key: cord-0910314-kx7rxihj
authors: Semmler, Georg; Pomej, Katharina; Bauer, David J. M.; Balcar, Lorenz; Simbrunner, Benedikt; Binter, Teresa; Hartl, Lukas; Becker, Jeannette; Pinter, Matthias; Quehenberger, Peter; Trauner, Michael; Mandorfer, Mattias; Lisman, Ton; Reiberger, Thomas; Scheiner, Bernhard
title: Safety of direct oral anticoagulants in patients with advanced liver disease
date: 2021-07-10
journal: Liver Int
DOI: 10.1111/liv.14992
sha: 7162055f713583375c246c666f38bca74ec9da24
doc_id: 910314
cord_uid: kx7rxihj

BACKGROUND & AIMS: While direct oral anticoagulants (DOACs) are increasingly used in patients with liver disease, safety data especially in advanced chronic liver disease (ACLD) are limited. METHODS: Liver disease patients receiving DOAC treatment (ACLD: n = 104; vascular liver disease: n = 29) or vitamin K antagonists (VKA)/low‐molecular‐weight heparin (LMWH; ACLD: n = 45; vascular: n = 13) between January 2010 and September 2020 were retrospectively included. Invasive procedures and bleeding events were recorded. Calibrated anti‐Xa peak levels and thrombomodulin‐modified thrombin generation assays (TM‐TGAs) were measured in a subgroup of 35/28 DOAC patients. RESULTS: Among patients receiving DOAC, 55 (41.3%) had advanced liver dysfunction (Child‐Pugh‐stage [CPS] B/C) and 66 (49.6%) had experienced decompensation. Overall, 205 procedures were performed in 60 patients and procedure‐related bleedings occurred in 7 (11.7%) patients. Additionally, 38 (28.6%) patients experienced spontaneous (15 minor, 23 major) bleedings during a median follow‐up of 10.5 (IQR: 4.0‐27.8) months. Spontaneous bleedings in ACLD patients were more common in CPS‐B/C (at 12 months: 36.9% vs CPS‐A: 15.9%, subdistribution hazard ratio [SHR]: 3.23 [95% CI: 1.59‐6.58], P < .001), as were major bleedings (at 12 months: 22.0% vs 5.0%, SHR: 5.82 [95% CI: 2.00‐16.90], P < .001). Importantly, CPS (adjusted SHR: 4.12 [91% CI: 1.82‐9.37], P < .001), but not the presence of hepatocellular carcinoma or varices, was independently associated with major bleeding during DOAC treatment. Additionally, ACLD patients experiencing bleeding had worse overall survival (at 12 months: 88.9% vs 95.0% without bleeding; P < .001). Edoxaban anti‐Xa peak levels were higher in patients with CPS‐B/C (345 [95% CI: 169‐395] vs CPS‐A: 137 [95% CI: 96‐248] ng/mL, P = .048) and were associated with lower TM‐TGA. Importantly, spontaneous bleeding rates were comparable to VKA/LMWH patients. CONCLUSIONS: Anticoagulants including DOACs should be used with caution in patients with advanced liver disease due to a significant rate of spontaneous bleeding events.

Patients with advanced chronic liver disease (ACLD) often present with profound changes of coagulation parameters. 1 While these patients were traditionally considered to be 'auto-anticoagulated', recent research has shown that even patients with advanced liver disease have a rebalanced equilibrium of pro-and anti-haemostatic factors. 2 However, when compared with liver-healthy subjects, this equilibrium is much more instable and easily tilts towards bleeding or thrombosis. In line, the risk of thrombotic events was shown to be 1.7-fold increase in patients with cirrhosis compared with the general population, 3 and intrasinusoidal microthrombosis followed by parenchymal extinction was even proposed as a driver for disease progression. 4 However, these patients are also exposed to an increased risk of bleeding due to clinically significant portal hypertension (CSPH) 5 and unstable haemostatic balance. 6 A substantial number of patients with ACLD or vascular liver diseases require anticoagulant therapy for the prevention/treatment of venous thromboembolism, 7 portal vein thrombosis (PVT), 8, 9 or Budd-Chiari syndrome (BCS). While current guidelines recommend the use of low-molecular-weight heparin (LMWH) and vitamin K antagonists (VKA) in this patient population, 10 both options have substantial drawbacks. 11 LMWH and VKA are rather unpopular treatments as they have to be injected subcutaneously or monitored by INR, which is commonly prolonged in patients with ACLD. Moreover, treatment with VKA interferes with the MELD score potentially masking a worsening of liver function and making timing for liver transplantation listing more difficult. In contrast, direct oral anticoagulants (DOACs) are an interesting alternative and may have practical benefits 12 : They do not require routine monitoring via INR, do not interfere with MELD score and are taken orally. 13 Unfortunately, patients with advanced liver disease were excluded from large randomized DOAC trials. [14] [15] [16] Therefore, available evidence largely derives from small retrospective studies suggesting that DOACs are a safe treatment option in patients with compensated ACLD. 17 However, there is only very limited data on the safety of DOAC treatment in patients with decompensated liver disease. 18 Additionally, these patients frequently need to undergo procedures such as endoscopic band ligation (EBL) and large-volume paracentesis (LVP), 19 and safety of DOAC treatment in this context has yet to be studied.

Even though routine monitoring of DOAC treatment is not required, calibrated anti-Xa levels may be required in special clinical situations including active bleeding, urgent invasive procedures, renal failure, extreme body weights and in patients that clinically appear resistant to therapy. Whether patients with advanced liver disease would benefit from monitoring is unclear. One study has shown similar anti-Xa levels in patients with mild cirrhosis on edoxaban compared with healthy individuals, 20 but whether drug accumulation may occur in patients with more advanced disease is currently unknown. Therefore, the aim of this study was to evaluate (a) the safety of DOAC treatment in patients with ACLD or vascular liver diseases in general, (b) the safety of DOAC treatment in liver patients undergoing invasive procedures; and (c) to compare calibrated anti-Xa-assay levels between patients with different degrees of liver dysfunction. between 1 January 2010 and 30 September 2020 were included in this study. Patient characteristics and information on spontaneous and procedure-related bleedings and the time of procedure and/or bleeding were collected from original patient records that include outpatient letters, discharge letters, procedural and radiological reports and all laboratory reports from a broad network of hospitals in Vienna. Patients with insufficient medical records were excluded. To investigate metabolization of DOACs, calibrated anti-Xa serum levels were measured in 35 prospectively sampled patients (ClinicalTrials.gov Identifier: NCT03541057) receiving either edoxaban or apixaban (as described below). Thrombomodulin-modified thrombin generation assays (TM-TGA) were performed in 28 of these patients to further assess coagulation status. Finally, we also included a cohort of patients with ACLD and/or vascular liver disease treated with LMWH/VKA (n = 58).

Procedure-related bleedings were defined as associated bleeding events within 4 weeks after EBL, LVP, liver biopsy or surgical interventions.

Bleeding events were graded as minor or major bleedings 21 :

Major bleedings were defined as fatal bleedings, symptomatic bleedings in a critical area or organ (i.e., intracranial, intraspinal, intraocular, retroperitoneal, intra-articular or pericardial, or intramuscular with compartment syndrome), bleeding with an associated decrease in haemoglobin level of ≥2 g/dL or bleeding leading to transfusion of two or more units of packed red blood cells. All other clinically evident bleedings were considered minor.

Decompensated liver disease was defined as history of or current ascites, hepatic encephalopathy or portal-hypertensive bleeding.

CSPH was defined as history of or current decompensation, presence of varices or portosystemic collaterals, or HVPG ≥ 10 mm Hg. However, due to the low number of patients in the subgroups, we did not differentiate between pre-hepatic, intra-hepatic and post-hepatic CSPH.

Blood samples for measurement of peak anti-Xa levels were drawn from a peripheral vein within 2-4 hours after drug intake and in a steady state after repeated dosing (no missing dose for at least 3 days). Anti-Xa levels were measured using a one-step chromogenic assay (STA-Liquid Anti-Xa assay, Diagnostica Stago, 92 600

Asnières-sur-Seine, France).

Blood samples for TM-TGA measurement were drawn from a peripheral vein at the same time as for the measurement of peak anti-Xa levels, immediately transferred to the lab, centrifuged once at 1972 g for 10 minutes and stored at −20℃. Stored samples were then transferred to the Surgical Research Laboratory, University Medical Center Groningen, the Netherlands, centrifuged again at 10 000 × g for 10 minutes and measured using a fluorometrical method, as previously described. [22] [23] [24] Coagulation was activated using commercially available reagents containing recombinant tissue factor and phospholipids in the presence of soluble thrombomodulin (TM).

The following parameters were recorded for this study: endogenous thrombin potential (ETP; representing the total enzymatic work performed by thrombin during the time that it was active) as well as peak thrombin levels. Landmark analyses were performed to assess survival after bleeding in order to correct for 'immortal time bias'. 25 In detail, spontaneous bleeding within 6 months or 12 months after DOAC initiation were considered as landmarks. Competing risk analysis was used to compare the incidence of spontaneous bleeding between patients with different severity of liver disease, with or without HCC as well as those receiving full versus reduced DOAC dose, considering death and orthotopic liver transplantation as a competing risk. Therefore, subdistribution hazard ratio (SHR) using the R package 'cmprsk' applying Fine and Gray competing risks regression model was used. 26 Finally, we applied a multivariable competing risks regression model to identify factors independently associated with spontaneous bleeding. A P-value ≤ .05 was considered statistically significant. 

In total, 133 patients on DOAC with a mean age of 58.1 ± 14.1 years were included. Majority of patients was male (n = 79, 59.4%). While in 104 patients (78.2%), a chronic parenchymal liver disease (ACLD) was diagnosed, 29 patients (21.8%) had vascular liver disease without evidence for ACLD including patients with PSVD (n = 10), PVT without evidence of ACLD (n = 18) and veno-occlusive disease (n = 1). The most prevalent aetiologies in ACLD patients were alcoholic (n = 25, 24.0%) and non-alcoholic fatty liver disease (n = 25, 24.0%). and a higher UNOS MELD-score (11.7 ± 4.2 vs 8.9 ± 2.7, P < .001).

More detailed patient characteristics are displayed in Table 1 .

The majority of our patients received edoxaban (n = 75, 56.4%), followed by apixaban (n = 24, 18.0%) and rivaroxaban (n = 24, 18.0%), while only 3 (2.4%) patients were taking dabigatran and 7 patients (5.3%) received more than one drug sequentially. Main indications for DOAC were PVT in 89 patients (66.9%), followed by atrial fibrillation (n = 16, 12.0%) and BCS (n = 9, 6.8%). Seventy-eight patients (58.6%) received full dose of DOAC (i.e., 60 mg edoxaban once daily, 5 mg apixaban twice daily, 20 mg rivaroxaban once daily or 150 mg dabigatran twice daily), while 55 patients (41.4%) received a reduced dose. Median treatment duration was 10.5 (4.0-27.8) months and treatment with DOAC was stopped in 38 patients (28.6%). The most common reasons for treatment discontinuation were bleeding events (n = 14, 10.5%), resolution of PVT (n = 8, 6.0%) and decision of the treating physician (n = 5, 3.8%). A detailed comparison between patients with ACLD and vascular liver disease can be found in Table 2 .

Almost half of patients (n = 60, 45.1%) underwent at least one intervention during DOAC therapy resulting in a total of 205 invasive procedures during the study period. Specifically, 14 patients (10.5%) underwent LVP resulting in a total of 87 LVPs, and 28 patients (21.1%) underwent EBL resulting in a total of 70 EBLs. DOAC treatment was paused prior to all EBLs as per the discretion of the treating physician. Bleedings during gastroduodenoscopy occurred in 4 patients (14.3%; 5.7% of all EBLs, 3 ACLD patients, 1 patient with vascular liver disease). Apart from these immediate bleedings, no procedurerelated bleeding occurred within 28 days after EBL. Additionally, one minor bleeding occurred after LVP, one minor bleeding occurred during a transurethral resection of the bladder and one major bleeding after endoscopic retrograde cholangiopancreaticography (ERCP).

Procedure-related bleeding events are described in detail in the Supplementary material. A detailed comparison between patients with ACLD and vascular liver disease can be found in Table 2 .

Thirty-eight patients (28.6%) experienced a spontaneous bleeding event during DOAC treatment, while in 4 patients (3.0%) ≥2 events were documented. These events were graded as minor in 15 patients (39.5%) and major in 23 patients (60.5%) of which one event (bleeding from Mallory-Weiss tear) was followed by acute-on-chronicliver-failure and death 9 days after the bleeding event (Table S1) Table 2 ).

Next, we compared the cumulative incidence of spontaneous bleeding events between patients with different severity of liver disease.

Since risk factors for bleeding may likely differ between ACLD patients and those with vascular liver disease, we focused on ACLD patients for the following analyses.

Interestingly, cumulative incidence of spontaneous bleeding after initiation of DOAC treatment was significantly higher in CPS-B/C patients when compared with patients with CPS-A cirrhosis after 12 months (B/C: 36.9% vs A: 15.9%, SHR: 3.23 [95% CI: 1.59-6.58], P = .001, Figure 1A ). These differences were also observed when only considering major bleedings (at 12 months: 22.0% vs 5.0%, SHR: 5.82 [95% CI: 2.00-16.90], P = .001, Figure 1B) results were obtained in the overall cohort ( Figure S1 ). While a higher incidence of spontaneous bleeding and spontaneous major bleeding could be confirmed in ACLD patients with a history of hepatic decompensation ( Figure S2) 

As only one immediately fatal bleeding complication occurred, we further investigated whether bleedings during DOAC therapy were associated with worse survival. Therefore, we performed landmarkanalyses and compared the overall survival of ACLD patients who experienced bleeding within 6 months from DOAC initiation to those without bleeding within 6 months. Importantly, bleeding within 6 months was associated with a worse overall survival (at F I G U R E 1 Competing risk analysis comparing the incidence of (A) spontaneous bleeding and (B) spontaneous major bleeding in ACLD patients among Child-Pugh stage (CPS) A vs CPS B/C considering death and liver transplantation (OLT) as competing risks 12 months: 88.9% vs 95.0%, log-rank P < .001; Figure 2A ). The same result was obtained when setting the landmark at 12 months after DOAC initiation (survival at 18 months: 74.1% vs 95.6%, log-rank P = .011, Figure 2B ) as well as in the overall cohort ( Figure S5 ).

In order to study changes in pharmacokinetics potentially explaining the substantial risk of spontaneous bleeding during DOAC treatment, we measured calibrated anti-Xa levels in 35 prospectively sampled patients. As shown in Table S3 , patients with anti-Xa measurement had less advanced liver disease compared with patients not undergoing anti-Xa measurements. Consecutively, overall bleeding incidence was lower in the anti-Xa cohort which is in line with our findings outlined above ( Figure S6 ). In total, anti-Xa peak levels were measured in 23 patients with edoxaban and in 12 patients with apixaban treatment. As shown in Figure 3 , peak edoxaban anti-Xa levels 

Next, we evaluated the correlation of peak anti-Xa values with ETP as measured by TM-TGA in 28 prospectively sampled patients.

Interestingly, and as depicted in Figure S7 , an exponential relation- (Table S4 ).

Finally, we compared the bleeding incidence in DOAC patients to patients receiving LMWH or VKA (n = 58). As shown in Table S5 , baseline characteristics of the two cohorts were comparable.

However, treatment indications were significantly different. While DOAC patients had more often portal vein thrombosis, atrial fibrillation was more common in patients with LMWH/VKA treatment ( 

DOACs are the treatment of choice for non-valvular atrial fibrillation and thromboembolism due to a more favourable safety profile compared with VKAs as well as the easier application compared with LMWH. Therefore, DOACs are commonly used in subjects with preserved liver and kidney function; however, their use remains offlabel in patients with ACLD, as patients with 'clinically significant liver disease' (apixaban), 14 'significant liver disease' (rivaroxaban) 15 or 'active liver disease' (edoxaban) 16 have been excluded from clinical trials. In line with the respective package inserts, these drugs are contraindicated in ACLD patients with coagulopathy and clinically relevant risk for bleeding complications. 27 Nevertheless, these drugs are also increasingly used in clinical practice in patients with advanced liver disease.

While DOACs seem to be safe in patients with compensated ACLD, data on patients with decompensated ACLD are scarce. 17, 28, 29 While bleeding rates reported by some small retrospective studies 17,30 were even lower when compared with historic controls treated with VKA or LMWH, 12,31 a recent study reported a substantial bleeding risk in patients with decompensated cirrhosis. In this study by Mort et al, 18 21% of patients with decompensated cirrhosis stopped DOAC treatment due to actual or 'perceived' bleeding.

In total, bleeding events occurred in every third patient in our as well as their study. However, the rate of major bleeding tended to be higher in our study (17.3% vs 8.0% in the US study). Of note, the median time of DOAC exposure was only 6.0 months in the latter study compared with 10.5 months in our cohort. Until results from such trials will be available, use of DOACs in patients with advanced liver disease is challenging as it is unknown whether portal hypertensive gastropathy/enteropathy influences drug uptake as well as possible effects of liver dysfunction on drug metabolism. 36 As DOACs are cleared by the liver and the kidney to a different extent, drug accumulation with a possibly increased risk for bleeding is a major concern. Interestingly, recent data published by Bos et al 20 suggested that even though edoxaban drug levels after 7 days of treatment were comparable to those in liver-healthy subjects, the anticoagulatory potential of edoxaban might be weaker in liver disease patients. However, this study mostly included CPS-A and did not include a sufficient number of patients with more advanced liver disease and thus does not provide information on patients with advanced liver dysfunction and portal hypertension, that is, those who at the same time show the most pronounced procoagulant imbalance and are at the highest risk of bleeding.

In our study, we found that peak anti-Xa levels were significantly higher in patients with more advanced liver disease, potentially explaining the increased bleeding incidence in this subgroup. In line, median peak levels in our cohort of CPS-B/C patients were considerably higher than the values reported in the general population. 37, 38 Additionally, when performing TM-TGA assays, thrombin generation was lower in patients with higher anti-Xa levels when compared with patients with low anti-Xa levels indicating that high anti-Xa levels may reflect an impaired haemostasis. 39 we are confident to have included all major and procedure-related bleedings since they usually require in-hospital therapy and consequently get followed at our institution. Secondly, we aimed at linking the incidence of bleeding to anti-Xa levels in the respective patients.

However, measurements were only performed in a subgroup of patients since the assays were only recently established, active intake of DOAC at the time of measurement and patient compliance were required and COVID-19 restrictions made sample collection more difficult. Nevertheless, we are confident that the above-mentioned results of the pharmacokinetic study may be extrapolated to the whole cohort. Thirdly, the correlation between peak anti-Xa values and ETP deserves further research since the low sample size and a high interindividual variability of these advanced coagulation tests limit their interpretation. Therefore, these results should be considered hypothesis-generating, and further research is needed to evaluate the utility of measuring anti-Xa levels as well as TM-TGA in ACLD patients with DOAC therapy. Finally, there was no statistically significant difference in the bleeding incidence between patients receiving DOAC and VKA/LMWH. However, this comparison may be biased by indication, as it was left to the discretion of the treating physician to choose from the available anticoagulation options.

In conclusion, we provide comprehensive data on DOAC safety in a large retrospective cohort of patients with ACLD or vascular liver diseases. When drugs are paused as recommended, DOAC therapy is not associated with a significant risk of procedure-related bleedings among patients with different stages of liver disease. However, we observed a significant association of spontaneous bleedings with liver disease severity. Therefore, DOACs should be used with caution in this patient group, and liver function should be monitored regularly. Finally, anti-Xa and TM-TGA measurements could be useful to evaluate the bleeding risk in individual ACLD patients requiring DOAC therapy.

The authors have nothing to disclose regarding the work under con- 

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The data that support the findings of this study are available from the corresponding author upon reasonable request.