Key Points:
- Both inflammatory risk and hyperlipidemia and crucial risk factors for MACE in patients at high risk of CVD.
- In a large collaborative study of patients combining data from the PROMINENT (N = 9,988), REDUCE-IT (N = 8,179) and STRENGTH (N = 13,078) trials, the effect of residual inflammatory risk (as measured by hsCRP) and LDL-C levels on MACE were assessed.
- Residual inflammatory risk as assessed by hsCRP was a stronger determinant of risk for future cardiovascular events and death than residual cholesterol risk as assessed by LDL-C.
Inflammation is a critical component of cardiometabolic risk. Among statin-users, randomized trial data demonstrate that adjunctive LDL-lowering therapy and adjunctive inflammation inhibition further reduce risk, but it is unclear whether clinicians should choose a second LDL-lowering agent for those already treated with a statin or alternatively choose an anti-inflammatory agent. In a breaking presentation at the 2023 ACC Conference today, Dr. Paul Ridker (Brigham and Women’s) and his team presented their study: “Relative Importance of Inflammation and Cholesterol as Determinants of Residual Cardiovascular Risk among 31,245 Contemporary Statin Treated Patients.”
The authors undertook a collaborative analysis of patients with—or at high risk of—atherosclerotic disease, including participants in the multinational PROMINENT REDUCE-IT, or STRENGTH trials. This study was designed to assess the relationships of hsCRP (a biomarker for residual inflammatory risk) and LDL-C with the incidence of MACE, CV mortality, and all-cause mortality among 31,245 statin-treated patients with or at high risk for future atherosclerotic disease. Statin treated participants in PROMINENT (N = 9,988), REDUCE-IT (N = 8,179) and STRENGTH (N = 13,078) were included. All analyses were adjusted for age, gender, BMI, smoking, blood pressure, history of CVD, and randomized treatment assignment. The primary endpoints included incident MACE, CV mortality, and all-cause mortality during trial follow-up (3 to 5 years).
In total 31,245 patients were analyzed; the average age was 64, and approximately 30% were women. The average BMI was 32. In primary analysis, both hsCRP (aHR 1.31, p < 0.0001) and LDL-C (aHR 1.07, p < 0.05) were related to incident MACE. When evaluated by quartile, hsCRP quartiles 3 and 4 (representative of high residual inflammatory risk) were both associated with incident MACE (aHR 1.17, 95% CI 1.07-1.28, p=0.001 for quartile 3 and aHR 1.31, 95% CI 1.20-1.43, p < 0.0001 for quartile 4), but no quartile of LDL-C had a significant association. hsCRP Quartiles 2-4 and LDL-C quartile 4 were associated with increased all-cause mortality and CV mortality, separately. On interaction analysis, hsCRP > 2mg/L was significantly associated with increased MACE regardless of LDL-C value (p < 0.0001 for both), but there was no significant association when hsCRP was <2mg/L regardless of LDL-C category.
When discussing the clinical implications of the study at ACC, Dr. Ridker stated: “Among contemporary statin-treated patients, residual inflammatory risk as assessed by hsCRP was a stronger determinant of risk for future cardiovascular events and death than residual cholesterol risk as assessed by LDL-C… in all three trials, individuals with elevated hsCRP were at high cardiovascular risk irrespective of LDL-C level… 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.”
