The Multi-Ethnic Study of Atherosclerosis (MESA)
The Multi-Ethnic Study of Atherosclerosis (MESA) is a NIH/NHLBI-funded population-based prospective cohort study aimed at describing the prevalence, progression, and significance of subclinical atherosclerosis. Details of the MESA study design have been previously published11
Between July 2000 and September 2002, MESA enrolled 6,814 individuals at six field centers (Baltimore; Chicago; Forsyth County, North Carolina; Los Angeles; New York; and St. Paul, Minnesota). The participants were required to be age 45 to 84 and have no known clinical cardiovascular disease at the time of enrollment. Participants were recruited at each site from lists of residents, dwellings, and telephone-company customers with emphasis on ethnic diversity.
Using baseline data (MESA, 2000–2002), we identified 2,083 MESA participants (31%) who fit the following JUPITER inclusion criteria: age ≥50 for men and ≥60 for women, LDL-C <130 mg/dL, not on lipid-lowering therapy, free of diabetes, triglycerides <500 mg/dL, and creatinine ≤2 mg/dL (). Of these 2,083 individuals comprising the “Total Study Population”, 950 (46%) had high hsCRP (hsCRP ≥2 mg/dL) and were thus eligible for the JUPITER trial (“MESA JUPITER” population, ).
Assembly of the Study Population
Cardiac CT Protocol
Cardiac CT was performed at 3 sites using a cardiac-gated electron-beam CT scanner and at 3 sites using 4-slice multidetector CT. Patients were scanned twice, with CAC (Agatston) scores averaged. Images were interpreted at the MESA CT reading center (Harbor-UCLA).
Carr et al. have reported details of the methods used by MESA for computed tomographic (CT) scanning and interpretation12
. The kappa statistic for agreement on presence of CAC was 0.92, and the mean rescan percentage absolute difference in CAC was 20.1% among those with CAC>0.
hsCRP and Study Covariates
As part of the baseline examination, clinical teams at each of the six centers collected information on cardiovascular risk factors. A central laboratory (University of Vermont, Burlington) measured levels of total and HDL cholesterol, triglycerides, plasma glucose, and high-sensitivity C-reactive protein after a 12-hour fast. hsCRP was determined by BNII nephelometer (N High Sensitivity CRP; Dade Behring Inc., Deerfield, IL). The lower limit of detection was 0.17 mg/L.
Follow-up and Event Adjudication
New coronary heart disease (CHD) and cardiovascular disease (CVD) events were recorded over a median follow-up of 5.8 years. At intervals of 9 to 12 months, an interviewer contacted each participant or a family member regarding interim hospital admissions, outpatient diagnoses of CHD and CVD, and deaths. MESA was successful in obtaining medical records for approximately 98% of hospitalized events and information on 95% of outpatient cardiovascular diagnostic encounters. Follow-up telephone interviews were completed in 92% of living participants.
Two physician members of the MESA mortality and morbidity review committee independently classified events, and in the event of disagreement, the full committee adjudicated. CHD events consisted of myocardial infarction, death from coronary heart disease, definite angina, probable angina followed by coronary revascularization, or resuscitated cardiac arrest. CVD events consisted of CHD events plus stroke (not TIA), stroke death, other atherosclerotic death, and other CVD death. A detailed description of the MESA follow-up methods is available at www.mesa-nhlbi.org
Baseline characteristics of the 2,083 study participants were analyzed according to hsCRP status (low [<2 mg/L] or high [≥2 mg/L]). Frequencies and proportions were calculated for categorical variables, and either means with standard deviations or medians with interquartile ranges calculated for continuous variables.
We used Kaplan-Meier estimates of cumulative event-free survival to describe the occurrence of CHD and CVD events over time. To determine if CAC could further risk stratify the JUPITER population, we compared absolute CHD and CVD event rates and Cox multivariable-adjusted hazard ratios after stratifying by both presence and burden of CAC (0, 1–100, >100). Models were adjusted for age, gender, race/ethnicity, hypertension, smoking, BMI, HDL-C, antihypertensive medication use, family history of myocardial infarction, education level (a measure of socioeconomic status), and MESA site.
To compare the relative predictive power of hsCRP and CAC, we compared absolute CHD and CVD event rates stratified by hsCRP and CAC status in the total study population. In addition, we tested for interaction/effect modification between hsCRP and CAC.
Number Needed to Treat Analysis
We calculated 5-year number needed to treat (NNT5
) for both CHD and CVD by applying the hazard ratio associated with rosuvastatin treatment in the JUPITER trial (0.56) to the event rates observed within each CAC strata. For this analysis, NNT were calculated directly as the reciprocal of the absolute risk difference at median follow-up of the cohort (5.8 years), based on Kaplan-Meier estimates, and then subsequently adjusted to a 5-year NNT5
according to the Altman-Anderson method13
. Sensitivity analyses were conducted using the upper and lower limits of the hazard ratio observed in JUPITER.