DOACs bests warfarin even in AF patients with liver disease?
DOACs* were better than warfarin in terms of efficacy and safety for stroke prevention in an Asian population with atrial fibrillation (AF) and liver disease, including patients with significant active liver disease who were usually excluded from pivotal clinical trials, suggests a study based on the Korean national database.
“In Asia, hepatitis carriers and patients with hepatitis-related liver cirrhosis are commonly encountered in clinical practice,” the researchers noted. “Advanced liver disease is known to increase the risk for bleeding and affects the hepatic clearance and metabolism of drugs.”
According to consensus guidelines, all four available DOACs are contraindicated in severe liver cirrhosis (Child-Turcotte-Pugh class C) due to exclusion of such patients from pivotal trials. [Eur Heart J 2018;39:1330-1393]
In the current retrospective analysis, treatment with DOACs was associated with a 36 percent lower risk of ischaemic stroke compared with oral warfarin in AF patients with liver disease during a mean follow-up of 1.2 years (hazard ratio [HR], 0.548, 95 percent confidence interval [CI], 0.485–0.618). [J Am Coll Cardiol 2019;73:3295-3308]
Safety outcomes in terms of the risk of major bleeding (HR, 0.650, 95 percent CI, 0.575–0.736), intracranial haemorrhage (ICH; HR, 0.479, 95 percent CI, 0.394–0.581), gastrointestinal (GI) bleeding (HR, 0.819, 95 percent CI, 0.619–0.949), and all-cause death (HR, 0.698, 95 percent CI, 0.636–0.765) were all significantly lower with DOACs than warfarin.
Collectively, patients receiving DOACs were 39 percent less likely to experience the composite efficacy and safety outcomes above compared with those on warfarin (HR, 0.610, 95 percent CI, 0.567–0.656).
“These benefits were generally consistent in patients with significant active liver disease who were excluded from the pivotal DOAC clinical trials,” said the researchers.
Subjects in the retrospective analysis were 37,353 AF patients in the Korean National Health Insurance Service database who had active liver disease and were treated with oral warfarin (n=12,778) or DOACs (n=24,575). Liver diseases were defined based on diagnostic codes in the database.
Thirteen percent of the total population were categorized as having significant active liver disease**, and the risk of the composite outcomes was similarly reduced by 31 percent with DOACs vs warfarin in these patients (HR, 0.691, 95 percent CI, 0.577–0.827).
In particular, the component outcome of ICH, ischaemic stroke, and hospitalization for major bleeding was also less frequent in the DOAC group than the warfarin group. There were also trends toward risk reduction for the component of hospitalization for GI bleeding and all-cause mortality, although these were not statistically significant.
“These results may rationalize careful use of DOACs for stroke prevention in patients with liver disease,” said the researchers.
However, noting that “significant active liver disease” was defined based on administrative codes rather than on Child-Pugh classification due to a lack of clinical and laboratory information, this definition is problematic for prescribing clinicians, according to Drs Elaine Hylek and Frank Anania from Boston University School of Medicine in Boston, Massachusetts and the Center for Drug Evaluation and Research at US FDA in Silver Spring, Maryland, US, respectively in an editorial. [J Am Coll Cardiol 2019;73:3309-3311]
“The current study cannot address [the question of whether DOACs might be safer than warfarin for patients with hepatic impairment],” they commented. “The current study really provides not much new information than what most prescribers are likely to have known, given that the definition of severe liver disease was exceedingly broad.”
“Research is needed with rigorously defined subgroups of patients with hepatic impairment across the spectrum of severity to best inform drug choice and dose,” wrote Hylek and Anania.