Critical appraisal of CRP measurement for the prediction of coronary heart disease events: new data and systematic review of 31 prospective cohorts

Abstract

Background: Non-uniform reporting of relevant relationships and metrics hampers critical appraisal of the clinical utility of C-reactive protein (CRP) measurement for prediction of later coronary events.

Methods: We evaluated the predictive performance of CRP in the Northwick Park Heart Study (NPHS-II) and the Edinburgh Artery Study (EAS) comparing discrimination by area under the ROC curve (AUC), calibration and reclassification. We set the findings in the context of a systematic review of published studies comparing different available and imputed measures of prediction. Risk estimates per-quantile of CRP were pooled using a random effects model to infer the shape of the CRP-coronary event relationship.

Results: NPHS-II and EAS (3441 individuals, 309 coronary events): CRP alone provided modest discrimination for coronary heart disease (AUC 0.61 and 0.62 in NPHS-II and EAS, respectively) and only modest improvement in the discrimination of a Framingham-based risk score (FRS) (increment in AUC 0.04 and -0.01, respectively). Risk models based on FRS alone and FRS + CRP were both well calibrated and the net reclassification improvement (NRI) was 8.5% in NPHS-II and 8.8% in EAS with four risk categories, falling to 4.9% and 3.0% for 10-year coronary disease risk threshold of 15%. Systematic review (31 prospective studies 84 063 individuals, 11 252 coronary events): pooled inferred values for the AUC for CRP alone were 0.59 (0.57, 0.61), 0.59 (0.57, 0.61) and 0.57 (0.54, 0.61) for studies of <5, 5-10 and >10 years follow up, respectively. Evidence from 13 studies (7201 cases) indicated that CRP did not consistently improve performance of the Framingham risk score when assessed by discrimination, with AUC increments in the range 0-0.15. Evidence from six studies (2430 cases) showed that CRP provided statistically significant but quantitatively small improvement in calibration of models based on established risk factors in some but not all studies. The wide overlap of CRP values among people who later suffered events and those who did not appeared to be explained by the consistently log-normal distribution of CRP and a graded continuous increment in coronary risk across the whole range of values without a threshold, such that a large proportion of events occurred among the many individuals with near average levels of CRP.

Conclusions: CRP does not perform better than the Framingham risk equation for discrimination. The improvement in risk stratification or reclassification from addition of CRP to models based on established risk factors is small and inconsistent. Guidance on the clinical use of CRP measurement in the prediction of coronary events may require updating in light of this large comparative analysis.

Figure 1

Predicted and observed risk of CHD based on Cox models derived using traditional risk factors alone and with the addition of CRP

Figure 2

Pooled relative risk of CHD: (a) by quartiles and (b) by quintiles of CRP concentration from 12 and 10 prospective studies, respectively. The pooled values were calculated using the inverse variance-weighted method under random effect models

Figure 3

Study-specific estimates of: (a) sensitivity (for a 10% false-positive rate; DR10) and (b) AUC for CRP obtained directly in NPHS-II, EAS and inferred from data extracted from 25 published reports. A sensitivity analysis by duration of follow up is also shown. The pooled values were calculated using the inverse variance-weighted method under random effect models

Figure 4

Observed AUC or C-statistic for Framingham-based models with and without the addition of CRP in NPHS-II, EAS and six published studies reporting these data with measures of dispersion. AUC or C-statistic for a further seven studies that did not report measures of dispersion were: Ridker 2002, 0.81 for Framingham alone and 0.81 for Framingham plus CRP; Koenig 2006, 0.735 for Framingham alone and 0.75 for Framingham plus CRP; St Pierre 2005, 0.74 for Framingham alone and 0.74 for Framingham plus CRP; Folsom 2006, 0.705 for Framingham alone and 0.706 for Framingham plus CRP; Cook 2006, 0.767 for Framingham alone and 0.77 for Framingham plus CRP; Sattar 2007, 0.813 for Framingham alone and 0.815 for Framingham plus CRP; Cao 2007, 0.63 for Framingham alone and 0.637 for Framingham plus CRP (Supplementary references W6, W8, W13, W15, W27, W28, W30)