By Will Boggs MD
NEW YORK (Reuters Health) - 4/7/2019
Direct oral anticoagulants (DOACs) are safer and more effective than warfarin in Asian patients with atrial fibrillation (AF) and liver disease, researchers from South Korea report.
"DOACs showed better effectiveness and safety compared to warfarin not only in those with mild liver disease, but also in those with significant active liver disease who were mostly excluded in previous randomized clinical trials," Dr. Eue-Keun Choi from Seoul National University Hospital told Reuters Health by email.
Limited data from small retrospective studies suggest that there are no differences in thromboembolic and major bleeding risks between DOACs and warfarin in patients with cirrhosis, but a recent meta-analysis found DOACs to be associated with a lower risk of bleeding in patients with AF with liver cirrhosis.
The pivotal DOAC clinical trials excluded individuals with active liver disease, so the effectiveness and safety of DOACs in such individuals remain unclear, Dr. Choi and colleagues note in the July 2 issue of the Journal of the American College of Cardiology.
The team used data from South Korea's National Health Insurance Service database to investigate the real-world effectiveness and safety of DOACs versus warfarin in more than 37,000 patients with AF and liver disease.
Compared with warfarin, DOAC use was associated with a 45% lower risk for ischemic stroke, a 35% risk reduction in hospitalization for major bleeding (including both intracerebral hemorrhage (ICH) and gastrointestinal bleeding), a 30% lower risk for all-cause death, and a 39% reduced risk for the composite outcome of all these events. All these reductions were statistically significant.
In the subpopulation of 13% of patients classified as having active liver disease, DOACs showed consistently better outcomes than warfarin for ischemic stroke, ICH, hospitalization for major bleeding, and the composite outcome, as well as a nonsignificant trend toward reduced risk for hospitalization for gastrointestinal bleeding and all-cause death.
Similarly, in the 2% of the study population with cirrhosis, DOAC users had a trend of lower risk for ischemic stroke or major bleeding and comparable risk for all-cause death, compared with warfarin users.
The results for all clinical outcomes were consistent in both regular and reduced doses of DOACs and across subgroups stratified by age, sex, body weight, liver function, renal function and hemoglobin level.
"Liver disease is a major cause of illness and death worldwide, and the prevalence of liver disease is increasing," Dr. Choi said. "Physicians will be faced with more patients with AF combining with liver disease in clinical practice. There is growing evidence of DOACs based on real-world evidence in patients with AF and liver disease."
"Further studies are needed to expand the safety zone of DOACs to patients with more than 'mild' liver disease (and) regarding the optimal DOAC dose regimen in patients with cirrhosis," he said.
"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," write Dr. Elaine H. Hylek of Boston University School of Medicine and Dr. Frank A. Anania of the U.S. Food and Drug Administration, in Silver Spring, Maryland, in a linked editorial.
"The authors did not provide any new evidence that these agents could be safely administered to Child-Pugh class A patients either. Research is needed with rigorously defined subgroups of patients with hepatic impairment across the spectrum of severity to best inform drug choice and dose."
Dr. Ron Chokesuwattanaskul of Chulalongkorn University and King Chulalongkorn Memorial Hospital, Thai Red Cross Society, in Bangkok, recently reviewed the efficacy and safety of anticoagulation for AF in patients with cirrhosis. He told Reuters Health by email, "The results of this study encourage physicians to be more comfortable to prescribe DOAC to patients with liver disease who meet the criteria for anticoagulation treatment."
"No matter which kind of DOAC prescription, we still should bear in mind that regular and meticulous follow-up to prevent any significant bleeding complication is the bottom line for management, as liver-disease patients have a bleeding diathesis compared with the general population," said Dr. Chokesuwattanaskul, who was not involved in the study. "In addition, DOAC seems to provide benefit over VKA (vitamin K antagonist) for this particular purpose."
Dr. Alvaro Alonso from Rollins School of Public Health at Emory University, in Atlanta, who has researched anticoagulants and the risk of liver injury in patients with AF, told Reuters Health by email, "These results support the use of DOACs rather than warfarin as first-line anticoagulant therapy in AF. In general, the results suggest that liver disease should not be a major consideration in deciding whether to use warfarin or DOAC."
Dr. Alonso, who also was not involved in the study, offered two additional considerations: "First, the study did not perform head-to-head comparisons of DOACs, so questions remain as to what DOAC may be of more benefit in patients with AF and liver disease. Second, these results should be seen in the context of potential for confounding by indication, in which healthier patients may be more likely to receive DOACs than warfarin."
J Am Coll Cardiol 2019.