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JUPITER: Using hsCRP to identify primary prevention patients who may benefit from statin therapy
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AHA Scientific Sessions 2008
High-sensitivity C-reactive protein could be a useful screening test to identify patients with normal LDL levels who may benefit from statin therapy.
Paul M. Ridker, MD, presented the results of the JUPITER trial at the American Heart Association Scientific Sessions 2008 in New Orleans yesterday and the study was then published online in The New England Journal of Medicine.
JUPITER enrolled apparently healthy men aged 50 years and older and women aged 60 years and older who had an LDL level less than 130 mg/dL, a high-sensitivity CRP level of 2 mg/L or more and no prior history of CVD or diabetes. The study participants were diverse; almost 30% were ethnic minorities.
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Researchers randomized the study participants to receive rosuvastatin (Crestor, AstraZeneca) 20 mg daily or placebo. The multicenter trial included 1,315 sites in 26 countries. The primary end point was the combination of nonfatal MI, nonfatal stroke, unstable angina requiring hospitalization, revascularization and cardiovascular death.
Study results
The study was stopped early after a median follow-up of 1.9 years because of a clear benefit seen in the rosuvastatin group compared with the placebo group. Rosuvastatin decreased the relative risk of the primary end point by 44% (HR for rosuvastatin as compared with placebo=0.56; 95% CI, 0.46 to 0.69). Those with a family history of premature CHD had an even greater relative risk reduction in the primary end point of about 65%.
When the components of the primary end point were evaluated individually, rosuvastatin significantly decreased the relative risk of MI (HR=0.46; 95% CI, 0.30-0.70), stroke (HR=0.52; 95% CI, 0.34-0.79), and revascularization (HR=0.54, 95% CI 0.41-0.72). Rosuvastatin did not increase the overall risk for adverse events. While a statistically significant increase in HbA1C was noted (5.9% in rosuvastatin group vs. 5.8% in placebo group, P<0.01), this difference is very unlikely to be clinically significant.
JUPITER is the first trial to demonstrate benefit of statin therapy in patients with no known CVD and low or normal LDL levels. All of the participants in JUPITER had an LDL <130, while the mean LDL in other primary prevention trials ranged from 131 to192. JUPITER is also unique in its use of hsCRP as a screening test to identify patients who are at higher risk of CV events and may benefit more from statin therapy.
Usefulness of hsCRP
The utility of hsCRP as a screening test has been evaluated by many numerous previous studies; hsCRP has been shown to reclassify patients in a global risk prediction algorithm who are classified as low-, moderate- or moderately high risk by the Framingham risk score (FRS). The Reynolds risk score was developed recently and includes hsCRP, family history and traditional risk factors in its risk prediction model.
Using the Reynolds risk score, many patients at intermediate risk (5% to 20% risk of a CV event over the next decade) by FRS are reclassified into higher or lower risk categories. However, a meta-analysis of 22 prospective studies found that hsCRP contributed less than expected to risk prediction after adjusting for other risk factors. In this meta-analysis, the odds ratio for CHD in the highest vs. lowest hsCRP tertiles was 1.6 (95% CI, 1.5-1.7) after adjusting for traditional risk factors.
Coronary calcium vs. hsCRP
Coronary artery calcium is an alternative screening test that can be used to identify patients who may benefit from more aggressive primary prevention strategies. The South Bay Heart Watch Study found that patients who have both high coronary calcium and a high hsCRP have a six-fold higher risk of nonfatal MI or coronary death.
In MESA, 30% of participants classified as intermediate risk by FRS had an hsCRP >3 mg/L and 33% had a coronary calcium score >100. However, only 9% of participants classified as intermediate risk had both an elevated hsCRP and an elevated coronary calcium score. Thus, the reclassification of intermediate-risk participants depends on the screening test used. Individuals who have a high hsCRP do not necessarily have a high coronary calcium and vice versa. It may be most informative to combine hsCRP with other screening tests such as coronary calcium as well as the metabolic syndrome.
In fact, JUPITER may have identified a higher risk population partly due to the high prevalence of the metabolic syndrome rather than due to increased hsCRP levels, as more than 40% of participants in JUPITER had the metabolic syndrome. It is likely that more than half of the subjects had at least two of the five components of the metabolic syndrome. Nevertheless, the relative risk reduction seen with rosuvastatin was slightly less in persons with the metabolic syndrome as compared with those without it.
Previous studies have been mixed with respect to the value of hsCRP in identifying patients who benefit from statin therapy. In a subgroup analysis of the AFCAPS/TEXCAPS trial, patients with low LDL levels and high hsCRP levels benefited from treatment with lovastatin whereas those with low LDL levels and low hsCRP levels did not benefit from treatment with lovastatin. A more recent study, PROSPER, demonstrated no clear predictive value of hsCRP in determining which elderly patients benefited from pravastatin.
Future changes in NCEP guidelines
JUPITER will undoubtedly change the way we treat primary prevention patients with low cholesterol levels. If data from the placebo group in the JUPITER trial is extrapolated over 10 years, the 10-year risk of CHD events (MI and CV death) in the placebo group was about 6%. For patients with a FRS of 10% to 20%, the updated ATP III guidelines from 2004 recommend an LDL goal of <130 mg/dL with an optional goal of <100 mg/dL. However, for patients with CV risk factors and FRS <10%, ATP III recommends considering pharmacologic therapy only if the LDL is ≥160 mg/dL. While rosuvastatin was clearly beneficial in the JUPITER population, most of the patients in the JUPITER study would not have received statin therapy according to the current ATP III guidelines.
JUPITER does leave us with a few answered questions (Table 1). For example, should an hsCRP level of ≥ 2 mg/L be the cut point for therapy in all adults? HsCRP values vary by gender and by race/ethnicity, with women having higher median levels of hsCRP than men and blacks and Hispanics having higher hsCRP levels than whites. JUPITER found no significant interaction of race/ethnicity or gender in determining the response to statin therapy. Nevertheless, given the differences in median hsCRP levels by race/ethnicity and gender, it is unclear whether the cut point of ≥2 mg/L should be used for everyone.
Table 1. Unanswered questions from JUPITER |
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Comparison with other primary prevention trials
Given the large RR reduction seen with 20 mg of rosuvastatin, another unanswered question is whether such a potent statin would decrease events almost as much in persons with a normal hsCRP and comparable LDL values to those in JUPITER. A comparison of JUPITER to previous lipid-lowering primary prevention studies is described in Table 2.
JUPITER used a more potent dose of statin therapy than other primary prevention studies, and the large relative risk reduction (44% RR reduction in the primary endpoint in JUPITER as compared with 31% to 37% RR reduction in other primary prevention studies) may have resulted from this marked degree of LDL reduction. Likewise, the number needed to treat over five years to prevent the occurrence of one primary end point in JUPITER was about 25, which is much lower than the number needed to treat in prior lipid-lowering primary prevention studies.
It is also unclear whether less-expensive generic statins such as simvastatin will be just as cost-effective for primary prevention as more potent brand-name statins such as rosuvastatin and atorvastatin (Lipitor, Pfizer). Simvastatin 40 mg generally provides a mean 40% reduction in LDL levels and comparable HDL increases with those seen with rosuvastatin.
These latest results from the JUPITER trial highlight the potential benefit of statin therapy in primary prevention patients with elevated hsCRP levels. Given the benefits of statin therapy seen in JUPITER, it would be reasonable to measure hsCRP levels in asymptomatic women 50 years and older and asymptomatic men 60 years and older in whom the decision to treat with statin therapy is unclear and to consider statin therapy for those with elevated hsCRP levels.
Table 2. Comparison of JUPITER population to previous primary prevention statin trials |
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Previous work from our laboratory (Cermak et al; Blood. 1993;82:513) may provide insights into these extraordinary findings. We found that C-reactive protein potently stimulates inflammatory cells to produce tissue factor. A recent paper by Redechal et al (J Clin Invest. 2008;118:3452) demonstrates that statins reduce tissue factor expression by activated inflammatory cells and protect, thereby, antiphospholopid-treated mice from placental infarction and pregnancy loss. Analagously, I suspect that statins are acting by diminishing CRP-activated, tissue-factor–mediated infarctions in at-risk cardiovascular patients.
– Harry S. Jacob, MD
HemOnc Today Chief Medical Editor
Roger Blumenthal, MD, is Professor of Medicine and Director, The Johns Hopkins Ciccarone Center for the Prevention of Heart Disease.
Catherine Y. Campbell, MD, is a Fellow in Preventive Cardiology at The Johns Hopkins Ciccarone Center for the Prevention of Heart Disease.
For more information:
- Ridker PM, Buring JE, Rifai N, Cook NR. Development and validation of improved algorithms for the assessment of global cardiovascular risk in women: the Reynolds Risk Score. JAMA. 2007;297:611-619.
- Danesh J, Wheeler JG, Hirschfield GM, et al. C-reactive protein and other circulating markers of inflammation in the prediction of coronary heart disease. N Engl J Med. 2004; 350:1387-1397.
- Park R, Detrano R, Xiang M, et al. Combined use of computed tomography coronary calcium scores and C-reactive protein levels in predicting cardiovascular events in nondiabetic individuals. Circulation. 2002;106:2073-2077.
- Lakoski SG, Cushman M, Blumenthal RS, et al. Implications of C-reactive protein or coronary artery calcium score as an adjunct to global risk assessment for primary prevention of CHD. Atherosclerosis. 2007;193:401-407.
- Ridker PM, Rifai N, Clearfield M, et al. Measurement of C-reactive protein for the targeting of statin therapy in the primary prevention of acute coronary events. N Engl J Med. 2001;344:1959-1965.
- Sattar N, Murray HM, McConnachie A, et al. C-reactive protein and prediction of coronary heart disease and global vascular events in the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER). Circulation. 2007;115:981-989.
- Grundy SM, Cleeman JI, Merz CN. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation. 2004;110:227-239.
- Lakoski SG, Cushman M, Criqui M, et al. Gender and C-reactive protein: data from the Multiethnic Study of Atherosclerosis (MESA) cohort. Am Heart J. 2006;152:593-598.
- Khera A, McGuire DK, Murphy SA. Race and gender differences in C-reactive protein levels. J Am Coll Cardiol. 2005;46:464-469.