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Authors: Melissa Martinez, Anand Tandra, Raj Vuppalanchi
Journal: Hepatology (2014)

Potential conflict of interest: Nothing to report. We thank Intagliata et al. and Potze et al. for sharing their clinical experience and in vitro data about the two factor Xa inhibitors, rivaroxaban (Xarelto, Bayer/Johnson & Johnson) and apixaban (Eliquis, Bristol‐Myers Squibb/Pfizer). Our report1 and subsequent response by the authors is reflective of the growing interest in the use of nontraditional anticoagulants for treatment of portal and superior mesenteric vein thrombosis (PVT/SMV) in patients with cirrhosis. Both factor Xa inhibitors exhibit reliable pharmacokinetics and pharmacodynamics, with a linear relation between plasma concentration of the drug and anticoagulant activity.2 Their plasma half‐life is short and is very similar to heparins.2 Impaired renal function results in a prolonged half‐life and increased anticoagulant effect of rivaroxaban much more than apixaban, but otherwise these drugs have similar characteristics with regard to absorption and metabolism.2 The report from Intagliata et al. of five patients with compensated cirrhosis (Child‐Pugh Class A) emphasizing the safety and efficacy of rivaroxaban and apixaban for treatment of acute PVT/SMV is very encouraging. Similar to our experience (Child‐Pugh Class A), complete resolution of the thrombus required a treatment duration of 6 months. No bleeding‐related adverse event were observed despite 6 months of therapy. However, data with regard to their use in decompensated cirrhosis is lacking, as manufacturers of both factor Xa inhibitors currently do not recommend the use of these agents in Child‐Pugh Class B and C for safety concerns. Interestingly, Potze et al. report a significantly lower in vitro anticoagulant potency of apixaban and rivaroxaban using a thrombin generation assay in plasma from patients with decompensated cirrhosis (Child‐Pugh Class B and C). The authors speculate that direct Xa inhibitors will therefore not likely to cause over‐anticoagulation in patients with decompensated cirrhosis, and as such may not be associated with increased risk of bleeding and could in fact be associated with treatment failure. Certain aspects of factor Xa inhibitors deserve further discussion before extrapolation of in vitro data to clinical care. The bioavailability of rivaroxaban is higher than apixaban (80% versus 66%) and is dependent on food intake, as it is strongly lipophilic.2 Both rivaroxaban and apixaban are highly protein bound (87‐95%) and it is quite possible that hypoalbuminemia associated with decreased synthetic function in decompensated cirrhosis may result in more active drug and perhaps more anticoagulant activity. Moreover, decompensated cirrhosis may be associated with decreased creatinine clearance from underlying hepatorenal syndrome. Use of rivaroxaban and not apixaban would be associated with increased anticoagulant activity.3 While in vitro studies use platelet‐poor plasma with the addition of phospholipids as a substitute in the presence of thrombomodulin, these assays only partially mimic in vivo physiology. Studies using whole blood clotting assays such as thromboelastography that reflect overall hemostatic balance would need to be performed to better understand the anticoagulant potency of factor Xa inhibitors in patients with cirrhosis with decompensated liver disease. Alternatively, reliably measuring factor Xa levels may be necessary in cirrhosis patients to ensure therapeutic doses of anticoagulation in order to avoid treatment failure. Hemostasis is a fine balance between pro‐ and anticoagulants and despite a lowering of actual levels, the thrombin generation potential may remain intact in cirrhosis patients. The increased risk of bleeding in these patients may be related mechanistically to portal hypertension rather than a decrease of coagulation factors. Until additional information is available, it may be prudent to limit use of factor Xa inhibitors to select cirrhosis patients without decompensation or decreased renal function.