Drug Use Evaluation of Direct Oral Anticoagulants (DOACs) in Patients With Advanced Cirrhosis

Abstract

Objectives: Low molecular weight heparin and vitamin K antagonists are commonly used in cirrhotic patients requiring anticoagulation. However, their monitoring with anti-factor Xa and international normalized ratio (INR) may not be reliable in cirrhosis. Direct oral anticoagulants (DOACs) do not need laboratory monitoring, making these agents a favorable alternative. However, apixaban and rivaroxaban have been avoided in advanced liver disease due to their metabolism in the liver. The purpose of this medication use evaluation was to assess the use of DOACs, specifically apixaban and rivaroxaban, in patients with cirrhosis. Methods: We performed a retrospective, single-center study. Inpatients who had a diagnosis of cirrhosis and received at least one dose of a DOAC (apixaban or rivaroxaban) from April 2016 through June 2020 at our hospital were included in the analysis. Data collected included the reason for admission, Child-Pugh classification, renal function, if this was a home medication or newly started as an inpatient medication, indication, and dosing. The clinical efficacy outcome (new venous thromboembolic event (VTE) or progression of old VTE), and clinical safety outcome (bleeding event) were analyzed. Results: 41 patients with cirrhosis were treated with apixaban or rivaroxaban. Based on the Child-Pugh classification, 29.3% (n=12/41) were placed on a DOAC outside of the FDA prescribing recommendations. In this subpopulation, 8.3% (n=1/12) patients had venous thromboembolism (VTE) and 16.6% (n=2/12) had bleeding events. Overall, 7.3% patients (n=3/41) had VTE and 4.8% (n=2/41) had bleeding events. In the Apixaban for the Initial Management of Pulmonary Embolism and Deep-Vein Thrombosis as First-Line Therapy (AMPLIFY) trial comparing the efficacy and safety profile of apixaban with enoxaparin/warfarin therapy in acute VTE, 2.3% of patients had VTE and 15% had bleeding events. Conclusion: Our study demonstrated that it may be possible to safely use DOACs in patients with advanced cirrhosis. Further studies are needed to evaluate the safety and efficacy of DOACs in this patient population, as our study was limited by the small sample size and its retrospective design.

Vitamin-K Antagonists vs. Direct Oral Anticoagulants on Severity of Upper Gastrointestinal Bleeding: A Retrospective Analysis of Italian and UK Data

“…Taking into account the comorbidities in the two groups, with a reasonable explanation we noted that mechanical heart valve replacement, history of alcoholism and cirrhosis (the latter two per-se related to each other) were mainly present in the VKA patients. The reason for this distribution has to be attributed to the main indication to use heparin or warfarin, while less data are present concerning DOAC use, both for mechanical heart valve replacement and for portal vein thrombosis, a known complication of cirrhosis-related portal hypertension [ 43 , 44 , 45 , 46 ]. No statistically significant differences came to light between the two groups concerning the other comorbidities considered for our purposes.…”

Risk of Bleeding in Liver Cirrhosis Receiving Direct Oral Anticoagulants: A Systematic Review and Meta-analysis

“…Gastrointestinal bleeding: twenty-five studies reported the incidence of gastrointestinal bleeding, in which 1,886 patients experienced 166 gastrointestinal bleeding episodes. 10,11,13,14,[38][39][40][41][42]44,45,[48][49][50][51][52][53][54][55][56][57][58][60][61][62] The pooled incidence of gastrointestinal bleeding was 8% (95% CI ¼ 5-11%) with significant heterogeneity (I 2 ¼ 67%; p < 0.01) Direct Oral Anticoagulants in Cirrhosis Li et al (►Supplementary Fig. S4, available in the online version).…”

“…Eighteen studies were comparative cohort studies with a control group (i.e., conventional anticoagulants group and no anticoagulants group). 10,11,13,14,[38][39][40][41][42][43][44][45][46][47][48][49][50][51] Twentyone studies were published as full texts, 10,11,13,14,[38][39][40][41][42][43][44][45]48,[50][51][52][53][54][55][56][57] and 8 as abstracts. 46,47,49,[58][59][60][61][62] They were published between 2016 and 2022.…”

“…46,47,49,[58][59][60][61][62] They were published between 2016 and 2022. Sixteen studies were performed in America, 10,11,39,[42][43][44][45][49][50][51][52][53]55,58,59,61 7 in Europe, 38,46,47,54,56 57,60 5 in Asia, 13,40,41,48,62 and 1 in Africa. 14 The indications for DOACs included stroke/embolism prevention in AF (n ¼ 4), 40,42,56,60 PVT prevention (n ¼ 1), 41 PVT treatment (n ¼ 8), 13,14,43,44,48,53,61,62 and DVT/PE treatment (n ¼ 1).…”

“…Characteristics of patients are shown in ►Table 2. Twenty studies 10,11,13,14,[38][39][40][41][42]45,[49][50][51][52][54][55][56][57][58][59] reported mean age, 19 proportion of male, 10,11,13,14,39-42,45,49-52,54-59 18 proportion of CTP C, 10,11,39,40,42,[45][46][47][48][50][51][52][53][55][56][57]59,62 8 proportion of varices, 11,40,45,[49][50][51]53,54 13 mean treatment duration, 10,11 13,41,44,45,48,50,51,54,55,60,62 14 mean platelet count, 10,11,13,14,40 41,42,49-51,54,55,57,58 10 mean total bilirubin, 10,13,14,40-42 45,50,51,55 and 12 mean albumin…”