Abstract

Aims

On the basis of the JUPITER trial, European health authorities recently approved the use of rosuvastatin to reduce first major cardiovascular events among ‘high' global risk primary prevention patients defined either by Framingham risk score >20% or European systematic coronary risk evaluation (SCORE) ≥5%. However, as these are post hoc analyses, data describing these subgroups have not previously been available to the clinical community.

Methods and results

We randomized 17 802 apparently healthy men aged ≥50 and women ≥60 with low-density lipoprotein cholesterol (LDL-C) <3.4 mmol/L, who were at an increased vascular risk due to elevated levels of C-reactive protein measured with a high-sensitivity (hs) assay to rosuvastatin 20 mg daily or placebo. Patients with high global cardiovascular risk at baseline were identified by 10-year Framingham risk score >20% or SCORE risk ≥5%. During 1.8-year median follow-up (maximum 5 years) of patients with Framingham risk >20%, the rate of myocardial infarction/stroke/cardiovascular death was 9.4 and 18.2 per 1000 person-years in rosuvastatin and placebo-allocated patients, respectively [hazard ratio (HR): 0.50, 95% confidence interval (CI): 0.27–0.93, P = 0.028]. Among patients with SCORE risk ≥5%, the corresponding rates were 6.9 and 12.0 using a model extrapolating risk for age ≥65 years (HR: 0.57, 95% CI: 0.43–0.78, P = 0.0003) and rates were 5.9 and 12.7 when risk for age was capped at 65 years (HR: 0.47, 95% CI: 0.32–0.68, P < 0.0001).

Conclusion

In primary prevention patients with elevated hs C-reactive protein who have high global cardiovascular risk (10-year Framingham risk score >20% or SCORE risk ≥5%), but LDL-C levels not requiring pharmacologic treatment, rosuvastatin 20 mg significantly reduced major cardiovascular events.

ClinicalTrial.gov Identifier: NCT00239681

Introduction

The Justification for Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) trial was designed to investigate whether rosuvastatin decreased first major cardiovascular events among patients with levels of low-density lipoprotein cholesterol (LDL-C) <3.4 mmol/L (130 mg/dL), but who were at increased cardiovascular risk due to elevated levels of high-sensitivity (hs) C-reactive protein.1 As previously reported, after median follow-up of 1.9 years (maximum 5 years), rosuvastatin use was associated with a 54% reduction in myocardial infarction (MI), a 48% reduction in stroke, a 46% reduction in revascularization, a 43% reduction in venous thromboembolism, and a 20% reduction in total mortality.1,2 On this basis, the United States Food and Drug Administration approved the use of rosuvastatin for primary prevention of cardiovascular events among JUPITER eligible participants with elevated hs C-reactive protein and at least one additional risk factor.3 In contrast, the Dutch Medical Agency (the MEB) and 18 other European health authorities have approved rosuvastatin for the subgroup of trial participants who were considered to be at ‘high risk' either on the basis of an estimated 10-year Framingham risk score >20% or an estimated systematic coronary risk evaluation (SCORE) risk of ≥5%.4 As neither of these criteria were used in the design of the JUPITER trial, these post hoc data, not published previously, are likely to be of utility for European practitioners and are thus presented here.

Methods

JUPITER was a double-blind, placebo-controlled trial which randomized apparently healthy men aged ≥50 and women aged ≥60, with LDL-C <3.4 mmol/L (130 mg/dL) and C-reactive protein ≥2 mg/L in 26 countries. Participants did not qualify for statin therapy according to guidelines in effect in 2003, but were at increased cardiovascular risk due to evidence of systemic inflammation.5

Full details of the trial protocol, procedures, and methods of confirming clinical endpoints and ascertaining adverse events have been presented previously.1,6 Trial exclusion criteria included use within 6 weeks before screening of any lipid-lowering therapies, the current use of post-menopausal hormone replacement therapy, evidence of hepatic dysfunction, serum creatinine >177 μmol/L, diabetes mellitus, prior cardiovascular or cerebrovascular events, chronic inflammatory conditions such as severe arthritis, lupus, or inflammatory bowel disease, or other serious medical conditions that might compromise safety or successful completion of the study.

Potentially eligible subjects underwent a 4-week placebo run-in phase; those with compliance >80% were randomly allocated to rosuvastatin 20 mg daily or placebo and followed for occurrence of the primary endpoint, a composite of MI, stroke, arterial revascularization, unstable angina, or confirmed death from cardiovascular causes. An independent endpoint committee adjudicated primary endpoint events. Evaluation of all-cause mortality, MI/stroke/cardiovascular death, fatal/non-fatal MI, and fatal/non-fatal stroke was pre-specified.

The trial's monitoring plan called for two interim efficacy analyses with the O'Brien–Fleming stopping boundaries determined by means of the Lan–DeMets approach. The stopping boundary was crossed at the first planned efficacy evaluation, and on 29 March 2008, the independent data and safety monitoring board recommended termination of the trial. The steering committee accepted that recommendation and only major cardiovascular events occurring prior to 30 March 2008 are included in this analysis. Reporting of adverse events and all-cause mortality continued in a blinded manner until each participant appeared for a closeout visit and discontinued study medication.

Clinic physicians reported adverse events as verbatim terms, which were coded to Medical Dictionary for Regulatory Activities (MedDRA) preferred terms7 by an automated system, over-read by trained coders. We report here treatment-emergent adverse events, i.e. events that either began or worsened after randomization.

Participants provided fasting blood samples for lipid profiles at baseline, annually thereafter, and at the final visit. Alanine aminotransferase was measured at baseline, 3 and 6 months after randomization, semi-annually thereafter, and at the final visit. Serum creatinine was measured at baseline, 1 year after randomization, and at the final visit. We estimated glomerular filtration rate by the Modification of Diet in Renal Disease study equation.8

Statistical analyses

For consistency with post hoc analyses performed for the European health authorities, all study participants were classified according to 10-year global risk estimates using the Framingham risk score9 and the European SCORE risk algorithm.10 The Framingham risk score estimates the 10-year risk of MI/coronary death on the basis of age, gender, smoking status, blood pressure, and total and high-density lipoprotein cholesterol (HDL-C), whereas the SCORE algorithm estimates the global 10-year risk of cardiovascular death on the basis of age, gender, smoking status, systolic blood pressure, total cholesterol, and geographic region. The regional risk was based on each participant's country of enrolment; those enrolled in Belgium, Canada, Chile, Israel, Mexico, the Netherlands, and Switzerland were categorized as low risk. Patients enrolled in Argentina, Brazil, Bulgaria, Colombia, Costa Rica, Denmark, El Salvador, Estonia, Germany, Norway, Panama, Poland, Romania, Russia, South Africa, UK, USA, Uruguay, and Venezuela were categorized as high risk.

The SCORE model is limited to ages 45–64 years. To account for the large proportion of subjects enrolled in JUPITER older than 65 years (n = 10 237), a modification of the SCORE model was used in which the risk conferred by age was extrapolated for patients aged 65 or older (extrapolated model). Extrapolation was based on the contribution of age to the risk of cardiovascular death as assessed in the algorithm for patients up to 65 years of age. The extrapolated model is the model cited in the European CRESTOR Summary of the Product Characteristics.4 An analysis was also performed using the SCORE algorithm capped at 65 years (capped model), in which all subjects 65 years or older were assigned the risk of a 64-year old. This more conservative approach resulted in fewer patients being classified as high risk; 52% of the JUPITER participants had SCORE risk ≥5% using the extrapolated model compared with 35% using the capped model. Analyses for patients with SCORE risk <5% are included as Supplemental data.

Analyses were performed on an intention-to-treat basis. Hazard ratios (HR) and 95% confidence intervals (CI) were calculated from the Cox proportional hazard models. Changes in lipoproteins and hs C-reactive protein levels were compared by the Wilcoxon signed-rank test. Baseline hs C-reactive protein is the mean of each participant's values at the screening and randomization visits. Analyses were performed using SAS version 8.2 (SAS Institute, Inc., Cary, NC, USA).

Results

JUPITER enrolled 17 802 men and women (6515 in Europe), and randomized 8901 each to rosuvastatin 20 mg daily and placebo. At baseline, 9% of the cohort was considered to be at ‘high risk’ for a first cardiovascular event on the basis of having a 10-year Framingham risk of MI/coronary death above 20%; 52% were considered to be at ‘high risk’ on the basis of having a 10-year SCORE risk of cardiovascular death of 5% or higher using the extrapolated model, and 35% were considered to be at ‘high risk' using the capped SCORE model. Baseline characteristics of these high-risk patients are shown by treatment allocation (Table 1). As anticipated, when compared with the entire JUPITER cohort, the higher-risk patients were older, more often male and more likely to smoke, have hypertension and low levels of HDL-C. Differences between the high-risk Framingham and SCORE groups reflect the patient characteristics included in the risk algorithms and their weighted contribution to individuals' estimated global cardiovascular risk. In particular, metabolic syndrome was more prevalent among high-risk Framingham patients.

Table 1

Baseline characteristics according to the estimated 10-year risk defined by the Framingham risk score or the systematic coronary risk evaluation risk algorithm

 Entire cohort Framingham 10-year risk >20%
 
SCORE 10-year risk ≥5%
 
    Extrapolated model
 
Capped model
 
  Rosuvastatin Placebo Rosuvastatin Placebo Rosuvastatin Placebo 
n 17 802 786 772 4619 4683 3130 3177 
Age (years) 66 74 74 70 70 67 67 
Female (%) 38 17 15 32 31 12 11 

 
Race or ethnic group (%) 
 White 71 68 67 72 72 74 74 
 Black 13 15 14 14 14 14 14 
 Hispanic 13 14 17 10 10 
 Other 

 
Hypertension (%) 57 87 86 67 67 69 68 
Current smoker (%) 16 32 31 21 22 30 31 
Family history premature CHDa (%) 12 11 10 10 10 10 
HDL-C < 1.0 mmol/L (%) 23 60 60 22 22 24 24 
Body mass index (kg/m228 28 28 28 28 28 28 
Metabolic syndromeb (%) 41 68 69 41 41 40 40 
Framingham 10-year risk score 10 25 25 16 16 16 16 
SCORE 10-year risk 14 14 10 10 
 Entire cohort Framingham 10-year risk >20%
 
SCORE 10-year risk ≥5%
 
    Extrapolated model
 
Capped model
 
  Rosuvastatin Placebo Rosuvastatin Placebo Rosuvastatin Placebo 
n 17 802 786 772 4619 4683 3130 3177 
Age (years) 66 74 74 70 70 67 67 
Female (%) 38 17 15 32 31 12 11 

 
Race or ethnic group (%) 
 White 71 68 67 72 72 74 74 
 Black 13 15 14 14 14 14 14 
 Hispanic 13 14 17 10 10 
 Other 

 
Hypertension (%) 57 87 86 67 67 69 68 
Current smoker (%) 16 32 31 21 22 30 31 
Family history premature CHDa (%) 12 11 10 10 10 10 
HDL-C < 1.0 mmol/L (%) 23 60 60 22 22 24 24 
Body mass index (kg/m228 28 28 28 28 28 28 
Metabolic syndromeb (%) 41 68 69 41 41 40 40 
Framingham 10-year risk score 10 25 25 16 16 16 16 
SCORE 10-year risk 14 14 10 10 

Values are median or n (%). SCORE, systematic coronary risk evaluation; CHD, coronary heart disease; HDL-C, high-density lipoprotein cholesterol.

aCHD in a male first-degree relative before age 55 or in a female first-degree relative before age 65.

bMetabolic syndrome defined as three or more of the following: waist circumference >102 cm (men) and 89 cm (women); triglycerides ≥1.7 mmol/L; HDL-C < 1.0 mmol/L (men) and 1.3 mmol/L (women); blood pressure ≥85 mmHg diastolic or 130 mmHg systolic or treated hypertension; fasting glucose ≥5.6 mmol/L.

For the entire JUPITER cohort, rosuvastatin lowered LDL-C by 50%, triglycerides by 17% and hs C-reactive protein by 37%, whereas it increased HDL-C by 4% compared with placebo (P < 0.001 for all from baseline to year 1).1 In the high-risk groups, effects of rosuvastatin on lipoproteins and hs C-reactive protein were similar to those seen for the entire cohort (Table 2), with significant reductions in LDL-C, triglycerides, and hs C-reactive protein (P< 0.0001 vs. placebo for all) and a significant increase in HDL-C (P < 0.0001).

Table 2

Lipoprotein and high-sensitivity C-reactive protein levels in high-risk subgroups

   SCORE 10-year risk ≥5%
 
 Framingham 10-year risk >20%
 
Extrapolated model
 
Capped model
 
 Rosuvastatin Placebo Rosuvastatin Placebo Rosuvastatin Placebo 
LDL-C (mmol/L) 
 Baseline 2.8 (2.5–3.1) 2.8 (2.5–3.1) 2.8 (2.5–3.1) 2.8 (2.5–3.1) 2.8 (2.5–3.1) 2.8 (2.5–3.1) 
 Year 1 1.3 (1.1–1.9) 2.8 (2.4–3.2) 1.4 (1.1–1.8) 2.8 (2.4–3.2) 1.4 (1.1–1.9) 2.8 (2.4–3.2) 
 % change −51 −49 +2 −49 +2 
P-value <0.0001 <0.0001 <0.0001 

 
Non-HDL-C (mmol/L) 
 Baseline 3.7 (3.3–4.0) 3.7 (3.3–4.0) 3.5 (3.1–3.87) 3.5 (3.1–3.8) 3.5 (3.1–3.8) 3.5 (3.1–3.8) 
 Year 1 2.0 (1.7–2.6) 3.6 (3.2–4.1) 2.0 (1.6–2.5) 3.5 (3.0–4.0) 2.0 (1.7–2.5) 3.5 (3.0–4.0) 
 % change −45 −43 +2 −42 +2 
P-value <0.0001 <0.0001 <0.0001 

 
HDL-C (mmol/L ) 
 Baseline 1.0 (0.9–1.1) 1.0 (0.9–1.1) 1.3 (1.1–1.6) 1.3 (1.1–1.6) 1.2 (1.0–1.5) 1.2 (1.0–1.5) 
 Year 1 1.1 (1.0–1.3) 1.0 (0.9–1.2) 1.3 (1.1–1.7) 1.3 (1.1–1.6) 1.3 (1.1–1.6) 1.3 (1.0–1.6) 
 % change +9 +3 +6 +6 
P-value <0.0001 <0.0001 <0.0001 

 
Triglycerides (mmol/L) 
 Baseline 1.7 (1.3–2.5) 1.7 (1.2–2.5) 1.3 (0.9–1.9) 1.3 (0.9–1.9) 1.3 (0.9–1.9) 1.3 (0.9–1.9) 
 Year 1 1.3 (1.0–1.8) 1.6 (1.2–2.4) 1.1 (0.8–1.5) 1.3 (1.0–1.8) 1.1 (0.8–1.6) 1.3 (1.0–1.9) 
 % change −22 −3 −16 −16 +1 
P-value <0.0001 <0.0001 <0.0001 

 
hs C-reactive protein (mg/L) 
 Baseline 4.6 (3.0–7.9) 4.6 (3.1–7.8) 4.2 (2.9–7.1) 4.4 (2.9–7.3) 4.2 (2.8–6.9) 4.4 (2.9–7.2) 
 Year 1 2.5 (1.3–4.8) 3.7 (2.3–6.7) 2.3 (1.3–4.6) 3.6 (2.0–6.4) 2.2 (1.2–4.5) 3.5 (2.0–6.4) 
 % change −49 −17 −46 −21 −46 −21 
P-value <0.0001 <0.0001 <0.0001 
   SCORE 10-year risk ≥5%
 
 Framingham 10-year risk >20%
 
Extrapolated model
 
Capped model
 
 Rosuvastatin Placebo Rosuvastatin Placebo Rosuvastatin Placebo 
LDL-C (mmol/L) 
 Baseline 2.8 (2.5–3.1) 2.8 (2.5–3.1) 2.8 (2.5–3.1) 2.8 (2.5–3.1) 2.8 (2.5–3.1) 2.8 (2.5–3.1) 
 Year 1 1.3 (1.1–1.9) 2.8 (2.4–3.2) 1.4 (1.1–1.8) 2.8 (2.4–3.2) 1.4 (1.1–1.9) 2.8 (2.4–3.2) 
 % change −51 −49 +2 −49 +2 
P-value <0.0001 <0.0001 <0.0001 

 
Non-HDL-C (mmol/L) 
 Baseline 3.7 (3.3–4.0) 3.7 (3.3–4.0) 3.5 (3.1–3.87) 3.5 (3.1–3.8) 3.5 (3.1–3.8) 3.5 (3.1–3.8) 
 Year 1 2.0 (1.7–2.6) 3.6 (3.2–4.1) 2.0 (1.6–2.5) 3.5 (3.0–4.0) 2.0 (1.7–2.5) 3.5 (3.0–4.0) 
 % change −45 −43 +2 −42 +2 
P-value <0.0001 <0.0001 <0.0001 

 
HDL-C (mmol/L ) 
 Baseline 1.0 (0.9–1.1) 1.0 (0.9–1.1) 1.3 (1.1–1.6) 1.3 (1.1–1.6) 1.2 (1.0–1.5) 1.2 (1.0–1.5) 
 Year 1 1.1 (1.0–1.3) 1.0 (0.9–1.2) 1.3 (1.1–1.7) 1.3 (1.1–1.6) 1.3 (1.1–1.6) 1.3 (1.0–1.6) 
 % change +9 +3 +6 +6 
P-value <0.0001 <0.0001 <0.0001 

 
Triglycerides (mmol/L) 
 Baseline 1.7 (1.3–2.5) 1.7 (1.2–2.5) 1.3 (0.9–1.9) 1.3 (0.9–1.9) 1.3 (0.9–1.9) 1.3 (0.9–1.9) 
 Year 1 1.3 (1.0–1.8) 1.6 (1.2–2.4) 1.1 (0.8–1.5) 1.3 (1.0–1.8) 1.1 (0.8–1.6) 1.3 (1.0–1.9) 
 % change −22 −3 −16 −16 +1 
P-value <0.0001 <0.0001 <0.0001 

 
hs C-reactive protein (mg/L) 
 Baseline 4.6 (3.0–7.9) 4.6 (3.1–7.8) 4.2 (2.9–7.1) 4.4 (2.9–7.3) 4.2 (2.8–6.9) 4.4 (2.9–7.2) 
 Year 1 2.5 (1.3–4.8) 3.7 (2.3–6.7) 2.3 (1.3–4.6) 3.6 (2.0–6.4) 2.2 (1.2–4.5) 3.5 (2.0–6.4) 
 % change −49 −17 −46 −21 −46 −21 
P-value <0.0001 <0.0001 <0.0001 

Values are median (interquartile range) or median (%); SCORE, systematic coronary risk evaluation; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; hs, high sensitivity.

At study closure (median follow-up 1.8 years; maximal follow-up 5 years), the occurrence of MI/stroke/cardiovascular death was lower among high-risk subjects allocated to rosuvastatin compared with placebo (HR: 0.50, 95% CI: 0.27–0.93 for Framingham risk score >20%; HR: 0.57, 95% CI: 0.43–0.78 for SCORE risk ≥5% extrapolated model; HR: 0.47, 95% CI: 0.32–0.68 for SCORE risk ≥5% capped model; Figure 1, Table 3). The proportional reduction in MI/stroke/cardiovascular death with rosuvastatin was similar for patients with Framingham risk score above or below 20% (P for interaction = 0.95), or SCORE risk above or below 5% (P for interaction = 0.37 capped model, 0.25 extrapolated model).

Table 3

Major cardiovascular events and all-cause mortality in high-risk subgroups

 Rosuvastatin
 
Placebo
 
ARR HR (95% CI) P-value 
 No. events Event ratea No. events Event rate    
Entire JUPITER cohort (n = 8901 rosuvastatin, 8901 placebo) 
 Primary endpoint 142 7.7 251 13.6 5.9 0.56 (0.46–0.69) <0.0001 
 MI/stroke/CV death 83 4.5 157 8.5 4.0 0.53 (0.40–0.69) <0.0001 
 Total mortality 198 10.0 247 12.5 2.5 0.80 (0.67–0.97) 0.02 

 
Baseline Framingham >20% (n = 786 rosuvastatin, 772 placebo) 
 Primary endpoint 29 17.2 38 24.1 6.9 0.70 (0.43–1.14) 0.155 
 MI/stroke/CV death 16 9.4 29 18.2 8.8 0.50 (0.27–0.93) 0.028 
 Total mortality 31 17.2 40 23.6 6.3 0.73 (0.46–1.17) 0.193 

 
Baseline SCORE ≥5% (extrapolated model; n= 4619 rosuvastatin, 4683 placebo) 
 Primary endpoint 111 11.5 183 18.8 7.3 0.61 (0.48–0.78) <0.0001 
 MI/stroke/CV death 67 6.9 118 12.0 5.1 0.57 (0.43–0.78) 0.0003 
 Total mortality 149 14.4 185 17.5 3.2 0.82 (0.66–1.02) 0.076 

 
Baseline SCORE ≥5% (age capped at 65 years; n = 3130 rosuvastatin, 3177 placebo) 
 Primary endpoint 71 11.1 130 20.1 9.0 0.56 (0.42–0.74) <0.0001 
 MI/stroke/CV death 38 5.9 83 12.7 6.9 0.47 (0.32–0.68) <0.0001 
 Total mortality 97 15 135 20.6 5.6 0.74 (0.57–0.96) 0.022 
 Rosuvastatin
 
Placebo
 
ARR HR (95% CI) P-value 
 No. events Event ratea No. events Event rate    
Entire JUPITER cohort (n = 8901 rosuvastatin, 8901 placebo) 
 Primary endpoint 142 7.7 251 13.6 5.9 0.56 (0.46–0.69) <0.0001 
 MI/stroke/CV death 83 4.5 157 8.5 4.0 0.53 (0.40–0.69) <0.0001 
 Total mortality 198 10.0 247 12.5 2.5 0.80 (0.67–0.97) 0.02 

 
Baseline Framingham >20% (n = 786 rosuvastatin, 772 placebo) 
 Primary endpoint 29 17.2 38 24.1 6.9 0.70 (0.43–1.14) 0.155 
 MI/stroke/CV death 16 9.4 29 18.2 8.8 0.50 (0.27–0.93) 0.028 
 Total mortality 31 17.2 40 23.6 6.3 0.73 (0.46–1.17) 0.193 

 
Baseline SCORE ≥5% (extrapolated model; n= 4619 rosuvastatin, 4683 placebo) 
 Primary endpoint 111 11.5 183 18.8 7.3 0.61 (0.48–0.78) <0.0001 
 MI/stroke/CV death 67 6.9 118 12.0 5.1 0.57 (0.43–0.78) 0.0003 
 Total mortality 149 14.4 185 17.5 3.2 0.82 (0.66–1.02) 0.076 

 
Baseline SCORE ≥5% (age capped at 65 years; n = 3130 rosuvastatin, 3177 placebo) 
 Primary endpoint 71 11.1 130 20.1 9.0 0.56 (0.42–0.74) <0.0001 
 MI/stroke/CV death 38 5.9 83 12.7 6.9 0.47 (0.32–0.68) <0.0001 
 Total mortality 97 15 135 20.6 5.6 0.74 (0.57–0.96) 0.022 

MI, myocardial infarction; CV, cardiovascular; HR, hazard ratio; CI, confidence interval; SCORE, systematic coronary risk evaluation; ARR, absolute rate reduction. Primary endpoint, time to occurrence of first MI/stroke/cardiovascular death/arterial revascularization/unstable angina.

Data for the entire JUPITER cohort are from reference 1. Extrapolated and capped SCORE models are described in the ‘Methods’ section.

aRates are per 1000 person-years.

Figure 1

Cumulative incidence of myocardial infarction/stroke/cardiovascular death in high-risk patients. The cumulative incidence of myocardial infarction/stroke/cardiovascular death is shown by the treatment group for patients with a 10-year Framingham risk score >20% (upper panel), 10-year systematic coronary risk evaluation risk ≥5% using the extrapolated model (middle panel), and systematic coronary risk evaluation risk ≥5% using the capped model (lower panel). NNT, number needed to treat.

Figure 1

Cumulative incidence of myocardial infarction/stroke/cardiovascular death in high-risk patients. The cumulative incidence of myocardial infarction/stroke/cardiovascular death is shown by the treatment group for patients with a 10-year Framingham risk score >20% (upper panel), 10-year systematic coronary risk evaluation risk ≥5% using the extrapolated model (middle panel), and systematic coronary risk evaluation risk ≥5% using the capped model (lower panel). NNT, number needed to treat.

Rosuvastatin significantly reduced the occurrence of the primary composite endpoint of MI/stroke/arterial revascularization/unstable angina/cardiovascular death as well as fatal/non-fatal MI and fatal/non-fatal stroke among patients with SCORE ≥5% (in both the extrapolated and capped models; Table 3, Figure 2) and reduced all-cause mortality in the capped SCORE model (Table 3).

Figure 2

Cumulative incidence of fatal/non-fatal myocardial infarction and stroke in high-risk patients. The cumulative incidence of fatal/non-fatal myocardial infarction and fatal/non-fatal stroke are shown by the treatment group among patients with a 10-year systematic coronary risk evaluation risk ≥5% using the extrapolated (upper panel) and capped models (lower panel).

Figure 2

Cumulative incidence of fatal/non-fatal myocardial infarction and stroke in high-risk patients. The cumulative incidence of fatal/non-fatal myocardial infarction and fatal/non-fatal stroke are shown by the treatment group among patients with a 10-year systematic coronary risk evaluation risk ≥5% using the extrapolated (upper panel) and capped models (lower panel).

In the higher-risk patients, there was no evidence of heterogeneity for the endpoint of MI/stroke/cardiovascular death in subgroups by gender, age, race/ethnicity, hypertension, smoking, family history of premature coronary heart disease, baseline HDL-C, or C-reactive protein (Figure 3). Patients with body mass index >30 kg/m2 at baseline appeared to benefit less from rosuvastatin treatment compared with non-obese patients, but this interaction between treatment assignment and body mass index was not observed for the JUPITER cohort as a whole and thus is likely to be more apparent than real.

Figure 3

Effects of rosuvastatin on myocardial infarction/stroke/cardiovascular death in high-risk patients, according to baseline characteristics. The hazard ratios and 95% confidence intervals for rosuvastatin when compared with placebo are shown for patients with Framingham risk score >20% and systematic coronary risk evaluation risk ≥5% (extrapolated and capped models). Size of the point estimate rectangle is proportional to the number of clinical events. The dashed vertical line indicates the relative risk reduction for the entire trial cohort. Also shown are P-values for the test of an interaction between the composite endpoint and categories within each subgroup.

Figure 3

Effects of rosuvastatin on myocardial infarction/stroke/cardiovascular death in high-risk patients, according to baseline characteristics. The hazard ratios and 95% confidence intervals for rosuvastatin when compared with placebo are shown for patients with Framingham risk score >20% and systematic coronary risk evaluation risk ≥5% (extrapolated and capped models). Size of the point estimate rectangle is proportional to the number of clinical events. The dashed vertical line indicates the relative risk reduction for the entire trial cohort. Also shown are P-values for the test of an interaction between the composite endpoint and categories within each subgroup.

In the high-risk patients, serious adverse events were reported with similar frequency in rosuvastatin and placebo-allocated patients (Table 4). A small excess of myalgia was reported with rosuvastatin in patients with Framingham risk score >20% (rosuvastatin 5.9% and placebo 5.3%) or SCORE risk ≥5% (rosuvastatin 7.9%, placebo 6.5% for the extrapolated model; 7.4 vs. 5.8% for the capped model). Myopathy, myositis, and rhabdomyolysis were reported with similar frequency in the two treatment groups. In the entire JUPITER cohort, investigator-reported diabetes, a non-adjudicated outcome, was more frequent with rosuvastatin (rosuvastatin 3.0% and placebo 2.4%; P = 0.01).1 Investigator-reported diabetes was not consistently more frequent with rosuvastatin in the higher-risk patients (HR: 0.70, 95% CI: 0.41–1.19, P = 0.19 for Framingham risk score >20%; HR: 1.11, 95% CI: 0.86–1.43, P = 0.43 for extrapolated SCORE risk ≥5%; HR: 0.99, 95% CI: 0.72–1.36, P = 0.95 for capped SCORE risk). At 2 years following randomization, a 0.1% greater increase in glycosylated haemoglobin was observed with rosuvastatin compared with placebo (P < 0.001 vs. placebo for the high-risk groups). However, on-treatment fasting glucose levels were similar in the two treatment groups (P = 0.95 vs. placebo for Framingham risk score >20%; P = 0.19 for extrapolated SCORE risk ≥5%; P = 0.52 for the capped SCORE model).

Table 4

Adverse events and laboratory abnormalities in high-risk subgroups

 Framingham risk >20%
 
SCORE risk ≥5%
 
 RSV Placebo Extrapolated model
 
Capped model
 
   RSV Placebo RSV Placebo 
n 786 772 4619 4683 3130 3177 
Any adverse event 626 (79.6) 617 (79.9) 3681 (79.7) 3704 (79.1) 2490 (79.6) 2510 (79.0) 
Any serious adverse event 154 (19.6) 153 (19.8) 855 (18.5) 878 (18.7) 544 (17.4) 587 (18.5) 

 
Muscle symptoms       
 Myalgia 46 (5.9) 41 (5.3) 363 (7.9) 303 (6.5) 233 (7.4) 183 (5.8) 
 Myositis 1 (0.1) 3 (0.1) 3 (0.1) 3 (0.1) 2 (0.1) 
 Myopathy 1 (0) 1 (0) 
 Rhabdomyolysis 1 (0) 1 (0) 

 
Newly diagnosed cancer 35 (4.5) 39 (5.1) 195 (4.2) 212 (4.5) 116 (3.7) 145 (4.6) 
Death from cancer 9 (1.1) 11 (1.4) 29 (0.6) 48 (1.0) 19 (0.6) 40 (1.3) 
Gastrointestinal disorder 206 (26.2) 214 (27.7) 1184 (25.6) 1175 (25.1) 763 (24.4) 737 (23.2) 
Renal disorder 100 (12.7) 87 (11.3) 487 (10.5) 523 (11.2) 355 (11.3) 354 (11.1) 
Hepatic disorder 19 (2.4) 14 (1.8) 103 (2.2) 101 (2.2) 65 (2.1) 57 (1.8) 
Investigator-reported diabetes 24 (3.1) 34 (4.4) 131 (2.8) 116 (2.5) 84 (2.7) 83 (2.6) 

 
Laboratory values       
 Creatinine >100% increase from baseline [n (%)] 1 (0.1) 7 (0.2) 3 (0.1) 6 (0.2) 2 (0.1) 
 eGFR at 12 months (mL/min/1.73 m265.0 (14.2) 64.4 (13.9) 66.9 (14.2) 66.4 (13.6) 69.2 (14.3) 68.7 (13.3) 
 ALT>3x ULN on consecutive visits [n (%)] 3 (0.4) 2 (0.3) 14 (0.3) 6 (0.1) 12 (0.4) 5 (0.2) 
 HbA1c at 24 months (%) 6.02 (0.53) 5.92 (0.53) 5.96 (0.49) 5.86 (0.46) 5.97 (0.48) 5.87 (0.46) 
 Fasting glucose at 24 months (mmol/L) 5.7 (0.9) 5.7 (1.3) 5.6 (1.1) 5.6 (0.9) 5.6 (1.0) 5.6 (0.9) 
 Framingham risk >20%
 
SCORE risk ≥5%
 
 RSV Placebo Extrapolated model
 
Capped model
 
   RSV Placebo RSV Placebo 
n 786 772 4619 4683 3130 3177 
Any adverse event 626 (79.6) 617 (79.9) 3681 (79.7) 3704 (79.1) 2490 (79.6) 2510 (79.0) 
Any serious adverse event 154 (19.6) 153 (19.8) 855 (18.5) 878 (18.7) 544 (17.4) 587 (18.5) 

 
Muscle symptoms       
 Myalgia 46 (5.9) 41 (5.3) 363 (7.9) 303 (6.5) 233 (7.4) 183 (5.8) 
 Myositis 1 (0.1) 3 (0.1) 3 (0.1) 3 (0.1) 2 (0.1) 
 Myopathy 1 (0) 1 (0) 
 Rhabdomyolysis 1 (0) 1 (0) 

 
Newly diagnosed cancer 35 (4.5) 39 (5.1) 195 (4.2) 212 (4.5) 116 (3.7) 145 (4.6) 
Death from cancer 9 (1.1) 11 (1.4) 29 (0.6) 48 (1.0) 19 (0.6) 40 (1.3) 
Gastrointestinal disorder 206 (26.2) 214 (27.7) 1184 (25.6) 1175 (25.1) 763 (24.4) 737 (23.2) 
Renal disorder 100 (12.7) 87 (11.3) 487 (10.5) 523 (11.2) 355 (11.3) 354 (11.1) 
Hepatic disorder 19 (2.4) 14 (1.8) 103 (2.2) 101 (2.2) 65 (2.1) 57 (1.8) 
Investigator-reported diabetes 24 (3.1) 34 (4.4) 131 (2.8) 116 (2.5) 84 (2.7) 83 (2.6) 

 
Laboratory values       
 Creatinine >100% increase from baseline [n (%)] 1 (0.1) 7 (0.2) 3 (0.1) 6 (0.2) 2 (0.1) 
 eGFR at 12 months (mL/min/1.73 m265.0 (14.2) 64.4 (13.9) 66.9 (14.2) 66.4 (13.6) 69.2 (14.3) 68.7 (13.3) 
 ALT>3x ULN on consecutive visits [n (%)] 3 (0.4) 2 (0.3) 14 (0.3) 6 (0.1) 12 (0.4) 5 (0.2) 
 HbA1c at 24 months (%) 6.02 (0.53) 5.92 (0.53) 5.96 (0.49) 5.86 (0.46) 5.97 (0.48) 5.87 (0.46) 
 Fasting glucose at 24 months (mmol/L) 5.7 (0.9) 5.7 (1.3) 5.6 (1.1) 5.6 (0.9) 5.6 (1.0) 5.6 (0.9) 

Values are n (%) or mean (standard deviation). SCORE, systematic coronary risk evaluation; RSV, Rosuvastatin; eGFR, estimated glomerular filtration rate; ALT, alanine aminotransferase; HbA1c, glycosylated haemoglobin; ULN, upper limit of normal.

Discussion

JUPITER investigated the effect of rosuvastatin 20 mg daily compared with placebo on major cardiovascular events in a population not requiring treatment under guidelines in effect in 2003,9,11 but at an increased cardiovascular risk on the basis of age and elevated hs C-reactive protein. To provide European practitioners access to post hoc subgroup data that were influential to the European health authorities, in this analysis, we limited the target population to select an even higher risk group using two global risk assessment algorithms, Framingham and SCORE. In these higher risk subgroups, rosuvastatin lowered LDL-C, triglycerides, and hs C-reactive protein and raised HDL-C, consistent with effects observed for the entire cohort. Rosuvastatin reduced the risk of the composite endpoint of MI/stroke/cardiovascular death by 50% in the high-risk Framingham group (P = 0.028 vs. placebo), 43% in the high-risk SCORE group using the extrapolated model (P = 0.0003) and 53% (P < 0.0001) using the capped model, consistent with the 47% reduction observed for the entire cohort.1 Adverse events and laboratory abnormalities were consistent with the known safety profile of rosuvastatin.12

Strengths of this analysis include the randomized, placebo-controlled design, broad geographic representation including a substantial number of Europeans, and inclusion of large numbers of women and ethnic minority participants. A limitation is the post hoc selection of the higher risk subgroups, which was undertaken in response to health authority requests.4 For example, analysis of JUPITER subgroups by SCORE strata was not pre-specified and since SCORE by design is limited to those under age 65, we needed to extrapolate findings for the many JUPITER participants over this age cut-off that clearly benefited from rosuvastatin.13 The subgroups by baseline characteristics in Figure 3 are drawn from within the subgroups of high-risk patients; as such, limited conclusions can be drawn from these data. Neither the Framingham nor the SCORE models include hs C-reactive protein evaluation; as all participants in JUPITER had hs C-reactive protein levels >2 mg/L and as elevated hs C-reactive protein has been shown to have a magnitude of risk prediction at least as large as that of elevated cholesterol,14 it is likely that both the Framingham and the SCORE systematically underestimate the true risk of JUPITER participants.

Also in keeping with health authority requests, the analyses here used a composite endpoint of MI/stroke/cardiovascular death rather than the pre-specified JUPITER primary endpoint. Nonetheless, the relative reduction in MI/stroke/cardiovascular death with rosuvastatin was remarkably consistent across a range of baseline participant characteristics and consistent with primary trial analyses of the full study population as pre-specified in the JUPITER protocol. Global risk prediction scores can be used to direct use of preventive therapies such as statins towards patients most likely to benefit.15,16 As expected, clinical event rates in the JUPITER placebo group were higher in the high-risk Framingham or SCORE groups compared with the entire cohort for the primary study endpoint as well as for the composite of MI/stroke/cardiovascular death and all-cause mortality. The magnitude of the absolute rate reduction for clinical events was correspondingly greater in the high-risk groups (Table 3).

Two factors contributing to the observed absolute reduction in clinical events in JUPITER were the underlying event rate in the placebo group, enhanced in this case by selecting patients with high global cardiovascular risk and elevated hs C-reactive protein, and the relative risk reduction due to treatment, enhanced by use of a high-efficacy statin. The reductions in LDL-C (49%) and clinical events (43–53% for MI/stroke/cardiovascular death) with rosuvastatin in the JUPITER patients with SCORE risk ≥5% are greater than reported for other statins.17,18 Although these data support the use of high-efficacy statin therapy, they do not minimize the roles of diet, exercise, and smoking cessation as the most important interventions for primary prevention. Despite the benefit derived from treatment with rosuvastatin in these high-risk patients, caution should be exercised when considering treatment of patients lacking any cardiovascular risk factors. Further, long-term compliance with statin therapy is critical for efficacy among those patients where pharmacologic therapy is indicated in addition to lifestyle interventions.

Although the analyses presented here parallel those requested by European Health Authorities, they do not address most patients actually studied in the JUPITER trial. For example, among the 7340 men and women with elevated hs C-reactive protein and the Framingham risk scores of 11–20%, where the 4.5-year absolute risk of a primary endpoint was 10.6% in the placebo group, rosuvastatin was associated with a 49% reduction in risk (HR: 0.51, 95% CI: 0.39–0.68, P < 0.0001). Similarly, among the 6091 participants with entry Framingham scores of 5–10%, where the 4.5-year absolute risk was 5.3%, a 45% reduction was observed with rosuvastatin (HR: 0.55, 95% CI: 0.36–0.84, P = 0.005), and among trial participants with elevated hs C-reactive protein with SCORE risk <5%, rosuvastatin was associated with a 56% reduction in vascular risk (HR: 0.44, 95% CI: 0.29–0.68). Thus, the JUPITER trial data also indicate that many individuals with elevated hs C-reactive protein who fall outside ‘high-risk’ subgroups defined by either Framingham or SCORE have both substantive absolute risk and large relative risk reductions when treated with rosuvastatin.

Supplementary material

Supplementary material is available at European Heart Journal online.

Funding

The JUPITER trial was investigator-initiated and supported by AstraZeneca. The sponsor of the study collected the trial data and monitored the study sites, but had no access to unblinded data until after drafting of the trial primary report. The sponsor supported preparation of this manuscript. Trial Principal Investigator (P.M.R.) had full access to all study data; W.K. had final responsibility for the decision to submit these data for publication. Funding to pay the Open Access publication charges for this article was provided by AstraZeneca.

Conflict of interest: During the period of this project, W.K. reports receiving research support grants from Dade–Behring and Glaxo SmithKline; lecture fees from AstraZeneca, Pfizer, Novartis, and Boehringer-Ingelheim; and consulting fees from GlaxoSmithKline and Roche. P.M.R. reports having received investigator-initiated research grant support from the National Heart Lung and Blood Institute, the National Cancer Institute, the Donald W Reynolds Foundation, the Leducq Foundation, AstraZeneca, Novartis, Merck, Abbott, Roche, and sanofi-aventis; consulting fees from AstraZeneca, Novartis, Merck, Merck-Schering Plough, sanofi-aventis, ISIS, Seimens, and Vascular Biogenics; and is listed as a co-inventor on patents held by the Brigham and Women's Hospital that relate to the use of inflammatory biomarkers in cardiovascular disease that have been licensed to Seimens and AstraZeneca.

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Supplementary data

Comments

3 Comments
Rosuvastatin for Those in High Cardiovascular Risk With Obesity in JUPITER Cohorts
23 November 2010
Gen-Min Lin (with Yi-Hwei Li, Kai-Min Chu, and Chih-Lu Han)

To the Editor:

We read with interest the work by Koenig and Ridker which reportedthat in primary prevention patients with elevated hs C-reactive protein who have high global cardiovascular risk (10-year Framingham risk score > 20% or SCORE risk >= 5%), but LDL-C levels not requiring pharmacologic treatment, rosuvastatin 20 mg significantly reduced major cardiovascular events . 1 Previously we have made several comments regarding the relatively ineffective response of rosuvastatin to reduce primary end points for the elderly and women with metabolic syndrome in the Annals of Internal Medicine. 2 Among these populations accounting for one fourth in JUPITER cohorts, the relative risk estimated 0.80 of the rosuvastatin arm to the placebo arm for cardiovascular hazards will be offset by the increased incidence rate of newly-developed diabetes (1.5 times for women and 1.3 times for the elderly). Accordingly, the use of rosuvastatin for women and the elderly with metabolic syndrome who fulfill the JUPITER criteria should be cautious. In the issue of European Heart Journal, we notice another important finding that the use of rosuvastatin is ineffective to reduce cardiovascular events as compared the placebo for the obese patients with a 10-year Framingham risk score > 20% or SCORE risk >= 5% (relative risk > 1) . This phenomenon is also observed for those with metabolic syndrome except the capped model which indicates that the younger men with metabolic syndrome still benefit from rosuvastatin therapy (table). However, how do we interpret such a result in this report? Â To answer this question, we have already provided some clues in the JUPITER trial before that is the phenomenon of reverse epidemiology, also known as obesity paradox. 2,3 As we know, those with high body mass index have shown the survival benefit in many established cardiovascular disease such as coronary artery disease and heart failure. 4,5 Similarly, the phenomenon of reverse epidemiology may become dominant for those with high cardiovascular risk in the JUPITER cohorts. Therefore, the obese patients in predicted high risk groups possibly have significant low cardiovascular incident rates leading to the ineffective response of rosuvastatin therapy although the mechanisms should be further investigated.

In summary, we echo our previous comments 6 that the use of rosuvastatin for some populations in JUPITER cohorts such as women and the elderly with metabolic syndrome and the obese in high cardiovascular risks should be cautious until further analysis of the benefits to hazards regarding this application for patients are clarified.

Table. Comparisons of the relative risks for the elderly, women and high-risk populations with obesity and metabolic syndrome of JUPITER cohorts.

.

(N, %)

BMI>30 (RR, %)

MS (RR, %)

Total JUPITER cohorts

17802, 100%

0.60, 37.5%

0.66, 41.4%

Women

6801, 38.2%

0.60, 17.1%

0.80, 17.7%

Age > 70 year

5695, 32.0%

0.61, 10.2%

0.80, 12.7%

Framingham 10-year risk > 20%

.

.

.

1558, 8.8%

>1.00, 3.1%

0.90, 6.0%

SCORE 10-year risk >= 5%

.

.

Extrapolated model

9302, 52.3%

1.00, 17.3%

0.85, 21.4%

Capped model

6307, 35.4%

1.00, 11.1%

0.60, 14.1%

N= number; BMI= body mass index; MS= metabolic syndrome; RR= relative risk: primary cardiovascular end points of rosuvastatin to that of placebo.

Reference

  1. Koenig W, Ridker PM. Rosuvastatin for primary prevention in patients with European systematic coronary risk evaluation risk >= 5% or Framingham risk >20%: post hoc analyses of the JUPITER trial requested by European health authorities. Eur Heart J. 2010 Oct 22. [Epub ahead of print]

  2. Glynn RJ, Koenig W, Nordestgaard BG, Shepherd J, Ridker PM. Rosuvastatin for primary prevention in older persons with elevated C-reactive protein and low to average low-density lipoprotein cholesterol levels: exploratory analysis of a randomized trial. Ann Intern Med 2010;152: 488-496

  3. Mora S, Glynn RJ, Hsia J, MacFadyen JG, Genest J, Ridker PM. Statins for the primary prevention of cardiovascular events in women with elevated high-sensitivity C-reactive protein or dyslipidemia: results from the Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) and meta-analysis of women from primary prevention trials. Circulation 2010;121:1069-1077.

  4. Kalantar-Zadeh K, Block G, Howich T, Fonarow GC. Reverse epidemiology of conventional card0iovascular risk factors in patients with chronic heart failure. J Am Coll Cardiol 2004; 43: 1439-1444.

  5. Lavie CJ, Milani RV, Ventura HO. Obesity and cardiovascular disease: risk factor, paradox, and impact of weight loss. J Am Coll Cardiol. 2009 ;53:1925-1932

  6. Lin GM, Chu KM , Han CL. The Elderly and Women With Metabolic Syndrome in JUPITER- response to Rosuvastatin for primary prevention in older persons with elevated C-reactive protein and low to average low-density lipoprotein cholesterol levels: exploratory analysis of a randomized trial. Ann Intern Med published online Aug 13, 2010

Conflict of Interest:

None declared

Submitted on 23/11/2010 7:00 PM GMT
Global risk assessment advised by authorities: is it really helpful to use stated risk charts ?
8 February 2011
Robert Berent (with Serge P. von Duvillard, Helmut Sinzinger)

We read with interest the article by Koenig and Ridker.1 Both scores (Framingham and SCORE) are based on data obtained 30-40 years ago meanwhile mortality markedly changed. In Austria, that ranks high on (cardiovascular) CV risk chart, mortality decreased by ~50% between 1980- 2006.2 Therefore CV risk calculation is much more complex than described by a few parameters.3 Accepted risk factors, i.e., lipoprotein(a), C- reactive protein (CRP), family history are not considered and were decades ago unknown or not assessed.4,5 Moreover, nutritional behavior and physical activity were quite different, the relevance of waist circumference unknown. Most of the used risk scores have been recalibrated for different populations and ethnic groups, creating an artificial risk index for comparison and calculation of risks across different population groups leading to an additional statistical bias.6,7,8 However, populations differ substantially in their absolute CV risk, due to distinct ethnic groups and religions with different (eating) habits, life-style and social behavior. Mobility and migration have not been considered. Different ethnic populations have a distinct and sometimes higher prevalence of metabolic syndrome, a challenge for adjustment of risk scores limiting their applicability.6 Surprisingly, European health authorities approved rosuvastatin for patients to be at 'high risk' only using one of the two scores.1 One of the pitfalls of these scores is the arbitrary separation into low and high risk countries. Individuals' risk may vary by up to 100% using a low or high risk chart, i.e., living in Austria (high) or Switzerland (low risk). Moreover, there are significant differences in risk profile between citizens of Vienna and the surrounding population or the western and eastern part of Austria being larger than estimating low and high risk charts. In Mediterranean countries, considered as low risk areas, people living at the coast are consuming more fish and life-style is healthier than living in the mountains show eating habits not differing from Central Europe.9 Therefore, the results of the charts reflect a mean value depending on where the majority of people live rather than providing an individual risk information.10 Furthermore, the range of age and sex distribution was 30-74 and 45-64 years in the Framingham study and in SCORE, 54% and 44% were females. To account for subjects enrolled in JUPITER >65 years, the risk conferred by age was extrapolated for those patients. Judging individuals risk from the charts rather than treating any single risk factor is not evidence based at all. Risk prediction equations target preventive care of asymptomatic intermediate or high risk patients, but subjects stratified as low risk still constitute one quarter to a third of all CV events.11 Overestimation of CV risk, mainly due to an unhealthy life style, leads to increased costs. Underestimation of low risk usually younger patients with higher prevalent genetic abnormalities results in inadequate or even no treatment. Calculating risk from an incomplete algorithm with not explicitly evaluated and thoroughly assessed risk profiles does make sense and is not evidence based.

We declare that we have no conflicts of interest.

*Robert Berent1, Serge P. von Duvillard2, Helmut Sinzinger3 robert.berent@aon.at *1Center for Cardiovascular Rehabilitation, Bad Schallerbach, Austria; 2Department of Biology and Physical Education, College of Idaho, Caldwell, ID, USA; 3ATHOS, Institute for Diagnosis and Treatment of Atherosclerosis and Lipid Disorders, Vienna, Austria

References

1 Koenig W, Ridker PM. Rosuvastatin for primary prevention in patients with European systematic coronary risk evaluation risk ?5% or Framingham risk >20%: post hoc analyses of the JUPITER trial requested by European health authorities. Eur Heart J 2011;32:75-83

2 Conroy RM, Pyorala K, Fitzgerald AP, Sans S, Menotti A, De Backer G, De Bacquer D, Ducimetiere P, Jousilahti P, Keil U, Njolstad I, Oganov RG, Thomsen T, Tunstall-Pedoe H, Tverdal A, Wedel H, Whincup P, Wilhelmsen L, Graham IM; SCORE Project Group. Estimation of ten-year risk of fatal cardiovascular disease in Europe: the SCORE project. Eur Heart J 2003;24:987-1003.

3 Ferket BS, Colkesen EB, Visser JJ, Spronk S, Kraaijenhagen RA, Steyerberg EW, Hunink MG. Systematic Review of Guidelines on Cardiovascular Risk Assessment. Arch Intern Med. 2010;170:27-40

4 Coleman RL, Stevens RJ, Retnakaran R, Holman RR. Framingham, SCORE, and DECODE risk equations do not provide reliable cardiovascular risk estimates in type 2 diabetes. Diabetes Care 2007;30:1292-1294.

5 Cook NR, Buring JE, Ridker PM. The effect of including C-reactive protein in cardiovascular risk prediction models for women. Ann Intern Med 2006;145:21-29.

6 Brindle P, Emberson J, Lampe F, Walker M, Whincup P, Fahey T, Ebrahim S. Predictive accuracy of the Framingham coronary risk score in British men: prospective cohort study. BMJ 2003;327:1267.

7 Marrugat J, D'Agostino R, Sullivan L, Elosua R, Wilson P, Ordovas J, Solanas P, Cordon F, Ramos R, Sala J, Masi? R, Kannel WB. An adaptation of the Framingham coronary heart disease risk function to European Mediterranean areas. J Epidemiol Community Health 2003;57:634-638

8 Onat A, Ceyhan K, Basar O, Erer B, Toprak S, Sansoy V. Metabolic syndrome: major impact on coronary risk in a population with low cholesterol levels--a prospective and cross-sectional evaluation. Atherosclerosis 2002;165:285-292.

9 Bergovec M, Reiner Z, Milici? D, Vrazi? H. Differences in risk factors for coronary heart disease in patients from continental and Mediterranean regions of Croatia. Wien Klin Wochenschr 2008;120:684-692.

10 Hense HW, Schulte H, Lowel H, Assmann G, Keil U. Framingham risk function overestimates risk of coronary heart disease in men and women from Germany--results from the MONICA Augsburg and the PROCAM cohorts. Eur Heart J 2003;24:937-45.

11 Milne R, Gamble G, Whitlock G, Jackson R. Framingham Heart Study risk equation predicts first cardiovascular event rates in New Zealanders at the population level. N Z Med J. 2003;116:U662.

Conflict of Interest:

None declared

Submitted on 08/02/2011 7:00 PM GMT
ASCOT versus JUPITER: who wins the war?
7 April 2011
Gen-Min Lin

Dr. Sever and colleagues presented the results of a post hoc study from ASCOT in American Heart Association scientific sessions 2010.1,2 They said "neither baseline nor on-treatment CRP provide any useful information about the efficacy of statin treatment to reduce cardiovascular events beyond LDL cholesterol reduction. These results do not support current proposals to measure CRP in the clinical setting either to assign statins to individuals on the basis of an elevated CRP alone or to monitor CRP levels as an indicator of the efficacy of statin treatment." Although the results of ASCOT seems against JUPITER, in fact, they are not different based on the following evidence.3 In a stratified cardiovascular risks result from JUPITER,4 the levels of CRP in patients with <5%, 5-10%, 10-20%, >20% 10-year risk by Framingham risk score were estimated 4.4 (2.9-7.2), 4.2 (2.8-7.0), 4.3 (2.8-7.1), 4.7 (3.1-7.9) mg/L respectively. In addition, the levels of CRP in the stratified risk groups by CRP- based Reynolds risk score were 3.8 (2.7-6.1), 4.2 (2.8-7.0), 4.4 (2.9-8.6), 4.9 (3.1-8.6) mg/L respectively. Compared to the traditional model (Framingham risk score) and CRP based models (Reynolds risk score), the addition of CRP picked up those in the highest cardiovascular risks more effectively (event rates: 2.34 vs. 2.84 in 10-year risk), but not those in the lowest cardiovascular risks (event rates: 0.34 vs. 0.41 in 10-year risk). Apparently, the addition of levels of CRP did not significantly exclude the JUPITER cohorts with low risks (<5% 10-year risk) who need not primary medical prevention. Actually, a U-shaped relationship between levels of CRP and cardiovascular events has been observed in the JUPITER cohorts in whom the lowest incidence rates occurred within CRP levels within 6-8mg/L.5 Therefore a single elevated CRP level alone (> 2 mg/L) does not predict the subsequent cardiovascular events, especially for those with low Framingham risk scores that are consistent to the findings of ASCOT. However, CRP indeed successfully classified a high risk population that over 70% JUPITER participants were with intermediate and high cardiovascular risk. Furthermore, the CRP-based Reynolds scores could identify more extensively and precisely patients with the highest risk than the traditional Framingham risk scores (number: 2651 vs. 1555; rates 2.84 vs. 2.41). Of note, the addition of CRP selected more patients without metabolic syndrome correctly to the highest cardiovascular risks group (the proportions of metabolic syndrome: 50% vs. 69%).6 In summary, from the incorporating evidence from ASCOT and JUPITER, the clinicians should estimate Framingham risk scores for each patient before deciding whether to test CRP levels. If low risk scores are obtained, then the patients need not receive CRP testing and without statins primary prevention. On the contrary, those with the intermediate Framingham risk scores are most worth testing CRP levels according to the benefits of Reynolds risk score further separating the population at high cardiovascular risk but without traditional factors in need of aggressive statins therapy.

Reference

1. Sever PS. LBCTIV, Abstract#21685. Presented at: American Heart Association Scientific Sessions 2010; Nov. 13-17; Chicago.

2. Sever PS, Dahl?f B, Poulter NR, Wedel H, Beevers G, Caulfield M, Collins R, Kjeldsen SE, Kristinsson A, McInnes GT, Mehlsen J, Nieminen M, O'Brien E, Ostergren J; ASCOT investigators. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo- Scandinavian Cardiac Outcomes Trial--Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial. Lancet. 2003; 361:1149-1158.

3. Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto AM Jr, Kastelein JJ, Koenig W, Libby P, Lorenzatti AJ, MacFadyen JG, Nordestgaard BG, Shepherd J, Willerson JT, Glynn RJ; JUPITER Study Group. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008; 359: 2195-2207

4. Ridker PM, Macfadyen JG, Nordestgaard BG, Koenig W, Kastelein JJ, Genest J, Glynn RJ. Rosuvastatin for primary prevention among individuals with elevated high-sensitivity c-reactive protein and 5% to 10% and 10% to 20% 10-year risk. Implications of the Justification for Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) trial for "intermediate risk". Circ Cardiovasc Qual Outcomes. 2010;3:447-452

5. Lin GM, Chu KM, Han CL. "A U-Shape Relationship between Stratified hsCRP Levels and Cardiovascular Events in JUPITER" response to Rosuvastatin for primary prevention in older persons with elevated C- reactive protein and low to average low-density lipoprotein cholesterol levels: exploratory analysis of a randomized trial. Ann Intern Med published online Aug 19, 2010

6. Lin GM, Chu KM, Han CL. The influence of inflammation outweighing the metabolic syndrome on cardiovascular risk and mortality. Int J Cardiol. 2010 Nov 19. [Epub ahead of print]

Conflict of Interest:

None declared

Submitted on 07/04/2011 8:00 PM GMT