High CV risk in atherosclerosis patients with highest levels of inflammatory biomarkers and LDL-c

Comparison of interleukin-6, C-reactive protein, and low-density lipoprotein cholesterol as biomarkers of residual risk in contemporary practice: secondary analyses from the Cardiovascular Inflammation Reduction Trial

Literature - Ridker PM, MacFadyen JG, Glynn RJ, et al. - Eur Heart J 2020, doi:10.1093/eurheartj/ehaa160

Introduction and methods

The inflammatory biomarkers C-reactive protein (CRP) and interleukin-6 (IL-6) are independent predictors of CV events, as was demonstrated in primary prevention cohorts that were started >30 years ago. The magnitude of prediction is similar to that of LDL-c [1-5]. For this reason high-sensitivity CRP (hsCRP) is commonly used in North America as a validated biomarker of inflammatory risk [6], but use in Europe is limited.

Polymorphism in the IL-6 pathway are associated with hsCRP levels and vascular risk, as demonstrated in Mendelian randomization studies [7,8]. Intervention trials, such as CANTOS and more recently COLCOT, showed that anti-inflammatory therapy reduces ischemic events [9-12].

In clinical practice, IL-6 may be the preferred inflammatory biomarker compared to hsCRP, as it may give an improved signal to noise ratio - IL-6 is a central inflammatory cytokine and hsCRP a downstream inflammatory biomarker. But translational evidence comparing the use of IL-6, hsCRP and LDL-c in prediction of CV risk is limited and comparative data among secondary prevention patients taking statins, which has concomitant anti-inflammatory effects are scarce. In addition, it is unknown whether aggressive adjunctive therapies beyond statins have an effect on the relationship between inflammation, lipids and vascular risk.

These issues were examined in a prospective cohort of 4168 North American patients with atherosclerotic disease (MI or multivessel coronary disease and T2DM or the metabolic syndrome). Data of the Cardiovascular Inflammation Reduction Trial (CIRT) [13] were used and contained baseline measurements of IL-6, hsCRP and LDL-c. The CIRT trial, which evaluated the effect of methotrexate in the prevention of recurrent CV events, showed no effect of methotrexate on IL-6, hsCRP and LDL-c levels, nor on CV events. Participants were followed up to 5 years for MACE (nonfatal myocardial infarction, non-fatal stroke, hospitalization for unstable angina requiring urgent revascularization, CV death) and all-cause mortality.

Main results

Baseline levels of IL-6, hsCRP and LDL-c predict future CV events. For MACE, adjusted HRs for the lowest to highest baseline quartiles of IL-6 were 1.0 (referent), 1.66 (1.18–2.35), 1.92 (1.36–2.70), and 2.11 (1.49–2.99; P< 0.0001), adjusted HRs for increasing quartiles of hsCRP were 1.0 (referent), 1.28 (0.92–1.79), 1.73 (1.25–2.38), and 1.79 (1.28–2.50; P< 0.0001) and adjusted HRs for increasing quartiles of LDL-c were 1.0 (referent), 1.12 (0.78–1.62), 1.25 (0.87–1.79), and 2.38 (1.72–3.30; P< 0.0001).
When assuming a linear association across quartiles, HR with each increasing quartile of IL-6 increased by 24% (95%CI:12–38; P< 0.0001), 22% for each increasing quartile of hsCRP (95%C: 10–35; P=0.0001) and 35% for each increasing quartile of LDL-c (95%CI: 22–50; P<0.001).
When adjusting for lipids, HR for each increasing quartile of IL-6 increased by 20% (95% CI 8–33 ; P=0.0008) as compared to an increase of 11% for each increasing quartile of hsCRP (95% CI 0–24; P=0.05). After additional adjustment for IL-6 and hsCRP rather than for lipid levels, each increasing quartile of LDL-c at baseline remained associated with a 35% increase in risk (95%CI 21–50, P<0.001).
Effect estimates for MACE were not statistically significant for comparisons between IL-6, hsCRP and LDL-c, but for the endpoint of all-cause mortality, magnitude of risk associated with IL-6 levels was greater than that observed for hsCRP or LDL-c.
Those with >median levels of IL-6 and hsCRP at baseline had an almost 2-fold increased risk of MACE compared to those with
Those with >median levels of IL-6 and hsCRP at baseline had more than 2-fold increased risk of all-cause mortality compared to those with
Those with highest quartiles of IL-6 and LDL-c had a 6-fold increased risk of MACE compared to those with lowest baseline quartiles of IL-6 and LDL-c (adjusted HR 6.36, 95%CI: 2.9-14.1, P<0.0001). And those with the highest quartiles of hsCRP and LDL-c had an almost 5-fold increase in risk compared to those with lowest baseline quartiles (adjusted HR 4.90, 95%CI: 2.6-9.4, P<0.0001).

Conclusion

Despite contemporary aggressive therapy, levels of LDL-c, IL-6 and hsCRP all still predict future CV events in a cohort of North American atherosclerosis patients. Those with highest quartiles of IL-6 or hsCRP and highest quartile of LDL-c had highest risk of MACE, suggesting that future combination therapies targeting both pathways could improve outcomes in atherosclerosis patients.

References

Show references

1. Ridker PM, Cushman M, Stampfer MJ, et al. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med 1997;336:973–979.

2. Ridker PM, Hennekens CH, Buring JE, Rifai N. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med 2000;342:836–843.

3. Ridker PM, Rifai N, Stampfer MJ, Hennekens CH. Plasma concentration of interleukin-6 and the risk of future myocardial infarction among apparently healthy men. Circulation 2000;101:1767–1772.

4. Emerging Risk Factors Collaboration. C-reactive protein concentration and risk of coronary heart disease, stroke, and mortality: an individual participant metaanalysis. Lancet 2010;375:132–140.

5. Kaptoge S, Seshasai SR, Gao P, et al. Inflammatory cytokines and risk of coronary heart disease: new prospective study and updated meta-analysis. Eur Heart J 2014;35:578–589.

6. Ridker PM. A test in context: high-sensitivity C-reactive protein. J Am Coll Cardiol 2016;67:712–723.

7. IL6R Genetics Consortium Emerging Risk Factors Collaboration et al. Interleukin-6 receptor pathways in coronary heart disease: a collaborative meta-analysis of 82 studies. Lancet 2012;379:1205–1213.

8. Interleukin-6 Receptor Mendelian Randomisation Analysis (IL6R MR) Consortium, et al. The interleukin-6 receptor as a target for prevention of coronary heart disease: a Mendelian randomisation analysis. Lancet 2012;379:1214–1224.

9. Ridker PM, Everett BM, Thuren T, et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med 2017;377:1119–1131.

10. Ridker PM, MacFadyen JG, Everett BM, et al. Relationship of C-reactive protein reduction to cardiovascular event reduction following treatment with canakinumab: a secondary analysis from the

CANTOS randomized controlled trial. Lancet 2018;391:319–328.

11. Ridker PM, Libby P, MacFadyen JG, et al. Modulation of the interleukin-6 signaling pathway and incidence rates of atherosclerotic events and all-cause mortality: analyses from the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS). Eur Heart J 2018;39:3499–3507.

12. Zhao TX, Mallat Z. Targeting the immune system in atherosclerosis. JACC stateof-the art review. J Am Coll Cardiol 2019;73:1691–1706.

13. Ridker PM, Everett BM, Pradhan A, et al. Low-dose methotrexate for the prevention of atherosclerotic events. N Engl J Med 2019;380:752–762.

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