CLINICAL OBSERVATIONS IN HEPATOLOGY Treatment of Acute Portal Vein Thrombosis by Nontraditional Anticoagulation Melissa Martinez,1 Anand Tandra,2 and Raj Vuppalanchi1
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atients with cirrhosis are at risk of developing acute portal vein thrombosis (PVT). Anticoagulation for at least 3 months is generally recommended for recanalization to avoid intestinal infarction and worsening of portal hypertension.1 Generally, unfractionated heparin or low molecular weight heparin is initiated with subsequent transition to oral anticoagulation with warfarin.1 Unfortunately, warfarin is limited by a narrow therapeutic window and a highly variable dose-response requiring frequent dose adjustments and monitoring. Rivaroxaban is the first oral anticoagulant agent available within the class of factor Xa inhibitors and is approved for use in prevention or treatment of stroke, deep vein thrombosis, and pulmonary embolism.2 The efficacy of rivaroxaban for treatment of PVT was recently evaluated in a single patient with complete resolution in 4 weeks.3 We report a case of acute PVT extending to the superior mesenteric vein (SMV) in a patient with cirrhosis that required 6 months of therapy with rivaroxaban for complete resolution.
Case Report A 50-year-old white man with extreme obesity, heart failure, hypertension, diabetes mellitus type 2 (Hgb A1C 6.4%), and obstructive sleep apnea presented with acute abdominal pain of 1 day duration. His physical exam showed normal vital signs; his weight and height were 187 kg and 203 cm, respectively (body mass index [BMI] 46.7 kg/m2); he had periumbilical tenderness with no rebound tenderness or Abbreviations: CT, computed tomography; MELD, Model for Endstage Liver Disease; PVT, portal vein thrombosis; SMV, superior mesenteric vein. From the 1Indiana University School of Medicine, Indianapolis, IN; 2Indiana Hemophilia and Thrombosis Center, Indianapolis, IN. Received September 14, 2013; accepted January 3, 2014. Address reprint requests to: Raj Vuppalanchi, M.D., Associate Professor of Medicine, Indiana University School of Medicine, RG 4100, 1050 Wishard Blvd., Indianapolis, IN 46202. E-mail: [email protected]; fax: 317-2781949. C 2014 by the American Association for the Study of Liver Diseases. Copyright V View this article online at wileyonlinelibrary.com. DOI 10.1002/hep.26998 Potential conflict of interest: Nothing to report.
ascites. His blood work was essentially normal (serum creatinine 0.6 mg/dL, international normalized ratio [INR] 1.1) with the exception of thrombocytopenia (platelet count of 66,000/mm3). A computed tomography (CT) of his abdomen showed cirrhotic liver, PVT, MVT, and thickened small bowel loops (Fig. 1A). An upper endoscopy revealed small esophageal varices. A diagnosis of nonalcoholic steatohepatitis related to Child-Pugh Class A cirrhosis (Model for Endstage Liver Disease [MELD] 12) complicated by acute PVT and MVT was made after workup for competing etiology. He was initiated on unfractionated heparin given intravenously with subsequent transition to oral rivaroxaban 20 mg per day. Genetic testing for JAK2 mutations for occult myeloproliferative syndromes was negative. Follow-up CT scan at 4 months (Fig. 1B) showed partial resolution of the clot and rivaroxaban was continued at the same dose. At the 6-month visit, a repeat CT scan showed complete resolution of the clot (Fig. 2A,B). During the follow-up visits, the patient did not report any adverse events including bleeding. Serum creatinine levels were obtained at the time of each imaging study and they were in the normal range. In conclusion, oral rivaroxaban is a very attractive therapeutic option for treatment of acute portal and mesenteric vein thrombosis in patients with compensated cirrhosis with preserved renal function. Predictable pharmacokinetics and pharmacodynamics allow a fixed dose of rivaroxaban without coagulation monitoring.2 It has a half-life of up to 12 hours, its absorption is not affected by food, and one-third of the drug is eliminated by the kidneys, while twothirds undergo metabolism in the liver.2 Specific labeling restrictions for rivaroxaban regarding impaired hepatic function are based on both the Child-Pugh classification and liver-related exclusion criteria applied in pivotal trials.2 It is currently contraindicated in patients with liver disease associated with coagulopathy, cirrhosis Child Class B or C, and clinically relevant bleeding risk.2 When compared to warfarin, rivaroxaban’s acquisition cost is higher, but this may be counterbalanced by costs of monitoring, 425
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Fig. 1. Contrast-enhanced abdominal CT, portal venous phase, axial images showing nonenhancing filling defect within the lumen of the portal vein. No evidence of ascites. (A) CT image showing PVT at the time of presentation with abdominal pain. (B) CT image after 4 months of therapy with rivaroxaban showing partial resolution of portal vein thrombus.
Fig. 2. CT, portal venous phase, axial images showing complete resolution of PVT after 6 months of rivaroxaban therapy.
patient’s inconvenience, and healthcare provider’s time required for managing test results.2 In fact, a recent study showed that rivaroxaban is more costeffective than warfarin for prevention of recurrent venous thromboembolism.4 Although major and clinically relevant nonmajor bleeding rates were similar between warfarin and rivaroxaban, the rates of intracranial bleeding were significantly lower in the rivaroxaban group, but significantly higher with regard to gastrointestinal bleed.5 Current concerns about the lack of an antidote for rivaroxaban may be alleviated when a promising agent such as Andexanet Alfa (Clinicaltrials.gov: NCT01758432) gains regulatory approval. Premature discontinuation of rivaroxaban, like any anticoagulant, can increase the risk of
thrombotic events and therefore documentation of complete clot resolution is essential.2
References 1. DeLeve LD, Valla DC, Garcia-Tsao G. Vascular disorders of the liver. HEPATOLOGY 2009;49:1729-1764. 2. Smythe MA, Fanikos J, Gulseth MP, Wittkowsky AK, Spilner SA, Dager WE, et al. Rivaroxaban: practical considerations for ensuring safety and efficacy. Pharmacotherapy 2013 [Epub ahead of print]. 3. Pannach S, Babatz J, Beyer-Westendorf J. Successful treatment of acute portal vein thrombosis with rivaroxaban. Thromb Haemost 2013;110. 4. Seaman CD, Smith KJ, Ragni MV. Cost-effectiveness of rivaroxaban versus warfarin anticoagulation for the prevention of recurrent venous thromboembolism: a U.S. perspective. Thromb Res 2013;132:647-651. 5. Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365:883-891.
P
atients with cirrhosis are at risk of developing acute portal vein thrombosis (PVT). Anticoagulation for at least 3 months is generally recommended for recanalization to avoid intestinal infarction and worsening of portal hypertension.1 Generally, unfractionated heparin or low molecular weight heparin is initiated with subsequent transition to oral anticoagulation with warfarin.1 Unfortunately, warfarin is limited by a narrow therapeutic window and a highly variable dose-response requiring frequent dose adjustments and monitoring. Rivaroxaban is the first oral anticoagulant agent available within the class of factor Xa inhibitors and is approved for use in prevention or treatment of stroke, deep vein thrombosis, and pulmonary embolism.2 The efficacy of rivaroxaban for treatment of PVT was recently evaluated in a single patient with complete resolution in 4 weeks.3 We report a case of acute PVT extending to the superior mesenteric vein (SMV) in a patient with cirrhosis that required 6 months of therapy with rivaroxaban for complete resolution.
Case Report A 50-year-old white man with extreme obesity, heart failure, hypertension, diabetes mellitus type 2 (Hgb A1C 6.4%), and obstructive sleep apnea presented with acute abdominal pain of 1 day duration. His physical exam showed normal vital signs; his weight and height were 187 kg and 203 cm, respectively (body mass index [BMI] 46.7 kg/m2); he had periumbilical tenderness with no rebound tenderness or Abbreviations: CT, computed tomography; MELD, Model for Endstage Liver Disease; PVT, portal vein thrombosis; SMV, superior mesenteric vein. From the 1Indiana University School of Medicine, Indianapolis, IN; 2Indiana Hemophilia and Thrombosis Center, Indianapolis, IN. Received September 14, 2013; accepted January 3, 2014. Address reprint requests to: Raj Vuppalanchi, M.D., Associate Professor of Medicine, Indiana University School of Medicine, RG 4100, 1050 Wishard Blvd., Indianapolis, IN 46202. E-mail: [email protected]; fax: 317-2781949. C 2014 by the American Association for the Study of Liver Diseases. Copyright V View this article online at wileyonlinelibrary.com. DOI 10.1002/hep.26998 Potential conflict of interest: Nothing to report.
ascites. His blood work was essentially normal (serum creatinine 0.6 mg/dL, international normalized ratio [INR] 1.1) with the exception of thrombocytopenia (platelet count of 66,000/mm3). A computed tomography (CT) of his abdomen showed cirrhotic liver, PVT, MVT, and thickened small bowel loops (Fig. 1A). An upper endoscopy revealed small esophageal varices. A diagnosis of nonalcoholic steatohepatitis related to Child-Pugh Class A cirrhosis (Model for Endstage Liver Disease [MELD] 12) complicated by acute PVT and MVT was made after workup for competing etiology. He was initiated on unfractionated heparin given intravenously with subsequent transition to oral rivaroxaban 20 mg per day. Genetic testing for JAK2 mutations for occult myeloproliferative syndromes was negative. Follow-up CT scan at 4 months (Fig. 1B) showed partial resolution of the clot and rivaroxaban was continued at the same dose. At the 6-month visit, a repeat CT scan showed complete resolution of the clot (Fig. 2A,B). During the follow-up visits, the patient did not report any adverse events including bleeding. Serum creatinine levels were obtained at the time of each imaging study and they were in the normal range. In conclusion, oral rivaroxaban is a very attractive therapeutic option for treatment of acute portal and mesenteric vein thrombosis in patients with compensated cirrhosis with preserved renal function. Predictable pharmacokinetics and pharmacodynamics allow a fixed dose of rivaroxaban without coagulation monitoring.2 It has a half-life of up to 12 hours, its absorption is not affected by food, and one-third of the drug is eliminated by the kidneys, while twothirds undergo metabolism in the liver.2 Specific labeling restrictions for rivaroxaban regarding impaired hepatic function are based on both the Child-Pugh classification and liver-related exclusion criteria applied in pivotal trials.2 It is currently contraindicated in patients with liver disease associated with coagulopathy, cirrhosis Child Class B or C, and clinically relevant bleeding risk.2 When compared to warfarin, rivaroxaban’s acquisition cost is higher, but this may be counterbalanced by costs of monitoring, 425
426
MARTINEZ ET AL.
HEPATOLOGY, July 2014
Fig. 1. Contrast-enhanced abdominal CT, portal venous phase, axial images showing nonenhancing filling defect within the lumen of the portal vein. No evidence of ascites. (A) CT image showing PVT at the time of presentation with abdominal pain. (B) CT image after 4 months of therapy with rivaroxaban showing partial resolution of portal vein thrombus.
Fig. 2. CT, portal venous phase, axial images showing complete resolution of PVT after 6 months of rivaroxaban therapy.
patient’s inconvenience, and healthcare provider’s time required for managing test results.2 In fact, a recent study showed that rivaroxaban is more costeffective than warfarin for prevention of recurrent venous thromboembolism.4 Although major and clinically relevant nonmajor bleeding rates were similar between warfarin and rivaroxaban, the rates of intracranial bleeding were significantly lower in the rivaroxaban group, but significantly higher with regard to gastrointestinal bleed.5 Current concerns about the lack of an antidote for rivaroxaban may be alleviated when a promising agent such as Andexanet Alfa (Clinicaltrials.gov: NCT01758432) gains regulatory approval. Premature discontinuation of rivaroxaban, like any anticoagulant, can increase the risk of
thrombotic events and therefore documentation of complete clot resolution is essential.2
References 1. DeLeve LD, Valla DC, Garcia-Tsao G. Vascular disorders of the liver. HEPATOLOGY 2009;49:1729-1764. 2. Smythe MA, Fanikos J, Gulseth MP, Wittkowsky AK, Spilner SA, Dager WE, et al. Rivaroxaban: practical considerations for ensuring safety and efficacy. Pharmacotherapy 2013 [Epub ahead of print]. 3. Pannach S, Babatz J, Beyer-Westendorf J. Successful treatment of acute portal vein thrombosis with rivaroxaban. Thromb Haemost 2013;110. 4. Seaman CD, Smith KJ, Ragni MV. Cost-effectiveness of rivaroxaban versus warfarin anticoagulation for the prevention of recurrent venous thromboembolism: a U.S. perspective. Thromb Res 2013;132:647-651. 5. Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365:883-891.
