Justification for the Use of Statins in Primary Prevention: An Intervention Trial Using Rosuvastatin (JUPITER) reported reduced cardiovascular and all-cause mortality with statin treatment in patients with elevated C-reactive protein (CRP) and average cholesterol levels who were not eligible for lipid-lowering treatment on the basis of existing guidelines. The aim of this study was to determine the prevalence of eligibility and mortality in a general population sample on the basis of eligibility for statin treatment using the JUPITER criteria. The study group consisted of 30,229 participants in the REasons for Geographic and Racial Differences in Stroke (REGARDS) cohort, an observational study of US African American and white participants aged ≥45 years, enrolled in their homes from 2003 to 2007 and followed biannually by telephone. Among 11,339 participants age eligible for JUPITER and without vascular diagnoses or using lipid-lowering treatment, 21% (n = 2,342) met JUPITER entry criteria. Compared with JUPITER participants, they had similar low-density lipoprotein cholesterol and CRP levels, were more often women, were more often black, had metabolic syndrome, and used aspirin for cardioprotection. Over 3.5 years of follow-up, the mortality rate in REGARDS participants eligible for JUPITER was 1.17 per 100 patient-years (95% confidence interval 0.94 to 1.42). Compared with those otherwise JUPITER eligible who had CRP levels <2 mg/L (n = 2,620), those with CRP levels ≥2 mg/L had a multivariate-adjusted relative risk of 1.5 (95% confidence interval 1.1 to 2.2) for total mortality. In conclusion, 21% not otherwise eligible would be newly eligible for lipid lowering treatment on the basis of JUPITER trial eligibility.
Justification for the Use of Statins in Primary Prevention: An Intervention Trial Using Rosuvastatin (JUPITER) reported that subjects without diabetes who were not eligible for lipid-lowering treatment and who had C-reactive protein (CRP) levels ≥2.0 mg/L had a 44% reduction of vascular events and cardiovascular mortality and a 20% reduction in all-cause mortality with rosuvastatin treatment compared with placebo. If these findings are translated to practice, current guidelines for statin use in primary prevention may change dramatically, leading to increased use of this treatment. We recently reported a high prevalence of elevated CRP in a biracial national United States population sample, the Reasons for Geographic and Racial Differences in Stroke (REGARDS) cohort. Among these black and white adults without cardiovascular disease, 40% had elevated CRP; this percentage was higher in women than men and in blacks than whites. In this study, we evaluated the potential impact of JUPITER on lipid-lowering prescriptions in United States blacks and whites by assessing the prevalence of eligibility for JUPITER among REGARDS participants. To address the potential impact of aggressive lipid lowering, we determined the mortality rates of JUPITER-eligible participants with and without CRP levels ≥2 mg/L.
Methods
The REGARDS study is a national population-based cohort study in the United States. From February 2003 and October 2007, 30,229 subjects aged >45 years were enrolled, targeted for equal representation of whites and blacks and of men and women. Fifty-six percent of the sample resided in the 10 southeastern “stroke belt” states, with the rest from the other 38 contiguous states. Subjects were recruited from a commercial list representing most of the population using mail and telephone contact. Exclusion criteria were race other than black or white (race was self-defined by participants, who chose from a list), active cancer treatment, medical conditions preventing long-term participation, cognitive impairment, inability to communicate in English, and residence in or presence on a waiting list for a nursing home. Race was assessed because the parent study aims to investigate black-white disparities in vascular disease. For consenting participants, demographic information and medical histories were obtained using a computer-assisted telephone interview. After this, during in-home examinations, blood pressure, anthropomorphic measures, electrocardiographic results, and medication inventories were assessed, and blood was drawn, using standardized protocols. Self-administered questionnaires were left with each participant to assess family history of stroke and heart disease. Participants are followed by telephone at 6-month intervals for surveillance of medical events, including death. For reported deaths, death certificates were sought, and medical records from hospitalizations temporally related to the death were retrieved to confirm death and the date of death. Study procedures were reviewed and approved by the institutional review boards at each study institution.
Phlebotomy was performed by centrally trained personnel using standardized procedures in each participant’s home after a 10- to 12-hour fast. Samples were centrifuged and serum or plasma separated and shipped overnight on gel ice packs to the University of Vermont. On arrival, samples were recentrifuged at 30,000 g and 4°C and either analyzed or aliquoted for storage at −80°C.
CRP was analyzed in periodic batches by particle enhanced immunonephelometry using the BNII nephelometer (N High Sensitivity CRP; Dade Behring, Inc., Deerfield, Illinois), with analytic interassay coefficients of variation of 2.1% to 5.7%. Cholesterol, high-density lipoprotein cholesterol, triglycerides, creatinine, and glucose were measured by colorimetric reflectance spectrophotometry using the Ortho Vitros Clinical Chemistry System 950IRC instrument (Johnson & Johnson Clinical Diagnostics, Rochester, New York), with low-density lipoprotein (LDL) cholesterol calculated using the Friedwald equation. The estimated glomerular filtration rate was calculated using the abbreviated Modification of Diet in Renal Disease equation after the calibration of creatinine values.
We applied JUPITER entry criteria to determine the proportion of REGARDS participants who would have been eligible for the trial. Of 30,229 participants, we excluded 581 men aged <50 years and 5,671 women aged <60 years. Second, 7,999 (30%) reporting vascular diagnoses at baseline (myocardial infarction, stroke, peripheral arterial disease, transient ischemic attack, carotid endarterectomy, peripheral artery bypass surgery or angioplasty, leg amputation, coronary artery angioplasty, or stenting) and 4,639 taking lipid-lowering medications (fibrates, niacin, bile acid sequestrants, or statins) were excluded. This resulted in a cohort of 11,339 participants who were evaluated further for JUPITER entry criteria. We considered the major entry criteria of LDL cholesterol <130 mg/dl, no diabetes, no current use of hormone replacement therapy, creatinine ≤2.0 mg/dl, and triglycerides <500 mg/dl. We excluded 645 participants with missing LDL cholesterol or diabetes status. For participants whose LDL could not be calculated because of triglyceride levels >400 mg/dl, we assumed that LDL was >130 mg/dl. REGARDS did not collect specific data on some JUPITER entry criteria: past lipid-lowering medication use, cancer within the past 5 years, elevated alanine aminotransferase or creatine kinase, recent alcohol or drug abuse, uncontrolled hypothyroidism, severe arthritis, lupus, inflammatory bowel disease, and taking cyclosporine, tacrolimus, azathioprine, or chronic glucocorticoids.
We defined risk factors using the same definitions as the JUPITER investigators whenever possible. Diabetes mellitus was defined by self-reported physician diagnosis, use of antidiabetic medications, fasting glucose ≥126 mg/dl, or nonfasting glucose >200 mg/dl. Cigarette smoking was categorized as current smoking or nonsmoking. Metabolic syndrome was defined according to American Heart Association and National Heart, Lung, and Blood Institute 2005 guidelines. Family history of coronary artery disease was defined as diagnosis in a parent or sibling before 60 years of age.
The Framingham 10-year heart disease risk score and the Reynolds risk score, which includes parental history of myocardial infarction and CRP concentration, were calculated.
SAS version 9.1 (SAS Institute Inc., Cary, North Carolina) was used for analysis. The numbers of REGARDS participants with each JUPITER exclusion criterion were tallied to yield a flow chart of eligibility. Prevalence of CRP ≥2 mg/L was determined, and baseline characteristics by CRP category were compared using Student’s t tests, analysis of variance, or chi-square tests. Characteristics of those with elevated CRP levels were compared descriptively to published characteristics of JUPITER participants. We compared the number eligible for statin treatment on the basis of JUPITER criteria (eligible and CRP ≥2 mg/L) to the number eligible by National Cholesterol Education Program Adult Treatment Panel (ATP) III guidelines.
We constructed Kaplan-Meier plots and used log-rank tests to compare the incidence of all-cause mortality in those with CRP ≥2 mg/L compared with <2 mg/L. Cox proportional-hazards models were used to calculate the hazard ratio, an estimate of relative risk, of all-cause death by CRP category in a crude model, a model adjusting for age, race, and gender, a model further adjusting for hypertension, smoking status, education level, body mass index, lipid and glucose levels, estimated glomerular filtration rate, and a model including all previously listed factors and metabolic syndrome. We censored subjects at death or last contact.
Results
A total of 11,339 participants were age eligible for JUPITER and did not report baseline cardiovascular disease. This population is referred to hereafter as the base population. From the base population, Figure 1 shows the number of REGARDS subjects who would have been eligible for the JUPITER trial on the basis of other entry criteria. The most common reason for exclusion was LDL cholesterol ≥130 mg/dl, followed by the presence of diabetes. Among 4,910 participants who would be eligible for JUPITER on the basis of standard risk factors up to the time of CRP testing, 52% had CRP levels <2 mg/L, and the remaining 48% had CRP levels ≥2 mg/L and so would have been eligible for the trial. Thus, 21% would be newly eligible for use of rosuvastatin for primary prevention. Considering only subjects without diabetes, this percentage was 25% (2,342/[11,399 − 1,688 with diabetes − 393 missing diabetes status]).
We applied ATP III guidelines for lipid lowering using the Framingham risk score to define 10-year risk for cardiovascular disease in subjects without diabetes in the base population (n = 9,258). There were 634 participants with a 10-year predicted risk >20% and LDL cholesterol ≥130 mg/dl; 376 had 10-year risk of 10% to 20% with LDL cholesterol ≥160 mg/dl, and 95 had 10-year predicted risk <10% with LDL ≥190 mg/dl. Thus, 1,105 (634 + 376 + 95), or 12%, would be newly eligible for lipid-lowering treatment using these criteria.
Compared with those ineligible, those eligible for JUPITER on the basis of elevated CRP were slightly older, more often female, more often black, and had lower educational levels ( Table 1 ). They had higher levels of all risk factors except total and LDL cholesterol, diastolic blood pressure, estimated glomerular filtration rate, and family history of coronary artery disease. Their Framingham and Reynolds risks scores were also higher. They did not differ in the frequency of aspirin use. In comparison to the published characteristics of JUPITER participants, REGARDS participants eligible for JUPITER were 0.8 years older, were much more often women or black, and were more highly educated. The body mass index was 0.4 kg/m 2 higher, the glomerular filtration rate was 12 ml/min/1.73 m 2 lower, and metabolic syndrome was more prevalent, while blood pressure and triglycerides were lower and glucose, CRP, LDL cholesterol, and high-density lipoprotein cholesterol were similar. Aspirin use was >2 times as prevalent in REGARDS participants, who also had a similar prevalence of a family history of heart disease and current smoking.
| Baseline Characteristic | CRP (mg/L) | p Value ⁎ | JUPITER Participants † | |
|---|---|---|---|---|
| <2 | ≥2 | |||
| (n = 2,568) | (n = 2,342) | |||
| Age (years) | 66.4 (60.7–73.3) | 67.1 (61.9–73.3) | <0.001 | 66.3 (60.9–71.8) |
| Women | 848 (33%) | 1086 (46%) | <0.001 | 38.2% |
| Black race | 802 (31%) | 981 (42%) | <0.001 | 12.5% |
| Education | <0.001 | |||
| High school degree | 744 (30%) | 906 (39%) | 59% | |
| Some college | 640 (25%) | 669 (29%) | 18% | |
| College degree | 628 (24%) | 405 (17%) | 15% | |
| Postgraduate | 555 (22%) | 362 (15%) | 8% | |
| Body mass index (kg/m 2 ) | 25.8 (23.2–28.8) | 28.8 (25.4–32.9) | <0.001 | 28.4 (25.3–32.0) |
| Systolic blood pressure (mm Hg) | 124 (117–136) | 127 (119–138) | <0.001 | 134 (124–145) |
| Diastolic blood pressure (mm Hg) | 78 (70–81) | 78 (71–83) | <0.001 | 80 (75–87) |
| Current smokers | 275 (11%) | 338 (15%) | <0.001 | 16% |
| Family history of coronary artery disease ‡ | 358 (14%) | 297 (13%) | 0.05 | 11% |
| Metabolic syndrome | 369 (17%) | 718 (36%) | <0.001 | 32% |
| Aspirin use | ||||
| Any report | 903 (35%) | 784 (33%) | 0.31 | 15% |
| Prophylactic | 775 (30%) | 678 (30%) | 0.46 | 14% |
| Total cholesterol (mg/dl) | 179 (163–195) | 179 (162–194) | 0.15 | 185 (169–200) |
| Low-density lipoprotein cholesterol (mg/dl) | 106 (90–118) | 106 (90–118) | 0.82 | 108 (94–119) |
| High-density lipoprotein cholesterol (mg/dl) | 52 (41–65) | 48 (39–59) | <0.001 | 49 (40–60) |
| Triglycerides (mg/dl) | 92 (68–133) | 105 (77–150) | <0.001 | 118 (85–169) |
| Glucose (mg/dl) | 91 (85–98) | 93 (87–101) | <0.001 | 94 (88–102) |
| Estimated glomerular filtration rate (ml/min/1.73 m 2 ) | 85 (74–98) | 85 (72–100) | 0.17 | NR § |
| Framingham risk score | 6.4 (3.7–10.6) | 7.0 (4.0–11.9) | <0.001 | NR |
| Reynolds risk score | 6.9 (3.6–12.0) | 8.9 (4.8–7.6) | <0.001 | NR |
| C-reactive protein (mg/L) | 0.84 (0.49–1.3) | 4.4 (2.9–7.6) | <0.001 | 4.3 (2.8–7.1) |
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