Associations between C-reactive protein, coronary artery calcium, and cardiovascular events: implications for the JUPITER population from MESA, a population-based cohort study

Abstract

Background: The JUPITER trial showed that some patients with LDL-cholesterol concentrations less than 3·37 mmol/L (<130 mg/dL) and high-sensitivity C-reactive protein (hsCRP) concentrations of 2 mg/L or more benefit from treatment with rosuvastatin, although absolute rates of cardiovascular events were low. In a population eligible for JUPITER, we established whether coronary artery calcium (CAC) might further stratify risk; additionally we compared hsCRP with CAC for risk prediction across the range of low and high hsCRP values.

Methods: 950 participants from the Multi-Ethnic Study of Atheroslcerosis (MESA) met all criteria for JUPITER entry. We compared coronary heart disease and cardiovascular disease event rates and multivariable-adjusted hazard ratios after stratifying by burden of CAC (scores of 0, 1-100, or >100). We calculated 5-year number needed to treat (NNT) by applying the benefit recorded in JUPITER to the event rates within each CAC strata.

Findings: Median follow-up was 5·8 years (IQR 5·7-5·9). 444 (47%) patients in the MESA JUPITER population had CAC scores of 0 and, in this group, rates of coronary heart disease events were 0·8 per 1000 person-years. 74% of all coronary events were in the 239 (25%) of participants with CAC scores of more than 100 (20·2 per 1000 person-years). For coronary heart disease, the predicted 5-year NNT was 549 for CAC score 0, 94 for scores 1-100, and 24 for scores greater than 100. For cardiovascular disease, the NNT was 124, 54, and 19. In the total study population, presence of CAC was associated with a hazard ratio of 4·29 (95% CI 1·99-9·25) for coronary heart disease, and of 2·57 (1·48-4·48) for cardiovascular disease. hsCRP was not associated with either disease after multivariable adjustment.

Interpretation: CAC seems to further stratify risk in patients eligible for JUPITER, and could be used to target subgroups of patients who are expected to derive the most, and the least, absolute benefit from statin treatment. Focusing of treatment on the subset of individuals with measurable atherosclerosis could allow for more appropriate allocation of resources.

Funding: National Institutes of Health-National Heart, Lung, and Blood Institute.

Figure 1. Assembly of the Study Population

The “MESA JUPITER” population was used to test the ability of CAC to risk stratify the JUPITER-eligible population. The “Total Study Population” was used to test the relative predictive value of CAC and hsCRP.

Figure 2. Distribution of Coronary Artery Calcium (CAC) Burden in the MESA JUPITER population

The number needed to scan (NNS) to identify one individual with CAC=0 is 2. The NNS to identify one individual with elevated CAC >100 is 4.

Figure 3. Kaplan-Meier Estimates of CHD and CVD Event-Free Survival by Coronary Artery Calcium (CAC) Burden in the MESA JUPITER Population

Figure 4. Kaplan-Meier Estimates of CHD and CVD Event-Free Survival by hsCRP Status in the Total Study Population

Event-free survival did not differ by hsCRP status (Log-rank p=0.55 for CHD events, p=0.87 for CVD events).

Figure 5. Absolute CHD and CVD Event Rates by Coronary Artery Calcium (CAC) Burden, Stratified by hsCRP Status

Overall event rates were similar in the low vs. high hsCRP groups: 7.6 vs. 6.4 CHD events [p=0.47] and 10.1 vs. 10.4 CVD events per 1000 patient-years [p=0.87]. CHD and CVD event rates were higher with increasing CAC in both hsCRP groups (each p<0.0001), and the event rate distribution was not significantly different when stratified by hsCRP status (p=0.41). In age, gender, and race adjusted survival analysis, there was no interaction between CAC and hsCRP for prediction of either CHD or CVD events (p=0.7).