STRUCTURED ABSTRACT
Objectives
To describe the proportion of “JUPITER-eligible” individuals and clinical outcomes of individuals based on high-sensitivity C-reactive protein (hs-CRP) and low-density lipoprotein cholesterol (LDL-C) strata in the Atherosclerosis Risk in Communities (ARIC) study.
Background
Questions remain after the JUPITER study including whether the observed cardiovascular disease (CVD) event rates would persist with time and how these event rates would compare with other populations (lower hs-CRP and/or higher LDL-C levels).
Methods
After stratification into 4 groups based on LDL-C and hs-CRP levels, with cutoffs at 130 mg/dL and 2.0 mg/L, respectively incident CVD events were examined (mean follow-up 6.9 years) and compared.
Results
Of 8,907 age-eligible participants, 18.2% (n=1,621) were “JUPITER-eligible” (hs-CRP ≥2.0 mg/L, LDL-C <130 mg/dL) and had an absolute CVD risk of ~10.9% over a mean follow-up of 6.9 years (1.57% per year). If JUPITER hazard ratios were applied to this group, the number needed to treat to prevent one CVD event would be estimated at 38 over 5 years and 26 over 6.9 years.
Conclusion
ARIC participants with elevated hs-CRP and low LDL-C had a CVD event rate of 1.57% per year over 6.9 years similar to the CVD event rate noted in the JUPITER study placebo group (1.36% per year over 1.9 years). The association of hs-CRP ≥2.0 mg/L with increased CVD risk and mortality regardless of LDL-C provides us a simple method of using age and hs-CRP for identifying higher risk individuals.
Keywords: hs-CRP, LDL-C, ARIC, lipids, cardiovascular disease
INTRODUCTION
Recently, rosuvastatin therapy was shown to reduce cardiovascular disease (CVD) events in men and women (≥50 years and ≥60 years of age, respectively) with low-density lipoprotein cholesterol (LDL-C) <130 mg/dL and high-sensitivity C-reactive protein (hs-CRP) ≥2.0 mg/L without known CVD in the Justification for the Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) (1).
Questions remained at the conclusion of JUPITER including: 1) would the absolute event rates and risk reduction persist if the trial was continued for a longer time given the short (1.9 years) follow-up 2) what percentage of the population may be eligible for therapy based on the study and 3) would similar findings have been observed if individuals with hs-CRP <2.0 mg/L were included. Although randomized-controlled trials may be required to answer some of these question (such as risk reduction), population-based studies may be ideal to evaluate JUPITER’s clinical implications and the natural history/ event rates in individuals with elevated hs-CRP and low LDL-C.
One analysis using the National Health and Nutrition Examination Survey (NHANES) 1999–2004 data suggested 8.07 million individuals(13.9%) of age-eligible individuals would meet JUPITER eligibility criteria, (2) while another analysis suggested that ~6.5 million individuals may be eligible (3). However, these studies lacked longitudinal follow-up for outcomes and the ability to provide actual CVD risk in a population. Other primary prevention studies compared CVD event rates in individuals by hs-CRP and LDL-C groups, but these analyses were performed post-hoc on randomized patients in clinical trials making them prone to selection bias; moreover, they used very different cutoff levels for hs-CRP and LDL-C.
Therefore, we examined JUPITER’s clinical implications in the Atherosclerosis Risk in Communities (ARIC) study, a population-based study of CVD disease incidence. We compared outcomes in the “JUPITER eligible” group to those in the other LDL-C and hs-CRP level strata (i.e., hs-CRP <2.0 mg/L and/or LDL-C ≥130 mg/dL).
METHODS
Study Population
The design and objectives of the ARIC study have been previously described (4). Briefly, the ARIC study is a prospective, biracial, observational study of CVD in 15,792 individuals between ages 45–64 years at the initial visit (1987–1989). Our analysis used Visit 4 (1996–1998) data which had hs-CRP levels available in 11,343 of 11,656 individuals. We applied JUPITER exclusion criteria (Figure 1) except that peripheral vascular disease (PVD) and current hormone replacement therapy (HRT) use in women were not excluded since adequate information for these variables were not available during ARIC Visit 4.. After exclusions, except for LDL-C and hs-CRP, there were 5,513 individuals, who were further stratified by LDL-C (<130 mg/dL vs. ≥130 mg/dL) and hs-CRP (<2.0 mg/L vs. ≥2.0 mg/L) into 4 groups (Figure 1).
Figure 1. Individuals meeting JUPITER criteria after exclusions in the ARIC population (1996–1998).
Inclusion and exclusion criteria are shown in sequential order of application to individuals at the 1996–1998 visit in the ARIC study. The group (Group 2) meeting the hs-CRP and LDL-C criteria of the JUPITER study has been labeled “JUPITER Eligible.”
Laboratory Methods
Plasma levels of hs-CRP were measured using an immunonephelometric assay (Dade Behring Marburg GmbH, USA) (5) (reliability coefficient 0.99 based on 421 blinded replicates).
Definition and Ascertainment of Outcomes
Our primary outcome of first major adverse cardiovascular event (MACE) was similar to JUPITER’s, which included nonfatal myocardial infarction (MI), nonfatal stroke, hospitalization for unstable angina, coronary arterial revascularization procedure (coronary arterial bypass graft/percutaneous coronary intervention), or confirmed cardiovascular death (fatal CHD or fatal stroke) except that fatal stroke (not previously defined and adjudicated in the ARIC study) was not included and fatal CHD was defined differently. Additionally, we evaluated a secondary composite endpoint of nonfatal MI, fatal CHD, nonfatal stroke and coronary revascularization (i.e., primary endpoint excluding unstable angina). Finally, like JUPITER, we evaluated deaths due to any cause or malignancy (ICD9 Codes 140-208 or ICD10 Codes C00-C97). The methods for ascertaining the various outcomes in ARIC have been previously published (4,6–8).
Statistical Analysis
The four groups (Figure 1) were compared for adjusted means, proportions, or incidence rates using linear, logistic, or Poisson models. Model adjustments included age, race, and gender. Each group had 10-year CHD risk calculated using ARIC coronary risk score (ACRS) and Framingham risk score (FRS), both calibrated to the ARIC initial examination (1986–1989) (9–11). Tests of contrasts of the beta coefficients from the linear or logistic regression models were used to calculate ‘p’-values. Hazard ratios (HR) were calculated using Cox proportional hazard models to compare groups within LDL-C and hs-CRP strata. Kaplan-Meier event free survival from any MACE was also examined.
We also tested whether significant cardiovascular risk due to elevated hs-CRP persisted within each LDL-C stratum after further adjustments for smoking status, family history of premature CHD, LDL-C levels, and Adult Treatment Panel III-defined metabolic syndrome (12).
RESULTS
Of the total Visit 4 participants (n=11,656), 1,621 (683 men and 938 women) were age-eligible, met all screening criteria, and had LDL-C <130 mg/dL and hs-CRP ≥2.0 mg/L (i.e., “JUPITER-eligible”). These 1,621 individuals (Group 2) constituted 29.4% of the screened group (n=5,513) and 18.2% of the age-eligible ARIC individuals (n=8,907) (Figure 1).
In both LDL-C categories (i.e., LDL-C <130 and ≥130 mg/dL), ~50% of the individuals had hs-CRP ≥2.0 mg/L (Figure 1). Individuals with hs-CRP ≥2.0 mg/L were more likely to be older, women, black, current smokers, and on aspirin or antihypertensive therapy, regardless of LDL-C category and had a higher prevalence of metabolic syndrome, which was supported by higher waist circumference, body mass index, systolic blood pressure, triglyceride level, and glucose level (Table 1).
Table 1.
Clinical characteristics by LDL-C/ hs-CRP categories, adjusted for age, gender, and race
| Variable | Group 1 (LDL-C <130 mg/dL, hs- CRP <2.0 mg/L) n=1,614 |
Group 2 (LDL-C <130 mg/dL, hs- CRP ≥2.0 mg/L) n=1,621 |
p-value (comparing Group 1, 2) |
Group 3 (LDL-C ≥130 mg/dL, hs- CRP <2.0 mg/L) n=1,132 |
Group 4 (LDL-C ≥130 mg/dL, hs- CRP ≥2.0 mg/L) n=1,146 |
p-value (comparing Group 3,4) |
|---|---|---|---|---|---|---|
| Age (years) | 64.1 (0.12) | 64.3 (0.12) | 0.17 | 63.8 (0.15) | 63.8 (0.15) | <0.002 |
| Males (%) | 64 (0.012) | 43 (0.012) | <0.0001 | 56 (0.014) | 48 (0.014) | <0.0001 |
| Whites (%) | 84 (0.009) | 78 (0.010) | <0.0001 | 84 (0.011) | 78 (0.012) | 0.0001 |
| Waist Circumference (cm) |
96.4 (0.32) | 103.1 (0.32) | <0.0001 | 97.4 (0.38) | 104.6 (0.38) | <0.0001 |
| Body Mass Index (kg/m2) |
26.5 (0.12) | 29.1 (0.12) | <0.0001 | 26.9 (0.15) | 29.3 (0.14) | <0.0001 |
| Hypertensive (%) |
35 (0.012) | 47 (0.012) | <0.0001 | 39 (0.014) | 43 (0.014) | 0.03 |
| Systolic Blood Pressure (mm Hg) |
125.4 (0.45) | 128.2 (0.45) | <0.0001 | 127.1 (0.54) | 128.8 (0.53) | 0.03 |
| Diastolic Blood Pressure (mm Hg) |
71.0 (0.25) | 71.0 (0.24) | 0.995 | 71.6 (0.29) | 71.6 (0.29) | 0.91 |
| Self-reported Anti- Hypertensive Use in last 2 weeks before Visit (%) |
23 (0.011) | 34 (0.012) | <0.0001 | 26 (0.013) | 29 (0.013) | 0.07 |
| Metabolic Syndrome (%) |
19 (0.010) | 33 (0.012) | <0.0001 | 25 (0.013) | 40 (0.014) | <0.0001 |
| Aspirin Use (%) |
47 (0.013) | 52 (0.013) | 0.02 | 46 (0.015) | 46 (0.015) | 0.005 |
| Current Smoker (%) |
13 (0.008) | 17 (0.010) | 0.0002 | 10 (0.009) | 21 (0.012) | <0.0001 |
| Former Smoker (%) |
44 (0.012) | 45 (0.012) | 0.35 | 41 (0.014) | 43 (0.015) | 0.27 |
| Non-Smoker (%) |
44 (0.012) | 38 (0.012) | 0.0002 | 49 (0.015) | 36 (0.014) | <0.0001 |
| Family History of Premature CHD (%) |
8 (0.007) | 9 (0.008) | 0.30 | 10 (0.009) | 10 (0.010) | 0.51 |
| Total Cholesterol (mg/dL) |
180.7 (0.62) | 179.3 (0.62) | 0.11 | 231.2 (0.74) | 230.8 (0.73) | 0.75 |
| Triglyceride (mg/dL) |
114.6 (1.54) | 133.4 (1.54) | < 0.0001 | 129.6 (1.83) | 145.6 (1.82) | <0.0001 |
| HDL-c (mg/dL) |
54.6 (0.38) | 50.8 (0.38) | < 0.0001 | 49.9 (0.45) | 45.8 (0.44) | <0.0001 |
| Calculated LDL-C (mg/dL) |
103.2 (0.52) | 101.8 (0.52) | 0.06 | 155.3 (0.62) | 156.0 (0.61) | 0.46 |
| Non-HDL-c (mg/dL) |
126.1 (0.63) | 128.5 (0.62) | 0.008 | 181.3 (0.74) | 185.1 (0.74) | 0.0003 |
| Glucose (mg/dL) |
97.5 (0.22) | 99.4 (0.22) | < 0.0001 | 98.7 (0.27) | 100.7 (0.26) | <0.0001 |
| hs-CRP (mg/L)* |
0.9 | 4.7 | 1.0 | 4.4 |
All values are percents or means (standard error), unless otherwise stated.
For age, race, and gender, each of these variables were adjusted for the other 2 variables (i.e., age was adjusted for race and gender; race, for age and gender; and gender, for age and race).
Unadjusted medians
LDL-C = low-density lipoprotein cholesterol
hs-CRP = high-sensitivity C-reactive protein
CHD = coronary heart disease
HDL-C = high-density lipoprotein cholesterol
The average predicted 10-year CHD risk of all groups using FRS or ACRS was “low” (i.e., 10-year CHD risk ≤10%) (Table 2). Individuals in the “JUPITER-eligible” group had the lowest average 10-year predicted CHD risk using either model (Table 2).
Table 2.
Categorization of individuals* by 10-year CHD risk calculated by Framingham risk score and ARIC risk score
| Variable | Group 1 (LDL-C <130 mg/dL, hs-CRP <2.0 mg/L) |
Group 2 (LDL-C <130 mg/dL, hs-CRP ≥2.0 mg/L) |
p-value (comparing Group 1, 2) |
Group 3 (LDL-C ≥130 mg/dL, hs-CRP <2.0 mg/L) |
Group 4 (LDL-C ≥130 mg/dL, hs-CRP ≥2.0 mg/L) |
p-value (comparing Group 3,4) |
|---|---|---|---|---|---|---|
| Mean Framingham 10-Year Risk (%) |
5.0% | 4.7% | <0.0001 | 6.3% | 7.1% | <0.0001 |
| Framingham Risk ≤5% |
980 (60.7%) | 1114 (68.7%) | <0.0001 | 559 (49.4%) | 586 (51.1%) | <0.0001 |
| Framingham Risk (5–10]% |
467 (28.9%) | 306 (18.9%) | <0.0001 | 371 (32.8%) | 289 (25.2%) | <0.0001 |
| Framingham Risk (10–20]% |
147 (9.1%) | 171 (10.5%) | <0.0001 | 184 (16.3%) | 220 (19.2%) | <0.0001 |
| Framingham Risk > 20% |
13 (0.8%) | 19 (1.2%) | <0.0001 | 16 (1.4%) | 45 (3.9%) | <0.0001 |
| Mean ARIC 10-Year Risk (%) |
5.9% | 5.6% | <0.0001 | 8.2% | 9.0% | <0.0001 |
| ARIC Risk ≤5% |
801 (49.6%) | 927 (57.2%) | <0.0001 | 454 (40.1%) | 459 (40.1%) | <0.0001 |
| ARIC Risk (5–10]% |
514 (31.8%) | 377 (23.3%) | <0.0001 | 301 (26.6%) | 270 (23.6%) | <0.0001 |
| ARIC Risk (10–20]% |
264 (16.4%) | 266 (16.4%) | <0.0001 | 314 (27.7%) | 298 (26.0%) | <0.0001 |
| ARIC Risk > 20% |
19 (1.2%) | 33 (2.0%) | <0.0001 | 59 (5.2%) | 109 (9.5%) | <0.0001 |
48 excluded due to missing variables. Except for mean 10-year CHD risks, values for risk categories are number (proportion). The omnibus test of any difference between the four LDL-C by hs-CRP groups in the distribution among the four risk level categories was significant (p <0.0001) for risk determined by the Framingham and the ARIC risk scores.
CHD = coronary heart disease
ARIC = Atherosclerosis Risk in Communities
LDL-C = low-density lipoprotein cholesterol
hs-CRP = high-sensitivity C-reactive protein
Over a mean follow-up of 6.9 years, the “JUPITER-eligible” group had a MACE rate of 15.73 events (primary outcome) per 1,000 person-years (adjusted for age, race and gender) (Table 3) which was elevated (hazard ratio [HR] of 1.65; 95% confidence interval [CI] 1.29, 2.11) when compared to Group 1 (LDL-C <130 mg/dL, hs-CRP <2.0 mg/L). Group 4 (LDL-C ≥130 mg/dL, hs-CRP ≥2.0 mg/L) had a MACE rate of 21.96 events per 1,000 person-years, which was the highest of all 4 groups, significantly higher than Group 3 (LDL-C ≥130 mg/dL, hs-CRP <2.0 mg/L; HR=1.80, 95% CI 1.39 to 2.33), and nonsignificantly higher than Group 2 (HR=1.27, 95% CI 0.96 to 1.67) (Table 4). However, all-cause mortality and deaths due to cancer were highest in the JUPITER group (14.82 and 6.30 deaths per 1,000 person-years, respectively). All event rates were higher in the groups with the elevated hs-CRP (i.e., Groups 2 and 4) for both LDL-C strata. Lower probability of event-free survival in these groups compared to their counterparts was also shown by Kaplan-Meier models (Figure 2). Men with elevated hs-CRP had greater event rates for all outcomes in all groups (Table 3 and Table 4). The number of clinical events in each group is shown in Supplemental Table 1.
Table 3.
Event rates per 1,000 person-years adjusted for age, race, and gender.
| Variable | Group 1 (LDL-C <130 mg/dL, hs-CRP < 2.0 mg/L) |
Group 2 (LDL-C <130 mg/dL, hs-CRP ≥2.0 mg/L) |
Group 3 (LDL-C ≥130 mg/dL, hs-CRP <2.0 mg/L) |
Group 4 (LDL-C ≥130 mg/dL, hs-CRP ≥2.0 mg/L) |
|---|---|---|---|---|
| Overall | ||||
| All major CV events |
9.56 | 15.73 | 12.17 | 21.96 |
| All MI, CVA, CABG/ PTCA |
8.80 | 13.92 | 10.56 | 20.22 |
| All-cause death |
9.51 | 14.82 | 7.73 | 12.29 |
| Death due to cancer |
3.74 | 6.30 | 3.29 | 5.44 |
| Men | ||||
| All major CV events |
13.47 | 20.35 | 16.20 | 34.26 |
| All MI, CVA, CABG/ PTCA |
12.44 | 18.58 | 14.55 | 31.17 |
| All-cause death |
11.25 | 21.71 | 11.06 | 15.63 |
| Death due to cancer |
4.57 | 8.31 | 3.86 | 7.82 |
| Women | ||||
| All major CV events |
5.70 | 10.63 | 8.20 | 12.60 |
| All MI, CVA, CABG/ PTCA |
5.27 | 8.94 | 6.63 | 11.62 |
| All-cause death |
7.28 | 8.52 | 4.45 | 8.62 |
| Death due to cancer |
3.10 | 4.36 | 2.83 | 3.17 |
CV = cardiovascular disease
MI = myocardial infacrtion
CVA = cerebrovascular accident
CABG/PTCA = coronary arterial bypass graft / percutaneous transluminal coronary angioplasty
LDL-C = low-density lipoprotein cholesterol
hs-CRP = high-sensitivity C-reactive protein
Table 4.
Hazard ratios (HR) (95% confidence intervals [CI]) adjusted for age, race, and gender comparing hs-CRP groups (≥2.0 mg/L to <2.0) within each LDL-C strata and comparing LDL-C groups (≥130 mg/dL to <130) within each hs-CRP strata.
| Comparison of hs-CRP groups within each LDL-C strata |
Comparison of LDL-C groups within each hs-CRP strata |
|||||||
|---|---|---|---|---|---|---|---|---|
| HR (95% CI) (comparing Groups 2 vs. 1) |
p-values (comparing Groups 2 vs. 1) |
HR (95% CI) (comparing Groups 4 vs. 3) |
p-values (comparing Groups 4 vs. 3) |
HR (95% CI) (comparing Groups 3 vs. 1) |
p-values (comparing Groups 3 vs. 1) |
HR (95% CI) (comparing Groups 4 vs. 2) |
p-values (comparing Groups 4 vs. 2) |
|
| Overall | ||||||||
| All major CV events |
1.65 (1.29, 2.11) |
<0.0001 | 1.80 (1.39, 2.33) |
<0.0001 | 1.38 (1.11, 1.73) |
0.005 | 1.27 (0.96, 1.67) |
0.09 |
| All MI, CVA, CABG/ PTCA |
1.60 (1.25, 2.07) |
<0.0002 | 1.94 (1.48, 2.53) |
<0.0001 | 1.46 (1.16, 1.83) |
0.001 | 1.21 (0.91, 1.60) |
0.20 |
| All-cause death |
1.66 (1.30, 2.11) |
<0.0001 | 1.59 (1.16, 2.19) |
0.004 | 0.82 (0.64, 1.05) |
0.12 | 0.85 (0.63, 1.17) |
0.32 |
| Death due to cancer |
1.71 (1.17, 2.49) |
0.006 | 1.66 (1.03, 2.68) |
0.04 | 0.86 (0.59, 1.25) |
0.43 | 0.88 (0.55, 1.42) |
0.61 |
| Men | ||||||||
| All major CV events |
1.56 (1.15, 2.10) |
0.004 | 2.06 (1.50, 2.83) |
<0.0001 | 1.60 (1.20, 2.14) |
0.001 | 1.21 (0.87, 1.68) |
0.25 |
| All MI, CVA, CABG/ PTCA |
1.52 (1.12, 2.07) |
0.008 | 2.18 (1.58, 3.01) |
<0.0001 | 1.68 (1.26, 2.26) |
0.0005 | 1.18 (0.84, 1.64) |
0.34 |
| All-cause death |
1.95 (1.45, 2.62) |
<0.0001 | 1.42 (0.96, 2.09) |
0.08 | 0.71 (0.52, 0.98) |
0.04 | 0.98 (0.68, 1.42) |
0.92 |
| Death due to cancer |
1.85 (1.16, 2.95) |
0.01 | 2.03 (1.10, 3.74) |
0.02 | 0.93 (0.58, 1.51) |
0.78 | 0.85 (0.47, 1.55) |
0.59 |
| Women | ||||||||
| All major CV events |
1.79 (1.13, 2.83) |
0.01 | 1.40 (0.90, 2.20) |
0.14 | 1.10 (0.77, 1.57) |
0.61 | 1.40 (0.83, 2.39) |
0.21 |
| All MI, CVA, CABG/ PTCA |
1.70 (1.06, 2.72) |
0.03 | 1.57 (0.97, 2.52) |
0.06s | 1.16 (0.80, 1.67) |
0.44 | 1.26 (0.72, 2.19) |
0.42 |
| All-cause death |
1.18 (0.78, 1.80) |
0.43 | 1.95 (1.12, 3.37) |
0.018 | 1.01 (0.68, 1.48) |
0.97 | 0.61 (0.35, 1.09) |
0.09 |
| Death due to cancer |
1.42 (0.75, 2.67) |
0.28 | 1.13 (0.52, 2.45) |
0.77 | 0.73 (0.39, 1.35) |
0.31 | 0.92 (0.42, 2.02) |
0.83 |
CV = cardiovascular disease
MI = myocardial infacrtion
CVA = cerebrovascular accident
CABG/PTCA = coronary arterial bypass graft / percutaneous transluminal coronary angioplasty
LDL-C = low-density lipoprotein cholesterol
hs-CRP = high-sensitivity C-reactive protein
Figure 2. Kaplan-Meier cardiovascular event-free survival curves of the four groups analyzed.
Cardiovascular event-free survival curves for the four groups are shown between 1996–1998 and December 31, 2005 (mean follow-up 6.9 years). At the end of available follow-up, the groups in descending order of probability event free survival are Groups 1, 3, 2, and 4.
After additional adjustments as detailed in the Methods section, the hazard ratios comparing hs-CRP ≥2.0 mg/L to <2.0 mg/L (i.e., Groups 2 vs. 1 and Groups 4 vs. 3) for MACE, mortality and cancer deaths remained significant (Supplemental Table 3); however, the hazard ratios comparing LDL-C ≥130 mg/dL to <130 mg/dL (i.e., Groups 3 vs. 1 and Groups 4 vs. 2) for the same outcomes, except mortality, became nonsignificant (Supplemental Table 3).
DISCUSSION
At the end of the JUPITER study, questions remained (13) as detailed in the Introduction. Our analysis examined some of these questions in the ARIC study and compared the characteristics, predicted 10-year CHD risk, and actual cardiovascular event rates over a long-term follow-up of those who were and were not “JUPITER-eligible.”
Cardiovascular Risk in JUPITER-eligible ARIC Participants over Longer Follow-up
The MACE rates in the JUPITER-eligible group in our study over a mean follow-up of 6.9 years was similar to the JUPITER placebo arm (Table 5) (1) suggesting that the event rates observed in JUPITER are likely to persist over longer observation periods. When the event reduction observed with rosuvasatin in JUPITER was applied to our “JUPITER-eligible” group, we determined the number needed to treat (NNT) to prevent one first MACE was ~38 individuals over 5 years and ~26 over 6.9 years using the Altman-Andersen method.
Table 5.
Comparison of ARIC JUPITER-eligible group, JUPITER placebo arm, JUPITER treated arm, and their respective event rates.
| Variable | ARIC Group 2* n = 1,621 (over 6.9 years) |
JUPITER Placebo Arm† n = 8,901 (over 1.9 years) |
JUPITER Treated Arm† n = 8,901 (over 1.9 years) |
|
|---|---|---|---|---|
| Baseline Characteristics | ||||
| Age (yrs) | 64.6 | 66.0 | 66.0 | |
| Male (%) | 42 | 62.1 | 61.5 | |
| White (%) | 78 | 71.1 | 71.4 | |
| BMI (kg/m2) | 29.1 | 28.4 | 28.3 | |
| Systolic blood pressure (mm Hg) |
128.2 | 134 | 134 | |
| Diastolic blood pressure (mm Hg) |
71.0 | 80 | 80 | |
| Current Smoker (%) | 17 | 16.0 | 15.7 | |
| Family history of premature CHD (%) |
9 | 11.8 | 11.2 | |
| Metabolic Syndrome (%) | 33 | 41.8 | 41.0 | |
| Aspirin use (%) | 52 | 16.6 | 16.6 | |
| Total Cholesterol (mg/dL) |
179.3 | 185 | 186 | |
| Triglycerides (mg/dL) | 133.4 | 118 | 118 | |
| HDL-c (mg/dL) | 50.8 | 49 | 49 | |
| LDL-C (mg/dL) | 101.8 | 108 | 108 | |
| Fasting glucose (mg/dL) | 99.4 | 94 | 94 | |
| Median hs-CRP (mg/L) | 4.7 | 4.3 | 4.2 | |
| Outcome | Event rates per 1,000 person-years |
Projected event rates in Group 2 based on RRR in JUPITER (95% CI) |
||
| All major CV events | 15.7 | 13.6 | 7.7 | 8.8 (6.5–11.1) |
| All-cause death | 14.8 | 12.5 | 10.0 | 11.9 (9.0–14.8) |
| Revascularization (CABG/PTCA) |
6.7 | 7.1 | 3.8 | 3.6(2.2–5.0) |
| Unstable angina | 4.7 | 1.4 | 0.9 | 2.8 (0.8–4.8) |
| Hospitalized myocardial infraction |
4.8 | 3.3 | 1.2 | 1.7 (0.7–2.7) |
| Hospitalized Strokes | 4.2 | 3.1 | 1.6 | 2.2 (1.0–3.4) |
All statistics from the ARIC study are means or proportions unless otherwise stated
All statistics from JUPITER are medians or proportions
ARIC = Atherosclerosis Risk in Communities
JUPITER = Justification for the Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin
CHD = coronary heart disease
HDL-C – high-density lipoprotein cholesterol
LDL-C = low-density lipoprotein cholesterol
hs-CRP = high-sensitivity C-reactive protein
CV = cardiovascular disease
CABG/PTCA = coronary arterial bypass graft / percutaneous transluminal coronary angioplasty
RRR= relative risk reduction
Comparison of 10-year Cardiovascular Risk by LDL-C and hs-CRP Groupings and its clinical implications
Although individuals in the “JUPITER-eligible” group numerically had the lowest average 10-year predicted CHD risk, they had a significantly higher MACE rate compared to Group 1, and a numerically higher MACE rate compared to individuals of Group 3. Group 4 individuals numerically had the highest average 10-year predicted CHD risk and the highest MACE rates of the four groups, confirming prior analyses from primary prevention trials which showed that the highest incidence of CVD occurred in “high” LDL-C and “high” hs-CRP groups (14,15).
Based on the known benefit of statins in those with LDL-C ≥130 mg/dL, it would be ethically difficult to conduct a placebo-controlled study in patients with LDL-C ≥130 mg/dL and hs-CRP ≥2.0 mg/L. Clinicians, therefore, may have to extrapolate the available data and consider all patients with hs-CRP ≥2.0 mg/L for statin treatment for the primary prevention of CVD.
Prevalence and Characteristics of the ARIC Population Meeting JUPITER Criteria (Group 2)
The “JUPITER-eligible” individuals in our study were similar to the treated and placebo arms of JUPITER at baseline; however, our study had more women and greater aspirin use (Table 5) (1). Our study showed that ~18.2% of age eligible individuals met LDL-C and hs-CRP criteria which were similar to the 19.8% reported in JUPITER. However, a NHANES analysis showed only ~13.9% of the age-eligible American population to be eligible (2). Therefore, the actual prevalence of “JUPITER-eligible” Americans may range between ~14% to ~20%. However, ~50% of either LDL-C strata (i.e., LDL-C <130 and ≥130 mg/dL) had hs-CRP ≥2.0 mg/L in our study. Therefore, if all individuals with hs-CRP ≥2.0 mg/L were considered eligible for statins (although not tested in JUPITER), the number would be significantly higher.
Other Observations
Groups with elevated hs-CRP (Groups 2, 4) had significantly higher all-cause and cancer mortality than their counterparts with low hs-CRP (Groups 1, 3). Groups with high LDL-C (Groups 3, 4) had nonsignificantly higher all-cause and cancer mortality than their counterparts with low LDL-C (Groups 1,2) (Table 4). Malignancy and inflammatory disorders were not excluded since they were not previously defined in the ARIC study. Regardless, it appears that those with elevated hs-CRP may have increased mortality which may merit further investigation.
Higher proportions of women were observed in groups with hs-CRP ≥2.0 mg/L (Groups 2, 4). Overall, women with hs-CRP ≥2.0 mg/L had higher event rates compared to counterparts with hs-CRP <2.0 mg/L. Importantly, despite women being generally considered at lower CVD risk than men, they were the majority in groups with hs-CRP ≥2.0 mg/L, which had the highest event rates.
Lastly, CVD risk and mortality remained significantly increased in those with elevated hs-CRP (Groups 2, 4) even after further adjustments for other risk factors. This finding suggests an association of elevated hs-CRP with increased cardiovascular risk independent of “traditional” risk factors. Likewise, the increased cancer death risk associated with elevated hs-CRP remained significant within each LDL-C stratum after these adjustments. Therefore, based on JUPITER and our analysis, the mere utilization of age (men ≥50 years, women ≥60 years) and hs-CRP ≥2.0 mg/L identified a population at higher CVD and mortality risk, which may be decreased with statin therapy. This simple way of identifying higher risk individuals using these 2 variables will make it easier for clinicians without having to use risk equations.
Limitations
The ARIC population consists predominantly of whites and blacks, limiting the generalizability to other ethnicities. HRT use in women (an exclusion criteria in JUPITER) and PVD presence were not excluded (see Methods section). JUPITER excluded only those with a “history” of symptomatic PVD and did not measure ABI’s on all participants. Other JUPITER exclusion criteria (e.g., immunosuppressant use, rheumatologic diseases, malignancy, inflammatory bowel disease, elevated creatinine kinase >3 times the upper limit of normal, or thyroid disorders) were not available for the ARIC participants.
Summary
Our study showed that ~18.2% of the age-eligible ARIC population would have been eligible for JUPITER, and they had an absolute CVD risk of ~10.9% over 6.9 years,,suggesting the CVD risk observed in the JUPITER study may persist over an extended period of time. Our study in concert with JUPITER supports a simple method of using age and hs-CRP for identification of higher risk individuals.
Supplementary Material
Event rates for each of the 4 groups are shown for outcomes of interest. Absolute event counts and event counts and rates by gender can be found in the accompanying Supplemental Tables. *All major CV events include fatal CHD, hospitalized MI, hospitalized stroke, unstable angina, and coronary revascularization
Acknowledgments
We thank staff and participants of ARIC for their contribution and Joanna Brooks, B.A., for editorial assistance.
Financial Support:The Atherosclerosis Risk in Communities Study is a collaborative study supported by National Heart, Lung, and Blood Institute contracts N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, and N01-HC-55022 from the National Heart, Lung, and Blood Institute (NHLBI), Bethesda, MD.
Abbreviations List
- hs-CRP
high-sensitivity C-reactive protein
- CVD
cardiovascular disease
- CHD
coronary heart disease
- LDL-C
low-density lipoprotein cholesterol
- ABI
ankle-brachial index
- MI
myocardial infarction
- ACRS
ARIC coronary risk score
- FRS
Framingham risk score
- PVD
peripheral vascular disease
- MACE
major adverse cardiovascular event
Footnotes
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Relationship with industry:
Vijay Nambi: Research collaboration with General Electric
Salim S. Virani: Speakers bureau for Abbott, Daiichi-Sankyo
Christie M. Ballantyne: Consultant for Abbott, AstraZeneca, Bristol-Myers/Squibb, GlaxoSmithKline, KOWA, Merck, Merck/Schering-Plough, Metabasis, Novartis, Pfizer, Sanofi-Synthelabo, Schering-Plough, Takeda; grant/research support from: Abbott, AstraZeneca, GlaxoSmithKline, Merck, Sanofi-Synthelabo, Schering-Plough, Takeda; honoraria from Abbott, AstraZeneca, GlaxoSmithKline, Merck, Merck/Schering-Plough, Novartis, Pfizer, Sanofi-Synthelabo, Schering-Plough, Takeda; and speakers bureau for AstraZeneca, GlaxoSmithKline, Merck, Merck/Schering-Plough, Pfizer, Schering-Plough.
Remaining authors have nothing to disclose.
The study has been registered in Clinicaltrials.gov (http://clinicaltrials.gov/ct2/show/NCT00005131), ID: NCT00005131.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Event rates for each of the 4 groups are shown for outcomes of interest. Absolute event counts and event counts and rates by gender can be found in the accompanying Supplemental Tables. *All major CV events include fatal CHD, hospitalized MI, hospitalized stroke, unstable angina, and coronary revascularization