IJE Advance Access originally published online on October 17, 2008
International Journal of Epidemiology 2009 38(1):217-231; doi:10.1093/ije/dyn217
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Critical appraisal of CRP measurement for the prediction of coronary heart disease events: new data and systematic review of 31 prospective cohorts
1Centre for Clinical Pharmacology, University College London, London, UK.
2Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, UK.
3Department of Epidemiology and Public Health, Imperial College London, London, UK.
4Vascular Physiology Unit, Institute of Child Health, University College London, UK.
5Division of Cardiovascular and Medical Sciences, University of Glasgow, Royal Infirmary, Glasgow, UK.
6Wolfson Unit for Prevention of Peripheral Vascular Diseases, Public Health Sciences, University of Edinburgh, Edinburgh, UK.
7Department of Epidemiology and Public Health, University College London, London, UK.
*Corresponding author. Centre for Clinical Pharmacology, British Heart Foundation Laboratories at UCL, London WC1E 6JJ, UK. E-mail: a.hingorani{at}ucl.ac.uk
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Abstract |
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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.
Keywords C-reactive protein, prediction, coronary heart disease, primary prevention, risk stratification
These authors contributed equally to this work. Accepted 3 September 2008
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