Opinion
VIEWPOINT
J. David Spence, MD, FRCPC Stroke Prevention and Atherosclerosis Research Centre, Robarts Research Institute, Western University, London, Ontario, Canada.
Corresponding Author: J. David Spence, MD, FRCPC, Stroke Prevention and Atherosclerosis Research Centre, Robarts Research Institute, Western University, 1400 Western Rd, London, ON N6G 2V2, Canada ([email protected]). jamaneurology.com
Measurement of Carotid Plaque Burden In light of the 2 recent decisions from US authorities regarding the use of carotid ultrasonography, it is timely to highlight the measurement of carotid plaque burden, as being distinct from assessment of severity of carotid stenosis or measurement of carotid intima-media thickness (IMT). The US Preventive Services Task Force recommended against screening for asymptomatic carotid stenosis, and the American Medical Association approved a category 1 reimbursement code for carotid IMT and plaque scanning. These seemingly contradictory decisions call for an explanation. Only approximately 2% of the population has asymptomatic carotid stenosis, and the vast majority of these patients (approximately 90%) would be better suited for intensive medical therapy than either carotid endarterectomy or carotid stenting. Screening the population to find patients for inappropriate intervention is therefore not a good idea. On the other hand, carotid imaging can identify high-risk patients who would benefit most from intensive medical therapy, so assessing preclinical atherosclerosis to find them makes sense. Treating patients to reduce their risk of cardiovascular events after they have been identified as already having cardiovascular disease leaves a large residual risk that could probably be diminished if preventive therapy, particularly lifestyle changes, was started earlier. Arguments for improved risk stratification using measurement of preclinical atherosclerosis were summarized in 2011 by Sillesen and Falk: “Most heart attacks and strokes occur in people at average risk-factor level who are misclassified by traditional risk factor scoring, as low or intermediate risk.”1(p645) Measurement of IMT has been widely used for risk prediction in the past, but it is increasingly recognized that IMT adds very little to risk prediction based on risk factors, and progression of IMT does not predict cardiovascular events.2 An important emerging alternative to IMT measurement is measurement of carotid plaque burden, either as 2-dimensional total plaque area (TPA) or 3-dimensional plaque volume. Three-dimensional carotid plaque burden is highly correlated with coronary calcium scores, whereas IMT is not.3 Carotid imaging by ultrasonography has important advantages compared with coronary calcium measurement with regard to cost and avoidance of radiation. The TPA was shown in 2002 to be a strong predictor of cardiovascular events.4 After adjustment for age, sex, blood pressure level, cholesterol level, smoking, diabetes mellitus, homocysteine level, and treatment of elevated blood pressure and cholesterol levels, patients in the top quartile of TPA had a 5-year risk of stroke, death, or myocardial infarction that was 3.4 times higher than that of the first quartile. There was a stepped increase in risk; the adjusted 5-year risk of those events by quartile was 5.6% in the first quartile, 10.7% in the sec-
ond quartile, 13.9% in the third quartile, and 19.5% in the top quartile. Patients in the top quartile of plaque area (>119 mm2) were at very high risk, approaching a 40% ten-year risk of stroke, death, or myocardial infarction, which warranted intensive medical therapy. Furthermore, patients with plaque progression (approximately half the patients) had twice the risk of those with stable plaque or regression of plaque area. These findings were validated in a prospective population-based study with more than 6000 participants in Tromsø, Norway, followed up now for more than 11 years. Mathiesen and colleagues5 found that the risk of both myocardial infarction and stroke were more strongly predicted by TPA than by IMT. A meta-analysis6 confirmed the superiority of TPA compared with IMT in cardiovascular risk prediction. Besides risk stratification, measurement of plaque burden is useful for genetic research. By saving residual scores in multiple regression (essentially, the distance off the regression line expressed in standard deviations), a quantitative trait is obtained that expresses the extent to which patients have more plaque or less plaque than would be predicted from risk factors. Extreme outliers can be identified; this approach reduces by three-fourths the sample size needed for genomewide association studies.7 Compared with IMT, measurement of carotid 3-dimensional plaque volume markedly reduces the sample size and duration of studies of new therapies for atherosclerosis (from 300 patients per group followed up for 2 years to 50 patients per group followed up for ⱕ6 months). The reason is that IMT changes only in thickness, whereas plaque volume changes in 3 dimensions— thickness, length, and circumferential extent of plaque. Measurement of carotid plaque volume is also more sensitive to the effects of therapy than is coronary intravascular ultrasonography because coronary plaques usually extend for the entire length of the arterial segment being measured and extend all around the circumference of the artery; change with therapy thus reduces to the average change in thickness along the length of the segment. Measurement of plaque burden can also be used to manage patients’ conditions beyond risk stratification. Based on the observation that half the patients in the 2002 article described above4 had progression of plaque, and their risk was twice that of patients with stable plaque or regression, a new approach to cardiovascular prevention, treating arteries instead of targeting risk factors, was developed. This approach markedly reduced risk among patients with asymptomatic carotid stenosis; after implementation of this approach, the 2-year risk of stroke declined from 8.8% to 1% and the risk of myocardial infarction dropped from 7.6% to 1%.8 “Treating arteries” cannot be done with IMT measurement because the annual change in IMT is only 0.15 mm (Reprinted) JAMA Neurology April 2015 Volume 72, Number 4
Copyright 2015 American Medical Association. All rights reserved.
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383
Opinion Viewpoint
Figure. Change in Plaque Burden in 3 Months A
384
April 15, 2009
B
July 23, 2009
A, Soft plaque is shown at the origin of the left external carotid artery in a man in his 60s taking ezetimibe alone because of myalgias and cramps when taking statins. His plaque area had progressed from 20 mm2 six months earlier to 28 mm2 after stopping treatment with rosuvastatin. B, After restarting rosuvastatin therapy, 5 mg/d, with coenzyme Q10, 200 mg/d, to prevent
myalgias, the plaque area regressed to 19 mm2 in just over 3 months. The plaque had also become denser, with regression of the soft plaque and more calcification. Reproduced with permission from Spence JD, Hackam DG. Treating arteries instead of risk factors: a paradigm change in management of atherosclerosis. Stroke. 2010;41(6):1193-1199.
and the resolution of carotid ultrasonography is twice that, so the changeinIMTcannotbemeasuredinindividualswithinclinicallymeaningful time frames. Measurement of plaque burden has revealed that plaques change much more quickly than most physicians would suspect. The Figure shows a significant change in both plaque area and plaque echolucency observed in just over 3 months in a patient whose statin regimen was restarted because of plaque progression.
Measurement of carotid plaque has the potential to significantly reduce the burden of strokes and vascular disease, which is expected to increase markedly with the aging of the population. This approach is likely to be the way atherosclerosis will be managed in the future. “Trying to treat arteries without measuring plaque would be like treating hypertension without measuring blood pressure.”9(p35)
ARTICLE INFORMATION
REFERENCES
Published Online: February 16, 2015. doi:10.1001/jamaneurol.2014.3002.
1. Sillesen H, Falk E. Why not screen for subclinical atherosclerosis? Lancet. 2011;378(9792):645-646.
Conflict of Interest Disclosures: Dr Spence reported receiving grants from the Canadian Institutes for Heath Research (grant CIHR MOP 106584) and the Heart & Stroke Foundation (HSF) (grant HSF NA5912). Lecture honoraria, travel support, and consulting fees were provided by Sanofi, Bayer, Merck, and Boehringer-Ingelheim. Research support for investigator-initiated projects was provided by Pfizer Inc (substantial donation in kind of medication to support an HSF grant for a clinical trial) and Merck (small funds to support a summer research student). Contract research was conducted with all of the above pharmaceutical companies and Takeda Pharmaceuticals, BristolMyers Squibb, Servier, Wyeth, Miles, Roussel-Uclaf, NMT, AGA, Gore, and AstraZeneca. Dr Spence reported being a shareholder and officer of Vascularis.com. He reported being a member of the editorial boards of Hypertension; Stroke; and Arteriosclerosis, Thrombosis, and Vascular Biology. He reported receiving royalties on books published by Vanderbilt University Press and McGraw-Hill Medical. No other disclosures were reported.
2. Lorenz MW, Polak JF, Kavousi M, et al; PROG-IMT Study Group. Carotid intima-media thickness progression to predict cardiovascular events in the general population (the PROG-IMT collaborative project): a meta-analysis of individual participant data. Lancet. 2012;379(9831):2053-2062. 3. Sillesen H, Muntendam P, Adourian A, et al. Carotid plaque burden as a measure of subclinical atherosclerosis: comparison with other tests for subclinical arterial disease in the High Risk Plaque BioImage study. JACC Cardiovasc Imaging. 2012;5 (7):681-689. 4. Spence JD, Eliasziw M, DiCicco M, Hackam DG, Galil R, Lohmann T. Carotid plaque area: a tool for targeting and evaluating vascular preventive therapy. Stroke. 2002;33(12):2916-2922. 5. Mathiesen EB, Johnsen SH, Wilsgaard T, Bønaa KH, Løchen ML, Njølstad I. Carotid plaque area and intima-media thickness in prediction of first-ever ischemic stroke: a 10-year follow-up of 6584 men and women: the Tromsø Study. Stroke. 2011;42(4):972-978.
6. Inaba Y, Chen JA, Bergmann SR. Carotid plaque, compared with carotid intima-media thickness, more accurately predicts coronary artery disease events: a meta-analysis. Atherosclerosis. 2012;220 (1):128-133. 7. Lanktree MB, Hegele RA, Schork NJ, Spence JD. Extremes of unexplained variation as a phenotype: an efficient approach for genome-wide association studies of cardiovascular disease. Circ Cardiovasc Genet. 2010;3(2):215-221. 8. Spence JD, Coates V, Li H, et al. Effects of intensive medical therapy on microemboli and cardiovascular risk in asymptomatic carotid stenosis. Arch Neurol. 2010;67(2):180-186. 9. Spence JD. Carotid plaque measurement is superior to IMT Invited editorial comment on: carotid plaque, compared with carotid intima-media thickness, more accurately predicts coronary artery disease events: a meta-analysisYoichi Inaba, M.D., Jennifer A. Chen M.D., Steven R. Bergmann M.D., Ph.D. Atherosclerosis. 2012;220(1): 34-35.
JAMA Neurology April 2015 Volume 72, Number 4 (Reprinted)
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://archneur.jamanetwork.com/ by a University of California - San Diego User on 06/02/2015
jamaneurology.com
VIEWPOINT
J. David Spence, MD, FRCPC Stroke Prevention and Atherosclerosis Research Centre, Robarts Research Institute, Western University, London, Ontario, Canada.
Corresponding Author: J. David Spence, MD, FRCPC, Stroke Prevention and Atherosclerosis Research Centre, Robarts Research Institute, Western University, 1400 Western Rd, London, ON N6G 2V2, Canada ([email protected]). jamaneurology.com
Measurement of Carotid Plaque Burden In light of the 2 recent decisions from US authorities regarding the use of carotid ultrasonography, it is timely to highlight the measurement of carotid plaque burden, as being distinct from assessment of severity of carotid stenosis or measurement of carotid intima-media thickness (IMT). The US Preventive Services Task Force recommended against screening for asymptomatic carotid stenosis, and the American Medical Association approved a category 1 reimbursement code for carotid IMT and plaque scanning. These seemingly contradictory decisions call for an explanation. Only approximately 2% of the population has asymptomatic carotid stenosis, and the vast majority of these patients (approximately 90%) would be better suited for intensive medical therapy than either carotid endarterectomy or carotid stenting. Screening the population to find patients for inappropriate intervention is therefore not a good idea. On the other hand, carotid imaging can identify high-risk patients who would benefit most from intensive medical therapy, so assessing preclinical atherosclerosis to find them makes sense. Treating patients to reduce their risk of cardiovascular events after they have been identified as already having cardiovascular disease leaves a large residual risk that could probably be diminished if preventive therapy, particularly lifestyle changes, was started earlier. Arguments for improved risk stratification using measurement of preclinical atherosclerosis were summarized in 2011 by Sillesen and Falk: “Most heart attacks and strokes occur in people at average risk-factor level who are misclassified by traditional risk factor scoring, as low or intermediate risk.”1(p645) Measurement of IMT has been widely used for risk prediction in the past, but it is increasingly recognized that IMT adds very little to risk prediction based on risk factors, and progression of IMT does not predict cardiovascular events.2 An important emerging alternative to IMT measurement is measurement of carotid plaque burden, either as 2-dimensional total plaque area (TPA) or 3-dimensional plaque volume. Three-dimensional carotid plaque burden is highly correlated with coronary calcium scores, whereas IMT is not.3 Carotid imaging by ultrasonography has important advantages compared with coronary calcium measurement with regard to cost and avoidance of radiation. The TPA was shown in 2002 to be a strong predictor of cardiovascular events.4 After adjustment for age, sex, blood pressure level, cholesterol level, smoking, diabetes mellitus, homocysteine level, and treatment of elevated blood pressure and cholesterol levels, patients in the top quartile of TPA had a 5-year risk of stroke, death, or myocardial infarction that was 3.4 times higher than that of the first quartile. There was a stepped increase in risk; the adjusted 5-year risk of those events by quartile was 5.6% in the first quartile, 10.7% in the sec-
ond quartile, 13.9% in the third quartile, and 19.5% in the top quartile. Patients in the top quartile of plaque area (>119 mm2) were at very high risk, approaching a 40% ten-year risk of stroke, death, or myocardial infarction, which warranted intensive medical therapy. Furthermore, patients with plaque progression (approximately half the patients) had twice the risk of those with stable plaque or regression of plaque area. These findings were validated in a prospective population-based study with more than 6000 participants in Tromsø, Norway, followed up now for more than 11 years. Mathiesen and colleagues5 found that the risk of both myocardial infarction and stroke were more strongly predicted by TPA than by IMT. A meta-analysis6 confirmed the superiority of TPA compared with IMT in cardiovascular risk prediction. Besides risk stratification, measurement of plaque burden is useful for genetic research. By saving residual scores in multiple regression (essentially, the distance off the regression line expressed in standard deviations), a quantitative trait is obtained that expresses the extent to which patients have more plaque or less plaque than would be predicted from risk factors. Extreme outliers can be identified; this approach reduces by three-fourths the sample size needed for genomewide association studies.7 Compared with IMT, measurement of carotid 3-dimensional plaque volume markedly reduces the sample size and duration of studies of new therapies for atherosclerosis (from 300 patients per group followed up for 2 years to 50 patients per group followed up for ⱕ6 months). The reason is that IMT changes only in thickness, whereas plaque volume changes in 3 dimensions— thickness, length, and circumferential extent of plaque. Measurement of carotid plaque volume is also more sensitive to the effects of therapy than is coronary intravascular ultrasonography because coronary plaques usually extend for the entire length of the arterial segment being measured and extend all around the circumference of the artery; change with therapy thus reduces to the average change in thickness along the length of the segment. Measurement of plaque burden can also be used to manage patients’ conditions beyond risk stratification. Based on the observation that half the patients in the 2002 article described above4 had progression of plaque, and their risk was twice that of patients with stable plaque or regression, a new approach to cardiovascular prevention, treating arteries instead of targeting risk factors, was developed. This approach markedly reduced risk among patients with asymptomatic carotid stenosis; after implementation of this approach, the 2-year risk of stroke declined from 8.8% to 1% and the risk of myocardial infarction dropped from 7.6% to 1%.8 “Treating arteries” cannot be done with IMT measurement because the annual change in IMT is only 0.15 mm (Reprinted) JAMA Neurology April 2015 Volume 72, Number 4
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://archneur.jamanetwork.com/ by a University of California - San Diego User on 06/02/2015
383
Opinion Viewpoint
Figure. Change in Plaque Burden in 3 Months A
384
April 15, 2009
B
July 23, 2009
A, Soft plaque is shown at the origin of the left external carotid artery in a man in his 60s taking ezetimibe alone because of myalgias and cramps when taking statins. His plaque area had progressed from 20 mm2 six months earlier to 28 mm2 after stopping treatment with rosuvastatin. B, After restarting rosuvastatin therapy, 5 mg/d, with coenzyme Q10, 200 mg/d, to prevent
myalgias, the plaque area regressed to 19 mm2 in just over 3 months. The plaque had also become denser, with regression of the soft plaque and more calcification. Reproduced with permission from Spence JD, Hackam DG. Treating arteries instead of risk factors: a paradigm change in management of atherosclerosis. Stroke. 2010;41(6):1193-1199.
and the resolution of carotid ultrasonography is twice that, so the changeinIMTcannotbemeasuredinindividualswithinclinicallymeaningful time frames. Measurement of plaque burden has revealed that plaques change much more quickly than most physicians would suspect. The Figure shows a significant change in both plaque area and plaque echolucency observed in just over 3 months in a patient whose statin regimen was restarted because of plaque progression.
Measurement of carotid plaque has the potential to significantly reduce the burden of strokes and vascular disease, which is expected to increase markedly with the aging of the population. This approach is likely to be the way atherosclerosis will be managed in the future. “Trying to treat arteries without measuring plaque would be like treating hypertension without measuring blood pressure.”9(p35)
ARTICLE INFORMATION
REFERENCES
Published Online: February 16, 2015. doi:10.1001/jamaneurol.2014.3002.
1. Sillesen H, Falk E. Why not screen for subclinical atherosclerosis? Lancet. 2011;378(9792):645-646.
Conflict of Interest Disclosures: Dr Spence reported receiving grants from the Canadian Institutes for Heath Research (grant CIHR MOP 106584) and the Heart & Stroke Foundation (HSF) (grant HSF NA5912). Lecture honoraria, travel support, and consulting fees were provided by Sanofi, Bayer, Merck, and Boehringer-Ingelheim. Research support for investigator-initiated projects was provided by Pfizer Inc (substantial donation in kind of medication to support an HSF grant for a clinical trial) and Merck (small funds to support a summer research student). Contract research was conducted with all of the above pharmaceutical companies and Takeda Pharmaceuticals, BristolMyers Squibb, Servier, Wyeth, Miles, Roussel-Uclaf, NMT, AGA, Gore, and AstraZeneca. Dr Spence reported being a shareholder and officer of Vascularis.com. He reported being a member of the editorial boards of Hypertension; Stroke; and Arteriosclerosis, Thrombosis, and Vascular Biology. He reported receiving royalties on books published by Vanderbilt University Press and McGraw-Hill Medical. No other disclosures were reported.
2. Lorenz MW, Polak JF, Kavousi M, et al; PROG-IMT Study Group. Carotid intima-media thickness progression to predict cardiovascular events in the general population (the PROG-IMT collaborative project): a meta-analysis of individual participant data. Lancet. 2012;379(9831):2053-2062. 3. Sillesen H, Muntendam P, Adourian A, et al. Carotid plaque burden as a measure of subclinical atherosclerosis: comparison with other tests for subclinical arterial disease in the High Risk Plaque BioImage study. JACC Cardiovasc Imaging. 2012;5 (7):681-689. 4. Spence JD, Eliasziw M, DiCicco M, Hackam DG, Galil R, Lohmann T. Carotid plaque area: a tool for targeting and evaluating vascular preventive therapy. Stroke. 2002;33(12):2916-2922. 5. Mathiesen EB, Johnsen SH, Wilsgaard T, Bønaa KH, Løchen ML, Njølstad I. Carotid plaque area and intima-media thickness in prediction of first-ever ischemic stroke: a 10-year follow-up of 6584 men and women: the Tromsø Study. Stroke. 2011;42(4):972-978.
6. Inaba Y, Chen JA, Bergmann SR. Carotid plaque, compared with carotid intima-media thickness, more accurately predicts coronary artery disease events: a meta-analysis. Atherosclerosis. 2012;220 (1):128-133. 7. Lanktree MB, Hegele RA, Schork NJ, Spence JD. Extremes of unexplained variation as a phenotype: an efficient approach for genome-wide association studies of cardiovascular disease. Circ Cardiovasc Genet. 2010;3(2):215-221. 8. Spence JD, Coates V, Li H, et al. Effects of intensive medical therapy on microemboli and cardiovascular risk in asymptomatic carotid stenosis. Arch Neurol. 2010;67(2):180-186. 9. Spence JD. Carotid plaque measurement is superior to IMT Invited editorial comment on: carotid plaque, compared with carotid intima-media thickness, more accurately predicts coronary artery disease events: a meta-analysisYoichi Inaba, M.D., Jennifer A. Chen M.D., Steven R. Bergmann M.D., Ph.D. Atherosclerosis. 2012;220(1): 34-35.
JAMA Neurology April 2015 Volume 72, Number 4 (Reprinted)
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://archneur.jamanetwork.com/ by a University of California - San Diego User on 06/02/2015
jamaneurology.com
