Inflammation strong predictor of recurrent CV events in CKD

Residual inflammation is a strong predictor of recurrent cardiovascular (CV) events than hyperlipidaemia in patients with atherosclerotic disease and impaired kidney function in a sub-study of the CANTOS* trial.

“Hyperlipidaemia and inflammation jointly contribute to atherosclerotic disease,” said lead investigator Dr Paul Ridker, director of the Center for Cardiovascular Disease Prevention at Brigham and Women’s Hospital in Boston, Massachusetts, US, at ACC.22. “Both are targets of pharmacologic therapy and lifestyle intervention. They both need to be addressed to get the greatest benefits for our patients.”

“Yet, the relative contributions of these processes may differ in important ways between various patient groups, particularly those with and without kidney dysfunction, a group with a very high risk for atherosclerotic events and substantial unmet clinical need,” he continued.

Findings from the randomized, double-blind, placebo-controlled CANTOS trial were reported years ago. Results showed that treatment with canakinumab, a monoclonal antibody that blocks an inflammatory pathway mediated by IL-1β, significantly reduced major CV events vs placebo in adults with a history of myocardial infarction (MI) and an elevated high sensitivity C-reactive protein (hsCRP) who were already on guideline-directed lipid-lowering therapy. [N Engl J Med 2017; 377:1119-1131]

“CANTOS served as a proof of principle that lowering inflammation lowered CV rates,” said Ridker. “But the question is: how important is residual inflammatory risk compared with residual cholesterol risk?”

Inflammation vs cholesterol

The CANTOS sub-study, presented at ACC.22, assessed the influence of residual inflammation vs residual cholesterol by measuring hsCRP and interleukin 6 (IL-6) – both inflammatory markers –  and LDL- cholesterol (LDL-C) and non-HDL cholesterol (non-HDL-C) in the entire cohort of roughly 10,000 patients with atherosclerosis, with or without CKD, included in the original CANTOS trial. What Ridker and team wanted to find out was how all these biomarkers predict the risk of future major adverse CV events (MACE), CV death, or all cause-mortality when stratified by estimated glomerular filtration rate (eGFR; preserved or impaired).

“The bottom line is among individuals with preserved kidney function, hsCRP, IL-6, LDL-C and non-HDL-C were strong predictors of recurrent CV events (p _trend <0.0001 for all),” reported Ridker.

“What’s interesting is that in this large population of patients aggressively treated with statins whose LDL-C was already reduced … in those with low kidney function, IL-6 and hsCRP remained very powerful predictors of future CV risk, but not LDL-C and non-HDL-C,” he continued. “These findings have both scientific and clinical implications.”

Additionally, in those with impaired kidney function, those in the highest quartile of hsCRP were four times more likely to die of CV causes vs those with preserved kidney function and low hsCRP levels (hazard ratio [HR, 4.08). Results were similar for all-cause mortality (HR, 4.06).

What this means for CKD patients

“The implication is that there is something unique about these CKD patients,” Ridker explained. “This apparent differential effect of inflammation predicting risk in CKD, compared with lipid, was particularly potent for CV mortality, and for all-cause mortality such that, in fact, those with elevated CRP or IL-6 had greatly increased rates of all-cause mortality in the setting of CKD.”

The next step after statins

From Ridker’s perspective, the finding was quite straightforward. “We want to lower lipids aggressively in all our patients, those with and without CKD. In CANTOS, patients are getting a high-intensity statin. But after statins, what’s the next step?”

“Our data suggest that residual inflammatory risk, in other words, the CRP and IL-6 have not been addressed and could be a very important target for future therapy in the setting of CKD,” he pointed out. “What patients need past their high-intensity statin may not be another lipid-lowering agent. They may need something that targets inflammation.”

What these data are telling us, according to Ridker, is that patients with CKD and atherosclerosis have a substantial residual risk, based in part on this inflammatory process.

“Nevertheless, if I’m going to pick a second drug, having given these patients a high-intensity statin, I may be more concerned about inflammation than I am about lipids, necessarily.” This, he added, is the subject of the new trial ZEUS.

“The CANTOS trial, broadly, has already changed the practice of medicine in a very dramatic way. In ZEUS, what we will try to find out is whether a novel interleukin-6 inhibitor, one step downstream from the interleukin-1 inhibitor that we used in CANTOS, could deliver CV event reduction in patients with CKD, atherosclerosis, and elevated CRP,” Ridker said, in parting. With reports from TRISTAN MANALAC