Thromboembolism in inflammatory bowel disease

Scandinavian Journal of Gastroenterology. 2014; 49: 820–825

ORIGINAL ARTICLE

Scand J Gastroenterol Downloaded from informahealthcare.com by Oslo universitetssykehus Aker on 09/18/14 For personal use only.

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

RUNE ISENE1,2, TOMM BERNKLEV2,3, OLE HØIE4, EBBE LANGHOLZ5, EPAMEONONDAS TSIANOS6, REINHOLD STOCKBRÜGGER7, SELWYN ODES8, MILADA SMÅSTUEN2,9, BJØRN MOUM1,2 & ON BEHALF OF THE EC-IBD STUDY GROUP 1

Department of Gastroenterology, Oslo University Hospital, Oslo, Norway, 2Institute of Clinical Medicine, University of Oslo, Oslo, Norway, 3Research and Developement Department, Telemark Hospital Trust, Skien, Norway, 4Department of Internal Medicine, Sørlandet Hospital, Arendal, Norway, 5Medical Department F, Gentofte Hospital, University of Copenhagen, Gentofte, Denmark, 61st Division of Internal Medicine, and Division of Gastroenterology, Faculty of Medicine, School of health Sciences, University of Ioannina, 45110 Ioannina, Greece, 7Department of Internal Medicine, University Hospital Ferrara, Ferrara, Italy, 8Department of Gastroenterology and Hepatology, Soroka Medical Center and Ben Gurion University, Beer Sheva, Israel, and 9Department 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: [email protected]

(Received 15 March 2014; revised 25 March 2014; accepted 27 March 2014) ISSN 0036-5521 print/ISSN 1502-7708 online 2014 Informa Healthcare DOI: 10.3109/00365521.2014.910545

Thromboembolism in ulcerative colitis and Crohn’s disease


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

821

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.

Number (%) Female n (%) Mean age at inclusion (SD) Total observation time, p.y.

UC

CD

Female

Male

Overall

781 (68%) 319 (48%) 42.0 (17) 7292

364 (32%) 158 (50%) 36.6 (17) 3342

552 (48%)

593 (52%)

39.1 (18) 5143

41.5 (17) 5491

1145 (100%) 552 (48%) 40.3 (17) 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