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Journal of Crohn's and Colitis: 10 (8)

Editor-in-Chief

Laurence J. Egan, Ireland

Associate Editors

Shomron Ben-Horin, IsraelSilvio Danese, ItalyPeter Lakatos, HungaryMiles Parkes, UKJesús Rivera-Nieves, USABritta Siegmund, GermanyGijs van den Brink, NLSéverine Vermeire, Belgium

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Thromboembolic events and cardiovascular mortality in inflammatory bowel diseases: A meta-analysis of observational studies

Mathurin Fumery, Cao Xiaocang, Luc Dauchet, Corinne Gower-Rousseau, Laurent Peyrin-Biroulet, Jean-Frédéric Colombel
DOI: http://dx.doi.org/10.1016/j.crohns.2013.09.021 469-479 First published online: 1 June 2014

Abstract

Objective Patients with inflammatory bowel disease (IBD) are at increased risk of having venous thromboembolism. The magnitude of this risk has yet to be determined. The question of whether IBD patients have an increased risk of arterial thromboembolism and cardiovascular (CV) mortality remains controversial.

Design We searched MEDLINE, Cochrane Library, EMBASE and international conference abstracts and included all controlled observational studies that evaluated the incidence of venous and/or arterial thromboembolic events (TE) and CV mortality in adult IBD.

Results 33 studies enrolling 207,814 IBD patients and 5,774,898 controls and capturing 3,253,639 hospitalizations of IBD patients and 936,411,223 hospitalizations of controls reported a risk of arterial and/or venous TE or CV mortality were included. The risk of venous TE was increased in IBD patients compared to the general population (RR, 1.96; 95% CI, 1.67–2.30) contrary to the risk of arterial TE (RR, 1.15; 95% CI, 0.91–1.45). There was an increased risk of deep venous thrombosis (RR, 2.42; 95% CI, 1.78–3.30), pulmonary embolism (RR, 2.53; 95% CI, 1.95–3.28), ischemic heart disease (RR, 1.35; 95% CI, 1.19–1.52) and mesenteric ischemia (RR, 3.46; 95% CI, 1.78–6.71). Differences in methodology were great between studies resulting in a significant heterogeneity in all previous analysis. CV mortality in IBD patients was not increased compared to the general population (SMR, 1.03; 95% CI, 0.93–1.14).

Conclusions The risk of TE is increased in patients with IBD. This difference is mainly due to an increased risk of venous TE. There is no increased risk of arterial TE or CV mortality in IBD patients, but an increased risk of both ischemic heart disease and mesenteric ischemia.

1 Introduction

Venous thromboembolism (TE) including deep venous thrombosis (DVT) and pulmonary embolism (PE) is a well-known and feared complication of inflammatory bowel diseases (IBDs).1,2 The incidence of venous TE is estimated to be 0.26% per year in both Crohn's disease (CD) and ulcerative colitis (UC).3 However, despite several large population-based studies,4 the true magnitude of the risk remains unclear as a result of methodological differences and heterogeneity across studies. Unlike venous TE, the risk of arterial TE and cardiovascular events in IBD is not well understood. Inflammation is involved throughout all stages of atherosclerosis pathogenesis, from plaque initiation to rupture and subsequent thrombosis.5 C-reactive protein, often elevated during IBD flares, has also been associated with an increased risk of coronary artery disease independent of traditional cardiovascular risk factors.6 Of note, other chronic inflammatory diseases such as rheumatoid arthritis are also associated with an increased risk of arterial TE and cardiovascular mortality.7,8

The aim of this meta-analysis was to determine the risk of venous and arterial TE, as well as the risk of cardio-vascular events and mortality in patients with IBD compared to the general population in referral center and population-based cohorts.

2 Materials and methods

We conducted a systematic review of the literature following the Meta-analysis Of Observational Studies in Epidemiology (MOOSE) guidelines.

2.1 Literature search and selection criteria

We conducted a computerized search of English and non-English language publications listed in the electronic databases of PUBMED (1966 to September 2012), the Cochrane Library (to June 2012), and EMBASE (1980 to June 2012), by two independent researchers (MF, CX). We searched for the following terms: “Inflammatory bowel disease”, “Crohn's disease”, “ulcerative colitis”, “thrombosis”, “arterial thrombosis”, “heart disease”, “vascular disease”, “atherosclerosis”, “coronary artery disease”, “myocardial infarction”, “cerebrovascular disorders”, “stroke”, “mesenteric ischemia”, “peripheral artery disease”, “deep venous thrombosis”, “pulmonary embolism”, “venous thromboembolism”, “mortality cause specific” and “mortality”. We also hand-searched abstracts from the annual meetings of Digestive Disease Week (2009 to 2012), the United European Gastroenterology Week (2008 to 2011), and the European Crohn and Colitis Organization congress (2009 to 2012) over the past three years, as well as references from review articles, meta-analyses, and published observational studies in order to identify additional articles. We did not employ any search software. Data abstraction was carried out independently by two investigators (MF, CX) using standardized data collection form. Discrepancies in data interpretation were resolved by a discussion and re-review of the studies and by consultation with the other clinical authors (LPB, LD). We selected peer-reviewed observational controlled data (case–control and cohort studies) originating from referral center, hospital and population based-studies. If data from a single study was reported in more than one article, only the results from the most recent study were included in the meta-analysis. If a population contributed to more than one publication, each publication could be included only if different study periods were involved.

2.2 Selection criteria

Inclusion and exclusion criteria were defined before commencement of the literature search. Selected peer-reviewed studies (case control and cohort studies) were included for analyses if all participants in the study were adult patients with IBD and if they reported either (a) a risk of thrombotic events in IBD (UC or CD) patients and controls expressed as odds ratios (ORs) or relative risks (RRs) with associated 95% confidence intervals or data for calculating them or (b) cardiovascular-disease-specific Standardized Mortality Ratio (SMR) with 95% confidence interval for IBD (UC or CD).

2.3 Outcome measures

The outcome measures were defined a priori. The meta-analysis evaluated different outcome variables including venous and arterial thromboembolic events and cardiovascular mortality. We evaluated ORs or RRs of thrombosis among IBD patients versus controls, RRs or ORs of arterial TE among IBD patients versus controls, and the proportion of venous TE in IBD patients and controls. We calculated a CV-disease-specific standardized mortality ratio (SMR) in IBD patients. When data were available we evaluated the RRs or ORs of ischemic heart disease (IHD), stroke, mesenteric ischemia, peripheral artery disease, DVT and PE in IBD patients and controls.

2.4 Statistical analysis

We calculated weighted–pooled summary estimates of RR (pooled RR) for all thrombotic events combined, arterial and venous thromboembolism, as well as for each outcome individually (arterial TE, IHD, Stroke, mesenteric ischemia, peripheral artery disease, venous TE, DVT, and PE). Similarly we calculated weighted–pooled summary estimates of the SMR for studies specifically evaluating CV mortality. Analyses were performed if at least two studies evaluating the same outcome could be combined.

For each meta-analysis, the method of Der Simonian and Laird9 was used. According to this method, studies were considered as a random sample from a population of studies. Statistical heterogeneity was tested for each analysis.10,11 Due to heterogeneity among studies a random effect model was used to analyze data. The overall effect was estimated by a weighted average of individual effects, with weights inversely proportional to the variance in observed effects. The effect measures estimated were the relative risks between the IBD and control groups, with 95% confidence intervals (CI).12 Metaregression was performed to assess the modulation effect of pathology (UC or CD). All analyses were performed using R software13 and metaphor package.14

3 Results

3.1 Literature search

Of the 68 studies identified following the literature search, 35 were excluded because of the lack of information on RRs or ORs for IBD patients and/or controls, lack of a control arm or reported confidence interval, or duplicates (Fig.1 ) leaving a total of 33 eligible studies1547 on the risk of arterial and/or venous TE (n = 18)1532 or CV (n = 15) mortality in IBD patients3347 (Tables 1 and 2 ). These 33 studies enrolled 207,814 IBD patients with 5,774,898 controls (n = 29) and recorded 3,253,639 hospitalizations of IBD patients with 936,411,223 hospitalizations of controls (n = 4).

1

Flow chart of study selection. RR: relative risk, OR: odds ratio, TE: thromboembolic, CV: cardiovascular, PE: pulmonary embolism, DVT: deep venous thrombosis, PAD: peripheral artery disease, MI: mesenteric ischemia, and IHD: ischemic heart disease.

View this table:
1

Characteristics of the 18 studies included in the meta-analyses to assess the risk of both venous and arterial thromboembolic events in patients with IBD.

AuthorsLocationStudy periodStudyData sourcePopulation sourceCaseCase (n)Events (n)Controls (n)CTL events (n)Thrombosis risk evaluated
Bernstein CN et al.15 Canada1984–2003CohortIBD epidemiology database/Manitoba Health administration databasePopulationPatient807243280,4893529Ischemic heart disease, cerebrovascular disease, and peripheral artery disease
Yarur Aj et al.16 USA1995–2009CohortJackson Memorial Hospital MiamiReferral centerPatient3564771233Coronary artery disease
Osterman et al.17United Kingdom1987–2003CohortGPRD DatabasePopulationPatient25,327390235,5923096Myocardial infarction
Haapamaki J et al.18 Finland2006–2008CohortNational Health InsurancePopulationPatient283162566279Chronic heart disease
Rungoe C et al.19 Danmark1997–2009CohortNational Patient RegisterPopulationPatient28,83311754,541,987243,844Ischemic heart disease
Andersohn F et al.20 United Kingdom1987–2005CohortGPRD DatabasePopulationPatient7948816,5541660Ischemic stroke
Huerta C et al.21 United Kingdom1994–2000Case–controlGPRD DatabasePopulationPatient131206275Mesenteric ischemia
Kappelman MD et al.23 Danmark1980–2007ControlDanish National Patient RegistryPopulationPatient49,7991181477,5046646Deep venous thrombosis and pulmonary embolism
Grainge MJ et al.24 United Kingdom1987–2001CohortGPRD DatabasePopulationPatient13,75613971,672165Venous thromboembolism
Merill A et al.25 USA2008CohortUse Data File of NSQIPPopulationPatient224957269,1192608Venous thromboembolism
Novacek G et al.26 Austria2006–2008CohortAustrian IBD center cohort/Thrombosis Center, AustriaReferral centerPatient86271255204Venous thromboembolism
Miehsler W et al.27 Austria/CohortAustrian Referral CenterReferral centerPatient6183861810Venous thromboembolism
Bernstein CN et al.28 Canada1984–1997CohortInsurance plan of ManitobaPopulationPatient552937455,290/Deep venous thrombosis and pulmonary embolism
Huerta C et al.29United Kingdom1994–2000Case–controlGPRD DatabasePopulationPatient16810616,3826444Deep venous thrombosis and pulmonary embolism
Sridhar AR et al.30 USA2006CohortNationwide Inpatient SampleHospitalHospitalization148,22911,74117,261,9522,260,802Mesenteric ischemia, ischemic heart disease, cerebrovascular occlusion, and venous thromboembolism
Nguyen GC et al.31 USA1998–2004CohortNationwide Inpatient SampleHospitalHospitalization116,842193352,27037213Venous thromboembolism
Saleh T et al.32 USA1979–2005CohortNational Hospital Discharge SurveyHospitalHospitalization2,932,00043,000918,570,00010,421,000Venous thromboembolism
Inamdar S et al.22 USA2009CohortNationwide Inpatient SampleHospitalHospitalization56,568/56,568/Myocardial infarction
View this table:
2

Characteristics of the 15 studies included in the meta-analyses to assess the risk of cardiovascular mortality in IBD patients.

AuthorsLocationYears at diagnosisStudyStudy sourceIBD population size (n)CD population size (n)CD CV SMR (CI 95%)UC population size (n)UC CV SMR (CI 95%)
Wolters FL et al.36 Europe Multicenter1991–1993CohortPopulation based3803801.49 (0.74–2.66)
Jess T et al.37 Danmark1962–1987CohortPopulation based3743740.9 (0.4–1.4)
Prior P et al.38 United Kingdom1932–76CohortHospital based5135130.8 (0.4–1.3)
Winther KV et al.39 Danmark1962–1987CohortPopulation based116011601.07 (0.8–1.3)
Gyde S et al.40 United Kingdom1940–76CohortHospital based676 6760.9 (0.4–1.0)
Davoli M et al.41 Italy1970–89CohortHospital based5085080.64 (0.26–1.3)
Viscido A et al.42 Italy1964–95CohortHospital based2066 20660.8 (0.5–1.1)
Hoie E et al.33 Europe Multicenter1997–1993CohortPopulation based775 7751.07 (0.71–1.54)
Ekbom A et al.43 Sweden1965–83CohortPopulation based397814691.1 (0.9–1.4)25090.9 (0.9–1.1)
Masala G et al.44 Italy1978–92CohortPopulation based9202310.65 (0.24–1.41)6890.67 (0.45–0.95)
Romberg-campus M et al.34 Netherlands1991–2002CohortPopulation based11874761.2 (0.5–2.3)6301.2 (0.7–1.8)
Jess T et al.45 USA1940–2001CohortPopulation based6923140.9 (0.3–1.8)3780.6 (0.2–1.3)
Persson PG et al.46 Sweden1955–1984CohortPopulation based279812510.94 (0.7–1.24)15471.11 (0.91–1.35)
Manninen P et al.35 Finland1986–2007CohortPopulation based19155501.28 (0.68–2.18)12541.04 (0.76–1.41)
Jess et al.47 Danmark1982–2010CohortPopulation based51,44115,3611.39 (1.28–1.51)36,0801.20 (1.1.26)

3.2 Venous thromboembolism

We identified 10 studies that assessed the risk of venous TE in IBD patients2332 including 72,205 IBD patients and 891,840 controls (n = 7) as well as 3,197,071 hospitalizations of IBD patients and 936,411,223 hospitalizations of controls (n = 3). The overall risk of venous TE in IBD patients was increased by 96% compared to the general population (RR, 1.96; CI 95%, 1.67–2.30) (I2 99%, Peth < 0.001) (Fig.2 ). Using meta-regression analysis, the increase risk in CD was not different from the increased risk in UC (p = 0.98). The magnitude of the risk was higher in studies including IBD patients in general (RR, 2.48; 95% CI, 2.04–3.00) (I2 89%, Peth < 0.001)2329 as compared to studies looking at hospitalized IBD patients (RR, 1.47; 95% CI, 1.17–1.86) (I2 100%, Peth < 0.001).3032 In studies only considering hospitalizations, the increased risk of VTE was greater in UC than in CD patients (p = 0.0029).

2

Meta-analysis of studies on venous thromboembolic events in IBD patients in both studies considering hospitalizations and IBD patients. CD, Crohn's disease; UC, ulcerative colitis.

3.3 Deep venous thrombosis

3 studies evaluated DVT risk in IBD patients compared to the general population23,28,29 including 55,496 IBD patients and 549,176 control patients. No data on hospitalizations of IBD patients were available. The risk was increased in IBD patients compared to the general population (RR, 2.42; 95% CI, 1.78–3.30) (I2 90%, Peth < 0.001), with no difference between CD and UC (p = 0.46).

3.4 Pulmonary embolism

We identified 3 studies assessing the risk of PE in IBD patients23,28,29 including 55,496 IBD patients and 549,176 control patients. No data on hospitalizations of IBD patients were available. An increased risk of PE was observed in IBD patients compared to the general population (RR, 2.53; 95% CI, 1.95–3.28) (I2 80%, Peth < 0.001) with no difference between CD and UC (p = 0.69).

3.5 Arterial thromboembolism

We identified 91522,30 studies that assessed the risk of arterial thrombo-embolic complications including 66,226 IBD patients and 4,883,058 controls (n = 7) and 204,797 hospitalizations of IBD patients and 17,318,520 hospitalizations of controls (n = 2). Overall, there was no increased risk of arterial thrombosis in IBD patients (RR, 1.15; 95% CI, 0.91–1.45) (I2 97%, Peth < 0.001) (Fig.3 ). No difference was observed between CD and UC (p = 0.49). When the analysis was restricted to IBD patients,1521 excluding studies on hospitalizations, the risk of arterial TE was increased (RR, 1.28; 95% CI, 1.16–1.42) (I2 64%, Peth < 0.001), whereas it was not increased when including only studies of hospitalized patients (RR, 0.93; 95% CI, 0.56–1.54) (I2 100%, Peth < 0.001).22,30

3

Meta-analysis of studies on arterial thromboembolic events in IBD patients, including stroke, peripheral artery disease (Periph. Art. Dis.), mesenteric ischemia (Mesent. Isch.) and ischemic heart disease (Isch. Heart Dis.). TE, thromboembolism; CD, Crohn's disease; UC, ulcerative colitis.

3.6 Ischemic heart disease

7 studies assessed the risk of ischemic heart disease including myocardial infarction in IBD patients1519,22,30 and included 65,419 IBD patients and 4,864,442 control patients (n = 5) and recorded 204,797 hospitalizations of IBD patients and 17,318,520 hospitalizations of controls (n = 2). Overall, there was no increased risk of ischemic heart disease (RR, 1.23; 95% CI, 0.94–1.62) (I2 98%, Peth < 0.001) (Fig.3). Among studies including only IBD patients,1519 the risk of arterial ischemic heart disease was increased (RR, 1.35; 95% CI, 1.19–1.52) (I2 74%, Peth < 0.001) (Fig.3), whereas this risk was not increased among studies on hospitalizations 22,30 (RR, 0.86; 95% CI, 0.40–1.84) (I2 100%, Peth < 0.001), with no difference between UC and CD (p = 0.89).

3.7 Stroke

We identified 3 studies assessing the risk of stroke in IBD patients 15,20,30 including 8,866 IBD patients and 97,043 controls (n = 2) and recorded 148,229 hospitalizations of IBD patients and 17,261,952 hospitalizations of controls (n = 1). The risk of stroke did not differ between IBD patients and the general population (RR, 0.79; 95% CI, 0.51–1.23) (I2 94%, Peth < 0.001) (Fig.3), with no difference between CD and UC (p = 0.62).

3.8 Peripheral artery disease

We identified 2 studies assessing the risk of peripheral artery disease n IBD patients15,20 including 8,072 IBD patients and 80,489 controls (n = 1) and 148,229 hospitalizations of IBD patients and 17,261,952 hospitalizations of controls (n = 1). The risk of peripheral artery disease did not differ between IBD patients and the general population (RR, 0.78; 95% CI, 0.46–1.32) (I2 87%, Peth < 0.001) (Fig.3).

3.9 Mesenteric ischemia

We identified 2 studies assessing the risk of mesenteric ischemia in IBD patients21,30 including 13 IBD patients and 2,062 controls (n = 1) and 148,229 hospitalizations of IBD patients and 17,261,952 hospitalizations of controls (n = 1). A significant increased risk of mesenteric ischemia was observed in IBD patients compared to the general population (RR, 3.46; 95% CI, 1.78–6.71) (I2 90%, Peth < 0.001) (Fig.3).

3.10 Cardiovascular mortality

We identified 15 studies evaluating CV mortality among IBD patients3347 (Table2): 10 were population-based and 4 were hospital-based studies. A total of 69,383 IBD patients (15,361 CD and 36,080 UC) were included. Overall, cardiovascular mortality was not increased among IBD patients when compared to the general population (pooled SMR, 1.03; 95% CI, 0.93–1.14) (I2 70%, Phet < 0.001) (Fig.4 ). Similar results were observed for CD and UC patients, with SMRs of 1.12 (95% CI, 0.94–1.32) and 0.98 (95% CI, 0.86–1.12) respectively. In a sensitivity analysis excluding the largest and most recent study,47 the RR was 0.96 (0.80–1.16) (I2 0%, Phet = 0.999). All the previous results have been summarized in Table 3 .

4

Meta-analysis of studies evaluating cardiovascular mortality in IBD patients.

View this table:
3

Relative risk of venous and arterial thromboembolism in inflammatory bowel disease patients.

All studies
(RR, CI 95%)
Studies including IBD patients
(RR, CI 95%)
Studies including hospitalizations of IBD patients (RR, CI 95%)
Venous and arterial thromboembolism1.60 [1.44–1.77]1.90 [1.69–2.14]1.13 [0.95–1.35]
Venous thromboembolism1.96 [1.67–2.30]2.48 [2.04–3.00]1.47 [1.17–1.86]
Deep venous thrombosis2.42 [1.78–3.30]//
Pulmonary Embolism2.53 [1.95–3.28]//
Arterial thromboembolism1.15 [0.91–1.45]1.28 [1.16–1.42]0.93 [0.56–1.54]
Ischemic heart disease1.23 [0.94–1.62]1.35 [1.19–1.52]0.86 [0.40–1.84]
Stroke0.79 [0.51–1.23]1.11 [0.94–1.33]/
Peripheral artery disease0.78 [0.46–1.32]//
Mesenteric ischemia3.46 [1.78–6.71]//

3.11 Heterogenity and publication bias

A statistical heterogeneity was observed for all analysis. The first analysis evaluating the risk of overall risk of thrombosis was associated with significant heterogeneity among studies (I2 98%, Peth < 0.001). A funnel plot (Supplementary Fig. 1) showed some asymmetry and suggested publication bias, as there were few studies with high precision (large sample size) and large RR. Nevertheless, the result of Egger's regression test for asymmetry was not significant (egger = 0.93). For the pooled analysis of cardiovascular mortality the funnel plot (Supplementary Fig. 2) showed some asymmetry (egger = 0.47) and there was a significant heterogeneity among studies (I2 70%, p < 0.05, Phet < 0.001).

4 Discussion

This is the first meta-analysis of observational studies designed to assess incidence of both venous and arterial thromboembolic events as well as cardiovascular mortality in patients with IBD. Despite great heterogeneity in design and clinical setting, our findings demonstrate that patients with IBD are at major risk for venous thromboembolism and mesenteric ischemia and, to a lesser degree, arterial thromboembolism and ischemic heart disease. Importantly, we did not find an increase in the risk of cardiovascular mortality in IBD patients.

Venous thromboembolic complications, including DVT and PE1 have been shown to be associated with IBD, but the magnitude of the thromboembolic risk is somewhat disputed.48 When analyzing a total of 5,982,712 patients and 939,664,862 hospitalizations, we found a 60% increase in the risk of TE in patients with IBD compared to the general population. This increase was largely attributed to venous TE events including both DVT and PE. Similar to the study by Grainge et al.,24 the risk of venous TE was lower in studies that included only hospitalized IBD patients. While this observation may initially appear counterintuitive given that hospitalized patients typically have the most severe disease, it may be explained by the use of prophylactic heparin in hospitalized patients in accordance with international recommendations.49,50 Reduction of venous thromboembolism by low molecular weight heparin or the new orally bioavailable anticoagulants,5154 may be further highlighted in future guidelines for both hospitalized and ambulatory patients. In studies including only inpatients, VTE increased risk was greater in UC than in CD patients (p = 0.0029). However, prophylaxis should be recommended both in UC and in CD.

Several studies have shown an increased carotid intima-media thickness in IBD patients, including pediatric cases, suggesting that atherosclerosis may be an early complication of these diseases.5558 When compared to the general population, the overall risk of arterial thrombosis was not significantly increased in IBD patients. However, there was a significant increased risk of ischemic heart disease and mesenteric ischemia. This increased risk was observed despite the absence of the traditional cardiovascular risk factors such as arterial hypertension, dyslipidemia, diabetes mellitus, age, male and family history of cardiovascular disease.16,18 The magnitude of the risk was similar in patients with CD who are more often smokers than the general population and in patients with UC who are often non-smokers.59 Chronic inflammation may be the most important driver of cardiovascular complications in IBD. C-reactive protein and interleukin-6, often elevated during IBD flares, have been associated with an increased risk of coronary artery disease and mesenteric ischemia independent of other cardiovascular risk factors.6,6062 In IBD, the increased expression of CD40L by platelets appears to contribute to the pro-inflammatory response1,63 while in atherosclerosis, the inflammation caused by CD40L–CD40 interaction leads to unstable plaque resulting in thrombosis.64

An increase in CV mortality compared to the general population is well documented in rheumatoid arthritis (RA) with higher death rates resulting from ischemic heart disease and cerebrovascular occlusion.7,8 As a result, aggressive cardiovascular disease primary prevention has become standard of care in RA.65 In contrast, a meta-analysis of 11 observational studies published 5 years ago found no increased risk of CV mortality in IBD patients.66 We confirmed and reinforced these findings by pooling 69,383 patients including those from the most recent European studies.3335,47 In RA part of this risk appears to be mediated by long-term inflammation. Traditional CV risk factors as smoking or metabolic syndrome also play an important role.67 In IBD, the impact of systemic inflammation on the cardiovascular risk may be different. Moreover, except smoking, more common in patients with Crohn's disease,68 the prevalence and impact of traditional cardiovascular risk factors remains unknown. This discrepancy between IBD and RA may also be explained by the inclusion in most IBD studies of a majority of young patients with a follow-up of less than 5 years.

Our study is not without limitations. We included cohorts from a variety of clinical settings with differences in diagnostic criteria, age at enrollment, period at risk and study design. In addition, the methodology, inclusion criteria and outcome measures differed between studies. Some studies are population-based cohorts, some are from referral centers, and others look only at hospitalized patients through discharge databases. As expected we found statistically significant heterogeneity among the studies included in this meta-analysis. Therefore we used a random-effect model to give an estimate of variability.69 Statistical heterogeneity was identified, because the magnitude of the association was different between studies. However the risk was consistent despite different study designs, populations and methods. Therefore our results confirmed higher risk of venous TE in IBD. The high heterogeneity observed suggests that relative risk may differ according to clinical setting therefore precise relative risk is hard to assess. In addition there were not enough studies to statified analysis by clinical setting. We determined that cohort source (patients or hospitalizations) explained some of the observed heterogeneity. Studies from large administrative databases of hospital admissions were included in the analysis. These studies report opposite results than other included studies. These different results may be explained by methodological defect. In addition, these studies have an important weight in the overall analysis. For this reason, sub-analysis including these studies was separately performed. Of note, most of the studies we included were retrospective with a relatively short average median duration of follow-up. Furthermore, well-established risk factors for TE such as smoking, personal or family history of cardiovascular events or BMI were not available in all studies and our results therefore could not be adjusted for them. Also, as a result of missing data, we were also unable to take into account age, sex, disease extension, disease severity and disease duration. Finally, we could not analyze the impact of IBD-related medications on our findings. This underlines the fact that new prospective high quality studies evaluating the risk of thrombosis in IBD are required.

In conclusion, IBD is associated with an overall increased risk of thrombovascular events. As a result, the prevention of DVT and PE in particular should be at the forefront of gastroenterologists' concerns. Unfortunately this is not the case: in a recent survey involving 591 US physicians, 29% were unaware of any recommendations addressing pharmacologic prophylaxis included in American College of Gastroenterology IBD guidelines. Furthermore only 35% reported that they would give pharmacologic VTE prophylaxis to a hospitalized patient with severe ulcerative colitis.70 In clinical practice, one study found that only 50% of patients hospitalized for severe ulcerative colitis at a referral center received pharmacologic venous thromboembolism prophylaxis.71 With respect to the risk of ischemic heart disease and mesenteric ischemia in IBD patients, more studies are needed to further characterize risk factors such as whether a tight control of inflammation could ultimately prevent these potentially devastating events.

Disclosures

No conflicts of interest exist in this manuscript for any author.

Footnotes

  • Specific author contributions: Mathurin Fumery: Generation, collection, assembly, interpretation of data and drafting of the manuscript. Cao Xiaocang: Generation, collection, assembly and interpretation of data. Luc Dauchet: Study design, statistical analysis, and critical revision of the manuscript. Corinne Gower-Rousseau: Concept and study design, interpretation of data, and critical revision of the manuscript. Laurent Peyrin-Biroulet: Concept and study design, interpretation of data, drafting the manuscript and approval of the final version of the manuscript. Jean-Frederic Colombel: Concept and study design, interpretation of data, drafting and critical revision of the manuscript and approval of the final version of the manuscript.

Abbreviations
CD,
Crohn's disease;
UC,
ulcerative colitis;
IBD,
inflammatory bowel disease;
TE,
thromboembolism;
CV,
cardiovascular;
DVT,
deep venous thrombosis;
PE,
pulmonary embolism;
IHD,
ischemic heart disease;
RR,
relative risk;
OR,
odds ratio.

References

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