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Inflammation stronger predictor of MACE than cholesterol levels

Presented By
Prof. Paul Ridker, Brigham and Women's Hospital, MA, USA
ACC 2023

A collaborative analysis of the PROMINENT, REDUCE-IT, and STRENGTH trials (n=31,245) showed that residual inflammatory risk is a better predictor of future major adverse cardiovascular events (MACE), cardiovascular (CV) death, and all-cause mortality than residual cholesterol risk in statin-treated patients. Thus, targeting low-density lipoprotein cholesterol (LDL-C) alone is unlikely to completely reduce atherosclerotic risk.

Prof. Paul Ridker (Brigham and Women’s Hospital, MA, USA) explained that the study aimed to determine the relative importance of high-sensitivity C-reactive protein (hsCRP) and LDL-C as determinants of risk for MACE, CV death, and all-cause death among patients receiving statins who were eligible for inclusion in these selected trials [1]. This could then resolve the clinically highly relevant question of whether to add a second LDL-lowering agent or rather an agent that inhibits inflammation to a statin.

Prof. Ridker and colleagues performed a collaborative analysis of patients with (a high risk of) atherosclerotic disease receiving contemporary statins who participated in the PROMINENT (NCT03071692), REDUCE-IT (NCT01492361), or STRENGTH (NCT02104817) trials. Included were 9,988, 8,179, and 13,078 participants from these respective studies, totalling 31,245 participants. Assessed were quartiles of increasing baseline hsCRP and LDL-C.

Comparing the highest (4th) quartile to the first (referent) quartile, residual inflammatory risk measured by hsCRP was significantly associated with:

  1. incident MACE (HR 1.31; 95% CI 1.20–1.43; P<0.0001);
  2. CV mortality (HR 2.68 95%; CI 2.22–3.23; P<0.0001); and
  3. all-cause mortality (HR 2.42 95%; CI 2.12–2.77; P<0.0001).

Residual cholesterol risk was not associated with MACE (HR 1.07; 95% CI 0.98–1.17; P=0.11). It was associated with CV death and all-cause death, but HRs were much lower: 1.27 (95% CI 1.07–1.50; P=0.0086) and 1.16 (95% CI 1.03–1.32; P=0.025), respectively.

In all 3 trials, patients with elevated hsCRP were at high CV risk irrespective of their LDL-C levels, Prof. Ridker concluded. So, which options are available to prescribe in addition to a statin? Prof. Ridker mentioned colchicine (0.5 mg) for patients with stable atherosclerosis and normal eGFR; bempedoic acid, which reduces both LDL-C and hsCRP; or SGLT2i and GLP1RAs, both of which have concomitant anti-inflammatory effects. “We believe the combined use of aggressive LDL-lowering and inflammation-inhibiting therapies will become standard of care for almost all atherosclerotic patients.”

  1. Ridker P, et al. Residual inflammatory risk in contemporary statin treated patients: A collaborative analyses of 31,197 participants in the PROMINENT, REDUCE-IT, and STRENGTH trials. Session 411-10, ACC Scientific Session 2023, 4–6 March, New Orleans, USA.


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