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Keywords:

  • bleeding;
  • cirrhosis;
  • coagulation;
  • deep venous;
  • thrombosis;
  • venous thromboembolism

Abstract

  1. Top of page
  2. Abstract
  3. Results
  4. Discussion
  5. Acknowledgements

Background

Hospitalized patients with cirrhosis are at risk to develop venous thromboembolism. Although current guidelines support the routine administration of thromboprophylaxis to hospitalized patients, there is limited data regarding the safety or efficacy of this practice in hospitalized cirrhosis patients.

Aims

We aimed to determine if administration of thromboprophylaxis was associated with increased complication rates for hospitalized cirrhosis patients.

Methods

Data were collected on patients admitted to the University of Virginia between 2007 and 2010. Study personnel systematically collected data on complications, including gastrointestinal bleed, venous thromboembolism and death directly from the medical record.

Results

A total of 235 patients (accounting for 355 discrete hospitalizations in which thromboprophylaxis was administered) met inclusion criteria accounting for 1660 person-days of thromboprophylaxis administered to patients. The mean age at admission was 58 (95% CI 57.1–59.2) years and 217 (61%) were male patients. The mean admission model for end-stage liver disease (MELD) score was 16.2 (95% CI 15.5–16.9). The mean hospital length of stay was 6.5 (95% CI 5.9–7.4) days. In patients who received thromboprophylaxis, the mean treatment length was 4.7 days (95% CI 4.2–5.2). There were nine gastrointestinal bleeding events (2.5% of admissions), five venous thromboembolisms (1.4% of admissions), two cases of heparin-induced thrombocytopenia (0.5% of admissions) and 14 deaths overall (3.9% of admissions).

Conclusions

The use of thromboprophylaxis in hospitalized cirrhosis patients is not associated with high rates of gastrointestinal bleeding or death.

Abbreviations
EGD

esophagogastroduodenoscopy

EV

esophageal varices

FFP

fresh frozen plasma

GAVE

gastric antral vascular ectasia

LMWH

low molecular weight heparin

MELD

model for end-stage liver disease

NAFLD

non-alcoholic fatty liver disease

PBC

primary biliary cirrhosis

PRBC

packed red blood cells

PSC

primary sclerosing cholangitis

PVT

portal vein thrombosis

RCT

randomized controlled trial

UGI

upper gastrointestinal

UFH

unfractionated heparin

VKA

vitamin K antagonist

VTE

venous thromboembolism

Hospitalized, acutely ill medical patients are at high risk for the development of venous thromboembolic disease (VTE), deep vein thrombosis and pulmonary embolism, when compared with the general population [1, 2]. Medical thromboprophylaxis with unfractionated heparin (UFH) or low molecular weight heparin (LMWH) decreases the risk of developing VTE in hospitalized medical patients [3-5]. Current guidelines give a class IA recommendation for the administration of thromboprophylaxis for ‘moderate risk’ hospitalized medical patients confined to a bed [6]. However, the actual practice of implementing this therapy is suboptimal [7].

Hospitalized cirrhosis patients are also at risk to develop VTE [8-15]. Many physicians perceive patients with liver disease to be protected from VTE from ‘auto-anticoagulation’ secondary to an elevated prothrombin time and thrombocytopaenia. Epidemiological evidence and cross-sectional studies now invalidate this flawed concept [16]. The coagulopathy of liver disease involves a complex interplay between pro and anticoagulant factors, which is not accurately assessed by standard biochemical indices [17-21]. Hospitalized patients with cirrhosis are often left immobile secondary to muscle wasting, encephalopathy and ascites placing them at risk for venous stasis. Although it is well established that thromboprophylaxis decreases the risk of VTE in hospitalized medical patients, it remains unclear if this benefit extends to patients with cirrhosis. Some experts now recommend that hospitalized cirrhosis patients should be considered for thromboprophylaxis [22]. Although recent data suggest that therapeutic and prophylactic doses of anticoagulation in the subsets of ambulatory cirrhosis patients are safe, large studies examining safety and efficacy in hospitalized patients are lacking [23-27]. While extrapolation of data from studies in both acutely ill medical patients and patients with liver disease is clinically reasonable, there is little direct evidence to refute or support the safety of thromboprophylaxis in hospitalized cirrhosis patients. In populations of general hospitalized medical and surgical patients, thromboprophylaxis is safe and studies demonstrate low rates of bleeding [3]. As cirrhosis patients are generally excluded from these trials, it remains unclear whether thromboprophylaxis would place cirrhosis patients at a higher risk for bleeding, which would potentially contribute to morbidity.

In this study, we examined outcomes of cirrh-osis patients exposed to thromboprophylaxis while hospitalized. We aimed to estimate rates of bleeding complications associated with thromboprophylaxis in hospitalized patients with cirrhosis receiving thromboprophylaxis.

Methods

In this retrospective case series, subjects were selected from hospital admissions using the following criteria: known diagnosis of cirrhosis, age above 18 years old and admission between the years 2007 and 2010 to the University of Virginia Medical Center, a tertiary liver transplant referral centre. During this time period, a hospital admission algorithm was introduced, which required the admitting provider to place every patient without contraindications, on VTE prophylaxis. We selected patients from a time period after this policy was implemented to assess the safety impact in cirrhosis patients. Each patient admission was reviewed systematically by study personnel, including every hospitalization over this period. Every patient admission over this time period was treated as a separate event during analysis. Adult cirrhosis patients were included if they were hospitalized for at least 2 days, treated for more than or equal to 2 days with UFH or LMWH and were admitted to a medicine or surgery non-intensive care unit (ICU) bed. Patients were excluded if admitted to an ICU, had a history of liver transplant, were admitted on therapeutic anticoagulation or carried a prior history of VTE. Patients with a documented history of either congenital or acquired thrombophilia disorder were excluded.

The available agents for thromboprophylaxis at our institution during this study period included: UFH 5000 units subcutaneously (SC) every 8 h; enoxaparin 40 mg SC every 24 h; and dalteparin 5000 units SC every 24 h. The choice of agent was often based on patient comorbidity (e.g. renal dysfunction), provider preference or formulary restrictions. An electronic order set prompt directed the provider to choose a method of thromboprophylaxis at the onset of every admission to the hospital. All patients admitted to this study centre routinely were prescribed sequential compression devices during the hospital stay unless contraindicated. Compliance with wearing these devices was not documented in the medical record.

Standard definitions of treatment outcomes and complications were identified and systematically recorded in this study population. Patient characteristic data were collected including age, gender, aetiology of cirrhosis and admission laboratory values. A diagnosis of cirrhosis was confirmed with pathology or, if unavailable, supporting evidence obtained from clinical history, imaging and laboratory studies. VTE was confirmed with the review of radiological imaging reports conducted during that hospitalization (ultrasound, computed tomography scan or venogram). To capture the largest possible percentage of complications, GI bleeding was liberally defined as any documentation of a bleeding event in the medical record during that hospitalization. Study personnel reviewed each hospital medical record in its entirety to verify and categorize these GI bleeding events. Heparin-induced thrombocytopenia (HIT) was defined by discharge diagnosis and established standard criteria [28].

All data analysis and manipulation were performed using SAS, version 9.2 (Cary, NC, USA). General demographics and subject characteristics were analysed using summary statistics. Predefined subgroup analyses were preformed between subjects that had bleeding events and those that did not. Categorical statistical comparisons were performed using the chi-square test or the Fisher's exact test as appropriate. Continuous comparisons were performed using the Student's t-test or Wilcoxon sign-rank as appropriate. All statistical tests were two-sided and the level for type-one error reaching statistical significance was set at P ≤ 0.05. Research use of clinical records was approved for this study by the University of Virginia Institutional Review Board for Human Research.

Results

  1. Top of page
  2. Abstract
  3. Results
  4. Discussion
  5. Acknowledgements

A total of 1138 adult patients with cirrhosis admitted to the University of Virginia were identified that met study entry criteria. Of these, 235 patients (accounting for 355 discrete hospitalizations in which VTE prophylaxis was administered) met inclusion criteria (Table 1). A majority of patients admitted were male gender (61%) with a mean age of 58 years (95% CI 57.1–59.2). The three most common aetiologies of cirrhosis in this population were viral hepatitis (42%), followed by alcohol (19%) and non-alcoholic fatty liver disease (15%). In cases where patients had a history of alcohol abuse and chronic viral hepatitis, a viral aetiology was recorded. Fifty (14%) patients underwent surgery during admission. Twenty per cent of admissions reviewed had a history of underlying malignancy. The majority of excluded admissions reviewed were excluded because no VTE prophylaxis was administered during that admission (data not shown).

Table 1. Patient baseline characteristics. Characteristics expressed as mean values and percentages or 95% confidence intervals in parenthesis. Laboratory values are expressed as mean with 95% confidence interval
 Admissions (n = 355)
  1. a

    MELD; Model for end-stage liver disease score = 11.2 ln (INR) + 3.78 ln (total bilirubin) + 9.57 ln (creatinine) + 6.43.

Age (years)58 (57.1–59.2)
Male Gender217 (61%)
Aetiology of cirrhosis
Viral151 (42%)
Alcohol67 (19%)
NAFLD53 (15%)
PBC/PSC15 (4%)
Autoimmune11 (3%)
Other58 (16%)
Length of treatment (days)4.7 (4.2–5.2)
Length of stay (days)6.5 (5.9–7.4)
Surgery during hospitalization50 (14%)
History of malignancy70 (20%)
Admission MELD scorea16.2 (15.5–16.9)
Total bilirubin (mg/dl)3.6 (3.0–4.1)
International normalized ratio (INR)1.46 (1.42–1.50)
Creatinine (mg/dl)1.49 (1.36–1.64)
Albumin (g/dl)3.2 (3.1–3.3)
Admission platelet count × 103/μl139 (131–147)

A total of 1660 person-days of thromboprophylaxis were evaluated wherein 274 patients (77.2%) received unfractionated heparin (UFH), 53 (14.9%) received enoxaparin and 36 (10.1%) received dalteparin. In some instances, patients received more than one type of thromboprophylaxis during a single hospitalization. In patients who received thromboprophylaxis, the mean treatment length was 4.7 days (95% CI 4.2–5.2). The mean length of stay was 6.5 days (95% CI 5.9–7.4). The mean MELD score at admission was 16.2 (95% CI 15.5–16.9).

In patients who were treated with thromboprophylaxis, nine of 355 (2.5%) had an episode of GI bleeding during hospitalization. HIT was diagnosed in two patients (0.5%) who received thromboprophylaxis. The VTE rate in patients receiving thromboprophylaxis was 1.4% (three non-splanchnic DVT, two PE and no catheter associated thrombotic events). Only one patient with VTE had a known diagnosis of malignancy (metastatic adenocarcinoma) during the hospitalization. No patient with VTE in this study had concurrent diagnosis of hepatocellular carcinoma. Two patients underwent surgery during the admission in which VTE was diagnosed. There were a total of 14 admissions (3.9%) resulting in death. No patients died directly from VTE-related complications.

Of those patients with GI bleeding, 89% (8/9 patients) received UFH, 11% (1/9) enoxaparin and 0% dalteparin (Table 2). In this group, admission diagnoses were primarily for volume overload, ascites, acute liver injury or other medical problems. No patients in this group were admitted for surgery or initially presented with bleeding. Of all the GI bleeding cases, only one resulted in a greater than 2 g/dl decline in haemoglobin. Five of the patients with GI bleed required a blood transfusion during admission. Comparison of characteristics between the group of patients who experienced GI bleeding and the group who did not revealed no statistical differences (Table 3). There were no significant differences between the type of anticoagulation and GI bleeding (UFH P = 0.69; enoxaparin P = 0.99; dalteparin P = 0.61). Similarly, there were no significant differences between patients with GI bleeding and all other patients with respect to age, admission MELD, admission haemoglobin, albumin, platelets or amount of blood product transfused.

Table 2. Admissions in which GI bleeding occurred
 Clinical signProphylaxis TypeGI bleed (day of HSP)VTE prophylaxis stopped? (day of HSP)Endoscopic examHgb deficita/ transfusionSource identified?In-hospital death
  1. UFH, unfractionated heparin; HSP, hospitalization; Hgb, haemoglobin; GAVE, gastric antral vascular ectasia.

  2. a

    Hgb deficit = hgb recorded prior to the report of GI bleeding event subtracted by the next hgb recorded (within 12 h).

  3. b

    Death secondary to GI bleed, patient transitioned to hospice care.

  4. c

    Death secondary to respiratory failure and pneumonia.

  5. d

    Death secondary to multiorgan failure.

1hematocheziaUFH12none−1.5/nononeno
2hematemesisUFH4noEGD0/noesophagitisno
3hematemesisUFH43none−3.7/yesnoneyesb
4melenaUFH1012EGD and colonoscopy−0.2/nononeyesc
5melenaUFH2noEGD−0.4/yesGAVEno
6melenaUFH13noEGD−0.2/yesGAVEno
7hematocheziaenoxaparin44none−0.1/nononeyesd
8hematemesisUFH55EGD−0.9/yesesoph. ulcer.no
9hematocheziaUFH10nocolonoscopy+0.2/yescolon massno
Table 3. Comparison of characteristics between patients who experienced GI bleeding and those who did not. Laboratory values are expressed as mean with 95% confidence interval
 GI bleed during admission (n = 9)No GI bleed during admission (n = 346)P-value
  1. PRBC, packed red blood cells; FFP, fresh frozen platelets; UFH, unfractionated heparin.

  2. a

    in some cases, two different therapies employed in one admission.

Admission MELD18.8 (12.5–25.2)16.1 (15.5–16.8)0.36
Admission haemoglobin (g/dl)10.8 (9.3–12.3)11.8 (11.6–12)0.17
Admission platelet (× 103/μl)172 (116–228)138 (130–146)0.20
Blood product transfused (units)
PRBC1.22 (0–2.5)0.52 (0.3–0.7)0.25
Platelets0.22 (0–0.7)0.25 (0.1–0.4)0.89
FFP0.11 (0–0.4)0.35 (0.1–0.6)0.13
Cryoprecipitate0.22 (0–0.7)0.05 (0–0.1)0.45
Treatment length (days)6.1 (1.4–10.8)4.6 (4.2–5.1)0.49
Length of stay (days)10.1 (5.2–15.1)6.4 (5.7–7)0.12
Type of therapy (admissions)a
UFH82660.69
Enoxaparin1520.99
Dalteparin0360.61

Discussion

  1. Top of page
  2. Abstract
  3. Results
  4. Discussion
  5. Acknowledgements

Recommendations for VTE prophylaxis in the cirrhosis population have historically been based on expert opinion and extrapolation from studies performed in hospitalized medical patients without cirrhosis. In acutely ill medical patients, both UFH and LMWH have been shown to reduce the incidence of VTE with low rates of complications [3-5]. These studies generally exclude patients with ‘hepatic insufficiency,’ an elevated INR or thrombocytopenia. Reported rates of major GI bleeding events are similar between patients exposed to thromboprophylaxis and controls in this population [3]. Rates of major bleeding events were 0.49% and minor bleeding events were 1.03% in a trial evaluating dalteparin vs. placebo [4]. A separate study examining enoxaparin prophylaxis vs. placebo reported higher rates of major bleeding (1.7%) and minor bleeding events (10.8%) [5]. However, these results were not statistically different from patients receiving placebo in both studies. In our study, only one patient receiving LMWH experienced a GI bleed during hospitalization. Analysis from a large, multi-centre observational study found that the presence of ‘hepatic failure’ was associated with an increased risk of in-hospital bleeding (including GI bleeding) in acutely ill medical patients irrespective of exposure to thromboprophylaxis [29]. The use of a limited definition of ‘hepatic failure’ (INR greater than 1.5) without specific mention of the presence of cirrhosis or portal hypertension raises some questions as to the generalizability of these results.

We found an overall rate of 2.5% of patients with documented GI bleeding events. Our definition of GI bleeding was intentionally broad and inclusive. The rate of clinically relevant bleeding is likely considerably less. There was only one patient with a decline in haemoglobin of greater than 2 g/dl and only five of the nine patients required transfusion of blood products (Table 2). According to standard consensus definitions of major bleeding, only three of the nine patients in this group meet criteria for major bleeding [30]. Admissions in which GI bleeding occurred showed no significant difference in mean number of blood products used when compared with all other admissions. There were no significant defining characteristics upon admission that were associated with GI bleeding (Table 3). Taken together, these results support the notion that the majority of GI bleeding in this cohort was not significant and unlikely directly attributable to thromboprophylaxis.

Several recent studies evaluated efficacy and safety of anticoagulation (LMWH and vitamin K antagonists) in cirrhosis patients (Table 4) [31]. While one retrospective study demonstrated substantial risk with therapeutic LMWH in cirrhosis patients [9], others, including two recent prospective studies examining therapeutic dosing of anticoagulation for portal vein thrombosis in cirrhosis patients, reported a low risk of associated bleeding complications [23-26, 32].

Table 4. Anticoagulation and liver disease
StudyVTETherapyDoseDurationGI bleedOther bleeding complicationsSample SizeType
  1. PVT, portal vein thrombosis; VKA, vitamin K antagonist; EV, esophageal variceal; RCT, Randomized control trial; IU, international units; kg, kilograms; UGI, upper gastrointestinal.

Therapeutic anticoagulation studies
Delgado et al. 2012 [25]PVTLMWH or VKA

Therapeutic

No dose given

6.8 months

(median)

6 EV bleed1 lower GI bleed1 ‘obscure’ GI bleed

1 Vaginal bleed

1 Surgical wound bleed

1 Bleed after tooth extraction

n = 55

Retrospective

Outpatient

Senzolo et al. 2012 [26]PVTNadroparin

95 antiXa-U/kg/day (treatment)

3800 antiXa-U/day (prophylaxis)

6 months after repermeation in responders

1 EV bleed in treated

5 EV bleeds in untreated(P = 0.09)

1 epistaxis

1 haematuria

1 cerebral haemorrhage

1 HIT

(all in treatment group)

n = 35 treated

n = 21 untreated

Prospective

Outpatient

Amitrano et al. 2010 [24]PVTEnoxaparin200 IU/kg/day (2 mg/kg/day)At least 6 months 2 anaemia from portal hypertensive gastropathy.n = 28

Prospective

Outpatient

Francoz et al. 2005 [23]PVT

VKA

Nadroparin

INR goal 2–3

5700 IU/day as bridge

8.1 months (mean)1 UGI bleed (post-banding ulcer) n = 19

Prospective

Outpatient

Garcia-Fuster et al. 2008 [9]

Non-splanchnic

thrombosis

LMWH

VKA

Therapeutic doses  14 bleeding events (6 severe- 5 on VKA, 1 on LMWH)n = 17

Retrospective

Hospitalized

Prophylactic anticoagulation studies
Villa et al.2012 [27]PVTEnoxaparin

4000 IU/day

(40 mg/day)

48 weeks

2 EV bleed in treated

1 in controls(P = 0.52)

2 epistaxis in treated

1 epistaxis in control

n = 34 treated

n = 36 controls

Prospective RCT

Outpatient

Bechmann et al. 2010 [33]

Non-splanchnic

thrombosis

Enoxaparin

40 mg/day (prophylactic)

Weight based (therapeutic)

Length of hospitalization

5/7 UGI bleed (proph)

2/7 UGI bleed (therap)

 

n = 75 prophylactic

n = 9 therapeutic

Prospective

Hospitalized

Vivarelli et al. 2010 [34]

Non-splanchnic

thrombosis

Nadroparin

Enoxaparin

0.3 ml/day

0.4 ml/day

Began day of surgery to 7 day post operation1 gastric bleeding5 (3 surgical drains, 2 intraperitoneal haemorrhage)n = 157

Retrospective

Hospitalized

(surgical patients)

There are three separate studies specifically examining the use of prophylactic anticoagulation in cirrhosis patients (Table 4). One study in hospitalized cirrhosis patients retrospectively reviewed 75 patients who received LMWH for VTE prophylaxis [33]. Five of 75 patients (6.7%) receiving prophylactic doses of LMWH developed a bleeding complication. A separate study retrospectively examined VTE prophylaxis in well-compensated cirrhosis patients undergoing hepatic resection for hepatocellular carcinoma [34]. 3.18% of patients who received LMWH developed a “hemorrhagic complication” compared to 1.38% of patients that did not receive prophylaxis (P = 0.38). Only one GI bleeding event was recorded, whereas other bleeding complications were related to surgical wound bleeding. Villa and colleagues recently evaluated the incidence of portal vein thrombosis in cirrhosis patients randomized to placebo vs. enoxaparin at prophylactic dose (40 mg daily) over the course of 1 year [27]. Administration of enoxaparin appeared to prevent the development of portal vein thrombosis while resulting in very few overt complications. In that study, there were only three GI bleeds reported (two in treated patients, one in controls; P = 0.52). Although the above studies differ substantially in design, population characteristics and measured outcomes, our results are concordant and demonstrate low rates of GI bleeding associated with prophylactic doses of UFH and LMWH.

Another perceived complication from prophylactic UFH or LMWH is HIT. The incidence of HIT in hospitalized medical patients receiving thromboprophylaxis is presumed to be small [35]. In this population, two patients developed HIT (0.5%). The risk for developing HIT with the administration of thromboprophylaxis is unknown in cirrhosis patients, but it has recently been documented with the therapeutic use of LMWH in this population [26].

Thromboprophylaxis was not associated with a high rate of mortality in this population, but did reveal a higher than expected rate of VTE. Specifically, five patients (1.4%) developed VTE while on thromboprophylaxis. It remains unclear exactly when the VTE initially occurred in these patients. Consequently, it is quite possible that thrombosis developed prior to hospitalization and the event was only discovered during the hospitalization for a separate complaint. Although the rate of VTE in this study appears higher than some previous reports, the rate is specific to this cohort and cannot be extrapolated. This group was not assigned to VTE prophylaxis randomly and it is possible that there was a perceived increased risk at admission making the clinician more likely to select the patient for prophylaxis. Further incidence studies requiring prospective diagnosis and therapy are now needed.

Although this study was not designed to evaluate the efficacy of VTE prophylaxis, it is notable that patients may have developed VTE despite exposure to medical thromboprophylaxis. Currently, it remains unclear if alternative dosing strategies are necessary in patients with cirrhosis or if they respond differently to certain types of VTE prophylaxis. As cirrhosis patients are prone to renal insufficiency, future studies should focus on risk of thrombosis in accordance with dosing of medical prophylaxis. In previous trials, hospitalized medical patients developed VTE during treatment with medical prophylaxis. For example, in one large study examining LMWH for VTE prophylaxis in hospitalized medical patients, 2.77% of patients receiving VTE prophylaxis were noted to develop VTE vs. 4.96% of patients receiving placebo [4]. As this study excluded patients with liver disease, a prospective, randomized study is necessary to better understand efficacy of thromboprophylaxis in cirrhosis patients.

Our study has weaknesses inherent to most retrospective studies. We do not know the motivation of the prescribing practitioner and, consequently, cannot determine if these patients were selected because of a lower perceived risk for bleeding or, conversely, a higher risk of VTE. We also did not evaluate the use of mechanical thromboprophylaxis, which may be a useful adjunct or substitution in this population. The retrospective nature of analysis did not allow for evaluation of other bleeding complications that may have occurred and contributed to morbidity or mortality.

In conclusion, administration of either UFH or LMWH in the hospitalized cirrhosis population appears safe and rates of bleeding and death are low. Although recent evidence suggests that LMWH may prevent the development of portal vein thrombosis [27], it remains unclear whether UFH and LMWH prevent the development of non-splanchnic VTE in hospitalized cirrhosis patients. Although it seems logical to administer thromboprophylaxis to cirrhosis patients at high risk to develop VTE, owing to the current lack of knowledge regarding dosing and efficacy, evidenced-based guidelines cannot be established to assist the clinician with the existing data. Prospective studies should now be designed to further assess safety of these agents, proper dosing and efficacy specific to the cirrhosis patient.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Results
  4. Discussion
  5. Acknowledgements

Funding support: There was no external funding for this study. Neeral Shah and Stephen Caldwell have received research funding from Behring and Hemosonics.

Conflicts of interest: The authors do not have any disclosures to report.

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