaban (Xarelto) or warfarin in patients with cirrhosis and atrial fibrillation (AF, Afib) in a nationwide cohort study.

Among more than 12,000 such patients in two U.S. claims databases, those who received anticoagulant therapy with rivaroxaban had a 47% higher rate of major hemorrhagic events compared with patients on apixaban (HR 1.47, 95% CI 1.11-1.94), reported researchers led by Joshua Lin, MD, MPH, of Brigham and Women's Hospital in Boston.

"Our estimates of absolute excess risk in those groups are notable, corresponding over just 1 year to 1 additional major hemorrhagic event for every 24 patients who initiate use of rivaroxaban instead of apixaban," the authors wrote in the . "Thus, our findings highlight the vital importance of careful DOAC selection in this high-risk patient population."

The findings add to existing data that have similarly shown increased bleeding with rivaroxaban compared with apixaban in the general population, Jim Cheung, MD, chair of the American College of Cardiology Electrophysiology Council, told app.

"This study provides some answers to a clinically relevant question that had not been previously addressed by clinical trials that had excluded patients with cirrhosis," said Cheung, who wasn't involved with the study.

Patients who received warfarin had a 38% higher rate of major hemorrhage compared with apixaban (HR 1.38, 95% CI 1.03-1.84), including nearly triple the risk of hemorrhagic stroke (HR 2.85, 95% CI 1.24-6.59).

Rivaroxaban and apixaban have become the preferred anticoagulants for Afib patients, including those with cirrhosis. The two drugs are used much more often than warfarin and account for nearly all prescriptions of direct anticoagulants (DOACs), Lin's group said.

No head-to-head trials, however, have directly compared individual DOACs in patients with Afib and cirrhosis, leaving clinicians without clear guidance.

"Our results show that in patients with cirrhosis and AF, apixaban might be preferable to rivaroxaban due to substantially lower rates of major hemorrhagic events and similar rates of major ischemic events," the researchers wrote, adding that the same is true compared with warfarin.

"However," they acknowledged, "although these findings are noteworthy, careful treatment selection must consider all risks, benefits, and alternatives."

Lin and colleagues analyzed claims data from 2013 to 2022 in both Medicare and Optum's Clinformatics Data Mart Database. The researchers used propensity scores to match patients prescribed apixaban versus rivaroxaban and apixaban versus warfarin. The study incorporated a clinical trial emulation analytical framework and a new-user, active comparator design, which has been shown to replicate findings from clinical trials, the authors said.

The researchers adjusted for more than 100 baseline variables including demographic factors, cause and severity of cirrhosis, liver decompensation events, comorbidities, and additional medications. One primary outcome was major hemorrhagic events, including hospitalization for hemorrhagic stroke, other intracranial bleeding, major gastrointestinal bleeding, or non-GI extracranial bleeding. The other primary outcome was major ischemic events, including hospitalization for ischemic stroke or systemic embolism.

Subgroup analyses showed the excess bleeding risk with rivaroxaban tended to be higher in patients initiating reduced-dose rivaroxaban versus apixaban, but the finding was not statistically significant (HR 1.65, 95% CI 0.94-2.9). The risk also was elevated in patients with decompensated cirrhosis. The severity of disease and comorbidity profiles in these two patient groups make them particularly susceptible to bleeding, the researchers said.

Overall, the differences in bleeding risk observed with rivaroxaban versus apixaban might be due to pharmacokinetic/pharmacodynamic profiles, Lin's group said, citing a directly comparing the two drugs in that regard. The study reported apixaban had less inter-subject variability in exposure, lower area under the curve for anti-factor Xa, and smaller peak-to-trough fluctuations in plasma concentration compared with rivaroxaban, suggesting apixaban provides more constant anticoagulation.

Limitations of the current study included the potential for residual confounding, Lin and colleagues said, as they lacked information on echocardiographic tests, details of socioeconomic status, duration of cirrhosis, severity of any thrombocytopenia or coagulopathy, alcohol use, and body mass index.

In addition, the study included only patients with Medicare or employer-sponsored health insurance. Therefore, the results might not be generalizable to patients with different insurance types or those lacking insurance coverage, given the potential differences in demographic characteristics, risk factors, and socioeconomic status, the study authors noted.

Cheung said another limitation was the retrospective design. "Despite the use of propensity score matched analysis, there may have still been significant residual confounding that could have explained the differences in event rates between the treatment groups," he said. But he praised the study for its "large study size and careful design."

"Together, these findings suggest apixaban may offer safety benefits over both rivaroxaban and warfarin in patients with cirrhosis and AF engaged in routine clinical care," Lin's group concluded.

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    Jeff Minerd is a freelance medical and science writer based in Rochester, NY.


The study was supported by grants from the National Institutes of Health and Massachusetts General Hospital.

Lin reported no conflicts of interest. One study author reported consulting for Bristol-Myers Squibb, the manufacturer of apixaban.

Primary Source

Annals of Internal Medicine

Simon TG, et al "Comparative effectiveness and safety of apixaban, rivaroxaban, and warfarin in patients with cirrhosis and atrial fibrillation" Ann Intern Med 2024; DOI: 10.7326/M23-3067.