Inflammation is a stronger predictor for risk of future cardiovascular events and death than cholesterol levels, according to a collaborative analysis of three randomized trials.
Findings gathered from more than 30,000 patients revealed that those with elevated high-sensitivity C-reactive protein (hsCRP) as a measure of residual inflammatory risk were at higher cardiovascular risk, irrespective of residual cholesterol risk as assessed by low density lipoprotein cholesterol (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,” said Featured Clinical Research session presenter and study author Paul M. Ridker, MD, Said during his presentation at the American College of Cardiology (ACC) Annual Scientific Session 2023 in New Orleans, “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.”
Ridker and colleagues conducted a collaborative analysis of patients with—or at high risk of—atherosclerotic disease.
The 31,245 patients were receiving contemporary statins and were participants in the multinational trials, PROMINENT (n=9,988), sponsored by Kowa; REDUCE-IT (n=8,179), sponsored by Amarin; or STRENGTH (n=13,078), sponsored by AstraZeneca.
Those taking part were between 63-64 years of age, 28% to 35% were female, and they had Type 2 Diabetes (100%, 58%, 70%) in each respective trial.
The endpoints for the trials included incidence of future major adverse cardiovascular events (MACE), cardiovascular mortality, and all-cause mortality during trial follow-up (3-5 years).
Calculation and methodology
Analysts in each trial calculated adjusted hazard ratios (HRs) in proportional hazard models addressing endpoint risk across increasing trial-specific hsCRP and LDL-C. quartiles.
All analyses were adjusted for age, gender, body mass index, smoking, blood pressure, history of cardiovascular disease (CVD), and randomized treatment assignment.
Analysts then performed a fixed-effects meta-analysis of hsCRP and LDL-C as determinants for each endpoint in which weighted quartile-specific HRs across the trials were pooled.
This was achieved by using the inverse variance of each trial-specific estimated log- hazard ratio, thus allowing for a single set of fully adjusted summary risk estimates.
In sensitivity analyses, risk estimates were also computed in stratum defined by each trial’s randomized treatment assignment, and in interaction analyses across clinical thresholds in wide use for both hsCRP and LDL-C.
Similar findings in each trial
Findings revealed that observed ranges for baseline hsCRP and LDL-C, and the relationships of each biomarker to subsequent cardiovascular event rates, were almost identical in the three trials.
Residual inflammatory risk was significantly associated with incident MACE (highest hsCRP quartile vs lowest hsCRP quartile, adjusted HR: 1.31; 95% confidence interval [CI]: 1.20–1.43; p<0.0001), cardiovascular mortality (adjusted HR: 2.68; 95% CI: 2.22–3.23; p<0.0001), and all-cause mortality (adjusted HR: 2.42; 95% CI: 2.12–2.77; p<0.0001).
By contrast, the relationship of residual cholesterol risk was neutral for MACE (highest LDL-C quartile vs lowest LDL-C quartile, adjusted HR: 1.07; 95% CI: 0.98–1.17; p=0.11).
This was, however, a case for the relationship of low magnitude for cardiovascular death (adjusted HR: 1.27; 95% CI: 1.07–1.50; p=0.0086) and all-cause death (adjusted HR: 1.16; 95% CI: 1.03–1.32; p=0.025).
Implications for future practice
“These data have implications for the selection of adjunctive treatments beyond statin therapy and suggest that combined use of aggressive lipid-lowering and inflammation-inhibiting therapies might be needed to further reduce atherosclerotic risk,” concluded the study, which was also simultaneously published online in The Lancet.
Discussing the implications of these results for practice, Ridker asked whether, following statin therapy, clinicians should elect to use a second lipid-lowering agent or an anti-inflammatory agent.
Suggestions he put forward include the use of colchicine 0.5 mg by mouth every day for those with stable atherosclerosis and normal estimated glomerular filtration rate (eGFR).
Similar to statin therapy, bempedoic acid could be considered, as it also reduces both LDL-C and hsCRP.
He also proposed the use of GLP1r agonists and SGLT2 inhibitors, as they have concomitant anti-inflammatory effects.
“It is not an either/or situation,” said Ridker, who is director for the Center for Cardiovascular Disease Prevention at Brigham and Women's Hospital in Boston.
“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,” he said.
“These data strongly support ongoing ACC/AHA [American Heart Association] efforts directed at diet, weight loss, exercise, and smoking cessation, all of which lower vascular inflammation and lower cardiovascular event rates.”
Ridker PM, Bhatt DL, Pradhan AD, et al. Inflammation and cholesterol as predictors of cardiovascular events among patients receiving statin therapy: a collaborative analysis of three randomised trials. Lancet. 2023 03 Mar 6 (Article in press).