Physicians' Academy for Cardiovascular Education

CRP levels are more strongly associated with fatal, than with nonfatal CV events

Literature - van Wijk DF, Boekholdt SM, Wareham NJ et al. - Arterioscler Thromb Vasc Biol. 2013 Sep 26


C-Reactive Protein, Fatal and Nonfatal Coronary Artery Disease, Stroke, and Peripheral Artery Disease in the Prospective EPIC-Norfolk Cohort Study.

 
van Wijk DF, Boekholdt SM, Wareham NJ et al.
Arterioscler Thromb Vasc Biol. 2013 Sep 26. [Epub ahead of print]
 

Background

C-reactive protein (CRP) is an acute phase protein, predominantly produced in the liver. During serious infections or major tissue damage, CRP-plasma levels can rise up to 1000-fold [1]. CRP is present in the atherosclerotic plaque [2]. It has been attributed proatherogenic effects [3-7], and it is now considered a potential causal factor in atherogenesis [7].
A causal role has however been debated on the basis of the observation that CRP polymorphisms associated with increased CRP levels were not proportionally associated with in increased risk of coronary artery disease (CAD)[8,9]. A large meta-analysis of individual records of over 160 000 people without a history of vascular disease, showed, however, a strong association between CRP levels and risk of CAD and ischemic stroke [10]. Studies usually considered the sum of both fatal and nonfatal CV events, but CRP may be differentially associated with nonfatal and fatal CAD. Indeed, recently CRP was shown to be more strongly associated with fatal than nonfatal vascular events in the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) trial [11,12]. Other, experimental studies show that inflammation in general, but also CRP itself, can aggravate myocardial infarction, leading to more severe CV events [13-16].
The authors therefore tested the hypothesis that CRP is more strongly associated with fatal than nonfatal CAD events, strokes and peripheral artery disease (PAD) in the general population, by making use of the EPIC-Norfolk prospective population study.
 

Main results

  • HRs for all fatal CV event were higher as compared with HRs for all nonfatal CV events, although they did not reached the predefined Bonferroni corrected P-value of 0.01.
  • Multivariate adjusted HR for 1 mg/L CRP increment for fatal CAD was 1.36 (95%CI: 1.27-1.46) and for nonfatal CAD events was 1.2 (95%CI: 1.15-1.26). These HRs differed significantly (mean difference: 13%, 95%CI: 5.1%-21.9%, P<0.001).
  • Multivariate adjusted HR for 1 mg/L CRP increment for fatal stroke and nonfatal stroke did not reach the multiple testing P-value, while unadjusted HR was 1.59 (95%CI; 1.24-2.04) for fatal stroke and 1.38 (95%CI; 1.23-1.52) for nonfatal stroke.
  • Multivariate adjusted HR for 1 mg/L CRP increment for fatal PAD not reach the multiple testing P-value, while the adjusted HR for nonfatal PAD events did (HR: 1.36, 95%CI: 1.26-1.48).
  • The C-statistic was 0.82 (95%CI: 0.81-0.83, P<0.001) for all combined fatal events (CAD, stroke and PAD) and 0.76 (95%CI: 0.75-0.77, P<0.001) for nonfatal events.
  • Using CRP in addition to established CVD risk factors to predict fatal CV events caused 126 individuals to be correctly reclassified into a higher risk category. 112 individuals were incorrectly reclassified into a lower risk category, 1121 individuals were correctly put into a lower category. 897 individuals were incorrectly moved to a higher category.
    Net reclassification improvement for fatal events was 2.1% (95%CI: 0.7%-3.5%, P<0.001).
    The net reclassification improvement for nonfatal events was similar with 1.9% (95%CI: 0.6%-3.3%, P<0.001).
  • The Integrated discrimination improvement (IDI) for fatal events was 0.008 (95%CI: 0.006-0.010, P<0.001), and IDI for nonfatal events was 0.003 (95%CI: 0.002-0.004, P<0.001).
 
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Conclusion

This study confirms earlier observations that elevated CRP levels are independently associated with increased risk of future CAD events in apparently healthy individuals. Furthermore, it shows that CRP levels are associated with PAD events as well.
The association of CRP levels with fatal CAD events is stronger than the one with nonfatal events. This may imply that CRP itself or inflammation in general has a role in promoting more severe CV events, thus yielding a higher propensity of an event to be fatal. This study underscores the need to investigate the efficacy of targeting inflammation for the prevention of CV events.
 

References

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