Published online before print March 25, 2004, doi: 10.1161/01.STR.0000125715.47831.37
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(Stroke. 2004;35:e87.)
© 2004 American Heart Association, Inc.
Letters to the Editor |
Ultrasound Measurement of Atherosclerosis
Director of Stroke Prevention and Atherosclerosis Research Centre, Robarts Research Institute, Prof. Neurology and Clinical Pharmacology, University of Western Ontario
To the Editor:
The recent review of intima-media thickness (IMT) measurements by Bots et al,1 while presenting cogent arguments for use of maximum versus mean carotid IMT for studies of interventions, failed to discuss important limitations of IMT. They claim as an important advantage of IMT, as opposed to morbidity and mortality as end-points, the considerable reduction in sample size and duration of study needed to show efficacy of new interventions; however they neglect to mention methodology that has significant advantages compared with IMT, namely the measurement of carotid plaque.
IMT is very insensitive to change in plaque, because plaque grows along the carotid in the axis of flow 2.4 times faster than it thickens.2 Thus, measurement of plaque, as opposed to measurement of IMT, detects change with treatment much more readily.
It is also very important to understand that ultrasound measurements of various aspects of atherosclerosis such as stenosis, plaque, or IMT assay biologically distinct phenomena. The main determinants of IMT are age and blood pressure; multiple regression with traditional risk factors gives an R2 of only 0.15 to 0.17 for IMT,3 compared with an R2 of 0.52 for carotid plaque area.4,5 This leads to important distinctions that must be made both for genetic studies of atherosclerosis and for studies of interventions aimed at atherosclerosis. These issues were discussed in a recent paper in Stroke.6
Total carotid plaque area is a stronger predictor of outcomes than IMT: patients in the top quartile of plaque area have 3.5 times the risk of stroke, death, or myocardial infarction when compared with patients in the lowest quartile,7 after adjustment for age, sex, blood pressure, cholesterol, smoking, diabetes, homocysteine, and treatment for lipids and blood pressure; in contrast, patients in the top quintile of IMT had a relative risk of 3.15 versus the lowest quintile, after adjustment for a smaller panel of risk factors.3
While IMT represents end-organ disease in the artery wall, it consists mainly of media and correlates poorly with coronary disease;8 it represents mainly hypertensive medial hypertrophy and correlates better with left ventricular mass than with coronary stenosis.9 Carotid plaque correlates better with coronary artery disease than does IMT.10,11
For the most successful study of carotid IMT, Bots et al provide sample size estimates ranging from 468 per group for a parallel clinical trial with an effect size of 30% over 2 years, to 30 per group for a 100% effect size over 3 years. This is far inferior to measurement of plaque: study of 2-D plaque area requires sample sizes of 150 per group for a 30% effect size over 2 years,2 and the study of 3-D plaque volume can show significant changes in 3 months in 20 patients per group with an effect size of 100% (presented at the AHA stroke meeting in February 2004).
Instead of fussing over what is the best way to use IMT, a 1980s technology, it would be better to move to 3-D ultrasound measurement of plaque volume12 for evaluating effects of interventions aimed at atherosclerosis. For genetic studies, it is important to distinguish among noninvasive phenotypes, as they will be influenced differently by genetic factors affecting blood pressure, oxidative stress, lipids, and other factors affecting atherosclerosis.6
References
1. Bots ML, Evans GW, Riley WA, Grobee 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.
2. Barnett PA, Spence JD, Manuck SB, Jennings JR. Psychological stress and the progression of carotid atherosclerosis. J Hypertens. 1997; 15: 49–55.[CrossRef][Medline] [Order article via Infotrieve]
3. O’Leary DH, Polak JF, Kronmal RA, Manolio TA, Burke GL, Wolfson SK Jr. Carotid-artery intima and media thickness as a risk factor for myocardial infarction and stroke in older adults. N Engl J Med. 1999; 340: 14–22.
4. Spence JD, Barnett PA, Bulman DE, Hegele RA. An approach to ascertain probands with a nontraditional risk factor for carotid atherosclerosis. Atherosclerosis. 1999; 144: 429–434.[CrossRef][Medline] [Order article via Infotrieve]
5. Spence JD, Ban MR, Hegele RA. Lipoprotein lipase (LPL) gene variation and progression of carotid artery plaque. Stroke. 2003; 34: 1178–1182.
6. Spence JD, Hegele RA. Noninvasive phenotypes of atherosclerosis: similar windows, but different views. Stroke. 2004; 35: 649–653.
7. Spence JD, Eliasziw M, DiCicco M, Hackam DG, Galir R, Lohmann T. Carotid plaque area: a tool for targeting and evaluating vascular preventive therapy. Stroke. 2002; 33: 2916–2922.
8. Adams MR, Nakagomi A, Keech A, Robinson J, McCredie R, Bailey BP, Freedman SB, Celermajer DS. Carotid intima-media thickness is only weakly correlated with the extent and severity of coronary artery disease. Circulation. 1995; 92: 2127–2134.
9. Megnien JL, Simon A, Gariepy J, Denarie N, Cocaul M, Linhart A, Levenson J. Preclinical changes of extracoronary arterial structures as indicators of coronary atherosclerosis in men. J Hypertens. 1998; 16: 157–163.[CrossRef][Medline] [Order article via Infotrieve]
10. Ebrahim S, Papacosta O, Whincup P, Wannamethee G, Walker M, Nicolaides AN, Dhanjil S, Griffin M, Belcaro G, Rumley A, Lowe GD. Carotid plaque, intima media thickness, cardiovascular risk factors, and prevalent cardiovascular disease in men and women: the British Regional Heart Study. Stroke. 1999; 30: 841–850.
11. Aminbakhsh A, Frohlich J, Mancini GBJ. Detection of early atherosclerosis with B mode ultrasonography: assessment of a new quantitative approach. Clin Invest Med. 1999; 22: 265–274.[Medline] [Order article via Infotrieve]
12. Landry A, Spence JD, Fenster A. Measurement of carotid plaque volume by 3-dimensional ultrasound. Stroke. In press.
Response: Carotid Intima-Media Thickness Measurements in Intervention Studies
University Medical Center, Utrecht, Netherlands
First, on behalf of Drs Evans, Riley, Grobbee, and myself, I would like to thank Dr David Spence for his supportive but critical remarks on our paper. He indicates that in our paper we failed to address the measurement of carotid plaque in randomized controlled clinical trials. Indeed, our paper was on carotid intima-media thickness (CIMT) measurements rather than focusing on plaques. However, in our discussion of the paper we provided a paragraph discussing some aspects of why our review was based on CIMT measurements and not plaque measurements. The main issues were that, when compared with plaque changes, CIMT is an established endpoint for efficacy studies; that relatively uniform definitions of CIMT exist, compared with much greater variety in plaque definitions across studies; that maximum CIMT measurements do capture plaque information, especially in recently developed elaborate protocols.1,2 Importantly, the paper discussed the pros and cons given that a trial is designed with CIMT progression as primary outcome.
We did not intend to address which minimally invasive or noninvasive measurement of the vasculature is the best measurement for use in randomized trials on the efficacy of interventions. Such a paper does indeed need a balanced discussion of the pros and cons of various techniques and approaches, such as CIMT, plaque measurement, coronary calcifications, and MRI for measurement of central aortic atherosclerosis. Apart from the techniques, issues around the ability to measure change over time comes into play.
In his letter, Spence provides strong arguments for using 2-D and 3-D plaque measurements in trials rather than CIMT. Based on our experience, we tend to disagree with some of the arguments, given that they are based on a limited set of references. In contrast to what Spence writes, we showed that smoking and elevated lipids, apart from age and blood pressure, were already related to increased CIMT at the age of 30 years.2 Also, the magnitude of the increased cardiovascular risks related to upper quintile CIMT measurements compared with the lowest quintile has been described as at least 4.8 in fully adjusted models.3 Furthermore, plaque measurements in the Rotterdam study were not better in predicting risk of stroke than CIMT; in fact, the reverse was true.4 Finally, when viewing the entire literature, there have been studies showing no association of CIMT with coronary heart disease, but also studies showing modest or even strong relations with coronary heart disease.
The noninvasive measurement of plaque is promising and important in research on determinants of atherosclerosis and its associated risks. We fully see the benefit of using 2-D and 3-D techniques in single and multiple center trials performed in a variety of populations. And indeed the data from Spence’s group on that issue is important and challenging, and certainly merits further application in other trials by his and other groups. In light of the discussion, a direct comparison with the CIMT technique would be ideal. In fact, this is currently being done in a randomized controlled trial performed by Dr P. Verhoef at the Wageningen University in the Netherlands with a main objective to study the effect of folic acid supplementation on CIMT progression (the FACIT study).
Yet, one should remember that the CIMT approach does provide information on risk even when no plaque is present.
References
1. Bots ML, Evans GW, Riley W, Meijer R, McBride KH, Paskett ED, Helmond FA, Grobbee DE, OPAL Investigators. The Osteoporosis Prevention and Arterial effects of TiboLone (OPAL) study: design and baseline characteristics. Control Clin Trials. 2003; 24: 752–775.[CrossRef][Medline] [Order article via Infotrieve]
2. Oren A, Vos LE, Uiterwaal CS, Gorissen WH, Grobbee DE, Bots ML. Cardiovascular risk factors and increased carotid intima-media thickness in healthy young adults: the Atherosclerosis Risk in Young Adults (ARYA) study. Arch Intern Med. 2003; 163: 1787–1792.
3. Iglesias del Sol A, Bots ML, Grobbee DE, Hofman A, Witteman JC. Carotid intima-media thickness at different sites: relation to incident myocardial infarction. The Rotterdam study. Eur Heart J. 2002; 23: 934–940.
4. Hollander M, Hak AE, Koudstaal PJ, Bots ML, Grobbee DE, Hofman A, Witteman JC, Breteler MM. Comparison between measures of atherosclerosis and risk of stroke. The Rotterdam study. Stroke. 2003; 34: 2367–2373.
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