N Engl J Med 2017;377:1119-1131Background The hypothesis tested in the CANTOS Trial reflected an emerging view of atherosclerosis development and progression - that it was not simply a matter of plasma cholesterol but also systemic inflammation. In the manuscript’s introduction the authors cite data on the independent association of certain inflammatory markers with an increased risk of cardiovascular events independent of lipid levels. For an anecdote that I suspect many cardiologists and general practitioners will relate to, I am involved with managing many younger women (<65 years of age) who lack “traditional” cardiovascular risk factors but have atherosclerotic CVD which typically presents as an ACS event. The thread that ties these women together is their history of a systemic inflammatory disorder like rheumatoid arthritis or inflammatory bowel disease. Since the publication of CANTOS and other trials, the relationship between systemic inflammatory disease and CVD has gained broader recognition but remains underrecognized. For a very general overview of this topic I would direct readers to the following link, which is free to read: Cardio-Rheumatology: Prevention of Cardiovascular Disease in Inflammatory Disorders - PubMed (nih.gov) The Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS) tested the hypothesis that Canakinumab, which is a fully human monoclonal antibody targeting interleukin-1 beta would reduce recurrent cardiovascular events in patients with a history of MI and persistent proinflammatory response.Patients Eligible patients had a history of MI and a hs-CRP level >/= 2 mg/L despite use of aggressive secondary prevention strategies. The trial sought to enroll stable patients and thus, broad exclusion criteria were applied which included any patient with a history of recurrent infection or with any condition that could render a patient immunocompromised, such as ongoing use of other systemic inflammatory treatments. Thus, it should be appreciated that patients with severe systemic inflammation were excluded.Cardiology Trial’s Substack is a reader-supported publication. To receive new posts and support our work, consider becoming a free or paid subscriber.Baseline characteristics There were 17,482 patients with a previous MI who underwent screening in the central laboratory and 10,061 (57.6%) were randomized. Among these patients, the most common exclusions were due to hs-CRP <2 mg/L (46%), active tuberculosis or tuberculosis risk factors (25%) and exclusionary concomitant disorders (10%). The mean age of participants was 61 years, 26% were women and 41% had diabetes. Nearly all patients were taking antithrombotic agents and lipid lowering agents. The median hs-CRP was 4.2 mg/L and the median LDL was 82 mg/dL. Procedures Patients were randomized 1.5:1:1:1 to receive placebo, canakinumab 50mg, canakinumab 150 mg or canakinumab 300 mg. All doses of canakinumab and placebo were administered subcutaneously once every 3 months; however, for the 300 mg canakinumab dose, the regimen was 300 mg every 2 weeks for the first 2 doses and then once every 3 months thereafter. Randomization was stratified by time from index MI.Endpoints The primary efficacy endpoint was a composite endpoint that included time to first occurrence of cardiovascular death, nonfatal MI or nonfatal stroke in a time-to-event analysis. Secondary endpoints included individual components of the primary endpoint as well as others. Endpoint adjudication was done by a committee blinded to treatment assignment. The trial was designed to have 90% power to detect a 20% lower event rate in the primary endpoint for at least 1 of the 3 doses of canakinumab compared to placebo. It was estimated that 17,200 patients would need to be enrolled in order to accrue 1,400 events over a 5 year period. While the trial was ongoing, at the request of the sponsor, the sample size was reduced to 10,000 and follow up was extended by 1 year in an effort to sti