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EAS2019 - Summary of the Keynote Lecture by Professor Ridker

Tuesday 4 June 2019   (0 Comments)
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Professor Paul Ridker discusses inflammation inhibition and atherothrombosis

Whether systemic inflammation is a marker or mediator of atherothrombosis has engendered much debate in the past. However, the CANTOS (Canakinumab Anti-inflammatory Thrombosis Outcomes Study) changed this.1 In patients managed with best evidence-based therapy, including very well controlled low-density lipoprotein cholesterol (LDL-C) levels at baseline, treatment with canakinumab, a monoclonal antibody to interleukin-1β (IL-1β), resulted in profound reduction in the high-sensitivity C-reactive protein levels (by 37 and41% with the two higher doses, 150 mg and 300 mg), and this was associated with significant reduction in major adverse cardiovascular events. Importantly, this benefit was independent of any change in plasma LDL-C levels. CANTOS was truly a proof-of-concept study that irrevocably changed thinking about inflammatory risk.

Secondary analyses of the CANTOS study showed that patients who achieved lower levels of hs-CRP or IL-6 following the therapy with canakinumab derived greater cardiovascular benefit,2,3 also in terms of cardiovascular and all-cause mortality.4

Previous observations had also indicated that chronic inflammation  plays a key role in cancer and  metastasis development. Once again, CANTOS provided proof-of-concept evidence that targeting inflammation has benefit in the setting of cancer, reducing total lung cancer by 67% and fatal lung cancer by 77%.5

More recently clonal haematopoiesis has been proposed as a shared pathway supporting the development of both atherosclerosis and cancer. Preclinical studies indicated that mice with a mutation in the gene encoding the epigenetic modifier enzyme TET2 critically involved in clonal haematopoiesis also showed accelerated atherosclerosis.6

From a clinical perspective, the results of CANTOS fit with the concept of personalised medicine. Categorisation of residual cardiovascular risk as either inflammatory or cholesterol risk will help in targeting treatment. Moreover, residual inflammatory risk is common, with data from the IMPROVE-IT trial with ezetimibe and simvastatin and SPIRE 1 and 2 with bococizumab indicating that at least one-third of patients exhibit residual inflammatory risk.7 Recognition of the magnitude of this issue is driving a number of novel approaches to targeting residual inflammatory risk; however, a more comprehensive strategy may be to combine a PCSK9 inhibitor with an anti-inflammatory agent, so that residual cholesterol and residual inflammatory risk can be concomitantly targeted.

The CANTOS study has been a game changer for defining the central role of inflammation in atherosclerotic cardiovascular disease and advancing a precision medicine approach to therapy. ‘CANTOS has vindicated the inflammation concept, now clinicians need new treatments targeting inflammatory risk in the appropriate patient population.’


1. Ridker PM, Everett BM, Thuren T, et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med 2017;377:1119-31.

2. 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 randomised controlled trial. Lancet 2018;391:319-28.

3. Ridker PM, Libby P, MacFadyen JG, et al. Modulation of the interleukin-6 signalling 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;39:3499-507.

4. Ridker PM. Mortality differences associated with treatment responses in CANTOS and FOURIER: insights and implications. Circulation 2018;137:1763-66.

5. Ridker PM, MacFadyen JG, Thuren T, et al. Effect of interleukin-1β inhibition with canakinumab on incident lung cancer in patients with atherosclerosis: exploratory results from a randomised, double-blind, placebo-controlled trial. Lancet 2017;390:1833-42.

6. Fuster JJ, MacLauchlan S, Zuriaga MA, et al. Clonal hematopoiesis associated with TET2 deficiency accelerates atherosclerosis development in mice. Science 2017;355:842-7.

7. Ridker PM. Clinician's guide to reducing inflammation to reduce atherothrombotic risk: JACC Review Topic of the Week. J Am Coll Cardiol 2018;72:3320-31.

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