Inflammation better CV risk predictor than LDL in patients intolerant to statins: CLEAR Outcomes analysis

"Inflammation assessed by high-sensitivity C-reactive protein (hs-CRP) predicted risk for future CV events and death more strongly than hyperlipidemia assessed by low-density lipoprotein cholesterol (LDLC)," the researchers reported in Circulation. "Bempedoic acid had similar efficacy compared with placebo for reducing CV risk across hsCRP and LDLC strata."

Previous studies have shown that among patients treated with statin therapy to guideline-recommended cholesterol levels, residual inflammatory risk assessed by hsCRP is at least as strong a predictor for future CV events as is residual risk assessed by LDLC. There is no clarity on whether these relationships are present among statin-intolerant patients with higher LDLC levels but they have implications for the choice of preventive therapies, including bempedoic acid, an agent that reduces both hs-CRP and LDLC.

Paul M. Ridker, Brigham and Women's Hospital, Boston, MA, and colleagues analyzed multinational CLEAR Outcomes, an ACL-Inhibiting Regimen Outcomes Trial. In the trial, 13970 statin-intolerant patients were randomly allocated to 180 mg of oral bempedoic acid daily or a matching placebo and followed for a 4-component composite of incident myocardial infarction (MI), coronary revascularization, stroke, or cardiovascular death, and all-cause mortality. Quartiles of increasingly baseline LDLC and hs-CRP were evaluated as predictors of future adverse events after adjustment for randomized treatment assignment and traditional risk factors.

Based on the study, the researchers reported the following findings:

• Compared with placebo, bempedoic acid reduced median hsCRP by 21.6% and mean LDLC levels by 21.1% at 6 months.
• Baseline hsCRP was significantly associated with the primary composite end point of major cardiovascular events (highest versus lowest hsCRP quartile; hazard ratio [HR], 1.43), all-cause mortality (HR, 2.21), and cardiovascular mortality (HR, 2.00).
• The relationship of baseline LDLC quartile (highest versus lowest) to future events was smaller in magnitude for the primary composite cardiovascular endpoint (HR, 1.19) and neutral for cardiovascular mortality (HR, 0.90) and all-cause mortality (HR, 0.95).
• Risks were high for those with elevated hsCRP irrespective of LDLC level.
• Bempedoic acid demonstrated similar efficacy in reducing cardiovascular events across all levels of hs-CRP and LDLC.

"Among statin-intolerant patients, vascular inflammation is a major determinant of atherosclerotic risk in a manner identical to that seen in statin-tolerant patients," the researchers wrote.

"These data suggest that targeting LDL-C alone is unlikely to completely reduce atherosclerotic risk and that inflammatory pathways have yet to be fully exploited for patient benefit.”

Reference:

Ridker PM, Lei L, Louie MJ, et al. Inflammation and cholesterol as predictors of cardiovascular events among 13 970 contemporary high-risk patients with statin intolerance. Circulation. 2023;Epub ahead of print.