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Risk of Cerebrovascular Accidents and Ischemic Heart Disease in Patients With Inflammatory Bowel Disease: A Systematic Review and Meta-analysis
Clinical Gastroenterology and Hepatology 2014;12:382–393
SYSTEMATIC REVIEWS AND META-ANALYSES Fasiha Kanwal, Section Editor
Risk of Cerebrovascular Accidents and Ischemic Heart Disease in Patients With Inflammatory Bowel Disease: A Systematic Review and Meta-analysis Siddharth Singh,* Harkirat Singh,‡ Edward V. Loftus Jr.,* and Darrell S. Pardi* *Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota; and ‡Department of Internal Medicine, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania This article has an accompanying continuing medical education activity on page e22. Learning Objectives—At the end of this activity, the successful learner will be able to recognize the association between inflammatory bowel diseases and risk of cerebrovascular accidents and ischemic heart disease.
BACKGROUND & AIMS:
Inflammatory bowel disease (IBD) is associated with an increased risk of venous thromboembolic disease. However, it is unclear whether IBD modifies the risk of arterial thromboembolic events, including cerebrovascular accidents (CVA) and ischemic heart disease (IHD).
METHODS:
We performed a systematic review and meta-analysis of cohort and case-control studies that reported incident cases of CVA and/or IHD in patients with IBD and a non-IBD control population (or compared with a standardized population). We calculated pooled odds ratios (ORs) with 95% confidence intervals (CIs).
RESULTS:
We analyzed data from 9 studies (2424 CVA events in 5 studies, 6478 IHD events in 6 studies). IBD was associated with a modest increase in the risk of CVA (5 studies; OR, 1.18; 95% CI, 1.09– 1.27), especially among women (4 studies; OR, 1.28; 95% CI, 1.17–1.41) compared with men (OR, 1.11; 95% CI, 0.98–1.25), and in young patients (<40–50 y old). The increase in risk was observed for patients with Crohn’s disease and in those with ulcerative colitis. IBD also was associated with a 19% increase in the risk of IHD (6 studies; OR, 1.19; 95% CI, 1.08–1.31), both in patients with Crohn’s disease and ulcerative colitis. This risk increase was seen primarily in women (4 studies; OR, 1.26; 95% CI, 1.18–1.35) compared with men (OR, 1.05; 95% CI, 0.92– 1.21), in young and old patients. IBD was not associated with an increased risk of peripheral arterial thromboembolic events. Considerable heterogeneity was observed in the overall analysis.
CONCLUSIONS:
IBD is associated with a modest increase in the risk of cardiovascular morbidity (from CVA and IHD)—particularly in women. These patients should be counseled routinely on aggressive risk factor modification.
Keywords: Myocardial Infarction; Coronary Artery Disease; Stroke; Inflammatory Bowel Disease.
hronic systemic inflammation is an independent risk factor for atherosclerosis by promoting plaque formation, inducing endothelial dysfunction, and promoting platelet activation and aggregation.1 Active inflammation also predisposes to thrombosis by altering the balance between physiological procoagulants and anticoagulants and inducing a state of hypofibrinolysis.2 Epidemiologic studies have shown that chronic inflammatory diseases such as rheumatoid arthritis and systemic lupus erythematosus are associated with premature atherosclerosis and an increased risk of cardiovascular morbidity3,4 and mortality.5 Several studies have shown that inflammatory bowel disease (IBD) is associated with an increased risk of
C
venous thromboembolism,6 particularly during severe flares.7 Chronic intestinal inflammation associated with IBD also has been associated with acute mesenteric ischemia.8,9 Similar to other chronic inflammatory diseases, patients with IBD have an increased thickness of the carotid intimal-media, which is a measure of atherosclerotic disease burden.10 However, it is unclear
Abbreviations used in this paper: CD, Crohn’s disease; CI, confidence interval; CVA, cerebrovascular accident; IBD, inflammatory bowel disease; IHD, ischemic heart disease; OR, odds ratio; UC, ulcerative colitis. © 2014 by the AGA Institute 1542-3565/$36.00 http://dx.doi.org/10.1016/j.cgh.2013.08.023
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whether IBD modifies the risk of cardiovascular arterial events, such as cerebrovascular accidents (CVA) or ischemic heart disease (IHD). Although some studies have shown an increased risk of CVA in patients with IBD,8,11 others have shown no such association.12,13 Likewise, the relationship between IBD and risk of myocardial infarction and IHD also is ambiguous.8,11,14 Sex- and phenotype-specific associations have been suggested, but remain controversial.8,13,15 Previous meta-analyses have found no association between IBD and cardiovascular disease mortality.16–18 However, cardiovascular mortality is a suboptimal surrogate for cardiovascular disease incidence; with advancements in medical management and interventional strategies, mortality from myocardial infarction has decreased.19 Hence, to better understand the association between IBD and cardiovascular morbidity, we conducted a systematic review and meta-analysis of observational studies that investigated the relationship between IBD and CVA, IHD, and extra-intestinal peripheral arterial thromboembolic disease. In addition, we explored phenotype-, sex-, and age-specific differences in the risk of cardiovascular morbidity in patients with IBD.
Methods This systematic review was conducted following guidance provided by the Cochrane handbook20 and is reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.21 The process followed an a priori established protocol.
Data Sources and Search Strategy First, a systematic literature search of PubMed (1966 through March 1, 2013), Embase (1988 through March 1, 2013), and Web of Science (1993 through March 1, 2013) databases was conducted to identify all relevant articles on the risk of cardiovascular events in patients with IBD. Medical subject heading terms used in the search included a combination of “cerebrovascular disease,” “stroke,” “coronary artery disease,” “ischemic heart disease,” “thromboembolism/arterial,” “peripheral vascular diseases,” as well as “mesenteric ischemia” (key word) and “inflammatory bowel disease,” “Crohn’s disease,” “ulcerative colitis.” The title and abstract of studies identified in the search were reviewed by 2 authors (S.S. and H.S.) independently to exclude studies that did not answer the research question of interest, based on prespecified inclusion and exclusion criteria (see later). The full text of the remaining articles was examined to determine whether it contained relevant information. The coefficient of agreement between the 2 reviewers for article selection (k ¼ 0.84; 95% CI, 0.72–0.94) was excellent. Conflicts in study selection were resolved by consensus, referring back to the original article and, if needed, in consultation with the principal investigator
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(D.S.P.). Second, we searched the bibliographies of these selected articles as well as related narrative and systematic review articles to identify any additional studies. Third, a manual search of abstracts from major gastroenterology conferences (Digestive Disease Week, the American College of Gastroenterology annual meeting, the Advances in Inflammatory Bowel Diseases meeting organized by the Crohn’s and Colitis Foundation of America, and the European Crohn’s and Colitis Organization annual meeting) from 2005 to 2012 was performed to identify additional abstracts on the topic.
Study Selection Studies considered in this meta-analysis were cohort or case-control studies that met the following inclusion criteria: (1) diagnosed IBD (Crohn’s disease [CD] and/or ulcerative colitis [UC]) according to well-defined criteria; (2) reported incident cases of CVA or IHD or extraintestinal peripheral arterial thromboembolic events after the diagnosis of IBD; (3) included a non-IBD population for which CVA, IHD, or extra-intestinal peripheral arterial thromboembolic event rates were calculated (or could be inferred as expected event rates from a reference population); and (4) reported relative risks (for cohort studies), odds ratios (OR) (for case-control studies), or standardized incidence rates (for studies comparing the rates of observed with expected cases) with 95% confidence intervals (CIs) or provided data for their calculation. Cross-sectional studies in which temporality could not be established (ie, the diagnosis of IBD was not clearly established before the first diagnosis of cardiovascular events) were excluded. Articles also were excluded from the analysis if there were insufficient data for determining a risk estimate and 95% CI. Inclusion was not otherwise restricted by study size, language, or publication type. When there were multiple publications from the same population, only data from the most recent comprehensive report were included. CVA was defined as a history of ischemic or hemorrhagic stroke and/or transient ischemic attack. IHD was defined in included studies based on medical diagnostic codes and included acute coronary syndrome, history of myocardial infarction, and/or angina. Congestive heart failure (without report of underlying etiology) and cardiac arrhythmias were not studied. Peripheral arterial thromboembolic disease was defined as acute or chronic peripheral arterial insufficiency (excluding intestinal vasculature).
Data Abstraction and Quality Assessment Data were abstracted independently onto a standardized form by 2 investigators (S.S. and H.S.). The following data were collected from each study: study design, time period of study/year of publication, country of the population studied, method of exposure ascertainment (IBD
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[CD and/or UC] and control population), primary outcome reported (CVA, IHD, and/or peripheral artery disease) and source of outcome assessment, total number of persons in each group (IBD vs non-IBD controls), relative risk/OR/ standardized incidence rates and 95% CIs with and without adjustment for potential confounders, and potential confounders used for adjustment. Data on the following confounding risk factors for CVA or IHD were extracted from each study: age, sex, race, cigarette smoking, body mass index, history of diabetes mellitus, hypertension, hyperlipidemia, personal and family history of CVA/IHD, and aspirin use. Conflicts in data abstraction were resolved by consensus, referring back to the original article and in consultation with the principal investigator (D.S.P.). The methodologic quality of case-control and cohort studies was assessed by 2 study investigators (S.S. and H.S.), independently using the Newcastle-Ottawa scale.22 In this scale, observational studies were scored across 3 categories: selection (4 questions) and comparability (2 questions) of study groups, and ascertainment of the outcome of interest (3 questions), with maximum 1 point for each question, except for comparability of study groups, for which separate points were awarded for controlling age and/or sex (maximum, 2 points). Any discrepancies were addressed by a joint re-evaluation of the original article.
Outcomes Assessed The primary analysis focused on assessing the risk of cardiovascular morbidity (CVA, IHD, and peripheral arterial thromboembolic disease) among patients with IBD. In addition, based on information available from individual studies, we assessed CD- and UC-specific risk estimates and explored sex- and age-specific differences in risk estimates.
Data Synthesis and Analysis We used the random-effects model described by DerSimonian and Laird23 to calculate summary ORs and 95% CIs. We assessed heterogeneity between studyspecific estimates using 2 methods.24 First, the Cochran Q statistical test for heterogeneity, which tests the null hypothesis that all studies in a meta-analysis have the same underlying magnitude of effect, was measured. Because this test is underpowered to detect moderate degrees of heterogeneity,25 a P value of less than .10 was considered suggestive of significant heterogeneity. Second, to estimate what proportion of total variation across studies was caused by study-related factors (clinical setting, methodologic or statistical differences) rather than chance, the I2 statistic was calculated. For this calculation, values of less than 30%, 31% to 60%, 61% to 75%, and greater than 75% were suggestive of low, moderate, substantial, and considerable heterogeneity, respectively.26 If significant heterogeneity was observed
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in the analysis, we explored potential causes of heterogeneity by stratifying for several methodologic and clinical features of studies. This included study design (case-control vs cohort), study location (North America vs Europe), study setting (hospital-based vs populationbased), and sex- or age-specific differences in risk estimates. In this analysis, a P value for differences between subgroups (referred to as Pinteraction) of less than .10 was considered statistically significant (ie, a value of P < .10 suggested that stratifying based on that particular study characteristic partly explained the heterogeneity observed in the analysis). Because of the small number of published studies, a formal statistical analysis of funnel plot asymmetry for assessment of publication bias was not used.27 All P values were 2-tailed. For all tests (except for heterogeneity), a probability level less than .05 was considered statistically significant. All calculations and graphs were performed using Comprehensive Meta-Analysis version 2 (Biostat, Englewood, NJ).
Results Search Results Among 688 unique studies that were identified using our search strategy, 9 studies met the defined inclusion criteria for this meta-analysis (6 case-control and 3 cohort studies).8,11–15,28–30 Three cross-sectional studies that reported the prevalence of CVA, IHD, and peripheral artery disease in patients with IBD were excluded.31–33 Figure 1 summarizes the process of study identification, inclusion, and exclusion. These studies cumulatively reported 2424 CVA, 6478 IHD, and 148 peripheral arterial thromboembolic events in 152,756 patients with IBD (at least 123,907 independent, nonoverlapping patients). Two population-based studies from Denmark included overlapping patients with IBD, but reported different outcomes (CVA and IHD) and, hence, were analyzed separately for the respective outcome11,15; a separate Danish cohort study on the same topic from common investigators was excluded.34 Likewise, 2 Swedish population-based studies from common investigators and the same cohort reported different outcomes (CVA and IHD) and, hence, were used for the respective analysis separately.29,30 Andersohn et al12 used the General Practice Research Database to identify CD patients with CVA, whereas Osterman et al28 used the same administrative database to identify IBD patients and their subsequent risk of IHD.
Characteristics and Quality of Included Studies The baseline characteristics of these studies and participants are shown in Tables 1 and 2. The earliest study period began in 1984, and the latest ended in 2009. All studies were performed in Western populations (3 in North America,8,13,14 6 in Europe).11,12,15,28–30 Five
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Figure 1. Flowchart summarizing study identification and selection.
studies were population-based,11,13,15,29,30 3 used administrative databases,8,12,28 and 1 study was hospitalbased.14 Seven studies included a control non-IBD population drawn from the same cohort,8,11–15,28 and 2 studies inferred rates of CVA and IHD from an age- and sexmatched general population.29,30 All studies relied on medical diagnostic codes to identify patients with IBD, with 5 studies having independently validated the accuracy of diagnosis in previous studies from the database,11–13,15,28 and 1 study performing an actual medical record review.14 Supplementary Table 1 and 2 show the methodologic quality of all studies. In all these studies, a temporal relation of the development of cardiovascular events after IBD was firmly established. Four studies explicitly excluded patients with a diagnosis of cerebrovascular and/or cardiovascular disease before diagnosis of IBD,11,14,15,28 and 3 studies adjusted for previous history of cardiovascular morbidity in the overall analysis.12,29,30 Table 2 shows the distribution of cardiovascular risk factors in patients with IBD and non-IBD controls for the included studies.
Risk of Cerebrovascular Accidents Five studies reported 2424 CVA events in 98,240 patients with IBD.8,11–13,29 On pooling unadjusted ORs from each study, IBD was associated with a 21% higher risk of CVA (unadjusted OR, 1.21; 95% CI, 1.12–1.31). After adjusting for potential confounders in all studies,
IBD conferred an 18% higher risk of CVA (adjusted OR, 1.18; 95% CI, 1.09–1.27) (Figure 2). This increased risk of CVA was seen in both patients with CD (5 studies; adjusted OR, 1.26; 95% CI, 1.14–1.39) and UC (4 studies; adjusted OR, 1.13; 95% CI, 1.05–1.23), with no significant difference between IBD subtypes (CD vs UC, Pinteraction ¼ .27). There was moderate heterogeneity observed in the overall analysis (Cochran Q: P ¼ .07; I2 ¼ 53%). Four studies reported sex-specific risk estimates of CVA.8,12,13,29 On meta-analysis of these studies, the risk of CVA was significantly higher in females (adjusted OR, 1.28; 95% CI, 1.17–1.41) compared with males (adjusted OR, 1.11; 95% CI, 0.98–1.25) with IBD (Pinteraction ¼ .05). By using data from 3 studies, patients with IBD could be classified as young (age, <40 y8,13 or <50 y12) or old (age >50 y,12 >60 y,13 or 40–59 y).8 In this analysis, the magnitude of increased CVA risk was higher in young patients with IBD (adjusted OR, 1.84; 95% CI, 1.28–2.66) compared with older patients with IBD (adjusted OR, 1.11; 95% CI, 1.02–1.21) (Pinteraction ¼ .01). Besides sex and age, heterogeneity also could be accounted for by study design, with one included cohort study reporting a significantly higher risk estimate as compared with pooled results from 4 case-control studies (Table 3).
Risk of Ischemic Heart Disease Six studies reported 6478 IHD events in 123,907 patients with IBD.8,13–15,28,30 No statistically significant
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increase in the risk of IHD was identified using unadjusted ORs for each study (unadjusted OR, 1.14; 95% CI, 0.95–1.38); however, on pooling maximally adjusted ORs, IBD was associated with a 18% increased risk of IHD (adjusted OR, 1.18; 95% CI, 1.08–1.31) (Figure 3). This increase in risk was seen in both CD and UC on meta-analysis of 5 studies that reported these data (CD: adjusted OR, 1.08; 95% CI, 1.03–1.13; UC: adjusted OR, 1.15; 95% CI, 1.05–1.25).8,13,15,28,30 There was considerable heterogeneity observed in the overall analysis (Cochran Q: P < .01; I2 ¼ 88%), with a positive outlier with a large risk estimate.14 On sex-specific analysis, the increased risk of IHD in patients with IBD was seen in females (4 studies; adjusted OR, 1.26; 95% CI, 1.18–1.35), but not in males (4 studies; adjusted OR, 1.05; 95% CI, 0.92–1.21).8,13,15,30 No difference in the risk of IHD was observed between younger (age <40–50 y, 3 studies8,13,14; adjusted OR, 1.40; 95% CI, 0.93–2.11) and older (age >60 y,13 >65 y,14 or 40–59 y8) patients with IBD (3 studies; adjusted OR, 1.29; 95% CI, 0.97–1.71) (Pinteraction ¼ .75). The overall heterogeneity could be explained by sex-specific differences in risk of IHD (Table 4).
Risk of Peripheral Arterial Thromboembolic Disease Two studies reported 148 patients with peripheral arterial disease in 25,559 patients with IBD.8,13 On pooled analysis of these 2 studies, IBD was not associated with a significant increase in the risk of peripheral arterial disease (adjusted OR, 1.15; 95% CI, 0.96–1.38) with minimal heterogeneity in the analysis (Cochran Q: P ¼ .48; I2 ¼ 0%). The results were stable in patients with CD (adjusted OR, 1.20; 95% CI, 0.92–1.57) or UC (adjusted OR, 1.12; 95 % CI, 0.88–1.41).
Sensitivity Analysis To assess whether any one study had a dominant effect on the meta-analytic OR, each study was excluded and its effect on the main summary estimate and Cochran Q test P value for heterogeneity was evaluated. The pooled OR remained significantly increased for CVA (range, 1.19–1.26) and IHD (range, 1.14–1.30), with the corresponding 95% CI bounds remaining greater than 1. On replacing 1 Danish study15 that assessed the risk of IHD in patients with IBD with another study,11 the risk estimates were stable (adjusted OR, 1.18; 95% CI, 1.07–1.31).
Discussion Previous systematic reviews have not shown a significant association between IBD (CD or UC) and cardiovascular mortality.16–18 In a recent meta-analysis of cause-specific standardized mortality ratios in population-based and inception cohort studies of
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patients with IBD, Bewtra et al35 observed that neither CD nor UC were associated with increased cardiovascular mortality in patients with IBD. Although cardiovascular mortality is a hard end point and less prone to ascertainment bias, it does not capture the entire spectrum of cardiovascular disease. With improving therapeutic modalities, mortality from cardiovascular disease is decreasing, and, hence, with low event rates of mortality, observational studies on the association between IBD and cardiovascular mortality often do not reach statistical significance. In addition, these studies on cardiovascular mortality only determine whether patients with IBD die of cardiovascular disease; they are unable to estimate whether patients with IBD may develop ischemic heart disease or stroke at a young age. In contrast, in this meta-analysis on the risk of cardiovascular morbidity in patients with IBD, we made several key observations. First, we identified a modest 18% increase in the risk of CVA and IHD in patients with IBD (both CD and UC), and this effect was stable across study design, setting, and location. Second, we observed that the increase in the risk of CVA and IHD was more prominent in females, without a significantly increased risk in males. Third, we observed that the magnitude of increased risk of CVA was higher in young adults with IBD than the excess risk of CVA in older individuals, while the risk of IHD was stable across age groups. Traditional risk factors for cardiovascular disease, such as diabetes, smoking, hyperlipidemia, obesity, and hypertension, are not universally over-represented in patients with IBD.36 On the other hand, chronic systemic inflammation increasingly is being recognized as a major risk factor for cardiovascular atherosclerotic disease. Immune cells dominate early atherosclerotic lesions, their effector molecules accelerate progression of the lesions, and activation of inflammation can elicit acute coronary syndromes.1 Patients with IBD have increased carotid intimal thickness and abnormal carotid arterial stiffness, which are surrogate markers of atherosclerosis.37,38 Both pediatric and adult patients with IBD have functional vascular changes suggestive of endothelial dysfunction, even before structural changes of atherosclerosis appear.39–41 In addition, several prothrombotic molecules such as homocysteine and vitamin B6, which predispose to coronary artery disease, also are increased in patients with IBD, particularly in CD owing to malabsorption.42,43 Other markers of inflammation such as C-reactive protein, adhesion molecules, and proinflammatory cytokines (such as tumor necrosis factor-a and interleukin-6) are seen at high levels in both IBD and atherosclerosis.44 Common polymorphisms in nucleotide-binding oligomerization domain-containing protein 2/caspase recruitment domain-containing protein 15 (NOD2/CARD15), which predispose to CD, also have been associated with an increased risk of clinically evident and angiographically documented coronary atherosclerosis and clinical destabilization of coronary plaques, suggesting a common genetic basis for these 2
Study
Study design Location Setting
Time period; follow-up period
Andersohn Nested et al,12 2010 C-C
UK
Population- 1987–2005; based 5.2–5.4 y
Bernstein Nested et al,13 2008 C-C
Canada
Population- 1984–2003; based 16.1–16.6 mean personyears
Ha et al,8 2009 Nested C-C
US
Healthclaims database
2001–2006; 3.2–4.1 y
Kristensen Nested Denmark Population- 1996–2009; et al,11 2013 C-C based 6.0–6.2 y Osterman Nested et al,28 2011 C-C
Yarur et al,14 2011
C-C
Population- 1987–2003; based 4.4–4.7 y
Denmark Population- 1997–2009 based US
Hospitalbased
1995–2009; 4.3–4.5 y
Controls
Definition of outcome
Total
CVA
IHD
PAD
Total
CVA
IHD
PAD
Acute ischemic stroke, medical diagnostic codes, inpatients and outpatients Incident cases, after IBD diagnosis, IHD (MI, old MI, angina, chronic IHD), CVA (subarachnoid hemorrhage, intracranial hemorrhage, ischemic stroke), other atheroembolic disease, medical diagnostic codes, inpatients only (hospitalized or emergency room visit) Incident cases, after IBD diagnosis, CVA (TIA, cerebrovascular occlusion); IHD (including acute MI, atherosclerosis), peripheral vascular disease, medical diagnostic codes, inpatients and outpatients Stroke, MI, cardiovascular death, medical diagnostic codes, inpatients and outpatients Incident acute MI, after IBD diagnosis, medical diagnostic codes, inpatients and outpatients Incident IHD, after IBD diagnosis, medical diagnostic codes, inpatients and outpatients Incident IHD event (unstable angina, MI; silent MI; abnormal angiogram) with independent validation, diagnosed >12 mo after IBD diagnosis
8054; all CD
89
-
-
161,078
1670
-
-
Adjusted fore 1,2,3,4,5, 6,7,8,9, 10,12,14 -
8072: CD, 4193, UC, 3879
161; 81, 80
238; 111, 127
33; 18, 15
80,489
1390
1884
255
17,487a: CD, 7480, UC, 9968
496b; 215, 279
1068; 477, 591
115; 49, 66
69,948
1804
4219
397
-
-
-
199,978
3327
-
-
3,4,5,6,8,9, 11,12,15
-
CD 92,987; UC 144,605
-
908; 2188
-
1,2,3,4,6, 8,9
4,541,987
-
243,844
-
3,4,5,6,8, 12,15
712
-
-
1,2,3,4,5,6, 10,13,16
456; NR, 20,795c: CD, 4732, NR UC, 13,622 25,327d: CD, 9829; UC, 15,498 28,833: CD, 7521, UC, 19,990 356: CD, 173; UC, 183
-
-
390; 110, 280 863f; 161f, 608f 47; 22, 25
-
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Rungoe et al,15 Cohort 2012
UK
IBD
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Table 1. Baseline Characteristics of the Included Studies Reporting the Association Between IBD and CVA, IHD, and/or Extra-intestinal Peripheral Arterial Thromboembolic Events
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388
Table 1. Continued
Zoller et al,29,30 Cohort 2012 (2 studies)
Time period; follow-up period
Sweden Population- 1987–2008 based
IBD Total
Definition of outcome Incident CVA or IHD requiring hospitalization, medical diagnostic codes
Controls
CVA
43,832: CD, 20,222; UC, 23,610
IHD
1222; 504, 718
PAD
3872; 1304, 2568
Total
-
CVA
IHD
PAD
Compared with population estimates of stroke and IHD
Adjusted fore 2,3,4,6,8, 13, 14,15
Singh et al
Study
Study design Location Setting
C-C, case-control, MI, myocardial infarction; PAD, extra-intestinal peripheral arterial thromboembolic events; TIA, transient ischemic attack. NOTE. Adjusted for: 1 ¼ smoking, 2 ¼ body mass index, 3 ¼ diabetes mellitus, 4 ¼ hypertension, 5 ¼ hyperlipidemia, 6 ¼ past history of coronary artery disease, 7 ¼ past history of cerebrovascular accident, 8 ¼ other coronary comorbidities (congestive heart failure, atrial fibrillation), 9 ¼ aspirin use, 10 ¼ IBD treatment, 11 ¼ IBD activity, 12 ¼ other medications (anticoagulants, oral contraceptives, hormone replacement therapy), 13 ¼ chronic kidney disease, 14 ¼ alcohol, 15 ¼ socioeconomic status, 16 ¼ family history of coronary artery disease. a Thirty-nine patients with IBD unclassified. b Two CVA events in patients with IBD unclassified. c A total of 2441 patients with IBD unclassified. d A total of 1322 patients who changed diagnosis between UC and CD during the follow-up period. e All studies were adjusted for age and sex. f Only cases of IHD diagnosed more than 1 year after IBD diagnosis.
Table 2. Distribution of Traditional Cardiovascular Risk Factors in Patients With IBD and Patients Without IBD in the Included Studies
Mean age, y
Sex, % male
Diabetes, % total
IBD
Non-IBD
IBD
Non-IBD
IBD
Andersohn et al12 Bernstein et al13 Ha et al8 Kristensen et al11 Osterman et al28a
39 36 CD, 42 UC 43 CD, 44 UC 44 44 CD, 50 UC
42 NR 43 43 43, 49
42.9 45.0 44.3 45.5 48.4, 41.0
46.0 45.0 44.2 45.2 40.9, 48
2.9
38 45
41 45
Rungoe et al15 Yarur et al14
Zoller et al29,30
NR
44 48.3
49 48.3
NR
NR, not reported. a Reports CD and UC, with separate control population for each. b Proportion of patients on antihypertensive and/or antihyperlipidemic medications. c Mean total cholesterol (in mg/dL).
Non-IBD 2.8
IBD
3.6 1.8 1.9, 3.6 5.8 6.7
3.5 0.1 1.7, 2.1 4.9 16.7
NR
Non-IBD
IBD
10.1
1.7
8.6
NR
Hyperlipidemia, % total (or obesity)
NR
2.2 NR
9.0 3.1 14.5, 18.5
6.5 1.2 10.5, 13.5
44.4b 20.5
39b 39.0
NR
Non-IBD
8.2 4.2 1.3, 2.1
6.0 2.7 1.1, 1.5 39b 190c
44.4b 177c
NR
Smoking, % total IBD
Non-IBD
56.4 (all CD) 50.4 NR NR NR 37.0 (CD) 28.9, 27.9 23.2 (UC) NR 30.3 (all); 27.1 30.1 (CD); 30.6 (UC) NR
Aspirin, % total IBD
Non-IBD
2.4
2.5 NR NR
5.9 5.2, 7.1
3.4 4.4, 6.1 NR NR
NR
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Study
Hypertension, % total
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Figure 2. Summary of ORs of studies assessing the risk of cerebrovascular accident in patients with IBD (overall), CD, and UC.
diseases.45 All of these data provide biological evidence in support of early atherosclerosis in IBD, and taken together with the epidemiologic association observed in our meta-analysis, lend support to a probable causative association. We observed that women with IBD have a significantly higher excess risk of CVA and IHD than men as compared with patients without IBD. This probably is related to the inherent differences in traditional and nontraditional risk factors for CVA and IHD in males and females. Despite less anatomic coronary artery disease, women have higher rates of myocardial ischemia and mortality as compared with age-matched men.46
Inflammation appears to play a greater role in IHD in women as compared with men; women have greater mean C-reactive protein levels compared with men and the relative risk of future IHD events increases proportionally with increasing levels of C-reactive protein in women, independent of the risk contributed by traditional cardiovascular risk factors.46,47 Endothelial and microvascular dysfunction, potentially induced by chronic inflammation and hormonal differences, appear to predispose women to abnormal coronary reactivity and myocardial ischemia.46 Use of oral contraceptives may be an additional procoagulant factor increasing the risk of thrombotic cardiovascular events in females.
Table 3. Subgroup Analysis of Studies on IBD and the Risk of CVA Subgroup Type of IBD Sex Ageb Study setting Study location Study design
a
Categories
Studies, n
Adjusted OR
95% CI
CD UC Males Females Young Old Population-based Hospital-based North America Europe C-C Cohort
5 4 4 4 3 3 4 1 2 3 4 1
1.25 1.13 1.11 1.28 1.84 1.11 1.21 1.10 1.12 1.21 1.13 1.28
1.14–1.39 1.05–1.23 0.98–1.25 1.17–1.41 1.28–2.66 1.02–1.21 1.12–1.30 1.00–1.22 1.03–1.22 1.11–1.33 1.06–1.20 1.21–1.36
Difference between groups (P value) .10 .05a .01a .15 .21 <.01a
Indicates significant difference between subgroups. Young refers to age younger than 40 years8,13 or younger than 50 years12 and old refers to age older than 50 years,12 older than 60 years,13 or 40 to 59 years.8
b
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Figure 3. Summary of ORs of studies assessing the risk of IHD in patients with IBD (overall), CD, and UC.
However, Andersohn et al12 did not observe any significant difference in oral contraceptive use in patients with or without CVA. We also observed that the excess risk of stroke compared with patients without IBD was significantly higher in young patients compared with elderly individuals. This has significant implications—a recent prospective cohort study showed that the longterm mortality after stroke among young adults (age, 18–50 y) is 4-fold higher than expected.48 Young patients with IBD are more likely to have extensive luminal and penetrating disease, require more courses of
corticosteroids and immunosuppressive medications, and have more frequent disease recurrences.49,50 On the other hand, elderly patients usually have less severe disease with a milder course of IBD, and often can be managed with mesalamines, with less than 20% requiring immunosuppressive medications.51,52 Because the severity of inflammation modifies the risk of venous as well as arterial thromboembolism,7,11 this may explain the higher magnitude of increased risk of stroke seen in younger individuals. With aging, traditional cardiovascular risk factors potentially may outweigh the risk afforded by mild inflammatory disease seen in elderly
Table 4. Subgroup Analysis of Studies on IBD and the Risk of IHD Subgroup Type of IBD Sex Ageb Study setting Study location Study design
a
Categories
Studies, n
Adjusted OR
95% CI
CD UC Males Females Young Old Population-based Hospital-based North America Europe Case-control Cohort
5 5 4 4 3 3 4 2 3 3 4 2
1.08 1.15 1.05 1.26 1.40 1.29 1.17 1.99 1.52 1.16 1.31 1.17
1.03–1.13 1.05–1.25 0.92–1.21 1.18–1.35 0.93–2.11 0.97–1.71 1.11–1.23 0.51–7.78 1.05–2.20 1.10–1.22 1.05–1.64 1.10–1.25
Difference between groups (P value) .22 .02a .75 .45 .15 .34
Indicates significant difference between subgroups. Young refers to age younger than 40 years8,13 or younger than 50 years12 and old refers to age older than 50 years,12 older than 60 years,13 or 40 to 59 years.8
b
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onset IBD. Finally, the absolute risk of cardiovascular events is much higher in older subjects, thus making it more difficult to show increased risk. There were several limitations that should be considered while interpreting the results of this study. First, we included studies from different clinical settings that had different diagnostic criteria, age at enrollment, period at risk, and study design. As expected, we found statistically significant heterogeneity in the results and, hence, we used the random-effects model to include an estimate of variability.24 In addition, we explored sources of heterogeneity through subgroup analysis and were able to identify important sex- and age-specific differences in the risk of cardiovascular events in patients with IBD. Second, given the retrospective nature of all of the included studies, the possibility of detection bias as a result of higher health care use in patients with IBD may contribute to the observed increase in the rate of cardiovascular events in this population. Although Rungoe et al15 observed a particularly high risk of cardiovascular events within the first year of IBD diagnosis, this increased risk also was observed on sensitivity analysis of IHD events occurring more than 1 year after IBD diagnosis. On analysis of a populationbased Danish cohort over 30 years, Jess et al53 also noted that cardiovascular mortality was highest in the first year of IBD diagnosis, suggesting ascertainment bias, but observed that the increased risk of cardiovascular mortality persisted with increasing duration of IBD. Third, the included studies did not uniformly adjust for all traditional and atypical risk factors for cardiovascular disease. However, in our analysis, there was no significant difference in the pooled analysis of unadjusted and maximally adjusted data from each study, suggesting that any difference attributable to using different confounders for adjustment likely is small. Fourth, we were unable to systematically study whether IBD disease activity or specific medications used to suppress inflammation modify the risk of cardiovascular events owing to lack of reporting in individual studies. A positive association between disease activity and cardiovascular events was seen in a population-based Danish cohort.11 Kristensen et al11 identified that, during flares and periods of persistent IBD activity, the risk of stroke, myocardial infarction, and cardiovascular death is 49% to 150% higher than age- and sex-matched controls; during periods of remission, the risk of these end points was not different from the control population. Another potential limitation that particularly applies to case-control studies evaluating cardiovascular events is recall bias. However, in most studies, medical diagnostic codes were used for establishing exposure and outcome, and, hence, the effects of this likely are minimal. Finally, some studies only reported CVA or IHD events for which a patient was hospitalized29,30 and, hence, may have missed chronic stable angina or transient ischemic attack, which do not require hospitalization, thereby
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underestimating the risk of cardiovascular morbidity in patients with IBD. In conclusion, IBD is associated with a modest increase in the risk of CVA and IHD, particularly in females and in young adults, although considerable statistical heterogeneity was observed in the analysis. This increased risk may be owing to chronic systemic inflammation present in these patients. Gastroenterologists should be cognizant of this relationship and should focus on better management of conventional risk factors, such as smoking cessation, recognition and control of hypertension and diabetes, as well as maintaining long-term remission in patients with IBD to minimize the risk of inflammationinduced cardiovascular events.
Supplementary Material Note: To access the supplementary material accompanying this article, visit the online version of Clinical Gastroenterology and Hepatology at www.cghjournal.org, and at http://dx.doi.org/10.1016/j.cgh.2013.08.023.
References 1. Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med 2005;352:1685–1695. 2. Piazza G, Goldhaber SZ. Venous thromboembolism and atherothrombosis: an integrated approach. Circulation 2010; 121:2146–2150. 3. Avina-Zubieta JA, Thomas J, Sadatsafavi M, et al. Risk of incident cardiovascular events in patients with rheumatoid arthritis: a meta-analysis of observational studies. Ann Rheum Dis 2012; 71:1524–1529. 4. Roman MJ, Shanker BA, Davis A, et al. Prevalence and correlates of accelerated atherosclerosis in systemic lupus erythematosus. N Engl J Med 2003;349:2399–2406. 5. Avina-Zubieta JA, Choi HK, Sadatsafavi M, et al. Risk of cardiovascular mortality in patients with rheumatoid arthritis: a meta-analysis of observational studies. Arthritis Rheum 2008; 59:1690–1697. 6. Murthy SK, Nguyen GC. Venous thromboembolism in inflammatory bowel disease: an epidemiological review. Am J Gastroenterol 2011;106:713–718. 7. Grainge MJ, West J, Card TR. Venous thromboembolism during active disease and remission in inflammatory bowel disease: a cohort study. Lancet 2010;375:657–663. 8. Ha C, Magowan S, Accortt NA, et al. Risk of arterial thrombotic events in inflammatory bowel disease. Am J Gastroenterol 2009; 104:1445–1451. 9. Di Fabio F, Obrand D, Satin R, et al. Intra-abdominal venous and arterial thromboembolism in inflammatory bowel disease. Dis Colon Rectum 2009;52:336–342. 10. Papa A, Santoliquido A, Danese S, et al. Increased carotid intima-media thickness in patients with inflammatory bowel disease. Aliment Pharmacol Ther 2005;22:839–846. 11. Kristensen SL, Ahlehoff O, Lindhardsen J, et al. Disease activity in inflammatory bowel disease is associated with increased risk of myocardial infarction, stroke and cardiovascular death–a Danish nationwide cohort study. PLoS One 2013;8:e56944.
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12. Andersohn F, Waring M, Garbe E. Risk of ischemic stroke in patients with Crohn’s disease: a population-based nested casecontrol study. Inflamm Bowel Dis 2010;16:1387–1392. 13. Bernstein CN, Wajda A, Blanchard JF. The incidence of arterial thromboembolic diseases in inflammatory bowel disease: a population-based study. Clin Gastroenterol Hepatol 2008;6:41–45. 14. Yarur AJ, Deshpande AR, Pechman DM, et al. Inflammatory bowel disease is associated with an increased incidence of cardiovascular events. Am J Gastroenterol 2011;106:741–747. 15. Rungoe C, Basit S, Ranthe MF, et al. Risk of ischaemic heart disease in patients with inflammatory bowel disease: a nationwide Danish cohort study. Gut 2013;62:689–694. 16. Dorn SD, Sandler RS. Inflammatory bowel disease is not a risk factor for cardiovascular disease mortality: results from a systematic review and meta-analysis. Am J Gastroenterol 2007; 102:662–667. 17. Duricova D, Pedersen N, Elkjaer M, et al. Overall and causespecific mortality in Crohn’s disease: a meta-analysis of population-based studies. Inflamm Bowel Dis 2010;16:347–353. 18. Jess T, Gamborg M, Munkholm P, et al. Overall and causespecific mortality in ulcerative colitis: meta-analysis of population-based inception cohort studies. Am J Gastroenterol 2007;102:609–617. 19. Ergin A, Muntner P, Sherwin R, et al. Secular trends in cardiovascular disease mortality, incidence, and case fatality rates in adults in the United States. Am J Med 2004;117:219–227. 20. Higgins JPT, Green S (eds). Cochrane handbook for systematic reviews of interventions version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available at: www.cochranehandbook.org. 21. Moher D, Liberati A, Tetzlaff J, et al. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Ann Intern Med 2009;151:264–269, W64. 22. Wells GA, O’Connell D, Peterson J, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. Volume 2012. Available at: http://www.ohri. ca/programs/clinical_epidemiology/oxford.asp. 23. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials 1986;7:177–188. 24. Higgins JP, Thompson SG, Deeks JJ, et al. Measuring inconsistency in meta-analyses. BMJ 2003;327:557–560. 25. Thompson SG, Pocock SJ. Can meta-analyses be trusted? Lancet 1991;338:1127–1130. 26. Guyatt GH, Oxman AD, Kunz R, et al. GRADE guidelines: 7. Rating the quality of evidence–inconsistency. J Clin Epidemiol 2011;64:1294–1302. 27. Sterne JA, Egger M, Smith GD. Systematic reviews in health care: investigating and dealing with publication and other biases in meta-analysis. BMJ 2001;323:101–105. 28. Osterman MT, Yang YX, Brensinger C, et al. No increased risk of myocardial infarction among patients with ulcerative colitis or Crohn’s disease. Clin Gastroenterol Hepatol 2011;9: 875–880. 29. Zoller B, Li X, Sundquist J, et al. Risk of subsequent ischemic and hemorrhagic stroke in patients hospitalized for immunemediated diseases: a nationwide follow-up study from Sweden. BMC Neurol 2012;12:41. 30. Zoller B, Li X, Sundquist J, et al. Risk of subsequent coronary heart disease in patients hospitalized for immune-mediated diseases: a nationwide follow-up study from Sweden. PLoS One 2012;7:e33442.
Clinical Gastroenterology and Hepatology Vol. 12, No. 3 31. Haapamaki J, Roine RP, Turunen U, et al. Increased risk for coronary heart disease, asthma, and connective tissue diseases in inflammatory bowel disease. J Crohns Colitis 2011; 5:41–47. 32. Sridhar AR, Parasa S, Navaneethan U, et al. Comprehensive study of cardiovascular morbidity in hospitalized inflammatory bowel disease patients. J Crohns Colitis 2011;5:287–294. 33. Inamdar S AS, Sultan K. Increased risk of coronary artery disease among patients with inflammatory bowel disease. Gastroenterology 2012;142:S792. 34. Lund Kristensen S, Ahlehoff O, Lindhardsen J, et al. [Increased risk of venous thromboembolism and arterial cardiovascular events in patients with inflammatory bowel disease]. Ugeskr Laeger 2012;174:3003–3006. 35. Bewtra M, Kaiser LM, TenHave T, et al. Crohn’s disease and ulcerative colitis are associated with elevated standardized mortality ratios: a meta-analysis. Inflamm Bowel Dis 2013; 19:599–613. 36. Gandhi S, Narula N, Marshall JK, et al. Are patients with inflammatory bowel disease at increased risk of coronary artery disease? Am J Med 2012;125:956–962. 37. Theocharidou E, Gossios TD, Giouleme O, et al. Carotid intima-media thickness in patients with inflammatory bowel disease: a systematic review. Angiology 2013 Feb 18. Epub ahead of print. 38. Zanoli L, Cannavo M, Rastelli S, et al. Arterial stiffness is increased in patients with inflammatory bowel disease. J Hypertens 2012;30:1775–1781. 39. Roifman I, Sun YC, Fedwick JP, et al. Evidence of endothelial dysfunction in patients with inflammatory bowel disease. Clin Gastroenterol Hepatol 2009;7:175–182. 40. Aloi M, Tromba L, Di Nardo G, et al. Premature subclinical atherosclerosis in pediatric inflammatory bowel disease. J Pediatr 2012;161:589–594 e1. 41. Kayahan H, Sari I, Cullu N, et al. Evaluation of early atherosclerosis in patients with inflammatory bowel disease. Dig Dis Sci 2012;57:2137–2143. 42. Oussalah A, Gueant JL, Peyrin-Biroulet L. Meta-analysis: hyperhomocysteinaemia in inflammatory bowel diseases. Aliment Pharmacol Ther 2011;34:1173–1184. 43. Saibeni S, Cattaneo M, Vecchi M, et al. Low vitamin B(6) plasma levels, a risk factor for thrombosis, in inflammatory bowel disease: role of inflammation and correlation with acute phase reactants. Am J Gastroenterol 2003; 98:112–117. 44. Hatoum OA, Binion DG. The vasculature and inflammatory bowel disease: contribution to pathogenesis and clinical pathology. Inflamm Bowel Dis 2005;11:304–313. 45. Galluzzo S, Patti G, Dicuonzo G, et al. Association between NOD2/CARD15 polymorphisms and coronary artery disease: a case-control study. Hum Immunol 2011;72: 636–640. 46. Shaw LJ, Bugiardini R, Merz CN. Women and ischemic heart disease: evolving knowledge. J Am Coll Cardiol 2009; 54:1561–1575. 47. Cook NR, Buring JE, Ridker PM. The effect of including C-reactive protein in cardiovascular risk prediction models for women. Ann Intern Med 2006;145:21–29. 48. Rutten-Jacobs LC, Arntz RM, Maaijwee NA, et al. Long-term mortality after stroke among adults aged 18 to 50 years. JAMA 2013;309:1136–1144.
March 2014 49. Romberg-Camps MJ, Dagnelie PC, Kester AD, et al. Influence of phenotype at diagnosis and of other potential prognostic factors on the course of inflammatory bowel disease. Am J Gastroenterol 2009;104:371–383. 50. Polito JM 2nd, Childs B, Mellits ED, et al. Crohn’s disease: influence of age at diagnosis on site and clinical type of disease. Gastroenterology 1996;111:580–586. 51. Charpentier C, Salleron J, Savoye G, et al. Natural history of elderly-onset inflammatory bowel disease: a population-based cohort study. Gut 2013 Feb 13. Epub ahead of print. 52. Katz S, Pardi DS. Inflammatory bowel disease of the elderly: frequently asked questions (FAQs). Am J Gastroenterol 2011; 106:1889–1897.
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53. Jess T, Frisch M, Simonsen J. Trends in overall and cause-specific mortality among patients with inflammatory bowel disease from 1982 to 2010. Clin Gastroenterol Hepatol 2013;11:43–48.
Reprint requests Address requests for reprints to: Darrell S. Pardi, MD, MS, 200 First Street SW, Rochester, Minnesota 55905. e-mail: [email protected]; fax: (507) 284-0538. Acknowledgment S.S. and H.S. contributed equally to this work. Conflicts of interest The authors disclose no conflicts.
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Supplementary Table 1. Newcastle-Ottawa Scale for Assessment of Quality of Included Cohort Studies Acceptable*
Rungoe et al15
Zoller et al29,30
Representative of average adult in community (age/sex/being at risk of disease) Drawn from same community as exposed cohort Secured records, structured interview Only incident cases of CVAs/IHD
*
*
* * *
* *
Yes Smoking, diabetes, hypertension, hyperlipidemia, family history of CVAs/IHD, aspirin use
* *
* *
Independent blind assessment, record linkage Follow-up period >4 y
* *
* *
Complete follow-up evaluation, or subjects lost to follow-up evaluation unlikely to introduce bias
*
*
9
8
Quality assessment criteria Selection Representativeness of exposed cohort? Selection of the nonexposed cohort? Ascertainment of exposure? Demonstration that outcome of interest was not present at start of study? Comparability Study controls for age/sex? Study controls for at least 3 additional risk factors? Outcome Assessment of outcome? Was follow-up period evaluation long enough for outcome to occur? Adequacy of follow-up evaluation of cohorts? Overall quality score (maximum, 9)
NOTE. Asterisk indicates that individual criterion within the subsection were fulfilled.
Supplementary Table 2. Newcastle-Ottawa Scale for Assessment of Quality of Included Case-Control Studies Quality assessment criteria
Acceptable*
Andersohn Bernstein Ha Kristensen Osterman Yarur et al13 et al8 et al11 et al28 et al14 et al12
Selection Is the case definition adequate? Yes, with independent validation Representativeness of cases? Consecutive or obviously representative series of cases Selection of controls? Community controls Definition of controls? No history of studied end point Comparability Study controls for age/sex Yes Study controls for at least 3 Smoking, diabetes, hypertension, additional factors hyperlipidemia, family history of CVAs/IHD, aspirin use Exposure Ascertainment of exposure? Secure record, structured interview by health care practitioner, blind to case/control status Same method of ascertainment Yes of cases/controls? Nonresponse rate? Same for both groups Overall quality score (maximum, 9)
NOTE. Asterisk indicates that individual criterion within the subsection were fulfilled.
*
* -
* *
*
* *
* -
* *
* *
* *
* *
* *
*
* *
* -
* -
* *
* *
* *
*
*
-
*
*
*
*
*
*
*
*
*
7
* 7
* 7
* 8
* 9
* 7
SYSTEMATIC REVIEWS AND META-ANALYSES Fasiha Kanwal, Section Editor
Risk of Cerebrovascular Accidents and Ischemic Heart Disease in Patients With Inflammatory Bowel Disease: A Systematic Review and Meta-analysis Siddharth Singh,* Harkirat Singh,‡ Edward V. Loftus Jr.,* and Darrell S. Pardi* *Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota; and ‡Department of Internal Medicine, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania This article has an accompanying continuing medical education activity on page e22. Learning Objectives—At the end of this activity, the successful learner will be able to recognize the association between inflammatory bowel diseases and risk of cerebrovascular accidents and ischemic heart disease.
BACKGROUND & AIMS:
Inflammatory bowel disease (IBD) is associated with an increased risk of venous thromboembolic disease. However, it is unclear whether IBD modifies the risk of arterial thromboembolic events, including cerebrovascular accidents (CVA) and ischemic heart disease (IHD).
METHODS:
We performed a systematic review and meta-analysis of cohort and case-control studies that reported incident cases of CVA and/or IHD in patients with IBD and a non-IBD control population (or compared with a standardized population). We calculated pooled odds ratios (ORs) with 95% confidence intervals (CIs).
RESULTS:
We analyzed data from 9 studies (2424 CVA events in 5 studies, 6478 IHD events in 6 studies). IBD was associated with a modest increase in the risk of CVA (5 studies; OR, 1.18; 95% CI, 1.09– 1.27), especially among women (4 studies; OR, 1.28; 95% CI, 1.17–1.41) compared with men (OR, 1.11; 95% CI, 0.98–1.25), and in young patients (<40–50 y old). The increase in risk was observed for patients with Crohn’s disease and in those with ulcerative colitis. IBD also was associated with a 19% increase in the risk of IHD (6 studies; OR, 1.19; 95% CI, 1.08–1.31), both in patients with Crohn’s disease and ulcerative colitis. This risk increase was seen primarily in women (4 studies; OR, 1.26; 95% CI, 1.18–1.35) compared with men (OR, 1.05; 95% CI, 0.92– 1.21), in young and old patients. IBD was not associated with an increased risk of peripheral arterial thromboembolic events. Considerable heterogeneity was observed in the overall analysis.
CONCLUSIONS:
IBD is associated with a modest increase in the risk of cardiovascular morbidity (from CVA and IHD)—particularly in women. These patients should be counseled routinely on aggressive risk factor modification.
Keywords: Myocardial Infarction; Coronary Artery Disease; Stroke; Inflammatory Bowel Disease.
hronic systemic inflammation is an independent risk factor for atherosclerosis by promoting plaque formation, inducing endothelial dysfunction, and promoting platelet activation and aggregation.1 Active inflammation also predisposes to thrombosis by altering the balance between physiological procoagulants and anticoagulants and inducing a state of hypofibrinolysis.2 Epidemiologic studies have shown that chronic inflammatory diseases such as rheumatoid arthritis and systemic lupus erythematosus are associated with premature atherosclerosis and an increased risk of cardiovascular morbidity3,4 and mortality.5 Several studies have shown that inflammatory bowel disease (IBD) is associated with an increased risk of
C
venous thromboembolism,6 particularly during severe flares.7 Chronic intestinal inflammation associated with IBD also has been associated with acute mesenteric ischemia.8,9 Similar to other chronic inflammatory diseases, patients with IBD have an increased thickness of the carotid intimal-media, which is a measure of atherosclerotic disease burden.10 However, it is unclear
Abbreviations used in this paper: CD, Crohn’s disease; CI, confidence interval; CVA, cerebrovascular accident; IBD, inflammatory bowel disease; IHD, ischemic heart disease; OR, odds ratio; UC, ulcerative colitis. © 2014 by the AGA Institute 1542-3565/$36.00 http://dx.doi.org/10.1016/j.cgh.2013.08.023
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whether IBD modifies the risk of cardiovascular arterial events, such as cerebrovascular accidents (CVA) or ischemic heart disease (IHD). Although some studies have shown an increased risk of CVA in patients with IBD,8,11 others have shown no such association.12,13 Likewise, the relationship between IBD and risk of myocardial infarction and IHD also is ambiguous.8,11,14 Sex- and phenotype-specific associations have been suggested, but remain controversial.8,13,15 Previous meta-analyses have found no association between IBD and cardiovascular disease mortality.16–18 However, cardiovascular mortality is a suboptimal surrogate for cardiovascular disease incidence; with advancements in medical management and interventional strategies, mortality from myocardial infarction has decreased.19 Hence, to better understand the association between IBD and cardiovascular morbidity, we conducted a systematic review and meta-analysis of observational studies that investigated the relationship between IBD and CVA, IHD, and extra-intestinal peripheral arterial thromboembolic disease. In addition, we explored phenotype-, sex-, and age-specific differences in the risk of cardiovascular morbidity in patients with IBD.
Methods This systematic review was conducted following guidance provided by the Cochrane handbook20 and is reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.21 The process followed an a priori established protocol.
Data Sources and Search Strategy First, a systematic literature search of PubMed (1966 through March 1, 2013), Embase (1988 through March 1, 2013), and Web of Science (1993 through March 1, 2013) databases was conducted to identify all relevant articles on the risk of cardiovascular events in patients with IBD. Medical subject heading terms used in the search included a combination of “cerebrovascular disease,” “stroke,” “coronary artery disease,” “ischemic heart disease,” “thromboembolism/arterial,” “peripheral vascular diseases,” as well as “mesenteric ischemia” (key word) and “inflammatory bowel disease,” “Crohn’s disease,” “ulcerative colitis.” The title and abstract of studies identified in the search were reviewed by 2 authors (S.S. and H.S.) independently to exclude studies that did not answer the research question of interest, based on prespecified inclusion and exclusion criteria (see later). The full text of the remaining articles was examined to determine whether it contained relevant information. The coefficient of agreement between the 2 reviewers for article selection (k ¼ 0.84; 95% CI, 0.72–0.94) was excellent. Conflicts in study selection were resolved by consensus, referring back to the original article and, if needed, in consultation with the principal investigator
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(D.S.P.). Second, we searched the bibliographies of these selected articles as well as related narrative and systematic review articles to identify any additional studies. Third, a manual search of abstracts from major gastroenterology conferences (Digestive Disease Week, the American College of Gastroenterology annual meeting, the Advances in Inflammatory Bowel Diseases meeting organized by the Crohn’s and Colitis Foundation of America, and the European Crohn’s and Colitis Organization annual meeting) from 2005 to 2012 was performed to identify additional abstracts on the topic.
Study Selection Studies considered in this meta-analysis were cohort or case-control studies that met the following inclusion criteria: (1) diagnosed IBD (Crohn’s disease [CD] and/or ulcerative colitis [UC]) according to well-defined criteria; (2) reported incident cases of CVA or IHD or extraintestinal peripheral arterial thromboembolic events after the diagnosis of IBD; (3) included a non-IBD population for which CVA, IHD, or extra-intestinal peripheral arterial thromboembolic event rates were calculated (or could be inferred as expected event rates from a reference population); and (4) reported relative risks (for cohort studies), odds ratios (OR) (for case-control studies), or standardized incidence rates (for studies comparing the rates of observed with expected cases) with 95% confidence intervals (CIs) or provided data for their calculation. Cross-sectional studies in which temporality could not be established (ie, the diagnosis of IBD was not clearly established before the first diagnosis of cardiovascular events) were excluded. Articles also were excluded from the analysis if there were insufficient data for determining a risk estimate and 95% CI. Inclusion was not otherwise restricted by study size, language, or publication type. When there were multiple publications from the same population, only data from the most recent comprehensive report were included. CVA was defined as a history of ischemic or hemorrhagic stroke and/or transient ischemic attack. IHD was defined in included studies based on medical diagnostic codes and included acute coronary syndrome, history of myocardial infarction, and/or angina. Congestive heart failure (without report of underlying etiology) and cardiac arrhythmias were not studied. Peripheral arterial thromboembolic disease was defined as acute or chronic peripheral arterial insufficiency (excluding intestinal vasculature).
Data Abstraction and Quality Assessment Data were abstracted independently onto a standardized form by 2 investigators (S.S. and H.S.). The following data were collected from each study: study design, time period of study/year of publication, country of the population studied, method of exposure ascertainment (IBD
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[CD and/or UC] and control population), primary outcome reported (CVA, IHD, and/or peripheral artery disease) and source of outcome assessment, total number of persons in each group (IBD vs non-IBD controls), relative risk/OR/ standardized incidence rates and 95% CIs with and without adjustment for potential confounders, and potential confounders used for adjustment. Data on the following confounding risk factors for CVA or IHD were extracted from each study: age, sex, race, cigarette smoking, body mass index, history of diabetes mellitus, hypertension, hyperlipidemia, personal and family history of CVA/IHD, and aspirin use. Conflicts in data abstraction were resolved by consensus, referring back to the original article and in consultation with the principal investigator (D.S.P.). The methodologic quality of case-control and cohort studies was assessed by 2 study investigators (S.S. and H.S.), independently using the Newcastle-Ottawa scale.22 In this scale, observational studies were scored across 3 categories: selection (4 questions) and comparability (2 questions) of study groups, and ascertainment of the outcome of interest (3 questions), with maximum 1 point for each question, except for comparability of study groups, for which separate points were awarded for controlling age and/or sex (maximum, 2 points). Any discrepancies were addressed by a joint re-evaluation of the original article.
Outcomes Assessed The primary analysis focused on assessing the risk of cardiovascular morbidity (CVA, IHD, and peripheral arterial thromboembolic disease) among patients with IBD. In addition, based on information available from individual studies, we assessed CD- and UC-specific risk estimates and explored sex- and age-specific differences in risk estimates.
Data Synthesis and Analysis We used the random-effects model described by DerSimonian and Laird23 to calculate summary ORs and 95% CIs. We assessed heterogeneity between studyspecific estimates using 2 methods.24 First, the Cochran Q statistical test for heterogeneity, which tests the null hypothesis that all studies in a meta-analysis have the same underlying magnitude of effect, was measured. Because this test is underpowered to detect moderate degrees of heterogeneity,25 a P value of less than .10 was considered suggestive of significant heterogeneity. Second, to estimate what proportion of total variation across studies was caused by study-related factors (clinical setting, methodologic or statistical differences) rather than chance, the I2 statistic was calculated. For this calculation, values of less than 30%, 31% to 60%, 61% to 75%, and greater than 75% were suggestive of low, moderate, substantial, and considerable heterogeneity, respectively.26 If significant heterogeneity was observed
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in the analysis, we explored potential causes of heterogeneity by stratifying for several methodologic and clinical features of studies. This included study design (case-control vs cohort), study location (North America vs Europe), study setting (hospital-based vs populationbased), and sex- or age-specific differences in risk estimates. In this analysis, a P value for differences between subgroups (referred to as Pinteraction) of less than .10 was considered statistically significant (ie, a value of P < .10 suggested that stratifying based on that particular study characteristic partly explained the heterogeneity observed in the analysis). Because of the small number of published studies, a formal statistical analysis of funnel plot asymmetry for assessment of publication bias was not used.27 All P values were 2-tailed. For all tests (except for heterogeneity), a probability level less than .05 was considered statistically significant. All calculations and graphs were performed using Comprehensive Meta-Analysis version 2 (Biostat, Englewood, NJ).
Results Search Results Among 688 unique studies that were identified using our search strategy, 9 studies met the defined inclusion criteria for this meta-analysis (6 case-control and 3 cohort studies).8,11–15,28–30 Three cross-sectional studies that reported the prevalence of CVA, IHD, and peripheral artery disease in patients with IBD were excluded.31–33 Figure 1 summarizes the process of study identification, inclusion, and exclusion. These studies cumulatively reported 2424 CVA, 6478 IHD, and 148 peripheral arterial thromboembolic events in 152,756 patients with IBD (at least 123,907 independent, nonoverlapping patients). Two population-based studies from Denmark included overlapping patients with IBD, but reported different outcomes (CVA and IHD) and, hence, were analyzed separately for the respective outcome11,15; a separate Danish cohort study on the same topic from common investigators was excluded.34 Likewise, 2 Swedish population-based studies from common investigators and the same cohort reported different outcomes (CVA and IHD) and, hence, were used for the respective analysis separately.29,30 Andersohn et al12 used the General Practice Research Database to identify CD patients with CVA, whereas Osterman et al28 used the same administrative database to identify IBD patients and their subsequent risk of IHD.
Characteristics and Quality of Included Studies The baseline characteristics of these studies and participants are shown in Tables 1 and 2. The earliest study period began in 1984, and the latest ended in 2009. All studies were performed in Western populations (3 in North America,8,13,14 6 in Europe).11,12,15,28–30 Five
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Figure 1. Flowchart summarizing study identification and selection.
studies were population-based,11,13,15,29,30 3 used administrative databases,8,12,28 and 1 study was hospitalbased.14 Seven studies included a control non-IBD population drawn from the same cohort,8,11–15,28 and 2 studies inferred rates of CVA and IHD from an age- and sexmatched general population.29,30 All studies relied on medical diagnostic codes to identify patients with IBD, with 5 studies having independently validated the accuracy of diagnosis in previous studies from the database,11–13,15,28 and 1 study performing an actual medical record review.14 Supplementary Table 1 and 2 show the methodologic quality of all studies. In all these studies, a temporal relation of the development of cardiovascular events after IBD was firmly established. Four studies explicitly excluded patients with a diagnosis of cerebrovascular and/or cardiovascular disease before diagnosis of IBD,11,14,15,28 and 3 studies adjusted for previous history of cardiovascular morbidity in the overall analysis.12,29,30 Table 2 shows the distribution of cardiovascular risk factors in patients with IBD and non-IBD controls for the included studies.
Risk of Cerebrovascular Accidents Five studies reported 2424 CVA events in 98,240 patients with IBD.8,11–13,29 On pooling unadjusted ORs from each study, IBD was associated with a 21% higher risk of CVA (unadjusted OR, 1.21; 95% CI, 1.12–1.31). After adjusting for potential confounders in all studies,
IBD conferred an 18% higher risk of CVA (adjusted OR, 1.18; 95% CI, 1.09–1.27) (Figure 2). This increased risk of CVA was seen in both patients with CD (5 studies; adjusted OR, 1.26; 95% CI, 1.14–1.39) and UC (4 studies; adjusted OR, 1.13; 95% CI, 1.05–1.23), with no significant difference between IBD subtypes (CD vs UC, Pinteraction ¼ .27). There was moderate heterogeneity observed in the overall analysis (Cochran Q: P ¼ .07; I2 ¼ 53%). Four studies reported sex-specific risk estimates of CVA.8,12,13,29 On meta-analysis of these studies, the risk of CVA was significantly higher in females (adjusted OR, 1.28; 95% CI, 1.17–1.41) compared with males (adjusted OR, 1.11; 95% CI, 0.98–1.25) with IBD (Pinteraction ¼ .05). By using data from 3 studies, patients with IBD could be classified as young (age, <40 y8,13 or <50 y12) or old (age >50 y,12 >60 y,13 or 40–59 y).8 In this analysis, the magnitude of increased CVA risk was higher in young patients with IBD (adjusted OR, 1.84; 95% CI, 1.28–2.66) compared with older patients with IBD (adjusted OR, 1.11; 95% CI, 1.02–1.21) (Pinteraction ¼ .01). Besides sex and age, heterogeneity also could be accounted for by study design, with one included cohort study reporting a significantly higher risk estimate as compared with pooled results from 4 case-control studies (Table 3).
Risk of Ischemic Heart Disease Six studies reported 6478 IHD events in 123,907 patients with IBD.8,13–15,28,30 No statistically significant
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increase in the risk of IHD was identified using unadjusted ORs for each study (unadjusted OR, 1.14; 95% CI, 0.95–1.38); however, on pooling maximally adjusted ORs, IBD was associated with a 18% increased risk of IHD (adjusted OR, 1.18; 95% CI, 1.08–1.31) (Figure 3). This increase in risk was seen in both CD and UC on meta-analysis of 5 studies that reported these data (CD: adjusted OR, 1.08; 95% CI, 1.03–1.13; UC: adjusted OR, 1.15; 95% CI, 1.05–1.25).8,13,15,28,30 There was considerable heterogeneity observed in the overall analysis (Cochran Q: P < .01; I2 ¼ 88%), with a positive outlier with a large risk estimate.14 On sex-specific analysis, the increased risk of IHD in patients with IBD was seen in females (4 studies; adjusted OR, 1.26; 95% CI, 1.18–1.35), but not in males (4 studies; adjusted OR, 1.05; 95% CI, 0.92–1.21).8,13,15,30 No difference in the risk of IHD was observed between younger (age <40–50 y, 3 studies8,13,14; adjusted OR, 1.40; 95% CI, 0.93–2.11) and older (age >60 y,13 >65 y,14 or 40–59 y8) patients with IBD (3 studies; adjusted OR, 1.29; 95% CI, 0.97–1.71) (Pinteraction ¼ .75). The overall heterogeneity could be explained by sex-specific differences in risk of IHD (Table 4).
Risk of Peripheral Arterial Thromboembolic Disease Two studies reported 148 patients with peripheral arterial disease in 25,559 patients with IBD.8,13 On pooled analysis of these 2 studies, IBD was not associated with a significant increase in the risk of peripheral arterial disease (adjusted OR, 1.15; 95% CI, 0.96–1.38) with minimal heterogeneity in the analysis (Cochran Q: P ¼ .48; I2 ¼ 0%). The results were stable in patients with CD (adjusted OR, 1.20; 95% CI, 0.92–1.57) or UC (adjusted OR, 1.12; 95 % CI, 0.88–1.41).
Sensitivity Analysis To assess whether any one study had a dominant effect on the meta-analytic OR, each study was excluded and its effect on the main summary estimate and Cochran Q test P value for heterogeneity was evaluated. The pooled OR remained significantly increased for CVA (range, 1.19–1.26) and IHD (range, 1.14–1.30), with the corresponding 95% CI bounds remaining greater than 1. On replacing 1 Danish study15 that assessed the risk of IHD in patients with IBD with another study,11 the risk estimates were stable (adjusted OR, 1.18; 95% CI, 1.07–1.31).
Discussion Previous systematic reviews have not shown a significant association between IBD (CD or UC) and cardiovascular mortality.16–18 In a recent meta-analysis of cause-specific standardized mortality ratios in population-based and inception cohort studies of
Clinical Gastroenterology and Hepatology Vol. 12, No. 3
patients with IBD, Bewtra et al35 observed that neither CD nor UC were associated with increased cardiovascular mortality in patients with IBD. Although cardiovascular mortality is a hard end point and less prone to ascertainment bias, it does not capture the entire spectrum of cardiovascular disease. With improving therapeutic modalities, mortality from cardiovascular disease is decreasing, and, hence, with low event rates of mortality, observational studies on the association between IBD and cardiovascular mortality often do not reach statistical significance. In addition, these studies on cardiovascular mortality only determine whether patients with IBD die of cardiovascular disease; they are unable to estimate whether patients with IBD may develop ischemic heart disease or stroke at a young age. In contrast, in this meta-analysis on the risk of cardiovascular morbidity in patients with IBD, we made several key observations. First, we identified a modest 18% increase in the risk of CVA and IHD in patients with IBD (both CD and UC), and this effect was stable across study design, setting, and location. Second, we observed that the increase in the risk of CVA and IHD was more prominent in females, without a significantly increased risk in males. Third, we observed that the magnitude of increased risk of CVA was higher in young adults with IBD than the excess risk of CVA in older individuals, while the risk of IHD was stable across age groups. Traditional risk factors for cardiovascular disease, such as diabetes, smoking, hyperlipidemia, obesity, and hypertension, are not universally over-represented in patients with IBD.36 On the other hand, chronic systemic inflammation increasingly is being recognized as a major risk factor for cardiovascular atherosclerotic disease. Immune cells dominate early atherosclerotic lesions, their effector molecules accelerate progression of the lesions, and activation of inflammation can elicit acute coronary syndromes.1 Patients with IBD have increased carotid intimal thickness and abnormal carotid arterial stiffness, which are surrogate markers of atherosclerosis.37,38 Both pediatric and adult patients with IBD have functional vascular changes suggestive of endothelial dysfunction, even before structural changes of atherosclerosis appear.39–41 In addition, several prothrombotic molecules such as homocysteine and vitamin B6, which predispose to coronary artery disease, also are increased in patients with IBD, particularly in CD owing to malabsorption.42,43 Other markers of inflammation such as C-reactive protein, adhesion molecules, and proinflammatory cytokines (such as tumor necrosis factor-a and interleukin-6) are seen at high levels in both IBD and atherosclerosis.44 Common polymorphisms in nucleotide-binding oligomerization domain-containing protein 2/caspase recruitment domain-containing protein 15 (NOD2/CARD15), which predispose to CD, also have been associated with an increased risk of clinically evident and angiographically documented coronary atherosclerosis and clinical destabilization of coronary plaques, suggesting a common genetic basis for these 2
Study
Study design Location Setting
Time period; follow-up period
Andersohn Nested et al,12 2010 C-C
UK
Population- 1987–2005; based 5.2–5.4 y
Bernstein Nested et al,13 2008 C-C
Canada
Population- 1984–2003; based 16.1–16.6 mean personyears
Ha et al,8 2009 Nested C-C
US
Healthclaims database
2001–2006; 3.2–4.1 y
Kristensen Nested Denmark Population- 1996–2009; et al,11 2013 C-C based 6.0–6.2 y Osterman Nested et al,28 2011 C-C
Yarur et al,14 2011
C-C
Population- 1987–2003; based 4.4–4.7 y
Denmark Population- 1997–2009 based US
Hospitalbased
1995–2009; 4.3–4.5 y
Controls
Definition of outcome
Total
CVA
IHD
PAD
Total
CVA
IHD
PAD
Acute ischemic stroke, medical diagnostic codes, inpatients and outpatients Incident cases, after IBD diagnosis, IHD (MI, old MI, angina, chronic IHD), CVA (subarachnoid hemorrhage, intracranial hemorrhage, ischemic stroke), other atheroembolic disease, medical diagnostic codes, inpatients only (hospitalized or emergency room visit) Incident cases, after IBD diagnosis, CVA (TIA, cerebrovascular occlusion); IHD (including acute MI, atherosclerosis), peripheral vascular disease, medical diagnostic codes, inpatients and outpatients Stroke, MI, cardiovascular death, medical diagnostic codes, inpatients and outpatients Incident acute MI, after IBD diagnosis, medical diagnostic codes, inpatients and outpatients Incident IHD, after IBD diagnosis, medical diagnostic codes, inpatients and outpatients Incident IHD event (unstable angina, MI; silent MI; abnormal angiogram) with independent validation, diagnosed >12 mo after IBD diagnosis
8054; all CD
89
-
-
161,078
1670
-
-
Adjusted fore 1,2,3,4,5, 6,7,8,9, 10,12,14 -
8072: CD, 4193, UC, 3879
161; 81, 80
238; 111, 127
33; 18, 15
80,489
1390
1884
255
17,487a: CD, 7480, UC, 9968
496b; 215, 279
1068; 477, 591
115; 49, 66
69,948
1804
4219
397
-
-
-
199,978
3327
-
-
3,4,5,6,8,9, 11,12,15
-
CD 92,987; UC 144,605
-
908; 2188
-
1,2,3,4,6, 8,9
4,541,987
-
243,844
-
3,4,5,6,8, 12,15
712
-
-
1,2,3,4,5,6, 10,13,16
456; NR, 20,795c: CD, 4732, NR UC, 13,622 25,327d: CD, 9829; UC, 15,498 28,833: CD, 7521, UC, 19,990 356: CD, 173; UC, 183
-
-
390; 110, 280 863f; 161f, 608f 47; 22, 25
-
33
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Rungoe et al,15 Cohort 2012
UK
IBD
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Table 1. Baseline Characteristics of the Included Studies Reporting the Association Between IBD and CVA, IHD, and/or Extra-intestinal Peripheral Arterial Thromboembolic Events
387
388
Table 1. Continued
Zoller et al,29,30 Cohort 2012 (2 studies)
Time period; follow-up period
Sweden Population- 1987–2008 based
IBD Total
Definition of outcome Incident CVA or IHD requiring hospitalization, medical diagnostic codes
Controls
CVA
43,832: CD, 20,222; UC, 23,610
IHD
1222; 504, 718
PAD
3872; 1304, 2568
Total
-
CVA
IHD
PAD
Compared with population estimates of stroke and IHD
Adjusted fore 2,3,4,6,8, 13, 14,15
Singh et al
Study
Study design Location Setting
C-C, case-control, MI, myocardial infarction; PAD, extra-intestinal peripheral arterial thromboembolic events; TIA, transient ischemic attack. NOTE. Adjusted for: 1 ¼ smoking, 2 ¼ body mass index, 3 ¼ diabetes mellitus, 4 ¼ hypertension, 5 ¼ hyperlipidemia, 6 ¼ past history of coronary artery disease, 7 ¼ past history of cerebrovascular accident, 8 ¼ other coronary comorbidities (congestive heart failure, atrial fibrillation), 9 ¼ aspirin use, 10 ¼ IBD treatment, 11 ¼ IBD activity, 12 ¼ other medications (anticoagulants, oral contraceptives, hormone replacement therapy), 13 ¼ chronic kidney disease, 14 ¼ alcohol, 15 ¼ socioeconomic status, 16 ¼ family history of coronary artery disease. a Thirty-nine patients with IBD unclassified. b Two CVA events in patients with IBD unclassified. c A total of 2441 patients with IBD unclassified. d A total of 1322 patients who changed diagnosis between UC and CD during the follow-up period. e All studies were adjusted for age and sex. f Only cases of IHD diagnosed more than 1 year after IBD diagnosis.
Table 2. Distribution of Traditional Cardiovascular Risk Factors in Patients With IBD and Patients Without IBD in the Included Studies
Mean age, y
Sex, % male
Diabetes, % total
IBD
Non-IBD
IBD
Non-IBD
IBD
Andersohn et al12 Bernstein et al13 Ha et al8 Kristensen et al11 Osterman et al28a
39 36 CD, 42 UC 43 CD, 44 UC 44 44 CD, 50 UC
42 NR 43 43 43, 49
42.9 45.0 44.3 45.5 48.4, 41.0
46.0 45.0 44.2 45.2 40.9, 48
2.9
38 45
41 45
Rungoe et al15 Yarur et al14
Zoller et al29,30
NR
44 48.3
49 48.3
NR
NR, not reported. a Reports CD and UC, with separate control population for each. b Proportion of patients on antihypertensive and/or antihyperlipidemic medications. c Mean total cholesterol (in mg/dL).
Non-IBD 2.8
IBD
3.6 1.8 1.9, 3.6 5.8 6.7
3.5 0.1 1.7, 2.1 4.9 16.7
NR
Non-IBD
IBD
10.1
1.7
8.6
NR
Hyperlipidemia, % total (or obesity)
NR
2.2 NR
9.0 3.1 14.5, 18.5
6.5 1.2 10.5, 13.5
44.4b 20.5
39b 39.0
NR
Non-IBD
8.2 4.2 1.3, 2.1
6.0 2.7 1.1, 1.5 39b 190c
44.4b 177c
NR
Smoking, % total IBD
Non-IBD
56.4 (all CD) 50.4 NR NR NR 37.0 (CD) 28.9, 27.9 23.2 (UC) NR 30.3 (all); 27.1 30.1 (CD); 30.6 (UC) NR
Aspirin, % total IBD
Non-IBD
2.4
2.5 NR NR
5.9 5.2, 7.1
3.4 4.4, 6.1 NR NR
NR
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Study
Hypertension, % total
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Figure 2. Summary of ORs of studies assessing the risk of cerebrovascular accident in patients with IBD (overall), CD, and UC.
diseases.45 All of these data provide biological evidence in support of early atherosclerosis in IBD, and taken together with the epidemiologic association observed in our meta-analysis, lend support to a probable causative association. We observed that women with IBD have a significantly higher excess risk of CVA and IHD than men as compared with patients without IBD. This probably is related to the inherent differences in traditional and nontraditional risk factors for CVA and IHD in males and females. Despite less anatomic coronary artery disease, women have higher rates of myocardial ischemia and mortality as compared with age-matched men.46
Inflammation appears to play a greater role in IHD in women as compared with men; women have greater mean C-reactive protein levels compared with men and the relative risk of future IHD events increases proportionally with increasing levels of C-reactive protein in women, independent of the risk contributed by traditional cardiovascular risk factors.46,47 Endothelial and microvascular dysfunction, potentially induced by chronic inflammation and hormonal differences, appear to predispose women to abnormal coronary reactivity and myocardial ischemia.46 Use of oral contraceptives may be an additional procoagulant factor increasing the risk of thrombotic cardiovascular events in females.
Table 3. Subgroup Analysis of Studies on IBD and the Risk of CVA Subgroup Type of IBD Sex Ageb Study setting Study location Study design
a
Categories
Studies, n
Adjusted OR
95% CI
CD UC Males Females Young Old Population-based Hospital-based North America Europe C-C Cohort
5 4 4 4 3 3 4 1 2 3 4 1
1.25 1.13 1.11 1.28 1.84 1.11 1.21 1.10 1.12 1.21 1.13 1.28
1.14–1.39 1.05–1.23 0.98–1.25 1.17–1.41 1.28–2.66 1.02–1.21 1.12–1.30 1.00–1.22 1.03–1.22 1.11–1.33 1.06–1.20 1.21–1.36
Difference between groups (P value) .10 .05a .01a .15 .21 <.01a
Indicates significant difference between subgroups. Young refers to age younger than 40 years8,13 or younger than 50 years12 and old refers to age older than 50 years,12 older than 60 years,13 or 40 to 59 years.8
b
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Figure 3. Summary of ORs of studies assessing the risk of IHD in patients with IBD (overall), CD, and UC.
However, Andersohn et al12 did not observe any significant difference in oral contraceptive use in patients with or without CVA. We also observed that the excess risk of stroke compared with patients without IBD was significantly higher in young patients compared with elderly individuals. This has significant implications—a recent prospective cohort study showed that the longterm mortality after stroke among young adults (age, 18–50 y) is 4-fold higher than expected.48 Young patients with IBD are more likely to have extensive luminal and penetrating disease, require more courses of
corticosteroids and immunosuppressive medications, and have more frequent disease recurrences.49,50 On the other hand, elderly patients usually have less severe disease with a milder course of IBD, and often can be managed with mesalamines, with less than 20% requiring immunosuppressive medications.51,52 Because the severity of inflammation modifies the risk of venous as well as arterial thromboembolism,7,11 this may explain the higher magnitude of increased risk of stroke seen in younger individuals. With aging, traditional cardiovascular risk factors potentially may outweigh the risk afforded by mild inflammatory disease seen in elderly
Table 4. Subgroup Analysis of Studies on IBD and the Risk of IHD Subgroup Type of IBD Sex Ageb Study setting Study location Study design
a
Categories
Studies, n
Adjusted OR
95% CI
CD UC Males Females Young Old Population-based Hospital-based North America Europe Case-control Cohort
5 5 4 4 3 3 4 2 3 3 4 2
1.08 1.15 1.05 1.26 1.40 1.29 1.17 1.99 1.52 1.16 1.31 1.17
1.03–1.13 1.05–1.25 0.92–1.21 1.18–1.35 0.93–2.11 0.97–1.71 1.11–1.23 0.51–7.78 1.05–2.20 1.10–1.22 1.05–1.64 1.10–1.25
Difference between groups (P value) .22 .02a .75 .45 .15 .34
Indicates significant difference between subgroups. Young refers to age younger than 40 years8,13 or younger than 50 years12 and old refers to age older than 50 years,12 older than 60 years,13 or 40 to 59 years.8
b
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onset IBD. Finally, the absolute risk of cardiovascular events is much higher in older subjects, thus making it more difficult to show increased risk. There were several limitations that should be considered while interpreting the results of this study. First, we included studies from different clinical settings that had different diagnostic criteria, age at enrollment, period at risk, and study design. As expected, we found statistically significant heterogeneity in the results and, hence, we used the random-effects model to include an estimate of variability.24 In addition, we explored sources of heterogeneity through subgroup analysis and were able to identify important sex- and age-specific differences in the risk of cardiovascular events in patients with IBD. Second, given the retrospective nature of all of the included studies, the possibility of detection bias as a result of higher health care use in patients with IBD may contribute to the observed increase in the rate of cardiovascular events in this population. Although Rungoe et al15 observed a particularly high risk of cardiovascular events within the first year of IBD diagnosis, this increased risk also was observed on sensitivity analysis of IHD events occurring more than 1 year after IBD diagnosis. On analysis of a populationbased Danish cohort over 30 years, Jess et al53 also noted that cardiovascular mortality was highest in the first year of IBD diagnosis, suggesting ascertainment bias, but observed that the increased risk of cardiovascular mortality persisted with increasing duration of IBD. Third, the included studies did not uniformly adjust for all traditional and atypical risk factors for cardiovascular disease. However, in our analysis, there was no significant difference in the pooled analysis of unadjusted and maximally adjusted data from each study, suggesting that any difference attributable to using different confounders for adjustment likely is small. Fourth, we were unable to systematically study whether IBD disease activity or specific medications used to suppress inflammation modify the risk of cardiovascular events owing to lack of reporting in individual studies. A positive association between disease activity and cardiovascular events was seen in a population-based Danish cohort.11 Kristensen et al11 identified that, during flares and periods of persistent IBD activity, the risk of stroke, myocardial infarction, and cardiovascular death is 49% to 150% higher than age- and sex-matched controls; during periods of remission, the risk of these end points was not different from the control population. Another potential limitation that particularly applies to case-control studies evaluating cardiovascular events is recall bias. However, in most studies, medical diagnostic codes were used for establishing exposure and outcome, and, hence, the effects of this likely are minimal. Finally, some studies only reported CVA or IHD events for which a patient was hospitalized29,30 and, hence, may have missed chronic stable angina or transient ischemic attack, which do not require hospitalization, thereby
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underestimating the risk of cardiovascular morbidity in patients with IBD. In conclusion, IBD is associated with a modest increase in the risk of CVA and IHD, particularly in females and in young adults, although considerable statistical heterogeneity was observed in the analysis. This increased risk may be owing to chronic systemic inflammation present in these patients. Gastroenterologists should be cognizant of this relationship and should focus on better management of conventional risk factors, such as smoking cessation, recognition and control of hypertension and diabetes, as well as maintaining long-term remission in patients with IBD to minimize the risk of inflammationinduced cardiovascular events.
Supplementary Material Note: To access the supplementary material accompanying this article, visit the online version of Clinical Gastroenterology and Hepatology at www.cghjournal.org, and at http://dx.doi.org/10.1016/j.cgh.2013.08.023.
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Reprint requests Address requests for reprints to: Darrell S. Pardi, MD, MS, 200 First Street SW, Rochester, Minnesota 55905. e-mail: [email protected]; fax: (507) 284-0538. Acknowledgment S.S. and H.S. contributed equally to this work. Conflicts of interest The authors disclose no conflicts.
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Supplementary Table 1. Newcastle-Ottawa Scale for Assessment of Quality of Included Cohort Studies Acceptable*
Rungoe et al15
Zoller et al29,30
Representative of average adult in community (age/sex/being at risk of disease) Drawn from same community as exposed cohort Secured records, structured interview Only incident cases of CVAs/IHD
*
*
* * *
* *
Yes Smoking, diabetes, hypertension, hyperlipidemia, family history of CVAs/IHD, aspirin use
* *
* *
Independent blind assessment, record linkage Follow-up period >4 y
* *
* *
Complete follow-up evaluation, or subjects lost to follow-up evaluation unlikely to introduce bias
*
*
9
8
Quality assessment criteria Selection Representativeness of exposed cohort? Selection of the nonexposed cohort? Ascertainment of exposure? Demonstration that outcome of interest was not present at start of study? Comparability Study controls for age/sex? Study controls for at least 3 additional risk factors? Outcome Assessment of outcome? Was follow-up period evaluation long enough for outcome to occur? Adequacy of follow-up evaluation of cohorts? Overall quality score (maximum, 9)
NOTE. Asterisk indicates that individual criterion within the subsection were fulfilled.
Supplementary Table 2. Newcastle-Ottawa Scale for Assessment of Quality of Included Case-Control Studies Quality assessment criteria
Acceptable*
Andersohn Bernstein Ha Kristensen Osterman Yarur et al13 et al8 et al11 et al28 et al14 et al12
Selection Is the case definition adequate? Yes, with independent validation Representativeness of cases? Consecutive or obviously representative series of cases Selection of controls? Community controls Definition of controls? No history of studied end point Comparability Study controls for age/sex Yes Study controls for at least 3 Smoking, diabetes, hypertension, additional factors hyperlipidemia, family history of CVAs/IHD, aspirin use Exposure Ascertainment of exposure? Secure record, structured interview by health care practitioner, blind to case/control status Same method of ascertainment Yes of cases/controls? Nonresponse rate? Same for both groups Overall quality score (maximum, 9)
NOTE. Asterisk indicates that individual criterion within the subsection were fulfilled.
*
* -
* *
*
* *
* -
* *
* *
* *
* *
* *
*
* *
* -
* -
* *
* *
* *
*
*
-
*
*
*
*
*
*
*
*
*
7
* 7
* 7
* 8
* 9
* 7