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CANTOS: The song about inflammation of atherosclerosis

by Uwe Nixdorff, EAPC Secretary

Prevention


Although inflammatory pathophysiology of atherosclerosis (vulnerable plaque) is known since more than 10 years (1); since JUPITER also in regard to anti-inflammatory potency of aggressive statin medication (2), an almost revolutionary introduction of CANTOS (= The Canakinumab Anti-inflammatory Thrombosis Outcome) by Professor Ridker at the annual ESC Congress in Barcelona and short-term later published in “The New England Journal of Medicine” has to be highlighted (3).

According the knowledge mentioned above an extensive, prospective, double-blinded, randomised study design has been invented, which compared the new antibody Canakinumab potentially acting against an interleukin essentially involved in inflammatory atherosclerosis, i.e. Interleukin-1β. Post-infarct patients with elevated high sensitivity CRP (≥ 2 mg/L) have been randomised with 50 mg, 150 mg, 300 mg Canakinumab or placebo by subcutaneous application in 3-months intervals and who have been followed –up over 48 months regarding the endpoints of non-fatal myocardial infarction, non-fatal stroke or cardiovascular death.

The power of this study has been 90%, for which initially the recruitment of n = 17,200 patients had been intended and which due to intermittent results could be limited to n = 10,061 (1,132 centres, 39 countries). Patient´s age has been 61 years; 25,7% have been women; 40,0% have had diabetes mellitus. Revascularisation therapy consisted of percutaneous coronary intervention (PCI) (66.7%) and coronary artery bypass grafting (CABAG) (14.0%). Post-infarct medication has been evidence-based; > 90% have taken a statin and the median LDL cholesterol has been 82.4 mg/dL. 

At 48 months the median reduction of high sensitivity CRP (C-reactive protein) has been 26% higher compared to baseline in the 50 mg group; 37% higher in the 150 mg group, and 41% higher in the 300 mg group (for all vs. placebo p < 0.001). Interestingly, this developed without any influence of cholesterol status. At median follow-up of 3.7 years the incidence of the endpoint has been 4.5 events/100 person years in the placebo group; 4.11 in the 50 mg group; 3,86 in the 150 mg group; and 3,90 in the 300 mg group. Hazard ratios (HR) vs. placebo have been 0.93 (p = 0,30) of the 50 mg group; 0.85 (p = 0.02) of the 150 mg group; and 0.86 (p = 0.03) of the 300 mg group. Thus, in the sense of dose finding the 150 mg application has been the most rational and most effective one with a 15% event reduction.

Fortunate has been the non expected"side effect“of significant reduction of incidence of malignant diseases by the verum (0.45 (all dose) vs. 0.64/100 person years in placebo). Unfortunate has been the side effect of induction of neutropenia and significant increase of mortality by infections or sepsis in the Canakinumab group (0.31 vs. 0.18 events/100 person years; p = 0.02); thus, all-cause mortality has been relativated again (HR 0.94; p = 0.31).

The medico economic aspect was neither taken into account by the presentation nor by the publication, so the following needs to be considered carefully: There are tremendous costs of the medication so far just accepted for its use in seldom autoimmune and rheumatologic diseases and specific periodic fever syndromes. In this sense the further, ongoing study of the National Heart Lung and Blood Institute (NHLBI) might be interesting (CIRT = Cardiovascular Inflammation Reduction Trial), which is driven by the hypothesis of reduced incidence of infarction by low-dose Methotrexat. Results are to be expected in a couple of years.

From a principal preventive cardiological view the further confirmation of inflammation intervention is dominating as an important prognostic measure. Several comments on the CANTOS trial concluded this as a paradigm shift („dual target hypothesis“) or have seen the significance of it in a concept of personalised medicine. Short term, there is also potential for lifestyle intervention (4), based on the recommendations on behavioural changes of the “2016 European Guidelines on Cardiovascular Disease Prevention in Clinical Practice” defined as evidence IA (5) and which are also confirmed by the PREDIMED study by nutrition modification demonstrating not just a 15% but even 30% reduction of events (6).

Note: The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology

References

Uwe Nixdorff commented on this article:

3) Ridker PM, et al. Anti-inflammatory therapy with Canakinumab for atherosclerotitc disease. N Engl J Med 2017; 377:1119-31.

Additional references:

1) Hansson GK. Inflammation; atherosclerosis, and coronary artery disease. N Engl J Med 2005; 352:1685-95.

2) Ridker PM, et al. Relation of baseline high-sensitivity C-reactive protein level to cardiovascular outcomes with Rosuvastatin in the justification for use of statins in prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER). Am J Cardiol 2010, 106:204-9.

4) Malthotra A, Redberg RF, Meier P. Saturated fat does not clog the arteries: coronary heart disease is a chronic inflammatory condition, the risk of which can be effectively reduced from healthy lifestyle interventions. Br J Sports Med 2017, April 25, online.

5) Piepoli MF, et al. 2016 European Guidelines on cardiovascular disease prevention in clinical practice: The Sixth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of 10 societies and by invited experts)Developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR). Eur Heart J 2016; 37:2315-81.

6) Rose E. The PREDIMED study. Endocrinol Diabetes Nutr 2017;64:63-6.