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Residual Inflammation in Statin-treated Patients Linked to Greater Risk for MACE, Mortality vs Residual Cholesterol


Residual inflammatory risk was a significantly stronger predictor of cardiovascular (CV) events and CV- and all-cause mortality than residual risk from low density lipoprotein cholesterol (LDL-C) levels among more than 31 000 patients either with or at high risk for atherosclerotic cardiovascular disease (ASCVD) and receiving contemporary statin therapy.

The findings, presented at the 2023 American College of Cardiology’s (ACC) Annual Scientific Session and published simultaneously in The Lancet, come from a meta-analysis conducted by resarchers at Brigham and Women's Hospital's (BWH), of 3 pivotal multinational trials--PROMINENT, REDUCE-IT, and STRENGTH.

Among the specific results, at 3 to 5 years among patients receiving guideline-directed statin therapy, the risks of CV death and all-cause mortality were more than 2 times as high among participants in the highest quartile of inflammation marker high sensitivity C-reactive protein (hsCRP) compared to those with the highest levels of LDL-C.

The prescribing environment

In persons not receiving treatment, vascular inflammation and hyperlipidemia contribute equally to atherothrombotic risk, write the authors in The Lancet. Most patients at high risk of atherosclerosis treated in contemporary cardiovascular settings are receiving statin therapy, they add, and so the relative contribution of the 2 biomarkers in determining residual CV risk could have shifted.

Adjunctive non-statin therapies (eg, PCSK9 inhibitors, ezetimibe, inclisiran, and bempedoic acid) effectively reduce relative risk of CV events in statin-treated patients and targeted antiinflammatory agents have also proven beneficial, with generic colchicine most recently demonstrating substantial risk reduction at a low cost. The uncertain—and also controversial—question still open, according to these investigators, is whether adding a second lipid lowering therapy or prescribing an antiinflammatory agent is advisable. The aim of their analysis was to evaluate the relative importance of residual inflammatory risk (hsCRP) and residual cholesterol risk as determinants for major adverse cardiovascular events (MACE), cardiovascular and all-cause mortality among patients receiving statins.

3-trial analysis

Data for the collaborative analysis were drawn from PROMINENT (n=9988), REDUCE-IT (n=8179), and STRENGTH (n=13 078) multinational trials assessing clinical outcomes of triglyceride-lowering therapy in statin-treated individuals. Investigators assessed quartiles of increasing baseline hsCRP and baseline LDLC as predictors of future major adverse cardiovascular events, cardiovascular death, and all-cause death. Analyses were adjusted for age, gender, BMI, smoking status, blood pressure, previous history of cardiovascular disease, and original randomized treatment group assignment.

The final pooled cohort numbered 31 245, had a mean age of 64 years, was approximately 30% women, and the majority of participants were White, according to the study. At enrollment, median LDL -C level was 76 mg/dL and triglyceride level 240 mg/dL. Median hsCRP was approximately 2.1 mg/L.

Approximately half of the pooled cohort was receiving high-intensity statin therapy at baseline and approximately two-thirds qualified as secondary prevention participants. The majority of participant’s clinical characteristics across the 3 trials were similar, the authors report.


The BWH team found that the ranges for baseline hsCRP and LDL-C were “almost identical;” across the 3 trials. Likewise, the relationships of each biomarker with subsequent CV event rates were nearly the same. CV event rates in the 3 trials approached 10% at 5 years.

The investigators report a significant association between residual inflammatory risk and incident MACE (highest vs lowest hsCRP quartile, adjusted HR [aHR]1.31, 95% CI 1.20–1.43; P<.001), CV mortality (aHR 2.68, 95% CI 2.22–3.23; P<.001), and all-cause mortality (aHR 2.42, 95% CI 2.12–2.77; P<.001).

In significant contrast to these findings, the research team found the relationship of residual cholesterol risk neutral for MACE (highest vs lowest LDL-C quartile, aHR 1.07, 95% CI 0.98–1.17; P=.11), and of low magnitude for CV death (aHR 1.27, 1.07–1.50; P=.0086) and all-cause death (aHR 1.16, 1.03–1.32; P=.025). They report no significant heterogeneity between trials.

“There is no doubt that lower is better for LDL-cholesterol and we need to aggressively reduce cholesterol whenever possible,” said corresponding author and BWH preventive cardiologist Paul Ridker, MD, in a BWH statement. “But if cardiologists want to eliminate cardiovascular disease, they clearly must target inflammation as well.”

The authors write in conclusion, “Although the current data must not be construed to diminish the crucial role of adjunctive lipid lowering beyond statins for patients with persistent or refractory hypercholesterolemia, they do suggest that targeting LDLC alone is unlikely to completely reduce atherosclerotic risk.” They add that known inflammatory pathways remain only partially exploited to reduce the rates of both fatal and non-fatal CV events.

“We believe that combined use of aggressive lipid-lowering and anti-inflammatory therapies might become standard of care for atherosclerotic disease in the future.”

Reference: Ridker PM, Bhatt DL, Pradhan AD, et al on behalf of the PROMINENT, REDUCE-IT, and STRENGTH Investigators. Inflammation and cholesterol as predictors of cardiovascular events among patients receiving statin therapy: a collaborative analysis of three randomised trials. The Lancet. Published online March 6, 2023. doi:10.1016/S0140-6736(23)00215-5

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