The authors have declared that no competing interests exist.
Conceived and designed the experiments: SLK PRH GHG OHN CTP OA RE JL GVJ. Performed the experiments: SLK PRH GHG OHN OA RE JL GVJ. Analyzed the data: SLK PRH GHG OHN CTP OA RE JL GVJ. Wrote the paper: SLK PRH GHG OHN CTP OA RE JL GVJ .
Chronic inflammatory diseases have been linked to increased risk of atherothrombotic events, but the risk associated with inflammatory bowel disease (IBD) is unclear. We therefore examined the risk of myocardial infarction (MI), stroke, and cardiovascular death in patients with IBD.
In a nationwide Danish population-based setting, a cohort of patients with incident IBD between 1996 and 2009 were identified in national registers. Hospitalizations with IBD as primary diagnosis, initiation of biological treatment and dispensed prescriptions of corticosteroids were all used as surrogate markers for disease activity, with flares classified as the first 120 days after diagnosis of IBD, and 120 days after a new corticosteroid prescription, biological treatment or IBD hospitalization, respectively. Continued corticosteroid prescriptions or IBD hospitalizations were defined as persistent activity, and periods free of such events were defined as remissions. Poisson regression was used to examine risk of MI, stroke, and cardiovascular death using a matched population-based comparison cohort as reference
We identified 20,795 IBD patients with a mean age of 40.3 years that were matched according to age and sex with 199,978 controls. During the study period, there were 365 patients with MI, 454 with stroke, and 778 with cardiovascular death. Patients with IBD had an overall increased risk of MI (rate ratio [RR] 1.17 [95% confidence interval 1.05–1.31]), stroke (RR 1.15 [1.04–1.27], and cardiovascular death (RR 1.35 [1.25–1.45]). During flares and persistent IBD activity the RRs of MI increased to 1.49 (1.16–1.93) and 2.05 (1.58–2.65), the RRs of stroke to 1.53 (1.22–1.92) and 1.55 (1.18–2.04) and for cardiovascular death 2.32 (2.01–2.68) and 2.50 (2.14–2.92). In remission periods, the risk of MI, stroke and cardiovascular death was similar to controls.
Inflammatory bowel disease is associated with increased risk of MI, stroke, and cardiovascular death during periods with active disease.
The pivotal role of inflammatory mechanisms in the progression of atherosclerosis has fuelled research aimed at whether diseases characterized by chronic inflammation, including inflammatory bowel disease (IBD), carry an increased risk of cardiovascular disease
The study was conducted and reported in accordance with the Strengthening the Reporting of Observational studies in Epidemiology (STROBE) recommendations
In the present matched cohort study we defined IBD cases as all individuals aged ≥15 years who received a first diagnosis of IBD, i.e. CD (K50 and 563.01) or UC (K51 and 569.04+563.01), during the period 1996–2009 in combination with a dispensed prescription for pharmacological IBD treatment, including one or more of the following agents (ATC codes): 5-aminosalicylic acid (A07EC02), sulfasalazine (A07EC01), oral corticosteroids (H02AB06), budesonide (A07EA), azathioprine (L04AX01), 6-mercaptopurine (L01BB02) and methotrexate (L01BA01) within one year before the time of diagnosis and hereafter. The index dates of IBD cases were the date of IBD ICD-10 code and drug prescription, whichever came last. Initiation of biological treatment with anti-tumor necrosis factor-α (TNF) agents was defined by the Danish procedural code (BHJ18A). Surgery for IBD was defined by procedure codes (KJF [colon and small intestine], KJG and KJH [perianal area] in combination with IBD-diagnosis). The IBD diagnoses in the National Patient Registry have been found to be accurate
Hospitalizations with IBD as primary diagnosis, initiation of anti-TNF treatment and dispensed prescription of corticosteroids were used as surrogate markers for disease activity. An IBD flare was defined as a 120 days period starting at the day of initiation of corticosteroid treatment, biological treatment and/or hospitalization for IBD, following 120 days free of corticosteroid prescription or hospitalizations due to IBD (
We assessed the presence of co-morbidity at study entry by hospitalization for the following prespecified diagnoses in the 5 years preceding study inclusion (ICD-10 and ICD-8 codes): Cardiac dysrhythmia (I44–I49 and 427.3, 427.4, 427.5, 427.6, 427.9), diabetes (E10–E14 and 250), chronic obstructive pulmonary disease (J42, J44 and 490–492), renal disease (N03, N04, N17, N18, N19, R34, I12, I13 and 582–588), hypertension (I10–I15 and 400–404), venous thromboembolic disease (I26, I80, I82 and 415, 453 excluding I80.8, I80.0 and I82.0), and heart failure (I42, I43, I50 and 110, 517)._ENREF_19Use of the following drugs (ATC codes) was defined at study inclusion : Glucose-lowering agents (A10), statins (C10A), loop diuretics (C03C), platelet inhibitors (B01AC), vitamin K antagonists (B01AA) and we identified patients with hypertension by treatment with at least two of the following classes of antihypertensive drugs: α-adrenergic blockers (C02A, C02B, C02C), non-loop diuretics (C02DA, C02L, C03A, C03B, C03D, C03E, C03X, C07C, C07D, C08G, C09BA, C09DA, C09XA52), vasodilators (C02DB, C02DD, C02DG), β blockers (C07), calcium channel blockers (C07F, C08, C09BB, C09DB), and renin-angiotensin system inhibitors (C09). Similarly we defined diabetes by either the hospital diagnosis (E10–E14) or use of glucose-lowering agents (A10). All information on cardiovascular medication and co-morbidity were continually updated throughout the follow-up period.
The following endpoints (ICD-10 codes) were used: MI (I21–I22), stroke (I60–I61, I63–I64), cardiovascular death (I00–I99) and a secondary composite endpoint of MI, stroke and cardiovascular death. The stroke and MI codes have previously been validated in the National Patient Register
Baseline characteristic were summarized as means with standard deviations for continuous variables and frequencies and percentages for categorical variables. Incidence rates (IRs) are presented per 1000 person-years. To estimate rate ratios (RRs) and 95% confidence intervals (CIs) for MI, stroke, cardiovascular death, and the composite endpoint, we fitted multivariable Poisson regression models in patients with IBD using the matched controls as reference. The models were adjusted for confounding factors, including socioeconomic status, and gender. Age, co-morbidity, use of cardiovascular medication (antihypertensive treatment, statins, loop diuretics, vitamin K antagonists), lipid-lowering agents, glucose-lowering medication, and IBD disease activity status were included as time-dependent variables. Subjects lost to follow-up due to emigration from Denmark were censored at time of emigration. To address potential differences in risk of cardiovascular disease in patients with CD, UC or unspecified IBD we evaluated overall risk and disease activity related risk for each endpoint in an IBD subtype-stratified analysis. In addition, we changed the flare duration to assess the potential impact of flare-definition on the risk estimates. We did subgroup analyses of patients that received anti-TNF agents (BHJ18A) and other immunomodulators including 6-mercaptopurine (L01BA01), azathioprine (L01BB02), and/or methotrexate (L04AX). We also did a subgroup analysis where we evaluated the influence of nine predefined risk factors (prior venous thromboembolism, heart failure, cardiac arrhythmias, chronic obstructive pulmonary disease [COPD], renal disease, hypertension, diabetes, and use of loop diuretics, lipid-lowering agents, and vitamin K antagonists) and stratified all IBD patients in groups of 0 (reference group), 1–2 or ≥3 risk factors. SAS version 9.2 and Stata version 11.1 were used for statistical analyses. Risk set matching was performed with Greedy matching macro (last accessed 5 September 2012 at
Register-based studies do not require ethical approval in Denmark as individual patients cannot be identified from the encrypted data that are available. The Danish Data protection agency approved the study (reference no. 2007-58-0015, international reference: GEH-2010-001).
A total of 26,293 IBD patients were identified with in the study period. After exclusion of patients with prior IBD, MI or stroke, the final study population included 20,795 patients (
Patient characteristics at index are displayed in
IBD patients n = 20,795 | Controls n = 199,978 | p -value | |
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9,455 (45.5) | 90,439 (45.2) | |
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11,340 (54.5) | 109,539 (54.8) | |
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43.8 (18.7) | 43.1 (18.7) | |
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6.04 | 6.17 | |
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125,558 | 1,233,010 | |
|
13,622 (65.5) | – | |
|
4,732 (22.8) | – | |
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2,441 (11.7) | – | |
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Antihypertensive treatment | 1,806 (8.7) | 10,362 (5.2) | <0.001 |
Statin | 871 (4.2) | 5,337 (2.7) | <0.001 |
Platelet inhibitor | 1,222 (5.9) | 6,845 (3.4) | <0.001 |
Loop diuretic | 829 (4.0) | 3,968 (2.0) | <0.001 |
Vitamin K antagonist | 233 (1.1) | 1,255 (0.6) | <0.001 |
Glucose-lowering medication | 479 (2.3) | 3,527 (1.8) | <0.001 |
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Cardiac dysrhythmia | 409 (2.0) | 1,938 (1.0) | <0.001 |
Heart failure | 221 (1.1) | 761 (0.4) | <0.001 |
Renal disease | 102 (0.5) | 275 (0.1) | <0.001 |
Diabetes | 375 (1.8) | 155 (0.1) | <0.001 |
Hypertension | 635 (3.1) | 2,335 (1.2) | <0.001 |
Venous thromboembolism | 195 (0.9) | 868 (0.4) | <0.001 |
Chronic obstructive pulmonary disease | 403 (1.9) | 1,125 (0.6) | <0.001 |
Disease activity periods (n [%]) | Mean duration (days) | Total duration of follow-up in IBD population (person-years) | |
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42,685 (42.8) | 117.0 | 13,674 (10.9) |
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17,542 (17.6) | 128.4 | 6,166 (4.9) |
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39,547 (29.1) | 976.4 | 105,718 (84.2) |
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99,774 (100) | 459.6 | 125,558(100) |
We observed a total of 365 MIs, 454 strokes and 778 cardiovascular deaths in the IBD cohort as compared to 2,389 MIs, 3,327 strokes and 4,738 cardiovascular deaths in the matched control group during follow-up.
IRs for MI were 2.93 (95% CI 2.64–3.24) and 1.95 (1.87–2.03) per 1000 person-years for IBD patients and matched controls. The risk of MI was increased both in unadjusted and adjusted analyses, with an adjusted overall risk of RR 1.17 (1.05–1.31). During flares RR was 1.49 (1.16–1.93) and during persistent activity the RR was 2.05 (1.58–2.65) (
CI: confidence interval. RR: Rate ratio.
Number of events | Incidence rate (unadjusted) | 95% CI | RR | 95% CI | |
|
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Ulcerative colitis | 272 | 3.42 | 3.03–3.85 | 1.17 | 1.03–1.33 |
Crohńs disease | 61 | 2.16 | 1.68–2.78 | 1.35 | 1.03–1.77 |
Unspecific IBD | 32 | 1.89 | 1.33–2.67 | 1.05 | 0.76–1.48 |
IBD total | 365 | 2.93 | 2.64–3.24 | 1.17 | 1.05–1.31 |
Age>45 years | 334 | 7.08 | 6.36–7.89 | 1.18 | 1.05–1.32 |
Flare | 60 | 4.36 | 3.38–5.61 | 1.49 | 1.16–1.93 |
Persistent activity | 60 | 9.73 | 7.56–12.53 | 2.05 | 1.58–2.65 |
Remission | 245 | 2.34 | 2.06–2.65 | 1.01 | 0.89–1.15 |
Controls | 2,389 | 1.95 | 1.87–2.03 | ref. | – |
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Ulcerative colitis | 309 | 3.88 | 3.47–4.34 | 1.10 | 1.02–1.19 |
Crohńs disease | 89 | 3.17 | 2.57–3.90 | 1.37 | 1.10–1.72 |
Unspecific IBD | 56 | 3.30 | 2.54–4.29 | 1.41 | 1.06–1.88 |
IBD total | 454 | 3.64 | 3.32–3.99 | 1.15 | 1.04–1.27 |
Age>45 years | 410 | 8.71 | 7.90–9.59 | 1.15 | 1.03–1.27 |
Flare | 77 | 5.60 | 4.48–7.00 | 1.53 | 1.22–1.92 |
Persistent activity | 53 | 8.60 | 6.57–11.25 | 1.55 | 1.18–2.04 |
Remission | 324 | 3.09 | 2.77–3.45 | 1.04 | 0.92–1.16 |
Controls | 3,327 | 2.72 | 2.62–2.81 | ref. | – |
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Ulcerative colitis | 540 | 6.73 | 6.19–7.32 | 1.25 | 1.14–1.37 |
Crohńs disease | 148 | 5.23 | 4.45–6.14 | 1.63 | 1.36–1.95 |
Unspecific IBD | 90 | 5.28 | 4.30–6.49 | 1.69 | 1.34–2.13 |
IBD total | 778 | 6.20 | 5.78–6.65 | 1.35 | 1.25–1.45 |
Age>45 years | 758 | 15.85 | 14.76–17.02 | 1.29 | 1.22–1.37 |
Flare | 192 | 13.89 | 12.06–16.01 | 2.32 | 2.01–2.68 |
Persistent activity | 168 | 26.91 | 23.13–31.30 | 2.50 | 2.14–2.92 |
Remission | 418 | 3.96 | 3.60–4.36 | 0.98 | 0.89–1.09 |
Controls | 4,738 | 3.84 | 3.73–3.95 | ref. | – |
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Ulcerative colitis | 869 | 10.99 | 10.28–11.74 | 1.17 | 1.09–1.26 |
Crohńs disease | 229 | 8.18 | 7.19–9.31 | 1.48 | 1.28–1.70 |
Unspecific IBD | 138 | 8.18 | 6.92–9.67 | 1.38 | 1.15–1.65 |
IBD total | 1,236 | 9.97 | 9.43–10.54 | 1.24 | 1.16–1.31 |
Age>45 years | 1,155 | 24.87 | 23.47–26.34 | 1.26 | 1.18–1.34 |
Flare | 266 | 19.41 | 17.22–21.89 | 1.97 | 1.74–2.22 |
Persistent activity | 205 | 33.67 | 29.36–38.60 | 2.07 | 1.80–2.39 |
Remission | 765 | 7.35 | 6.84–7.88 | 1.00 | 0.93–1.08 |
Controls | 8,056 | 6.60 | 6.46–6.75 | ref. | – |
The composite endpoint was myocardial infarction, stroke and cardiovascular death combined. IBD: inflammatory bowel disease. The model was adjusted for age, gender, co-morbidity, cardiovascular medication and socioeconomic status.
The incidence of stroke was also highest during periods of flares (IR 5.60 [4.48–7.00]) and persistent activity (IR 8.60 [6.57–11.25]) and as compared to controls (IR 2.72 [2.62–2.81]). The overall adjusted RR for stroke was 1.15 (1.04–1.27), and the risk was evenly increased in periods of flare and persistent activity with RR 1.53 (1.22–1.92) and RR 1.55 (1.18–2.04). Again, the risk during remission was negligible with RR 1.04(0.92–1.16) and significantly lower than periods with persistent activity (p = 0.008) and flares (p = 0.003)
Concerning cardiovascular death the IRs were markedly increased during flares (IR 13.89 [12.06–16.01]) and persistent activity (IR 26.91 [23.13.31.30]) compared to remission (IR 3.96 [3.60–4.36]) and matched controls (IR 3.84 [3.73–3.95]). The augmented risk in the IBD cohort was prominent for cardiovascular death with an overall increased RR of 1.35 (1.25–1.45) in the adjusted analysis. The risk of cardiovascular death was more than two-fold increased both in periods of flares (RR 2.32 [2.01–2.68]) and periods of persistent activity (RR 2.50 [2.14–2.92]). Again, the RRs were higher for flares and periods with persistent activity in comparison with remission periods (both p<0.0001). For IBD in remission, the risk was similar to matched controls (RR 0.98 [0.89–1.09]; p = 0.96). Finally for the composite endpoint of MI, stroke, and cardiovascular death, the RR was 1.97 (1.74–2.22) during flares and 2.07 (1.80–2.39) in periods with persistent activity. Once more there was no increased risk during remission RR 1.00 (0.93–1.08).
We saw no differences in cardiovascular risk between men and women with IBD, and we observed no interaction between IBD subtypes and the cardiovascular risk stratified by disease activity. The overall risk was similar for MI and augmented for stroke and cardiovascular death in CD patients as compared to UC patients (MI: RR 1.35 [1.03–1.77] vs. 1.17 [1.03–1.33] p = 0.81, stroke: RR 1.37 [1.10–1.72] vs. 1.10 [1.02–1.19] p = 0.02 and cardiovascular death: RR 1.63 [1.36–1.95] vs. 1.25 [1.14–1.37] p = 0.04). In IBD activity analyses without corticosteroid prescriptions as activity marker, we found that the higher cardiovascular risk in periods of IBD disease activity persisted (not shown). When we removed hospitalization from our IBD disease activity definition, we found similar risks of MI (RR 1.43 [1.09–1.87] vs. 1.49 [1.16–1.93]) and stroke (RR 1.46 [1.15–1.86] vs. 1.53 [1.22–1.92]) during flares. Additionally we compared the risk 120 days after surgery due to pancolitis (K51.0) and proctitis (K51.2) in UC patients, and surgery for isolated colon disease (K50.1) versus more widespread CD disease (K50.8) in CD patients, respectively. In general, we found elevated risks during this period (all RŔs >2) but due to low number of events no significant differences were found between the aforementioned groups (not shown).
When we reduced flare length to 60 days, the risk for the composite endpoint in periods with persistent activity was RR 2.67 (2.25–3.18) and during flares RR 2.08 (1.82–2.37). Also, when flare duration was increased to 180 days the corresponding RR was 1.92 (1.68–2.20) in periods with persistent activity and RR 1.75 (1.57–1.98) during flares. We identified 679 (3.3 %) patients who received anti-TNF agents in the period from inclusion to end of study. These patients were younger (median [IQR] age 27.6 [20.7–37.6] years) and had shorter (median 1.2 years) follow up time than the general IBD cohort. We found no cardiovascular events among the patients treated with anti-TNF agents within the study period.
In total 6,017 patients (28.9 %) who received treatment with 6-mercaptopurine, azathioprine and/or methotrexate. In these subjects, we found no significant differences on the risks of MI, stroke and cardiovascular death as compared to the total IBD population (MI: RR 1.15 vs. 1.17 p = 0.88, stroke RR 1.16 vs. 1.14 p = 0.79 and cardiovascular death RR: 1.23 vs. 1.35 p = 0.33). In a sensitivity analysis where we excluded patients with COPD, we found the overall risks of the cardiovascular endpoints for IBD patients essentially unchanged (MI: RR 1.16 [1.03–1.32] vs. 1.18 [1.05–1.31]], stroke: RR 1.15 [1.04–1.27] vs. 1.15 [1.04–1.27]], and cardiovascular death: RR 1.33 [1.22–1.45] vs. 1.28 [1.18–1.38]).
When we compared IBD patients with and without present cardiovascular risk factors, particularly the risk of MI was correlated to presence of risk factors, with RRs 9.09 (7.89–10.49) and 23.14 (20.00–26.77) when comparing 0 vs. 1–2, and 0 vs. ≥3 risk factors, respectively. The corresponding RRs were somewhat lower for stroke (RR 5.29 [4.80–5.87] and RR 8.21 [7.39–9.12]) and cardiovascular death (RR 2.41 [2.24–2.60] and RR 4.36 [4.04–4.70]). IBD patients without any notable cardiovascular risk factors at the time of events comprised 9.0 % of MIs, 13.2 % of strokes, and 11.8 % of cardiovascular deaths.
This present study examined the incidence of MI, stroke, and cardiovascular death in a nationwide cohort of more than 20,000 patients with a new onset of IBD who were followed for a mean period of 6 years. Compared to controls, we found that the risks of MI, stroke, and cardiovascular death were significantly increased during periods of IBD activity including flares and persistent activity, whereas there was no increased risk of these adverse outcomes during periods of IBD remission. The observed IBD activity-dependent increased risk suggests that systemic inflammation contributes to the pathophysiological mechanisms leading to atherothrombosis and the results parallel recent findings of IBD activity-dependent augmented risk of venous thromboembolic disease
While increased risk of venous thromboembolic events in subjects with IBD is now well-established, the risk of atherothrombotic disease including MI and stroke has been the topic of debate
The current results add considerably to the existing literature by demonstrating a significantly increased risk of MI, stroke, and cardiovascular death in a large and unselected population of patients with IBD. A novel finding was that the risk was related to IBD activity with highest risk during flares and periods of persistent activity, while in remission periods the risk of MI and stroke was only marginally increased and in the latter periods the risk of cardiovascular death was comparable to the reference population. In agreement with our results, a study from the same nationwide population published during the preparation of our manuscript also reported an increased risk of ischaemic heart disease including MI in patients with IBD, with particularly high risk in the first 3 months after IBD diagnosis and in patients with a history of treatment with oral corticosteroids
Atherosclerosis is a chronic inflammatory disease characterized by inflammation both in the arterial wall and systemically in the body, and atherothrombotic disease is associated with increased inflammation as exemplified by elevated levels of C-reactive protein
Our subgroup analysis which stratified IBD patients according to presence of cardiovascular risk factors showed a strong correlation between the number of risk factors and the risk of adverse cardiovascular endpoints. Only approximately 10 % of cardiovascular events occurred in IBD patients with no notable risk factors at the time of the event.
The major strength of this study was the large number of IBD patients included and the completeness of data that covered the entire population of Denmark independent of race, socioeconomic status, age, or participation in health insurance programs. Also, the IBD, MI, and stroke diagnoses have been validated in the National Patient Register, with a sensitivity of 94% for both the CD and UC diagnoses and positive predictive values of 97% and 90%, respectively, and for MI a positive predictive value for MI of 93.6 % and sensitivity of 77.6 %
The main study limitation was inherent to the observational design which precludes conclusions on causality and allows for confounding. The higher prevalence of co-morbidities found among IBD-patients could be related, in part, to their more frequent contact to the health care system and hence increased likelihood of a receiving other diagnoses and treatment (detection bias). We lacked information on important cardiovascular risk factors, e.g. lipid levels, obesity, blood pressure, and smoking, although some of these unmeasured risk factors were adjusted for, in part, by use of time-dependent surrogates including medical treatment (e.g. statins for hyperlipidaemia and antihypertensive agents for hypertension) and diagnoses (e.g. COPD for smoking). Adjustment for socioeconomic status at baseline is also likely to have integrated factors such as obesity and smoking. In addition, detection bias may have contributed to increased prevalence of co-morbidities in IBD patients owing to more frequent medical control in these subjects. These limitations notwithstanding, our study design that focused on the importance of IBD disease activity for the cardiovascular risk is likely to have reduced the importance of confounders.
Misclassifications of risk factors such as untreated hypertension, diabetes, or dyslipidaemia may be present and result in unmeasured confounding. The definition of hypertension used has been validated in a randomly selected cohort of people from the Danish population aged ≥16 years, with a positive predictive value of 80% and specificity of 94.7 %
An unmeasured confounder, must be prevalent, unevenly distributed and carry a very high risk to nullify the findings, for example the increased cardiovascular risk during flare periods. We estimated that such a confounder should have a prevalence of 20% and increase RR by a factor of >2 for MI and stroke, and >6 for cardiovascular death. Comparable estimates for hypothetical ‘rule out’ confounders were apparent for persistent activity, rendering its existence unlikely
This nationwide study of IBD patients found a significantly increased risk of MI, stroke, and cardiovascular mortality as compared to matched controls. This risk was predominantly present in periods of IBD activity, including flares and persistent activity, whereas the risk was insignificantly raised for MI and stroke and not increased for cardiovascular death during remission disease stages. The results suggest that effective treatment of IBD aimed at disease remission may reduce cardiovascular risk in these patients, and that treatment strategies for atherothrombotic risk reduction during periods of IBD activity should be explored.