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Why the CANTOS Is a Game Changer in Cardiovascular Medicine.

On August 27, 2017, in occasion of the European Society of Cardiology congress, the results of the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS) were presented and simultaneously published in the New England Journal of Medicine1 and in the Lancet.2 The results of the CANTOS have been covered by medical news at the time of presentation. I would like to discuss in this article the reasons why the CANTOS trial is a game changer in cardiovascular medicine. First, the CANTOS confirms that patients with previous myocardial infarction (MI) and elevated C-reactive protein (CRP) (greater than 2 mg/L) remain at an unacceptably high risk of major adverse cardiac events.1 This high incidence of events, predicted by previous studies and meta-analyses,3 averaged 4%–5% per year in the placebo cohort. Second, the CANTOS introduces a new drug, canakinumab, that has a unique mechanism of action, hitherto unexplored in any large-scale cardiovascular clinical trial. Canakinumab is a human monoclonal antibody blocking interleukin-1b (IL-1b). First in class of IL-1b antibodies,4 it followed anakinra and rilonacept in the IL-1 blockers, also being explored in phase II cardiovascular clinical trials.5 Canakinumab is currently commercially available as Ilaris and indicated for the use of cryopyrin-associated periodic syndromes, a rare genetic disease.5 In the CANTOS trial,1 canakinumab was tested as an add-on, in one of 3 doses (50, 150, or 300 mg every 3 months) in comparison with placebo. Canakinumab 150 mg every 3 months significantly reduced with an HR of 0.85, the primary end point of cardiac death, nonfatal MI, and nonfatal stroke, largely due to a reduction in MI, in patients with previous MI and residual inflammatory risk, defined as plasma levels of CRP greater than 2 mg/L. Given the uniqueness of the mechanism of action of canakinumab, the effects on CRP despite low-density lipoprotein cholesterol baseline levels close to accepted goals and unchanged with canakinumab treatment, and the lack of other treatments targeting the residual inflammatory risk, canakinumab is the only antiinflammatory drug shown to reduce the risk in patients with cardiovascular disease. Canakinumab offers also the advantage of a subcutaneous injection every 3 months, as compared to the more frequent injections with anakinra or rilonacept. Third, the CANTOS data set is very robust. Although it may appear as 1 single trial, the CANTOS is actually a sort of a combination of 3 separate trials with a common placebo arm: each of the canakinumab dose is indeed compared separately with placebo. It is therefore reassuring to see that a dose response is seen within most if not all end points by which the 50-mg dose appears insufficient, the 150 mg is significantly associated with a benefit, and that for some of the end points, the 300 mg is as well and provides a dosedependent response. It is also very reassuring that for the primary end point and most of the other efficacy end points, both the 150and 300-mg dose groups compared favorably with placebo. Fourth, the benefits of canakinumab in the CANTOS are seen across the various components of the primary end point and the other cardiovascular outcomes. Although the benefits are largely driven by a 24% reduction in recurrent MI, there is also a nonsignificant trend for a 10% reduction in cardiovascular death. The effects on stroke seem less pronounced, which is in line with the different pathogenesis of MI and stroke. It is also encouraging to see a 36% reduction in urgent revascularization and a 37% reduction in cardiac arrest.