Measurement of C-Reactive Protein for the Targeting of Statin Therapy in the Primary Prevention of Acute Coronary Events
Paul M. Ridker, M.D., M.P.H., Nader Rifai, Ph.D., Michael Clearfield, D.O., John R. Downs, M.D., Stephen E. Weis, D.O., J. Shawn Miles, M.D., Antonio M. Gotto, Jr., M.D., D.Phil., for the Air Force/Texas Coronary Atherosclerosis Prevention Study Investigators
Background Elevated levels of C-reactive protein, even in theabsence of hyperlipidemia, are associated with an increasedrisk of coronary events. Statin therapy reduces the level ofC-reactive protein independently of its effect on lipid levels.We hypothesized that statins might prevent coronary events inpersons with elevated C-reactive protein levels who did nothave overt hyperlipidemia.
Methods The level of C-reactive protein was measured at baseline and after one year in 5742 participants in a five-yearrandomized trial of lovastatin for the primary prevention ofacute coronary events.
Results The rates of coronary events increased significantlywith increases in the base-line levels of C-reactive protein.Lovastatin therapy reduced the C-reactive protein level by 14.8percent (P<0.001), an effect not explained by lovastatin-inducedchanges in the lipid profile. As expected, lovastatin was effectivein preventing coronary events in participants whose base-lineratio of total cholesterol to high-density lipoprotein (HDL)cholesterol was higher than the median ratio, regardless ofthe level of C-reactive protein (number needed to treat forfive years to prevent 1 event, 47; P=0.005). However, lovastatinwas also effective among those with a ratio of total to HDLcholesterol that was lower than the median and a C-reactiveprotein level higher than the median (number needed to treat,43; P=0.02). In contrast, lovastatin was ineffective among participantswith a ratio of total to HDL cholesterol and a C-reactive proteinlevel that were both lower than the median (number needed totreat, 983; P=0.87).
Conclusions Statin therapy may be effective in the primary preventionof coronary events among persons with relatively low lipid levelsbut with elevated levels of C-reactive protein.
Both the Air Force/Texas Coronary Atherosclerosis PreventionStudy (AFCAPS/TexCAPS) and the West of Scotland Coronary PreventionStudy demonstrated that inhibitors of hydroxymethylglutarylcoenzyme A (HMG-CoA) reductase (statins) reduce the risk offirst coronary events.1,2 However, the use of statins for primaryprevention has not been widely adopted, in part because thenumber of persons who need to be treated to prevent one clinicalevent is relatively large and the cost of this approach is substantial.3
A method of distinguishing high-risk from low-risk patientsmight make possible better targeting of statin therapy for primaryprevention.4 For example, restricting statin use to those withovert hyperlipidemia improves the cost effectiveness of thetherapy,5 and the current guidelines of the National CholesterolEducation Program recommend that statins be prescribed for primaryprevention when low-density lipoprotein (LDL) cholesterol levelsexceed 160 mg per deciliter (4.14 mmol per liter).6 Unfortunately,half of all coronary events occur in persons without overt hyperlipidemia.7Thus, lipid screening alone may fail to identify all high-risksubgroups that are likely to benefit from statin therapy.
Several studies suggest that measurement of the inflammatorymarker C-reactive protein may provide a useful method of assessingthe risk of cardiovascular disease in apparently healthy persons,particularly when lipid levels are low.8,9,10,11,12 Furthermore,statin therapy has been shown to reduce C-reactive protein levelsindependently of its effect on cholesterol,13,14 and statinsmay have antiinflammatory properties.15 Although the additionof an evaluation of C-reactive protein levels to standard lipidscreening has been shown to improve risk prediction in the primaryprevention of acute coronary events,9,16 there are no data demonstratingthat C-reactive protein screening can identify subgroups ofpatients who are more or less likely to benefit from statintherapy.
To address this issue, we measured the level of C-reactive proteinboth at base line and after one year of follow-up among 5742of the 6605 participants enrolled in a randomized, double-blind,placebo-controlled trial of lovastatin in the primary preventionof acute coronary events in persons with average levels of totalcholesterol and below-average levels of high-density lipoprotein(HDL) cholesterol.1
Methods
AFCAPS/TexCAPS was a primary-prevention trial of lovastatin,conducted between 1990 and 1998, that included 6605 men andwomen at two sites in Texas, the Lackland Air Force Base andthe University of North Texas Health Science Center.1,17 Men45 to 73 years old and postmenopausal women 55 to 73 years oldwho had average levels of total and LDL cholesterol and below-averagelevels of HDL cholesterol were eligible. Persons with uncontrolledhypertension, secondary hyperlipidemia, diabetes requiring insulin,or a body mass 50 percent greater than desirable were excluded.
Participants who provided written informed consent, met allthe entrance criteria, and completed a 12-week run-in periodduring which they followed the American Heart Association StepI diet were randomly assigned to receive either lovastatin (20mg per day) or matching placebo. The dose of lovastatin wasincreased in a double-blind manner to 40 mg of lovastatin perday if the LDL cholesterol level was higher than 110 mg perdeciliter (2.84 mmol per liter) at the three-month visit. Weconducted follow-up for an average of 5.2 years to monitor theoccurrence of first acute coronary events, which were prospectivelydefined as fatal or nonfatal myocardial infarction, unstableangina, or sudden death from cardiac causes. As we previouslyreported,1 assignment to the lovastatin group was associatedwith a rate of reaching this primary clinical end point thatwas 37 percent lower than that in the placebo group (relativerisk, 0.63; 95 percent confidence interval, 0.50 to 0.79; P<0.001).
Laboratory Analyses
A highly sensitive latex-based immunoassay (Dade Behring, Newark,Del.) was used to determine the levels of C-reactive proteinin blood obtained at the time of randomization and at one year.18Lipid levels were measured in a laboratory accredited by theLipid Standardization Program of the Centers for Disease Controland Prevention. In total, 5742 of the 6605 participants (87percent) had blood available for analysis and underwent successfulevaluation for high-sensitivity C-reactive protein and lipidlevels. The median LDL cholesterol level (149.1 mg per deciliter[3.86 mmol per liter]) and the median ratio of total to HDLcholesterol (5.96) among these 5742 participants were virtuallyidentical to the median level and ratio (149.3 mg per deciliter[3.86 mmol per liter] and 5.98, respectively) in the study cohortas a whole.
Statistical Analysis
After the study cohort had been divided into quartiles on thebasis of C-reactive protein levels, Cox regression analysiswas used to test for an association between base-line levelsof C-reactive protein and the risk of acute coronary events.Adjusted risk estimates were obtained from analyses that alsocontrolled for age, sex, smoking status, hypertension, parentalhistory with respect to coronary disease, and lipid levels.19
Spearman correlation coefficients were used to evaluate potentialrelations between C-reactive protein levels and lipid levelsat study entry and between the change in C-reactive proteinlevels and the change in lipid values by the end of one yearof therapy. The percentage change in C-reactive protein levelsthat was associated with the use of lovastatin was also computedand compared with the percentage change in C-reactive proteinlevels among those assigned to the placebo group.
To evaluate the efficacy of lovastatin as compared with placeboin subgroups defined according to base-line levels of lipidsand C-reactive protein, we divided the study cohort into fourgroups of approximately equal size: those with an LDL cholesterollevel lower than the median (less than 149.1 mg per deciliter)and a C-reactive protein level lower than the median (less than0.16 mg per deciliter) (1448 participants); those with an LDLcholesterol level lower than the median and a C-reactive proteinlevel higher than the median (1428 participants); those withan LDL cholesterol level higher than the median and a C-reactiveprotein level lower than the median (1420 participants); andthose with an LDL cholesterol level higher than the median anda C-reactive protein level higher than the median (1446 participants).We then computed the reductions in relative risk associatedwith lovastatin as compared with placebo in each of these fourgroups, as well as the number of persons who would have to betreated for five years to prevent one acute coronary event.
To determine whether any observed effects within these groupswere sensitive to the choice of lipid variable and to addressthe fact that the AFCAPS/TexCAPS trial enrolled participantswith below-average HDL cholesterol levels, we repeated theseanalyses using the median base-line ratio of total to HDL cholesterol(5.96) rather than the median base-line LDL cholesterol level.
Results
The overall distribution of C-reactive protein values in thisstudy was similar to that reported in previous studies of primaryprevention.8,9,10,11 The mean and median levels of C-reactiveprotein were 0.31 and 0.16 mg per deciliter, respectively, andthe ranges of C-reactive protein levels in the four quartileswere less than 0.08 mg per deciliter, 0.08 to less than 0.16mg per deciliter, 0.16 to 0.35 mg per deciliter, and greaterthan 0.35 mg per deciliter.
Our data provided minimal evidence of an association betweenbase-line C-reactive protein levels and base-line lipid levels;the Spearman correlation coefficients for the relations betweenC-reactive protein levels and total, LDL, and HDL cholesteroland triglyceride levels and the ratio of total to HDL cholesterolwere 0.069, 0.012, –0.058, 0.129, and 0.092, respectively.Thus, less than 2 percent of the variance in base-line C-reactiveprotein levels was determined by lipid factors.
Overall, the rates of coronary events increased with the base-linelevels of C-reactive protein, so that the relative risks ofcoronary events in participants assigned to the placebo groupas compared with those in the lovastatin group were 1.0, 1.2,1.3, and 1.7 for the lowest to highest quartile of base-linelevels of C-reactive protein (P=0.01). In unadjusted analyses,the risk of acute coronary events increased by 21 percent witheach increasing quartile of base-line C-reactive protein levels(95 percent confidence interval, 4 to 41 percent). In similaranalyses with control for age, sex, smoking status, hypertension,parental history with respect to coronary disease, and lipidlevels, the increase in risk associated with a one-quartileincrease in the C-reactive protein level (17 percent; 95 percentconfidence interval, 3 to 33 percent) was almost identical inmagnitude to that associated with an increase of 1.0 in theratio of total to HDL cholesterol (18 percent; 95 percent confidenceinterval, 5 to 33 percent).
Lovastatin therapy was associated with a statistically significant14.8 percent reduction in the median level of C-reactive protein(95 percent confidence interval, 12.5 to 17.4 percent; P<0.001)at the end of the first year of treatment (Table 1). By contrast,assignment to the placebo group had no effect on the medianlevel of C-reactive protein (median percentage change, 0.0;95 percent confidence interval, 0.0 to 5.3 percent), althoughthere were more participants with an increase in C-reactiveprotein levels than with a decrease. Thus, the difference betweenthe lovastatin group and the placebo group in terms of the changein C-reactive protein levels over time was significant (P<0.001).This effect of lovastatin on the level of C-reactive proteinwas not related to the effect of lovastatin on lipid levels;among the participants in the lovastatin group, the Spearmancorrelation coefficients for the relation between the percentagechange in C-reactive protein level and the percentage changein total, LDL, and HDL cholesterol and triglyceride levels andthe ratio of total to HDL cholesterol were –0.001, 0.014,–0.079, –0.013, and 0.061, respectively. Thus, virtuallynone of the observed variance in the effect of lovastatin onC-reactive protein levels could be explained by lovastatin-inducedchanges in lipid fractions.
Table 1. Median C-Reactive Protein Levels at Base Line and after One Year of Therapy in the Lovastatin and Placebo Groups.
Table 2 presents the results of efficacy analyses for lovastatinin subgroups of participants delineated according to LDL cholesteroland C-reactive protein levels. As expected, given the overallfindings of the trial, lovastatin was clinically effective amongparticipants with LDL cholesterol levels higher than the median,regardless of their C-reactive protein levels (relative riskof acute coronary events, 0.53; 95 percent confidence interval,0.37 to 0.77; number needed to treat, 42; P=0.001). However,lovastatin was also clinically effective among those with LDLcholesterol levels lower than the median and C-reactive proteinlevels higher than the median (relative risk, 0.58; 95 percentconfidence interval, 0.34 to 0.98; number needed to treat, 48;P=0.04). In contrast, among the participants with LDL cholesteroland C-reactive protein levels that were both lower than themedian, the point estimate did not indicate that lovastatinreduced the risk of acute coronary events (relative risk, 1.08;95 percent confidence interval, 0.56 to 2.08; P=0.74). In theseanalyses, formal testing for a multiplicative interaction amonglovastatin, lipids, and C-reactive protein indicated borderlinestatistical significance (P=0.06).
Table 2. Numbers of Acute Coronary Events, Rates of Events, Relative Risks, and Numbers Needed to Treat with Lovastatin to Prevent One Event, According to Base-Line Levels of LDL Cholesterol and C-Reactive Protein.
We evaluated the robustness of these analyses by stratifyingthe study cohort on the basis of the median base-line ratioof total to HDL cholesterol, rather than on the basis of thebase-line LDL cholesterol level, and the results were nearlyidentical (Table 3). Specifically, lovastatin was highly effectiveamong participants with a base-line ratio of total to HDL cholesterolthat was higher than the median (number needed to treat, 47;P=0.005). However, lovastatin was also highly effective amongthose with a ratio of total to HDL cholesterol lower than themedian and a C-reactive protein level higher than the median(number needed to treat, 43; P=0.02). In contrast, lovastatinwas far less effective among those with a ratio of total toHDL cholesterol lower than the median who also had a C-reactiveprotein level lower than the median (number needed to treat,983; P=0.87) (Table 3).
Table 3. Numbers of Acute Coronary Events, Rates of Events, Relative Risks, and Numbers Needed to Treat with Lovastatin to Prevent One Event, According to Base-Line Ratio of Total to HDL Cholesterol and C-Reactive Protein Level.
The rates of events among the participants in the placebo groupwho had lipid levels lower than the median and C-reactive proteinlevels higher than the median were just as high as the ratesof events among those with overt hyperlipidemia (Table 2 andTable 3). Moreover, lovastatin was clinically effective in reducingthe risk of acute coronary events among participants with lipidlevels lower than the median and C-reactive protein levels higherthan the median, but not among those with lipid levels and C-reactiveprotein levels that were both lower than the median (Figure 1).
Figure 1. Relative Risks (and 95 Percent Confidence Intervals) Associated with Lovastatin Therapy, According to Base-Line Lipid and C-Reactive Protein Levels.
Data are shown for LDL cholesterol levels (Panel A) and the ratio of total to HDL cholesterol (Panel B). Open boxes reflect analyses for all participants with LDL cholesterol levels higher than the median (in Panel A) and ratios of total to HDL cholesterol higher than the median (in Panel B).
In these data, the observed efficacy of lovastatin in preventingacute coronary events was not statistically significant amongthe participants with lipid levels and C-reactive protein levelsthat were both higher than the median (Figure 1). However, ineach of the two subgroups defined according to these criteria,the point estimates of effect indicate an overall net benefitwith lovastatin. Furthermore, there was no evidence of any statisticallysignificant difference between the efficacy of lovastatin amongthe participants with lipid levels and C-reactive protein levelsthat were both higher than the median and its efficacy amongthose with lipid levels higher than the median but C-reactiveprotein levels lower than the median; these data suggest thatany small differences between the results in these subgroupsprobably represent the effects of chance. Finally, because therates of events were high among participants with lipid levelsand C-reactive protein levels that were both higher than themedian, the number needed to treat in these subgroups was wellbelow the number considered the threshold for justifying treatmentfor primary prevention. Indeed, the number needed to treat amongparticipants with lipid levels and C-reactive protein levelsthat were both higher than the median was of similar magnitudeto that found in subgroups in which the efficacy of lovastatinwas clearly statistically significant (Table 2 and Table 3).
Discussion
Among the participants in AFCAPS/TexCAPS, base-line C-reactiveprotein levels were an independent predictor of first acutecoronary events. Furthermore, lovastatin appeared to be highlyeffective in reducing the risk of acute coronary events in participantswith elevated C-reactive protein levels but no hyperlipidemia.Indeed, among participants with either an LDL cholesterol levelor a ratio of total to HDL cholesterol that was lower than themedian but a C-reactive protein level higher than the median,the number needed to treat with lovastatin to prevent one clinicalevent was virtually identical to that among participants withlipid levels higher than the median. These analyses thus raisethe possibility that statin therapy may be clinically effectivein persons without hyperlipidemia and suggest that evaluationof the C-reactive protein level may provide a method for theappropriate targeting of statin therapy for primary prevention.20Finally, lovastatin significantly reduced C-reactive proteinlevels independently of its effect on lipids.
The results of this study have several implications. First,the current data confirm in a large population of apparentlyhealthy men and women that C-reactive protein can be used todetermine the risk of acute coronary events. The effect of theC-reactive protein level on risk was independent of all otherfactors, including lipid levels, known to predict clinical coronaryoutcomes. Thus, as in our earlier studies,8,9,16 the currentdata are consistent with the hypothesis that the addition ofan evaluation of the C-reactive protein level to the standardlipid evaluation may provide an improved method of identifyingpersons at high risk.
Second, in this double-blind trial, the use of lovastatin resultedin a 14.8 percent reduction in median C-reactive protein levelsafter one year (P<0.001), whereas no change in C-reactiveprotein levels occurred in participants in the placebo group.Thus, the current data also confirm the findings of the Cholesteroland Recurrent Events (CARE) trial, in which assignment to pravastatintherapy led to a 17.4 percent reduction in median C-reactiveprotein levels over a five-year period.13 As in the CARE trial,the effect of lovastatin on C-reactive protein levels in ourstudy appeared to be unrelated to any effect of HMG-CoA reductaseinhibition on plasma lipid levels. Together, these clinicaldata provide evidence of nonlipid effects of this class of agents13,14,15and suggest that statins may lead to the stabilization of plaquein part through antiinflammatory mechanisms.21,22,23
Third, although our study is hypothesis-generating, the factthat lovastatin was highly effective among participants withoutmarked hyperlipidemia but with elevated levels of C-reactiveprotein may have implications for the use of HMG-CoA reductaseinhibitors in primary prevention. As outlined in the currentguidelines of the National Cholesterol Education Program, strategiesto target statin therapy in primary prevention rely largelyon LDL cholesterol screening, an approach that results in areduction in the number needed to treat to prevent one eventand improves the cost effectiveness of these agents.5,6 However,as the current data suggest, lovastatin may be highly effectiveamong persons with average and below-average LDL cholesterollevels who have C-reactive protein levels higher than the median.Thus, if the number needed to treat is used to estimate theeffect of therapy in primary prevention, then C-reactive proteinscreening might provide an additional method for targeting theuse of statins, particularly when lipid levels are normal orlow.
In the current study, the magnitude of the increase in riskassociated with higher levels of C-reactive protein is somewhatsmaller than that observed in previous studies.8,9,10,11 Severalaspects of the design of our study probably account for thisdifference. For example, obese persons and diabetic patientsrequiring insulin were excluded from the study. Since thesegroups have elevated C-reactive protein levels and are at increasedrisk for cardiovascular disease,24 their exclusion would tendto lead to underestimation of the predictive value of the C-reactiveprotein level. Similarly, because C-reactive protein and lipidlevels appear additive in their ability to predict the riskof cardiovascular disease,9,16 the further exclusion from thestudy of persons with severe hyperlipidemia would also tendto reduce the predictive value of the C-reactive protein level.Finally, nearly 20 percent of the participants in AFCAPS/TexCAPSwere taking aspirin, a drug that has also been shown to reducethe effect of C-reactive protein on vascular risk.8 For allof these reasons, estimates of the risk associated with C-reactiveprotein derived from data from our study cohort would be expectedto be lower than those found in unselected populations.20 Theseissues would not, however, affect the validity of observationsmade in the context of this study with regard to statin therapyand C-reactive protein, since the participants were assignedto treatment groups in a double-blind manner, without knowledgeof C-reactive protein values.
From a clinical perspective, it is important to recognize thathalf of all heart attacks occur among persons without overthyperlipidemia7 and thus that novel approaches to the determinationof the risk of cardiovascular disease as well as to interventionare needed to improve resource allocation in the primary preventionof myocardial infarction.25 In a recent study of patients witha history of myocardial infarction, randomized use of statintherapy reduced the risk of recurrent coronary events associatedwith elevated levels of C-reactive protein.26 In the currentstudy of primary prevention, statin therapy was found to reducethe risk of acute coronary events associated with C-reactiveprotein, even in the absence of hyperlipidemia. Thus, thesehypothesis-generating clinical studies, together with the recognitionthat, biologically, atherosclerosis is in part an inflammatorydisease21 and that the lowering of lipid levels may representan antiinflammatory process,22 appear to provide a rationalefor considering wider use of statins than is typically achievedin current practice. Nonetheless, despite large differencesin the number needed to treat in this study, the absolute numberof events that occurred in each of the four subgroups of participantswas small, and formal testing for a multiplicative interactionamong lovastatin, lipids, and C-reactive protein indicated borderlinestatistical significance (P=0.06). Thus, randomized trials ofstatin therapy among persons without overt hyperlipidemia butwith evidence of systemic inflammation are needed in order totest these hypotheses directly.
Supported by grants from the National Heart, Lung, and BloodInstitute (HL58755) and the Leducq Foundation, Paris. Dr. Ridkeris also the recipient of an Established Investigator Award fromthe American Heart Association and a Doris Duke DistinguishedClinical Scientist Award from the Doris Duke Charitable Foundation.The AFCAPS/TexCAPS trial was supported by grants from Merck.
Dr. Ridker is named as a coinventor on patent applications filedfor the use of inflammatory markers in coronary artery disease.Drs. Gotto, Clearfield, Downs, and Weis have either served asconsultants to Merck (the manufacturer of lovastatin) or receivedhonorariums from Merck.
We are indebted to Ms. JoAnne Emerson and Mr. Thomas Cook fortheir assistance with this project.
Source Information
From the Center for Cardiovascular Disease Prevention, Brigham and Women's Hospital and Harvard Medical School, Boston (P.M.R., N.R., J.S.M.); the University of North Texas Health Science Center, Fort Worth (M.C., S.E.W.); Wilford Hall Medical Center, Lackland Air Force Base, San Antonio, Tex. (J.R.D.); and Weill Medical College of Cornell University, New York (A.M.G.).
Address reprint requests to Dr. Ridker at the Center for Cardiovascular Disease Prevention, Brigham and Women's Hospital, 900 Commonwealth Ave. E., Boston, MA 02215, or at pridker{at}partners.org.
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