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Keynote Lecturer Professor Peter Libby on CANTOS and the renaissance of inflammation

Tuesday 8 May 2018   (0 Comments)
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In his Key Note Lecture, Professor Peter Libby (Brigham and Women’s Hospital and Harvard Medical School, Boston, USA) overviewed the therapeutic potential of anti-inflammatory therapy in resolution of inflammation, from bench to bedside evidence.

The involvement of inflammation in atherosclerosis is not in dispute given that atherosclerosis is established as a chronic inflammatory disease. Indeed, it is now well known that inflammation drives all phases of atherosclerosis, from inception, through progression, and ultimately acute thrombotic complications (plaque rupture and plaque erosion). This does not detract in any way from the role of low-density lipoprotein cholesterol, which is established as causal for atherosclerotic cardiovascular disease.1 Given biological plausibility, could targeting inflammation impact atherosclerotic cardiovascular disease? Since plaque rupture and erosion cause most acute coronary syndromes, anti-inflammatory treatments may have the potential to limit myocardial infarction and cardiovascular death. Furthermore, beyond interrupting inflammation-related plaque disruption, such treatments may also ameliorate the propensity to thrombosis once the trigger (plaque rupture or erosion) has occurred.

The question, then, is which inflammatory mediator could be an appropriate therapeutic target.  Attention focused on interleukin-1β (IL-1β), a proinflammatory cytokine that is synthesized as an inactive precursor, and subsequently undergoes activation by caspase-1 under a variety of conditions which predispose to inflammation. Multiple lines of evidence implicate this inflammatory cytokine in atherogenesis; indeed, triggers within the atherosclerotic plaque are involved in activation of IL-1β locally.2  C-Reactive Protein (CRP), in contrast, is now established as high fidelity indicator of inflammation. 

The availability of a specific monoclonal antibody therapy to IL-1β, canakinumab, provided the opportunity to test whether targeting inflammation could reduce cardiovascular events in high risk patients in the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS). This landmark study clearly established that targeted anti-inflammatory therapy significantly reduced major cardiovascular events by 15%, a similar magnitude of benefit as seen in the PCSK9 inhibitor trials, FOURIER and ODYSSEY Outcomes.3-5 Importantly, there was evidence that individuals who showed the greatest response to canakinumab (reduction in high-sensitivity CRP [hsCRP] ≥median at 3 months, i.e. ≥1.8 mg/dl) derived significantly greater clinical benefit from this therapy, both in terms of reduction in  major adverse cardiovascular events as well as reduction in total and all-cause mortality.6

As with any novel therapy, it is important to consider the benefit versus risk of treatment. While canakinumab was associated with a significantly higher rate of fatal infection compared to placebo (predicted from its known biology), there were also significantly fewer reports of arthritis, gout and osteoarthritis compared with placebo, as well as reduction in cancer mortality.7 Once again, the link between inflammation and cancer is predictable given that chronic inflammation is not only a hallmark of cancer but also indispensable for metastasis development.

Anti-inflammatory does not in any way detract from the role of statin therapy as guideline-recommended first line therapy for preventing cardiovascular events by lowering LDL cholesterol. Instead, the findings suggest a nuanced approach in therapeutic strategies. Beyond a background of well controlled LDL cholesterol levels on statin therapy, individuals with residual inflammatory risk, about one-third of patients, would benefit from this approach.8 As with the PCSK9 inhibitors, however, cost is likely to be a major deterrent to use. The search is on for alternative less costly approaches to targeting residual inflammatory risk.

And, in the Late Breaking News session, Professor Libby discussed recent novel insights from CANTOS. Despite large reductions in hsCRP and IL-6, canakinumab did not reduce the incidence of new onset diabetes over a median period of 3.7 years. It was, however, important to note that patients with prediabetes derived the same benefits from canakinumab in terms of cardiovascular outcomes.9 And in a subsequent analysis, treatment with canakinumab did not impact the known profile progression of estimated glomerular filtration rate or creatinine clearance over time (Data presented at the Scientific Sessions of the American College of Cardiology, Orlando, 2018).

CANTOS has been a landmark study showing that targeting inflammation reduces major cardiovascular events.  It is clear that we are on the cusp on a new era for cardiovascular disease prevention.

References

1. Ference BA, Ginsberg HN, Graham I, Ray KK, Packard CJ, Bruckert E, Hegele RA, Krauss RM, Raal FJ, Schunkert H, Watts GF, Borén J, Fazio S, Horton JD, Masana L, Nicholls SJ, Nordestgaard BG, van de Sluis B, Taskinen MR, Tokgözoglu L, Landmesser U, Laufs U, Wiklund O, Stock JK, Chapman MJ, Catapano AL. Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel. Eur Heart J 2017;38:2459-2472.

2. Libby P. Interleukin-1 beta as a target for atherosclerosis therapy: biological basis of CANTOS and beyond. J Am Coll Cardiol 2017;70:2278-2289.

3. Sabatine MS, Giugliano RP, Keech AC et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med 2017;376:1713-22.

4. ACC News Story. http://www.acc.org/latest-in-cardiology/articles/2018/03/05/15/53/sat-9am-odyssey-outcomes-cv-outcomes-with-alirocumab-after-acs-acc-2018

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

6. Ridker PM, MacFadyen JG, Everett BM, Libby P, Thuren T, Glynn RJ; CANTOS Trial Group. 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;391:319-328.

7. Ridker PM, MacFadyen JG, Thuren T, Everett BM, Libby P, Glynn RJ; CANTOS Trial Group. 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;390:1833-1842.

8. Ridker PM. Canakinumab for residual inflammatory risk. Eur Heart J 2017;38:3545-3548.

9. Everett BM, Donath MY, Pradhan AD, Thuren T, Pais P, Nicolau JC, Glynn RJ, Libby P, Ridker PM. Anti-Inflammatory therapy with canakinumab for the prevention and management of diabetes. J Am Coll Cardiol 2018 doi: 10.1016/j.jacc.2018.03.002. [Epub ahead of print]


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