Alimentary Pharmacology and Therapeutics
The use of pharmacological prophylaxis against venous thromboembolism in hospitalised patients with severe active ulcerative colitis J. L. Pleet*, B. P. Vaughn†, J. A. Morris‡, A. C. Moss† & A. S. Cheifetz†
*Department of Medicine, Beth-Israel Deaconess Medical Center, Boston, MA, USA. † Division of Gastroenterology, BethIsrael Deaconess Medical Center, Boston, MA, USA. ‡ Department of Educational Psychology, University of Illinois at Urbana-Champaign, Champaign, IL, USA.
Correspondence to: Dr J. L. Pleet, Division of Internal Medicine, Beth-Israel Deaconess Medical Center, HCA, Shapiro 6th Floor, 330 Brookline Ave., Boston, MA 02215, USA. E-mail: [email protected]
Publication data Submitted 10 November 2013 First decision 12 December 2013 Resubmitted 16 January 2014 Accepted 16 February 2014 EV Pub Online 10 March 2014 This article was accepted for publication after full peer-review.
SUMMARY Background Hospitalised patients with inflammatory bowel disease are 1.5- to 3.5-fold more likely to develop venous thromboembolism compared to controls. Clinical guidelines recommend pharmacological prophylaxis. Aim To determine the rate of pharmacological venous thromboembolism prophylaxis prescription and administration in a cohort of hospitalised patients with severe active ulcerative colitis and to assess predictors of failure to order pharmacological prophylaxis at 24 h. Methods This is a retrospective review of hospitalised patients with severe active ulcerative colitis, identified by ICD-9-CM discharge code 556.x, admitted to a single tertiary care hospital from 1 January 2005 to 31 August 2012. Adequate thromboembolism prophylaxis was defined as an order for low-dose unfractionated heparin two to three times daily, low-molecular weight heparin 40 mg daily or fondaparinux 2.5 mg daily ordered and administered for >80% of the admission. Patient related factors associated with failure to order prophylaxis at 24 h were accessed as secondary outcomes. Results Three hundred and thirty-six patients were hospitalised with severe active ulcerative colitis. Hospitalists had prescribed appropriate pharmacological prophylaxis by 48 h in only 37% of cases. Of these, nurses administered all prescribed doses in 18% of cases. Only 7% of patients (22/304, 95% CI: 5– 11%) received adequate pharmacological prophylaxis for >80% of their hospitalisation. Hematochezia (P = 0.002), elevated platelets (P = 0.008), male gender coupled with younger age (P = 0.005) and admission on a biologic (P = 0.03) were associated with failure to order prophylaxis. Conclusion Hospitalised patients admitted with severe active ulcerative colitis are not receiving appropriate pharmacological venous thromboembolism prophylaxis. Aliment Pharmacol Ther 2014; 39: 940–948
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ª 2014 John Wiley & Sons Ltd doi:10.1111/apt.12691
Thromboembolism prophylaxis in severe active ulcerative colitis INTRODUCTION There are over 750 000 patients with ulcerative colitis (UC)1 in the United States. It is estimated that 15% of these patients will experience a flare of their disease that requires hospitalisation.2 Furthermore, multiple studies have demonstrated that patients with inflammatory bowel disease (IBD) are at a 1.5- to 3.5-fold increased risk of developing symptomatic venous thromboembolism (VTE) when compared to non-IBD patients.3–10 The increased risk of VTE is particularly elevated during periods of active disease and especially during hospitalisation.4 Importantly, the mortality from symptomatic VTE in patients with IBD has been reported to be as high as 22%11 and two-fold higher than non-IBD patients with VTE.7 Low-molecular-weight heparin, unfractionated heparin, fondaparinux and dalteparin are effective at decreasing the risk of symptomatic VTE in hospitalised medical patients.12–20 Prophylactic VTE doses of unfractionated heparin and low-molecular-weight heparin have been demonstrated to be safe,21 and possibly therapeutic in patients with active ulcerative colitis.22, 23 Several clinical guidelines recommend the use of pharmacological VTE prophylaxis for hospitalised patients with IBD, particularly for those patients with severe acute UC.24–28 However, few studies have examined the adequate use of VTE prophylaxis in this population. One recent retrospective study showed that 68% of patients had at least one order for VTE prophylaxis.29 Similarly, two recent surveys noted that only 34.6–72% of gastroenterologists were likely to prescribe pharmacological VTE prophylaxis in hospitalised IBD patients.30, 31 Increasingly, hospitalists are the primary care provider for an in-patient during a UC flare and may be less aware of the increased risk of VTE and the recommendations regarding appropriate VTE prophylaxis in this patient population. Therefore, we set out to determine the rate of pharmacological venous thromboembolism prophylaxis prescription and administration in a cohort of hospitalised patients with severe ulcerative colitis. We also set out to assess predictors of failure to order appropriate pharmacological VTE prophylaxis. MATERIALS AND METHODS Chart review This was a retrospective cohort study of adult patients admitted to Beth Israel Deaconess Medical Center (Boston, MA, USA) between 1 January 2005 and 31 August 2012. All patients were under the care of the hospitalist Aliment Pharmacol Ther 2014; 39: 940-948 ª 2014 John Wiley & Sons Ltd
management team, with the gastroenterology service following in consultation. Patients were identified using electronic records and a discharge diagnosis of ulcerative colitis (ICD-9 code 556.x). The electronic medical records contain all discharge summaries, laboratory results and radiology, pathology and procedure reports. Additionally, physician orders were available through an electronic ordering system that included the date and times associated with all orders. Starting in June 2008, the nursing medication administration records were scanned into the electronic medical record and available for review. Medical records including electronic orders and scanned nursing records were manually reviewed by two physicians (JLP, BPV). Study data including admission characteristics (date, hospital transfer, length of stay, primary service) and patient characteristics (duration of disease, medication regimen on admission, extent of disease, UC symptoms including number of bowel movements and hematochezia, admission labs, in-patient UC therapy and diagnosis of VTE) were collected and managed using REDCap electronic data capture tools hosted at BIDMC. REDCap (Research Electronic Data Capture) is a secure, web-based application designed to support data capture for research studies. Study data including VTE prophylaxis recommendations (drug and dosing) made on initial consultation by the gastroenterology consulting service were obtained for years 2011 and 2012, when initial consultation notes were documented consistently in the online medical record. Patients were included more than once if they had multiple unique admissions over the study period.
Inclusion and exclusion criteria Patients were included in the study if they had a severe UC flare, defined as having one or more of the entry criteria: (i) Having greater than six bowel movements per day, (ii) Requiring treatment with intravenous steroids, infliximab or cyclosporine, (iii) Undergoing colectomy for treatment of UC flare during the admission. Patients were excluded if they were determined to have Crohn’s disease, indeterminate colitis or mild or moderate UC flare. Patients were also excluded if they were admitted on a therapeutic dose of anti-coagulation or had a VTE diagnosed on day 1 of admission. See Figure S1 for a flow chart of the cases reviewed. Outcomes definitions The primary outcome of this study was to define the incidence of adequate VTE prophylaxis for patients hos941
J. L. Pleet et al. pitalised with severe UC. Adequate VTE prophylaxis was defined as appropriately dosed pharmacological VTE prophylaxis ordered and administered for >80% of the hospitalisation. We first identified whether patients were ordered for appropriate VTE prophylaxis, which included low-dose subcutaneous unfractionated heparin two or three times daily, subcutaneous low-molecular-weight heparin 40 mg daily or subcutaneous fondaparinux 2.5 mg daily. We assessed for the presence of active orders within 24 h and 48 h of admission. We also documented the per cent of hospital days for which the patient had an active order written. We defined a patient as having an adequate VTE prophylaxis prescription if they had an active order for >80% of their hospitalisation. Data on nonpharmacological VTE prophylaxis, such as ambulation at least three times daily or intermittent pneumatic compression devices, was examined but did not qualify as adequate VTE prophylaxis. Nursing records were reviewed to establish the VTE prophylaxis administration rate. Adherence was defined as administration of ordered VTE prophylaxis for >80% of the prescribed doses. The administration rate was recorded using the following ranges: 100%, 80–99%, 50– 79%, 25–49% or 80% of the hospitalisation but did not have nursing records to review were excluded from this portion of the study. Our secondary outcome was to identify predictors of failure to order prophylaxis within 24 h. Patient related factors including age, gender, day of admission, year of admission, admitting service, hematochezia, stool frequency, medication on admission, admission haemoglobin, admission platelets and admission C-reactive protein were analysed as possible predictors of pharmacological VTE prophylaxis ordering.
Statistical analysis Descriptive data are presented as a mean with standard deviation or median with inter-quartile range. Nominal variables were analysed with v2 or Fisher’s exact test as appropriate. Continuous variables were analysed with t-test or Wilcoxan Rank-Sum as appropriate. The primary outcome of incidence of adequate VTE prophylaxis 942
is presented as a rate with binomial confidence intervals. For the secondary outcome, we analysed all covariates that achieved statistical significance (P < 0.1) from the univariate model, into a forward, stepwise multiple logistic regression analysis. In addition, covariates (age, gender, admission service and weekend admission) that did not achieve statistical significance in the univariate model, but were felt a priori to be associated with the secondary outcome, were included in the final logistic regression analysis. In order to attain an odds ratio, we dichotomized platelets into elevated (platelet counts >440 K/lL) or not. A P-value of 6 bowel movements Not recorded Median C-reactive protein on admission (IQR), mg/L Median erythrocyte sedimentation rate (IQR), mm/hr Median white blood count (IQR), K/lL Median haemoglobin on admission (IQR), g/dL Median platelets (IQR), K/lL Median Creatinine (IQR), mg/dL Median albumin (IQR), g/dL Admission service Medicine NonMedicine Weekend admission
VTE prophylaxis ordered (N = 126)
No VTE prophylaxis ordered (N = 210)
42 (30,57)
36 (26,51)
58 68 3 24 7 105 12
(46%) (54%) (1,8) (21,29) (6%) (83%) (10%)
111 99 3 24 7 199 24
2 19 21 16 39 29
(1%) (15%) (17%) (13%) (31%) (23%)
3 17 32 39 57 62
(53%) (47%) (1,7) (20, 27) (3%) (95%) (11%)
P 0.01† 0.23† 0.41 0.33 0.31 0.001‡ 0.58
(1%) (8%) (15%) (19%) (27%) (30%)
0.22
67 (53%) 19 (15%) 40 (32%)
107 (51%) 43 (20%) 60 (29%)
0.45
75 30 10 15
127 42 33 23
(60%) (20%) (16%) (11%)
0.89 0.40 0.04§ 0.78
(11%) (75%) (14%) (8.7,65.7) (15,60) (7.8,13.5) (10.6,13.5) (289,506) (0.7,1.0) (0.6)
0.24
22 88 16 27.0 36 10.3 12.1 359 0.8 3.4
(60%) (24%) (8%) (12%) (17%) (70%) (13%) (4.0,93.9) (10,63) (7.2,13.7) (10.4,13.2) (272,463) (0.7,1.0) (0.7)
121 (96%) 5 (4%) 23 (18%)
23 158 29 29.8 36 10.2 12.1 381 0.8 3.4
205 (98%) 5 (2%) 46 (22%)
0.91 0.65 0.75 0.98 0.05¶ 0.19 0.68 0.41 0.42
* Venous thromboembolism. † Evidence of effect modification was found on age by gender, P = 0.005. ‡ Hematochezia remained statistically significant in multiple regression analysis, P = 0.002. § Admission on a biologic remained statistically significant in multiple regression analysis, P = 0.04. ¶ Platelets remained statistically significant in multiple regression analysis, P = 0.008.
more appropriate VTE prophylaxis was seen over time (P = 0.06). Of the patients admitted in 2011 and 2012, initial gastroenterology consultation notes were available in 99% (88/89) of cases and of those cases the initial gastroenterology consult recommendation mentioned Aliment Pharmacol Ther 2014; 39: 940-948 ª 2014 John Wiley & Sons Ltd
VTE prophylaxis in 9.0% (8/88) of cases. Thirteen per cent (1/8) included specific drug recommendations. None of the gastroenterology consult notes included specific dosing recommendations. Of the eight cases in which VTE prophylaxis was recommended by the 943
J. L. Pleet et al. nursing records were available in 69% (113/164) of cases. Table 3 shows the rates of nursing administration of VTE prophylaxis. When prescribed, only 30% (34/113) of patients were administered >80% of their doses. Only 7% (22/304, 95% CI: 5–11%) of patients met the primary endpoint of receiving adequate VTE prophylaxis (appropriate pharmacological VTE prophylaxis ordered and administered for >80% of the hospitalisation). When assessing factors associated with failure to order pharmacological VTE prophylaxis, age, hematochezia, admission on biologics and admission platelets had a P-value of 80% doses ordered Adequate prophylaxis for >80% hospitalisation
37.5 30 7
* Venous thromboembolism.
gastroenterology consultants, seven patients were ordered for pharmacological VTE prophylaxis at 48 h (P = 0.14). For patients in whom pharmacological prophylaxis was ordered for >80% of the hospitalisation, scanned 60
Percentage of study patients (%)
51 50 40 31 30 18
20 10 0
1–80
0
> 80
Percentage of hospital days venous thromboembolism prophylaxis was ordered (%)
Figure 1 | Percentage of hospital days with venous thromboembolism prophylaxis ordered.
60
Percent VTE prophylaxis ordered at 24 h
P = 0.06 50
40
30
20
10
0 2004
944
2005
2006
2007
2008 2009 Year
2010
2011
2012
2013
Figure 2 | Pharmacologic venous thromboembolism prophylaxis ordered at 24 h by year. VTE, venous thromboembolism. Aliment Pharmacol Ther 2014; 39: 940-948 ª 2014 John Wiley & Sons Ltd
Thromboembolism prophylaxis in severe active ulcerative colitis Table 3 | Nursing administration of pharmacological VTE* prophylaxis Percentage of doses administered (%)
N = 113
440 K/lL, only 30% had an order for VTE prophylaxis compared to 42% with patients whose platelet count was 80% of the hospital course. The Aliment Pharmacol Ther 2014; 39: 940-948 ª 2014 John Wiley & Sons Ltd
majority of the patients who developed a symptomatic VTE did not receive any pharmacological VTE prophylaxis (73.3%, 11/15).
DISCUSSION In our cohort of patients with severe UC, only 7% (95% CI: 5–11%) of patients received adequate VTE prophylaxis despite existing recommendations.24–28 Fewer than 40% of patients have an adequate pharmacological order for VTE prophylaxis within 24 h of hospital admission. Even when adequate VTE prophylaxis was ordered, only 30% of patients received >80% of the prescribed dose. It is encouraging that the overall prescription of VTE prophylaxis seems to be increasing with time, with just over 50% of patients ordered for prophylaxis in 2012. This overall trend likely represents the dissemination of information from guidelines and increased physician awareness regarding the increased risk of VTE and need for prophylaxis. While the gastroenterology service did not frequently provide recommendations regarding VTE prophylaxis, when they did, most patients were ordered for appropriate VTE prophylaxis. Our rates of VTE prophylaxis are lower than reported by Tinsley et al.,29 which showed a 67.6% prescribing rate at a single tertiary care centre, with 66% of those doses administered to patients. The definition of VTE prophylaxis in the study by Tinsley et al.29 is likely to account for some of the difference. Their endpoint for VTE prophylaxis was ‘at least one order for pharmacological prophylaxis at any point during the admission.’ This endpoint does not account for the total amount of time a patient was ordered for prophylaxis during the admission. Our outcomes were more stringent and looked at active orders at 24 (and 48) h and percentage of days there was an active order for VTE prophylaxis. The definition of adequate VTE prophylaxis in our study required an order for >80% of the hospitalisation. Additionally, we found that having hematochezia, being a young male, having elevated platelets and being admitted on a biologic, all were associated with failure to order VTE prophylaxis at 24 h. With ongoing rectal bleeding, physicians may be more likely to withhold pharmacological prophylaxis for fear of exacerbating the bleeding. However, it has been demonstrated that prophylactic doses of anti-coagulation medications are safe in patients with active ulcerative colitis.21 In addition, physicians may assume that young men may be at less risk of VTE, possibly because ambulation is presumed; however this has not been demonstrated. It is not clear 945
J. L. Pleet et al. why there would be a relationship between admission platelet count and ordering of VTE prophylaxis. Platelets are an acute phase reactant and may be a surrogate for disease activity. Thus, patients with elevated platelet counts may have had more active disease resulting in more significant mucosal bleeding and iron deficiency anaemia, which may have deterred physicians from ordering prophylaxis. In this case, ordering physicians may have neglected VTE prophylaxis given the acuity of the presentation. While there was no association with C-reactive protein or erythrocyte sedimentation rate and VTE prophylaxis ordering, there were incomplete data for these parameters. Similarly, being admitted on a biologic may have been a surrogate for disease severity. However, it is also possible that this is a chance association given the low number of patients admitted on biologics. We also demonstrated that even when appropriate VTE prophylaxis was ordered, it often was not administered. In most instances, the reason for not giving prophylaxis was not recorded by the nurse. When the rationale was documented, patient ambulation and patient refusal were the two most common explanations for not administering the medication. To improve patient and nursing adherence, it may be more effective to prescribe a once-daily-prophylactic medication instead of a twice or thrice-daily medication, as previously demonstrated.32 In addition, patient and nursing education regarding the importance of pharmacological VTE prophylaxis is also likely to be beneficial. Studies are needed to further delineate why pharmacological prophylaxis is not prescribed and administered regularly as advised by current guidelines. Our study also suggests that the incidence of symptomatic VTE in hospitalised UC patients may be higher than previously described. Our VTE incidence of 5.3% (95% CI, 3.4–8.2%) is higher than the incidence of 2.03% (95% CI, 1.36–2.69%) quoted in an earlier study by Wang et al.9 which looked at VTE diagnosed on admission or at some point during admission. While the overall incidence of 6.1% perhaps represents the most appropriate risk for severe UC patients, the incidence of 4.5% (diagnosed during hospitalisation and within 1 month of discharge, but not on admission) better represents hospitalised UC patients’ risk for VTE. Regardless of which definition is used, VTE prophylaxis may be even more important than previously thought. There are several limitations to our study. This is a retrospective analysis, which may lead to confounding. 946
Additionally, this study was performed at a single tertiary referral centre, which may limit its generalizability. While most of the information was accessible in the electronic record and extensively documented, nursing notes were not available in 30% of cases. Thus, while we did obtain the ordering rates of nonpharmacological VTE prophylaxis, we were unable to completely evaluate adherence to these orders. Also, we defined adequate prophylaxis as pharmacological and viewed nonpharmacological prophylaxis as inadequate. Though some may view intermittent pneumatic compression devices or frequent ambulation as adequate VTE prophylaxis in lower risk patients, this is not supported by the current guidelines and so we did not feel this was sufficient for IBD patients who are at significantly elevated risk of VTE.
CONCLUSIONS Despite the recommendation that patients admitted to the hospital with ulcerative colitis flare should be given pharmacological venous thrombosis prophylaxis, our study found that most patients are not receiving adequate prophylaxis. This was due both to under-prescribing by physicians and inconsistent administration by the nursing staff. Given the high incidence of VTE demonstrated in this patient population, adequate prophylaxis is imperative. Quality improvement efforts focusing on physician and nursing education regarding the risk of VTE and the safety of VTE prophylaxis are needed to improve compliance. AUTHORSHIP Guarantor of the article: Julia L. Pleet. Author contributions: Julia L. Pleet and Byron P. Vaughn had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Pleet, Vaughn, Moss and Cheifetz: Concept and design. Pleet and Vaughn: Collection and management of data. Pleet, Vaughn and Morris: Analysis and Interpretation of data. Pleet, Vaughn, Moss and Cheifetz: Drafting of the manuscript. Pleet, Vaughn, Morris, Moss and Cheifetz: Critical revision of the manuscript for important intellectual content. Pleet, Vaughn and Morris: Statistical analysis. All authors approved the final version of the manuscript. ACKNOWLEDGEMENTS Declaration of personal interests: Moss has served on the advisory board of Janssen Pharmaceuticals and Aliment Pharmacol Ther 2014; 39: 940-948 ª 2014 John Wiley & Sons Ltd
Thromboembolism prophylaxis in severe active ulcerative colitis Abbvie formerly Abbot, and has received research funding from NIDDK, Helmsley Charitable Trust, Salix, Shire and Pfizer. Cheifetz has served on advisory boards for Jannsen Pharmaceuticals and Abbvie (formerly Abbot). Declaration of funding interests: None.
SUPPORTING INFORMATION Additional Supporting Information may be found in the online version of this article: Figure S1. Flow chart of cases reviewed. Table S1. Association of age and gender with failure to order venous thromboembolism prophylaxis.
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Aliment Pharmacol Ther 2014; 39: 940-948 ª 2014 John Wiley & Sons Ltd
The use of pharmacological prophylaxis against venous thromboembolism in hospitalised patients with severe active ulcerative colitis J. L. Pleet*, B. P. Vaughn†, J. A. Morris‡, A. C. Moss† & A. S. Cheifetz†
*Department of Medicine, Beth-Israel Deaconess Medical Center, Boston, MA, USA. † Division of Gastroenterology, BethIsrael Deaconess Medical Center, Boston, MA, USA. ‡ Department of Educational Psychology, University of Illinois at Urbana-Champaign, Champaign, IL, USA.
Correspondence to: Dr J. L. Pleet, Division of Internal Medicine, Beth-Israel Deaconess Medical Center, HCA, Shapiro 6th Floor, 330 Brookline Ave., Boston, MA 02215, USA. E-mail: [email protected]
Publication data Submitted 10 November 2013 First decision 12 December 2013 Resubmitted 16 January 2014 Accepted 16 February 2014 EV Pub Online 10 March 2014 This article was accepted for publication after full peer-review.
SUMMARY Background Hospitalised patients with inflammatory bowel disease are 1.5- to 3.5-fold more likely to develop venous thromboembolism compared to controls. Clinical guidelines recommend pharmacological prophylaxis. Aim To determine the rate of pharmacological venous thromboembolism prophylaxis prescription and administration in a cohort of hospitalised patients with severe active ulcerative colitis and to assess predictors of failure to order pharmacological prophylaxis at 24 h. Methods This is a retrospective review of hospitalised patients with severe active ulcerative colitis, identified by ICD-9-CM discharge code 556.x, admitted to a single tertiary care hospital from 1 January 2005 to 31 August 2012. Adequate thromboembolism prophylaxis was defined as an order for low-dose unfractionated heparin two to three times daily, low-molecular weight heparin 40 mg daily or fondaparinux 2.5 mg daily ordered and administered for >80% of the admission. Patient related factors associated with failure to order prophylaxis at 24 h were accessed as secondary outcomes. Results Three hundred and thirty-six patients were hospitalised with severe active ulcerative colitis. Hospitalists had prescribed appropriate pharmacological prophylaxis by 48 h in only 37% of cases. Of these, nurses administered all prescribed doses in 18% of cases. Only 7% of patients (22/304, 95% CI: 5– 11%) received adequate pharmacological prophylaxis for >80% of their hospitalisation. Hematochezia (P = 0.002), elevated platelets (P = 0.008), male gender coupled with younger age (P = 0.005) and admission on a biologic (P = 0.03) were associated with failure to order prophylaxis. Conclusion Hospitalised patients admitted with severe active ulcerative colitis are not receiving appropriate pharmacological venous thromboembolism prophylaxis. Aliment Pharmacol Ther 2014; 39: 940–948
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ª 2014 John Wiley & Sons Ltd doi:10.1111/apt.12691
Thromboembolism prophylaxis in severe active ulcerative colitis INTRODUCTION There are over 750 000 patients with ulcerative colitis (UC)1 in the United States. It is estimated that 15% of these patients will experience a flare of their disease that requires hospitalisation.2 Furthermore, multiple studies have demonstrated that patients with inflammatory bowel disease (IBD) are at a 1.5- to 3.5-fold increased risk of developing symptomatic venous thromboembolism (VTE) when compared to non-IBD patients.3–10 The increased risk of VTE is particularly elevated during periods of active disease and especially during hospitalisation.4 Importantly, the mortality from symptomatic VTE in patients with IBD has been reported to be as high as 22%11 and two-fold higher than non-IBD patients with VTE.7 Low-molecular-weight heparin, unfractionated heparin, fondaparinux and dalteparin are effective at decreasing the risk of symptomatic VTE in hospitalised medical patients.12–20 Prophylactic VTE doses of unfractionated heparin and low-molecular-weight heparin have been demonstrated to be safe,21 and possibly therapeutic in patients with active ulcerative colitis.22, 23 Several clinical guidelines recommend the use of pharmacological VTE prophylaxis for hospitalised patients with IBD, particularly for those patients with severe acute UC.24–28 However, few studies have examined the adequate use of VTE prophylaxis in this population. One recent retrospective study showed that 68% of patients had at least one order for VTE prophylaxis.29 Similarly, two recent surveys noted that only 34.6–72% of gastroenterologists were likely to prescribe pharmacological VTE prophylaxis in hospitalised IBD patients.30, 31 Increasingly, hospitalists are the primary care provider for an in-patient during a UC flare and may be less aware of the increased risk of VTE and the recommendations regarding appropriate VTE prophylaxis in this patient population. Therefore, we set out to determine the rate of pharmacological venous thromboembolism prophylaxis prescription and administration in a cohort of hospitalised patients with severe ulcerative colitis. We also set out to assess predictors of failure to order appropriate pharmacological VTE prophylaxis. MATERIALS AND METHODS Chart review This was a retrospective cohort study of adult patients admitted to Beth Israel Deaconess Medical Center (Boston, MA, USA) between 1 January 2005 and 31 August 2012. All patients were under the care of the hospitalist Aliment Pharmacol Ther 2014; 39: 940-948 ª 2014 John Wiley & Sons Ltd
management team, with the gastroenterology service following in consultation. Patients were identified using electronic records and a discharge diagnosis of ulcerative colitis (ICD-9 code 556.x). The electronic medical records contain all discharge summaries, laboratory results and radiology, pathology and procedure reports. Additionally, physician orders were available through an electronic ordering system that included the date and times associated with all orders. Starting in June 2008, the nursing medication administration records were scanned into the electronic medical record and available for review. Medical records including electronic orders and scanned nursing records were manually reviewed by two physicians (JLP, BPV). Study data including admission characteristics (date, hospital transfer, length of stay, primary service) and patient characteristics (duration of disease, medication regimen on admission, extent of disease, UC symptoms including number of bowel movements and hematochezia, admission labs, in-patient UC therapy and diagnosis of VTE) were collected and managed using REDCap electronic data capture tools hosted at BIDMC. REDCap (Research Electronic Data Capture) is a secure, web-based application designed to support data capture for research studies. Study data including VTE prophylaxis recommendations (drug and dosing) made on initial consultation by the gastroenterology consulting service were obtained for years 2011 and 2012, when initial consultation notes were documented consistently in the online medical record. Patients were included more than once if they had multiple unique admissions over the study period.
Inclusion and exclusion criteria Patients were included in the study if they had a severe UC flare, defined as having one or more of the entry criteria: (i) Having greater than six bowel movements per day, (ii) Requiring treatment with intravenous steroids, infliximab or cyclosporine, (iii) Undergoing colectomy for treatment of UC flare during the admission. Patients were excluded if they were determined to have Crohn’s disease, indeterminate colitis or mild or moderate UC flare. Patients were also excluded if they were admitted on a therapeutic dose of anti-coagulation or had a VTE diagnosed on day 1 of admission. See Figure S1 for a flow chart of the cases reviewed. Outcomes definitions The primary outcome of this study was to define the incidence of adequate VTE prophylaxis for patients hos941
J. L. Pleet et al. pitalised with severe UC. Adequate VTE prophylaxis was defined as appropriately dosed pharmacological VTE prophylaxis ordered and administered for >80% of the hospitalisation. We first identified whether patients were ordered for appropriate VTE prophylaxis, which included low-dose subcutaneous unfractionated heparin two or three times daily, subcutaneous low-molecular-weight heparin 40 mg daily or subcutaneous fondaparinux 2.5 mg daily. We assessed for the presence of active orders within 24 h and 48 h of admission. We also documented the per cent of hospital days for which the patient had an active order written. We defined a patient as having an adequate VTE prophylaxis prescription if they had an active order for >80% of their hospitalisation. Data on nonpharmacological VTE prophylaxis, such as ambulation at least three times daily or intermittent pneumatic compression devices, was examined but did not qualify as adequate VTE prophylaxis. Nursing records were reviewed to establish the VTE prophylaxis administration rate. Adherence was defined as administration of ordered VTE prophylaxis for >80% of the prescribed doses. The administration rate was recorded using the following ranges: 100%, 80–99%, 50– 79%, 25–49% or 80% of the hospitalisation but did not have nursing records to review were excluded from this portion of the study. Our secondary outcome was to identify predictors of failure to order prophylaxis within 24 h. Patient related factors including age, gender, day of admission, year of admission, admitting service, hematochezia, stool frequency, medication on admission, admission haemoglobin, admission platelets and admission C-reactive protein were analysed as possible predictors of pharmacological VTE prophylaxis ordering.
Statistical analysis Descriptive data are presented as a mean with standard deviation or median with inter-quartile range. Nominal variables were analysed with v2 or Fisher’s exact test as appropriate. Continuous variables were analysed with t-test or Wilcoxan Rank-Sum as appropriate. The primary outcome of incidence of adequate VTE prophylaxis 942
is presented as a rate with binomial confidence intervals. For the secondary outcome, we analysed all covariates that achieved statistical significance (P < 0.1) from the univariate model, into a forward, stepwise multiple logistic regression analysis. In addition, covariates (age, gender, admission service and weekend admission) that did not achieve statistical significance in the univariate model, but were felt a priori to be associated with the secondary outcome, were included in the final logistic regression analysis. In order to attain an odds ratio, we dichotomized platelets into elevated (platelet counts >440 K/lL) or not. A P-value of 6 bowel movements Not recorded Median C-reactive protein on admission (IQR), mg/L Median erythrocyte sedimentation rate (IQR), mm/hr Median white blood count (IQR), K/lL Median haemoglobin on admission (IQR), g/dL Median platelets (IQR), K/lL Median Creatinine (IQR), mg/dL Median albumin (IQR), g/dL Admission service Medicine NonMedicine Weekend admission
VTE prophylaxis ordered (N = 126)
No VTE prophylaxis ordered (N = 210)
42 (30,57)
36 (26,51)
58 68 3 24 7 105 12
(46%) (54%) (1,8) (21,29) (6%) (83%) (10%)
111 99 3 24 7 199 24
2 19 21 16 39 29
(1%) (15%) (17%) (13%) (31%) (23%)
3 17 32 39 57 62
(53%) (47%) (1,7) (20, 27) (3%) (95%) (11%)
P 0.01† 0.23† 0.41 0.33 0.31 0.001‡ 0.58
(1%) (8%) (15%) (19%) (27%) (30%)
0.22
67 (53%) 19 (15%) 40 (32%)
107 (51%) 43 (20%) 60 (29%)
0.45
75 30 10 15
127 42 33 23
(60%) (20%) (16%) (11%)
0.89 0.40 0.04§ 0.78
(11%) (75%) (14%) (8.7,65.7) (15,60) (7.8,13.5) (10.6,13.5) (289,506) (0.7,1.0) (0.6)
0.24
22 88 16 27.0 36 10.3 12.1 359 0.8 3.4
(60%) (24%) (8%) (12%) (17%) (70%) (13%) (4.0,93.9) (10,63) (7.2,13.7) (10.4,13.2) (272,463) (0.7,1.0) (0.7)
121 (96%) 5 (4%) 23 (18%)
23 158 29 29.8 36 10.2 12.1 381 0.8 3.4
205 (98%) 5 (2%) 46 (22%)
0.91 0.65 0.75 0.98 0.05¶ 0.19 0.68 0.41 0.42
* Venous thromboembolism. † Evidence of effect modification was found on age by gender, P = 0.005. ‡ Hematochezia remained statistically significant in multiple regression analysis, P = 0.002. § Admission on a biologic remained statistically significant in multiple regression analysis, P = 0.04. ¶ Platelets remained statistically significant in multiple regression analysis, P = 0.008.
more appropriate VTE prophylaxis was seen over time (P = 0.06). Of the patients admitted in 2011 and 2012, initial gastroenterology consultation notes were available in 99% (88/89) of cases and of those cases the initial gastroenterology consult recommendation mentioned Aliment Pharmacol Ther 2014; 39: 940-948 ª 2014 John Wiley & Sons Ltd
VTE prophylaxis in 9.0% (8/88) of cases. Thirteen per cent (1/8) included specific drug recommendations. None of the gastroenterology consult notes included specific dosing recommendations. Of the eight cases in which VTE prophylaxis was recommended by the 943
J. L. Pleet et al. nursing records were available in 69% (113/164) of cases. Table 3 shows the rates of nursing administration of VTE prophylaxis. When prescribed, only 30% (34/113) of patients were administered >80% of their doses. Only 7% (22/304, 95% CI: 5–11%) of patients met the primary endpoint of receiving adequate VTE prophylaxis (appropriate pharmacological VTE prophylaxis ordered and administered for >80% of the hospitalisation). When assessing factors associated with failure to order pharmacological VTE prophylaxis, age, hematochezia, admission on biologics and admission platelets had a P-value of 80% doses ordered Adequate prophylaxis for >80% hospitalisation
37.5 30 7
* Venous thromboembolism.
gastroenterology consultants, seven patients were ordered for pharmacological VTE prophylaxis at 48 h (P = 0.14). For patients in whom pharmacological prophylaxis was ordered for >80% of the hospitalisation, scanned 60
Percentage of study patients (%)
51 50 40 31 30 18
20 10 0
1–80
0
> 80
Percentage of hospital days venous thromboembolism prophylaxis was ordered (%)
Figure 1 | Percentage of hospital days with venous thromboembolism prophylaxis ordered.
60
Percent VTE prophylaxis ordered at 24 h
P = 0.06 50
40
30
20
10
0 2004
944
2005
2006
2007
2008 2009 Year
2010
2011
2012
2013
Figure 2 | Pharmacologic venous thromboembolism prophylaxis ordered at 24 h by year. VTE, venous thromboembolism. Aliment Pharmacol Ther 2014; 39: 940-948 ª 2014 John Wiley & Sons Ltd
Thromboembolism prophylaxis in severe active ulcerative colitis Table 3 | Nursing administration of pharmacological VTE* prophylaxis Percentage of doses administered (%)
N = 113
440 K/lL, only 30% had an order for VTE prophylaxis compared to 42% with patients whose platelet count was 80% of the hospital course. The Aliment Pharmacol Ther 2014; 39: 940-948 ª 2014 John Wiley & Sons Ltd
majority of the patients who developed a symptomatic VTE did not receive any pharmacological VTE prophylaxis (73.3%, 11/15).
DISCUSSION In our cohort of patients with severe UC, only 7% (95% CI: 5–11%) of patients received adequate VTE prophylaxis despite existing recommendations.24–28 Fewer than 40% of patients have an adequate pharmacological order for VTE prophylaxis within 24 h of hospital admission. Even when adequate VTE prophylaxis was ordered, only 30% of patients received >80% of the prescribed dose. It is encouraging that the overall prescription of VTE prophylaxis seems to be increasing with time, with just over 50% of patients ordered for prophylaxis in 2012. This overall trend likely represents the dissemination of information from guidelines and increased physician awareness regarding the increased risk of VTE and need for prophylaxis. While the gastroenterology service did not frequently provide recommendations regarding VTE prophylaxis, when they did, most patients were ordered for appropriate VTE prophylaxis. Our rates of VTE prophylaxis are lower than reported by Tinsley et al.,29 which showed a 67.6% prescribing rate at a single tertiary care centre, with 66% of those doses administered to patients. The definition of VTE prophylaxis in the study by Tinsley et al.29 is likely to account for some of the difference. Their endpoint for VTE prophylaxis was ‘at least one order for pharmacological prophylaxis at any point during the admission.’ This endpoint does not account for the total amount of time a patient was ordered for prophylaxis during the admission. Our outcomes were more stringent and looked at active orders at 24 (and 48) h and percentage of days there was an active order for VTE prophylaxis. The definition of adequate VTE prophylaxis in our study required an order for >80% of the hospitalisation. Additionally, we found that having hematochezia, being a young male, having elevated platelets and being admitted on a biologic, all were associated with failure to order VTE prophylaxis at 24 h. With ongoing rectal bleeding, physicians may be more likely to withhold pharmacological prophylaxis for fear of exacerbating the bleeding. However, it has been demonstrated that prophylactic doses of anti-coagulation medications are safe in patients with active ulcerative colitis.21 In addition, physicians may assume that young men may be at less risk of VTE, possibly because ambulation is presumed; however this has not been demonstrated. It is not clear 945
J. L. Pleet et al. why there would be a relationship between admission platelet count and ordering of VTE prophylaxis. Platelets are an acute phase reactant and may be a surrogate for disease activity. Thus, patients with elevated platelet counts may have had more active disease resulting in more significant mucosal bleeding and iron deficiency anaemia, which may have deterred physicians from ordering prophylaxis. In this case, ordering physicians may have neglected VTE prophylaxis given the acuity of the presentation. While there was no association with C-reactive protein or erythrocyte sedimentation rate and VTE prophylaxis ordering, there were incomplete data for these parameters. Similarly, being admitted on a biologic may have been a surrogate for disease severity. However, it is also possible that this is a chance association given the low number of patients admitted on biologics. We also demonstrated that even when appropriate VTE prophylaxis was ordered, it often was not administered. In most instances, the reason for not giving prophylaxis was not recorded by the nurse. When the rationale was documented, patient ambulation and patient refusal were the two most common explanations for not administering the medication. To improve patient and nursing adherence, it may be more effective to prescribe a once-daily-prophylactic medication instead of a twice or thrice-daily medication, as previously demonstrated.32 In addition, patient and nursing education regarding the importance of pharmacological VTE prophylaxis is also likely to be beneficial. Studies are needed to further delineate why pharmacological prophylaxis is not prescribed and administered regularly as advised by current guidelines. Our study also suggests that the incidence of symptomatic VTE in hospitalised UC patients may be higher than previously described. Our VTE incidence of 5.3% (95% CI, 3.4–8.2%) is higher than the incidence of 2.03% (95% CI, 1.36–2.69%) quoted in an earlier study by Wang et al.9 which looked at VTE diagnosed on admission or at some point during admission. While the overall incidence of 6.1% perhaps represents the most appropriate risk for severe UC patients, the incidence of 4.5% (diagnosed during hospitalisation and within 1 month of discharge, but not on admission) better represents hospitalised UC patients’ risk for VTE. Regardless of which definition is used, VTE prophylaxis may be even more important than previously thought. There are several limitations to our study. This is a retrospective analysis, which may lead to confounding. 946
Additionally, this study was performed at a single tertiary referral centre, which may limit its generalizability. While most of the information was accessible in the electronic record and extensively documented, nursing notes were not available in 30% of cases. Thus, while we did obtain the ordering rates of nonpharmacological VTE prophylaxis, we were unable to completely evaluate adherence to these orders. Also, we defined adequate prophylaxis as pharmacological and viewed nonpharmacological prophylaxis as inadequate. Though some may view intermittent pneumatic compression devices or frequent ambulation as adequate VTE prophylaxis in lower risk patients, this is not supported by the current guidelines and so we did not feel this was sufficient for IBD patients who are at significantly elevated risk of VTE.
CONCLUSIONS Despite the recommendation that patients admitted to the hospital with ulcerative colitis flare should be given pharmacological venous thrombosis prophylaxis, our study found that most patients are not receiving adequate prophylaxis. This was due both to under-prescribing by physicians and inconsistent administration by the nursing staff. Given the high incidence of VTE demonstrated in this patient population, adequate prophylaxis is imperative. Quality improvement efforts focusing on physician and nursing education regarding the risk of VTE and the safety of VTE prophylaxis are needed to improve compliance. AUTHORSHIP Guarantor of the article: Julia L. Pleet. Author contributions: Julia L. Pleet and Byron P. Vaughn had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Pleet, Vaughn, Moss and Cheifetz: Concept and design. Pleet and Vaughn: Collection and management of data. Pleet, Vaughn and Morris: Analysis and Interpretation of data. Pleet, Vaughn, Moss and Cheifetz: Drafting of the manuscript. Pleet, Vaughn, Morris, Moss and Cheifetz: Critical revision of the manuscript for important intellectual content. Pleet, Vaughn and Morris: Statistical analysis. All authors approved the final version of the manuscript. ACKNOWLEDGEMENTS Declaration of personal interests: Moss has served on the advisory board of Janssen Pharmaceuticals and Aliment Pharmacol Ther 2014; 39: 940-948 ª 2014 John Wiley & Sons Ltd
Thromboembolism prophylaxis in severe active ulcerative colitis Abbvie formerly Abbot, and has received research funding from NIDDK, Helmsley Charitable Trust, Salix, Shire and Pfizer. Cheifetz has served on advisory boards for Jannsen Pharmaceuticals and Abbvie (formerly Abbot). Declaration of funding interests: None.
SUPPORTING INFORMATION Additional Supporting Information may be found in the online version of this article: Figure S1. Flow chart of cases reviewed. Table S1. Association of age and gender with failure to order venous thromboembolism prophylaxis.
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