Relative Importance of Inflammation and Cholesterol as Determinants of Residual Cardiovascular Risk Among 31,245 Contemporary Statin Treated Patients

Presented at the ACC.23 by: Paul M. Ridker, MD - Boston, MA, USA

Introduction and methods

In patients with atherosclerotic disease—or who are at high risk thereof—who are taking statin therapy, adjunctive lipid-lowering and anti-inflammatory treatment can reduce the risk of CV events. However, it is uncertain what the relative importance is of cholesterol compared to inflammation as determinants for residual CV risk in patients on statins.

The relative importance of hs-CRP (clinical biomarker of residual inflammatory risk) and LDL-c (clinical biomarker of residual cholesterol risk) as predictors for adverse clinical outcomes in statin-treated patients was evaluated in a collaborative analysis of data from the recent multinational PROMINENT (n=9988), REDUCE-IT (n=8179), and STRENGTH (n=13,078) trials. Each of these RCTs enrolled patients with moderately elevated triglyceride levels who required primary or secondary prevention of CV events and who were treated with statins. The endpoints of this analysis were MACE, CV death, and all-cause mortality during trial follow-up (3 to 5 years).

Main results

• Patients with hs-CRP levels in the 3rd and 4th quartile had an increased risk of MACE compared to patients in the lowest quartile (adjusted HR for 3rd quartile vs. lowest hs-CRP quartile: 1.17, 95%CI 1.07-1.28, P=0.001; adjusted HR for 4th quartile vs. lowest hs-CRP quartile: 1.31, 95%CI 1.20-1.43, P<0.0001). In contrast, there were no significant differences between any of the LDL-c quartiles for the risk of MACE.
• hs-CRP was a powerful predictor of CV death. Patients in the 2nd, 3rd and 4th quartile of hs-CRP had a significantly higher risk of CV death compared to patients in the lowest quartile (2nd vs. lowest quartile: adjusted HR 1.34, 95%CI 1.09-1.64, P=0.008; 3rd vs. lowest quartile: adjusted HR 1.68, 95%CI 1.38-2.04, P<0.0001; 4th vs. lowest quartile: adjusted HR 2.68, 95%CI 2.22-3.23, P<0.0001). Only the highest quartile of LDL-c was associated with increased CV death compared to the lowest LDL-c quartile (adjusted HR 1.27, 95%CI 1.07-1.50, P=0.009).
• Similar to CV death, the risk of all-cause mortality was significantly increased in patients in the 2nd, 3rd and 4th quartile of hs-CRP, compared to patients in the lowest hs-CRP quartile (2nd vs. lowest quartile: adjusted HR 1.34, 95%CI 1.16-1.55, P=0.0001; 3rd vs. lowest quartile: adjusted HR 1.59, 95%CI 1.38-1.83, P<0.0001; 4th vs. lowest quartile: adjusted HR 2.42, 95%CI 2.12-2.77, P<0.0001). Again, only the highest quartile of LDL-c was associated with increased all-cause death compared to the lowest LDL-c quartile (adjusted HR 1.16, 95%CI 1.03-1.32, P=0.025).
• In all 3 trials, more than half of the participants had an hs-CRP level ≥2 mg/L. Interaction analyses showed an increased risk of CV death for patients with hs-CRP ≥2 mg/L, irrespective of their LDL-c being above or below 70 mg/dL (both P<0.0001). In contrast, patients with hs-CRP<2 mg/L but LDL-c ≥70mg/dL had no increased risk of CV death compared to patients with hs-CRP <2 mg/dL and LDL-c <70 mg/dL.

Conclusion

A collaborative analysis of the PROMINENT, REDUCE-IT, and STRENGTH trials (n=31,245) showed that residual inflammatory risk (as assessed by hs-CRP) was a better predictor of future MACE, CV death, and all-cause mortality than residual cholesterol risk (as assessed by LDL-c) in statin-treated patients. Those with an elevated hs-CRP level were at high risk of CV death, irrespective of their LDL-c level.

Prof Ridker stressed that “While these data must not be construed to diminish the proven and crucial role of adjunctive lipid-lowering for those with persistent or refractory hypercholesterolemia, they do suggest that targeting of LDL-c alone is unlikely to completely reduce atherosclerotic risk and that inflammatory pathways have yet to be fully exploited to reduce fatal and nonfatal CV events.” He further stated that “In the future, we believe the combined use of aggressive LDL-lowering and inflammation inhibiting therapies will become standard of care for almost all atherosclerotic patients.”

-Our reporting is based on the information provided at the ACC.23-

The results of this study were simultaneously published in The Lancet. Watch a video by Prof. Ridker on this analysis