Dr Alan Begg reviews the JUPITER study results and discusses whether C-reactive protein can be used as a marker for statin treatment

Recently there has been increased interest in the role that C-reactive protein (CRP), a component of the acute phase response, may play in terms of the cause of cardiovascular disease (CVD) and its association with risk of a cardiovascular (CV) event.

C-reactive protein levels and cardiovascular events

Support for the role of CRP in the pathogenesis of atherosclerosis has been provided by epidemiological studies, which have consistently demonstrated an association between elevated CRP levels and CV events.1 However, it is not clear if this association is related to a causal factor or simply reflects risk factors. C-reactive protein is particularly susceptible to confounding because traditional CV risk factors, such as smoking, hypertension, obesity, lack of physical exercise, and low socio-economic status, all relate independently to elevated plasma levels of CRP.1

In a recent study by Zacho et al, the link between CRP and ischaemic vascular disease was investigated by measuring high-sensitivity CRP (hsCRP).2 This is a different test from the CRP measurement routinely carried out in UK laboratories, which do not usually report a level of CRP <3 mg/l. In the paper by Zacho et al, low levels of hsCRP were classified as <1 mg/l, average levels 1 to 3 mg/l and high levels >3 mg/l. In the study, levels of hsCRP were measured and the effect of CRP genotypes on CRP protein levels were determined.2 It was concluded that CRP polymorphisms are associated with increased CRP levels, but are not associated with a greater risk of CVD. The results suggest that CRP is only a marker of underlying atherosclerosis and is not in itself a causal factor of the disease process.2 To definitively prove that this is the case, it would be necessary to conduct a clinical trial investigating the effect of a CRP inhibitor on the occurrence of CV events. However, this is unlikely to occur because of the probable negative outcome.

The JUPITER trial

The Justification for the Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) was designed with the aim of identifying patients at higher risk of CV events on the basis of their hsCRP levels.3 This followed the results of the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS), which demonstrated the benefits of statin therapy in patients with average cholesterol levels (between 4.65 and 6.82 mmol/l),4 but did not provide evidence that statin therapy lowered vascular risk in patients with neither a raised cholesterol or an elevated hsCRP.5

The JUPITER study included 17,802 men and women with a low density lipoprotein (LDL) cholesterol of <3.4 mmol/l and a hsCRP level of ?2 mg/l or higher; participants received either 20 mg rosuvastatin daily or placebo. The combined primary end point was the occurrence of a first major CV event defined as non-fatal myocardial infarction (MI), non-fatal stroke, hospitalisation for unstable angina, an arterial revascularisation procedure, or confirmed death from CV causes.3

Results

The trial was stopped by the Data and Safety Monitoring Board after a median follow-up period of 1.9 years instead of the planned 4 years because of significant reduction in the primary end point among those assigned to receive rosuvastatin. At the time the study was terminated, 142 first major CV events had occurred in the rosuvastatin group compared with 251 in the placebo group. The rates of the primary end point per 100 person-years of follow up was 0.77 for the rosuvastatin group compared with 1.36 in the placebo group (hazard ratio for rosuvastatin 0.56; 95% confidence interval [CI] 0.46–0.69, p<0.00001.) On this basis, the number of patients who would need to be treated with rosuvastatin for 2 years to prevent the occurrence of one primary event is 95; if treated for over 4 years this falls to 31 patients. The number needed to treat reduces further to 25 if the risk is projected over a 5-year treatment period. Rosuvastatin was also associated with a significant reduction in the rates for the individual components of the primary end point as shown in Table 1.3

In the group receiving rosuvastatin, a small but significant increase was recorded in both the rate of physician-reported diabetes and in the median value of glycated haemoglobin (HbA1c), although the authors point out that this has been reported in trials with three of the other commonly used statins (pravastatin, simvastatin, and atorvastatin) in current clinical practice.3

Table 1: Individual components of the primary end point in the JUPITER trial

  Event rates per 100 person years of follow up Hazard ratio (95% confidence interval) p value
Active Placebo

Fatal or non-fatal MI

0.17

0.37

0.46

(0.30–0.70)

0.0002

Fatal or non-fatal stroke

0.18

0.34

0.52

(0.34–0.79)

0.002

Arterial revascularisation or unstable angina

0.41

0.77

0.53

(0.40–0.70)

<0.00001

Non-fatal MI, non-fatal stroke, or death from cardiovascular causes

0.45

0.85

0.53

(0.40–0.69)

<0.00001

MI=myocardial infarction

Should patients at low risk of cardiovascular disease receive statin therapy?

The use of statin therapy in the primary prevention of CV mortality and events has been looked at in a recently published meta-analysis. Pooling the data showed a relative risk of:6

  • 0.93 (95% CI 0.87–0.99; p=0.03) for all-cause mortality in 19 trials
  • 0.89 (95% CI 0.81–0.98; p=0.02) for CV deaths in 17 trials
  • 0.85 (95% CI 0.77–0.95; p= 0.004) for major CV events in 17 trials.

The conclusion from this analysis was that if all patients who are at risk of CV events were treated, this would involve large numbers, and associated costs would inevitably be high. Patients at low risk of developing CVD are likely to receive little benefit from statin therapy whereas those at moderate and high risk are likely to receive substantial benefit from treatment,6 and therefore, the present policy of treating these groups should continue.

Will the JUPITER trial results influence management of patients?

The JUPITER trial has demonstrated clear benefits in terms of CV outcomes for the use of rosuvastatin, and the absence of a positive outcome trial can no longer be given as a reason for not using this drug.3 It has also provided evidence for the safety of the drug—the total number of serious adverse effects was similar in the treated and placebo groups with no significant differences with regard to muscle weakness, newly diagnosed cancer, or disorders of the haematological, gastrointestinal, hepatic, or renal systems.7 Drug cost reductions have made the economic case for the use of rosuvastatin on cost effectiveness terms, as accepted by the NICE technology appraisal on statins,8 even more robust.

It is unlikely that the publication of the JUPITER trial will lead to an increase in the measurement of hsCRP in patients at possible risk of CVD. A case could, however, be made for this measurement to be seen as a useful marker for stratification and therapeutic decision making in some patients;9 for example, in those patients who have an intermediate level of risk based on standard clinical risk factors, CRP level may be useful as an additional piece of information, which could help the clinician decide whether or not to commence statin therapy. A major drawback of the JUPITER study was that the trial did not compare patients with and without raised levels of hsCRP, nor did it compare the level of hsCRP with the use of other markers of CV risk.9

The NICE guideline on lipid modification and the technology appraisal on the use of statins recommend this therapy for the primary prevention of CVD in adults who have a ?20% 10-year risk.8,10 This level is based on what is feasible and perhaps cost-effective.10 The relative risk reductions achieved with the use of statin therapy in the JUPITER trial were clearly significant, although it has to be noted that the absolute reduction of risk was small.9 The trial results are, however, likely to lead to even more of the general population being treated with a statin because they will give GPs the confidence to treat patients at lower risk with this drug.

At present, the NICE, SIGN, and JBS2 guidelines are consistent with each other and use the ?20% 10-year risk value as a threshold.10–12 Future guideline development groups may need to consider lowering this threshold, but they will need to take into account the possible benefits versus the potential risks from statin use and the cost of this therapy.

  1. Schunkert H, Samani N. Elevated C-reactive protein in atherosclerosis—chicken or egg? N Engl J Med 2008; 359 (18): 1953–1955.
  2. Zacho J, Tybjaerg-Hansen A, Jensen J et al. Genetically elevated C-reactive protein and ischemic vascular disease. N Engl J Med 2008; 359 (18): 1897–1908.
  3. Ridker P, Danielson E, Fonseca F et al. JUPITER Study Group. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008; 359 (21): 2195–2207.
  4. Downs J, Clearfield M, Weis S et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. JAMA 1998; 279 (20): 1615–1622.
  5. Ridker P, Rifai N, Clearfield M et al. Air Force/Texas Coronary Atherosclerosis Prevention Study Investigators. Measurement of C-reactive protein for the targeting of statin therapy in the primary prevention of acute coronary events. N Engl J Med 2001; 344 (26): 1959–1965.
  6. Mills E, Rachlis B, Wu P et al. Primary prevention of cardiovascular mortality and events with statin treatments: a network meta-analysis involving more than 65,000 patients. J Am Coll Cardiol 2008; 52 (22): 1769–1781.
  7. Bellosta S, Paoletti R, Corsini A. Safety of statins: focus on clinical pharmacokinetics and drug interactions. Circulation 2004; 109 (23 Suppl 1): III50–57.
  8. National Institute for Health and Care Excellence. Statins for the prevention of cardiovascular events. Technology Appraisal 94. London: NICE, 2008.
  9. Hlatky M. Expanding the orbit of primary prevention—moving beyond JUPITER. N Engl J Med 2008; 359 (21): 2280–2282.
  10. National Institute for Health and Care Excellence.Lipid modification: Cardiovascular risk assessment and the modification of blood lipids for the primary and secondary prevention of cardiovascular disease. Clinical Guideline 67. London: NICE, 2008.
  11. Scottish Intercollegiate Guidelines Network. Risk estimation and the presentation of cardiovascular disease. A national clinical guideline. SIGN 97. Edinburgh: SIGN, 2007.
  12. JBS2: Joint British Societies’ guidelines on prevention of cardiovascular disease in clinical practice. Heart 2005; 91 (suppl v): v1–v52.G