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CLINICAL RESEARCH: CLINICAL TRIAL

The ATHEROMA (Atorvastatin Therapy: Effects on Reduction of Macrophage Activity) Study

Evaluation Using Ultrasmall Superparamagnetic Iron Oxide-Enhanced Magnetic Resonance Imaging in Carotid Disease

Tjun Y. Tang, MB, BChir^_*,, Simon P.S. Howarth, BMBCh (Oxon)^_*,, Sam R. Miller, MSc^||, Martin J. Graves, MSc^_*, Andrew J. Patterson, PhD^_*, Jean-Marie U-King-Im, PhD^_*, Zhi Y. Li, PhD^_*, Stewart R. Walsh, MSc, Andrew P. Brown, BSc^¶, Peter J. Kirkpatrick, FmedSci, Elizabeth A. Warburton, DM, Paul D. Hayes, MD, Kevin Varty, MD, Jonathan R. Boyle, MD^,_*, Michael E. Gaunt, MD, Andrew Zalewski, PhD^# and Jonathan H. Gillard, MD^_*,_*

^_* University Department of Radiology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom
Cambridge Vascular Unit, Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom
Academic Department of Neurosurgery, Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom
Department of Clinical Neurosciences, Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom
^|| Discovery Biometrics, GlaxoSmithKline, Harlow, United Kingdom
^¶ GlaxoSmithKline Clinical Imaging Centre, Imperial College, Hammersmith Hospital, London, United Kingdom
^# Novartis Pharmaceuticals Corporation, East Hanover, New Jersey

Manuscript received September 15, 2008; revised manuscript received January 22, 2009, accepted March 2, 2009.

^_* Reprint requests and correspondence: Dr. Jonathan H. Gillard, Box 219, Level 5, University Department of Radiology, Cambridge University Hospitals NHS Foundation Trust, Hills Road, Cambridge CB2 2QQ, United Kingdom (Email: jhg21{at}cam.ac.uk).

Objectives: The aim of this study was to evaluate the effects of low-dose (10 mg) and high-dose (80 mg) atorvastatin on carotid plaque inflammation as determined by ultrasmall superparamagnetic iron oxide (USPIO)-enhanced carotid magnetic resonance imaging (MRI). The hypothesis was that treatment with 80 mg atorvastatin would demonstrate quantifiable changes in USPIO-enhanced MRI-defined inflammation within the first 3 months of therapy.

Background: Preliminary studies indicate that USPIO-enhanced MRI can identify macrophage infiltration in human carotid atheroma in vivo and hence may be a surrogate marker of plaque inflammation.

Methods: Forty-seven patients with carotid stenosis >40% on duplex ultrasonography and who demonstrated intraplaque accumulation of USPIO on MRI at baseline were randomly assigned in a balanced, double-blind manner to either 10 or 80 mg atorvastatin daily for 12 weeks. Baseline statin therapy was equivalent to 10 mg of atorvastatin or less. The primary end point was change from baseline in signal intensity (SI) on USPIO-enhanced MRI in carotid plaque at 6 and 12 weeks.

Results: Twenty patients completed 12 weeks of treatment in each group. A significant reduction from baseline in USPIO-defined inflammation was observed in the 80-mg group at both 6 weeks (SI 0.13; p = 0.0003) and at 12 weeks (SI 0.20; p < 0.0001). No difference was observed with the low-dose regimen. The 80-mg atorvastatin dose significantly reduced total cholesterol by 15% (p = 0.0003) and low-density lipoprotein cholesterol by 29% (p = 0.0001) at 12 weeks.

Conclusions: Aggressive lipid-lowering therapy over a 3-month period is associated with significant reduction in USPIO-defined inflammation. USPIO-enhanced MRI methodology may be a useful imaging biomarker for the screening and assessment of therapeutic response to "anti-inflammatory" interventions in patients with atherosclerotic lesions. (Effects of Atorvastatin on Macrophage Activity and Plaque Inflammation Using Magnetic Resonance Imaging [ATHEROMA]; NCT00368589)

Key Words: carotid stenosis • atherosclerosis • USPIO • MRI • inflammation • statin • plaque vulnerability

Abbreviations and Acronyms   ES = emboli signal   HDL-C = high-density lipoprotein cholesterol   LDL = low-density lipoprotein   LDL-C = low-density lipoprotein cholesterol   Lp-PLA2 = lipoprotein-associated phospholipase A2   MRI = magnetic resonance imaging   ROI = region of interest   SI = ultrasmall superparamagnetic iron oxide-enhanced magnetic resonance imaging signal change   TCD = transcranial Doppler   USPIO = ultrasmall superparamagnetic iron oxide

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