C-Reactive Protein, but Not Low-Density Lipoprotein Cholesterol Levels, Associate with Coronary Atheroma Regression and Cardiovascular Events Following Maximally Intensive Statin Therapy

Study Questions:

Baseline C-reactive protein (CRP) levels predict major adverse cardiovascular events (MACE) (death, myocardial infarction, stroke, coronary revascularization, and hospitalization for unstable angina). Is there an association between changes in CRP levels with plaque progression and MACE in the setting of maximally intensive statin therapy?

Methods:

The SATURN trial employed serial intravascular ultrasound (IVUS) measures of coronary atheroma volume in patients with at least a single lumen stenosis >20% who were treated with rosuvastatin 40 mg or atorvastatin 80 mg for 24 months. Target vessel for assessment was a single vessel with no stenosis >50%.

Results:

The mean age was 57.6 ± 8.5 years, with 73.4% male. On trial low-density lipoprotein cholesterol (LDL-C) decreased by 44% from 120.3 ± 28 mg/dl to 65.9 ± 23 mg/dl, high-density lipoprotein cholesterol (HDL-C) increased by 12% from 44.9 ± 11 mg/dl to 49.4 ± 12 mg/dl, and CRP decreased by 33% from 1.6 (0.8, 3.5) mg/L to 1.1 (0.5, 2.3) mg/L. The groups did not differ significantly in the change from baseline of percent atheroma volume (PAV) on IVUS, CRP-modulating effects, or MACE rates, thus allowing for a (prespecified) post-hoc analysis to test associations between changes in CRP levels with coronary disease progression and MACE. Patients with nonincreasing CRP levels (levels n = 621) had higher baseline (2.3 [1.1, 4.7] vs. 1.1 [0.5, 1.8] mg/L, p < 0.001) and lower follow-up CRP levels (0.8 [0.5, 1.7] vs. 1.6 [0.7, 4.1] mg/L, p < 0.001) versus those with increasing CRP levels (n = 364). Multivariable analysis revealed a nonincreasing CRP level to independently associate with greater PAV regression (p = 0.01). While the (log) change in CRP did not associate with MACE (hazard ratio [HR], 1.18; 95% confidence interval [CI], 0.93-1.50; p = 0.17), the (log) on-treatment CRP associated significantly with MACE (HR, 1.28; 95% CI, 1.04-1.56; p = 0.02). On-treatment LDL-C levels did not correlate with MACE (HR, 1.09; 95% CI, 0.88-1.35; p = 0.45).

Conclusions:

Following 24 months of potent statin therapy, on-treatment CRP levels were associated with MACE. Inflammation may be an important driver of residual cardiovascular risk in patients with coronary artery disease despite aggressive statin therapy.

Perspective:

To date, there has been no convincing evidence that the on-treatment CRP has prognostic value in patients whose LDL-C is <70 mg/dl. The SATURN trial was designed to assess the effect of maximal dose statins on atherosclerosis progression/regression, and the implications of inflammation, as measured by the CRP. The results add to the evidence that lower on-treatment CRP or the absence of rising CRP on maximal dose statins is a marker of risk and atherosclerosis regression, and supports clinical outcome trials designed to target inflammation.

Clinical Topics: Dyslipidemia, Atherosclerotic Disease (CAD/PAD), Lipid Metabolism, Nonstatins, Novel Agents, Statins

Keywords: Fluorobenzenes, Inflammation, Coronary Artery Disease, Myocardial Infarction, Stroke, Follow-Up Studies, Plaque, Atherosclerotic, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Pyrimidines, Risk Factors, Heptanoic Acids, Constriction, Pathologic, Pyrroles, Cholesterol, C-Reactive Protein, Biological Markers, Troponin I, Pravastatin, Confidence Intervals, Sulfonamides, Disease Progression


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