Justification for the Use of Statins in Primary Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) study

• Summary:
  • JUPITER trial enrolled healthy subjects who did not have high cholesterol levels, according to conventional benchmarks
    • entry criterion of a low-density lipoprotein (LDL) cholesterol level of less than 130 mg per deciliter (3.4 mmol per liter) is below the currently recommended threshold for initiating pharmacologic treatment for primary prevention, although treatment at this level is indicated in patients who have clinical coronary disease or diabetes
    • in JUPITER, a high-sensitivity C-reactive protein level of 2.0 mg per liter or higher was an additional entry criterion to identify higher-risk subjects
      
      • primary outcome was the occurrence of a first major cardiovascular event, defined as nonfatal myocardial infarction, nonfatal stroke, hospitalization for unstable angina, an arterial revascularization procedure, or confirmed death from cardiovascular causes
      • trial of nearly 18,000 patients was stopped, with only 1.9 of its proposed 4 years of follow-up concluded, when the data and safety monitoring board noted a significant reduction in the primary end point among participants assigned to receive rosuvastatin (142 primary events, vs. 251 in the placebo group; hazard ratio, 0.56; 95% confidence interval [CI], 0.46 to 0.69)
        • there was a similar reduction in a combination of the more important hard outcomes: myocardial infarction, stroke, or death from cardiovascular causes (83 events in the rosuvastatin group vs. 157 in the placebo group; hazard ratio, 0.53; 95% CI, 0.40 to 0.69)
        • authors concluded that:
          • apparently healthy persons without hyperlipidemia but with elevated high-sensitivity C-reactive protein levels, rosuvastatin significantly reduced the incidence of major cardiovascular events
• Jupiter Trial Details
  
  • increased levels of the inflammatory biomarker high-sensitivity C-reactive protein predict cardiovascular events
    • current treatment algorithms for the prevention of myocardial infarction, stroke, and death from cardiovascular causes recommend statin therapy for patients with established vascular disease, diabetes, and overt hyperlipidemia
      • however, half of all myocardial infarctions and strokes occur among apparently healthy men and women with levels of low-density lipoprotein (LDL) cholesterol that are below currently recommended thresholds for treatment
      • measurement of high-sensitivity C-reactive protein, an inflammatory biomarker that independently predicts future vascular events, improves global classification of risk, regardless of the LDL cholesterol level
        • it has previously been shown that statin therapy reduces high-sensitivity C-reactive protein levels and that among healthy persons patients with stable coronary disease and those with the acute coronary syndrome, the magnitude of the benefit associated with statin therapy correlates in part with the achieved high-sensitivity C-reactive protein level
  • trial design:
    • randomly assigned 17,802 apparently healthy men and women with low-density lipoprotein (LDL) cholesterol levels of less than 130 mg per deciliter (3.4 mmol per liter) and high-sensitivity C-reactive protein levels of 2.0 mg per liter or higher to rosuvastatin, 20 mg daily, or placebo and followed them for the occurrence of the combined primary end point of myocardial infarction, stroke, arterial revascularization, hospitalization for unstable angina, or death from cardiovascular causes
      • men 50 years of age or older and women 60 years of age or older were eligible for the trial if they did not have a history of cardiovascular disease and if, at the initial screening visit, they had an LDL cholesterol level of less than 130 mg per deciliter (3.4 mmol per liter) and a high-sensitivity C-reactive protein level of 2.0 mg per liter or more. Other requirements for inclusion were a willingness to participate for the duration of the trial, provision of written informed consent, and a triglyceride level of less than 500 mg per deciliter (5.6 mmol per liter)
        • exclusion criteria were previous or current use of lipid-lowering therapy, current use of postmenopausal hormone-replacement therapy, evidence of hepatic dysfunction (an alanine aminotransferase level that was more than twice the upper limit of the normal range), a creatine kinase level that was more than three times the upper limit of the normal range, a creatinine level that was higher than 2.0 mg per deciliter (176.8 µmol per liter), diabetes, uncontrolled hypertension (systolic blood pressure >190 mm Hg or diastolic blood pressure >100 mm Hg), cancer within 5 years before enrollment (with the exception of basal-cell or squamous-cell carcinoma of the skin), uncontrolled hypothyroidism (a thyroid-stimulating hormone level that was more than 1.5 times the upper limit of the normal range), and a recent history of alcohol or drug abuse or another medical condition that might compromise safety or the successful completion of the study. Because a core scientific hypothesis of the trial concerned the role of underlying low-grade inflammation as evidenced by elevated high-sensitivity C-reactive protein levels, patients with inflammatory conditions such as severe arthritis, lupus, or inflammatory bowel disease were excluded, as were patients taking immunosuppressant agents such as cyclosporine, tacrolimus, azathioprine, or long-term oral glucocorticoids
        • all potentially eligible subjects underwent a 4-week run-in phase during which they received placebo. The purpose of this phase was to identify a group of willing and eligible participants who demonstrated good compliance (defined as the taking of more than 80% of all study tablets) during that interval. Only subjects who successfully completed the run-in phase were enrolled
    • primary outcome was the occurrence of a first major cardiovascular event, defined as nonfatal myocardial infarction, nonfatal stroke, hospitalization for unstable angina, an arterial revascularization procedure, or confirmed death from cardiovascular causes. Secondary end points included the components of the primary end point considered individually - arterial revascularization or hospitalization for unstable angina, myocardial infarction, stroke, or death from cardiovascular causes - and death from any cause
  • trial results:
    • the trial was stopped after a median follow-up of 1.9 years (maximum, 5.0). Rosuvastatin reduced LDL cholesterol levels by 50% and high-sensitivity C-reactive protein levels by 37%
    • rates of the primary end point were 0.77 and 1.36 per 100 person-years of follow-up in the rosuvastatin and placebo groups, respectively (hazard ratio for rosuvastatin, 0.56; 95% confidence interval [CI], 0.46 to 0.69; P<0.00001)
      • rates of 0.17 and 0.37 for myocardial infarction (hazard ratio, 0.46; 95% CI, 0.30 to 0.70; P=0.0002), 0.18 and 0.34
      • stroke (hazard ratio, 0.52; 95% CI, 0.34 to 0.79; P=0.002), 0.41 and 0.77 for revascularization or unstable angina (hazard ratio, 0.53; 95% CI, 0.40 to 0.70; P<0.00001), 0.45 and 0.85 for the combined end point of myocardial infarction, stroke, or death from cardiovascular causes (hazard ratio, 0.53; 95% CI, 0.40 to 0.69; P<0.00001
      • among those assigned to rosuvastatin, the median LDL cholesterol level at 12 months was 55 mg per deciliter (1.4 mmol per liter) (interquartile range, 44 to 72 [1.1 to 1.9]), and the median high-sensitivity C-reactive protein level was 2.2 mg per liter (interquartile range, 1.2 to 4.4)
        • at the 12-month visit, the rosuvastatin group, as compared with the placebo group, had a 50% lower median LDL cholesterol level (mean difference, 47 mg per deciliter [1.2 mmol per liter]), a 37% lower median high-sensitivity C-reactive protein level, and a 17% lower median triglyceride level (P<0.001 for all three comparisons)
          • effects persisted throughout the study period.
          • at 12 months, the median HDL cholesterol level was 4% higher in the rosuvastatin group than in the placebo group (P<0.001), but this effect was not present at the time of study completion (P=0.34)
      • at time of study termination (median follow-up, 1.9 years; maximal follow-up, 5.0 years), 142 first major cardiovascular events had occurred in the rosuvastatin group, as compared with 251 in the placebo group
        • rates of the primary end point were 0.77 and 1.36 per 100 person-years of follow-up in the rosuvastatin and placebo groups, respectively (hazard ratio for rosuvastatin, 0.56; 95% confidence interval [CI], 0.46 to 0.69; P<0.00001)
      • rosuvastatin also significantly reduced the incidence of death from any cause
      • effects were consistent in all subgroups evaluated, including subgroups customarily considered to be at low risk, such as people with Framingham risk scores of 10% or less, those with LDL cholesterol levels of 100 mg per deciliter or less, those without the metabolic syndrome, and those with elevated levels of high-sensitivity C-reactive protein but no other major risk factor
        • trial also showed robust reductions in cardiovascular events with statin therapy in women and black and Hispanic populations for which data on primary prevention are limited
      • rosuvastatin group did not have a significant increase in myopathy or cancer but did have a higher incidence of physician-reported diabetes
  • apparently healthy persons without hyperlipidemia but with elevated high-sensitivity C-reactive protein levels, rosuvastatin significantly reduced the incidence of major cardiovascular events

Notes:

• CRP as a screening test for identifying patients at risk of cardiovascular disease
  • in evaluating how to use high-sensitivity C-reactive protein testing in practice, it is important to understand how the participants in JUPITER were selected
    • 89,890 subjects who attended a clinic visit appear to have been prescreened to exclude those who had previous lipid-lowering therapy, diabetes, elevated serum creatinine levels, or poorly controlled hypertension
      • at the screening visit, approximately 80% of the remaining subjects were excluded, most because of LDL cholesterol or high-sensitivity C-reactive protein levels. To understand who might benefit from high-sensitivity C-reactive protein testing, there should be a detailed analysis of how the estimated (and actual) cardiovascular risk of the screened subjects changed on the basis of their high-sensitivity C-reactive protein levels, particularly in relation to generally accepted risk thresholds and in key subgroups such as women
• relative risk:
  • relative risk reductions achieved with the use of statin therapy in JUPITER were clearly significant
    • previous statin trials (most of which used LDL cholesterol level criteria for enrollment) have generally reported a 20% reduction in vascular risk for each 1 mmol per liter (38.7 mg per deciliter) of absolute reduction in the LDL cholesterol level
      • would have predicted a proportionate reduction in the number of events in our study of approximately 25%. However, the reduction in the hazard seen in JUPITER, in which enrollment was based on elevated high-sensitivity C-reactive protein levels rather than on elevated LDL cholesterol levels, was almost twice this magnitude and revealed a greater relative benefit than that found in most previous statin trials
    • however...absolute differences in risk are more clinically important than relative reductions in risk in deciding whether to recommend drug therapy, since the absolute benefits of treatment must be large enough to justify the associated risks and costs
      • proportion of participants with hard cardiac events in JUPITER was reduced from 1.8% (157 of 8901 subjects) in the placebo group to 0.9% (83 of the 8901 subjects) in the rosuvastatin group; thus, 120 participants were treated for 1.9 years to prevent one event
• risk of diabetes
  • significantly higher glycated hemoglobin levels and incidence of diabetes in the rosuvastatin group in JUPITER (3.0%, vs. 2.4% in the placebo group; P=0.01)

Reference:

• 1. Ridker PM et al. and the JUPITER Study Group Rosuvastatin to Prevent Vascular Events in Men and Women with Elevated C-Reactive Protein NEJM 2008
• 2. Editorial. Expanding the Orbit of Primary Prevention - Moving beyond JUPITER NEJM 2008.