Thromboembolism in inflammatory bowel disease: results from a prospective, population-based European inception cohort

Scandinavian Journal of Gastroenterology. 2014; 49: 820 825 ORIGINAL ARTICLE Thromboembolism in inflammatory bowel disease: results from a prospective, population-based European inception cohort RUNE ISENE 1,2, TOMM BERNKLEV 2,3, OLE HØIE 4, EBBE LANGHOLZ 5, EPAMEONONDAS TSIANOS 6, REINHOLD STOCKBRÜGGER 7, SELWYN ODES 8, MILADA SMÅSTUEN 2,9, BJØRN MOUM 1,2 & ON BEHALF OF THE EC-IBD STUDY GROUP 1 Department of Gastroenterology, Oslo University Hospital, Oslo, Norway, 2 Institute of Clinical Medicine, University of Oslo, Oslo, Norway, 3 Research and Developement Department, Telemark Hospital Trust, Skien, Norway, 4 Department of Internal Medicine, Sørlandet Hospital, Arendal, Norway, 5 Medical Department F, Gentofte Hospital, University of Copenhagen, Gentofte, Denmark, 6 1st Division of Internal Medicine, and Division of Gastroenterology, Faculty of Medicine, School of health Sciences, University of Ioannina, 45110 Ioannina, Greece, 7 Department of Internal Medicine, University Hospital Ferrara, Ferrara, Italy, 8 Department of Gastroenterology and Hepatology, Soroka Medical Center and Ben Gurion University, Beer Sheva, Israel, and 9 Department of Biostatistics, Oslo University Hospital, Oslo, Norway Abstract Background. Patients with inflammatory bowel disease (IBD) have proven an increased risk of venous thromboembolism (VTE), particularly when hospitalized. The estimate of the true risk varies considerably between studies, primarily due to differences in methodology. We set out to determine the incidence of VTE in a population-based European inception cohort. Methods. IBD patients were incepted into a cohort that was prospectively followed from the early 1990s to the early 2000s. A total of 1145 patients were followed for a total of 10,634 patient-years (p.y.). Results. A total of 19 thromboembolic events were identified 13 deep vein thrombosis and 6 with pulmonary embolism. The incidence rate of VTE was 1.8 per 1000 p.y. Conclusion. The risk of VTE was elevated in this IBD cohort but lower than previously reported. The highest risk was seen in hospitalized patients, but corticosteroids-requiring disease in outpatients also conferred some risk. Key Words: Crohn s disease, thromboembolism, ulcerative colitis Introduction Venous thromboembolism (VTE) includes deep vein thrombosis (DVT) and pulmonary embolism (PE). The elevated risk of VTE in inflammatory bowel disease (IBD) has been recognized for at least 75 years, primarily in ulcerative colitis (UC), when Bargen and Barker at the Mayo Clinic in 1936 published a report of VTE as a complication of UC, with a prevalence of 1.2% in a cross-sectional study of 1500 patients [1]. Subsequent cross-sectional studies put the risk of UC at 6 7% [2 4], but little consideration was given to risk over time. A necropsy study from 1966 found VTE in 39% of UC patients [5], much higher than in the previous clinical cohorts, implying that a significant proportion of VTE went unrecognized antemortem. The first report of an increased risk in Crohn s disease (CD) was published in 1986 [6]. The first population-based cohort study was published in 2001 [7], and after that two major population-based studies have been published [8,9]. Recently, much effort has been made to quantify the risk of VTE in ambulatory patients with active disease, which appears elevated as well [10]. The increased risk of VTE due to hypercoagulability is caused by variety of factors; many of them present in IBD: elevated number of platelets, platelet activation, elevated thrombin, decreased levels of Correspondence: Prof. Bjørn Moum, Department of Gastroenterology, Oslo University Hospital and Faculty Clinics of Medicine, University of Oslo, Oslo, Norway. E-mail: bjorn.moum@medisin.uio.no (Received 15 March 2014; revised 25 March 2014; accepted 27 March 2014) ISSN 0036-5521 print/issn 1502-7708 online Ó 2014 Informa Healthcare DOI: 10.3109/00365521.2014.910545

Thromboembolism in ulcerative colitis and Crohn s disease 821 activated protein C, and reduced tissue plasminogen activator, which may all contribute to the risk. Genetic defects in the anticoagulation system appear to play a minor role. The primary aim of the present study was to describe in a population-based inception cohort of IBD patients, the incidence rate (IR) of thromboembolic disease during the first decade after diagnosis. Secondary aims were to assess the impact of disease activity and of other risk factors on the incidence of VTE. Material and methods The present study is a part of the EC-IBD project the European Collaborative Study of Inflammatory Disease [11]. From 1 October 1991 to 30 September 1993, the Study Group incepted a population-based cohort of patients with IBD, aged 16 years, who were subsequently followed prospectively. The 10-year follow-up study was conducted between 1 August 2002 and 31 January 2004. Patients had been followed from inception to at least 10 years, until death, or lost to follow up, whatever happened first. Study population Totally nine centers from Norway, Denmark, the Netherlands, Spain, Italy (2 centers), Greece (2 centers), and Israel complied. Of the 1145 available patients for analysis, 111 died during follow up (9.7%) and 154 more were lost to follow up (13.4%). The median follow-up time was 10.1 years (range 0.1 12.0). Two-thirds of the patients had UC. These were on average significantly older than patients with CD, with median age at diagnosis being 36.5 years (range 16 88). The total patient-years (p.y.) comprised 6268 p.y. in the age group 16 44 years, 3849 p.y. in the age group 45 74 years, and 517 p.y. in the age group above 74 (Table I). Data acquisition Patients were treated at their individual centers according to the practice and standard of care as given by their physicians. Inpatient and outpatient records were cumulatively reviewed regarding diagnosis of VTE, hospitalization, drug therapy, surgery, cancer, and for other information. Data were entered into a database (physically hosted/located at the University Hospital in Maastricht) by investigators at each center using internet-based data acquisition tools. Details of the methods used in this follow-up study project have been extensively described elsewhere [11 13]. Classification and definitions CD and UC were defined as per the criteria of Lennard-Jones and Truelove and Witts, with diagnosis determined at inception and revised later as required [11]. All subsequent clinical data were recorded prospectively in patient records at each center, and extracted for study purposes at the 10-year time point. DVT was defined as thrombosis in the deep veins of the lower or upper extremity, PE as embolism in the pulmonary arteries. All cases had to be confirmed by radiological methods. Information about all surgical procedures and incident cancers were extracted as well. Hospitalizations were recorded with admission and discharge dates. Information about use of glucocorticoid as well as other medication was registered in 3-month intervals. Information about past and present smoking habits and contraceptive use was gathered in a patient interview at the 10-year time point. To assess the impact of disease activity on thrombosis risk, patients were at any given time point classified as belonging to one of three mutually exclusive states of activity: IBD requiring hospitalization, with or without surgery; IBD requiring systemic glucocorticoids in an ambulatory setting; and IBD in an ambulatory setting not requiring systemic glucocorticoids. Patients moved in and out of the different disease states over the total course of the observation time, contributing time at risk to each category. It was assumed that disease activity increased across the three categories, with IBDrelated hospitalization as the most severe, ambulatory steroid-treated flare as intermediate, and ambulatory stage, (hospitalization- and steroid-free) as the least severe. Although other factors beside disease activity (age, comorbidity) will impact on the decision to Table I. Patient characteristics. UC CD Female Male Overall Number (%) 781 (68%) 364 (32%) 552 (48%) 593 (52%) 1145 (100%) Female n (%) 319 (48%) 158 (50%) 552 (48%) Mean age at inclusion (SD) 42.0 (17) 36.6 (17) 39.1 (18) 41.5 (17) 40.3 (17) Total observation time, p.y. 7292 3342 5143 5491 10,634

822 R. Isene et al. hospitalize a patient with IBD, in general it will be the most severe cases that will need hospitalization. The duration of the time of VTE risk will be uncertain and to the best estimates. To be conservative, that is not to overestimate, we have used the exact time that patients were in hospital as the time at risk. For outpatients treated with systemic glucocorticoids, the time at risk was assumed to be the time when glucocorticoids are used. Since such therapy is rarely or never used for maintenance of remission, but for induction of remission, this seems a valid assumption. Statistical analyses Data were described with median and range for continuous variables and with proportions and percentages for categorical ones. Observation time was calculated from the date of IBD diagnosis to VTE, death, date when lost to follow up or study end, whichever appeared first. Times to VTE were modeled using Cox proportional hazards model and the results are expressed as hazard rate ratios (HR) with 95% confidence intervals (CI). Both IRs and IR ratios (IRRs) were calculated using Poisson regression. The IRs for VTE were calculated for the whole sample and separately for each age group and for type of disease activity. The IRRs were computed according to disease activity and place of treatment with remission being the reference rate. The results are presented as IR with 95% CI and IRR with disease activity in remission as reference. The p-values <0.05 were considered statistically significant. All tests were two-sided. All analyses were performed using SPSS and Stata. Ethical considerations Each participating center secured the approval of their regional or national ethics committee. All participants were given information orally and in writing, and were asked to provide written consent. Results Incidence of VTE There were 19 cases of VTE over the course of 10,634 p.y. of observation. The crude IR was 1.79 per 1 000 p.y. (95% CI: 1.08 2.79 per 1000 p.y.) Age standardization to the WHO World Population Standard gives a standardized IR of 1.48 per 1000 p.y. (95% CI: 0.84 2.38). There were 18 cases of DVT, for an IR of 1.69 per 1000 p.y. (95% CI: 1.00 2.68). There were five cases of PE, among which DVT was concurrently diagnosed in four cases. The IR of PE was 0.56 per 1000 p.y. (95% CI: 0.21 1.23). Age distribution of VTE The risk of VTE in the study population increased with age. (Table II). Gender Males were more at risk of having VTE compared to females, IRR = 3.5 (95% CI: 1.1 14.5), p = 0.02. Unadjusted gender-specific IR were 14/5491 = 2.73 per 1000 p.y. (95%CI: 1.53 4.51) for males and 4/5143 = 0.78 (95% CI: 0.21 1.99) for females. IBD diagnosis Fifteen patients with VTE had UC, four had CD, and UC patients were 5.5 years older. Unadjusted specific IR were 15/7292 = 2.06 per 1000 p.y. (1.15 3.39) for UC and 4/3342 = 1.20 per 1000 p.y. (0.33 3.07) for CD. UC patients were 1.7 times more at risk of having VTE compared to CD patients; however, this difference did not reach statistical significance, IRR = 1.7 (0.6 7.1). VTE and disease activity There were 1376 IBD-related hospital admissions for a total of 18,257 hospital days, corresponding to 50 p. y. of hospital time. Admissions had a median duration of 10 days and a range of 1 272 days. A total of 584 patients had flares that required glucocorticoids at any time. Of these, 338 had UC (44% of UC patients) and 246 had CD (71% of CD patients). There were in total 904 p.y. of recorded use of systemic glucocorticoids, of which 879 were for ambulatory patients. The remaining 9,705 p.y. (of a total of 10,634) were spent in the hospitalization- and steroid-free states (remission as defined above). The Exact Poisson regression analysis indicates a trend toward increasing risk of VTE with increasing disease activity; however, this trend did not reach statistical significance most likely due to limited statistical power (Table III). The IRRs of VTE Table II. Age stratified risk of VTE. Age group Cases P.y. IR per 1000 p.y. (CI) 16 44 7 6266 1.12(1.09;1.15) 45 74 8 3848 2.08 (2.01;2.15) 75+ 4 517 7.74 (7.29;8.19)

Thromboembolism in ulcerative colitis and Crohn s disease 823 Table III. VTE and disease activity according to the place of treatment. Disease activity were higher in the hospitalized category than in the steroid-requiring category, and the IRR was higher in the steroid-requiring category than in the remission category (Table III). Surgery Two patients had VTE during admissions for surgery one of them for an elective subtotal colectomy and the other for an elective ileocecal resection. Cancer No patient had VTE subsequent to the diagnosis of cancer. However, one patient had a possible cancerrelated VTE this was a male patient with CD, 76 years of age at diagnosis of IBD, who had a DVT and died 1 year later, with small-cell lung carcinoma diagnosed at autopsy. Smoking Time (p.y.) There was no significant difference in VTE rate among patients who were smoking or not smoking during the time of the study or who had been (or not) smokers at any time (n = 747). Oral contraceptives VTE events IR per 1000 p.y. IRR* Hospitalization 50.0 5 100 88.5 2 surgical patients 3 medical patients Ambulatory 879 3 3.4 3.0 flare Remission 9705 11 1.13 1 (reference) Sum 10,634 19 1.8 (1.1, 2.8) - *Compared to IR per 1000 p.y. in remission. There was no significant difference in VTE rate among women who did or did not use oral contraceptives at the time of the study (n = 232) or who had or had not at any time used oral contraceptives (n = 378). Pregnancy None of the recorded VTEs occurred during pregnancy or the immediate post-partum (first month) period. Mortality One patient who was 75 years old died within 30 days after diagnosis of VTE and PE. When adjusted for age, mortality was not higher among IBD patients with VTE than without. Discussion The incidence of VTE in IBD is low only 19 cases in 1145 patients who were followed for 10,634 p.y. We estimate the incidence of VTE in IBD in this European cohort to be around 1.8 cases per 1000 p.y. Although figures vary with methodology, studies of VTE risk place the incidence of VTE in the general population at 0.66 1.43 per 1000 p.y. Thus, the risk of VTE appears elevated in IBD, but less so than was reported in other population-based studies. We find a nonsignificant trend toward increasing risk of VTE with increasing disease activity and, in the remission disease state, the risk of VTE is low (Table III), perhaps approaching that in the general population. Thus, one reason for the low overall incidence of VTE in the cohort as a whole may be that a small proportion of the follow-up time is spent in active disease states. In our study, 9705 of 10,634 p.y. are spent in hospitalization- and steroid-free remission, that is, 91%, and less than 10% in active disease states. In contrast, in a population-based study by Grainge et al. published in 2010 [8], where the definitions of remission and flares are the same as ours, the proportion of follow-up time spent in remission is 75%. The Grainge et al. study seems to be composed to a large degree of shorter follow-up times than ours, reporting a mean of 3.9 p.y. One might speculate that since IBD is more active in the first years after diagnosis, and then in many patients more quiescent disease course later on, a short average follow up will give more time spent in active disease and a higher overall risk of VTE. Grip et al. in 2000 found a very low incidence of VTE among IBD patients of 1.5/1000 p.y. [10]., which was in fact no higher than the incidence in the background population. However, the mean age of IBD patients with VTE was significantly lower than in controls, meaning that the ratio of the standardized IR is probably elevated. The authors restricted their conclusion that IBD promotes VTE at younger age.

824 R. Isene et al. Bernstein et al. in 2001 found an IR of 4.6/1000 p. y., with an IRR compared to age- and sex-matched controls of 3.5 [7]. Grainge et al. in 2010 found an IR (risk) of 2.6/1000 p.y., but incidence in the control population was low at 0.6/1000 p.y., giving a HR of 3.4 compared to age- and sex-matched controls when further controlling for body mass index, smoking, and malignancy [8]. Finally, Kappelman et al. in 2011 found an IR of 2.4/1000 p.y., with an IR in controls of 1.3/1000 p.y., giving an IRR of 2.0 [9]. Additionally, Grainge et al. for the first time showed that the risk of VTE is significantly increased also in active disease not severe enough to warrant hospitalization, although absolute rates were lower than in the hospitalized group [8]. The present study lends some support to this notion, with a strongly increased IR in hospitalized patients, but also an elevated IR in ambulatory patients during flares requiring steroids, although the latter difference did not reach statistical significance. However, the IR in this group is one-half of that found in the study by Grainge et al. None of the known major risk factors for VTE appeared to play a significant role in the present study, suggesting that the risk is conferred by IBD itself. It should, however, be emphasized that low absolute event numbers prohibit studying the importance of this relevant risk factors with precision. The strength of the present study is the prospectively population-based and incepted nature of the cohort. The follow up of this large population of IBD cases have further been over a considerable time period, and even that the registered number of events is restricted. This study which was closed after the 10 years of follow up could if continued have revealed further cases and increased the numbers for analytical precision and more definitive conclusions. We do however think, as discussed previously, the highest risk of VTE is at the beginning of the disease course, and that the incidence of VTE steadily declines as years pass from diagnosis. The limitation is the low number of VTE events; thus, our estimates are of limited precision and CIs are wide. Moreover, we fail to reach levels of statistical significance in our Poisson model. Possibilities for bias are present. We use hospitalization and systemic steroid use as markers for disease activity. The precision of these markers will be lowered by the fact that these states are dependent on other factors besides disease activity availability of hospital facilities, local tradition, and so on. However, we maintain that in aggregate, hospitalized patients will on average be sicker than ambulant ones, and steroid-treated patients will be sicker than those without steroid treatment. There is also the problem of underdiagnosis: it is known from the general population that VTE is frequently unrecognized, and we are unable to ascertain the extent of this underdiagnosis in our cohort. This, however, is common to all the published population-based studies of VTE in IBD. Detection bias could also be present, where an increased index of suspicion is present in IBD leading to an increase in diagnosis of VTE; however, the major publications demonstrating this association were unpublished at the time of follow up for most of this study (the 1990s). Finally, all clinical information were gathered retrospectively from patients interviews and hospital records, possibly underreporting some of the events, which can provide a lower incidence even if the planning of the study was prospectively performed. Is the risk of VTE in ambulatory patients with active disease sufficient to warrant prophylactic anticoagulation? We would tend to think not, given that the present study finds an even lower absolute rate of VTE than Grainge et al. [8] study population. However, in selected patients with additional risk factors, the benefit may possibly outweigh the risk for instance, ambulant IBD patients with active disease who have had a previous VTE, or who have cancer. We further think that according to guidelines, hospitalized patients who in general is sicker, should have anticoagulation [14]. The role of such complex risk stratification schemes could possibly be elucidated in further research. In summary, the overall risk of VTE found in our study is even lower than previous reported. Active disease with or without hospitalization and previous risk factors of VTE could warrant prophylactic anticoagulant therapy. Why the incidence of VTE in our study is lower than in similar populations in addition to what have been discussed must be considered in the study setting. The time of the follow up in the late 1990s to the mid 2000s, close monitoring by dedicated IBD specialists in multidisciplinary teams, and treatment with newer anti-inflammatory drugs available, have all been crucial. This should result in cautious recommendations for the care and monitoring of IBD to illustrate the gain produced by this study for patients and society. Acknowledgement This study was supported in part by the European Commission as a fifth framework shared cost action (QLG4-CT-2000-01414). Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

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