Clinical Usefulness of Very High and Very Low Levels of C-Reactive Protein Across the Full Range of Framingham Risk Scores

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1 Cliical Usefuless of Very High ad Very Low Levels of C-Reactive Protei Across the Full Rage of Framigham Risk Scores Paul M Ridker, MD, MPH; Nacy Cook, ScD Backgroud High-sesitivity C-reactive protei (hscrp) is a strog idepedet risk factor for cardiovascular evets, ad levels of hscrp of 1,1to 3, ad 3 mg/l have bee suggested to defie low-, moderate-, ad high-risk groups. However, the positive predictive value of very low ( 0.5 mg/l) ad very high levels of hscrp ( 10.0 mg/l) is ucertai. Methods ad Results Baselie levels of hscrp were evaluated amog apparetly healthy wome who were followed up for myocardial ifarctio, stroke, coroary revascularizatio, or cardiovascular death. Crude ad Framigham Risk Score (FRS) adjusted relative risks (s) of icidet cardiovascular evets were calculated across a full rage of hscrp levels. Cardiovascular risks icreased liearly from the very lowest (referet) to the very highest levels of hscrp. Crude s for those with baselie hscrp levels of 0.5, 0.5 to 1.0, 1.0 to 2.0, 2.0 to 3.0, 3.0 to 4.0, 4.0 to 5.0, 5.0 to 10.0, 10.0 to 20.0, ad 20.0 mg/l were 1.0, 2.2, 2.5, 3.1, 3.7, 4.2, 4.9, 6.3, ad 7.6, respectively (P for tred 0.001). After adjustmet for FRS, these risks were 1.0, 1.6, 1.6, 1.7, 1.9, 2.2, 2.3, 2.8, ad 3.1 (P for tred 0.001). All risk estimates remaied sigificat i aalyses stratified by FRS ad after cotrol for diabetes. Of the total cohort, 15.1% had hscrp 0.50 mg/l, ad 5.4% had hscrp 10.0 mg/l. Coclusios Both very low ( 0.5 mg/l) ad very high ( 10 mg/l) levels of hscrp provide importat progostic iformatio o cardiovascular risk. hscrp is cliically useful for risk predictio across a full rage of values ad across a full rage of FRS. (Circulatio. 2004;109: ) Key Words: risk factors prevetio epidemiology iflammatio C-reactive protei High-sesitivity C-reactive protei (hscrp) has emerged as a strog idepedet risk factor for future cardiovascular evets that adds progostic iformatio at all levels of LDL cholesterol, at all levels of the Framigham Risk Score (FRS), ad at all levels of the metabolic sydrome. 1 O the basis of published data from large, prospective cohorts, 2 9 the Ceters for Disease Cotrol ad Prevetio ad the America Heart Associatio (CDC/AHA) i Jauary of 2003 issued the first set of cliical guidelies for hscrp as a part of global risk predictio ad suggested that levels of hscrp of 1,1to 3, ad 3 mg/l be used to represet low, moderate, ad high vascular risk. 10 However, as cliicias have begu usig hscrp o a regular basis, questios about the usefuless of both very high ad very low levels of hscrp have emerged. I particular, some physicias have raised cocer that very high levels of hscrp ( 10 mg/l) may represet ospecific iflammatio ad therefore lack positive predictive value. At the same time, others have voiced cocer that very low levels of hscrp might give patiets a false sese of security, particularly whe other traditioal risk factors are preset. We addressed these cliical issues i the large-scale Wome s Health Study, i which baselie levels of hscrp as well as FRS were measured amog apparetly healthy wome who were followed up over a 9-year period for the occurrece of first cardiovascular evets. Methods The Wome s Health Study is a ogoig trial of aspiri ad vitami E i primary prevetio beig coducted amog America wome age 45 years with o previous history of cardiovascular disease or cacer. Participats were erolled betwee November 1992 ad July 1995, at which time they provided detailed iformatio o demographic, lifestyle, ad behavioral risk factors. Amog wome erolled, provided a baselie blood sample, of which uderwet successful measuremet of LDL cholesterol, HDL cholesterol, ad hscrp. 9 As described elsewhere, all wome have bee followed up for icidet cardiovascular evets, icludig ofatal myocardial ifarctio, ofatal ischemic stroke, coroary revascularizatio procedures, ad cardiovascular death. 9 Received December 15, 2003; revisio received February 3, 2004; accepted February 3, From the Doald W. Reyolds Ceter for Cardiovascular Research ad the Ceter for Cardiovascular Disease Prevetio, Brigham ad Wome s Hospital, Harvard Medical School, Bosto, Mass. Dr Ridker is listed as a coivetor o patets held by the Brigham ad Wome s Hospital that relate to the use of iflammatory biomarkers i cardiovascular disease. Correspodece to Dr Paul Ridker, Ceter for Cardiovascular Disease Prevetio, 900 Commowealth Ave East, Bosto, MA pridker@parters.org 2004 America Heart Associatio, Ic. Circulatio is available at DOI: /01.CIR A8 1955

2 1956 Circulatio April 27, 2004 TABLE 1. >3 mg/l Crude ad Relative Risks of First Cardiovascular Evets Accordig to hscrp Cutpoits of <1, 1 to <3, ad hscrp, mg/l Crude Crude Adjusted (ref) 1.0 (ref) 1.0 (ref) (ref) 1.0 (ref) 1.0 (ref) ( ) 1.2 ( ) 1.2 ( ) ( ) 1.2 ( ) 1.1 ( ) ( ) 1.7 ( ) 1.5 ( ) ( ) 1.9 ( ) 1.6 ( ) P for tred idicates relative risk; FRS, adjusted for the Framigham Risk Score age; ad FRS DM, adjusted for FRS ad diabetes mellitus. Values represet (95% CI) compared with the referet (ref) group. Followig guidelies issued by CDC/AHA, 10 we iitially classified all study participats ito 3 groups o the basis of baselie hscrp levels of 1, 1 to 3, ad 3 mg/l. Cox proportioal-hazards models were the used to compute relative risks of future cardiovascular evets across these 3 study groups. We the addressed the issue of whether very high or very low levels of hscrp have cliical relevace for risk predictio i 2 stages. First, to avoid the possibility of data-derived fidigs, we iitially reclassified all participats ito 1 of 10 groups based o icreasig deciles of the distributio of hscrp. Secod, to icrease cliical usefuless, we repeated these aalyses after classifyig all participats ito 1 of the followig categories of baselie hscrp: 0.5, 0.5 to 1.0, 1.0 to 2.0, 2.0 to 3.0, 3.0 to 4.0, 4.0 to 5.0, 5.0 to 10.0, 10.0 to 20.0, ad 20.0 mg/l. I each istace, Cox proportioal-hazards models were used to compute relative risks across the full spectrum of hscrp levels. For all models, we computed both crude relative risks ad relative risks adjusted for the FRS ad additioally for diabetes. Because hormoe replacemet therapy (HRT) is kow to elevate hscrp levels, we repeated all aalyses for the subgroup of wome ot usig these agets at study etry. Results The risk factor profile of participats i the Wome s Health Study is similar to that of the geeral populatio i terms of both lipid levels ad the proportio havig metabolic sydrome. 11 Amog the wome evaluated i this aalysis, 12% were smokers at study etry, 2.5% had diabetes, ad 25% had a history of hypertesio. The mea body mass idex was 25.9 kg/m 2. Betwee study iitiatio ad time of this aalysis, 698 first cardiovascular evets were reported ad cofirmed by the ed-poits committee. Table 1 presets the crude ad FRS-adjusted relative risks of future cardiovascular evets accordig to the cliical cutpoits set by the CDC/AHA guidelies. Compared with wome with baselie levels of hscrp 1 mg/l, the crude relative risk for those with baselie hscrp levels betwee 1 ad 3 mg/l was 1.7 (95% CI, 1.4 to 2.2), whereas the relative risk for those with baselie hscrp levels 3 mg/l was 3.0 (95% CI, 2.4 to 3.7) (P for tred across groups 0.001). As expected, these risks were atteuated but remaied statistically sigificat i models adjusted for FRS ad additioally for diabetes. As also show i Table 1, these effects remaied statistically sigificat i the subgroup aalysis of those wome ot takig HRT at study etry (P for tred across groups 0.001). Table 2 presets crude ad FRS-adjusted relative risks of future cardiovascular evets i aalyses i which hscrp levels were classified ito 10 groups based o exact decile cutpoits. As show, there is a strog ad highly sigificat liear associatio betwee baselie hscrp ad future cardiovascular risk across the full spectrum of hscrp levels. Specifically, crude relative risks from the very lowest (referet) to very highest deciles of baselie hscrp were 1.0, 1.3, 2.6, 2.2, 3.0, 3.4, 3.6, 4.2, 5.1, ad 6.3 (P for tred across groups 0.001). After adjustmet for FRS, these risk estimates were 1.0, 0.9, 1.7, 1.3, 1.7, 1.6, 1.7, 1.9, 2.1, ad 2.4 (P for tred across groups 0.001). Almost idetical fidigs were observed i the subgroup ot takig HRT at study etry (P for tred 0.001). Table 3 presets crude ad adjusted relative risks of future cardiovascular evets i aalyses i which baselie hscrp values were defied accordig to cliically useful cutpoits of hscrp rather tha strict deciles. Agai, i aalyses of both the total cohort ad those ot takig HRT, a highly sigificat relatioship betwee hscrp ad risk was observed across the full spectrum of hscrp values. Specifically, the very lowest risk was observed amog those i the referet group with hscrp levels 0.5 mg/l, whereas risk was almost 8-fold higher amog those with levels of hscrp i excess of 20 mg/l (crude relative risk, 7.6; 95% CI, 4.7 to 12.1). These effects were eve stroger i the o HRT-usig subgroup, i which the crude relative risk for those with hscrp levels 20 mg/l was icreased early 10-fold. All fidigs remaied statistically sigificat after adjustmet for FRS ad additioally for diabetes (P for tred across groups for both the total cohort ad o HRT users). Figure 1 presets the relative impact of both very high ad very low levels of hscrp o future vascular risk usig cliically relevat cutpoits for hscrp. For compariso, the CDC/AHA cutpoits of 1,1to 3, ad 3 mg/l used to determie low, moderate, ad high risk are also show. Figure 2 shows the predictive value of hscrp levels amog those with calculated 10-year Framigham Risks above ad below 10%. Fially, because diabetes is ofte cosidered a coroary risk equivalet, we repeated our aalyses for those wome free of diabetes at study etry. Amog such wome, the relative risks for those with baselie hscrp levels 0.5, 0.5 to 1.0, 1.0 to 2.0, 2.0 to 3.0, 3.0 to 4.0, 4.0 to 5.0, 5.0 to 10.0, 10.0 to 20.0, ad 20.0 mg/l were 1.0, 2.1, 2.6, 3.0, 3.6, 4.0, 4.6, 5.0, ad 7.4, respectively (P for tred 0.001).

3 Ridker ad Cook Cliical Usefuless of Levels of C-Reactive Protei 1957 TABLE 2. Crude ad Relative Risks of First Cardiovascular Evets Accordig to Icreasig Deciles of hscrp With Cutpoits Also Provided Decile hscrp, mg/l Crude Crude-Adjusted (ref) 1.0 (ref) 1.0 (ref) (ref) 1.0 (ref) 1.0 (ref) ( ) 0.9 ( ) 0.9 ( ) ( ) 0.6 ( ) 0.6 ( ) ( ) 1.7 ( ) 1.7 ( ) ( ) 1.1 ( ) 1.1 ( ) ( ) 1.3 ( ) 1.3 ( ) ( ) 1.7 ( ) 1.7 ( ) ( ) 1.7 ( ) 1.7 ( ) ( ) 1.3 ( ) 1.3 ( ) ( ) 1.6 ( ) 1.6 ( ) ( ) 1.6 ( ) 1.5 ( ) ( ) 1.7 ( ) 1.6 ( ) ( ) 1.7 ( ) 1.6 ( ) ( ) 1.9 ( ) 1.8 ( ) ( ) 1.8 ( ) 1.7 ( ) ( ) 2.1 ( ) 1.9 ( ) ( ) 2.4 ( ) 2.0 ( ) ( ) 2.4 ( ) 2.1 ( ) ( ) 2.8 ( ) 2.3 ( ) P for tred Abbreviatios as i Table 1. Values represet (95% CI) compared with the referet (ref) group. hscrp cutpoits show are for the total cohort. Decile cutpoits for hscrp for the group ot takig HRT are 0.29, , , , , , , , , ad 6.61 mg/l. I all aalyses, virtually idetical results were obtaied whe idividual compoets of the FRS were used. Discussio These prospective data idicate that the predictive value of hscrp for future cardiovascular evets is liear across a full rage of values. Most importatly, these data demostrate that both very high ( 10 mg/l) ad very low ( 0.5 mg/l) levels of hscrp provide importat progostic iformatio o vascular risk across a full rage of FRS. These observatios were cosistet i aalyses usig deciles of hscrp as well as cliically relevat cutpoits ad were preset i the total cohort as well as i the subgroups of those ot takig HRT ad those without diabetes. The preset data have both cliical ad pathophysiological relevace. From a cliical perspective, these data demostrate that the predictive value of hscrp is strogly liear across the full rage of values. Thus, ot oly is there o evidece i these data of ay threshold effect, but there is also o evidece that uusually low or uusually high values represet false-positive fidigs. Quite to the cotrary, these data idicate that there is cosiderable predictive value of hscrp levels beyod the rages suggested by the recet CDC/AHA guidelies for use of hscrp. 10 Thus, i additio to the high-risk group defied by the CDC/AHA as havig levels of hscrp betwee 3 ad 10 mg/l, there appears to be a very-high-risk group with levels of hscrp i excess of 10 mg/l (which i our study represeted 5.5% of the total TABLE 3. Crude ad Relative Risks of First Cardiovascular Evets Across a Full Rage of Cliically Set hscrp Cutpoits hscrp, mg/l Crude Crude Adjusted (ref) 1.0 (ref) 1.0 (ref) (ref) 1.0 (ref) 1.0 (ref) ( ) 1.6 ( ) 1.6 ( ) ( ) 2.1 ( ) 2.1 ( ) ( ) 1.6 ( ) 1.6 ( ) ( ) 1.8 ( ) 1.8 ( ) ( ) 1.7 ( ) 1.7 ( ) ( ) 2.1 ( ) 1.9 ( ) ( ) 1.9 ( ) 1.9 ( ) ( ) 2.4 ( ) 2.3 ( ) ( ) 2.2 ( ) 2.0 ( ) ( ) 3.3 ( ) 2.9 ( ) ( ) 2.3 ( ) 2.0 ( ) ( ) 3.1 ( ) 2.6 ( ) ( ) 2.8 ( ) 2.4 ( ) ( ) 4.0 ( ) 3.3 ( ) ( ) 3.1 ( ) 2.4 ( ) ( ) 3.9 ( ) 2.9 ( ) P for tred Abbreviatios as i Table 1. Values represet (95% CI) compared with the referet (ref) group. Data are show for the total cohort ad for those wome ot takig HRT.

4 1958 Circulatio April 27, 2004 Figure 1. Relative risks of future cardiovascular evets across a full cliical rage of hscrp values. Black bars represet crude relative risks; gray bars, risks adjusted for FRS. populatio). Moreover, although levels of hscrp 20 mg/l were rare (2.2% of the total populatio), these idividuals were observed to have the very highest risk of future vascular evets. By cotrast, risk appeared to be very low for idividuals at the other ed of the spectrum with hscrp levels 0.5 mg/l (15.1% of the study populatio). Ideed, this group appeared to have very low risk eve whe compared with those with hscrp levels betwee 0.5 ad 1.0 mg/l. As show i our multivariate aalyses, this was true eve whe other risk factors were preset ad after adjustmet for the FRS ad additioally for diabetes. From a pathophysiological perspective, these aalyses also raise several itriguig issues. First, the observatio that idividuals with exceptioally low levels of hscrp have very low risks of future cardiovascular evets provides cliical support for the cocept that CRP itself may have a direct role i atherothrombosis ad raises the possibility that a virtual absece of CRP may i fact be protective. For example, mice trasgeic for huma CRP ot oly begi to express elevated CRP levels for the first time but also have icreased rates of arterial thrombosis, at least compared with wild-type mice that miimally express CRP. 12 Recet work further idicates that CRP ca be produced withi the vascular smooth muscle of diseased coroary arteries 13,14 ad that this productio may directly lead to the expressio of several mediators of the atherothrombotic process, icludig adhesio molecule iductio, reduced NO productio, ad altered fibriolytic fuctio. 15 Thus, idividuals without expressed CRP levels may largely be free of these proatherogeic resposes. Coversely, our observatio that idividuals with very high levels of hscrp are at very high vascular risk is cosistet with the hypothesis that CRP may have direct arterial effects or be a surrogate for these effects. I this regard, rather tha suggestig that markedly elevated levels of hscrp represet a false-positive respose, the curret cliical data raise the possibility that chroic iflammatio from ay of several causes may well icrease vascular risk. As such, these data are cosistet with reports suggestig that several chroic coditios icludig arthritis, periodotal disease, ad chroic low-grade ifectio may all predispose to atherothrombotic evets. 16 Our data also reiforce the eed to use high-sesitivity assays for the evaluatio of CRP. Although older assays for CRP might be able to reliably detect levels i excess of 10 mg/l (the very-high-risk group), it is oly with use of hscrp assays that cliical detectio across a full rage ca be assessed. As demostrated i these data, that rage must iclude those at high risk (hscrp betwee 3 ad 10 mg/l) as well as those at very low risk ( 0.5 mg/l) ad itermediate risk (hscrp betwee 1.0 ad 3.0 mg/l), all levels udetectable without high-sesitivity assays. A importat limitatio of our study is that we evaluated hscrp levels oly oce at baselie ad thus caot elimiate the possibility that some of the marked elevatios observed might well reflect a cliically silet acute-phase respose. However, this potetial misclassificatio bias amog those with high levels of hscrp ca lead oly to a uderestimatio of true effects, ot a falsely high risk estimate. Thus, the magitude of predictive values foud here for hscrp are, if aythig, likely to be uderestimates of true effects. Cliicias ca largely avoid this difficulty by simply measurig hscrp twice wheever levels are i excess of 10 mg/l. This Figure 2. Relative risks of future cardiovascular evets amog those with calculated 10-year Framigham risks 10% (left) ad betwee 10% ad 20% (right).

5 Ridker ad Cook Cliical Usefuless of Levels of C-Reactive Protei 1959 practice is cosistet with the recet CDC/AHA guidelies ad, as has bee foud i several reports, greatly reduces ay residual variatio i levels that may be observed i outpatiet cliical use. 17,18 Fially, absolute evet rates withi the Wome s Health Study are low i compariso to the geeral populatio because of the healthy cohort effect ad the fact that our participats are healthcare providers. However, the fact that hscrp has bee show to predict vascular risk with similar magitude i multiple other studies of me ad wome suggests that the relative risks described here are geeralizable. Ackowledgmets This study was fuded by grats from the Natioal Heart, Lug, ad Blood Istitute with additioal support from the Doald W. Reyolds Foudatio (Las Vegas, Nev), the Doris Duke Charitable Foudatio (New York, NY), ad the Leducq Foudatio (Paris, Frace). Refereces 1. Ridker PM. Cliical applicatio of C-reactive protei for cardiovascular disease detectio ad prevetio. Circulatio. 2003;107: Ridker PM, Cushma M, Stampfer MJ, et al. Iflammatio, aspiri, ad the risk of cardiovascular disease i apparetly healthy me. N Egl J Med. 1997;336: Tracy RP, Lemaitre RN, Psaty BM, et al. Relatioship of C-reactive protei to risk of cardiovascular disease i the elderly: results from the Cardiovascular Health Study ad the Rural Health Promotio Project. Arterioscler Thromb Vasc Biol. 1997;17: Koeig W, Sud M, Frohlich M, et al. C-reactive protei, a sesitive marker of iflammatio, predicts future risk of coroary heart disease i iitially healthy middle-aged me: results from the MONICA (Moitorig Treds ad Determiats i Cardiovascular Disease) Augsburg Cohort Study, 1984 to Circulatio. 1999;99: Ridker PM, Heekes CH, Burig JE, et al. C-reactive protei ad other markers of iflammatio i the predictio of cardiovascular disease i wome. N Egl J Med. 2000;342: Daesh J, Whicup P, Walker M, et al. Low grade iflammatio ad coroary heart disease: prospective study ad updated meta-aalyses. BMJ. 2000;321: Ridker PM, Rifai N, Clearfield M, et al. Measuremet of C-reactive protei for the targetig of stati therapy i the primary prevetio of acute coroary evets. N Egl J Med. 2001;344: Ridker PM, Stampfer MJ, Rifai N. Novel risk factors for systemic atherosclerosis: a compariso of C-reactive protei, fibrioge, homocysteie, lipoprotei(a), ad stadard cholesterol screeig as predictors of peripheral arterial disease. JAMA. 2001;285: Ridker PM, Rifai N, Rose L, et al. Compariso of C-reactive protei ad low-desity lipoprotei cholesterol levels i the predictio of first cardiovascular evets. N Egl J Med. 2002;347: Pearso TA, Mesah GA, Alexader RW, et al. Markers of iflammatio ad cardiovascular disease: applicatio to cliical ad public health practice: a statemet for healthcare professioals from the Ceters for Disease Cotrol ad Prevetio ad the America Heart Associatio. Circulatio. 2003;107: Ridker PM, Burig JE, Cook NR, et al. C-reactive protei, the metabolic sydrome, ad risk of icidet cardiovascular evets: a 8-year follow-up of iitially healthy America wome. Circulatio. 2003;107: Daeberg HD, Szalai AJ, Swamiatha RV, et al. Icreased thrombosis after arterial ijury i huma C-reactive protei trasgeic mice. Circulatio. 2003;108: Jabs WJ, Theissig E, Nitschke M, et al. Local geeratio of C-reactive protei i diseased coroary artery veous bypass grafts ad ormal vascular tissue. Circulatio. 2003;108: Calabro P, Willerso JT, Yeh ET. Iflammatory cytokies stimulated C-reactive protei productio by huma coroary artery smooth muscle cells. Circulatio. 2003;108: Szmitko PE, Wag CH, Weisel RD, et al. New markers of iflammatio ad edothelial cell activatio: part I. Circulatio. 2003;108: Libby P, Ridker PM, Maseri A. Iflammatio ad atherosclerosis. Circulatio. 2002;105: Koeig W, Sud M, Frohlich M, et al. Refiemet of the associatio of serum C-reactive protei cocetratio ad coroary heart disease risk by correctio for withi-subject variatio over time: the MONICA Augsburg studies, 1984 ad Am J Epidemiol. 2003;158: Ledue TB, Rifai N. Preaalytic ad aalytic sources of variatios i C-reactive protei measuremet: implicatios for cardiovascular disease risk assessmet. Cli Chem. 2003;49: