ORIGINAL ARTICLE
Venous Thromboembolism Is Associated With Adverse Outcomes in Hospitalized Patients With Acute Pancreatitis A Population-Based Cohort Study Guru Trikudanathan, MD,* Chandraprakash Umapathy, MD,† Satish Munigala, MBBS, MPH,‡ Mahesh Gajendran, MD, MPH,† Darwin L. Conwell, MD,§ Martin L. Freeman, MD,* and Somashekar G. Krishna, MD, MPH§
Objectives: The systemic inflammatory cascade and vascular stasis in hospitalized patients with acute pancreatitis (AP) serve as a milieu for development of venous thromboembolism (VTE). Our aim was to estimate the prevalence and risk factors of VTE in AP and to evaluate its impact on clinical outcomes of AP. Methods: The Nationwide Inpatient Sample (2002–2011) was reviewed to identify all patients hospitalized with AP. Patients with a concomitant diagnosis of VTE were compared with those without. The primary clinical outcome (inpatient mortality) and secondary resources outcomes (length of stay and total hospital charges) were analyzed using univariate and multivariate comparisons. Results: Among 2,382,426 patients with AP, 22,205 (0.93%) had VTE. Multivariate analysis showed patients with greater comorbidity (odds ratio [OR], 1.47), white race (OR, 1.11), acute kidney injury (OR, 1.08), acute respiratory failure (OR, 1.40), pseudocyst (OR, 1.41), total parenteral nutrition (OR, 1.28), and central venous catheter placement (OR, 3.01) were associated with a diagnosis of VTE. Venous thromboembolism was also independently associated with increased mortality (OR, 1.31) and prolonged duration of hospitalization by 6.5 days (P < 0.001) and contributed to an excess $44,882 (P < 0.001) in hospitalization costs. Conclusions: Venous thromboembolism is adversely associated with mortality and health care resource utilization in AP. Key Words: acute pancreatitis, deep vein thrombosis, pulmonary embolus, venous thromboembolism
From the *Division of Gastroenterology, Hepatology and Nutrition, University of Minnesota, Minneapolis, MN; †Division of General Internal Medicine, University of Pittsburgh, Pittsburgh, PA; ‡Saint Louis University Center for Outcomes Research, St Louis, MO; and §Division of Gastroenterology, Hepatology and Nutrition, The Ohio State University Wexner Medical Center, Columbus, OH. Received for publication November 3, 2016; accepted August 3, 2017. Address correspondence to: Somashekar G. Krishna, MD, MPH, Division of Gastroenterology, Hepatology, and Nutrition, The Ohio State University Wexner Medical Center, 395 W 12th Ave, 2nd Floor, Columbus, OH 43210 (e‐mail: [email protected]). This study was presented as a poster of distinction at the American Pancreatic Association 2016 Annual Meeting at Boston, MA. Author contributions: G.T. conceptualized and designed the study, drafted the manuscript, and critically revised the manuscript for important intellectual content. C.U. performed acquisition, analysis, and interpretation of data and statistical analysis. S.M. performed statistical analysis. M.G. performed acquisition of data. D.L.C. and M.L.F. critically revised the manuscript for important intellectual content. S.G.K. conceptualized and designed the study and critically revised the manuscript for important intellectual content. M.L.F. is a consultant for Boston Scientific, Cook Medical, XLumena Corp, and Neometrics. The other authors declare no conflict of interest. Supplemental digital contents are available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.pancreasjournal.com). Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved. DOI: 10.1097/MPA.0000000000000906
Pancreas • Volume 46, Number 9, October 2017
(Pancreas 2017;46: 1165–1172)
A
cute pancreatitis (AP) can range from mild, self-limiting disease to severe disease wherein local inflammation escalates into systemic inflammation with release of proinflammatory mediators. Among the systemic complications, vascular complications are seen in 25% patients with AP with substantial morbidity and mortality.1,2 While splanchnic vein thromboses have been extensively reported in AP, there is limited literature on prevalence and outcomes of deep vein thrombosis (DVT) of extremity and pulmonary embolus complicating AP.1 Venous thromboembolism (VTE), which includes DVT and pulmonary embolism (PE), has an incidence of 1 person per 1000 population per year.3 In hospitalized patients, the incidence of PE and DVT is approximately 0.4% and 1.3% of admissions, respectively, with the incidence of DVT increasing progressively over the years.4 Deep vein thrombosis is associated with early mortality with death rates of approximately 6% within the first month of diagnosis.3 The systemic inflammatory milieu of AP together with prolonged immobilization during hospitalization may uniquely predispose such patients to VTE, which is often underrecognized.2,5,6 Thus, identification of VTE prevalence and risk factors in AP is crucial. The aims of our study were to evaluate the clinical and health care resource utilization impact of concurrent VTE in patients with AP. In addition, we sought to estimate the prevalence and risk factors for VTE in AP.
MATERIALS AND METHODS Data Source The Nationwide Inpatient Sample (NIS) is an all-payer, administrative claims-based database maintained as part of the Healthcare Cost and Utilization Project sponsored by the Agency for Healthcare Research and Quality (AHRQ).7 It is a data compilation of more than 8 million inpatient admissions annually from approximately 1000 hospitals in the United States. These databases reflect a 20% stratified sample of nonfederal, acute-care hospitals in the United States. The sampling frame includes community and general hospitals and academic medical centers in the United States. All data were extracted from the NIS between 2002 and 2011 using the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) diagnosis and procedure codes. Hospitalizations for AP were selected using the ICD-9-CM diagnostic code 577.0 as the primary discharge diagnosis. Etiological factors for AP, associated procedures, and complications were www.pancreasjournal.com
Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.
1165
Pancreas • Volume 46, Number 9, October 2017
Trikudanathan et al
queried for using respective ICD-9-CM codes (Supplemental Table 1, http://links.lww.com/MPA/A610). For identifying patients with a secondary diagnosis of VTE, specific diagnostic codes were utilized (Supplemental Table 1, http://links.lww.com/MPA/A610). These codes for VTE have been used in prior publications using administrative databases.8–11 The data contained within these specific data sets are neither identifiable nor private and thus do not meet the federal definition of “human subject” as defined in 45 CFR 46.102. Therefore, these research projects do not need to be reviewed and approved by the institutional review board.
Study Population Patient-level variables included age, sex, race, and insurance status. Certain states do not document race on discharge records, and hence, these were analyzed as a separate category. Comorbidities for risk adjustment were derived from AHRQ comorbidity measures based on the methods by Elixhauser et al.12 Patients were given a score of less than 3 or 3 or greater based on the number of comorbidities. Potential hospital-related confounders were hospital region, location, hospital bed size, and teaching status. The “cases” were defined as patients with a primary discharge diagnosis of AP who also had concurrent secondary diagnostic codes for VTE. The “controls” were defined as patients with a primary discharge diagnosis of AP without a diagnostic code for VTE.
including solid tumor without metastasis, lymphoma, and metastatic cancer; (5) cirrhosis; (6) inflammatory bowel disease; (7) recent surgery; (8) fracture of neck of femur and lower limb; (9) arthroplasty of hip and knee; (10) treatment of fracture or dislocation of the hip; and (11) transverse myelitis.
Statistical Analysis Descriptive summary statistics are presented as means and standard deviation (SD) for continuous variables and frequencies with percentages for categorical variables. Categorical and continuous variables were tested for statistical significance using χ2 tests and t-tests, respectively. Temporal trends were assessed using the Cochrane-Armitage trend test. Statistical significance was defined by P < 0.05. Univariate regression analysis was performed to identify variables associated with a diagnosis of VTE. Univariate predictor variables with P < 0.05 were included in the multivariate analysis. Similar analysis was performed to identify the independent effect of diagnosis of VTE on in-hospital mortality, length of stay, and total hospitalization charges. Multivariate logistic regression models were fit for each dichotomous outcome, and multivariate linear regression models were fit if the outcome variables were continuous. All results in the regression models were represented by an odds ratio (OR) and 95% confidence interval (CI). All regression models were performed separately. These analyses were performed on weighted data from the NIS database using IBM SPSS software version 23 (SPSS Inc, Armonk, NY) and SAS software version 9.3 (SAS Institute Inc, Cary, NC).
Study Outcomes The study schema is illustrated in Figure 1. The primary clinical outcome was mortality in hospitalized patients with AP. The secondary outcomes were “length of hospital stay” and “total hospital charges,” referred to collectively as health care resource utilization.
Exclusions The following exclusion criteria were used: (1) age of 17 years or younger at the time of admission; (2) patients transferred from an outside hospital as the duration and complications of prior hospitalization could not be explained; (3) pregnancy; (4) malignancies
RESULTS Temporal Trends in AP and VTE There were a total of 2,382,426 discharges with a primary diagnosis of AP from 2002 to 2011. The prevalence of AP among all hospitalizations increased annually, from 221,087 (0.58%) cases in 2002 to 262,626 (0.68%) cases in 2011 (P < 0.001) (Fig. 2A). A total of 22,205 patients (0.93%) were diagnosed as having concurrent VTE; 80% had DVT alone, 15% had PE alone, and 5% had both DVT and PE. Among those with a primary diagnosis of AP, the number of patients with concomitant VTE increased during the study period (1866 [0.84%] to 2359 [0.90%]; P = 0.013) (Fig. 2B). For all patients with primary diagnosis of AP, all-cause inpatient mortality decreased with a significant trend (2946 [1.33%] to 1854 [0.71%]; P < 0.001) (Fig. 2C). Patients with AP and VTE failed to demonstrate a statistically significant decreasing trend (115 [6.18%] to 108 [4.60%]; P = 0.070) (Fig. 2D).
Risk Factors for VTE Among Hospitalized Patients With AP Univariate analysis comparing AP patients with and without VTE (Table 1) revealed that patients with VTE were older (median age, 53 vs 51 years; P < 0.005) and had more comorbid conditions (AHRQ-Elixhauser ≥3 conditions in 55.7% vs 40.6%; P < 0.005). For both groups, significant intravariable differences existed in racial distribution, insurance type, hospital size and type, and disposition. Venous thromboembolism was more frequently observed in patients with AP-related complications such as acute kidney injury, acute respiratory failure, pseudocyst, and need for mechanical ventilation. Furthermore, VTE was associated with total parenteral nutrition (TPN) (16.3 vs 3.2%; P < 0.005) and central venous catheter/line (CVL) placement (37% vs 7.8%; P < 0.005). The main outcomes of mortality, length of stay, and hospitalization
FIGURE 1. Study flowchart.
1166
www.pancreasjournal.com
© 2017 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.
Pancreas • Volume 46, Number 9, October 2017
Venous Thromboembolism in Acute Pancreatitis
FIGURE 2. Trends of number of hospitalizations for a primary diagnosis of AP (A) and proportion of inpatients with AP and concomitant VTE using the NIS from 2002 to 2011 (B). Trends in the all-cause inpatient mortality among patients with AP (C) and AP with VTE (D) observed in the NIS from 2002 to 2011.
costs were significantly higher in patients with VTE. On multivariate analysis (Table 2), greater comorbidity (as reflected by ≥3 AHRQElixhauser measures) (OR, 1.47; 95% CI, 1.43–1.51), longer duration of hospitalization (OR, 1.04; 95% CI, 1.04–1.05), white race (OR, 1.11; 95% CI, 1.06–1.16), Medicare patients (OR, 1.09; 95% CI, 1.04–1.13), complications attributable to AP such as acute kidney injury (OR, 1.08; 95% CI, 1.04–1.13), acute respiratory failure (OR, 1.40; 95% CI, 1.33–1.48), pseudocyst (OR, 1.41; 95% CI, 1.35–1.47), TPN (OR, 1.28; 95% CI, 1.22–1.33), and CVL placement (OR, 3.01; 95% CI, 2.90–3.11) were independently associated with VTE. In addition, larger hospitals and those located in the urban areas incurred more patients with VTE.
Outcomes of AP Patients With VTE A multivariate logistic regression analysis adjusting for patient demographics, hospital characteristics, comorbidities, and etiologies for AP demonstrated that, overall, VTE (OR, 1.31; 95% CI, 1.21–1.42; P < 0.005) was independently associated with increased mortality (Table 3). Furthermore, multivariate linear regression revealed that VTE prolonged the length of hospital stay by 6.5 days (14.7 [SD, 16.4] days in cases vs 5 [SD, 5.3]days in controls) and contributed to an excess $44,882 ($89,830 [SD, $141,578] in cases vs $25,557 [SD, $39,348] in controls) in total hospital charges (Table 4).
DISCUSSION In this study, we demonstrate that VTE in patients with AP is associated with adverse clinical outcome of mortality and increased health care resource utilization. Nearly 1% of all hospitalizations for AP are complicated by concurrent VTE. The background rate of VTE among hospitalized patients during the same study period was 0.75%. After adjusting for demographics, comorbidity, insurance status, length of stay, and number of procedures, on multivariate logistic regression, hospitalized patients with AP © 2017 Wolters Kluwer Health, Inc. All rights reserved.
had greater odds of having VTE than patients without AP (OR, 1.52; P < 0.05). This study further confirms the increasing annual prevalence of AP hospitalizations including that of concomitant VTE. While the overall mortality from AP seems to be decreasing, there has been no decrement in the mortality of AP patients with concurrent VTE. Occurrence of VTE was associated with several AP-related adverse outcomes and patient's comorbidities including duration of hospitalization and severe AP. Effectively, complicated AP signified VTE, and in turn thromboembolic events adversely influenced clinical outcomes. To our knowledge, these associations have not been demonstrated in prior studies, and the study findings have significant implications in the management of AP. We chose the NIS because AP represents the most common gastrointestinal cause for hospital admission in the United States, accounting for nearly 274,000 hospitalizations at an estimated cost of $2.6 billion every year.13 Even in its mildest form, it may necessitate a 2- to 5-day hospital stay, with severe cases warranting a much longer and complicated hospital course.14,15 Previous studies have revealed hospitalization as a significant risk factor for VTE.16 Because patients with AP are frequently hospitalized, it is not surprising that they are susceptible to VTE. Complicated disease portends VTE in AP, and VTE in turn adversely influences clinical outcome in AP. Management strategies to intervene and prevent adverse prognostication include preventing disease progression in AP, decreasing risk of VTE in severe and complicated AP, and preventing VTE associated complications in AP. Although the exact mechanisms predisposing to VTE remain poorly understood, several explanations have been proposed. Acute pancreatitis provokes a marked proinflammatory milieu that induces intrinsic endothelial damage at a microvascular level and makes vascular events more likely.5 The release of pancreatic enzymes may in turn further promote a hypercoagulable state from pancreatic enzyme release, activating clotting processes within the inflamed pancreas and leading to thrombophilic changes in venous www.pancreasjournal.com
Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.
1167
Pancreas • Volume 46, Number 9, October 2017
Trikudanathan et al
TABLE 1. Univariate Analysis of Demographic and Hospital Characteristics, Etiologies, Interventions, Complications, and Outcomes of AP With and Without VTE: Analysis of the NIS 2002–2011 VTE Absent (n = 2,360,221 [99.1%]), n (%) Age, median (IQR), y Sex Male Female Race White Black Hispanic Other/missing Insurance Medicare Medicaid Private (including HMO) Other, self-pay, no charge Hospital type Rural Urban nonteaching Urban teaching Hospital bed size* Small Medium Large Hospital region Northeast Midwest South West AHRQ-Elixhauser comorbidity index†
Venous Thromboembolism Is Associated With Adverse Outcomes in Hospitalized Patients With Acute Pancreatitis A Population-Based Cohort Study Guru Trikudanathan, MD,* Chandraprakash Umapathy, MD,† Satish Munigala, MBBS, MPH,‡ Mahesh Gajendran, MD, MPH,† Darwin L. Conwell, MD,§ Martin L. Freeman, MD,* and Somashekar G. Krishna, MD, MPH§
Objectives: The systemic inflammatory cascade and vascular stasis in hospitalized patients with acute pancreatitis (AP) serve as a milieu for development of venous thromboembolism (VTE). Our aim was to estimate the prevalence and risk factors of VTE in AP and to evaluate its impact on clinical outcomes of AP. Methods: The Nationwide Inpatient Sample (2002–2011) was reviewed to identify all patients hospitalized with AP. Patients with a concomitant diagnosis of VTE were compared with those without. The primary clinical outcome (inpatient mortality) and secondary resources outcomes (length of stay and total hospital charges) were analyzed using univariate and multivariate comparisons. Results: Among 2,382,426 patients with AP, 22,205 (0.93%) had VTE. Multivariate analysis showed patients with greater comorbidity (odds ratio [OR], 1.47), white race (OR, 1.11), acute kidney injury (OR, 1.08), acute respiratory failure (OR, 1.40), pseudocyst (OR, 1.41), total parenteral nutrition (OR, 1.28), and central venous catheter placement (OR, 3.01) were associated with a diagnosis of VTE. Venous thromboembolism was also independently associated with increased mortality (OR, 1.31) and prolonged duration of hospitalization by 6.5 days (P < 0.001) and contributed to an excess $44,882 (P < 0.001) in hospitalization costs. Conclusions: Venous thromboembolism is adversely associated with mortality and health care resource utilization in AP. Key Words: acute pancreatitis, deep vein thrombosis, pulmonary embolus, venous thromboembolism
From the *Division of Gastroenterology, Hepatology and Nutrition, University of Minnesota, Minneapolis, MN; †Division of General Internal Medicine, University of Pittsburgh, Pittsburgh, PA; ‡Saint Louis University Center for Outcomes Research, St Louis, MO; and §Division of Gastroenterology, Hepatology and Nutrition, The Ohio State University Wexner Medical Center, Columbus, OH. Received for publication November 3, 2016; accepted August 3, 2017. Address correspondence to: Somashekar G. Krishna, MD, MPH, Division of Gastroenterology, Hepatology, and Nutrition, The Ohio State University Wexner Medical Center, 395 W 12th Ave, 2nd Floor, Columbus, OH 43210 (e‐mail: [email protected]). This study was presented as a poster of distinction at the American Pancreatic Association 2016 Annual Meeting at Boston, MA. Author contributions: G.T. conceptualized and designed the study, drafted the manuscript, and critically revised the manuscript for important intellectual content. C.U. performed acquisition, analysis, and interpretation of data and statistical analysis. S.M. performed statistical analysis. M.G. performed acquisition of data. D.L.C. and M.L.F. critically revised the manuscript for important intellectual content. S.G.K. conceptualized and designed the study and critically revised the manuscript for important intellectual content. M.L.F. is a consultant for Boston Scientific, Cook Medical, XLumena Corp, and Neometrics. The other authors declare no conflict of interest. Supplemental digital contents are available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.pancreasjournal.com). Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved. DOI: 10.1097/MPA.0000000000000906
Pancreas • Volume 46, Number 9, October 2017
(Pancreas 2017;46: 1165–1172)
A
cute pancreatitis (AP) can range from mild, self-limiting disease to severe disease wherein local inflammation escalates into systemic inflammation with release of proinflammatory mediators. Among the systemic complications, vascular complications are seen in 25% patients with AP with substantial morbidity and mortality.1,2 While splanchnic vein thromboses have been extensively reported in AP, there is limited literature on prevalence and outcomes of deep vein thrombosis (DVT) of extremity and pulmonary embolus complicating AP.1 Venous thromboembolism (VTE), which includes DVT and pulmonary embolism (PE), has an incidence of 1 person per 1000 population per year.3 In hospitalized patients, the incidence of PE and DVT is approximately 0.4% and 1.3% of admissions, respectively, with the incidence of DVT increasing progressively over the years.4 Deep vein thrombosis is associated with early mortality with death rates of approximately 6% within the first month of diagnosis.3 The systemic inflammatory milieu of AP together with prolonged immobilization during hospitalization may uniquely predispose such patients to VTE, which is often underrecognized.2,5,6 Thus, identification of VTE prevalence and risk factors in AP is crucial. The aims of our study were to evaluate the clinical and health care resource utilization impact of concurrent VTE in patients with AP. In addition, we sought to estimate the prevalence and risk factors for VTE in AP.
MATERIALS AND METHODS Data Source The Nationwide Inpatient Sample (NIS) is an all-payer, administrative claims-based database maintained as part of the Healthcare Cost and Utilization Project sponsored by the Agency for Healthcare Research and Quality (AHRQ).7 It is a data compilation of more than 8 million inpatient admissions annually from approximately 1000 hospitals in the United States. These databases reflect a 20% stratified sample of nonfederal, acute-care hospitals in the United States. The sampling frame includes community and general hospitals and academic medical centers in the United States. All data were extracted from the NIS between 2002 and 2011 using the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) diagnosis and procedure codes. Hospitalizations for AP were selected using the ICD-9-CM diagnostic code 577.0 as the primary discharge diagnosis. Etiological factors for AP, associated procedures, and complications were www.pancreasjournal.com
Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.
1165
Pancreas • Volume 46, Number 9, October 2017
Trikudanathan et al
queried for using respective ICD-9-CM codes (Supplemental Table 1, http://links.lww.com/MPA/A610). For identifying patients with a secondary diagnosis of VTE, specific diagnostic codes were utilized (Supplemental Table 1, http://links.lww.com/MPA/A610). These codes for VTE have been used in prior publications using administrative databases.8–11 The data contained within these specific data sets are neither identifiable nor private and thus do not meet the federal definition of “human subject” as defined in 45 CFR 46.102. Therefore, these research projects do not need to be reviewed and approved by the institutional review board.
Study Population Patient-level variables included age, sex, race, and insurance status. Certain states do not document race on discharge records, and hence, these were analyzed as a separate category. Comorbidities for risk adjustment were derived from AHRQ comorbidity measures based on the methods by Elixhauser et al.12 Patients were given a score of less than 3 or 3 or greater based on the number of comorbidities. Potential hospital-related confounders were hospital region, location, hospital bed size, and teaching status. The “cases” were defined as patients with a primary discharge diagnosis of AP who also had concurrent secondary diagnostic codes for VTE. The “controls” were defined as patients with a primary discharge diagnosis of AP without a diagnostic code for VTE.
including solid tumor without metastasis, lymphoma, and metastatic cancer; (5) cirrhosis; (6) inflammatory bowel disease; (7) recent surgery; (8) fracture of neck of femur and lower limb; (9) arthroplasty of hip and knee; (10) treatment of fracture or dislocation of the hip; and (11) transverse myelitis.
Statistical Analysis Descriptive summary statistics are presented as means and standard deviation (SD) for continuous variables and frequencies with percentages for categorical variables. Categorical and continuous variables were tested for statistical significance using χ2 tests and t-tests, respectively. Temporal trends were assessed using the Cochrane-Armitage trend test. Statistical significance was defined by P < 0.05. Univariate regression analysis was performed to identify variables associated with a diagnosis of VTE. Univariate predictor variables with P < 0.05 were included in the multivariate analysis. Similar analysis was performed to identify the independent effect of diagnosis of VTE on in-hospital mortality, length of stay, and total hospitalization charges. Multivariate logistic regression models were fit for each dichotomous outcome, and multivariate linear regression models were fit if the outcome variables were continuous. All results in the regression models were represented by an odds ratio (OR) and 95% confidence interval (CI). All regression models were performed separately. These analyses were performed on weighted data from the NIS database using IBM SPSS software version 23 (SPSS Inc, Armonk, NY) and SAS software version 9.3 (SAS Institute Inc, Cary, NC).
Study Outcomes The study schema is illustrated in Figure 1. The primary clinical outcome was mortality in hospitalized patients with AP. The secondary outcomes were “length of hospital stay” and “total hospital charges,” referred to collectively as health care resource utilization.
Exclusions The following exclusion criteria were used: (1) age of 17 years or younger at the time of admission; (2) patients transferred from an outside hospital as the duration and complications of prior hospitalization could not be explained; (3) pregnancy; (4) malignancies
RESULTS Temporal Trends in AP and VTE There were a total of 2,382,426 discharges with a primary diagnosis of AP from 2002 to 2011. The prevalence of AP among all hospitalizations increased annually, from 221,087 (0.58%) cases in 2002 to 262,626 (0.68%) cases in 2011 (P < 0.001) (Fig. 2A). A total of 22,205 patients (0.93%) were diagnosed as having concurrent VTE; 80% had DVT alone, 15% had PE alone, and 5% had both DVT and PE. Among those with a primary diagnosis of AP, the number of patients with concomitant VTE increased during the study period (1866 [0.84%] to 2359 [0.90%]; P = 0.013) (Fig. 2B). For all patients with primary diagnosis of AP, all-cause inpatient mortality decreased with a significant trend (2946 [1.33%] to 1854 [0.71%]; P < 0.001) (Fig. 2C). Patients with AP and VTE failed to demonstrate a statistically significant decreasing trend (115 [6.18%] to 108 [4.60%]; P = 0.070) (Fig. 2D).
Risk Factors for VTE Among Hospitalized Patients With AP Univariate analysis comparing AP patients with and without VTE (Table 1) revealed that patients with VTE were older (median age, 53 vs 51 years; P < 0.005) and had more comorbid conditions (AHRQ-Elixhauser ≥3 conditions in 55.7% vs 40.6%; P < 0.005). For both groups, significant intravariable differences existed in racial distribution, insurance type, hospital size and type, and disposition. Venous thromboembolism was more frequently observed in patients with AP-related complications such as acute kidney injury, acute respiratory failure, pseudocyst, and need for mechanical ventilation. Furthermore, VTE was associated with total parenteral nutrition (TPN) (16.3 vs 3.2%; P < 0.005) and central venous catheter/line (CVL) placement (37% vs 7.8%; P < 0.005). The main outcomes of mortality, length of stay, and hospitalization
FIGURE 1. Study flowchart.
1166
www.pancreasjournal.com
© 2017 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.
Pancreas • Volume 46, Number 9, October 2017
Venous Thromboembolism in Acute Pancreatitis
FIGURE 2. Trends of number of hospitalizations for a primary diagnosis of AP (A) and proportion of inpatients with AP and concomitant VTE using the NIS from 2002 to 2011 (B). Trends in the all-cause inpatient mortality among patients with AP (C) and AP with VTE (D) observed in the NIS from 2002 to 2011.
costs were significantly higher in patients with VTE. On multivariate analysis (Table 2), greater comorbidity (as reflected by ≥3 AHRQElixhauser measures) (OR, 1.47; 95% CI, 1.43–1.51), longer duration of hospitalization (OR, 1.04; 95% CI, 1.04–1.05), white race (OR, 1.11; 95% CI, 1.06–1.16), Medicare patients (OR, 1.09; 95% CI, 1.04–1.13), complications attributable to AP such as acute kidney injury (OR, 1.08; 95% CI, 1.04–1.13), acute respiratory failure (OR, 1.40; 95% CI, 1.33–1.48), pseudocyst (OR, 1.41; 95% CI, 1.35–1.47), TPN (OR, 1.28; 95% CI, 1.22–1.33), and CVL placement (OR, 3.01; 95% CI, 2.90–3.11) were independently associated with VTE. In addition, larger hospitals and those located in the urban areas incurred more patients with VTE.
Outcomes of AP Patients With VTE A multivariate logistic regression analysis adjusting for patient demographics, hospital characteristics, comorbidities, and etiologies for AP demonstrated that, overall, VTE (OR, 1.31; 95% CI, 1.21–1.42; P < 0.005) was independently associated with increased mortality (Table 3). Furthermore, multivariate linear regression revealed that VTE prolonged the length of hospital stay by 6.5 days (14.7 [SD, 16.4] days in cases vs 5 [SD, 5.3]days in controls) and contributed to an excess $44,882 ($89,830 [SD, $141,578] in cases vs $25,557 [SD, $39,348] in controls) in total hospital charges (Table 4).
DISCUSSION In this study, we demonstrate that VTE in patients with AP is associated with adverse clinical outcome of mortality and increased health care resource utilization. Nearly 1% of all hospitalizations for AP are complicated by concurrent VTE. The background rate of VTE among hospitalized patients during the same study period was 0.75%. After adjusting for demographics, comorbidity, insurance status, length of stay, and number of procedures, on multivariate logistic regression, hospitalized patients with AP © 2017 Wolters Kluwer Health, Inc. All rights reserved.
had greater odds of having VTE than patients without AP (OR, 1.52; P < 0.05). This study further confirms the increasing annual prevalence of AP hospitalizations including that of concomitant VTE. While the overall mortality from AP seems to be decreasing, there has been no decrement in the mortality of AP patients with concurrent VTE. Occurrence of VTE was associated with several AP-related adverse outcomes and patient's comorbidities including duration of hospitalization and severe AP. Effectively, complicated AP signified VTE, and in turn thromboembolic events adversely influenced clinical outcomes. To our knowledge, these associations have not been demonstrated in prior studies, and the study findings have significant implications in the management of AP. We chose the NIS because AP represents the most common gastrointestinal cause for hospital admission in the United States, accounting for nearly 274,000 hospitalizations at an estimated cost of $2.6 billion every year.13 Even in its mildest form, it may necessitate a 2- to 5-day hospital stay, with severe cases warranting a much longer and complicated hospital course.14,15 Previous studies have revealed hospitalization as a significant risk factor for VTE.16 Because patients with AP are frequently hospitalized, it is not surprising that they are susceptible to VTE. Complicated disease portends VTE in AP, and VTE in turn adversely influences clinical outcome in AP. Management strategies to intervene and prevent adverse prognostication include preventing disease progression in AP, decreasing risk of VTE in severe and complicated AP, and preventing VTE associated complications in AP. Although the exact mechanisms predisposing to VTE remain poorly understood, several explanations have been proposed. Acute pancreatitis provokes a marked proinflammatory milieu that induces intrinsic endothelial damage at a microvascular level and makes vascular events more likely.5 The release of pancreatic enzymes may in turn further promote a hypercoagulable state from pancreatic enzyme release, activating clotting processes within the inflamed pancreas and leading to thrombophilic changes in venous www.pancreasjournal.com
Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.
1167
Pancreas • Volume 46, Number 9, October 2017
Trikudanathan et al
TABLE 1. Univariate Analysis of Demographic and Hospital Characteristics, Etiologies, Interventions, Complications, and Outcomes of AP With and Without VTE: Analysis of the NIS 2002–2011 VTE Absent (n = 2,360,221 [99.1%]), n (%) Age, median (IQR), y Sex Male Female Race White Black Hispanic Other/missing Insurance Medicare Medicaid Private (including HMO) Other, self-pay, no charge Hospital type Rural Urban nonteaching Urban teaching Hospital bed size* Small Medium Large Hospital region Northeast Midwest South West AHRQ-Elixhauser comorbidity index†
