CRP, other biomarkers, not clinically useful to predict CVD risk
June 30, 2009 | Lisa Nainggolan
Malmo, Sweden - There is currently no justification to screen for contemporary biomarkers, such as C-reactive protein (CRP), in addition to assessing conventional cardiovascular risk factors to predict future events in a community setting, a new study by Dr Olle Melander (Malmo University Hospital, Sweden) and colleagues in the July 1, 2009 issue of the Journal of the American Medical Association (JAMA) concludes . The results provide "a clearer picture of the strengths and limitations of potential biomarker strategies in primary prevention," they say.
Senior author Dr Thomas J Wang (Massachusetts General Hospital, Boston) explained to heartwire that there has been debate about whether biomarkers, in particular CRP, are useful for predicting future events in relatively healthy people, with some studies-notably JUPITER-suggesting they are helpful and others not. One criticism of previous research has included the statistical methods used, he noted. "The purpose of this new study was to revisit whether biomarkers are useful using a pretty contemporary set of biomarkers, a large population-based sample with a lot of events, a long period of follow-up, and the most state-of-the-art statistical approach we could identify," he said.
"Even if you add a bunch of new cardiovascular biomarkers to the conventional risk factors, the new biomarkers add only modestly to risk prediction."
"But despite all these newer attributes, our conclusions are relatively similar to some of those older studies-namely, that even if you add a bunch of new cardiovascular biomarkers to the conventional risk factors, the new biomarkers add only modestly to risk prediction. It's not that they don't add any information, they do add a little bit-in fact, some of these increments in information were statistically significant-but the magnitude of difference that they made was not very large," he says. "My position on this is that we are not yet at a stage where testing should be routine. I could not recommend that any of these biomarkers be measured on every adult, for instance."
But Dr Erica Spatz (Yale University School of Medicine, New Haven, CT), who was the lead author on a recent JUPITER analysis, commenting on this study and a related genetics report in the same issue of JAMA, told heartwire: "I don't think these studies address the important questions that JUPITER has raised and how clinicians should use CRP in the future.
"I don't think these studies address the important questions that JUPITER has raised and how clinicians should use CRP in the future."
"Clearly we still have more to learn about CRP and its role in cardiovascular disease. However, considering the results from the JUPITER study-a randomized controlled trial in which persons with low LDL and no cardiovascular disease but with elevated hs-CRP levels received benefit from statins-we need to move beyond risk models based on observational trials to better understand the more pressing questions of how to use CRP in the clinical setting.
"Currently, it is not clear who should be screened for hs-CRP, and if [it is] elevated, who should be treated," she notes. "Also, it is not clear whether screening all persons or targeting populations at risk would be cost-effective."
Effect of biomarkers "modest"
Melander et al used 5067 participants from the population-based, prospective epidemiologic Malmo Diet and Cancer (MDC) study, with an average age of 58, who were without cardiovascular disease at baseline (1991-1994).
They assessed both older-CRP and N-terminal pro-B-type natriuretic peptide (NT-proBNP)-and newer-cystatin C, lipoprotein-associated phospholipase 2 (Lp-PLA2), midregional proadrenomedullin (MR-proADM) and midregional proatrial natriuretic peptide (MR-proANP)-biomarkers, individually and in combination, compared with a basic model including conventional risk factors.
"We are not yet at a stage where testing should be routine."
Wang said one of the newer statistical methods they employed-"as embraced by the cardiology community"-was how many people were reclassified into a different risk category on the basis of the biomarkers.
The participants underwent follow-up until 2006 (a median of 12.8 years) using the Swedish national hospital-discharge and cause-of-death registers and the Stroke in Malmo register for first cardiovascular events (MI, stroke, coronary death). There were 418 cardiovascular and 230 coronary events.
The incremental value of the biomarkers, individually and in combination, to predict future events was "modest" and failed to substantially improve model discrimination or risk reclassification beyond traditional demographics and risk factors, the researchers say.
The best combinations of biomarkers were CRP and NT-proBNP for predicting cardiovascular events and MR-proADM and NT-proBNP for predicting coronary events.
Individual biomarkers and incident cardiovascular and coronary events*
*Analyses based on a sample restricted to individuals with biomarkers shown in analyses of first CV events (n=4483 [364 events]) and first coronary events (n=4600 [216 events]). Adjusted for age, sex, antihypertensive treatment, systolic and diastolic BP, body-mass index, diabetes, levels of LDL and HDL cholesterol, and current smoking
The proportion of participants reclassified into a different risk category was 8% for cardiovascular risk and 5% for coronary risk. Greater improvements were seen in analyses restricted to intermediate-risk individuals, the researchers note, but with the caveat that correct reclassification was almost entirely confined to down-classification of individuals without events rather than up-classification of those with events.
"Selected biomarkers may be used to predict future cardiovascular events, but the gains over conventional risk factors are minimal. Risk classification improved in intermediate-risk individuals, mainly through the identification of those unlikely to develop events," they conclude.
Biomarkers might be useful in selected patients
In an accompanying editorial , Drs Svati H Shah (Duke University Medical Center, Durham, NC) and James A de Lemos (University of Texas Southwestern Medical Center, Dallas) say, "the largely null conclusions of this study are consistent with some, but in sharp distinction to other, population-based studies."
They suggest several possible factors that could explain the findings of this study, including the fact that the study population was "generally low risk and biomarkers perform less well in such populations." Also, biomarkers are better predictors of mortality and heart failure than they are of the end points used in this study-nonfatal ischemic events and stroke, they observe.
Wang commented to heartwire: "We can't exclude that there could be some selected patients in whom measuring a biomarker may be useful. For example, the physician may be uncertain whether to choose one therapy or another, and in such patients, a biomarker might push things one way or another and impact therapy."
But he believes it will take the discovery of newer biomarkers to really bring such assessments into routine clinical use. "There are a lot of technologies that are now being used for novel biomarker discovery that I think will bear fruit in coming years and will leave us in a better position than we are today."
"There is nothing that leads me to believe that the addition of one or two other biomarkers would really have changed things."
Questioned by heartwire about Lp(a), a newer biomarker not included in this study but which researchers recently claimed was a causal factor for MI in another paper in JAMA, Wang said he believed the magnitude of association of Lp(a) and "any of the other biomarkers we didn't measure aren't really much different from the biomarkers we did measure. There is nothing that leads me to believe that the addition of one or two other biomarkers would really have changed things."
But "none of this excludes the possibility that in the near future we'll be able to add another set of biomarkers that are new and that will add information," he concluded.
Shah and de Lemos agree: "In the future, better biomarkers and more creative strategies for combining them will be needed, along with comprehensive statistical and functional evaluation of causality, to fulfill the promise of biomarkers for personalized medicine."
Gene studies show no association of CRP with risk of CHD
London, UK - In another paper, also published in JAMA this week, Dr Paul Elliott (Imperial College London, UK) and colleagues find little concordance between CRP genotypes and CRP levels and their effects on CHD .
They identified a single nucleotide polymorphism (SNP) in the CRP gene strongly associated with CRP levels using a genomewide association study (GWAS). A systematic review of 35 observational studies predicted that CHD risk would be reduced by 6% for this degree of CRP reduction. They also conducted a Mendelian randomization experiment, in which this SNP was not associated with CHD in polled studies, nor were two other CRP SNPs associated with CHD in separate meta-analyses. The result "argues against a causal association of CRP with CHD," Elliott et al conclude.
In their editorial, Shah and de Lemos also comment on this study, noting that Mendelian randomization may be particularly helpful when direct-intervention studies are not feasible due to the absence of a specific inhibitor of the biomarker. "In the case of CRP, intervention trials to date have used drugs that affect multiple other risk factors, such as lipids, body weight, and glucose metabolism and thus cannot definitively link lowering CRP levels to outcomes.
"The current findings from the study by Elliott et al, considered together with prior Mendelian randomization studies, strongly challenge a causal effect of CRP levels on CHD," the editorialists say.
"Studies such as these [Elliott et al and Melander et al] will help determine which biomarkers are likely to be useful as specific drug targets but also whether they have a potential role in risk assessment or even therapeutic selection," they conclude.
Melander, Wang, and coauthors Drs Christopher Newton-Cheh (Massachusetts General Hospital) and Joachim Struck (BRAHMS AG, Hennigsdorf, Germany) are coinventors on a patent application for the use of proadrenomedullin for risk stratification in primary prevention; coauthor Dr Andreas Bergmann (BRAHMS AG) holds stock in BRAHMS, which holds patent rights on the MR-proADM and MR-proANP assays. Editorialist de Lemos receives grant support from Biosite/Inverness and Roche Diagnostics and modest consulting income from Biosite/Inverness, Roche Diagnostics, Johnson & Johnson, and Tethys Biomedical related to biomarkers. He has received speaking honoraria from Merck/Schering-Plough and Pfizer for lectures on cholesterol lowering and income for participation on a clinical-end-point committee for AstraZeneca for a clinical trial not related to biomarkers or cardiac prevention.
1. Melander O, Newton-Cheh C, Almgren P, et al. Novel and conventional biomarkers for prediction of incident cardiovascular events in the community. JAMA 2009; 302:49-57.
2. Shah SH and de Lemos JA. Biomarkers and cardiovascular disease. Determining causality and quantifying contribution to risk assessment. JAMA 2009; 302:92-93.
3. Elliott P, Chambers JC, Zhang W, et al. Genetic loci associated with C-reactive protein levels and risk of coronary heart disease. JAMA 2009; 302:37-48.
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