High-dose statin therapy rapidly reduces atherosclerotic plaque inflammation

Tawakol A, Fayad ZA, Mogg R et al.
J Am Coll Cardiol. 2013 May 30. doi: 10.1016/j.jacc.2013.04.066.

Background

Inflammation is important from the initiation phase to the atherothrombosis phase of atherosclerosis [1,2]. Statin treatment is known to reduce atherothrombotic risk and the circulating levels of markers of inflammation. It is, however, unknown how statins affect atherosclerotic plaque inflammation.
Arterial inflammation can be visualised by 2-18F-fluoro-2-deoxy-D-glucose (FDG), since it is taken up by activated macrophages. FDG uptake correlates to the burden of cardiovascular risk factors [3-6]. FDG-PET can be used for non-invasive evaluation of plaque inflammation, to serially test the efficacy of therapy.
An initial study observed reduced vascular FDG uptake after 12 weeks of low-dose simvastatin treatment, as compared to patients given dietary advice only [7]. This randomized, double-blind study explores the relation between statin treatment and plaque inflammation in more detail. Since clinical endpoint trials have demonstrated reductions in CV endpoints as early as one month after initiation of statin therapy [8,9], this study questions whether changes in vascular inflammation can be measured at that time. 83 Patients with arterial inflammation were randomised to either atorvastatin 10 mg plus 80 mg matching placebo daily, or atorvastatin 80 mg and 10 mg matching placebo daily. PET/CT images were obtained at randomization and after 4 and 12 weeks.

Main results

• Target-to-background ratio (TBR) within the most diseased segment (MDS) of the index vessel was statistically significantly reduced after 12 weeks as compared to baseline, in the atorvastatin 80 mg group (-14.4%, 95%CI: -8.7 to -19.8, P<0.0001), while this was not the case in the 10 mg group.
  Fewer arterial FDG uptake was seen, with significant additional reduction in FDG uptake within the MDS (-10.6%, 95%CI: 18.3 to -2.2, P=0.01) in patients receiving atorvastatin 80mg vs 10 mg. FDG uptake measured at 4 weeks was generally consistent with what was seen at 12 weeks.
• Dose-dependent reductions from baseline were seen for total plasma cholesterol, LDL-C and triglycerides, but no statistically significant correlation between these parameters and TBR.
• A subgroup of patients randomised to atorvastatin 80 mg who received a low-dose statin prior to randomisation (n=18), showed a significant reduction in MDS TBR at 12 weeks, as compared to baseline (-13.4%, 95%CI: -20.6 to -5.6, P<0.01).

Conclusion

A rapid reduction in vascular inflammation was seen after statin therapy, to a larger extent in response to high-dose statin treatment. FDG-PET can function as a tool to detect changes in vascular inflammation early in the course of treatment. Further studies implementing imaging within a clinical endpoint trial will help evaluate whether decreasing plaque inflammation can diminish CV events.

References

1. Libby P. Inflammation in atherosclerosis. Nature 2002;420:868-74.
2. Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med 2005;352:1685-95
4. Bural GG, Torigian DA, Chamroonrat W et al. FDG-PET is an effective imaging modality to detect and quantify age-related atherosclerosis in large arteries. Eur J Nucl Med Mol Imaging 2008;35:562-9.
4. Joly L, Djaballah W, Koehl G et al. Aortic inflammation, as assessed by hybrid FDGPET/CT imaging, is associated with enhanced aortic stiffness in addition to concurrent calcification. Eur J Nucl Med Mol Imaging 2009;36:979-85.
5. Rudd JH, Myers KS, Bansilal S et al. Relationships among regional arterial inflammation, calcification, risk factors, and biomarkers: a prospective fluorodeoxyglucose positron-emission tomography/computed tomography imaging study. Circ Cardiovasc Imaging 2009;2:107-15.
6. Kim TN, Kim S, Yang SJ et al. Vascular inflammation in patients with impaired glucose tolerance and type 2 diabetes: analysis with 18F-fluorodeoxyglucose positron emission tomography. Circ Cardiovasc Imaging 2010;3:142-8.
7. Tahara N, Kai H, Ishibashi M et al. Simvastatin Attenuates Plaque Inflammation: Evaluation by Fluorodeoxyglucose Positron Emission Tomography. Journal of the American College of Cardiology  2006:j.jacc.2006.03.069.
8. Schwartz GG, Olsson AG, Ezekowitz MD et al. Effects of Atorvastatin on Early Recurrent Ischemic Events in Acute Coronary Syndromes. JAMA: The Journal of the American Medical Association 2001;285:1711-1718.
9. Cannon CP, Braunwald E, McCabe CH et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med 2004;350:1495-504.

Find this article on Pubmed