Atorvastatin Therapy: Effects on Reduction of Macrophage Activity - ATHEROMA
The goal of this trial was to evaluate the effects of low-dose (10 mg) versus high-dose (80 mg) atorvastatin on macrophage activity in carotid atherosclerotic plaques using serial ultrasmall super-paramagnetic iron oxide (USPIO)-enhanced T2*-weighted magnetic resonance imaging (MRI), a marker for inflammation.
High-dose statin therapy is associated with a greater reduction in macrophage activity, and therefore in inflammation, in patients with carotid atherosclerotic disease, as measured by USPIO-enhanced MRI.
Patients Screened: 64
Patients Enrolled: 40
Mean Follow Up: 12 weeks
Mean Patient Age: 67.6 years
- Age 19-79 years
- Female patients had to be of nonchildbearing potential
- Carotid stenosis >40% on duplex ultrasonography
- Intraplaque accumulation of USPIO on MRI at baseline
- Positive USPIO-enhanced MRI of carotid plaque confirmed by an attending neuroradiologist
- Statin naïve or on a stable dose of a statin for ≥4 weeks before screening, with no evidence of statin intolerance
- <10% signal drop in two or more quadrants on T2*-weighted imaging sequences
- Required continued use of nonstatin lipid-modifying therapies (e.g., fibric acid derivatives, niacin, resins, ezetimibe, fish-oil supplement) or therapy with any other lipid-regulating medications not specified (dietary supplements or multivitamins containing a daily dose of niacin 250 mg were allowed)
- History of statin intolerance
- History of chronic viral hepatitis or other chronic hepatic disorders, or alanine aminotransferase or aspartate aminotransferase >1.5 times the upper limit of normal, or alkaline phosphatase or total bilirubin >1.5 times the upper limit of normal of laboratory reference range at screening
- Creatinine clearance <50 ml/min
- History of myopathy or inflammatory muscle disease, or elevated total serum creatine kinase (3 times upper limit of normal) at screening visit
- Doppler assessment of <40% stenosis or carotid occlusion during screening assessment
- History of clinically significant atopy (e.g., anaphylaxis, skin rash to medication or topical therapies, hypersensitivity to iodinated contrast media, allergies to food such as shellfish, bronchial asthma) and allergies to dextran and iron salts
- Clinical contraindications to MRI including but not limited to intracranial aneurysm clips (except Sugita) with an appropriate operative conformation, history of intraorbital metal fragments, pacemakers and non-MRI compatible heart valves, inner ear implants, or history of claustrophobia in MRI
- Planned carotid surgery or endovascular intervention earlier than 10 weeks within the study period
- Serum triglycerides >400 mg/dl at screening
- Untreated or uncontrolled hypothyroidism or thyrotoxicosis
- Poorly controlled diabetes mellitus glycated hemoglobin ≥8.5%
- Poorly controlled hypertension
- History of malignancy within the past 2 years
- Evidence of recent severe infection (within 4 weeks)
- Current life-threatening condition other than vascular disease (e.g., very severe chronic airways disease, human immunodeficiency virus positive, life-threatening arrhythmias) that may prevent subject from completing the study
- History of myocardial infarction or cerebrovascular accident within the previous 2 weeks of screening
- Concomitant use of potent CYP450 3A4 inhibitors (e.g., clarithromycin, grapefruit juice [240 ml daily], itraconazole, ketoconazole)
- Chronic use of nonsteroidal anti-inflammatory drugs and oral steroid therapy
- Use of immunosuppressants (cyclosporine, methotrexate)
- Use of an investigational drug within 30 days or five half-lives (whichever is the longer) preceding the first dose of study medication
- Prior ipsilateral carotid endarterectomy or neck irradiation
- Alcohol or drug abuse within the past 6 months
- Change from baseline in signal intensity on USPIO-enhanced MRI in carotid plaque at 6 and 12 weeks
- Total embolic count on transcranial Doppler
Patients with carotid stenosis >40% on duplex ultrasonography and who demonstrated intraplaque accumulation of USPIO on MRI at baseline were randomized in a double-blind manner to either 10 mg or 80 mg atorvastatin daily for 12 weeks. Follow-up imaging was obtained at 6 and 12 weeks.
Antiplatelet agent (95%)
A total of 40 patients were enrolled, 20 to each arm. The baseline characteristics between the two arms were comparable. About 10% had diabetes mellitus, and 28% had hyperlipidemia; the mean percent luminal stenosis was 61.7.
As expected, atorvastatin 80 mg significantly reduced total cholesterol (15.4%) compared with atorvastatin 10 mg (3.3%) (p = 0.03) at 12 weeks. Similarly, low-density lipoprotein cholesterol was reduced by 29% with 80 mg of atorvastatin and by 1% with 10 mg of atorvastatin (p = 0.0006) at 12 weeks. A significant reduction from baseline in USPIO-defined signal intensity was observed in the 80 mg group at both 6 weeks (0.13; p = 0.0003) and at 12 weeks (0.20; p < 0.0001). No significant difference was observed in the low-dose arm at 6 weeks (0.048, p = 0.15) and at 12 weeks (0.038, p = 0.3).
At 12 weeks, the mean signal difference between the two groups was 0.24 (p < 0.0001). The mean emboli count at 12 weeks was significantly lower in the high-dose atorvastatin group (difference = 94%, 95% confidence interval 84%-98%; p < 0.0001).
The results of this surrogate endpoint study indicate that aggressive lipid-lowering therapy with 80 mg of atorvastatin daily is associated with significant reduction in USPIO-defined inflammation in carotid plaques. USPIO-defined inflammation represents a novel imaging biomarker. However, these findings are not very surprising, given the known anti-inflammatory actions of statins. Moreover, although this is an interesting finding, it is unclear if this will translate into better outcomes such as fewer strokes and deaths.
Tang TY, Howarth SP, Miller SR, et al. The ATHEROMA (Atorvastatin Therapy: Effects on Reduction of Macrophage Activity) study: evaluation using ultrasmall superparamagnetic iron oxide-enhanced magnetic resonance imaging in carotid disease.
J Am Coll Cardiol 2009;53:2039-50.
Effects of Aggressive Versus Conventional Lipid-Lowering Therapy by Atorvastatin on Inflammatory Activity in Human Carotid Atherosclerotic Plaques: A Prospective Randomised Double-Blind Trial With USPIO-Enhanced High Resolution Magnetic Resonance Imaging. Presented by Dr. Tjun Tang at the SCAI-ACC i2 Summit/American College of Cardiology Annual Scientific Session, Chicago, IL, March/April 2008.
Keywords: Inflammation, Stroke, Follow-Up Studies, Plaque, Atherosclerotic, Macrophages, Hyperlipidemias, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Heptanoic Acids, Constriction, Pathologic, Magnetic Resonance Imaging, Ferric Compounds, Lipoproteins, LDL, Pyrroles, Biological Markers, Confidence Intervals, Carotid Stenosis, Diabetes Mellitus
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