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Reduction in cardiovascular events with Rosuvastatin correlates with hsCRP levels in healthy patients with "normal" cholesterol values.

Lance Ray, Pharm.D.*
May, 2009

Article Reviewed: Ridker PM, Danielson E, Fonseca FA, et al. Reduction in C-reactive protein and LDL cholesterol and cardiovascular event rates after initiation of rosuvastatin: a prospective study of the JUPITER trial. Lancet 2009; 373: 1175-82.

In a sub-group analysis from the JUPITER trial, Ridker and colleagues show that reduction in both LDL cholesterol to < 70 mg/dL and high-sensitivity C-reactive protein (hsCRP) to < 2 mg/L are independently associated with a lower cardiovascular event rate in healthy individuals with "normal" cholesterol levels. Moreover, this study also shows that a reduction in hsCRP to below 1.0 mg/L reduces event rates further independent of the achieved LDL-C levels.1

Background:
Recent studies show that high-sensitivity C-reactive protein (hsCRP) independently predicts future vascular events. The JUPITER trial was a randomized, double-blind, placebo-controlled study of apparently healthy persons without hyperlipidemia (LDL<130 mg/dL) but with elevated hsCRP levels. Rosuvastatin 20mg significantly reduced the incidence of major cardiovascular events when compared to placebo in this population. Rosuvastatin reduced the median LDL cholesterol by 50% (p<0.001) and the median hsCRP by 37% (p<0.001).2 It is important to note that the JUPITER study was stopped early due to a clear benefit in the treatment population.

While JUPITER showed that Rosuvastatin reduced events in non-hyperlipidemic patients but with elevated hsCRP (>/=2.0 mg/L), this most recent subanalysis of the JUPITER data show that clinical outcomes actually improve after achieving these lower hsCRP levels.

This prospective study of the JUPITER trial data assessed 87% of the original full cohort or 17,802 to find whether clinical outcomes improved after achieving lower hsCRP levels (<2.0 mg/L and then <1.0mg/L). Primary endpoints were the same as used for the JUPITER study (nonfatal myocardial infarction, nonfatal stroke, hospitalization for unstable angina, an arterial revascularization procedure, or confirmed death from cardiovascular causes).2

Baseline characteristics were similar in these groups, and patients were followed for a median of 1.9 years (until study termination). Baseline and 1-year levels of hsCRP and LDL-C were used for this study.

This study assessed the clinical effect of lowering LDL-C, hsCRP, both, neither, or one of the two and then assessed the magnitude of clinical effect in each one of these combinations. Results were reported as event rate per 100 person-years, then as an age-adjusted hazard ratio. Unlike the original JUPITER article, number needed to treat (NNT) to prevent one event was not reported, so it is calculated here within this summary.

Table 1 Events in patients with hsCRP above and below 2
Achieved levels Event rate (per 100 person-years) Hazard Ratio* (95%CI) NNT
-- 1.11 (placebo) 1.00 --
LDL = 70, hsCRP = 2.0 1.11 1.06 (0.72-1.55) 577
LDL < 70, hsCRP = 2.0 0.54 0.54 (0.27-1.10) 76
LDL = 70, hsCRP < 2.0 0.62 0.55 (0.39-0.77) 99
LDL < 70, hsCRP < 2.0 0.38 0.35 (0.23-0.54) 64
*HR is age-adjusted; significant 95% CIs in bold

Patients that achieved hsCRP concentrations <1.0 mg/L clinically did better than those who only acheived values of <2.0.

Table 2 Events in patients with hsCRP above and below 1
Achieved levels Event rate (per 100 person-years) Hazard Ratio* (95%CI) NNT
-- 1.11 (placebo) 1.00 --
LDL = 70, hsCRP = 1.0 0.95 0.91 (0.64-1.30) 203
LDL < 70, hsCRP = 1.0 0.64 0.65 (0.21-2.03) 88
LDL = 70, hsCRP < 1.0 0.56 0.50 (0.38-0.67) 87
LDL < 70, hsCRP < 1.0 0.24 0.21 (0.09-0.52) 52
*HR is age-adjusted; significant 95% CIs in bold.

This trial confirms hsCRP as an independent risk factor for cardiovascular events. Also, by statistically isolating hsCRP goals that were achieved, this subanalysis of the JUPITER study shows that whether or not low LDL concentrations are achieved, lowering hsCRP levels independently confer a significant reduction in cardiovascular events. The greatest benefit was found with patients who achieved LDL cholesterol <70 mg/dL and hsCRP concentrations < 1.0 mg/L.

The authors also looked at magnitude in decrease of hsCRP values, and found that this was directly related to magnitude of clinical benefit. LDL-C and hsCRP reductions of <50% and =50% were analyzed to show benefit of intense lowering of these values, and these results fall in line with the above tables. As expected, LDL-C and hsCRP reductions of 50% or more resulted in significantly fewer events.1

Unlike in the original JUPITER paper, data for those patients who were followed for 4 years were not presented in a separate manner in this analysis. So, the numbers needed to treat (NNT) that are included above are comprised of overall rates. The original JUPITER paper reported an overall NNT of 95, a 4-year NNT as 31, then adjusted the NNT at 5 years as 25. It would seem that, if included in this analysis, the NNT at 5 years for this data subset would likewise be impressive.1,2

Strengths of this study:

  • This study was preformed in healthy men and women, which eliminates confounding variables seen in previous statin trials.

  • Overall, achieved LDL-C and hsCRP values were weakly correlated (r=0.10). This fact actually strengthens the case for hsCRP as an indicator since less than 2% of the variance in achieved hsCRP is explained by the variance in LDL cholesterol. Correlations between hsCRP levels and other variables measured (apolipoprotein B, percentage reduction in LDL-C) were also small (r=0.10 and 0.15, respectively).1

  • Because of beliefs that other cholesterol markers (non-HDL cholesterol, apolipoprotein B, apolipoprotein B to apolipoprotein A1 ratio) may be better for monitoring statin therapy, analysis was done with these markers. A similar risk reduction was shown with patients achieving low hsCRP levels and low alternative protein levels as well. Moreover, a risk-reduction was observed with lower hsCRP levels irrespective of which lipid marker was used.

This study rasies the issue of the anti-inflammatory effects of statins as well as their antihyperlipidemic effects. Since atheroslcerosis is an inflammatory process, it is intuitive that measuring inflammatory markers such as hsCRP should prove useful in treating this disease. Treatment guidelines may soon reflect this evidence from the JUPITER study.

References:

  1. Ridker PM, Danielson E, Fonseca FA, et al. Reduction in C-reactive protein and LDL Cholesterol and Cardiovascular Event Rates after Initiation of Rosuvastatin: a Prospective Study of the JUPITER trial. Lancet 2009; 373: 1175-82.

  2. Ridker PM, Danielson E, Fonseca FA, et al. Rosuvastatin to Prevent Vascular Events in Men and Women with Elevated C-Reactive Protein. N Engl J Med 2008;359:2195-207.

*ClotCare guest author Lance Ray, Pharm.D.
Pharmacist
Harris Methodist Hospital Fort Worth
(no financial disclosures/conflicts of interest)

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