Antiinflammatory Therapy in Clinical Care: The CANTOS Trial and Beyond

Abstract

Inflammation is a critical pathway in the pathogenesis of atherosclerosis. Previous studies have shown that plasma levels of high-sensitivity C-reactive protein (hsCRP), a marker of inflammation, are associated with cardiovascular disease independent of traditional risk factors. Randomized trial data have also shown that statins reduce not only hsCRP but also cardiovascular event rates independent of their effect on low-density lipoprotein cholesterol (LDL-C) level. More recently, the CANTOS trial showed that directly reducing inflammation with canakinumab, an interleukin (IL)-1β neutralizing monoclonal antibody, could also reduce cardiovascular event rates. These mark the first phase 3 trial results validating inflammation as a viable target for preventing cardiovascular disease. In this review, we recap the role of inflammation in cardiovascular disease and highlight previous trial data showing its modulation with statins and other agents. We also detail the CANTOS trial results and discuss its implications for clinicians as well as future directions for anti-inflammatory therapy in the prevention of cardiovascular disease.

Keywords: atherosclerosis; canakinumab; prevention; randomized trials; vascular inflammation.

Figure 1

Effects of canakinumab on hsCRP, IL-6, and LDL-C in CANTOS.Ridker (34).

Figure 2

Cumulative endpoints for individuals receiving 150 or 300 mg subcutaneous canakinumab every 3 months vs. placebo in CANTOS. (Left) Primary endpoint of myocardial infarction, stroke, or cardiovascular death (MACE). (Right) Secondary endpoint additional including hospitalization for unstable angina requiring urgent revascularization (MACE-plus). HR, hazard ratio; CI, confidence interval; SC, subcutaneous. Ridker et al. (35).

Figure 3

Cumulative incidence and hazard ratios of cardiovascular mortality (Left) and all-cause mortality (Right) among CANTOS participants allocated to either placebo or canakinumab according to whether post-randomization on-treatment hsCRP levels were above or below 2 mg/L. Hazard ratios are adjusted for age, sex, smoking status, hypertension, diabetes, body mass index, baseline concentration of hsCRP, and baseline concentration of LDL-C. HR, hazard ratio; CI, confidence interval. Ridker (37).

Figure 4

Cumulative incidence of fatal lung cancer among CANTOS participants. HR, hazard ratio; CI, confidence interval. Ridker et al. (38).