Is hsCRP Back on Board?
适合当头像的图片
Implications from the JUPITER Trial
Wolfgang Koenig 1*
Identifying Individuals at Risk for Cardiovascular Dias:The Traditional Approach
In primary prevention,measurement of traditional risk factors is considered a uful first step in determin-ing tho at risk for cardiovascular dia (CVD).2In the era of “global risk asssment,”the u of scores such as the Framingham Risk Score or the European Society of Cardiology SCORE (Systematic Coronary Risk Evaluation),derived from multivariable statistical models,is recommended (1).However,it has been noted that a considerable number of tho at risk can-not be identified on the basis of traditional risk factors alone (2),and it has also been shown that the scores are not generally applicable becau they lead to over-estimation of actual risk in various populations and thus must be adapted to the true background risk of the population.As a conquence of the issues and oth-ers,acceptance of the u of the scores in general practice is rather low.Although this situation does not invalidate the concept of traditional risk factors,it highlights some of the inherent problems of the global risk asssment approach.
Global risk asssment brings about yet another problem.Application of the algorithms yields an es-timation of absolute 10-year risk,which for Framing-ham Risk Score is considered to be high when higher than 20%and low when it is lower than 6%–10%.For either high-or low-risk individuals,recommendations in the guidelines are clear:reevaluate tho at very low risk after 3–5years,advi lifestyle changes,and even-tually prescribe a statin to tho at high risk.This leaves an intermediate-risk group,comprising approximately 25%–40%(3)of the total population,for whom there is no guidance regarding what to do.
The Potential Role of Biomarkers to Refine Risk Stratification for CVD
The gap in our preventive strategy has prompted the arch for novel biomarkers of cardiovascular risk to help improve risk prediction.Potentially uful bio-markers include various blood biomarkers relevant to the pathophysiology of atherothrombosis,such as markers of inflammatory respon,coagulation,plate-let aggregation,and lipoproteins or lipid-related vari-ables and genetic markers.Markers of subclinical dis-ea,such as coronary calcium and carotid intima media thickness,may also aid in improved risk predic-tion.A large panel of blood biomarkers have been shown to be associated with CVD in prospective stud-ies,but most of them are not yet applicable in routine clinical practice (4,5).A reason for the delay in clinical application is that the clinical utility of a
biomarker must be demonstrated by additional criteria beyond relative risk in association studies to determine whether the marker provides incremental information above and beyond global risk asssment.Process in-volved in biomarker investigation include discrimina-tion,calibration,and reclassification.Until recently we have desperately tried to demonstrate a significant in-crea in the area under the curve in ROC analys for various markers,and we must admit that by and large we have failed for various reasons.Few studies using reclassification strategies have been reported,but their results look promising (6).Thus,debate is ongoing regarding the clinical value of various emerging bi-omarkers,including C-reactive protein (CRP)mea-sured with high-nsitivity methods (hsCRP).
THE PARTICULAR ROLE OF hsCRP
Among emerging biomarkers,one of the largest data-bas exists for hsCRP,the classical acute-pha pro-tein.The hsCRP measurement procedure is well stan-dardized and automated,and high-nsitive assays with sufficient imprecision are available.On the basis of substantial evidence of a contribution of inflamma-tion to atherothrombosis,a recent American Heart As-sociation/CDC connsus report has recommended the measurement of hsCRP in asymptomatic individ-uals at intermediate risk for future coronary events (10-year risk of 10%–20%).As mentioned above,howeve
r,
1
Department of Internal Medicine II—Cardiology,University of Ulm Medical Center,Ulm,Germany.
*Address correspondence to the author at:Dept.of Internal Medicine II—Cardiology,University of Ulm Medical Center,Albert-Einstein-Allee 23,D-89081Ulm,Germany.Fax ϩϩ49-731-500-45021;e-mail wolfgang.koenig@uniklinik-ulm.de.珊瑚礁
Received November 10,2008;accepted November 12,2008.DOI:10.1373/clinchem.2008.1159152
Nonstandard abbreviations:CVD,cardiovascular dia;CRP,C-reactive pro-tein;hsCRP,high-nsitivity CRP;C,cholesterol;JUPITER,Justification for the U of Statins in Prevention:An Intervention Trial Evaluating Rosuvastatin.
cad图层Clinical Chemistry 55:2216–218(2009)
Perspective
216
the decision on the clinical utility of hsCRP is still
pending.
The JUPITER Trial
乐山大佛在哪个省Posthoc analys from the Air Force/Texas Coronary
Atherosclerosis Prevention Study of more than6605
hyperlipidemic men and women with particularly low
HDL-cholesterol(HDL-C)have shown that the thera-
peutic benefit of lovastatin was en not only in indi-
viduals with high LDL-C[higher than the median of
4.12mmol/L(159mg/dL)]and normal or incread
hsCRP(higher than the median of1.62mg/L)but also
in tho with incread hsCRP but an LDL-C below the
median.By contrast,no effect was en in tho with
both LDL-C and hsCRP below the median.The data
form the basis of the scientific rationale for the Justifi-
cation for the U of Statins in Prevention:An Inter-
vention Trial Evaluating Rosuvastatin(JUPITER)trial
(7)to test the hypothesis that daily treatment with20
怀柔雁栖湖mg rosuvastatin compared to placebo would decrea
the rate of first major cardiovascular events in individ-
uals with LDL-CϽ3.37mmol/L(130mg/dL),who
were thus below the current treatment threshold for a
乌梅
statin,and signs of a low-grade inflammatory respon
indicated by an hsCRPՆ2mg/L after repeat measure-
ments.JUPITER was an investigator-initiated study
conducted in17802apparently healthy persons from
1315sites in26countries.The study included men age Ն50years and women ageՆ60years without a prior history of CVD.Main baline data showed an average
LDL-C of2.80mmol/L(108mg/dL)and an hsCRP of
4.2mg/L.The study population was38%women;71%
were white and29%were either black,hispanic,or of
other ethnicity.More than40%had metabolic syn-
drome.Participants showed the lowest LDL-C values
and the highest HDL-C values among all studies in pri-
mary prevention.JUPITER was designed to provide
90%power to detect a25%reduction in hazard for the
occurrence of a first major cardiovascular event,de-
fined as nonfatal myocardial infarction,nonfatal
stroke,hospitalization for unstable angina,arterial re-
vascularization procedure,or confirmed cardiovascu-
lar death.Secondary endpoints included components
of the primary endpoints individually,and all-cau-
mortality.The trial was halted prematurely on March
31,2008,owing to unequivocal evidence of benefit af-
ter a median follow-up of only1.9years.Rosuvastatin
reduced LDL-C by50%and hsCRP by39%,achieving
an LDL-C of1.42mmol/L(55mg/dL)and an hsCRP of
1.8mg/L.The main composite endpoint was reduced
by44%compared to placebo(rate per100person-
years:0.77versus1.36).The occurrence of myocardial
infarction was reduced by54%,stroke by48%,and revascularization and unstable angina by47%.Finally, a reduction in total mortality of20%was en in the abnce of myopathy and cancer.Importantly,groups typically assumed to be at low risk also benefited:non-smokers and individuals of normal weight,tho with-out metabolic syndrome,and tho with a Framing-ham Risk Score of10%or less.
WHAT MESSAGE CAN WE TAKE FROM JUPITER?
There are veral important lessons to learn from JUPITER.First,in this population LDL-C was safely decread to1.42mmol/L(55mg/dL)without an in-crea in adver events,in particular no incread
in-cidence of myopathy.There was also no increa in cancer incidence,but we have to keep in mind the rel-atively short follow-up period.Second,JUPITER in-cluded38%women,the largest number in any primary prevention trial,and thus will provide reliable data on treatment efficacy in women.Third,for traditional risk factors,the JUPITER study population had the lowest risk profile among all primary prevention trials(lowest LDL-C,highest HDL-C,no prior CVD,no history of diabetes,low percentage of smokers and of positive family history,and low prevalence of hypertension). Nevertheless,incread hsCRPϾ2mg/L identified a group of individuals who clearly benefited from statin therapy despite the fact that they were not candidates according to current National Cholesterol Education Program guidelines.Surprisingly,the benefit was larger than that obrved in any previous primary pre-vention trial.The JUPITER lection criterion,which differed from prior statin trials,was hsCRP rather than LDL-C,and provides a possible explanation for the un-expected results.Such robust reductions in vascular risk have2possible interpretations:hsCRP must be considered as a marker that integrates the risk of tradi-tional risk factors,becau many of tho are correlated with hsCRP,albeit moderately,and/or the modest in-crea in hsCRP reprents an incread inflammatory respon carrying its own risk.That the reduction in vascular risk was larger than one would have expected from the lowering of LDL-C alone(20%for each38.7 mg/dL or1.00mmol/L of LDL-C)supports the latter argument.
Returning to the initial question,should we mea-sure hsCRP in clinical practice?Certainly,we do not need to measure hsCRP if a patient is a candidate for statin therapy on the basis of an LDL-CϾ3.37mmol/L (130mg/dL).But in individuals with lower LDL-C, hsCRP measurement may well make n.The fact that rosuvastatin showed similar efficacy in various subgroups,including tho with a Framingham Risk ScoreՅ10%,rais the provocative question of whether global risk asssment is uful,especially in light of its low acceptance rate,and whether or not
Perspective
Clinical Chemistry55:2(2009)217
incread hsCRP might rve as a diagnostic criterion to initiate statin treatment.JUPITER has a random-ized,controlled,state-of-the-art trial design,and a number needed to treat of25for the primary endpoint projected for5years is being considered acceptable. More data are needed,however,to prove that this treat-ment strategy is cost-effective.
Conclusions
JUPITER provides provocative data not only from a public health perspective but also from the patho
phys-iological point of view.In the context of existing guide-lines regarding statin treatment,the conclusions may be as follows:if the patient has coronary heart dia, treat;if the patient is diabetic,treat;if the patient has an LDL-CϾ4.14mmol/L(160mg/dL),treat;and if the patient has none of the above but has hsCRPϾ2mg/L, then also treat.Discussions on whether or not to u hsCRP to identify at-risk individuals who would bene-fit from treatment with a statin will continue,but JUPITER has revitalized the discussion and will make it more difficult in the future to neglect the evidence built around hsCRP and cardiovascular risk.The story
Author Contributions:All authors confirmed they have contributed to the intellectual content of this paper and have met the following3re-quirements:(a)significant contributions to the conception and design, acquisition of data,or analysis and interpretation of data;(b)drafting or revising the article for intellectual content;and(c)final approval of the published article.
Authors’Disclosures of Potential Conflicts of Interest:Upon manuscript submission,all authors completed the Disclosures of Poten-tial Conflict of Interest form.Potential conflicts of interest: Employment or Leadership:W.Koenig has been an investigator in the JUPITER trial and a member of the Steering Committee. Consultant or Advisory Role:W.Koenig,GlaxoSmithKline,Roche Diagnostics,and Anthera.
Stock Ownership:None declared.
Honoraria:W.Koenig,AstraZeneca,GlaxoSmithKline,and Roche Diagnostics.
Rearch Funding:W.Koenig,Roche Diagnostics.
Expert Testimony:None declared.
Role of Sponsor:The funding organizations played no role in the design of study,choice of enrolled patients,review and interpretation of data,preparation or approval of manuscript.
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