Quantification of Coronary Atherosclerosis and Inflammation to Predict Coronary Events and All-Cause Mortality

Study Questions:

Does the combined presence of coronary artery calcium (CAC) and elevated high-sensitivity C-reactive protein (hs-CRP) improve discrimination and stratification of hard coronary events and all-cause mortality in the general population?

Methods:

The Heinz Nixdorf Recall (HNR) study is a German population registry-based cohort study designed to assess the predictive value of novel markers of risk when used in addition to traditional risk factors. Eligible persons were 45-75 years old and 50% were planned to be women. Persons with known coronary disease and hs-CRP >10 mg/dl were excluded. Framingham risk variables, hs-CRP, and CAC were measured in 3,966 subjects without known coronary artery disease or acute inflammation. After 5 years, incident coronary deaths, nonfatal myocardial infarction, and all-cause mortality were determined.

Results:

Mean age was 60 years and 53% were women. After 5.1 ± 0.3 years of follow-up, 91 subjects (2.29%) had a coronary event. CAC and hs-CRP independently predicted coronary events (adjusted hazard ratios [HRs], log2(CAC+1) = 1.25 [95% CI, 1.16-1.34], p < 0.0001; hs-CRP = 1.11 [95% CI, 1.02-1.21], p = 0.019) and 130 deaths (adjusted HRs, log2(CAC+1) = 1.12 [95% CI, 1.06-1.19], p < 0.0001; hs-CRP = 1.11 [95% CI, 1.04-1.19], p = 0.004). For coronary events, net reclassification improvement (NRI) was 23.8% (p = 0.0007) for CAC and 10.5% (p = 0.026) for hs-CRP. Adding CAC to Framingham risk variables and hs-CRP further improved discrimination of coronary risk, but not vice versa. Among persons without CAC, those with hs-CRP >3 mg/L versus <3 mg/L had a significantly higher coronary risk (p = 0.006). For all-cause mortality, integrated discrimination improvement (IDI) was positive when CAC or hs-CRP were added to age and sex (+0.51%, p < 0.001 and +0.43%, p = 0.012, respectively). Adjusted HRs in the highest versus lowest category of a risk index derived from established CAC and hs-CRP thresholds (i.e., CAC = 100 and hs-CRP = 3 mg/L) were 5.92 (95% CI, 3.14-11.16) for coronary events and 3.02 (95% CI, 1.82-5.01) for all-cause mortality (p < 0.0001 each). The adjusted HR for coronary events in intermediate-risk subjects was 6.98 (95% CI, 2.47-19.73; p < 0.001).

Conclusions:

The risk of coronary events and all-cause mortality that is mediated by the presence of coronary atherosclerosis and systemic inflammation can be estimated by CAC and hs-CRP. An improvement in coronary risk prediction and discrimination was predominantly driven by CAC, whereas hs-CRP appears to have a role especially in persons with very low CAC scores.

Perspective:

The results of this study are similar to that of the MESA study in the United States. Whether CAC-driven and hs-CRP-driven risk-modifying therapy is justified by improved outcome must be tested in clinical trials. However, Michael Blaha and colleagues presented an abstract at the 2010 American Heart Association Scientific Sessions. Of 6,814 patients in the Multi-Ethnic Study of Atherosclerosis (MESA), they identified 2,083 patients who met the criteria for the JUPITER trial (hs-CRP >2 mg/dl and low-density lipoprotein cholesterol <130 mg/dl). These patients, 40% of whom were female, averaged 67 years old, had a mean hs-CRP level of 4.3 mg/dl, and a mean 10-year Framingham risk score of 10%. Almost one-half of patients in the MESA cohort had no coronary calcification assessed by computed tomography. Among those with a CAC of zero, the number-needed-to-treat (NNT) was 549 to prevent one coronary heart disease event and 124 to prevent one cardiovascular disease event. Most events occurred in individuals with a CAC >100, and among these patients, the NNT to prevent one coronary heart disease and cardiovascular disease event was 24 and 19, respectively.

Clinical Topics: Dyslipidemia, Noninvasive Imaging, Atherosclerotic Disease (CAD/PAD), Lipid Metabolism, Nonstatins

Keywords: Cholesterol, Coronary Artery Disease, Myocardial Infarction, C-Reactive Protein, Follow-Up Studies, Atherosclerosis, Biological Markers, Tomography, Risk Factors, United States, Calcium


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