CRP per se, but about targeting inflammatory pathways more broadly to discern whether such an intervention might have the potential to both treat and prevent cardiovascular disease. 8 We now understand that many of the early distinctions between the lipid hypothesis and the inflammation hypothesis may themselves have been artificial. For example, the recognition that cholesterol crystals can serve as endogenous danger signals that trigger the nucleotide-binding leucine-rich repeatcontaining pyrin receptor 3 inflammasome and the subsequent production of IL-1β provides a direct linkage between cholesterol deposition and arterial inflammation. 9 Moreover, recent Mendelian randomization studies suggest that genetic polymorphisms in the IL-6 receptor signaling pathway concordantly associate with lower lifelong levels of CRP and fibrinogen as well as proportional reductions in cardiovascular event rates. 10, 11 With this hindsight, our decade-old observation that statin therapy lowers low-density lipoprotein-cholesterol and reduces inflammation seems less controversial. 12 Multiple major clinical trials confirm that patients who achieve low levels of inflammation after initiation of statin therapy are protected against recurrent events in a manner analogous to those who achieve low levels of low-density lipoprotein-cholesterol, and that the greatest benefits of statin therapy accrue among those with low levels of both biomarkers. 13 Furthermore, patients with lower CRP in response to statin therapy also seem to be those most likely to have regression of atherosclerosis, presumably a reflection of upstream changes in the inflammatory response that are detected by downstream CRP levels, even if CRP itself has no direct activity. 14–16 Collaborative work by investigators worldwide presently underway could bring the issue of inflammation and vascular disease full circle. To address the inflammatory hypothesis of atherothrombosis directly, the clinical trials community has initiated 2 hard-outcomes studies using pathway approaches that reduce upstream proinflammatory cytokines (such as IL-1, tumor necrosis factor-α, and IL-6) as well as downstream biomarkers (such as CRP and fibrinogen). The first trial, the Canakinumab Anti-inflammatory Thrombosis Outcomes Trial (CANTOS), is almost fully enrolled and addresses whether a human monoclonal antibody with high specificity for IL-1β can reduce recurrent vascular events. 17 The second trial, the National Heart, Lung, and Blood Institute–sponsored Cardiovascular Inflammation Reduction Trial (CIRT), has just begun enrollment and addresses whether low-dose methotrexate, a generic anti-inflammatory drug widely used to treat rheumatoid arthritis, can safely reduce recurrent vascular events. 18 These 2 multinational trials, involving 17 000 patients, represent a major movement beyond the marker versus mediator debate and on to a translational endgame testing whether inflammation inhibition will or will not have a major role in cardiovascular clinical practice.