New Study Indicates Inflammation Could Be Major Driver of Atherosclerotic Risk


An analysis of the PROMINENT, REDUCE-IT, and STRENGTH trials provides insight into the atherosclerotic cardiovascular risk associated with high-sensitivity C-reactive protein.

Paul Ridker, MD Courtesy: Brigham and Women's Hospital

Paul Ridker, MD
Courtesy: Brigham and Women's Hospital

Data from a collaborative analysis presented on the final day of the American College of Cardiology’s (ACC) 2023 Annual Scientific Session Together with the World Congress of Cardiology may have flown under the radar, could be laying the groundwork for a revolution of atherosclerotic risk assessment.

An analysis of data from the PROMINENT, STRENGTH, and REDUCE-IT trials, results of the study provide new insight into the effects of residual inflammatory risk, which was assessed via high-sensitivity C-reactive protein (hsCRP), was associated with a 30% increase in relative risk of cardiovascular events and a more than doubling in risk of cardiovascular and all-cause mortality in fully adjusted analyses accounting for LDL-C and residual cholesterol risk.

“In this analysis of 31,245 patients receiving contemporary statins, residual inflammatory risk assessed by high-sensitivity CRP was a stronger predictor of risk for future cardiovascular events and death than residual cholesterol risk assessed by LDL-C,” wrote investigators. “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 LDL-C alone is unlikely to completely reduce atherosclerotic risk and that inflammatory pathways have yet to be fully exploited to reduce fatal and non-fatal cardiovascular event rates."

As clinicians have developed a greater understanding of the drivers of atherosclerotic cardiovascular risk, an interest in a more in-depth understanding of the role of inflammation has begun to emerge. With an intent of investigating this role, Paul Ridker, MD, director of the Center for Cardiovascular Disease Prevention at Brigham and Women’s Hospital, designed the current research endeavor with the intent of detailing the relative importance of hsCRP and LDL-C as risk factors for major adverse cardiovascular events (MACE), cardiovascular death, and all-cause death among patients receiving statins.

With this in mind, Ridker and a team of colleagues designed the current study as a collaborative analysis of the PROMINENT, REDUCE-IT, and STRENGTH trials, which provided investigators with data related to 31,245 patients for inclusion in their analyses. For the purpose of analysis, investigators planned to compared quartiles of increasing baseline hsCRP and LDL-C as predictors of MACE, cardiovascular death, and all-cause death, with this risk expressed through hazard ratios (HR) in analysis adjusted for age, gender, BMI, smoking status, blood pressure, previous history of cardiovascular disease, and randomized treatment group assignment.1

Investigators noted the observed ranges for baseline hsCRP and LDL-C as well as their relationship with subsequent cardiovascular event rates were almost identical between the 3 trials.1

Upon analysis, when compared to those in the highest quartile to those in the lowest quartile, results indicated residual inflammatory risk was significantly associated with incident MACE (HR, 1.31 [95% CI, 1.20-1.43]; P <.0001), cardiovascular mortality (HR, 2.68 [95% CI, 2.22-3.23]; P <.0001), and all-cause mortality (HR, 2.42 [95% CI, 2.12-2.77]; P <.0001). When comparing the highest quartile of LDL-C against the lowest quartile of LDL-C, results indicated the relationship of residual cholesterol risk was neutral for MACE and of low magnitude for cardiovascular death (HR, 1.27 [95% CI, 1.07-1.50]; P=.0086) and all-cause mortality (HR, 1.16 [95% CI, 1.03-1.32]; P=.025).1

Investigators noted multiple limitations that inhibit the overall generalizability of their study results. These included a lack of evidence in any of the trials that selection of patients with intermediate elevation of triglycerides altered the underlying distribution of hsCRP or LDL-C, interpretation of previous evidence being restricted by an inability to ensure that all participants received guideline-directed medical care, and a lack of evidence of effect modification by any of the interventions tested in the trials.

“As shown in these contemporary data from 31,245 patients already taking statin therapy, residual inflammatory risk appears to be more strongly associated with future cardiovascular events than residual cholesterol risk,” investigators added.1 “Our findings have clinical and research implications.”


  1. Ridker PM, Bhatt DL, Pradhan AD, Glynn RJ, MacFadyen JG, Nissen SE. Inflammation and cholesterol as predictors of cardiovascular events among patients receiving statin therapy: A collaborative analysis of three randomised trials. The Lancet. 2023. doi:10.1016/s0140-6736(23)00215-5
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