Carotid-artery intima–media thickness, measured noninvasively with the use of carotid-artery ultrasonography, is an independent predictor of new cardiovascular events in persons without a history of cardiovascular disease. The intima–media thickness of the internal carotid artery, but not of the common carotid artery, significantly improved two metrics used to determine the value of a biomarker for cardiovascular risk prediction: the C statistic, derived from multivariable Cox-proportional-hazards models, and the net reclassification index for Framingham risk score categories. The intima–media thickness of the internal carotid artery also modestly but significantly added predictive value to the Framingham risk score when dichotomized at a threshold used to define plaque (>1.5 mm, vs. ≤1.5 mm for no plaque).
Ultrasonographic measurements of intima–media thickness can be limited to the common carotid artery,5,7
averaged across multiple carotid-artery segments,4,6
or combined as a score.3
A review of eight epidemiologic studies showed that the intima–media thickness of the common carotid artery by itself (in all eight studies) or combined with the intima–media thickness of the internal carotid artery and presented as a score (in one of the eight studies) had independent predictive power with respect to cardiovascular events.24
Three studies with separate measurements for the common and internal carotid arteries showed significant associations of cardiovascular events with intima–media thickness.4,25,26
Our study confirms that intima–media thickness of the common carotid artery and that of the internal carotid artery are independent predictors of cardiovascular outcomes.
It is not clear whether the intima–media thickness incrementally adds value to the Framingham risk factors for cardiovascular-risk prediction. The addition of intima–media thickness measurements slightly increased the predictive power with respect to cardiovascular risk assessment in one study14
and with respect to stroke in another study.27
The presence of plaque (defined as an internal-carotid-artery intima–media thickness ≥1.9 mm) has been shown to be associated with increased event rates.28
Our data clearly show that addition of the intima–media thickness of the internal carotid artery increases the net reclassification index for risk categories based on the Framingham risk factors.
Reclassification is a practical approach to gauging the effects of adding new risk factors to the traditional Framingham risk factors when differences in the C statistic are marginal.23
A recent meta-analysis reviewed studies suggesting that a new risk factor added predictive value to the Framingham risk score.29
We performed our study according to the criteria proposed in the meta-analysis: verification of regression calibration, predictive value of the new risk factor in a multivariable model with the Framingham risk factors, positive change in the C statistic, and an increased net reclassification index. The intima–media thickness of the internal carotid artery satisfied all these metrics, whereas the intima–media thickness of the common carotid artery did not. The Atherosclerosis Risk in Communities study (ARIC; ClinicalTrials.gov number, NCT00005131)4
showed an increase in the area under the curve from 0.742 to 0.755 and an increase in the net reclassification index of 9.9%15
for predicting incident coronary heart disease with the use of the intima–media thickness of the common carotid artery in combination with the presence or absence of plaque, whereas the results with the use of the intima–media thickness of the common carotid artery alone were modest.
Our study differs from the ARIC study in several respects. The mean follow-up period was 7.2 years in our study, as compared with 10 years in the ARIC study; our study was smaller (2946 participants, as compared with 13,145); and we excluded plaques from our measurement of intima–media thickness in the common carotid artery, whereas in the ARIC study, plaques were included.15,30
Plaque in the common carotid artery may account for the weak positive associations between intima–media thickness of the common carotid artery and outcomes in the ARIC study. Further clarification of the predictive power of risk factors and intima–media thickness will most likely require verification in other epidemiologic cohorts and attention to differences in the protocol for measurement of the intima–media thickness.
We chose to assess the net reclassification index for three clinically relevant risk categories.21,23
These categories were intended to reflect clinical practice, in which high risk may suggest the need for treatment, low risk indicates the absence of clinical symptoms of any form of cardiovascular disease, and intermediate risk reflects the state in between. Similar categories are used in widely applied national guidelines for lipid-lowering interventions.31
Splitting the middle category into two would introduce the potential for additional movement between categories that may not have clinical implications unless attention is given to specific risk factors.31
Even within the three Framingham risk categories we used, the presence of plaque, defined as an intima–media thickness of more than 1.5 mm, was a significant predictor of cardiovascular events (), suggesting that further analyses are needed to evaluate the effect of plaque on risk stratification.
A limitation of our study is the white race of our population, such that our results may not be applicable to other races or ethnic groups. However, the Framingham risk factors and the risk score have been successfully applied to various ethnic groups,32,33
and intima–media thickness seems to be similarly applicable.34
Another limitation is our 7.2-year follow-up period, which is shorter than the 10-year period for which the Framingham risk score is calculated.35
This discrepancy may have decreased the overall power of our observations. In addition, we relied on a single experienced and supervised sonographer to obtain high-quality measurements during carotid-artery ultrasonography, but this might affect the implementation of our findings in primary prevention, since we believe that the sonographer’s judgment and experience affect the assessment for plaque in the internal carotid artery.19
One benefit of using the sonographer, however, was that data on intima–media thickness in the internal carotid artery were missing for only 19 of our 2965 participants.
Our results may affect how intima–media thickness is assessed for the primary prevention of cardiovascular disease. The recent American College of Cardiology Foundation–American Heart Association guidelines13
give carotid intima–media thickness a level IIa recommendation for cardiovascular risk evaluation (the same as the recommendation level for the ankle–brachial index and coronary-artery calcium scoring), with an emphasis on an indication of high risk if the common-carotid-artery intima–media thickness is above the 75th percentile.10
The 75th-percentile threshold is also adopted in the report of the Screening for Heart Attack Prevention and Education Task Force,12
and its use is currently reimbursed in one state.36
However, these two guidelines lack quantitative criteria for the intima–media thickness of the internal carotid artery.
Our results show that plaque in the internal carotid artery, either measured as part of the continuous intima–media thickness or assumed to be present if the thickness exceeds a set point of 1.5 mm, offers modest incremental value to the Framingham risk score in predicting cardiovascular events. We believe the intima–media thickness of the internal carotid artery should be measured in addition to the thickness of the common carotid artery for purposes of cardiovascular risk assessment. One limitation, however, may be the method used to measure the intima–media thickness of the internal carotid artery. We used a continuous tracing of the contour of the wall and an automatic algorithm to determine the maximum value.19
The results of these offline measurements may differ from the results of measurements made with the calipers available on an ultrasonographic imaging device.
We conclude that the intima–media thickness of the common carotid artery and the intima–media thickness of the internal carotid artery are independent predictors of cardiovascular events among participants in the Framingham Offspring Study. The maximum intima–media thickness of the internal carotid artery, as either a continuous measurement or a surrogate for the presence of plaque (above a threshold of 1.5 mm), contributed significantly but modestly to the predictive power of the risk factors used in calculating the Framingham risk score and improved risk classification on the basis of the Framingham risk score.