CRP predicts mortality and MI, but not stroke

Susan Jeffrey

October 29, 2009

New York, NY - A new analysis of data from the Northern Manhattan Study (NOMAS) finds that high-sensitivity C-reactive protein (hs-CRP) was modestly associated with mortality and MI but not ischemic stroke in this multiethnic population.

"In our cohort, CRP predicted risk of heart disease and death as well, but it didn't predict stroke" after adjustment for other risk factors such as diabetes and hypertension, lead author Dr Mitchell SV Elkind, (Columbia University College of Physicians and Surgeons, New York, NY) said in an interview.

"When using hs-CRP in populations or even in individual patients, it's important to take account of the characteristics of the population or patient," Elkind added. "It's likely to be less valuable in older people who already have other risk factors."

The findings are published in the October 20, 2009 issue of Neurology.

Stroke discrepancy

CRP and serum amyloid A (SAA) are inflammatory acute-phase proteins that have been proposed as markers of atherosclerosis and predictors of both cardiovascular and cerebrovascular end points, the authors write. A consensus statement issued jointly by the American Heart Association and the Centers for Disease Control and Prevention in 2003 identified hs-CRP as the optimal marker to estimate risk in primary prevention but recommended limiting its use to those whose traditional risk factors already placed them at "intermediate" risk, they note.

"Most of the studies have been in heart disease, but there have been a few that have looked at stroke as well, and there has been some discrepancy in the literature, particularly with regard to stroke," Elkind said. "It seems that CRP is probably a better predictor of stroke risk among certain populations than others, particularly among young people and people who don't have as much vascular disease."

NOMAS is a prospective cohort study examining a multiethnic urban population who were stroke-free at baseline. "Over 50% of our cohort is Hispanic, and there's a high burden of vascular risk factors like diabetes, smoking, and high blood pressure, so our cohort, while not like some of the other younger healthier cohorts where people have looked at CRP, is perhaps like a lot of the US population," Elkind noted.

For this analysis, the researchers used data from 2240 NOMAS participants for whom hs-CRP and SAA measures were available. Mean age was about 69 years, and the median hs-CRP was 2.5 mg/L.

Compared with those with hs-CRP of less than 1 mg/L, those with hs-CRP above 3 mg/L did have an increased risk for stroke in a model adjusted for demographics, but the effect was reduced after adjustment for other risk factors.

NOMAS: Risk for stroke by hs-CRP level >3 vs <1 mg/L

Analysis Hazard ratio 95% CI
Adjusted for demographic factors 1.60 1.06-2.41
Adjusted for other risk factors 1.20 0.78-1.86

However, hs-CRP above 3 mg/L was associated with a significantly increased risk for MI and death even after adjustment.

NOMAS: Risk for MI and death associated with hs-CRP >3 mg/L vs <1 mg/L

End point Adjusted hazard ratio 95% CI
MI 1.70 1.04-2.77
Death 1.55 1.23-1.96

SAA was not associated with stroke risk in these analyses.

One question these findings raise is what they mean in the context of the Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER), a randomized study that showed a benefit of rosuvastatin treatment in reducing all cardiovascular outcomes, including stroke.

JUPITER included otherwise-healthy subjects with normal cholesterol levels but hs-CRP levels of 2 mg/L or greater, which the authors point out is a "new clinical threshold." In this paper, Elkind and colleagues evaluated this 2-mg/L threshold in NOMAS patients who would also have qualified for JUPITER.

They found no difference in vascular outcomes for those with hs-CRP levels >2-mg/L vs those below it, although there was evidence that use of a cholesterol-lowering agent decreased the risk for vascular events over follow-up. "Our data thus do not confirm that hs-CRP >2 mg/L should be used generally to determine use of statin therapy, because the benefits may extend to those with levels <2 as well," the authors write, although they hasten to add their study was not designed specifically to address statin therapy.

"While it is true that in JUPITER, use of rosuvastatin was associated with a benefit in terms of reduction in risk of stroke, this was true among all of those enrolled in the study," Elkind added. "Statins are of benefit, but it's not clear that the benefit is related to CRP lowering or that we need to measure CRP to determine who will benefit from statins."

Modest sample size

Asked for comment on these findings, Dr Paul Ridker (Brigham and Women's Hospital, Boston, MA), who is credited with much of the work linking hs-CRP with cardiovascular risk, said that the hazard ratio of 1.6 seen in this study "is fully consistent with many larger studies indicating that hs-CRP levels predict incident stroke as well as myocardial infarction.

"That this risk estimate is no longer statistically significant in this cohort after multivariate adjustment may thus be due to modest sample size rather than a true biologic difference between studies," he added.

The study was supported by the National Institutes of Health/National Institutes of Neurological Disorders and Stroke (NIH/NINDS). Elkind serves as resident and fellow section editor for Neurology, serves as a consultant to Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership, GlaxoSmithKline, Jarvik Heart, Tethys Bioscience, and Daiichi-Sankyo; serves on speakers' bureaus for Boehringer-Ingelheim and Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership; receives research support from diaDexus, Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership, and the NIH/NINDS; and has given expert testimony on behalf of Merck Serono, Pfizer, and Novartis. Ridker was lead investigator of the JUPITER trial and is coinventor of patents held by the Brigham and Women's Hospital related to the use of inflammatory biomarkers that have been licensed to Dade-Behring and AstraZeneca.


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