Research Article
Chemoprophylaxis Use and Risk of Venous Thromboembolism and Death in Adult Patients following Orthotopic Liver Transplantation
Journal of Pharmacy Practice 1-6 ª The Author(s) 2015 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0897190014566304 jpp.sagepub.com
Brianna R. Alexander, PharmD, BCPS1, Abigail D. Antigua, PharmD2, Amy F. Rosenberg, PharmD, BCPS2, Lawrence J. Caruso, MD3, Stacy A. Voils, PharmD, MS, BCPS4, and Aime´e C. LeClaire, PharmD, BCPS5
Abstract Background: Coagulation abnormalities in end-stage liver disease may preclude patients from receiving venous thromboembolism (VTE) prophylaxis immediately following orthotopic liver transplantation. Methods: To identify risk factors for VTE and death following liver transplantation, a retrospective chart review was conducted in adult liver transplant recipients from January 1, 2001, to October 1, 2011. Results: In 716 transplantations in 701 patients, the overall incidence of VTE was 2.1%. The incidence was 3.6% in patients who received chemoprophylaxis compared to 1.4% in those without chemoprophylaxis (P ¼ .06). Most patients (69.5%) did not receive chemoprophylaxis postsurgery during their hospitalization. Multivariate logistic regression modeling revealed no association between the use of chemoprophylaxis (adjusted odds ratio [OR] 1.5 [0.45-4.7], P ¼ .53) and VTE. A significant positive association was observed between the use of chemoprophylaxis (adjusted OR 3.2 [1.3-8.0], P ¼ .01) and death. Conclusion: Use of chemoprophylaxis and increasing amounts of blood products following orthotopic liver transplant was associated with increased mortality. A significant positive association was observed between blood product administration and VTE, while chemoprophylaxis use was not significantly associated with VTE. Larger prospective studies are necessary to further examine the significance of this finding. Keywords anticoagulation, enoxaparin, unfractionated heparin, liver transplantation, venous thromboembolism
Introduction Coagulation abnormalities in end-stage liver disease often preclude patients from receiving venous thromboembolism (VTE) prophylaxis following orthotopic liver transplantation (OLT). Liver disease historically has been described as the ‘‘epitome of bleeding disorders’’ because of hemostasis alterations such as a decrease in procoagulant factors, reduced platelet production, and an increase in tissue plasminogen activator.1 These deficiencies often manifest as prolonged clotting time and an increased international normalized ratio (INR) which add to the perception of an increased risk of bleeding and ‘‘autoanticoagulation.’’1,2 However, research in patients with liver disease suggests that prothrombotic defects also occur, such as decreased production of proteins C and S and increased von Willebrand factor and factor VIII.1,3 The prothrombotic and antithrombotic effects occurring simultaneously restore the balance of the coagulation system, but patients with liver disease may have reduced capacity to respond to stress therefore causing an imbalance.2
Major surgery, such as liver transplantation, is a well-known risk factor for thrombosis. In addition to the thrombotic risk factors that are present because of liver disease, postoperative patients are also at risk from prolonged immobilization, anesthesia, and use of central venous catheters.4 Liver transplantation specifically increases the risk of clotting because 1
Department of Pharmacy, Duke University Hospital, Durham, NC, USA Department of Pharmacy, University of Florida Health Shands Hospital, Gainesville, FL, USA 3 Department of Anesthesiology, Division of Critical Care Medicine, University of Florida, Gainesville, FL, USA 4 Department of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, Gainesville, FL, USA 5 Department of Pharmacy, University of Florida Health Shands Hospital, Gainesville, FL, USA 2
Corresponding Author: Brianna R. Alexander, Department of Pharmacy, Duke University Hospital, Duke University Medical Center, 3089, Durham, NC 27710, USA. Email: [email protected]
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of possible migration of thrombi formed around the pulmonary artery catheter, central venous catheter, or at the site of a transjugular intrahepatic portosystemic shunt.5,6 Other mechanisms are the use of hemostatic agents and the use of venovenous bypass that entails the use of a catheter that may directly injure the vein.5,6 Therefore, VTE prophylaxis may be warranted but is not always given posttransplant due to conflicting concerns.3 Literature describing VTE risk postliver transplant is limited. One study reported a VTE rate of 3.7% in patients only receiving mechanical prophylaxis; the rate of deep vein thrombosis (DVT) specifically was 2.7% and 1% for pulmonary embolism (PE).6 A PE rate of 0.37% has been reported in liver transplant patients receiving unfractionated heparin prophylaxis.7 The Antithrombotic and Thrombolytic Therapy: American College of Chest Physicians Evidenced Based Clinical Practice Guidelines do not provide specific recommendations for VTE prevention after liver transplantation. The recommendation for abdominal surgery is to use chemoprophylaxis in patients at moderate to high risk of VTE.8 Due to the lack of evidence recommending prophylaxis postliver transplantation, many patients at our institution do not receive chemoprophylaxis and may be at risk of clotting. The aims of this study are (1) to determine the incidence of VTE in patients with OLT who received VTE prophylaxis versus those who did not and (2) to identify risk factors for VTE and death following OLT.
Methods A retrospective chart review was conducted in adult patients admitted to our institution between January 1, 2001, and October 1, 2011, who underwent a liver transplantation. Shands at the University of Florida (UF) is an 852-bed academic medical center with a liver transplant program established in 1985. UF Health Shands Hospital receives many liver transplant patient referrals from smaller community hospitals around the state with varying degrees of severity and disease processes. This study was approved by the Institutional Review Board and performed in accordance with Helsinki Declaration of 1975. Patients were identified using the International Classification of Diseases, Ninth Revision (ICD-9) codes, 50.51 and 50.59, for liver transplantation. Data were included from the transplantation admission only and patients less than 18 years old were excluded. Patients with a second encounter for a retransplantation were included twice as separate hospitalizations. Intraabdominal clots were excluded from the overall event rate because these clots were seen as primarily a complication of surgery. The primary outcome was an in-hospital VTE event defined as any DVT, upper or lower extremity, or PE. The diagnosis of DVT was made using a Doppler ultrasound, and for PE, the diagnosis was made using a chest computed tomography (CT) scan. Patients with a VTE were identified retrospectively with the use of previously validated ICD-9 codes (415.1X, 451.1X, 451.2, 451.8X, 451.9, 453.4X, 453.8, 453.9).9 Liver transplant patients identified as having an event using these codes then underwent chart review to confirm radiographic
presence of the VTE. Secondary outcomes were time to posttransplant VTE, chemoprophylaxis use, time to chemoprophylaxis initiation posttransplant, blood product use after transplantation, and in-hospital mortality. Patients were included in the chemoprophylaxis group if they had at least one dose ordered. An estimation of missed days was made for the patients with events using missing medication charges. Blood products included were fresh frozen plasma and packed red blood cells given after postoperative day 2. Patients with VTE who subsequently received treatment dosing of unfractionated heparin or enoxaparin for an event were not included in the analysis of blood product use. Weight, height, and laboratory values were collected when readily available in the medical record. Normally distributed data are presented as mean with standard deviation (SD) and nonnormally distributed data are presented as median with interquartile range (IQR). Baseline characteristics were compared in patients who received pharmacologic VTE prophylaxis and those who did not using chisquare test of homogeneity or Fisher’s exact test for binary variables and Student’s t test for continuous variables. Association of the following covariates with VTE and mortality was assessed in univariate analyses: administration of pharmacologic VTE prophylaxis, race, sex, age, length of stay (LOS), and units of blood products received. In addition to these variables, Model for End-Stage Liver Disease (MELD) score was assessed in a univariate analysis of mortality. Variables with P < .20 in the univariate analyses were included in multivariate logistic regression models. All statistical analyses were performed using SAS 9.3 (SAS Institute, Cary, North Carolina).
Results There were 722 transplants performed in 707 patients during the specified time frame (Figure 1). Fifteen patients underwent transplantation twice during a separate hospitalization. Twenty-one patients were identified as having at least 1 VTE event. However, 6 of those patients were excluded from the analysis (Figure 1). Patient demographics and baseline characteristics are presented in Table 1. The 2 groups were similar except patients in the chemoprophylaxis group were older, had longer hospital length of stay, and had higher MELD scores. The overall VTE incidence was 2.1%. Eight VTE events occurred in the chemoprophylaxis group for an incidence of 3.6% compared to 7 events in the nonchemoprophylaxis group for an incidence of 1.4% (P ¼ .06; Table 2). Of the 12 patients with a DVT in either group, 7 were upper extremity and 5 were lower extremity. One patient in the chemoprophylaxis group had both a DVT and a PE during the same hospitalization. The median time the event occurred posttransplant was 18.5 days (IQR 11.8-35) in the chemoprophylaxis group and 6 days (IQR 6-15.5) in the nonchemoprophylaxis group (P ¼ .05). Most patients (69.5%) did not receive chemoprophylaxis during their hospitalization. Of those who received
Downloaded from jpp.sagepub.com at UNIV OF LETHBRIDGE on November 14, 2015
Alexander et al
3
6 Paents Excluded
722 Paents
1 paent’s chart not available 2 paents had missing documentaon 1 paent’s event was presurgical 2 paents had intraabdominal clots 716 Paentsa
220 paents
496 paents
Figure 1. Study group selection. a716 transplantations occurred in 701 patients; 15 patients underwent transplantation a second time in a different hospitalization with each transplant included in the study as a separate patient encounter.
chemoprophylaxis, the median time to initiation was 3 days (IQR 2-9) posttransplant. Patients who had an event missed a median of 17 (IQR 11-28.25) days of prophylactic anticoagulation once started. The mean INR on the day that prophylaxis was initiated was 1.4 þ 0.4 and the median platelet count was 69 (IQR 53-104). Patients in the chemoprophylaxis group received significantly more fresh frozen plasma and packed red blood cells compared to those without chemoprophylaxis (Table 2). The mortality rate was 11.8% and 3.0% in patients with chemoprophylaxis and no chemoprophylaxis, respectively (P < .001). One patient who had a PE died within 24 hours of their event. This patient did not receive chemoprophylaxis. In the multivariate logistic regression analyses, blood product administration was significantly associated with VTE and death (c ¼ 0.76; Table 3). In addition, patients who received chemoprophylaxis were significantly more likely to die when compared to those who did not receive prophylaxis (c ¼ 0.82). The characteristics of patients who experienced a VTE are listed in Tables 4 and 5. The mean age and weight were 59.3 years and 90.2 kg in the patients with VTE who received chemoprophylaxis and 49.6 years and 74.7 kg in patients with VTE who did not receive chemoprophylaxis. The median time that chemoprophylaxis was initiated in patients with VTE was 8.5 days. The patients who experienced an event carried other risk factors for thrombosis; 53.3% were previous smokers and 13.3% had a history of cancer.
Discussion This study represents one of the largest studies to date characterizing risk factors for VTE and death in patients undergoing OLT, with particular focus on the effect of administration of pharmacologic VTE prophylaxis. Salami et al reported a
symptomatic VTE rate of 4.6% when compared to 2.1% in this study.10 However, VTE events were recorded up to 1 year after transplant in contrast to our study which included VTE events that occurred during the index hospitalization so that we were able to characterize the contribution of administration of VTE prophylaxis medications on the outcome. There are no guidelines regarding pharmacologic VTE prophylaxis in patients in the immediate period after liver transplantation. The only risk factor for VTE identified in our study was blood product administration, likely reflecting overall severity of illness. However, blood product administration has been associated with an increased risk of VTE in other populations, possibly due to an increase in blood viscosity.11,12 Other risk factors for VTE in OLT have been reported such as a history of end-stage renal disease, diabetes, alcoholism, and a history of previous VTE.10 Surprisingly, the odds of death was over 3 times higher in patients with administration of pharmacologic VTE prophylaxis, even after controlling for other risk factors including MELD score. A detrimental effect of administration of pharmacologic VTE prophylaxis cannot be ruled out as noted by the increased number of blood products administered in the prophylaxis group. As other authors suggest, laboratory tests such as thromboelastography (TEG) may assist in recognizing hypercoagulability and identifying those at risk of VTE.10 Blood product administration also increased the odds of death which has been observed in numerous studies.13-15 Literature describing risk of VTE in patients with liver disease varies. Northup and colleagues performed a case–control study in a tertiary care hospital including 113 hospitalized patients with cirrhosis and reported the incidence of VTE to be approximately 0.5%.16 Aldawood and colleagues performed a similar study in hospitalized patients with cirrhosis and found incidence of VTE to be 2.7%.17 A case–control study found the incidence of VTE in patients with cirrhosis to be 1.8% compared to the matched controls with an incidence of 0.9%.18 An additional study reported the incidence of VTE in patients with cirrhosis to be 6.3%.19 The reported rates of chemoprophylaxis were 7% and 12% in 2 of the studies mentioned earlier.16,17 The rate of prophylaxis use in our study was reported to be higher at 30.5%. These studies show a risk is apparent in the population with liver disease and still may be present immediately posttransplant, especially with the additional risk factors that the surgery or hospitalization may contribute. This is supported by Ishitani et al reporting a VTE incidence of 3.7% postliver transplantation.6 There are some limitations to this study including its retrospective design and identification of patients with a VTE using diagnosis codes. If patients were coded improperly, an event could have been missed. Events may have also been missed if they occurred after the transplant hospitalization. This study also assumed that all subjects are independent, regardless of VTE event or transplantation. This may have underestimated the proportion of thrombotic events, especially on patient transplanted twice. However, the number of retransplanted patients was small (n ¼ 15) and likely irrelevant. Medication doses and
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Table 1. Baseline Characteristics of Liver Transplant Recipients. Characteristics Age (mean þ SD), years LOS, median (IQR), days Male, n (%) Caucasian, n (%) Baseline INR (mean þ SD) Baseline platelet count, median (IQR) MELD score, median (IQR)
Chemoprophylaxis (n ¼ 220)
No chemoprophylaxis (n ¼ 496)
P
53.1 þ 9.3 24.5 (14-49) 137 (62) 187 (85) 1.8 þ 0.8a 85.5 (55-113.3) 103/mLc 23 (21-27)e
51.2 þ 10.7 11.5 (9-18) 335 (68) 408 (82) 1.7 þ 0.6b 88.5 (71-124.3) 103/mLd 22 (20-25)f
.02
Chemoprophylaxis Use and Risk of Venous Thromboembolism and Death in Adult Patients following Orthotopic Liver Transplantation
Journal of Pharmacy Practice 1-6 ª The Author(s) 2015 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0897190014566304 jpp.sagepub.com
Brianna R. Alexander, PharmD, BCPS1, Abigail D. Antigua, PharmD2, Amy F. Rosenberg, PharmD, BCPS2, Lawrence J. Caruso, MD3, Stacy A. Voils, PharmD, MS, BCPS4, and Aime´e C. LeClaire, PharmD, BCPS5
Abstract Background: Coagulation abnormalities in end-stage liver disease may preclude patients from receiving venous thromboembolism (VTE) prophylaxis immediately following orthotopic liver transplantation. Methods: To identify risk factors for VTE and death following liver transplantation, a retrospective chart review was conducted in adult liver transplant recipients from January 1, 2001, to October 1, 2011. Results: In 716 transplantations in 701 patients, the overall incidence of VTE was 2.1%. The incidence was 3.6% in patients who received chemoprophylaxis compared to 1.4% in those without chemoprophylaxis (P ¼ .06). Most patients (69.5%) did not receive chemoprophylaxis postsurgery during their hospitalization. Multivariate logistic regression modeling revealed no association between the use of chemoprophylaxis (adjusted odds ratio [OR] 1.5 [0.45-4.7], P ¼ .53) and VTE. A significant positive association was observed between the use of chemoprophylaxis (adjusted OR 3.2 [1.3-8.0], P ¼ .01) and death. Conclusion: Use of chemoprophylaxis and increasing amounts of blood products following orthotopic liver transplant was associated with increased mortality. A significant positive association was observed between blood product administration and VTE, while chemoprophylaxis use was not significantly associated with VTE. Larger prospective studies are necessary to further examine the significance of this finding. Keywords anticoagulation, enoxaparin, unfractionated heparin, liver transplantation, venous thromboembolism
Introduction Coagulation abnormalities in end-stage liver disease often preclude patients from receiving venous thromboembolism (VTE) prophylaxis following orthotopic liver transplantation (OLT). Liver disease historically has been described as the ‘‘epitome of bleeding disorders’’ because of hemostasis alterations such as a decrease in procoagulant factors, reduced platelet production, and an increase in tissue plasminogen activator.1 These deficiencies often manifest as prolonged clotting time and an increased international normalized ratio (INR) which add to the perception of an increased risk of bleeding and ‘‘autoanticoagulation.’’1,2 However, research in patients with liver disease suggests that prothrombotic defects also occur, such as decreased production of proteins C and S and increased von Willebrand factor and factor VIII.1,3 The prothrombotic and antithrombotic effects occurring simultaneously restore the balance of the coagulation system, but patients with liver disease may have reduced capacity to respond to stress therefore causing an imbalance.2
Major surgery, such as liver transplantation, is a well-known risk factor for thrombosis. In addition to the thrombotic risk factors that are present because of liver disease, postoperative patients are also at risk from prolonged immobilization, anesthesia, and use of central venous catheters.4 Liver transplantation specifically increases the risk of clotting because 1
Department of Pharmacy, Duke University Hospital, Durham, NC, USA Department of Pharmacy, University of Florida Health Shands Hospital, Gainesville, FL, USA 3 Department of Anesthesiology, Division of Critical Care Medicine, University of Florida, Gainesville, FL, USA 4 Department of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, Gainesville, FL, USA 5 Department of Pharmacy, University of Florida Health Shands Hospital, Gainesville, FL, USA 2
Corresponding Author: Brianna R. Alexander, Department of Pharmacy, Duke University Hospital, Duke University Medical Center, 3089, Durham, NC 27710, USA. Email: [email protected]
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of possible migration of thrombi formed around the pulmonary artery catheter, central venous catheter, or at the site of a transjugular intrahepatic portosystemic shunt.5,6 Other mechanisms are the use of hemostatic agents and the use of venovenous bypass that entails the use of a catheter that may directly injure the vein.5,6 Therefore, VTE prophylaxis may be warranted but is not always given posttransplant due to conflicting concerns.3 Literature describing VTE risk postliver transplant is limited. One study reported a VTE rate of 3.7% in patients only receiving mechanical prophylaxis; the rate of deep vein thrombosis (DVT) specifically was 2.7% and 1% for pulmonary embolism (PE).6 A PE rate of 0.37% has been reported in liver transplant patients receiving unfractionated heparin prophylaxis.7 The Antithrombotic and Thrombolytic Therapy: American College of Chest Physicians Evidenced Based Clinical Practice Guidelines do not provide specific recommendations for VTE prevention after liver transplantation. The recommendation for abdominal surgery is to use chemoprophylaxis in patients at moderate to high risk of VTE.8 Due to the lack of evidence recommending prophylaxis postliver transplantation, many patients at our institution do not receive chemoprophylaxis and may be at risk of clotting. The aims of this study are (1) to determine the incidence of VTE in patients with OLT who received VTE prophylaxis versus those who did not and (2) to identify risk factors for VTE and death following OLT.
Methods A retrospective chart review was conducted in adult patients admitted to our institution between January 1, 2001, and October 1, 2011, who underwent a liver transplantation. Shands at the University of Florida (UF) is an 852-bed academic medical center with a liver transplant program established in 1985. UF Health Shands Hospital receives many liver transplant patient referrals from smaller community hospitals around the state with varying degrees of severity and disease processes. This study was approved by the Institutional Review Board and performed in accordance with Helsinki Declaration of 1975. Patients were identified using the International Classification of Diseases, Ninth Revision (ICD-9) codes, 50.51 and 50.59, for liver transplantation. Data were included from the transplantation admission only and patients less than 18 years old were excluded. Patients with a second encounter for a retransplantation were included twice as separate hospitalizations. Intraabdominal clots were excluded from the overall event rate because these clots were seen as primarily a complication of surgery. The primary outcome was an in-hospital VTE event defined as any DVT, upper or lower extremity, or PE. The diagnosis of DVT was made using a Doppler ultrasound, and for PE, the diagnosis was made using a chest computed tomography (CT) scan. Patients with a VTE were identified retrospectively with the use of previously validated ICD-9 codes (415.1X, 451.1X, 451.2, 451.8X, 451.9, 453.4X, 453.8, 453.9).9 Liver transplant patients identified as having an event using these codes then underwent chart review to confirm radiographic
presence of the VTE. Secondary outcomes were time to posttransplant VTE, chemoprophylaxis use, time to chemoprophylaxis initiation posttransplant, blood product use after transplantation, and in-hospital mortality. Patients were included in the chemoprophylaxis group if they had at least one dose ordered. An estimation of missed days was made for the patients with events using missing medication charges. Blood products included were fresh frozen plasma and packed red blood cells given after postoperative day 2. Patients with VTE who subsequently received treatment dosing of unfractionated heparin or enoxaparin for an event were not included in the analysis of blood product use. Weight, height, and laboratory values were collected when readily available in the medical record. Normally distributed data are presented as mean with standard deviation (SD) and nonnormally distributed data are presented as median with interquartile range (IQR). Baseline characteristics were compared in patients who received pharmacologic VTE prophylaxis and those who did not using chisquare test of homogeneity or Fisher’s exact test for binary variables and Student’s t test for continuous variables. Association of the following covariates with VTE and mortality was assessed in univariate analyses: administration of pharmacologic VTE prophylaxis, race, sex, age, length of stay (LOS), and units of blood products received. In addition to these variables, Model for End-Stage Liver Disease (MELD) score was assessed in a univariate analysis of mortality. Variables with P < .20 in the univariate analyses were included in multivariate logistic regression models. All statistical analyses were performed using SAS 9.3 (SAS Institute, Cary, North Carolina).
Results There were 722 transplants performed in 707 patients during the specified time frame (Figure 1). Fifteen patients underwent transplantation twice during a separate hospitalization. Twenty-one patients were identified as having at least 1 VTE event. However, 6 of those patients were excluded from the analysis (Figure 1). Patient demographics and baseline characteristics are presented in Table 1. The 2 groups were similar except patients in the chemoprophylaxis group were older, had longer hospital length of stay, and had higher MELD scores. The overall VTE incidence was 2.1%. Eight VTE events occurred in the chemoprophylaxis group for an incidence of 3.6% compared to 7 events in the nonchemoprophylaxis group for an incidence of 1.4% (P ¼ .06; Table 2). Of the 12 patients with a DVT in either group, 7 were upper extremity and 5 were lower extremity. One patient in the chemoprophylaxis group had both a DVT and a PE during the same hospitalization. The median time the event occurred posttransplant was 18.5 days (IQR 11.8-35) in the chemoprophylaxis group and 6 days (IQR 6-15.5) in the nonchemoprophylaxis group (P ¼ .05). Most patients (69.5%) did not receive chemoprophylaxis during their hospitalization. Of those who received
Downloaded from jpp.sagepub.com at UNIV OF LETHBRIDGE on November 14, 2015
Alexander et al
3
6 Paents Excluded
722 Paents
1 paent’s chart not available 2 paents had missing documentaon 1 paent’s event was presurgical 2 paents had intraabdominal clots 716 Paentsa
220 paents
496 paents
Figure 1. Study group selection. a716 transplantations occurred in 701 patients; 15 patients underwent transplantation a second time in a different hospitalization with each transplant included in the study as a separate patient encounter.
chemoprophylaxis, the median time to initiation was 3 days (IQR 2-9) posttransplant. Patients who had an event missed a median of 17 (IQR 11-28.25) days of prophylactic anticoagulation once started. The mean INR on the day that prophylaxis was initiated was 1.4 þ 0.4 and the median platelet count was 69 (IQR 53-104). Patients in the chemoprophylaxis group received significantly more fresh frozen plasma and packed red blood cells compared to those without chemoprophylaxis (Table 2). The mortality rate was 11.8% and 3.0% in patients with chemoprophylaxis and no chemoprophylaxis, respectively (P < .001). One patient who had a PE died within 24 hours of their event. This patient did not receive chemoprophylaxis. In the multivariate logistic regression analyses, blood product administration was significantly associated with VTE and death (c ¼ 0.76; Table 3). In addition, patients who received chemoprophylaxis were significantly more likely to die when compared to those who did not receive prophylaxis (c ¼ 0.82). The characteristics of patients who experienced a VTE are listed in Tables 4 and 5. The mean age and weight were 59.3 years and 90.2 kg in the patients with VTE who received chemoprophylaxis and 49.6 years and 74.7 kg in patients with VTE who did not receive chemoprophylaxis. The median time that chemoprophylaxis was initiated in patients with VTE was 8.5 days. The patients who experienced an event carried other risk factors for thrombosis; 53.3% were previous smokers and 13.3% had a history of cancer.
Discussion This study represents one of the largest studies to date characterizing risk factors for VTE and death in patients undergoing OLT, with particular focus on the effect of administration of pharmacologic VTE prophylaxis. Salami et al reported a
symptomatic VTE rate of 4.6% when compared to 2.1% in this study.10 However, VTE events were recorded up to 1 year after transplant in contrast to our study which included VTE events that occurred during the index hospitalization so that we were able to characterize the contribution of administration of VTE prophylaxis medications on the outcome. There are no guidelines regarding pharmacologic VTE prophylaxis in patients in the immediate period after liver transplantation. The only risk factor for VTE identified in our study was blood product administration, likely reflecting overall severity of illness. However, blood product administration has been associated with an increased risk of VTE in other populations, possibly due to an increase in blood viscosity.11,12 Other risk factors for VTE in OLT have been reported such as a history of end-stage renal disease, diabetes, alcoholism, and a history of previous VTE.10 Surprisingly, the odds of death was over 3 times higher in patients with administration of pharmacologic VTE prophylaxis, even after controlling for other risk factors including MELD score. A detrimental effect of administration of pharmacologic VTE prophylaxis cannot be ruled out as noted by the increased number of blood products administered in the prophylaxis group. As other authors suggest, laboratory tests such as thromboelastography (TEG) may assist in recognizing hypercoagulability and identifying those at risk of VTE.10 Blood product administration also increased the odds of death which has been observed in numerous studies.13-15 Literature describing risk of VTE in patients with liver disease varies. Northup and colleagues performed a case–control study in a tertiary care hospital including 113 hospitalized patients with cirrhosis and reported the incidence of VTE to be approximately 0.5%.16 Aldawood and colleagues performed a similar study in hospitalized patients with cirrhosis and found incidence of VTE to be 2.7%.17 A case–control study found the incidence of VTE in patients with cirrhosis to be 1.8% compared to the matched controls with an incidence of 0.9%.18 An additional study reported the incidence of VTE in patients with cirrhosis to be 6.3%.19 The reported rates of chemoprophylaxis were 7% and 12% in 2 of the studies mentioned earlier.16,17 The rate of prophylaxis use in our study was reported to be higher at 30.5%. These studies show a risk is apparent in the population with liver disease and still may be present immediately posttransplant, especially with the additional risk factors that the surgery or hospitalization may contribute. This is supported by Ishitani et al reporting a VTE incidence of 3.7% postliver transplantation.6 There are some limitations to this study including its retrospective design and identification of patients with a VTE using diagnosis codes. If patients were coded improperly, an event could have been missed. Events may have also been missed if they occurred after the transplant hospitalization. This study also assumed that all subjects are independent, regardless of VTE event or transplantation. This may have underestimated the proportion of thrombotic events, especially on patient transplanted twice. However, the number of retransplanted patients was small (n ¼ 15) and likely irrelevant. Medication doses and
Downloaded from jpp.sagepub.com at UNIV OF LETHBRIDGE on November 14, 2015
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Table 1. Baseline Characteristics of Liver Transplant Recipients. Characteristics Age (mean þ SD), years LOS, median (IQR), days Male, n (%) Caucasian, n (%) Baseline INR (mean þ SD) Baseline platelet count, median (IQR) MELD score, median (IQR)
Chemoprophylaxis (n ¼ 220)
No chemoprophylaxis (n ¼ 496)
P
53.1 þ 9.3 24.5 (14-49) 137 (62) 187 (85) 1.8 þ 0.8a 85.5 (55-113.3) 103/mLc 23 (21-27)e
51.2 þ 10.7 11.5 (9-18) 335 (68) 408 (82) 1.7 þ 0.6b 88.5 (71-124.3) 103/mLd 22 (20-25)f
.02
