April 11, 2022
3 min read
Ridker PM, et al. Featured Clinical Research III. Presented at: American College of Cardiology Scientific Session; April 2-4, 2022; Washington, DC (hybrid meeting).
Novartis funded the CANTOS trial. Ridker reports receiving grants from Kowa, Novartis and Pfizer, personal fees from AstraZeneca, CSL-Behring, Eisai, Janssen, Novartis, Sanofi and Teva and has patents with royalties paid to AstraZeneca and Siemens.
WASHINGTON — Among adults with atherosclerotic CVD and impaired kidney function, residual inflammation is a stronger predictor of recurrent CV events than hyperlipidemia, particularly for CV and all-cause mortality, researchers reported.
New data from a secondary analysis of the CANTOS trial may have clinical implications for the CV risk stratification of people with chronic kidney disease and for the development of novel agents that target inflammatory processes in this high-risk group of patients, according to Paul M. Ridker, MD, MPH, director of the Center for Cardiovascular Disease Prevention at Brigham and Women’s Hospital and Eugene Braunwald Professor of Medicine at Harvard Medical School.
“Hyperlipidemia and inflammation jointly contribute to atherosclerotic disease, and both have proven to be effective targets for pharmacologic therapy and lifestyle intervention,” Ridker said during a featured clinical research presentation at the American College of Cardiology Scientific Session. “Yet, within this constant, the relative contributions of these processes may differ in important ways between various patient groups, in particular those with and without kidney dysfunction, a group with very high risk for atherosclerotic events and substantial unmet clinical need.”
Impact of inflammation, hyperlipidemia
Paul M. Ridker, MD, MPH
In the CANTOS trial, Ridker and colleagues analyzed data from 9,151 adults with a history of MI and an elevated high-sensitivity C-reactive protein already treated with guideline-directed lipid lowering therapy (baseline LDL, 82 mg/dL) who were assigned canakinumab (Novartis) or placebo.
For the new analyses, researchers compared the relative contributions of residual cholesterol risk, as measured by LDL and non-HDL, and residual inflammatory risk, as measured by hsCRP and interleukin-6, as determinants of recurrent major adverse CV events, CV death or all-cause mortality. Results were stratified by baseline estimated glomerular filtration rate (eGFR) above or below 60 mL/min/1.73m2. Participants were followed for up to 5 years.
As anticipated, among CANTOS participants with stable kidney function (n = 7,949), increasing quartiles of plasma hsCRP, interleukin-6, LDL and non-HDL all positively associated with risks for recurrent major adverse CV events (P for trend for all < .0001).
For participants with impaired kidney function (n = 1,192), researchers observed increasing quartiles of hsCRP and interleukin-6 significantly predicted recurrent major adverse CV events, whereas increasing LDL and non-HDL did not. Compared with participants in the lowest quartile, HRs for those in the highest quartile were 1.51 for hsCRP (P= .006) and 1.75 for interleukin-6 (P= .018). Increasing quartiles of LDL (P for trend = .72) and non-HDL (P for trend = .96) were not predictors of recurrent CV events. Results persisted after adjustment for a wide range of potential confounding factors, including randomized treatment assignment, Ridker said.
“Quite interestingly, we do not have similar evidence for LDL and non-HDL,” Ridker said. “I want to be very clear … I aggressively lower the lipids in my CKD patients. They are already prescribed a statin. The question is, what do we do next? The data is suggesting that there may be some difference here in terms of what is driving the recurrent events, at least in our CKD population.”
Link between inflammation and death
Findings in the subgroup with impaired kidney function were “particularly striking” for the additional endpoints of CV death and all-cause mortality, Ridker said. For these patients, those in the highest quartile of hsCRP were four times more to die of CV causes compared with those with preserved kidney function and low hsCRP levels (HR = 4.08; 95% CI, 3.21-5.19).
“A somewhat surprising finding was that LDL cholesterol did not give us incremental information above and beyond what we already knew with the eGFR and understanding these patients are already on high-intensity statins,” Ridker said.
Results were similar for all-cause mortality, with an HR of 4.06 for adults with impaired kidney function in the highest quartile of hsCRP compared with participants with preserved kidney function and low inflammation levels (95% CI, 3.36-4.9).
“The same theme is there in an even more aggressive way,” Ridker said.
Ridker said the data show that residual inflammatory risk plays a substantial role in determining the risk for recurrent CV events among patients with ASCVD and impaired kidney function.
Ridker said the findings also provide strong rationale for the ongoing ZEUS randomized controlled trial of ziltivekimab (Novo Nordisk), a novel interleukin-6 ligand monoclonal antibody being tested to lower CV event rates in the setting of stage 3 and 4 CKD and ASCVD. ace Healio previously reportedthe magnitude of change with ziltivekimab on hsCRP was nearly twice as large in the RESCUE trial as that observed in CANTOS.