Apixaban May Have Advantages in Patients With Liver Cirrhosis and AF

The use of apixaban for stroke prevention in patients with atrial fibrillation (AF) and liver cirrhosis appears to be safer than other common anticoagulants, a new observational study shows.

When compared with another factor Xa inhibitor, rivaroxaban (Xarelto; Bayer/Janssen), apixaban (Eliquis; Bristol Myers Squibb) was associated with fewer major hemorrhagic events and similar rates of ischemic outcomes and mortality. Apixaban was also associated with fewer major hemorrhagic events, including stroke, when compared with warfarin.

“Having some evidence to guide the decision-making when choosing between available medications is something we've been needing for a long time,” said Tracey G. Simon, MD (Massachusetts General Hospital, Boston), who led the analysis, which was published this week in the Annals of Internal Medicine.

“In my clinical practice, seeing patients with cirrhosis regularly, it is certainly a question that comes up,” she told TCTMD.

Arman Qamar, MD (Endeavor Health, Evanston, IL), who has investigated the use of oral anticoagulation in this population, agreed, saying the presence of liver disease is a “double-edged sword” in that patients are at high risk for both bleeding and thrombotic events. With the absence of randomized evidence, even with warfarin, physicians have had to make treatment decisions on a case-by-case basis in this “fragile” patient population.

“It appears that based on this analysis, apixaban might have a comparatively lower incidence of bleeding, especially gastrointestinal bleeding,” he commented to TCTMD. “For patients with liver disease, the most common cause of bleeding is GI bleeding, because they are more prone to have gastropathy, ulceration, portal hypertension, and of all of that. And patients with liver cirrhosis, they may not tolerate GI bleeding all that well.”

Additionally, many patients with liver cirrhosis tend to have kidney disease, said Qamar. “From that perspective, too, apixaban may be preferred because we know it has less clearance by the kidneys.”

Excluded From RCTs

AF is common in patients with liver cirrhosis, more so than in the general population. These patients are “treated very delicately,” said Simon. Historically, warfarin is used, largely because it was the only oral anticoagulant available for a long time, but it’s problematic because coagulopathy often occurs in patients with cirrhosis, which makes monitoring prothrombin times difficult, she said. 

The landmark randomized trials establishing the efficacy of direct oral anticoagulants (DOACs) for stroke prevention in patients with AF, including RE-LY, ROCKET-AF, ARISTOTLE, and ENGAGE-AF TIMI 48, all excluded patients with liver cirrhosis. The DOACs are contraindicated in patients with advanced liver disease, although they may be considered in those with less severe impairment. As a result, DOACs are typically used off-label for those with AF and liver disease, and in the absence of good data.

“With the advent of these novel oral anticoagulants, hepatologists were very excited by the possibility of something that might be safer and more effective in our patients,” said Simon. “Obviously, patients with cirrhosis were excluded from those major clinical trials which makes this kind of study important because the real-world evidence from large datasets is really the only feasible way in which we can glean how safe or effective medications might be.”

The researchers turned to two US claims datasets—Medicare and Optum’s Clinformatics Data Mart (CDM)—to evaluate the safety and effectiveness of apixaban versus rivaroxaban and of apixaban versus warfarin in adults with AF and liver cirrhosis. In total, the analysis included 5,570 matched patients initiated with either apixaban or rivaroxaban and 5,704 matched patients started with either warfarin or apixaban.

In the first comparison, those started on rivaroxaban had a significantly higher incidence of major hemorrhagic events—such as hemorrhagic stroke, other intracranial bleeding, major GI bleeding, or non-GI extracranial bleeding—than those treated with apixaban (86.9 vs 51.0 per 1,000 person-years; absolute rate difference of 33.1 events per 1,000 person-years). Major GI bleeding was also significantly more common with rivaroxaban than with apixaban (absolute rate difference of 19.3 per 1,000 person-years). Among those with decompensated cirrhosis, there were also significantly fewer hemorrhagic events with apixaban.

There was no difference in the incidence of major ischemic events or death between the two DOACs in the propensity-matched analysis.

In the second analysis, the incidence of major hemorrhagic events was significantly higher with warfarin than with apixaban (78.9 vs 50.6 per 1,000 person-years). This difference was driven by higher rates of hemorrhagic stroke with warfarin. No matter whether patients had compensated or decompensated liver cirrhosis, absolute rates of major hemorrhagic stroke were significantly higher with warfarin than with apixaban, while the absolute rate of all-cause mortality was higher with warfarin in those with compensated cirrhosis. Rates of ischemic events were similar between the two treatments.  

CVD Risk Equivalents

Simon pointed out that the highest absolute risk of bleeding events was seen in patients with decompensated cirrhosis, which reinforces the importance of “being very careful and judicious about medication selection in that group.”

To TCTMD, Qamar noted that patients with liver cirrhosis are at very high risk for cardiovascular disease, something that is underappreciated. The diseases share multiple risk factors, he said, noting that the most common causes of cirrhosis include nonalcoholic steatohepatitis and alcohol use. At their center, the presence of liver disease is considered a cardiovascular disease risk equivalent, he added.

It’s unlikely that a randomized, controlled trial will be conducted with DOACs in patients with AF and liver cirrhosis. Simon noted that while warfarin has historically been used in this setting, there is no randomized-trial evidence supporting its use either. However, she’s hopeful that the new findings will help physicians care for those with AF and liver disease.

“We are always very worried about causing a bleeding complication or predisposing one of these patients to the development of thromboses, tipping them over one way or another,” she said. “That’s led to the underuse of these medications in [patients with] cirrhosis—there isn’t data to help inform decision-making.”

Qamar added that the advantage of apixaban over rivaroxaban in those with liver cirrhosis is consistent with several other studies in the general AF population. The data are observational, and while propensity-matched, the study is subject to limitations such as confounding. Additionally, it doesn’t suggest that rivaroxaban shouldn’t be used, he said, noting there will be patients better suited to it than other DOACs.

Qamar continued: physicians might also consider use of left atrial appendage closure in patients at high risk for stroke. “Since they are at a very high risk for bleeding, consideration should be made for perhaps left atrial appendage occlusion therapy sooner rather than later,” he said.