Received Date : 08-Oct-2016

Revised Date : 16-Nov-2016

Accepted Date : 19-Dec-2016
Article type : Original Article
Accepted Article
The efficacy and safety of direct oral anticoagulants vs. traditional
anticoagulants in cirrhosis.

Justine Hum MD, 1 Joseph J. Shatzel MD, 2 Janice H. Jou MD, 3 Thomas G. Deloughery MD,
MACP, FAWM 2
1
Oregon Health & Science University, Department of Internal Medicine
2
Oregon Health & Science University, Knight Cancer Center. Department of Hematology
3
Oregon Health & Science University, Department of Gastroenterology

Running head: DOAC effectiveness and safety in cirrhosis

Keywords: anticoagulation; bleeding; cirrhosis; rivaroxaban; warfarin

Corresponding Author:

Justine Hum

Internal Medicine Residency Program

Oregon Health & Sciences University

Mail Code VA P-3-GP1

3181 SW Sam Jackson Park Road

Portland, Oregon 97239

humj@ohsu.edu

Abstract:

Introduction: The coagulopathy of cirrhosis is complex, placing patients at risk for both bleeding

and thrombosis. Direct oral anticoagulants (DOACs) have equivalent or superior efficacy and

safety as compared to vitamin K antagonists (VKA); however, their efficacy and safety in liver

This article has been accepted for publication and undergone full peer review but has not
been through the copyediting, typesetting, pagination and proofreading process, which may
lead to differences between this version and the Version of Record. Please cite this article as
doi: 10.1111/ejh.12844
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 cirrhosis has not been studied. To better define this, we evaluated outcomes of cirrhotic patients

prescribed DOACS compared to other anticoagulants at our center.

Accepted Article
Methods: Retrospective cohort study of cirrhotic patients prescribed therapeutic anticoagulation

over a 3 year period for thrombosis or prevention of stroke in patients with atrial fibrillation. The

primary outcomes of interest were bleeding events and recurrent thrombosis or stroke.

Results: During the study period, 27 cirrhotic patients were prescribed a DOAC and 18 were

prescribed VKA or low molecular weight heparin (LMWH). Both groups had similar total

bleeding events (8 DOAC vs.10 other, p = 0.12). There were significantly less major bleeding

episodes in the DOAC group, (1 (4%) vs. 5 (28%), p = 0.03). Recurrent thrombosis occurred in

1 patient receiving a DOAC (4%) and 1 patient (6%) receiving other anticoagulation (p = 1.0).

Conclusions: DOAC use in cirrhotics may be as safe as traditional anticoagulants. Patients with

cirrhosis at our center prescribed DOACs had less major bleeding events, while maintaining

efficacy at preventing stroke or thrombosis.

Introduction

DOACs are now used routinely for several indications, including the treatment and prevention of

venous thromboembolism (VTE) and stroke prophylaxis in atrial fibrillation. They are

recommended as first line therapy for certain indications by the American College of Clinical

Pharmacy guidelines [1]. DOACs have been trialed against VKAs in multiple settings and have

been found to be non-inferior or superior at preventing stroke in patients with atrial fibrillation

and are non-inferior to VKAs in the treatment of VTE, with pooled data consistently showing that

DOACs provoke less bleeding then VKAs. However, all prospective trials of DOACs to date

have excluded patients with clinically significant liver disease [2-6].

Patients with cirrhosis have been shown to have both a higher rate of thrombosis and bleeding

events compared to healthy non-cirrhotic patients [7, 8], and those requiring anticoagulation

carry a significant bleeding risk [9]. In vitro data has also suggested that anticoagulation may not

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 have uniform potency in patients with cirrhosis suggesting clinical unpredictability [10]. This,

along with a lack of clinical data has led to hesitation in the use of DOACs in cirrhotic patients.
Accepted Article
Recently, a small retrospective study of DOACs in cirrhotic patients found similar rates of

bleeding when compared to VKA and LMWH, although data is lacking and limited elsewhere to

case reports [11]. No data exists comparing the efficacy of DOACs to more traditional

anticoagulants in cirrhosis. In order to better define these outcomes we retrospectively

evaluated patients with cirrhosis who were prescribed anticoagulation for VTE or atrial fibrillation

at our center in an attempt to better define their safety and efficacy.

Methods

We performed an institutional review board approved single center retrospective cohort study.

The study population was assembled from an administrative database query for patients treated

at the Oregon Health & Science University from January 2012 to December 2015. For inclusion,

patients were prescribed either a DOAC, VKA or LMWH at treatment dosing in either the

inpatient or outpatient setting, for a planned extended period of time, and had a diagnosis of

cirrhosis as established through ICD-9 coding and confirmed by review of the medical records

including pathology reports, imaging reports and progress notes specifically stating that the

patient had cirrhosis. The Included Indications for anticoagulation were atrial fibrillation or

venous thromboembolism, including portal vein thrombosis and deep vein thrombosis. Only

therapeutic does of anticoagulation were included ( apixaban 5mg BID, with or without a 10mg

BID load, rivaroxaban 15mg daily, with or without a 20mg daily load, LMWH 1mg/kg BID or

1.5mg/kg daily, or warfarin dosed to an INR goal of 2-3 or an INR 1 unit greater then baseline).

We did not consider bridging anticoagulation IE: patients who received a short course of LMWH

before initiating warfarin. Such patients were triaged to the VKA group in this study. We

excluded patients already on anticoagulation prior the start of the study period, those prescribed

prophylactic dosing after surgeries, or patients with insufficient evidence of cirrhosis.

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 Variables abstracted for each patient included: age at start of anticoagulation, indication for

anticoagulation, sex, etiology for cirrhosis, MELD-XI score (excluding INR), Child-Turcotte-Pugh
Accepted Article
(CTP) score, INR at start of anticoagulation, platelets at start of anticoagulation, duration of

treatment in days, evidence of esophageal varices at start of therapy, concurrent use of

antiplatelet therapy, concurrent diagnosis of malignancy, any bleeding event during

anticoagulation use, and any treatment failure of anticoagulation. Bleeding events were

characterized as minor, moderate, or major. Minor events did not require intervention or

discontinuation of medication and were not considered clinically relevant. Moderate events were

non-life threatening, but required transfusion or intervention. Major events included fatal

bleeding, symptomatic bleeding in a critical organ area, or bleeding causing a fall in hemoglobin

level >2 or leading to transfusion of 2+ units of blood [12]. Failure of anticoagulation included

ischemic stroke, progression of VTE, or new VTE.

Data was analyzed using GraphPad Prism 6. The Fisher Exact Test was used for measurement

of statistical significance.

Results

There were 85 adult patients with an ICD-9 code corresponding to “Chronic Liver Disease and

Cirrhosis” (571.0 -571.9) with a prescription for VKA or LMWH and 89 adult patients with a

prescription for a DOAC during the study period. In the traditional anticoagulant group, 18 of the

85 patients were newly started on a traditional anticoagulant during the specified dates and had

a chart diagnosis of cirrhosis (extended LMWH n=3 (17%) and VKA n=15 (83%)). In the DOAC

group, 27 of the 89 patients satisfied the aforementioned criteria (rivaroxaban n=17 (64%) and

apixaban n= 10 (47%)).

There were no statistical differences in baseline characteristics of the two groups which

included, gender, age, etiology of the patient’s cirrhosis, and indication for the therapeutic

anticoagulation. Most patients were being treated for atrial fibrillation. The majority of patients in

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 both groups fell into Child-Turcotte-Pugh class B with an average MELD-XI (excluding INR)

score 10.1 in the traditional group and 8.9 in the DOAC group, p= 0.28. Both groups had similar
Accepted Article
rates of malignancy, concurrent antiplatelet use and findings of esophageal varices. The

traditional group had a higher mean starting INR, owing to 2 patients who were initiated on

warfarin with an INR>6, however the average MELD-XI (excluding INR), platelets, albumin, total

bilirubin were not statistically different between the groups (Table 1).

There were 10 total bleeds in the traditional group and 8 in the DOAC group, p= 0.12. There

were more major bleeds in the traditional group (n= 5 (28%)) compared to the DOAC group, (n=

1 (4%)), p= 0.03. In the traditional group, 3 of these major bleeds occurred during the first year

of anticoagulation, while in the DOAC group, none of the major bleeds occurred during the first

year of use, p= 0.06. There were 3 intracranial bleeds in the traditional group and none in the

DOAC group, p= 0.06. There were 4 gastrointestinal bleeds in the traditional group and 5 in the

DOAC group, p= 1.00. The risk of bleeding was not statistically different between both groups

with concurrent use of antiplatelet agents or for those with malignancy (Table 2).

In our efficacy analysis, there was only 1 patient in each group where the therapeutic

anticoagulation failed, both with progression of a DVT while on therapy. There were no cerebral

vascular accidents or progression of portal vein thrombosis in either group.

Discussion

Overall, the safety findings in this study, including decreased rates of severe bleeding, were

similar to the larger prospective studies comparing DOACS to VKAs in patients without

cirrhosis, as well as the findings of a single similar retrospective series [11]. This is the first

study to our knowledge to evaluate efficacy, which suggests that DOACs may be as effective

as, and safer than, traditional anticoagulants in selected patients with cirrhosis.

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 Many authors suggest LMWH as the anticoagulant of choice in patients with liver disease,

based on small prospective series and retrospective evaluations [13-15]. VKAs alternately are
Accepted Article
difficult to monitor in cirrhotic patients with baseline coagulopathy, leading to the threat of

significant time outside of therapeutic range [16]. DOACs offer a convenient alternative to

subcutaneous LMWH in cirrhotic patients and may lead to more compliance due to ease of

administration. Our analysis showed that both providers and patients with cirrhosis are willing to

trial these drugs despite a lack of data on their safety and efficacy. Indeed, we found roughly an

equal number of DOACs prescribed as compared to traditional anticoagulants at our center.

The pharmacokinetics of DOACs are altered with hepatic impairment to varying degrees,

suggesting that lower doses may be needed to obtain the same degree of anticoagulation with

worsening hepatic function [17]. While mild hepatic impairment has been shown to have minimal

impact on the pharmacodynamics of rivaroxaban for instance, patients with moderate hepatic

impairment (CTP class B) have significantly increased exposure (Area under the curve (AUC)

increased by 127%) compared to healthy subjects, and patients with severe liver disease have

not been studied [18]. Alternately, the AUC for apixaban is relatively unchanged between CTP

class A vs CTP class B patients (1.03 vs 1.09), suggesting more consistent drug

pharmacokinetics [19]. Currently there is insufficient data to recommend dose adjustment in

patients with moderate to severe liver dysfunction with either drug. Most patients in this study

were CTP class A and B and few patients in this study were CTP class C. Thus, the safety and

efficacy suggestions from this study would not necessarily be the same for patients with severe

and complicated hepatic impairment, although the same dose of DOAC was prescribed to

patients in all CTP classes in this study. Potentially, patients with CTP class C could have a

higher risk of bleeding with certain DOACs. A study with a larger sample size involving more

cirrhotic patients might show this finding.

A major finding in this analysis was the significant difference in major bleeding, particularly CNS

bleeding, with 3 CNS bleeds occurring in the group that received traditional anticoagulation, and

none in those receiving DOACs. This is in line with prior studies of DOACs, which have been

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 routinely found to have less CNS bleeding [3]. The majority of the patients in the traditional

anticoagulation group were receiving VKAs, which are prone to significant time outside of the
Accepted Article
therapeutic range [20]. It is possible that supratheraputic values in patient with cirrhosis are

more dangerous than in patients without hepatic impairment, and while DOAC metabolism in

cirrhosis may lead to higher mean therapeutic levels with certain DOACs, it is likely consistent,

with less extreme peaks and troughs.

It is also significant to note that three of the five major bleeds that occurred in the traditional

group happened within the first year of therapy and the one major bleed in the DOAC group

occurred after that time period. This is consistent with population studies that have suggested

that the rate of hospitalizations for bleeding on warfarin occur early on in therapy, with the peak

occurring within the first 30 days [21]. This also may suggest more variable levels of VKA in the

serum especially while first titrating the medication for a specific patient.

Another important point is the similarity in the rates of GI bleeding. Certain DOAC including

rivaroxaban have been associated with increased rates of GI bleeding as compared to VKAs

[22]. We found roughly similar rates, (4 vs 5 patients). This is an important consideration,

particularly in patients prone to variceal bleeding.

It is also important to note that the average amount of days patients received traditional

anticoagulation was greater in our study than the average amount of days patients received

DOACs. This finding might be attributed, in part, to the fact that despite bleeding, there were

four patients who continued on traditional anticoagulation until the end of the study period;

whereas patients who had a bleeding event on DOACs were taken off the medication

permanently. This might suggest providers have higher comfort levels with warfarin and the

ability to reverse the effects of warfarin should additional bleeding occur. Additionally, there was

only one DOAC prescribed in 2012 at our institution for a cirrhotic patient, whereas four

traditional anticoagulants were prescribed in 2012. This might suggest that providers were more

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 wary of prescribing DOACs in cirrhotic patients at that time. These findings may help explain

why the mean overall time period of observation for patients on traditional anticoagulants was
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greater.

While this study may suggest clinical utility, it is important to note that it has limitations, including

the small sample size, inability to control the prescribing and discontinuation decisions of

providers, and its retrospective nature. The sample size in particular is a strong limitation which

increases the possibility of false positive results and suggests that larger studies are certainly

needed to help guide anticoagulation in patients with liver disease. This study also lacks a

preponderance of patients with CTP class C liver disease as stated above. Along with previous

reports, this study does however, suggest that clinicians are using DOACs in selected cirrhotic

patients [11], and adds to the literature that it might be as safe and as effective in patients with

minimal or intermediate hepatic insufficiency as traditional anticoagulants.

Author Contributions:

J. Hum: project conception and design, data accumulation, data analysis, manuscript drafting. J. Shatzel:

project conception and design, manuscript drafting, critical revisions. J. Jou: critical revisions. T.

Deloughery: critical revisions.

Acknowledgement:

This study was unfunded.

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Table 1: Characteristics of Included Patients

TRADITIONAL (N = 18) DOAC (N = 27) P VALUE

GENDER (% MALE) 14 (78%) 18 (67%) 0.51
AGE (YEARS) 58 (34-80) 61 (26-90) 0.45
ETIOLOGY 0.36
ETOH 5 (28%) 6 (22%)
VIRAL 9 (50%) 7 (26%)
NASH 1 (5%) 3 (11%)
OTHER 5 (28%) 12 (44%)
CHILD-TURCOTTE-PUGH SCORE 0.25
CTP A 7 (39%) 11 (41%)
CTP B 9 (50%) 12 (44%)
CTP C 2 (11%) 4 (15%)
MELD-XI 10.1, SD 3.8 8.9, SD 3.4 0.28
HISTORY OF MALIGNANCY 5 (28%) 5 (18%) 0.48
ANTIPLATELET THERAPY 3 (17%) 4 (15%) 1.00
ESOPHAGEAL VARICES PRESENT 2 (11%) 4 (15%) 1.00

LABS AT TIME OF PRESCRIPTION

ALBUMIN (g/dL) 2.8, SD 0.8 3.0, SD 0.8 0.51
TOTAL BILIRUBIN (mg/dL) 2.5, SD 6.1 1.5, SD 1.7 0.41
CREATININE (mg/dL) 1.3, SD 0.7 1.1, SD 0.5 0.27
INR 3.0, SD 3.4 1.6, SD 0.8 0.05

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 PLATELETS (k/dL) 153, SD 96 202, SD 142 0.20

INDICATION FOR ANTICOAGULATION 0.21

PORTAL VEIN THROMBOSIS 3 (17%) 4 (15%)
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DEEP VEIN THROMBOSIS 8 (44%) 12 (44%)
ATRIAL FIBRILLATION 9 (50%) 15 (56%)
OTHER 1 (6%) 0
ANTICOAGULATION MEDICATION
RIVAROXABAN - 17 (63%)
APIXAPAN - 10 (47%)
WARFARIN 15 (83%) -
ENOXAPARIN 3 (17%) -
MEAN DAYS ON ANTICOAGULATION 574, SD 498 319, SD 289 0.04*
MEDIAN DAYS ON ANTICOAGULATION 317 225

Table 2: Bleeding and efficacy rates based on type of anticoagulation

TRADITIONAL (N = 18) DOAC (N = 27) P VALUE

TOTAL BLEEDS 10 (56%) 8 (30%) 0.12

MAJOR BLEEDS 5 (28%) 1 (4%) 0.03*

MODERATE BLEEDS 5 (28%) 4 (15%) 0.45

MINOR BLEEDS 0 (0%) 3 (11%) 0.26

INTRACRANIAL BLEEDS 3 (17%) 0 (0%) 0.06

GI BLEEDS 4 (22%) 5 (18%) 1.00

BLEEDS IN FIRST YEAR 8 (44%) 7 (26%) 0.21

MAJOR BLEEDS IN FIRST YEAR 3 (17%) 0 (0%) 0.06

DAYS TO BLEED 308, SD 374 181, SD 132 0.37

BLEEDING WITH CONCURRENT 3 (30%) 5 (63%) 0.34

MALIGNANCY

BLEEDING PT ON CONCURRENT ANTI- 2 (11%) 1 (4%) 0.55

PLATELET

FAILED EFFICACY ANTICOAGULATION 1 (6%) 1 (4%) 1.00

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