CAC Score and hs-CRP Improve Risk Prediction Over Framingham

March 24, 2011

March 24, 2011 (Essen, Germany) — Combining measurements of atherosclerosis assessed by coronary artery calcium (CAC) screening and high-sensitivity C-reactive protein (hs-CRP) independently and accurately predicted coronary events and all-cause mortality in healthy subjects without physician-diagnosed coronary artery disease, according to the results of a new study [1]. In addition, both hs-CRP and CAC added incremental prognostic information to the Framingham risk score to improve the prediction of coronary events, with coronary risk prediction predominately driven by CAC, while hs-CRP improved prediction in individuals with low CAC scores.

"The analysis is really about risk stratification," lead investigator Dr Stefan Möhlenkamp (University Clinic, Essen, Germany) told heartwire . "Based on risk stratification, you have not yet saved one life, not yet prevented one event. The important thing is that you have identified those persons at highest highest and lowest risk. I believe, and I think our data add to this concept, that both inflammation risk. I believe, and I think our data add to this concept, that both inflammation and coronary atherosclerosis burden are measurable, one by high-sensitivity CRP and one by coronary calcium, and provide information that has strong predictive ability beyond what we currently know based on traditional risk-factor assessment."

Published in the March 29, 2011 issue of the Journal of the American College of Cardiology, the study is an analysis of 3966 subjects participating in the Heinz Nixdorf Recall Study, a study that initially began with the goal of determining whether modern technology, primarily CAC screening, could improve coronary risk prediction above and beyond traditional approaches. The purpose of this latest analysis was to directly compare hs-CRP and CAC and to determine whether the two markers might be additive in their ability to predict coronary events and all-cause mortality.

After five years of follow-up, there were 91 coronary events, with 29 subjects dying of coronary heart disease and 62 individuals having a nonfatal MI. In addition, there were 98 noncoronary deaths, with approximately half of these deaths caused by cancer. Hazard ratios of coronary events and all-cause mortality increased with increasing CAC score and hs-CRP categories.

Adjusted Hazard Ratio* of Coronary Events and All-Cause Mortality by CAC Scores and hs-CRP Levels

Measure Coronary events, adjusted HR (95% CI) All-cause mortality, adjusted HR (95% CI)
CAC score    
0 1.0 1.0
>0-99 1.48 (0.72–3.07) 2.45 (1.37–4.38)
100–399 3.03 (1.44–6.38) 2.82 (1.48–5.36)
>400 5.92 (2.82–12.45) 3.71 (1.89–7.28)
hs-CRP    
<1 mg/L 1.0 1.0
1–3 mg/L 0.95 (0.55–1.64) 1.72 (1.06–2.79
>3 mg/L 1.82 (1.05–3.15) 2.53 (1.52–4.23)

*Adjusted for Framingham risk score, cardiovascular disease or cardiovascular medications, body-mass index, and hs-CRP or CAC

In measuring the net reclassification index (NRI), a measure of how many patients were reclassified into different risk categories when CAC score and hs-CRP were added to a model based on Framingham risk factors for coronary event risk assessment, investigators report improved measures of discrimination with both CAC and hs-CRP. Adding hs-CRP improved the prediction of coronary events by 10.5% and adding CAC improved prediction by 23.8%. The investigators also report that adding CAC to a model that included Framingham risk scores and hs-CRP further improved discrimination for coronary risk, but adding hs-CRP to a model that included CAC and Framingham risk scores did not.

"The interesting thing is the coronary artery calcium in our study was a much stronger predictor of coronary events than high-sensitivity CRP," said Möhlenkamp. "Both markers had a predictive value for coronary events that was observed in previous studies. When we added high-sensitivity CRP to coronary artery calcium, we didn't get much more predictive information overall. However, if we add coronary calcium to traditional risk factor analysis and to high-sensitivity CRP, you do get significantly more prognostic information."

hs-CRP and All-Cause Mortality

To heartwire , Möhlenkamp noted that there was one subgroup--individuals with very low atherosclerosis burden measured by CAC--that particularly benefited from hs-CRP screening. Among these individuals with a CAC score of zero, individuals with hs-CRP levels >3.0 mg/L were more than four and a half times more likely to have a coronary event than individuals with no measurable inflammation. "If individuals have no or a very low burden of atherosclerosis, these are people in whom high-sensitivity CRP has predictive value," said Möhlenkamp.

Despite coronary risk prediction and discrimination being better served by CAC screening, Möhlenkamp said he views CAC and hs-CRP measurements as complementary. In the assessment of all-cause mortality, for example, hs-CRP and CAC scores were both similar in their predictive value, he said.

"Inflammatory markers might be of particular value in individuals with a low burden of atherosclerosis," said Möhlenkamp. "We have to take into account that there are a great number of individuals with chronic inflammatory disease, such as diabetes, rheumatoid arthritis, chronic obstructive lung disease, HIV, psoriasis, etc. The implication of the paper would be that these individuals might be at particularly high risk of clinical events, in part mediated by the presence and extent of atherosclerosis and inflammation."

In an editorial accompanying the study [2], Drs Christian Hamm, Holger Nef, Andreas Rolf, and Helge Möllmann (Heart and Thorax Center, Bad Nauheim, Germany) note that socioeconomic aspects need to be considered in the era of limited healthcare resources. For example, the relatively low event rate in the Heinz Nixdorf Recall Study and low number of reclassified patients means that the "number needed to reclassify" patients--that being the number of patients who must undergo hs-CRP or CAC screening--is high. In addition, it remains unknown how to best treat these patients.

Not So Easy to Predict Behavior

Speaking with heartwire , Dr James Stein (University of Wisconsin, Madison), who was not involved in the EISNER analysis, said the "interesting and important" study confirms the results observed from other observational studies showing that doctors respond to subclinical atherosclerosis, usually by prescribing treatments such as aspirin, lipid-lowering drugs, and blood-pressure medications. However, he noted the effects observed in the individual risk factors were small.

Regarding analyses such as EISNER, which he praised for its randomized, controlled design and long-term follow-up, Stein said studies assessing the effects of imaging on behavior are difficult to perform and that they can be "self-fulfilling prophesies." If a clinician sees subclinical atherosclerosis on any imaging scan, the reaction of most is to prescribe medication. Regarding patient behavior, however, it depends on what the individual is told about the calcification and the risks it poses in the short and long term. Even then, he said, the individual behavior change through lifestyle and diet is unpredictable. His group recently published data in the Archives of Internal Medicine showing that patients undergoing carotid ultrasound imaging who received intensive counseling about the results as well as recommendations still had "inappropriate risk perception, decay in recall over time, and poor adoption of lifestyle changes."

"We're in a position where we're playing 'armchair psychologists,' " said Stein. "The change the individual makes depends on how he or she perceives the threat. We're trained as cardiologists, not as psychologists, and it's naive for us to think that seeing the atherosclerosis on an imaging scan is sufficient to change an individual's behavior. I know it's counterintuitive--we think we can show them a picture and then they’ll change their behavior--but in the long term we can't predict how it will affect their lifestyle choices."

Stein noted that for every patient presented with evidence of subclinical atherosclerosis and "who gets religion"--that being a change in lifestyle through smoking cessation, dietary changes, and the adoption of physical activity--there is another patient who doesn't return to his office. “We just tend to remember the ones who really changed--because it fits our expectations.”

In addition, Dr Paul Ridker (Brigham and Women's Hospital, Boston, MA) took issue with the conclusions of Rozanski and colleagues, pointing instead to the lack of significant difference between those scanned and those not scanned for changes in end points such as diastolic blood pressure, total- and HDL-cholesterol levels, triglyceride levels, glucose, and medication adherence. "Given these primary end points, how then do we state with confidence that CAC scanning is associated with superior CAD risk-factor control?" he questioned in an email to heartwire .

To heartwire , on the other hand, Berman said that the EISNER data provide support for the recent American College of Cardiology Foundation (ACCF)/American Heart Association (AHA) class IIa recommendation for the use of computed tomography (CT) to measure coronary calcium. According to the ACCF/AHA, the use of CAC "is reasonable for cardiovascular risk assessment in asymptomatic adults at intermediate risk (10% to 20% 10-year risk)."

Möhlenkamp et al report no conflicts of interest. Hamm reports receiving honorarium from Siemens. Nef has received speaker's fees from Siemens.

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