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 (). A total of 199,978 matched controls were enrolled in the study.
Flowchart for the study population, IBD: Inflammatory bowel disease.
Patient characteristics at index are displayed in . The mean age of the study population was 43.8 (SD 18.7) years, and 54.5 % were women. Loss to follow-up due to emigration was 2.0 % among the included IBD cases and 3.5 % among controls. The frequencies of co-morbidities were significantly higher among IBD patients compared to the matched controls, and use of cardiovascular drugs and glucose-lowering agents at baseline was significantly higher in the IBD group. Distribution of IBD disease activity is shown in .
Baseline characteristics of the study population. IBD: inflammatory bowel disease.
Disease activity periods and follow-up time in study cohort with inflammatory bowel disease (IBD).
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) ( and ). During remission the RR for MI was not increased (1.01 [0.89–1.15]) and it was significantly lower than RRs during flares (p
0.005) and in periods with persistent activity of IBD (p<0.0001).
Risk of myocardial infarction, stroke and cardiovascular death stratified by inflammatory bowel disease activity.
Number of events, incidence rates per 1000 person-years, adjusted rate ratios (RRs) and 95% confidence intervals (CIs).
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
Concerning cardiovascular death the IRs were markedly increased during flares (IR 13.89 [12.06–16.01]) and persistent activity (IR 26.91 [220.127.116.11]) 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.