PHARMACOLOGY CONSULT
Should patients with chronic liver disease receive venous thromboembolism prophylaxis? Justin D. Dang, PharmD; Lindsay E. Davis, PharmD, BCPS
ABSTRACT Chronic liver disease has long been considered the prime example of acquired bleeding disorders due to its associated coagulopathies, namely elevated international normalized ratio (INR) and thrombocytopenia. Recent evidence has shown that patients with chronic liver disease also are at risk for hospital-acquired venous thromboembolism (VTE). The safety and efficacy of low-dose anticoagulants for VTE prophylaxis have not been firmly established in this patient population. However, recent studies also indicate pharmacologic VTE prophylaxis can be used with caution in hospitalized patients with chronic liver disease. Keywords: chronic liver disease, cirrhosis, end-stage liver disease, venous thromboembolism, VTE prophylaxis
A
hallmark of advancing chronic liver disease is the development of bleeding diathesis, which can be objectively measured by elevated international normalized ratio (INR) and thrombocytopenia. The coagulopathy resulting from chronic liver disease is complex and has been thoroughly described in the literature.1 Injury to hepatic cells can briefly impair liver function, resulting in reduced synthesis of clotting factors II, VII, IX, X, and thrombopoietin. The liver produces procoagulants and anticoagulants, which can be affected by the disease process (Table 1). With this mix of effects on hemostatic factors, patients with chronic liver disease might be characterized as having a uniquely fragile balance of hemostasis that puts them at increased risk for bleeding and clotting when compared with patients without chronic liver disease.1 Because of the elevated baseline INR in advancing chronic liver disease, patients have been referred to as “autoanticoagulated.”1,2 This term implies that the patient’s inherent coagulopathy reduces the risk for venous thromboembolism Justin D. Dang is a staff pharmacist at Banner Estrella Medical Center in Phoenix, Ariz. Lindsay E. Davis is an assistant professor at Midwestern University’s College of Pharmacy in Glendale, Ariz. The authors have disclosed no potential conflicts of interest, financial or otherwise. Mary Lou Brubaker, PharmD, PA-C, department editor DOI: 10.1097/01.JAA.0000463876.73116.91 Copyright © 2015 American Academy of Physician Assistants
(VTE). But clinicians cannot assume that patients with chronic liver disease are protected from hospital-acquired VTE compared with general hospitalized medical patients. The incidence of VTE in general hospitalized medical patients is about 0.2% to 6.7%; the rate of VTE in hospitalized medical patients with chronic liver disease is not well defined in the literature.3 A retrospective cohort study of 190 hospitalized patients with chronic liver disease sought to determine the incidence of VTE and the relationship between baseline INR and VTE.2 This study found a 6.3% incidence of VTE in patients with chronic liver disease. No significant difference in the incidence of VTE between INR quartiles or Child-Pugh class was identified. VTE prophylaxis was only used in 9% of patients (17 of 190). One limitation of these data is that the baseline malignancy rate was 23.5%, which could confound these results (malignancy is a well-established risk factor for VTE). The authors concluded that the theory of autoanticoagulation is unfounded given that the elevated baseline INR did not confer protection against VTE in this cohort of patients with chronic liver disease.2 The incidence of hospitalacquired VTE in patients with chronic liver disease in this study is similar to the cited incidence of VTE in general hospitalized medical patients, which supports the conclusion that “autoanticoagulation” is not a true phenomenon.2,3 IS STANDARD THERAPY SAFE? Despite the risk of hospital-acquired VTE in patients with chronic liver disease, mitigating this risk through the use of standard treatment options is uncertain. Standard treatment for VTE prophylaxis in hospitalized patients includes pharmacologic prophylaxis with low-dose subcutaneously administered anticoagulants such as unfractionated heparin (UFH) and enoxaparin, mechanical prophylaxis with sequential compression devices (SCDs), and/or early ambulation. The efficacy and safety of anticoagulants is well documented in general hospitalized patients; however, their use is not as clear for patients with chronic liver disease, who often are excluded in study protocols. Only a few studies have assessed the safety and efficacy of anticoagulants for VTE prophylaxis in patients with chronic liver disease, and consequently the CHEST guidelines offer limited recommendations for this population.2-4 Given the paucity of data, some providers may feel uncomfortable or uncertain about prescribing pharmacologic
JAAPA Journal of the American Academy of Physician Assistants
Copyright © 2015 American Academy of Physician Assistants
www.JAAPA.com
27
PHARMACOLOGY CONSULT
TABLE 1. Effect
of chronic liver disease on hemostatic factors
Factor
Physiologic role
Effect of chronic liver disease on factor
Patients with chronic liver disease are at increased risk of
Clotting factors (II, VII, IX, X)
Antihemostasis (assists with clot formation to regain hemostasis after vascular insult/injury)
Decreased synthesis
Bleeding
Platelets
Antihemostasis
Decreased production due to decreased synthesis of thrombopoietin and splenic sequestration
Bleeding
von Willebrand factor
Antihemostasis
Increased synthesis in endothelial cells
Clotting
Proteins C and S
Prohemostasis (prevents excessive clot formation)
Decreased synthesis
Clotting
Antithrombin
Prohemostasis
Decreased synthesis
Clotting
Reversal of ECG changes
Anticoagulant factors
VTE prophylaxis for hospitalized patients with chronic liver disease and may rely on inferior methods of VTE prophylaxis, including SCDs.5 Providers may be concerned about patients’ perceived increased risk of bleeding with the use of anticoagulants, or believe that the drugs’ action may be attenuated because of patients’ reduced antithrombin levels (UFH and low-molecular-weight heparin are antithrombin-dependent).1 Further studies are necessary to definitively determine if patients with chronic liver disease are at increased bleeding risk from VTE prophylaxis and to determine if antithrombin-dependent anticoagulants are effective for VTE prophylaxis in these patients. Target-specific oral anticoagulants such as dabigatran, apixaban, and rivaroxaban do not require antithrombin to exert their anticoagulant effect. These drugs have recently gained approval for the treatment and prevention of VTE, and information about their usefulness in patients with chronic liver disease may become available as their use in everyday practice increases. A 2013 study is the largest study identified to date that documents the safety and efficacy of VTE prophylaxis in patients with chronic liver disease.4 The study was a singlecenter retrospective cohort analysis that included 1,581 hospitalized adult patients with chronic liver disease. The study compared pharmacologic VTE prophylaxis at usual doses (UFH 5,000 units subcutaneously every 8 to 12 hours, enoxaparin 30 to 40 mg subcutaneously every 24 hours) with no VTE prophylaxis. The researchers found that patients who received pharmacologic VTE prophylaxis had a reduced incidence of hospital-acquired VTE (0.5%) compared with those who did not receive prophylaxis (1.8%, P=0.50). Furthermore, use of pharmacologic VTE prophylaxis was protective against VTE (odds ratio, 0.34; 95% confidence interval [CI] 0.04-0.88). A subgroup analysis based on bleeding history found that patients without a history of bleeding 28
who received pharmacologic VTE prophylaxis showed the greatest benefit of use, having a lower incidence of VTE (0.3% versus 1.5%, P=0.043) with no increased risk of bleeding (0.3 versus 1.1%, P=0.129) when compared with patients who did not receive prophylaxis. Finally, multivariate regression identified three risk factors for VTE in patients with chronic liver disease: active malignancy (odds ratio, 8.76; 95% CI 2.56-29.58), trauma or surgery during hospitalization (odds ratio, 10.29; 95% CI 1.18-89.51), and history of VTE (odds ratio, 26.48; 95% CI 6.93-101.16). The strengths of this study include its large sample size and minimal exclusion criteria. Limitations of the study include retrospective study design, inability to assess use of mechanical VTE prophylaxis, and differences in baseline characteristics (history of bleeding, surgery or trauma, Child-Pugh class, platelet levels, and length of stay). The authors concluded that pharmacologic VTE prophylaxis reduces the incidence of hospital-acquired VTE in patients with chronic liver disease without increasing the rate of bleeding.4 BLEEDING ISSUES The use of pharmacologic VTE prophylaxis is concerning in any patient with thrombocytopenia, and patients with chronic liver disease are no exception. A multinational observational study followed 10,866 hospitalized medical patients and determined major risk factors for bleeding. The three risk factors with odds ratios greater than 3 were active gastroduodenal ulcer, bleeding in the last 3 months, and platelet count less than 50×109/L.6 Stemming from this study, platelet count less than 50×109/L has been used as the cutoff to reconsider use of anticoagulation per American College of Chest Physicians guidelines.2,3 Patients with thrombocytopenia are generally considered to be at increased risk for bleeding; however, in vitro studies have shown that patients with cirrhosis have increased von
www.JAAPA.com
Volume 28 • Number 6 • June 2015
Copyright © 2015 American Academy of Physician Assistants
PHARMACOLOGY CONSULT
Willebrand factor, which may compensate for having fewer platelets.7 In a review of several studies of thrombocytopenia in patients with chronic liver disease, negligible bleeding risk was found for invasive procedures (endoscopy, biopsy, dental extractions) for patients with platelet counts greater than 50×109/L, and a nonnegligible bleeding risk was found for patients with platelet counts less than 50×109/L.8 CONCLUSION Pharmacologic VTE prophylaxis should be considered for patients with chronic liver disease and platelet counts greater than 50×109/L. Standard doses of anticoagulants for VTE prophylaxis are recommended, as no studies have been done using alternative dosing strategies. Mechanical prophylaxis should be considered for patients with platelet counts less than 50×109/L.9 Monitor patients on pharmacologic VTE prophylaxis for signs and symptoms of bleeding or clotting, and regularly assess platelet counts and renal function. Additional prospective, multicenter studies are needed to validate the current literature and to explore future directions in this area. Potential research questions include investigating the optimized dosing for VTE prophylaxis in patients with chronic liver disease, defining subgroups at highest risk for VTE or bleeding, and the potential usefulness of targetspecific oral anticoagulants in this population. Risk factors associated with acute inpatient VTE in patients with chronic liver disease are active malignancy, trauma or
30
surgery during hospitalization, and history of VTE. Patients without a history of bleeding appear to be most likely to benefit; use caution in patients with a history of bleeding. JAAPA REFERENCES 1. Tripodi A, Mannucci PM. The coagulopathy of chronic liver disease. N Engl J Med. 2011;365(2):147-156. 2. Dabbagh O, Oza A, Prakash S, et al. Coagulopathy does not protect against venous thromboembolism in hospitalized patients with chronic liver disease. Chest. 2010;137(5):1145-1149. 3. Kahn SR, Lim W, Dunn AS, et al. Prevention of VTE in nonsurgical patients: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012;141(2 suppl):e195S-e226S. 4. Barclay SM, Jeffres MN, Nguyen K, Nguyen T. Evaluation of pharmacologic prophylaxis for venous thromboembolism in patients with chronic liver disease. Pharmacotherapy. 2013;33(4):375-382. 5. Walsh KA, Lewis DA, Clifford TM, et al. Risk factors for venous thromboembolism in patients with chronic liver disease. Ann Pharmacother. 2013;47(3):333-339. 6. Decousus H, Tapson VF, Bergmann JF, et al. Factors at admission associated with bleeding risk in medical patients: findings from the IMPROVE investigators. Chest. 2011;139(1):69-79. 7. Lisman T, Bongers TN, Adelmeijer J, et al. Elevated levels of von Willebrand factor in cirrhosis support platelet adhesion despite reduced functional capacity. Hepatology. 2006;44(1):53-61. 8. Afdhal N, McHutchison J, Brown R, et al. Thrombocytopenia associated with chronic liver disease. J Hepatol. 2008;48(6):1000-1007. 9. Tufano A, Guida A, Di Minno MN, et al. Prevention of venous thromboembolism in medical patients with thrombocytopenia or with platelet dysfunction: a review of the literature. Semin Thromb Hemost. 2011;37(3):267-274.
www.JAAPA.com
Volume 28 • Number 6 • June 2015
Copyright © 2015 American Academy of Physician Assistants
Should patients with chronic liver disease receive venous thromboembolism prophylaxis? Justin D. Dang, PharmD; Lindsay E. Davis, PharmD, BCPS
ABSTRACT Chronic liver disease has long been considered the prime example of acquired bleeding disorders due to its associated coagulopathies, namely elevated international normalized ratio (INR) and thrombocytopenia. Recent evidence has shown that patients with chronic liver disease also are at risk for hospital-acquired venous thromboembolism (VTE). The safety and efficacy of low-dose anticoagulants for VTE prophylaxis have not been firmly established in this patient population. However, recent studies also indicate pharmacologic VTE prophylaxis can be used with caution in hospitalized patients with chronic liver disease. Keywords: chronic liver disease, cirrhosis, end-stage liver disease, venous thromboembolism, VTE prophylaxis
A
hallmark of advancing chronic liver disease is the development of bleeding diathesis, which can be objectively measured by elevated international normalized ratio (INR) and thrombocytopenia. The coagulopathy resulting from chronic liver disease is complex and has been thoroughly described in the literature.1 Injury to hepatic cells can briefly impair liver function, resulting in reduced synthesis of clotting factors II, VII, IX, X, and thrombopoietin. The liver produces procoagulants and anticoagulants, which can be affected by the disease process (Table 1). With this mix of effects on hemostatic factors, patients with chronic liver disease might be characterized as having a uniquely fragile balance of hemostasis that puts them at increased risk for bleeding and clotting when compared with patients without chronic liver disease.1 Because of the elevated baseline INR in advancing chronic liver disease, patients have been referred to as “autoanticoagulated.”1,2 This term implies that the patient’s inherent coagulopathy reduces the risk for venous thromboembolism Justin D. Dang is a staff pharmacist at Banner Estrella Medical Center in Phoenix, Ariz. Lindsay E. Davis is an assistant professor at Midwestern University’s College of Pharmacy in Glendale, Ariz. The authors have disclosed no potential conflicts of interest, financial or otherwise. Mary Lou Brubaker, PharmD, PA-C, department editor DOI: 10.1097/01.JAA.0000463876.73116.91 Copyright © 2015 American Academy of Physician Assistants
(VTE). But clinicians cannot assume that patients with chronic liver disease are protected from hospital-acquired VTE compared with general hospitalized medical patients. The incidence of VTE in general hospitalized medical patients is about 0.2% to 6.7%; the rate of VTE in hospitalized medical patients with chronic liver disease is not well defined in the literature.3 A retrospective cohort study of 190 hospitalized patients with chronic liver disease sought to determine the incidence of VTE and the relationship between baseline INR and VTE.2 This study found a 6.3% incidence of VTE in patients with chronic liver disease. No significant difference in the incidence of VTE between INR quartiles or Child-Pugh class was identified. VTE prophylaxis was only used in 9% of patients (17 of 190). One limitation of these data is that the baseline malignancy rate was 23.5%, which could confound these results (malignancy is a well-established risk factor for VTE). The authors concluded that the theory of autoanticoagulation is unfounded given that the elevated baseline INR did not confer protection against VTE in this cohort of patients with chronic liver disease.2 The incidence of hospitalacquired VTE in patients with chronic liver disease in this study is similar to the cited incidence of VTE in general hospitalized medical patients, which supports the conclusion that “autoanticoagulation” is not a true phenomenon.2,3 IS STANDARD THERAPY SAFE? Despite the risk of hospital-acquired VTE in patients with chronic liver disease, mitigating this risk through the use of standard treatment options is uncertain. Standard treatment for VTE prophylaxis in hospitalized patients includes pharmacologic prophylaxis with low-dose subcutaneously administered anticoagulants such as unfractionated heparin (UFH) and enoxaparin, mechanical prophylaxis with sequential compression devices (SCDs), and/or early ambulation. The efficacy and safety of anticoagulants is well documented in general hospitalized patients; however, their use is not as clear for patients with chronic liver disease, who often are excluded in study protocols. Only a few studies have assessed the safety and efficacy of anticoagulants for VTE prophylaxis in patients with chronic liver disease, and consequently the CHEST guidelines offer limited recommendations for this population.2-4 Given the paucity of data, some providers may feel uncomfortable or uncertain about prescribing pharmacologic
JAAPA Journal of the American Academy of Physician Assistants
Copyright © 2015 American Academy of Physician Assistants
www.JAAPA.com
27
PHARMACOLOGY CONSULT
TABLE 1. Effect
of chronic liver disease on hemostatic factors
Factor
Physiologic role
Effect of chronic liver disease on factor
Patients with chronic liver disease are at increased risk of
Clotting factors (II, VII, IX, X)
Antihemostasis (assists with clot formation to regain hemostasis after vascular insult/injury)
Decreased synthesis
Bleeding
Platelets
Antihemostasis
Decreased production due to decreased synthesis of thrombopoietin and splenic sequestration
Bleeding
von Willebrand factor
Antihemostasis
Increased synthesis in endothelial cells
Clotting
Proteins C and S
Prohemostasis (prevents excessive clot formation)
Decreased synthesis
Clotting
Antithrombin
Prohemostasis
Decreased synthesis
Clotting
Reversal of ECG changes
Anticoagulant factors
VTE prophylaxis for hospitalized patients with chronic liver disease and may rely on inferior methods of VTE prophylaxis, including SCDs.5 Providers may be concerned about patients’ perceived increased risk of bleeding with the use of anticoagulants, or believe that the drugs’ action may be attenuated because of patients’ reduced antithrombin levels (UFH and low-molecular-weight heparin are antithrombin-dependent).1 Further studies are necessary to definitively determine if patients with chronic liver disease are at increased bleeding risk from VTE prophylaxis and to determine if antithrombin-dependent anticoagulants are effective for VTE prophylaxis in these patients. Target-specific oral anticoagulants such as dabigatran, apixaban, and rivaroxaban do not require antithrombin to exert their anticoagulant effect. These drugs have recently gained approval for the treatment and prevention of VTE, and information about their usefulness in patients with chronic liver disease may become available as their use in everyday practice increases. A 2013 study is the largest study identified to date that documents the safety and efficacy of VTE prophylaxis in patients with chronic liver disease.4 The study was a singlecenter retrospective cohort analysis that included 1,581 hospitalized adult patients with chronic liver disease. The study compared pharmacologic VTE prophylaxis at usual doses (UFH 5,000 units subcutaneously every 8 to 12 hours, enoxaparin 30 to 40 mg subcutaneously every 24 hours) with no VTE prophylaxis. The researchers found that patients who received pharmacologic VTE prophylaxis had a reduced incidence of hospital-acquired VTE (0.5%) compared with those who did not receive prophylaxis (1.8%, P=0.50). Furthermore, use of pharmacologic VTE prophylaxis was protective against VTE (odds ratio, 0.34; 95% confidence interval [CI] 0.04-0.88). A subgroup analysis based on bleeding history found that patients without a history of bleeding 28
who received pharmacologic VTE prophylaxis showed the greatest benefit of use, having a lower incidence of VTE (0.3% versus 1.5%, P=0.043) with no increased risk of bleeding (0.3 versus 1.1%, P=0.129) when compared with patients who did not receive prophylaxis. Finally, multivariate regression identified three risk factors for VTE in patients with chronic liver disease: active malignancy (odds ratio, 8.76; 95% CI 2.56-29.58), trauma or surgery during hospitalization (odds ratio, 10.29; 95% CI 1.18-89.51), and history of VTE (odds ratio, 26.48; 95% CI 6.93-101.16). The strengths of this study include its large sample size and minimal exclusion criteria. Limitations of the study include retrospective study design, inability to assess use of mechanical VTE prophylaxis, and differences in baseline characteristics (history of bleeding, surgery or trauma, Child-Pugh class, platelet levels, and length of stay). The authors concluded that pharmacologic VTE prophylaxis reduces the incidence of hospital-acquired VTE in patients with chronic liver disease without increasing the rate of bleeding.4 BLEEDING ISSUES The use of pharmacologic VTE prophylaxis is concerning in any patient with thrombocytopenia, and patients with chronic liver disease are no exception. A multinational observational study followed 10,866 hospitalized medical patients and determined major risk factors for bleeding. The three risk factors with odds ratios greater than 3 were active gastroduodenal ulcer, bleeding in the last 3 months, and platelet count less than 50×109/L.6 Stemming from this study, platelet count less than 50×109/L has been used as the cutoff to reconsider use of anticoagulation per American College of Chest Physicians guidelines.2,3 Patients with thrombocytopenia are generally considered to be at increased risk for bleeding; however, in vitro studies have shown that patients with cirrhosis have increased von
www.JAAPA.com
Volume 28 • Number 6 • June 2015
Copyright © 2015 American Academy of Physician Assistants
PHARMACOLOGY CONSULT
Willebrand factor, which may compensate for having fewer platelets.7 In a review of several studies of thrombocytopenia in patients with chronic liver disease, negligible bleeding risk was found for invasive procedures (endoscopy, biopsy, dental extractions) for patients with platelet counts greater than 50×109/L, and a nonnegligible bleeding risk was found for patients with platelet counts less than 50×109/L.8 CONCLUSION Pharmacologic VTE prophylaxis should be considered for patients with chronic liver disease and platelet counts greater than 50×109/L. Standard doses of anticoagulants for VTE prophylaxis are recommended, as no studies have been done using alternative dosing strategies. Mechanical prophylaxis should be considered for patients with platelet counts less than 50×109/L.9 Monitor patients on pharmacologic VTE prophylaxis for signs and symptoms of bleeding or clotting, and regularly assess platelet counts and renal function. Additional prospective, multicenter studies are needed to validate the current literature and to explore future directions in this area. Potential research questions include investigating the optimized dosing for VTE prophylaxis in patients with chronic liver disease, defining subgroups at highest risk for VTE or bleeding, and the potential usefulness of targetspecific oral anticoagulants in this population. Risk factors associated with acute inpatient VTE in patients with chronic liver disease are active malignancy, trauma or
30
surgery during hospitalization, and history of VTE. Patients without a history of bleeding appear to be most likely to benefit; use caution in patients with a history of bleeding. JAAPA REFERENCES 1. Tripodi A, Mannucci PM. The coagulopathy of chronic liver disease. N Engl J Med. 2011;365(2):147-156. 2. Dabbagh O, Oza A, Prakash S, et al. Coagulopathy does not protect against venous thromboembolism in hospitalized patients with chronic liver disease. Chest. 2010;137(5):1145-1149. 3. Kahn SR, Lim W, Dunn AS, et al. Prevention of VTE in nonsurgical patients: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012;141(2 suppl):e195S-e226S. 4. Barclay SM, Jeffres MN, Nguyen K, Nguyen T. Evaluation of pharmacologic prophylaxis for venous thromboembolism in patients with chronic liver disease. Pharmacotherapy. 2013;33(4):375-382. 5. Walsh KA, Lewis DA, Clifford TM, et al. Risk factors for venous thromboembolism in patients with chronic liver disease. Ann Pharmacother. 2013;47(3):333-339. 6. Decousus H, Tapson VF, Bergmann JF, et al. Factors at admission associated with bleeding risk in medical patients: findings from the IMPROVE investigators. Chest. 2011;139(1):69-79. 7. Lisman T, Bongers TN, Adelmeijer J, et al. Elevated levels of von Willebrand factor in cirrhosis support platelet adhesion despite reduced functional capacity. Hepatology. 2006;44(1):53-61. 8. Afdhal N, McHutchison J, Brown R, et al. Thrombocytopenia associated with chronic liver disease. J Hepatol. 2008;48(6):1000-1007. 9. Tufano A, Guida A, Di Minno MN, et al. Prevention of venous thromboembolism in medical patients with thrombocytopenia or with platelet dysfunction: a review of the literature. Semin Thromb Hemost. 2011;37(3):267-274.
www.JAAPA.com
Volume 28 • Number 6 • June 2015
Copyright © 2015 American Academy of Physician Assistants
