Letter by Ridker and Everett Regarding Article, “The Inflammatory Hypothesis: Any Progress in Risk Stratification and Therapeutic Targets?”
To the Editor:
We read with interest the recent editorial by Blankenberg and Yusuf1 discussing C-reactive protein (CRP) and atherothrombosis. Whereas Blankenberg and Yusuf write that data from Bos et al2 add “valuable knowledge to the current discussion because no previous studies have examined the impact of CRP on stroke as a unique end point,” we are aware of at least 9 previous publications on this topic. These include data from the Physicians Health Study; the Leiden 85-Plus Study; the National Health and Nutrition Examination Survey (NHANES); the Framingham Heart Study; the Cardiovascular Health Study; the Health, Aging and Body Study; the Honolulu Heart Program; the Atherosclerosis Risk in Communities (ARIC) study; and the Women’s Health Study. In all 9 of these cohorts, CRP positively associates with future stroke. In virtually all studies with adequate power, this association is independent of traditional risk factors. For example, the Framingham Study reported a fully adjusted relative risk of future ischemic stroke of 2.1 (95% CI, 1.2–3.8) for women and 1.6 (95% CI, 0.9–3.1) for men in the highest versus the lowest quartiles of CRP, whereas the ARIC study reported a relative risk of future stroke of 1.9 (95% CI, 1.1–3.1) for those with CRP >3.0 mg/L.3,4 In the Women’s Health Study, the risk of future stroke for women in the highest versus the lowest tertiles of CRP was 1.9 (95% CI, 1.3–3.0) and was even higher for those women not using hormone therapy.5
Blankenberg and Yusuf also write that data from the Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE IT) trial, regarding the role of CRP among patients treated with statin therapy, have not been reproduced, although fully confirmatory analyses using clinical and ultrasound end points have already been published by the Aggrastat to Zocor (A to Z) and Reversal of Atherosclerosis With Aggressive Lipid Lowering (REVERSAL) investigators.
Finally, the statement by Blankenberg and Yusuf that all prospective, population-based studies have “failed to demonstrate an improved incremental value of CRP in predicting cardiovascular disease when added to other risk factors” is at odds with the published literature. For example, the addition of CRP resulted in 20% to 30% of those at intermediate risk by Framingham criteria being correctly reclassified at higher or lower risk, an impact greater than that of lipid levels.6 Similarly, in a major European prospective study using contemporary data, the impact of CRP on risk matched or exceeded those of all other traditional risk factors.7
Perhaps Blankenberg and Yusuf intended to argue that the c statistic is only marginally increased in predictive models incorporating CRP—a statement with which we agree. However, the c statistic is designed for retrospective case-control studies or for diagnostic testing where the outcome in known—not for prospective cohort settings, where the probability of future events is the focus. Also, cholesterol, blood pressure, and smoking have only marginal impact on the c statistic in prospective cohort studies. As such, use of the c statistic as a tool to select variables for risk-prediction models is ill advised, because it would force the elimination of proven risk factors from our models of global cardiovascular risk.8
Dr Ridker is listed as a coinventor on patents held by the Brigham and Women’s Hospital that relate to the use of inflammatory biomarkers in cardiovascular disease. Dr Everett has no conflicts to disclose.
Blankenberg S, Yusuf S. The inflammatory hypothesis: any progress in risk stratification and therapeutic targets? Circulation. 2006; 114: 1557–1560.
Bos MJ, Schipper CM, Koudstaal PJ, Witteman JC, Hofman A, Breteler MM. High serum C-reactive protein level is not an independent predictor for stroke: the Rotterdam study. Circulation. 2006; 114: 1591–1598.
Rost NS, Wolf PA, Kase CS, Kelly-Hayes M, Silbershatz H, Massaro JM, D’Agostino RB, Franzblau C, Wilson PW. Plasma concentration of C-reactive protein and risk of ischemic stroke and transient ischemic attack: the Framingham Study. Stroke. 2001; 32: 2575–2579.
Ballantyne CM, Hoogeveen RC, Bang H, Coresh J, Folsom AR, Chambless LE, Myerson M, Wu KK, Sharrett AR, Boerwinkle E. Lipoprotein-associated phospholipase A2, high-sensitivity C-reactive protein, and risk for incident ischemic stroke in middle-aged men and women in the Atherosclerosis Risk in Communities (ARIC) study. Arch Intern Med. 2005; 165: 2479–2484.
Boekholdt SM, Hack CE, Sandhu MS, Luben R, Bingham SA, Wareham NJ, Peters RJ, Jukema JW, Day NE, Kastelein JJ, Khaw KT. C-reactive protein levels and coronary artery disease incidence and mortality in apparently healthy men and women: the EPIC-Norfolk prospective population study 1993–2003. Atherosclerosis. 2006; 187: 415–422.
Cook NR. Use and misuse of the receiver operating characteristic curve in risk prediction. Circulation. 2007; 115: 928–935.