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

Puri R, Nissen SE, Libby P, et al.
Circulation. Originally published September 16, 2013. doi: 10.1161/CIRCULATIONAHA.113.004243

Background

Although statin-mediated cholesterol-lowering improves clinical outcomes, many individuals still show atheroma progression and further cardiovascular events [1]. Relative risk reductions obtained with the current best medical therapies are at most 30-40%, leaving a substantial residual cardiovascular risk in patients prescribed statins for secondary prevention [2]. Novel targets and therapeutic strategies need to be identified to effectively combat this residual risk.
Several lines of evidence point at inflammation as a factor involved in the initiation, progression and instability of atherosclerotic plaques [3,4]. In particular C-reactive protein (CRP) seems to be a relevant prognostic biomarker consistent with CV risk [5,6]. However, there is an ongoing debate about whether statin-induced CRP-lowering is simply a function of parallel changes in LDL-c or, whether CRP follows a separate pathway.
SATURN (Study of Coronary Atheroma by Intravascular Ultrasound: Effect of Rosuvastatin Versus Atorvastatin) directly compared the anti-atherosclerotic effect of two potent statins on coronary atherosclerosis progression, in patients with angiographically demonstrable coronary disease [7]. Treatment with both agents was associated with regression of coronary atheroma, but change in percent atheroma volume (PAV) did not differ between the two groups, neither did safety or clinical event rates.
This is a post hoc analysis on the pooled data of both treatment groups that examined the prognostic effect of changes in CRP levels on both coronary atheroma progression and major adverse cardiovascular events (MACE) in patients who had 24 months of maximally intensive statin therapy.

Main results

• In the overall population, PAV decreased by 1.23+0.09% (P<0.001). 67% of patients showed regression.
• Baseline PAV did not differ between patients whose CRP levels increased and did not increase from baseline. Patients with increasing CRP levels demonstrated less PAV regression as compared to patients whose CRP levels did not increase (-0.91±0.15% vs. -1.42±0.11%, P=0.007).
• Lumen volume only expanded in patients without increasing CRP levels (+2.30+1.17 mm³, P=0.05 from baseline), not when CRP increased (=1.00+1.53 mm³, P=0.52 from baseline). Multivariable analysis demonstrated an independent association between a lack of on-treatment rise in CRP and PAV regression (P=0.01).
• Change in CRP correlated weakly but significantly with changes in LDL-c (r=0.07, P=0.02), non-HDL-c (r=0.1, P=0.001), triglycerides (r=0.1, P=0.001) and ApoB levels (r=0.09, P=0.008).
• After correction for the use of ACE inhibitors, diabetes mellitus and baseline CRP, change in CRP did not associated with MACE (HR: 1.20, 95%CI: 0.94-1.52, P=0.14), whereas on-treatment CRP level did significantly and independently associate with MACE (HR: 1.29, 95%CI: 1.05-1.58, P=0.01).
• Kaplan-Meier survival analysis according to quartiles of on-treatment CRP levels shows a stepwise relationship between increasing on-treatment CRP levels and MACE. The 2-year cumulative incidence of MACE in the highest quartile was 9.5%, as opposed to 7.6%, 6.6% and 5.9% for the lower respective quartiles.

Conclusion

In this population of patients of whom most achieved LDL-c levels below 70 mg/dL, 37% of individuals showed increasing on-treatment CRP levels, despite potent statin therapy. These patients showed less atheroma regression than those with decreasing CRP levels. Decreasing CRP levels independently associated with coronary atheroma regression.
Although the absolute change in CRP had no prognostic value, on-treatment CRP level did independently associate with MACE. Also, a step-wise relationship was observed between on-treatment CRP levels and time to first MACE.
Taken together, these results underscore the potential importance of on-treatment CRP levels, thus systemic inflammation, contributing to residual cardiovascular risk in individuals with coronary artery disease who are treated according to current lipid-lowering guidelines.

References

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