REVIEWS Epidemiology, risk factors and management of cardiovascular diseases in IBD Siddharth Singh, Iftikhar J. Kullo, Darrell S. Pardi and Edward V. Loftus Jr Abstract | IBD is an established risk factor for venous thromboembolism. In the past few years, studies have suggested that patients with IBD might also be at an increased risk of coronary heart disease and stroke. The increased risk is thought to be similar to the level of risk seen in patients with other chronic systemic inflammatory diseases such as rheumatoid arthritis. The risk of developing these conditions is particularly increased in young adults with IBD, and more so in women than in men. Conventional cardiovascular risk factors are not over-represented in patients with IBD, so the increased risk could be attributable to inflammation-mediated atherosclerosis. Patients with IBD often have premature atherosclerosis and have biochemical and genetic markers similar to those seen in patients with atherosclerotic cardiovascular disease. The role of chronic inflammation in IBD-associated cardiovascular disease merits further evaluation. Particular attention should be given to the increased risk observed during periods of increased disease activity and potential modification of the risk by immunosuppressive and biologic therapies for IBD that can modify the disease activity. In addition, preclinical studies suggest that cardiovascular medications such as statins and angiotensin-converting enzyme inhibitors might also favourably modify IBD disease activity, which warrants further evaluation. Singh, S. et al. Nat. Rev. Gastroenterol. Hepatol. advance online publication 2 December 2014; doi:10.1038/nrgastro.2014.202

Introduction

Division of Gastroenterology and Hepatology (S.S., D.S.P., E.V.L.), Division of Cardiovascular Diseases (I.J.K.), Mayo Clinic, Rochester, MN 55905, USA.

IBD is a well-recognized risk factor for venous thrombo­ embolism (VTE), as patients with IBD have a twofold to threefold higher risk of VTE than the general population.1,2 This risk is particularly increased during an acute disease flare, as active inflammation alters the balance between procoagulants and anticoagulants and induces a state of hypofibrinolysis related to IBD.3 VTE might also be associated with an increased risk of arterial thromboembolic events, as the two conditions have shared risk factors (such as obesity, hypertension, diabetes mellitus, smoking and the metabolic syndrome) and shared pathophysiology (including systemic inflammation, endothelial injury and hypercoagulability).4 A Danish population-based study in the general population observed that patients with VTE have a twofold to threefold higher risk of hospitalization for myocardial infarction and stroke than individuals without VTE;5 a systematic review of 17 observational studies confirmed this association.6 Studies published in the past 5 years have observed that patients with IBD might have an increased risk of arterial thromboembolic events such as myocardial infarction and stroke,7–9 with the magnitude of the increased risk similar to that seen in other chronic inflammatory diseases such as rheumatoid arthritis, systemic lupus erythema­tosus and psoriasis.10–13 This Review discusses the epidemiology, pathophysiology, risk factors (in particular, the role of IBD

Correspondence to: S.S. singh.siddharth2@ mayo.edu

Competing interests The authors declare no competing interests.

activity and IBD-related medications) and management of cardio­vascular disease in patients with IBD. We also discuss the potential effect of cardiovascular ­medications on IBD.

Epidemiology

Population-based studies have observed a modest increase in the risk of coronary heart disease (CHD) and stroke in patients with IBD. For example, a nationwide study from Denmark assessed the risk of newonset CHD in 28,833 patients with IBD but no baseline cardio­vascular disease from 1997 to 2009, and the risk was compared with that of >4.5 million people without IBD.9 Over a mean follow-up of 13 years, the incidence of CHD was 59% higher in patients with IBD than in control individuals after adjusting for use of antidiabetic, antihypertensive, antihyperlipidaemic and antithrombotic medications. In the same cohort, another study found an increased risk of stroke in patients with IBD (incidence rate ratio [IRR] 1.15, 95% CI 1.05–1.27) compared with control individuals matched for age and sex 8 and an increased risk of hospitalization for heart failure (IRR 1.37, 95% CI 1.26–1.49).14 In a study from Manitoba, Canada, patients with IBD had a 26% higher incidence of CHD than the general population (IRR 1.26, 95% CI 1.11–1.44) and a trend towards an increased risk of stroke (IRR 1.16, 95% CI 0.98–1.36).7 Even though population-based cohorts have a low risk of selection bias, they often use administrative diagnostic codes that increase the risk of misclassification bias and

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REVIEWS Key points ■■ Patients with IBD have a modestly increased risk of coronary heart disease and stroke ■■ In patients with IBD, the magnitude of the increase in cardiovascular risk is higher in women than in men and in young adults (50–60 years) ■■ Patients with IBD have evidence of premature vascular disease with structural, functional and biochemical changes indicative of subclinical atherosclerosis; IBD also promotes spontaneous platelet activation and aggregation, predisposing patients to atherothrombosis ■■ Although conventional cardiovascular risk factors are not over-represented in patients with IBD, nonconventional chronic inflammation-based risk factors (IBD disease activity) are directly related to risk of cardiovascular events ■■ Aggressive disease-modifying biologic therapy might favourably modify the risk of cardiovascular events in patients with IBD ■■ Commonly used cardiovascular medications, such as statins, could improve IBD disease activity

might not reliably adjust for all confounders. A hospitalbased case–control study found that patients with IBD had a 2.6 times higher risk of CHD than primary-care patients matched for age and sex (adjusted HR 2.62, 95% CI 1.50–4.57), even after adjusting for CHD risk factors.15 Supplementary Table 1 online summarizes key studies evaluating the risk of cardiovascular disease in patients with IBD. A systematic review of six studies reporting on 6,478 CHD events in 123,907 patients with IBD found a 19% increased risk of CHD in patients with IBD (OR 1.19, 95% CI 1.08–1.31), with the increased risk seen in patients with Crohn’s disease (OR 1.08, 95% CI 1.03–1.13) and those with ulcerative colitis (OR 1.15, 95% CI 1.05–1.25).16 Although IBD is associated with an increased risk of cardiovascular morbidity, cardiovascular mortality is not increased in these patients. A meta-analysis of 11 studies in >14,000 patients with IBD showed no increase in the risk of cardiovascular mortality (standardized mortality ratio [SMR] 1.0, 95% CI 0.8–1.1 for patients with Crohn’s disease and SMR 0.9, 95% CI 0.8–1.0 for patients with ulcerative colitis) compared with the general population.17 Cardiovascular mortality is a hard end point that is less prone to ascertainment bias than cardiovascular morbidity; however, it does not capture the entire spectrum of cardiovascular disease.18 With improving therapeutic modalities, mortality attributable to cardiovascular disease is decreasing, with the result that observational studies on the association between IBD and c­ardiovascular mortality often do not reach statistical significance. The risk of cardiovascular events seems to differ between men and women with IBD. Analysis of a health claims database observed an increased risk of myocardial infarction and stroke in women, but not in men.19 In a systematic review of four studies, women (OR 1.26, 95% CI 1.18–1.35), but not men (OR 1.05, 95% CI 0.92–1.21), with IBD had an increased risk of CHD;19 similarly, the risk of stroke was higher in women (OR 1.28, 95% CI 1.17–1.41) than in men (OR 1.11, 95% CI 0.98–1.25) with IBD. These observations are probably related to inherent differences (in both presence and relative contribution of risk factors) in conventional and nonconventional risk factors for stroke and CHD in men and women. Despite

having less extensive coronary artery disease (women have less extensive obstructive coronary artery disease and are less likely to have three-vessel disease), women have higher rates of myocardial ischaemia and mortality than men.20,21 Inflammation seems to have a greater role in CHD in women than in men; women have higher levels of C‑reactive protein (CRP) than men, and the relative risk of CHD events increases with increasing levels of CRP in women, independent of conventional cardio­vascular risk factors.22 Endothelial dysfunction, potentially induced by chronic inflammation and the differing hormonal profiles of men and women, predisposes women to abnormal coronary reactivity and myocardial ischaemia.20 Use of oral contraceptives might be an additional procoagulant factor that increases the risk of thrombotic cardiovascular events in women. However, a study found no statistically significant difference in oral contraceptive use between individuals with or without stroke.23 On age-stratified analysis, younger patients with IBD (50–60 years). For instance, in a nested case–control study using the General Practice Research Database, it was observed that younger adults with Crohn’s disease (18–49 years old) had an increased risk of stroke compared with control individuals without Crohn’s disease (OR 2.93, 95% CI 1.44–5.98), which was not seen in older adults with Crohn’s disease (50–80 years old; OR 0.99, 95% CI 0.75–1.30).23 No such age-specific difference has been observed in the risk of CHD between younger and older individuals. In a systematic review of three studies, it was observed that the risk of CHD was increased in both younger (OR 1.40, 95% CI 0.93–2.11) and older (OR 1.29, 95% CI 0.97–1.71) patients with IBD, compared with the general population.16 The greater inflammation observed in young patients with IBD than in older individuals might modify the risk of cardio­ vascular events. With ageing, conventional cardiovascular risk factors might outweigh the risk attributable to the mild inflammatory disease seen in elderly-onset IBD. In summary, IBD (both Crohn’s disease and ulcerative colitis) is associated with a modest increase in the risk of CHD and stroke, particularly in women and in young adults. However, the risk of cardiovascular mortality is not increased in patients with IBD.

Pathogenesis

Increasingly, atherosclerosis is being recognized as a chronic inflammatory disease in which immune cells infiltrate the arterial wall in response to chemotactic signals generated by activated endothelial cells.24 These immune cells dominate early ‘silent’ atherosclerotic lesions, and their effector molecules accelerate progression of the lesions. In addition, activated macrophages, T cells and mast cells found at sites of plaque rupture produce several molecules that destabilize lesions, such as proinflammatory cytokines (IL‑6 and TNF), proteases, coagulation factors, free oxygen radicals and vaso­active molecules. These molecules inhibit the formation of stable fibrous caps and attack cap collagen, initiating plaque activation, rupture, thrombosis and ischaemia.25,26

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REVIEWS Several lines of evidence suggest that patients with IBD have premature subclinical atherosclerosis (Box 1). Some of the evidence pertains to structural (carotid intima– media thickness, aortic and arterial stiffness) and functional (endothelial dysfunction) vascular changes, as well as biochemical (increased levels of CRP and homocysteine) and genetic (mutations in NOD2) changes that are common to both IBD and atherosclerosis. Patients with IBD also have abnormal platelet function and coagulation that predispose them to arterial thromboembolism and VTE.

Structural changes Arterial smooth muscle hyperplasia, as measured by carotid intima–media thickness, is an early step in atherogenesis. In fact, carotid intima–media thickness is a reliable predictor of future cardiovascular events.27 Patients with IBD might have increased carotid intima– media thickness compared with control individuals.28 In a systematic review of six studies, three studies reported a higher carotid intima–media thickness in patients with IBD than in control individuals, whereas three studies did not. However, the six studies were small and had consider­able heterogeneity (differences in disease pheno­ type, duration, activity and therapy that introduced considerable variability in inflammatory burden in participants). Hence, the quality of evidence supporting the presence of increased carotid intima–media thickness in IBD is low.29 Arterial stiffness, measured using aortic pulse wave velocity, is also a surrogate marker for cardiovascular disease. A systematic review of 17 cohort studies that evaluated serial aortic pulse wave velocity in 15,877 participants from the general population observed 2.3 times more cardiovascular events in patients with the highest tertile of aortic pulse wave velocity compared with the lowest tertile.30 Patients with IBD are known to have increased aortic stiffness, even in the absence of conventional cardiovascular risk factors. For instance, a study has found increased aortic and arterial stiffness in patients with IBD who had no conventional cardiovascular risk factors, compared with control individuals matched for age, sex and blood pressure level.31 Furthermore, patients with IBD and active inflammation (increased levels of CRP) had higher aortic pulse wave velocity than patients in remission. In a follow-up cohort study, the use of immunomodulators and anti‑TNF medications, but not aminosalicylates, might be associated with a decrease in aortic stiffness in patients with IBD.32 Functional changes Endothelial dysfunction is a critical event in athero­ sclerosis. Normal endothelium produces reactive hyperaemia mediated by nitric oxide in response to ischaemia; in patients with endothelial dysfunction, this vasodilatory response is blunted and might even be replaced by paradoxical vasoconstriction.33 Microvascular endothelial function, a predictor of future cardiovascular events, can be measured using pulse arterial tonometry and shear stress at peak reactive hyperaemia.34,35 Macrovascular

Box 1 | Changes in patients with IBD* Structural changes ■■ Increased carotid intima–media thickness ■■ Increased aortic and arterial stiffness ■■ Functional changes ■■ Microvascular endothelial dysfunction, with low pulse arterial tonometry and blunted shear stress at peak reactive hyperaemia ■■ Macrovascular endothelial dysfunction, with decreased brachial artery flow-mediated dilation Biochemical changes ■■ Raised levels of C‑reactive protein and calprotectin ■■ Increased homocysteine levels Genetic changes ■■ Polymorphisms in NOD2 *These changes are associated with premature subclinical atherosclerosis.

endothelial dysfunction, which usually occurs later in the development of atherosclerosis than microvascular dysfunction, can be measured using brachial artery flowmediated dilation.33 Patients with several chronic inflammatory diseases that are associated with atherosclerotic cardiovascular diseases (for example, rheumatoid arthritis or systemic lupus erythematosus) demonstrate endothelial dysfunction,36 as do patients with IBD.37 Compared with healthy control individuals, patients with IBD have a lower pulse arterial tonometry index and blunted shear stress at peak reactive hyperaemia, which indicates microvascular endothelial dysfunction; no correlation was found between disease activity and degree of endothelial dysfunction.37 A separate study found lower flowmediated dilation values in patients with IBD than in control individuals, even after adjusting for conventional ca­rdiovascular risk factors.38 These structural and endothelial changes are also observed in children with IBD. In one study, children with IBD had higher carotid intima–media thickness and lower flow-mediated dilation than healthy control individuals, which correlated with Crohn’s disease activity but not ulcerative colitis activity.39

Biochemical changes Several inflammation-associated biochemical changes are observed in both IBD and cardiovascular disease. Patients with IBD and active inflammation frequently have raised levels of CRP, which is independently associated with an increased risk of cardiovascular events. In a meta-analysis of 22 prospective cohort studies in the general population, patients in the highest tertile of CRP levels had a 1.3 times increased risk of coronary artery disease (RR 1.33, 95% CI 1.22–1.44) compared with patients in the lowest tertile, after adjustment for conventional cardiovascular risk factors.40 Calprotectin, another biomarker of inflammation in IBD, might have a role in atherogenesis;41,42 raised levels of calprotectin are predictive of cardiovascular events, independent of conventional cardiovascular risk factors.43,44 Levels of homocysteine are considerably higher in patients with IBD than in control individuals, and

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REVIEWS hyperhomocysteinaemia is 4.6 times more frequent in these patients,45 particularly in those with active IBD, than in controls.46 Homocysteine has also been implicated in atherogenesis as it increases oxidative stress and decreases levels of nitric oxide, which results in endothelial dysfunction and promotes the formation of atherosclerotic plaques.47 The prevalence of hyperhomocysteinaemia is 13–47% in patients with cardiovascular disease compared with 5% in the general population.47 Multiple studies and systematic reviews have suggested an association between hyperhomocysteinaemia and cardiovascular disease.48 Patients with IBD also have an increased prevalence of antiphospholipid antibodies, including anticardio­ lipin antibodies (15.6–18.1% and 3.0% in patients with IBD and healthy control individuals, respectively). 49 However, no statistically significant difference has been demonstrated in the prevalence of these antibodies in patients with IBD with or without diagnosed venous or arterial thromboembolic events.49 Similarly, patients with Crohn’s disease, but not those with ulcerative colitis, have raised levels of lipoprotein(a), a known independent risk factor for thrombosis and atherosclerotic disease, c­ompared with the general population.50

agents, independent of disease activity.56 Flow cytometric analysis has demonstrated that in patients with IBD, platelets circulate in a highly activated state regardless of disease activity, as measured by expression of surface activation markers such as P‑selectin and GP53, and measurements of serum levels of the platelet activation marker β‑thromboglobulin and platelet factor 4.57 Compared with healthy individuals, platelets from patients with IBD also have higher expression of surface CD40 ligand, which is a potent immunoregulatory and proinflammatory molecule.58 In summary, patients with IBD have evidence of premature vascular changes using surrogate markers, with structural changes of increased carotid intima–media thickness and increased arterial stiffness, as well as microvascular and macrovascular endothelial dysfunction. In addition, patients with IBD also share biochemical and genetic factors with patients with cardiovascular disease that predispose them to atherosclerosis and vascular thrombosis, with raised levels of CRP, calprotectin, homocysteine, lipoprotein(a) and anticardiolipin antibodies. IBD also promotes spontaneous platelet activation and intravascular aggregation, which predisposes patients to atherothrombosis.

Genetic changes Polymorphisms in NOD2 that predispose carriers to complicated Crohn’s disease51 have also been associated with atherosclerosis and destabilization of coronary plaques, which suggests a potential common genetic basis for these two diseases.52 In a case–control study of 109 patients with coronary artery disease demonstrated with an angiograph (and 109 healthy control individuals matched for age and sex), it was observed that the prevalence of the Leu1007fsinsC polymorphism was significantly higher in cases than in controls (11.9% versus 1.8%; adjusted OR 7.2, 95% CI 1.5–32.9), especially in those presenting with an acute coronary syndrome (adjusted OR 5.7, 95% CI 1.1–39.7) compared with stable angina.52 By contrast, the Gly908Arg polymorphism is associated with a decreased risk of coronary athero­genesis (prevalence of 1.8% versus 6.4%, OR 0.05, 95% CI 0.01–0.69). Polymorphisms in the NOD2 gene impair the nuclear factor-κB activation pathway and attenuate the subsequent inflammatory cascade in response to bacterial components. However, although the expression of NOD2 is upregulated in coronary artery atheroma, genetic variants of NOD2 are not reported to be a­ssociated with CHD.53

Risk factors

Platelet dysfunction In addition to their role in haemostasis and thrombosis, platelets regulate a variety of inflammatory responses and are key factors in atherothrombosis.54 Patients with IBD have several abnormalities in platelet number (reactive thrombocytosis), size (reduced mean platelet volume) and density (augmented granular content), which correlate with disease activity.55 As well as these changes, patients with IBD demonstrate spontaneous platelet aggregation and increased susceptibility to aggregating

Conventional cardiovascular risk factors As in the general population, conventional cardiovascular risk factors such as hypertension, diabetes mellitus, obesity, hyperlipidaemia, smoking and a family history of coronary artery disease contribute to increased cardio­ vascular risk in patients with IBD. However, these risk factors do not seem to be over-represented in patients with IBD. Studies investigating the prevalence of conventional cardiovascular risk factors have reported contrasting results (Supplementary Table 1 online). Three studies have reported a higher prevalence of hypertension in patients with IBD,8,19,59 whereas two studies observed a lower prevalence15,60 than in control individuals. In a populationbased cross-sectional study, the prevalence of hypertension (8.1% and 7.5% in patients with IBD and controls, respectively) and diabetes mellitus (2.3% and 2.6%, r­espectively) were comparable in the two groups.61 Abnormalities in lipid levels are also observed in patients with IBD, which are attributable to mal­nutrition, malabsorption, intestinal resection, altered intestinal transit and systemic inflammation.62 However, the pattern is inconsistent and difficult to interpret with regard to cardio­vascular risk. Systemic inflammation, as seen in rheumatoid arthritis or sepsis, might result in a paradoxical inversion of the usual relationship between cardiovascular risk and lipid levels (that is, an increased cardiovascular risk being associated with low lipid levels).63 In this setting, treatment with anti-inflammatory agents increases cholesterol levels. Some reports suggest that patients with IBD, particularly those with active disease, have low levels of HDL cholesterol and high levels of LDL cholesterol,64,65 whereas others report low levels of total cholesterol and LDL cholesterol.66 In a small study

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REVIEWS of 22 patients with IBD, treatment with infliximab resulted in increased levels of total cholesterol and HDL cholesterol, which is consistent with the ‘lipid paradox’ of chronic inflammatory disorders described above.67 Hence, conventional risk scores to predict risk of cardio­ vascular events might not accurately identify patients with IBD who are at risk of CHD, as they do not account for systemic inflammation and its confounding influence on lipid profiles. An example of these conventional risk scores is the Framingham risk score, a validated sexspecific algorithm to predict 10-year individual cardiovascular risk, on the basis of conventional cardiovascular risk factors including age, smoking status, cholesterol levels and systolic blood pressure level, originally derived from the Framingham Heart Study.68 In a cross-sectional study, the calculated Framingham risk score was lower in patients with IBD and cardiovascular disease than in control individuals with cardiovascular disease but not IBD who were matched for age and sex.69

Nonconventional cardiovascular risk factors Disease severity In a Danish population-based study that used IBDrelated hospitalizations and corticosteroid and anti-TNF prescriptions as measures of disease severity, Kristensen and colleagues8,14 observed an increased risk of myocardial infarction, stroke, hospitalization for heart failure and cardiovascular-related death during an IBD flare and during persistent disease activity, but not during remission, compared with IBD-free control individuals matched for age and sex after adjusting for conventional cardiovascular risk factors. In another hospital-based case–control study, anaemia (HR 1.94, 95% CI 0.98–4.02) and leucocytosis (HR 1.23, 95% CI 1.55–3.44), which are both potential markers of severe IBD, were associated with an increased risk of cardiovascular disease.15 However, no studies have used objective markers of disease severity, such as endoscopic or radiological disease activity, or biochemical markers such as faecal levels of calprotectin, to estimate variability in cardiovascular disease risk with varying disease activity. In other chronic inflammatory conditions such as rheumatoid arthritis and systemic lupus erythematosus, markers of disease activity such as CRP and end-organ damage have been associated with increased risk of cardiovascular events.12 Disease duration Unlike the situation in rheumatoid arthritis, increasing disease duration does not increase cardiovascular risk in patients with IBD. A Danish nationwide cohort study found a markedly higher risk of cardio­vascular events within 3 months (IRR 4.6, 95% CI 3.9–5.4) and 1 year (IRR 2.1, 95% CI 1.9–2.4) of IBD diagnosis; subsequently, the risk of CHD was modestly increased for the 1–13 years after diagnosis (IRR range, 1.2–1.3).9 In the UK General Practice Research Database, risk of myocardial infarction was decreased with increasing duration of Crohn’s disease (HR 0.50, 95% CI 0.27–0.95 for disease duration >20 years versus ≤5 years).59 Whether the increased cardio­vascular risk observed early in the course of IBD is related to

ascertainment bias or high disease activity observed at the time of diagnosis is unclear.18 We suggest that reduced cardiovascular risk with long-standing Crohn’s disease might be related to evolution from an inflammatory to a fibrostenotic p­henotype with increasing disease duration. IBD-directed therapy Treatment of IBD might decrease cardiovascular risk by decreasing the inflammatory burden. However, observational studies are limited in their ability to infer the effect of disease-modifying therapy on cardiovascular risk as a result of confounding by disease severity (that is, patients with severe IBD, who have a higher inherent cardiovascular risk, will probably be treated with more potent IBD medications than patients with mild disease), so the benefit of therapy might not be apparent. Corticosteroids have been associated with an increased risk of cardiovascular events in patients with IBD. In a Danish cohort of patients with IBD, a significantly higher risk of CHD was observed in patients treated with corticosteroids (IRR 1.37, 95% CI 1.25–1.50) than those who had never received corticosteroids (IRR 1.23, 95% CI 1.12–1.36); control individuals without IBD were used as a reference.9 In a case–control study of 8,054 patients with Crohn’s disease, it was observed that patients who had experienced a stroke were more likely to have received a recent corticosteroid prescription (within the past 3 months) than patients who had not had a stroke.23 Whether the association between corticosteroid use and cardiovascular disease is related to unfavourable modification of conventional cardio­ vascular risk factors (increased insulin resistance and diabetes mellitus, as well as weight gain) or if cortico­ steroid use serves as a surrogate marker of disease severity, is unclear. Corticosteroid use has also been associated with cardiovascular events in the general population. In a population-based cohort study, a 2.6-fold higher risk of cardiovascular events was observed in patients on high-dose corticosteroids (>7.5 mg per day; RR 2.56, 95% CI 2.18–2.99), but not in patients on lower doses of c­orticosteroids, compared with nonusers.70 Use of 5‑aminosalicylates (5‑ASA) might be associated with a reduced risk of cardiovascular events. In a Danish cohort, the risk of CHD in patients with IBD treated with or without 5‑ASA was compared to the risk in the general population (patients without IBD); the magnitude of increased risk was lower for the patients with IBD treated with 5‑ASA (IRR 1.16, 95% CI 1.06– 1.26, compared with the general population) than in patients with IBD not treated with 5‑ASA (IRR 1.36, 95% CI 1.22–1.51, compared with the general population). The differences in risk were dose-dependent and were only seen in patients treated with corticosteroids.9 This finding might be related to a decrease in inflammation, or inhibition of platelet activation, by 5‑ASA.71 Epidemiological studies have not shown any notable effect of immunomodulator agents on cardio­ vascular risk. In a population-based cohort study of 20,795 patients with IBD (28.9% treated with

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REVIEWS Box 2 | Risk factors in patients with IBD Conventional cardiovascular risk factors ■■ Hypertension: conflicting evidence whether increased or decreased prevalence in IBD ■■ Diabetes mellitus: conflicting evidence whether increased or decreased prevalence in IBD ■■ Hyperlipidaemia: conflicting evidence whether increased or decreased prevalence in IBD; ‘lipid paradox’ seen in patients with high systemic inflammatory burden ■■ Smoking: might have decreased prevalence in patients with Crohn’s disease ■■ Family history of coronary artery disease: unclear representation in patients with IBD Nonconventional cardiovascular risk factors, unique to IBD ■■ IBD disease activity: severe, active disease is associated with increased cardiovascular risk ■■ Disease duration: longer disease duration might be associated with decreased cardiovascular risk ■■ Disease-modifying IBD-related therapy: 5‑aminosalicylates might be protective; corticosteroids might be harmful (primary effect versus marker of disease severity); immunomodulators have an unclear role; anti-TNF therapy has an unclear role, but might be protective

immunomodulators), no significant difference in the risk of myocardial infarc­tion (RR 1.15 versus 1.17, P = 0.88), stroke (RR 1.16 versus 1.18, P = 0.79) or cardio­vascular death (RR 1.23 versus 1.35, P = 0.33) were found in patients treated with immunomodulators compared with the entire IBD population.8 Using in vitro and ex vivo models, a study published in 2014 demonstrated that 6‑mercaptopurine can induce phenotypic transformation of vascular smooth muscle cells, which would predispose patients to arteriosclerosis, potentially increasing the risk of cardiovascular events.72 Anti‑TNF agents do not seem to modify cardiovascular risk in observational studies in IBD; whether this finding represents a true inability to modify cardiovascular risk with treatment of systemic inflammation, or simply an inability to account for confounding by disease severity remains unclear. For instance, a comparable risk of CHD was seen in patients treated with anti-TNF agents (IRR 0.60, 95% CI 0.25–1.44) and in patients not on antiTNF agents (IRR 1.24, 95% CI 1.16–1.32), using patients without IBD as a reference.9 However, only five cardiovascular events were observed in the group treated with anti‑TNF agents, hence, the study was underpowered to detect a statistically significant difference. Of note, anti‑TNF agents are contraindicated in patients with moderate to severe heart failure as a result of the increased mortality and morbidity observed in these patients.73 By contrast, well-designed observational studies in patients with rheumatoid arthritis have demonstrated a beneficial effect of anti‑TNF agents on cardiovascular morbidity. In a prospective cohort study of patients with rheumatoid arthritis who were treated with anti‑TNF agents, ‘responders’ to anti‑TNF therapy had a lower incidence of myocardial infarction than ‘nonresponders’ (IRR 0.36, 95% CI 0.19–0.69).74 Interventional studies in patients with inflammatory arthritis have demonstrated

short-term and long-term improvements in endothelial dysfunction with the use of anti‑TNF agents.75 Anti‑TNF agents also improve arterial stiffness and carotid atherosclerosis in patients with inflammatory arthritis. In a prospective cohort study of 67 patients with ankylosing spondylitis, long-term anti‑TNF use slowed progression of atherosclerosis, compared with short-term use.76 In a randomized controlled trial of 40 patients with active rheumatoid arthritis, patients treated with methotrexate and infliximab had a greater reduction in aortic stiffness than patients treated with methotrexate alone, which was accompanied by a decrease in rheumatoid arthritis disease activity.77 In light of the lack of data on how anti‑TNF agents might modify the risk of cardio­vascular disease in patients with IBD, these findings provide i­ndirect evidence of a potential beneficial effect. In summary, nonconventional chronic in­flammationbased risk factors make a notable contribution to the observed cardiovascular risk in patients with IBD. Disease activity, but not disease duration, considerably modifies the risk of cardiovascular events; aggressive disease-modifying biologic therapy might favourably modify this risk (Box 2). Future prospective studies that adjust for the propensity to prescribe biologic agents and account for disease activity are needed.

Effect of cardiovascular medications Aspirin Aspirin is used for primary and secondary prevention of cardiovascular disease in high-risk patients. The evidence for the effect of aspirin on development and progression of IBD is conflicting. In a prospective cohort study, aspirin use was associated with an increased risk of developing Crohn’s disease (OR 6.14, 95% CI 1.76–21.35) but not ulcerative colitis.78 By contrast, in the Nurses’ Health Study cohort, an association was not observed between aspirin use and development of Crohn’s disease (HR 0.89, 95% CI 0.49–1.61) or ulcerative colitis (HR 1.00, 95% CI 0.56–1.78).79 Similarly, the effect of aspirin on exacerbation of IBD in patients with established disease is also ambiguous. Whereas high-dose NSAIDs increase the risk of an IBD flare,80 a similar effect of low-dose aspirin has not been demonstrated. In a small retrospective cohort study, no statistically significant difference was found in the risk of IBD exacerbation in patients with IBD treated with antiplatelet agents and control individuals not treated with these agents who were matched for age, sex, disease phenotype and disease duration.81 Thus, it might be safe to continue using low-dose aspirin for secondary prophylaxis in patients with IBD. Clopidogrel As platelets are an important link between inflammation, thrombosis and atherogenesis, antiplatelet agents might exert beneficial effects in patients with IBD. Clopidogrel is an oral, thienopyridine antiplatelet agent that exerts its effect by irreversibly inhibiting the P2Y12 subtype of the adenosine diphosphate receptor, which is important in activation of platelets and eventual cross-linking by fibrin. Only a small number of studies have investigated

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REVIEWS New diagnosis of IBD Evaluate for presence of conventional and nonconventional cardiovascular risk factors at initial visit and annual follow-up visits

Conventional risk factors Hypertension Hyperlipidaemia (preferably at time of quiescent or mildly active disease) Diabetes mellitus Smoking Family history of cardiovascular disease

Nonconventional risk factors Disease activity Disease-modifying therapy

Modification of risk factors

To be performed by a gastroenerologist or in conjunction with primary-care physician Blood pressure control Treatment of diabetes mellitus and hyperlipidaemia Smoking cessation Promote healthy lifestyle with physical activity and weight control

Promote endoscopic remission through disease-modifying therapy

Figure 1 | Suggested algorithm for Nature the management of cardiovascular risk in Reviews | Gastroenterology & Hepatology patients with IBD. This algorithm was developed based on findings from this Review and the authors’ experience, in conjunction with an expert cardiologist (I.J.K.). In patients who develop cardiovascular disease, IBD should be managed in close consultation with a cardiologist and primary-care physician.

the effect of clopidogrel on colitis. In an experimental model of Crohn’s disease induced by trinitrobenzene sulphonic acid and an oxazolone-induced model of ulcerative colitis, administration of high doses of clopidogrel resulted in improved clinical symptoms, body weight and tissue and histological evidence of colonic inflammation.82 However, small clinical trials of a similar antiplatelet agent (ridogrel, a combined thromboxane synthase inhibitor and thromboxane/prostaglandin endoperoxide antagonist) showed no therapeutic benefit for induction of clinical remission over placebo.83,84 Importantly, the use of these antiplatelet agents is not associated with any safety issues, including no increase in risk of bleeding. Hence, antiplatelet agents such as clopidogrel might be safe to continue to use in patients with IBD, and could have beneficial anti-inflammatory effects.

Statins Statins reduce cardiovascular morbidity and mortality. Beyond their effect on cholesterol synthesis, statins inhibit proinflammatory mediators, such as TNF, interleukins, CRP and transforming growth factor (TGF)‑β.85 Statins reduce inflammatory activity 86–88 and decrease intestinal fibrosis in mouse models of IBD.89 In an interventional study of 10 patients with mild Crohn’s disease, 13 weeks of treatment with atorvastatin decreased clinical and biochemical Crohn’s disease activity.90 In a large retrospective cohort study, patients with IBD who had been exposed to statins were less likely than patients who had not taken statins to need corticosteroids (HR 0.82, 95% CI 0.71–0.94), after adjustment for comorbidities,

health-care utilization and the use of other diseasemodifying agents.91 In patients with IBD, statins were also associated with a trend towards reduced risk of hospitalization (HR 0.88, 95% CI 0.74–1.05), IBD-related surgery (HR 0.80, 95% CI 0.63–1.02) and need for antiTNF agents (HR 0.72, 95% CI 0.46–1.11).91 Whether these findings represent a true anti-inflammatory benefit of statins, or reverse causality (patients with severe IBD might have reduced levels of cholesterol as a result of the inflammation-associated ‘lipid paradox’ and are therefore less likely to be prescribed statins than patients with mild disease) merits further evaluation. Statin use might also decrease the risk of colitis-associated colorectal cancer, according to experimental studies92 and population-based observational studies.93

Angiotensin-converting enzyme inhibitors Angiotensin-converting enzyme (ACE) inhibitors are routinely used in patients with myocardial infarction, heart failure and hypertension because of their bene­ ficial effect on ventricular remodelling. In IBD, early preclinical evidence suggested that patients with Crohn’s disease might have a higher expression of mucosal angiotensin, compared with healthy individuals and patients with ulcerative colitis.94 In a subsequent study with a trinitrobenzenesulphonic-acid-induced colitis model, captopril decreased macroscopic and histological inflammation and prevented fibrosis by blocking TGFβ‑1 overexpression and/or by direct downregulation of the TGFβ‑1 transcript.95 However, this evidence is preliminary, and the effect of ACE inhibitors, if any, in humans with IBD is unclear. In summary, findings from preclinical studies suggest that commonly used cardiovascular medications such as statins and ACE inhibitors might favourably modify IBD activity. Well-designed observational studies might help clarify this association, before large prospective interventional studies are embarked upon. If deemed useful, these medications might become inexpensive, safe and effective adjunctive therapies in IBD.

Management of cardiovascular disease

Patients with IBD are managed by multiple health-care providers, and coordination of care is critical for optimal outcomes. Although data from cohorts of patients with IBD are lacking, data from other cohorts, such as patients with rheumatoid arthritis, suggest that patients with inflammatory diseases are less likely than is recommended to receive primary and secondary heart disease prevention.96 Patients with rheumatoid arthritis are less likely to undergo screening and treatment for hyperlipid­ aemia, have delayed recognition of cardiac chest pain, and are less likely to receive reperfusion therapy, coronary artery bypass grafting and medications for secondary prophylaxis such as statins than other groups of patients.96 Gastroenterologists and primary-care physicians should be cognizant of the increased risk of cardiovascular events in patients with IBD. Favourable modification of conventional cardiovascular risk factors such as smoking cessation, recognition and treatment of hypertension,

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REVIEWS hyperlipidaemia and diabetes mellitus should be encouraged, as well as promotion of a healthy lifestyle. In addition, maintaining long-term remission in patients with IBD might also decrease inflammation-associated cardio­ vascular events. Figure 1 describes our approach to the management of cardiovascular risk in patients with IBD. As a result of the increased risk of cardiovascular events at the time of an IBD flare, special attention should be paid to patients with a severe IBD flare. Although pharma­cological prophylaxis with low-molecular-weight heparin is warranted to minimize the risk of VTE, it is unclear whether such an intervention would be helpful for preventing cardiovascular events. In the absence of evidence, the use of antiplatelet agents (such as aspirin) should not be initiated for primary prophylaxis of cardio­ vascular disease; however, patients who are already on low-dose aspirin can continue to take this medication at the time of their flare without a notable increase in the risk of gastrointestinal bleeding.81 Patients taking antiplatelet agents for secondary prophylaxis (that is, those with a history of cardiovascular events) must be continued on aspirin during their IBD flare to minimize the risk of stroke and CHD. Although it might be safe (and potentially beneficial) to continue dual antiplatelet therapy in most patients at the time of an IBD flare, the risk to benefit profile should be reconsidered in patients with notable gastrointestinal bleeding. Any decisions on withholding antiplatelet therapy in a patient with a prior cardio­vascular event should be made in close d­iscussion with a cardiologist. A limited amount of data is available on the efficacy and safety of cardiovascular interventions in patients with IBD. In a hospital-based, retrospective case–control study of 131 patients with IBD and CHD who underwent coronary angiography, it was observed that patients with IBD were less likely to have severe left anterior descending disease (56% versus 73%, P