CORRESPONDENCE: LETTER TO THE EDITOR
Measuring Effects of Antiatherosclerotic Therapies
J. David Spence, MD, FRCPC, FAHA*
* Stroke Prevention and Atherosclerosis Research Centre, Robarts Research Institute, 1400 Western Road, London, Ontario, Canada N6G 2V2 (Email: dspence{at}robarts.ca).
Corti et al. (1) found no difference in vessel wall area measured by magnetic resonance imaging (MRI) between simvastatin 80 mg and 20 mg daily over 18 months of follow-up. This might have been due to the small sample size of 51 subjects, but it also was probably partly due to the method of measurement.
It is important to understand that methods for measuring atherosclerosis give biologically distinct phenotypes (2). Traditional risk factors account for 53% of variance (R2) of carotid plaque area, but only 13% of carotid stenosis measured by Doppler velocities, and only 15% to 17% of intima-media thickness (IMT). Including IMT in a measurement of "atherosclerosis" introduces the noise of the medial hypertrophy that is due to blood pressure. For maximum carotid IMT, sample sizes are from 468 per group for a 30% effect size, to 30 per group for a 100% effect size over 3 years (3).
Sensitivity of measurements to effects of therapy also depends on the location and method of the measurement. Carotid plaques grow along the artery 2.4 times faster than they thicken (4). Most carotid plaques are focal, with a proximal and distal end, which can progress or regress, and this change can be captured by measuring plaque area (5). Plaque volume is even more sensitive to effects of treatment. We recently found that a sample of 20 patients per group was sufficient to detect regression of plaque with high-dose atorvastatin versus placebo in three months (6). Because coronary plaques are diffuse, without a proximal and distal end, change in coronary plaque volume reduces to a change in thickness. Therefore, sample sizes and duration of therapy required to show effects of treatment with intravascular ultrasound are substantially larger: in the REVERSAL (Reversal of Atherosclerosis with Aggressive Lipid-Lowering) (7) study, 654 patients were followed 18 months to show a difference between high-dose atorvastatin and pravastatin.
Finally, investigators wishing to measure effects of antiatherosclerotic therapy would be well served by measuring carotid plaque volume using three-dimensional ultrasound.
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References
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- Corti R, Fuster V, Fayad ZA, et al. Effects of aggressive versus conventional lipid-lowering therapy by simvastatin, on human atherosclerotic lesionsa prospective, randomized, double-blind trial with high resolution MRI. J Am Coll Cardiol 2005;46:106-112.[Abstract/Free Full Text]
- Spence JD, Hegele RA. Noninvasive phenotypes of atherosclerosis Arterioscler Thromb Vasc Biol 2004;24:e188-e189.[Free Full Text]
- Bots ML, Evans GW, Riley WA, Grobbee DE. Carotid intima-media thickness measurements in intervention studies: design options, progression rates, and sample size considerations: a point of view Stroke 2003;34:2985-2994.[Abstract/Free Full Text]
- Barnett PA, Spence JD, Manuck SB, Jennings JR. Psychological stress and the progression of carotid artery disease J Hypertens 1997;15:49-55.[CrossRef][ISI][Medline]
- Spence JD, Eliasziw M, DiCicco M, et al. Carotid plaque areaa tool for targeting and evaluating vascular preventive therapy. Stroke 2002;33:2916-2922.[Abstract/Free Full Text]
- Ainsworth CD, Blake CC, Tamayo A, Landry AM, et al. Measurement of change in carotid plaque volumea 3-dimensional ultrasound tool for rapid evaluation of new therapies. Stroke 2005;35:1904-1909.
- Nissen SE, Tuzcu EM, Schoenhagen P, et al. REVERSAL Investigators Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosisa randomized controlled trial. JAMA 2004;291:1071-1080.[Abstract/Free Full Text]
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