Statin therapy in people with elevated hsCRP but without elevated LDL-C Findings and issues raised by the JUPITER trial

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26 October 2009

Administered to individuals with apparently no other risk factors than elevated hsCRP levels, high-dose rosuvastatin reduced by 44% the relative risk of major cardiovascular events over a 1.9-year period. This trial however was not designed to estimate CVD risk reduction in patients receiving optimal standards of care.

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

STUDY SUMMARY

Methods

The study rationale was based on two lines of thought:
1. Half of acute myocardial infarctions occur in patients with LDL cholesterol (LDL-C) levels that are below recommended thresholds for treatment.
2. The magnitude of the benefit associated with statin therapy correlates in part with the achieved level of high-sensitivity C-reactive protein (hsCRP), a low-grade systemic inflammation biomarker that independently predicts future vascular events.1
The primary objective of the Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) was to investigate whether treatment with rosuvastatin, 20 mg daily, as compared with placebo, would decrease the rate of first major cardiovascular events in individuals:

aged 50 years or older (men) or 60 years or older (women)
without prior history of cardiovascular disease
LDL-C < 130 mg/dL (3.4 mmol/L)
hsCRP ≥ 2.0 mg/L
previous or current use of lipid-lowering therapy as exclusion criterion.

The primary outcome was the occurrence of a first major cardiovascular event (nonfatal
myocardial infarction, nonfatal stroke, hospitalization for unstable angina, arterial revascularization procedure, or confirmed death from cardiovascular causes).

Before being randomized to rosuvastatin or placebo, all eligible subjects underwent a 4-week run-in phase during which they received placebo and had to demonstrate good compliance (taking at least 80% of study tablets). Only good compliers were included in the study.

Main results

The trial was terminated on the recommendation of the Independent Data Monitoring Board after a median follow-up of 1.9 years because of unequivocal evidence of clinical benefit with rosuvastatin, including a significant 44% reduction of major CVD events and a 20% reduction of the secondary endpoint (death from any cause).

Table 1. Main results after a mean 1.9-year follow-up
Endpoint	Hazard ratio (95% CI)	p value
Major CVD events (primary outcome)	0.56 (0.46 to 0.69)	<0.00001
Myocardial infarction	0.46 (0.30 to 0.70)	0.0002
Stroke	0.52 (0.34 to 0.79)	0.002
Revascularization or unstable angina	0.53 (0.40 to 0.70)	0.00001
Combined end point of myocardial infarction, stroke, or death from cardiovascular cause	0.53 (0.40 to 0.69)	0.00001
Death from any cause	0.80 (0.67 to 0.97)	0.02

COMMENT

The JUPITER trial explored new territories for primary cardiovascular prevention with statin therapy beyond its traditional targets of patients at risk of CVD events and/or with elevated LDL-C levels.
Results of the trial indicate that clinical benefits can be obtained in apparently healthy men and women with elevated hsCRP and lend support for the inflammatory hypothesis of atherothrombosis and for a modifiable component of it.

Relevance for assessing reduction in residual CHD risk

In terms of clinical implications, the issues raised by JUPITER are related to a possible extension of indications for statin treatment, to the usefulness of routine measurement of hsCRP, and to long-term safety of very low levels of LDL-C. Few lessons, if any can be drawn regarding reduction of residual CVD risk in patients receiving current standards of care.

An editorial commenting on the original JUPITER publication stresses that absolute risk reduction is clinically more important than relative risk reduction. In JUPITER, 0.9% of subjects in the rosuvastatin group and 1.8% of those in the placebo group had a major CVD event, which corresponds to an absolute risk reduction of 0.9%. Whether such a reduction justifies the long-term cost of treatment should be considered.

The JUPITER investigators propose another method to interpret their results. Owing to Kaplan-Meier estimates (Figure 1), the number of patients needed to treat to prevent one event would be 95 for 2 years, 31 for 4 years, and 25 for 5 years. However, “Meta-regression is not a reliable technique,” writes the author of the editorial and early termination of JUPITER “probably exaggerated the results to some degree.”2

JUPITER did not compare two groups with elevated or normal hsCRP, which prevents any interpretation regarding the usefulness of routine measurement of hsCRP in clinical practice. Whether the clinical efficacy of high-dose rosuvastatin was due to its effect on LDL-C or on hsCRP or on both is unclear. Subgroup analyses noted no difference in efficacy between subjects people with the metabolic syndrome (a population known to have high hsCRP levels) and subjects without it.

The median LDL-C level at 12 months was 55 mg/dL (1.4 mmol/L) in subjects treated with rosuvastatin. The long-term safety of such markedly-lowered LDL-C levels is unknown. During the study period, there were slightly but significantly higher glycated hemoglobin levels (5.9% in the rosuvastatin group and 5.8% in the placebo group; p=0.001) and reported incidence of diabetes (3.0 % vs. 2.4%, respectively; p=0.01).

JUPITER provides evidence of the efficacy of rosuvastatin in reducing CVD risk in people who would not normally be considered for statin therapy according to current indications. Whether achieving the very low level of LDL-C obtained in JUPITER would reduce residual CVD risk in populations classically targeted by statin therapy (patients with elevated LDL-C and/or other CVD risk factors) is beyond the scope of this study.

Figure 2. Kaplan-Meier estimates (meta-regression) of the reduction in major CVD events
in patients treated with rosuvastatin20 mg/day. The study was actually terminated after 1.9 years.

References

Pearson TA, Mensah GA, Alexander RW, et al. Markers of inflammation and cardiovascular disease: application to clinical and public health practice: a statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association. Circulation 2003;107:499-511.
Hlatky MA. Expanding the orbit of primary prevention – Moving beyond JUPITER. New Engl J Med 2008;359:2280-82.