The Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS) study continues to shed new light on the link between inflammation and atherosclerosis. Here, Trial Chairman Paul Ridker MD, talks to Cardio Debate about the latest results from the CANTOS trial that were presented at the ESC2018.

CANTOS One-Year Later

In the year that has passed since the formal presentation of CANTOS (the Canakinumab Anti-inflammatory Thrombosis Outcomes Study) we have seen a rapid-change in our understanding of atherosclerosis not only as a disorder of cholesterol accumulation, but also as a disorder of innate immune function.

CANTOS has definitively proven that targeted anti-inflammatory therapy – at least with interleukin-1b inhibition – can significantly lower rates of heart attack and cardiovascular death in the absence of any effects on lipids or blood pressure. [1] Perhaps equally important, the magnitude of clinical benefit associated with canakinumab use appears to be related in large part to the magnitude of reduction observed in hsCRP; for example, those who achieved levels of hsCRP below 2 mg/L after a single dose of canakinumab enjoyed a 31 percent reduction in cardiovascular as well as all-cause mortality with continued therapy. [2] CANTOS has thus opened the floodgates for research into novel anti-inflammatory approaches to atherosclerosis.

A critical question coming out of CANTOS is what the appropriate target for treatment is. By selectively blocking IL-1b, canakinumab also lowers IL-6. In our most recent analysis presented at the ESC in Munich, we reported that the benefits of therapy also directly related to the magnitude of IL-6 reduction after a single dose of canakinumab. [3] Moreover, this effect was minimally attenuated not only after multi-variable adjustment for all known determinants of IL-6 levels, but even after a sophisticated causal inference analysis. This provides considerable evidence that the benefits of IL-6 lowering are due to drug effects and not to participant characteristics.

Why are the new data important? Clearly targeting IL-1b works. The next steps might include going one step-upstream to target the NLRP3 inflammasome, but that is a technical challenge several years away. On the other hand, there are already multiple IL-6 inhibitors approved for clinical use to treat disorders such as rheumatoid arthritis and other immune conditions. Such agents might well have cardiovascular benefits, and thus treatment trials of these agents are needed.

In the meantime, clinicians must incorporate the idea of “residual inflammatory risk” into practice. We know that patients with elevated hsCRP are at high risk even if LDL levels are low, and we now know that targeting this residual inflammatory risk can reduce event rates. Yet if we don’t measure hsCRP, we simply cannot know what the underlying biology driving risk is in individual patients. So the time to move beyond simple lipid biomarkers has clearly come.

References

1. Ridker PM, Everett B, Thuren T, Macfadyen JG, Chang WH, Ballantyne C, Fonseca F, Nicolau J, Koenig W, Anker SD, Kastelein JJP, Cornel JH, Pais P, Pella D, Genest J, Cifkova A, Lorenzatti A, Forster T, Kobalava Z, Vida-Smith L, Flather M, Shimokowa H, Ogawa H, Dellborg M, Rossi PRF, Troquay RPT, Libby P, Glynn RJ for the CANTOS Trial Group. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med 2017;377:1119-1131.
2. Ridker PM, MacFadyen JG, Everett BM, Libby P, Thuren T, Glynn RJ on behalf of the CANTOS Trial Group. Relationship of C-reactive protein reduction to cardiovascular event reduction following treatment with canakinumab: a secondary analysis from the CANTOS randomized controlled trial. Lancet 2018;391:319-28.
3. Ridker PM, Libby P, MacFadyen JG, Thuren T, Ballantyne C, Fonseca F, Koenig W, Shimokawa H, Everett BM, Glynn RJ on behalf of the CANTOS Trial Group. Relationships of interleukin-6 reduction to atherosclerotic events and all-cause mortality: analyses from the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS). Eur Heart J 2018 (published online August 2018)