The results of this study demonstrate that when CACS is added to traditional risk factors it results in a significant improvement in the classification of risk for the prediction of CHD events in an asymptomatic population-based sample of men and women drawn from four U.S. ethnic groups. Our results highlight improvements in risk classification when utilizing CACS. Incorporation of an individual’s CACS leads to a more refined estimation of future risk for CHD events than traditional risk factors alone. The intermediate risk group achieved a substantially higher NRI than the overall cohort, and therefore appear to benefit the most from a CACS-adjusted strategy. This study provides strong evidence that there may be a significant amount of clinically useful reclassification when CACS is added to risk assessment in asymptomatic intermediate risk patients.
Considerable debate remains about how best to use CACS for risk assessment. Current American College of Cardiology/American Heart Association statements recommend that asymptomatic individuals at intermediate Framingham risk may be reasonable candidates for CHD testing using CACS.17
However, particular concern has been raised about the safety and cost associated with the widespread use of CACS. One recent study suggested an elevated cancer risk if a calcium score is obtained every five years.18
Others have questioned whether a CACS-guided strategy may actually cost more money and prevent fewer events than simply treating all patients at intermediate risk.19
In the setting of such uncertainty it is important to understand how to maximize the potential benefits of using CACS, while minimizing harm.
Direct comparisons to studies evaluating the NRI with other biomarkers should be made with caution, because the number of risk categories used, definition of the primary outcome, and length of follow-up often differs between studies. However, it is of interest that the NRI achieved with the addition of lipoprotein particles was negligible, glycosylated hemoglobin was 0.034, midregional proadrenomedullin (MR-proADM) with N-terminal pro-B-type natriuretic peptide was 0.047 and high-sensitivity C-reactive protein with family history was 0.068.20-23
In another study from MESA the use of brachial artery flow-mediated dilation resulted in an NRI of 0.29.24
However, this included a substantial proportion of inappropriate reclassifications downward among individuals who experienced events (23%). An important impact of a marker for the prediction of risk is the number people identified as having a higher disease risk and consequently become eligible to receive more intensive therapy as a result of screening. A relatively small proportion of the total MESA population, 5.1%, was reclassified to high risk. Importantly, almost 60% of the events (123/209) occurred among individuals who were not classified as high risk – either by traditional risk factors or CACS. The smaller number of participants who were classified to high risk is likely, in part, a reflection of the study population. More than half of the MESA cohort is in the lowest 5-year risk category based on traditional risk factors. Participants who were low risk required very elevated CACS to be reclassified to high risk. In contrast, the proportions of individuals reclassified were larger among the intermediate risk participants (16% to high risk and 39% to low risk). Almost half of the events among participants who were intermediate risk based on traditional risk factors alone occurred in individuals who were reclassified to high risk based on their CACS (48/115).
Inspection of the relative contribution of correct reclassification for events and nonevents also reveals important strengths and weaknesses of a CACS-adjusted strategy. For the entire cohort the NRI for events was 0.23, whereas the NRI for nonevents was 0.02. The results suggest that when applied to a general population a CACS-adjusted strategy may effectively identify more individuals who experience events, but this comes at the expense of identifying many other individuals as higher risk who do not experience events. With the availability of generic statins and years of data confirming their tolerability, the disadvantages of “overtreatment” may have become less significant over time. However, the improvement in risk classification is more balanced among the intermediate risk individuals (0.29 for events and 0.26 for nonevents), again suggesting that a CACS-adjusted strategy may be most clinically useful in this group.
Another metric of a risk marker’s utility is whether it separates individuals into more clinically relevant risk categories, as seen by the risk stratification capacity. Ideally, a model would reclassify most of the individuals out of the intermediate risk group and into the highest or lowest risk categories. When CACS is added to the model more than half of the intermediate risk individuals are reclassified to high and low risk, where treatment strategies are better established.
The values in the margins of the reclassification table best represent the net effect of including a novel marker into a risk prediction model.16
However, looking at individual cells can shed light on the potential limits of applying a marker to the clinical setting. Only four out of more than 3,000 low risk individuals were reclassified as high risk, suggesting that CACS may not be an efficient screening tool among low risk individuals. An additional concern is whether physicians can safely withhold or decrease therapy for patients who are reclassified to lower risk categories. We report that individuals who were reclassified from high to low risk experienced an event rate that was higher than predicted by the model with CACS. While the absolute number of events was small, our data support the recommendation that patients who are high risk should be treated regardless of their CACS, and as a result should not undergo CAC testing for additional risk assessment.
A critical question not answered in this study is whether screening for subclinical disease with CACS improves patient outcomes. In a recent American Heart Association scientific statement, the steps needed before widespread adoption of a risk marker were outlined.5
Initial phases of evaluation should demonstrate that a marker can differentiate between people with and without events, prospectively predict future events, and add predictive information to traditional risk factors – all of which have been accomplished with CACS. The results in the current report address the fourth phase, in which a marker must be shown to adjust predicted risk sufficiently to change recommended therapy. Whether the use of a marker improves clinical outcomes enough to justify the associated cost should be tested in the final phase, preferably with a randomized clinical trial.
Our study has limitations which should be acknowledged. Our results will need to be validated in additional populations. Had our study population contained a larger proportion of higher risk individuals, we may have seen higher event rates and different rates of reclassification. It is also possible that with longer follow-up and additional events our results could change.
In MESA the CACS was revealed to participants and their physicians. This could have affected our results in two ways. Knowledge of a high CACS may have biased the diagnosis of angina, and thus could have increased the NRI. Alternatively, participants with a high CACS may have had more intensive risk factor modification thereby reducing the number of events, and decreasing the NRI. We do not expect that the diagnosis of major coronary events would have been influenced by CACS.
In conclusion, we found that use of CACS plus traditional risk factors substantially enhances the ability to classify a multi-ethnic cohort of asymptomatic people without known CVD into clinically accepted categories of risk of future CHD events. The results provide encouragement for moving to the next stage of evaluation to assess the use of CACS on clinical outcomes.