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C-reactive protein and cardiovascular risk: more fuel to the fire - Comment
 
 
 
 
The Lancet, Early Online Publication, 22 December 2009 doi:10.1016/S0140-6736(09)62098-5Cite or Link Using DOI
 
S Matthijs Boekholdt a bEmail Address, John JP Kastelein b
a Department of Cardiology, Academic Medical Center, 1100DD Amsterdam, Netherlands
b Vascular Medicine, Academic Medical Center, 1100DD Amsterdam, Netherlands
 
"The debate can only be resolved by randomised trials with agents that specifically target CRP, and such compounds are currently under development."....."even if CRP might not be involved in the causal pathway of atherogenesis and plaque rupture, it may still be a valuable tool in cardiovascular medicine. A post-hoc analysis of the AFCAPS-TexCAPS trial showed that in primary prevention, lovastatin therapy was more cost effective in people with increased CRP concentrations.12 Also, the JUPITER trial recently showed that, in people with relatively normal LDL cholesterol concentrations and CRP higher than 2 mg/L, rosuvastatin reduced cardiovascular risk.13 In fact, reductions in LDL cholesterol and CRP achieved on statin therapy predicted the efficacy of this treatment.14 So, even if CRP turns out to be not directly causal in cardiovascular disease, it might be useful to identify individuals at cardiovascular risk and to quantify the efficacy of our interventions."
 
Over the past two decades, insights into the role of inflammation in the pathogenesis of atherosclerosis and its clinical manifestations have led us to understand how the atherosclerotic plaque can lie dormant for a long period but can suddenly rupture and cause clinical events.1 Ever since the first report that the inflammatory marker C-reactive protein (CRP) can be used to predict cardiovascular events,2 few studies in this field have not measured CRP concentrations at least once.
 
In view of the ongoing interest in this inflammatory marker, it is highly relevant to obtain proper documentation on the strength and shape of associations between CRP concentrations, established cardiovascular risk factors, and disease risk. In The Lancet today, the Emerging Risk Factors Collaboration (ERFC)3 reports a comprehensive meta-analysis on exactly these issues. The coordinating centre and participating investigators from over 50 prospective studies worldwide are to be commended for this impressive collaboration that has led to a combined dataset on more than 160 000 people and comprises 131 million person-years at risk and nearly 28 000 fatal or non-fatal disease outcomes. Log-transformed CRP concentrations were linearly associated with most established risk factors and with several other inflammatory markers, including fibrinogen and interleukin 6 (the biological mediator of hepatic CRP production). CRP concentrations were also strongly associated with the risk of coronary heart disease, ischaemic stroke, vascular mortality, and even non-vascular mortality. As expected, the associations with cardiovascular outcomes were confounded considerably by established risk factors. These observations will fuel the ongoing debate about the relevance of CRP in clinical practice.
 
One of the prominent topics in this debate is CRP's role in guiding decision making for the primary prevention of cardiovascular disease. Current guidelines advise the use of established risk factors to quantify an individual's cardiovascular risk.4 These guidelines recommend that people at high risk should be treated, whereas for people at intermediate risk additional information should be obtained to guide decision-making. CRP measurement might be valuable in the fine-tuning of the choice of treatment in this specific subgroup.5 Opponents have put forward that CRP provides little improvement in risk prediction compared with established risk factors,6 whereas proponents have argued that CRP does help to reclassify individuals into clinically relevant risk categories.7 Unfortunately, most of these studies did not focus on people at intermediate risk, which is highly relevant as the predictive role of inflammatory biomarkers differs substantially between the entire risk spectrum and the subgroup at intermediate risk.8 The wealth of data collected by ERFC will be an excellent source for future analyses to more accurately define the role of CRP in clinical decision making.
 
A second topic of debate is whether CRP has a causal role in the development of cardiovascular disease. Evidence suggests that CRP might have biological effects on endothelial function, coagulation and fibrinolysis, oxidation of LDL, and plaque stability.9 By contrast, several Mendelian randomisation studies have reported a lack of concordance between the associations among CRP genotypes, CRP concentrations, and cardiovascular risk, which has been interpreted as an argument against causality.10, 11 In the ERFC collaborative analysis, associations between CRP concentrations and various cardiovascular outcomes were attenuated on adjustment for known risk factors, and the investigators interpret these findings as supportive of non-causality. Although these findings add weight to the evidence against causality, it should be noted that neither classical epidemiological nor Mendelian randomisation studies can provide a definite answer in this debate. The debate can only be resolved by randomised trials with agents that specifically target CRP, and such compounds are currently under development.
 
Moreover, even if CRP might not be involved in the causal pathway of atherogenesis and plaque rupture, it may still be a valuable tool in cardiovascular medicine. A post-hoc analysis of the AFCAPS-TexCAPS trial showed that in primary prevention, lovastatin therapy was more cost effective in people with increased CRP concentrations.12 Also, the JUPITER trial recently showed that, in people with relatively normal LDL cholesterol concentrations and CRP higher than 2 mg/L, rosuvastatin reduced cardiovascular risk.13 In fact, reductions in LDL cholesterol and CRP achieved on statin therapy predicted the efficacy of this treatment.14 So, even if CRP turns out to be not directly causal in cardiovascular disease, it might be useful to identify individuals at cardiovascular risk and to quantify the efficacy of our interventions.
 
We declare that we have no conflicts of interest.
 
 
 
 
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