Elevated hs-CRP as a Risk Marker of Cardiovascular Events
Elevated hs-CRP as a Risk Marker of Cardiovascular Events
The study population for this analysis was derived from the Atherosclerosis Risk in Communities (ARIC) Study. ARIC is a large multicenter cohort study of persons who were between 45 and 64 years of age at the time of enrollment in 1987–1989. The ARIC Study is conducted at 4 field centers in Washington County, Maryland; Forsyth County, North Carolina; Jackson, Mississippi; and Minneapolis, Minnesota. Details of the design of the ARIC Study have been described previously. All participants who completed the visit 4 screening with a serum draw for measurement of hs-CRP and cholesterol were eligible for inclusion in this analysis (n = 11,148). Participants were excluded if they 1) had known coronary artery disease, defined as a history of myocardial infarction, coronary bypass or angioplasty, or electrocardiogram-diagnosed myocardial infarction (n = 922); 2) were taking a cholesterol-lowering medication (n = 1,168); or 3) were missing other important covariates (n = 111). The study population in this analysis after exclusions consisted of 8,947 participants.
At each visit, standardized and validated interviewer-administered questionnaires were used to collect demographic information; smoking and alcohol consumption status; and history of cancer, diabetes, and hypertension. Smoking and alcohol consumption were categorized into never, former, and current groups. Height, body weight, and blood pressure were measured at each visit. Weight change in this analysis was defined as the difference in body weight between visits 3 and 4. Prevalent diabetes was defined as a fasting glucose level of 126 mg/dL or higher. Carotid intimal-medial thickness was measured by ultrasound at either visit 1 or visit 2 as described previously. Twelve-hour fasting plasma total cholesterol, low-density lipoprotein (LDL) cholesterol, triglyceride, and high-density lipoprotein cholesterol levels were measured in a centralized laboratory at each visit. The assays and their performance have been reported. LDL cholesterol was calculated with the Friedewald formula. All measures followed a common protocol to maximize comparability across persons and visits. At visit 4, hs-CRP was measured in a central laboratory on plasma frozen at −80°C with an immunonephelometric assay on a BNII analyzer (Siemens Healthcare Diagnostics, Deerfield, Illinois) according to the manufacturer's protocol. The reliability coefficient for the hs-CRP assay was 0.99 and was based on 421 blinded replicates. In the present analysis, we used the Justification for the Use of Statins in Primary Prevention cutpoint of 2 mg/L or higher to classify participants with an elevated hs-CRP level.
The primary outcome of this analysis was incident CHD, defined as one of the following: silent infarction diagnosed by electrocardiogram, myocardial infarction, coronary artery bypass or angioplasty, or death from CHD before January 2009. Incident cases were verified by 2 reviewers from the ARIC Morbidity and Mortality Classification Committee, and any differences between reviewers were adjudicated by the committee chairperson.
Statistical analyses were performed in Stata, version 11 (StataCorp LP, College Station, Texas). Analyses were conducted separately for those less than 65 and those 65 years of age or older. Within each age category, participants were grouped according to level of hs-CRP. An extension of the Wilcoxon rank-sum test was used to compare continuous variables, and the χ test was used to compare categorical variables. Crude incident rates were calculated per 1,000 person-years and compared by Poisson regression. Mean change in cholesterol level was calculated by taking the average difference between serum cholesterol level at visit 4 and at each previous visit. Cox proportional-hazard models were used to calculate hazard ratios and confidence intervals for the primary outcome for each age group by hs-CRP category. The proportional-hazards assumption was not violated on the basis of Schoenfeld residual testing. The interaction between total cholesterol level and hs-CRP category was assessed within each age group and between age groups. We examined the continuous interaction between age, hs-CRP level, and cholesterol level (total and LDL) by using a fully adjusted hazards model and also by using an additive model. The same models were used for LDL cholesterol. Covariates adjusted for in model 1 were age, sex, and race. Model 2 adjusted for age, sex, race, current smoking, diabetes, hypertension, and body mass index. Model 3 adjusted for all covariates in model 2, plus high-density lipoprotein cholesterol level. Sensitivity analyses were conducted with fully adjusted Cox proportional-hazards models stratified by sex, race, diabetes, and years of follow-up, and with exclusion of participants with an hs-CRP level greater than 10 mg/L.
Materials and Methods
Study Design and Population
The study population for this analysis was derived from the Atherosclerosis Risk in Communities (ARIC) Study. ARIC is a large multicenter cohort study of persons who were between 45 and 64 years of age at the time of enrollment in 1987–1989. The ARIC Study is conducted at 4 field centers in Washington County, Maryland; Forsyth County, North Carolina; Jackson, Mississippi; and Minneapolis, Minnesota. Details of the design of the ARIC Study have been described previously. All participants who completed the visit 4 screening with a serum draw for measurement of hs-CRP and cholesterol were eligible for inclusion in this analysis (n = 11,148). Participants were excluded if they 1) had known coronary artery disease, defined as a history of myocardial infarction, coronary bypass or angioplasty, or electrocardiogram-diagnosed myocardial infarction (n = 922); 2) were taking a cholesterol-lowering medication (n = 1,168); or 3) were missing other important covariates (n = 111). The study population in this analysis after exclusions consisted of 8,947 participants.
Exposure Variables
At each visit, standardized and validated interviewer-administered questionnaires were used to collect demographic information; smoking and alcohol consumption status; and history of cancer, diabetes, and hypertension. Smoking and alcohol consumption were categorized into never, former, and current groups. Height, body weight, and blood pressure were measured at each visit. Weight change in this analysis was defined as the difference in body weight between visits 3 and 4. Prevalent diabetes was defined as a fasting glucose level of 126 mg/dL or higher. Carotid intimal-medial thickness was measured by ultrasound at either visit 1 or visit 2 as described previously. Twelve-hour fasting plasma total cholesterol, low-density lipoprotein (LDL) cholesterol, triglyceride, and high-density lipoprotein cholesterol levels were measured in a centralized laboratory at each visit. The assays and their performance have been reported. LDL cholesterol was calculated with the Friedewald formula. All measures followed a common protocol to maximize comparability across persons and visits. At visit 4, hs-CRP was measured in a central laboratory on plasma frozen at −80°C with an immunonephelometric assay on a BNII analyzer (Siemens Healthcare Diagnostics, Deerfield, Illinois) according to the manufacturer's protocol. The reliability coefficient for the hs-CRP assay was 0.99 and was based on 421 blinded replicates. In the present analysis, we used the Justification for the Use of Statins in Primary Prevention cutpoint of 2 mg/L or higher to classify participants with an elevated hs-CRP level.
Outcomes
The primary outcome of this analysis was incident CHD, defined as one of the following: silent infarction diagnosed by electrocardiogram, myocardial infarction, coronary artery bypass or angioplasty, or death from CHD before January 2009. Incident cases were verified by 2 reviewers from the ARIC Morbidity and Mortality Classification Committee, and any differences between reviewers were adjudicated by the committee chairperson.
Statistical Methods
Statistical analyses were performed in Stata, version 11 (StataCorp LP, College Station, Texas). Analyses were conducted separately for those less than 65 and those 65 years of age or older. Within each age category, participants were grouped according to level of hs-CRP. An extension of the Wilcoxon rank-sum test was used to compare continuous variables, and the χ test was used to compare categorical variables. Crude incident rates were calculated per 1,000 person-years and compared by Poisson regression. Mean change in cholesterol level was calculated by taking the average difference between serum cholesterol level at visit 4 and at each previous visit. Cox proportional-hazard models were used to calculate hazard ratios and confidence intervals for the primary outcome for each age group by hs-CRP category. The proportional-hazards assumption was not violated on the basis of Schoenfeld residual testing. The interaction between total cholesterol level and hs-CRP category was assessed within each age group and between age groups. We examined the continuous interaction between age, hs-CRP level, and cholesterol level (total and LDL) by using a fully adjusted hazards model and also by using an additive model. The same models were used for LDL cholesterol. Covariates adjusted for in model 1 were age, sex, and race. Model 2 adjusted for age, sex, race, current smoking, diabetes, hypertension, and body mass index. Model 3 adjusted for all covariates in model 2, plus high-density lipoprotein cholesterol level. Sensitivity analyses were conducted with fully adjusted Cox proportional-hazards models stratified by sex, race, diabetes, and years of follow-up, and with exclusion of participants with an hs-CRP level greater than 10 mg/L.
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