Background Inflammation may be important in the pathogenesisof atherothrombosis. We studied whether inflammation increasesthe risk of a first thrombotic event and whether treatment withaspirin decreases the risk.
Methods We measured plasma C-reactive protein, a marker forsystemic inflammation, in 543 apparently healthy men participatingin the Physicians' Health Study in whom myocardial infarction,stroke, or venous thrombosis subsequently developed, and in543 study participants who did not report vascular disease duringa follow-up period exceeding eight years. Subjects were randomlyassigned to receive aspirin or placebo at the beginning of thetrial.
Results Base-line plasma C-reactive protein concentrations werehigher among men who went on to have myocardial infarction (1.51vs. 1.13 mg per liter, P<0.001) or ischemic stroke (1.38vs. 1.13 mg per liter, P = 0.02), but not venous thrombosis(1.26 vs. 1.13 mg per liter, P = 0.34), than among men withoutvascular events. The men in the quartile with the highest C-reactiveprotein values had three times the risk of myocardial infarction(relative risk, 2.9; P<0.001) and two times the risk of ischemicstroke (relative risk, 1.9; P = 0.02) of the men in the lowestquartile. Risks were stable over long periods, were not modifiedby smoking, and were independent of other lipid-related andnon–lipid-related risk factors. The use of aspirin wasassociated with significant reductions in the risk of myocardialinfarction (55.7 percent reduction, P = 0.02) among men in thehighest quartile but with only small, nonsignificant reductionsamong those in the lowest quartile (13.9 percent, P = 0.77).
Conclusions The base-line plasma concentration of C-reactiveprotein predicts the risk of future myocardial infarction andstroke. Moreover, the reduction associated with the use of aspirinin the risk of a first myocardial infarction appears to be directlyrelated to the level of C-reactive protein, raising the possibilitythat antiinflammatory agents may have clinical benefits in preventingcardiovascular disease.
Thrombus formation is the proximate cause of myocardial infarction,but atherosclerosis, the chief underlying cause, is a chronicdisease that progresses over decades of life.1 Laboratory andpathological data support the idea that inflammation has a rolein both the initiation and the progression of atherosclerosis,and antiinflammatory agents may have a role in the preventionof cardiovascular disease.2,3,4,5 However, there are few datato indicate whether inflammation increases the risk of firstmyocardial infarction, stroke, and venous thrombosis or whetherantiinflammatory therapy decreases that risk.
C-reactive protein is an acute-phase reactant that is a markerfor underlying systemic inflammation. Elevated plasma concentrationsof C-reactive protein have been reported in patients with acuteischemia6 or myocardial infarction7,8 and have been found topredict recurrent ischemia among those hospitalized with unstableangina.9 C-reactive protein is also associated with a risk ofmyocardial infarction among patients with angina pectoris10and with a risk of fatal coronary disease among smokers withmultiple risk factors for atherosclerosis.11 However, sinceconcentrations of C-reactive protein and other acute-phase reactantsincrease after acute ischemia6 and are directly related to cigarettesmoking,11,12 it has been uncertain whether associations observedin previous studies of acutely ill patients9 or high-risk populations10,11are causal or are due to short-term inflammatory changes orto interrelations with other risk factors, in particular smokingand hyperlipidemia.
To address these issues, we measured base-line plasma C-reactiveprotein concentrations in 1086 apparently healthy men participatingin the Physicians' Health Study13,14; myocardial infarction,stroke, or venous thrombosis subsequently developed in 543.We hypothesized a priori that levels of C-reactive protein wouldpredict the risk of myocardial infarction and stroke but notof venous thrombosis — an occlusive vascular disease generallynot associated with chronic atherosclerosis. After providingbase-line blood samples, study participants were randomly assignedto receive aspirin or placebo. Thus, we had the unique opportunityto evaluate directly whether aspirin, an agent with both antiplateletand antiinflammatory properties, might modify any relation betweenC-reactive protein and the risk of first myocardial infarction.
Methods
Study Population and Collection of Plasma Samples
The Physicians' Health Study was a randomized, double-blind,placebo-controlled two-by-two factorial trial of aspirin andbeta carotene in the primary prevention of cardiovascular diseaseand cancer. A total of 22,071 U.S. male physicians 40 to 84years of age in 1982, with no history of myocardial infarction,stroke, transient ischemic attack, or cancer, were assignedto one of four treatments: 325 mg of aspirin on alternate days(Bufferin, provided by Bristol-Myers), 50 mg of beta caroteneon alternate days (Lurotin, provided by BASF Corporation), both,or neither. The aspirin component of the study was terminatedearly, on January 25, 1988, primarily because of a statisticallyextreme 44 percent reduction in the risk of a first infarctionin the aspirin group.13 The beta carotene component continueduntil the study's scheduled termination on December 31, 1995.14
Before randomization, between August 1982 and December 1984,potential participants were asked to provide base-line bloodsamples during a 16-week run-in period during which all subjectswere given aspirin and none received placebo. Blood-collectionkits, including EDTA Vacutainer tubes, were sent to participantswith instructions for taking blood. Participants were askedto have their blood drawn into the EDTA tubes, centrifuge thetubes, and return the plasma (accompanied by a cold pack providedto participants) by overnight courier. The specimens were thendivided into aliquots and stored at -80°C. Of the 22,071participants in the Physicians' Health Study, 14,916 (68 percent)provided base-line plasma samples. Over the 14 years of thetrial, no specimen inadvertently thawed during storage.
Confirmation of End Points and Selection of Controls
We requested hospital records (and for fatal events, death certificatesand autopsy reports) for all reported cases of myocardial infarction,stroke, and venous thrombosis. The records were reviewed bya committee of physicians using standardized criteria to confirmor refute reported events. Reviewers of end points were unawareof treatment assignments.
Reported myocardial infarction was confirmed if its symptomsmet World Health Organization (WHO) criteria and it was associatedwith either elevated plasma concentrations of enzymes or characteristicelectrocardiographic changes. Silent myocardial infarctionswere not included, since they could not be dated accurately.Deaths due to coronary disease were confirmed on the basis ofautopsy reports, symptoms, circumstances of death, and a historyof coronary disease. Reported stroke was confirmed on the basisof medical records showing a neurologic deficit of sudden orrapid onset that persisted for more than 24 hours or until death.Strokes were classified as ischemic or hemorrhagic. Computedtomographic scans were available for more than 95 percent ofthe confirmed strokes. Reported deep venous thrombosis was confirmedby the documentation of a positive venography study or a positiveultrasound study; deep venous thromboses documented only byimpedance plethysmography or Doppler examination without ultrasoundwere not considered confirmed. Reported pulmonary embolism wasconfirmed by a positive angiogram or a completed ventilation-perfusionscan demonstrating at least two segmental perfusion defectswith normal ventilation.
Each participant who provided an adequate base-line plasma sampleand had a confirmed myocardial infarction, stroke, or venousthrombosis after randomization was matched with one control.Controls were participating physicians who provided base-lineplasma samples and reported no cardiovascular disease at thetime the patient reported his event. Controls were selectedrandomly from among study participants who met the matchingcriteria of age (±1 year), smoking status (smoking currently,smoked in the past, or never smoked), and length of time sincerandomization (in 6-month intervals). Using these methods, weevaluated 543 patients and 543 controls in this prospective,nested, case–control study.
Laboratory Analysis
For each patient and control, plasma collected and stored atbase line was thawed and assayed for C-reactive protein by enzyme-linkedimmunosorbent assay (ELISA) based on purified protein and polyclonalanti–C-reactive protein antibodies (Calbiochem).15 Antibodieswere used to coat microtiter-plate wells, and biotinylated C-reactiveprotein, together with the patient's plasma, was diluted 1:700in assay buffer (phosphate-buffered saline with 0.1 percentTween 20 and 1 percent bovine serum albumin). The excess wasthen washed off and the amount of biotinylated protein estimatedby the addition of avidin–peroxidase (Vectastain, VectorLaboratories). Purified C-reactive protein was used as the standard,with protein concentrations as determined by the manufacturer.The C-reactive protein assay was standardized according to theWHO First International Reference Standard and had a sensitivityof 0.08 µg per microliter, with a standard reference rangeof between 0.5 and 2.5 mg per liter. Methods used to measureplasma total and high-density lipoprotein (HDL) cholesterol,triglyceride, lipoprotein(a), total homocysteine, fibrinogen,d-dimer, and endogenous tissue plasminogen activator (t-PA)antigen have been described elsewhere.16,17,18,19,20
Blood specimens were analyzed in blinded pairs, with the positionof the patient's specimen varied at random within the pairsto reduce the possibility of systematic bias and decrease interassayvariability. The mean coefficient of variation for C-reactiveprotein across assay runs was 4.2 percent.
Statistical Analysis
Means or proportions for base-line risk factors were calculatedfor patients and controls. The significance of any differencein means was tested by using Student's t-test, and the significanceof any differences in proportions was tested by using the chi-squarestatistic. Because C-reactive protein values are skewed, medianconcentrations were computed and the significance of any differencesin median values between patients and controls was assessedby using Wilcoxon's rank-sum test. Geometric mean concentrationsof C-reactive protein were also computed after log transformationthat resulted in nearly normal distribution. We used tests fortrend to assess any relation of increasing C-reactive proteinvalues with the risk of future vascular disease after dividingthe sample into quartiles defined by the distribution of thecontrol values. We obtained adjusted estimates by using conditionallogistic-regression models that accounted for the matching variablesand controlled for the random treatment assignment, body-massindex, diabetes, history of hypertension, and parental historyof coronary artery disease. Similar models were employed toadjust for measured base-line plasma concentrations of totaland HDL cholesterol, triglyceride, lipoprotein(a), t-PA antigen,fibrinogen, d-dimer, and homocysteine. To evaluate whether aspirinaffected these relations, analyses were repeated for all casesof myocardial infarction occurring on or before January 25,1988 — the date when randomized aspirin assignment wasterminated. All P values are two-tailed, and confidence intervalswere calculated at the 95 percent level.
Results
Table 1 shows the base-line characteristics of the study participants.As expected, those in whom myocardial infarction subsequentlydeveloped were more likely than those who remained free of vasculardisease to have a history of hypertension or hyperlipidemiaor a parental history of coronary artery disease. Similarly,those in whom stroke subsequently developed were more likelyto be hypertensive. Because of the matching, patients and controlswere similar in age and history of smoking.
Table 1. Base-Line Characteristics of the Study Participants.
Geometric mean and median plasma concentrations of C-reactiveprotein at base line were significantly higher among those inwhom any vascular event subsequently developed than among thosewho remained free of vascular disease (P<0.001). The differencebetween patients and controls was greatest for those in whommyocardial infarction subsequently developed (1.51 vs. 1.13mg per liter, P<0.001), although differences were also significantfor stroke (P = 0.03), particularly ischemic stroke (P = 0.02).In contrast, concentrations of C-reactive protein were not significantlyhigher among those in whom venous thrombosis subsequently developed(P = 0.34) (Table 2).
Table 2. Base-Line Plasma Concentrations of C-Reactive Protein in Study Participants Who Remained Free of Vascular Disease during Follow-up (Controls) and in Those in Whom Myocardial Infarction, Stroke, or Venous Thrombosis Developed (Patients).
The relative risk of first myocardial infarction increased significantlywith each increasing quartile of base-line concentrations ofC-reactive protein (P for trend across quartiles, <0.001),in such a way that the men in the highest quartile had a riskof future myocardial infarction almost three times that amongthose in the lowest quartile (relative risk, 2.9; 95 percentconfidence interval, 1.8 to 4.6; P<0.001) (Table 3). Similarly,men with the highest base-line C-reactive protein values hadtwice the risk of future ischemic stroke (relative risk, 1.9;95 percent confidence interval, 1.1 to 3.3; P = 0.02). No significantassociations were observed for venous thrombosis. The findingswere similar in analyses limited to nonfatal events.
Table 3. Relative Risk of Future Myocardial Infarction, Stroke, and Venous Thrombosis According to Base-Line Plasma Concentrations of C-Reactive Protein.
To evaluate whether increased base-line C-reactive protein valueswere associated with early rather than late thrombosis, we stratifiedthe analysis of myocardial infarction according to the numberof years of follow-up. The relative risk of future myocardialinfarction that was associated with the highest quartile ofC-reactive protein (as compared with the lowest quartile) rangedfrom 2.4 for events occurring in the first two years of follow-upto 3.2 for events occurring six or more years into follow-up(Table 4). Similarly, the relative risk of future myocardialinfarction that was associated with a one-quartile change inthe C-reactive protein concentration was stable over long periods(Figure 1).
Table 4. Relative Risk of First Myocardial Infarction Associated with the Highest Quartile of Base-Line Plasma C-Reactive Protein Concentrations as Compared with the Lowest Quartile, According to the Year of Study Follow-up.
Figure 1. Relative Risk (and 95 Percent Confidence Intervals) of a First Myocardial Infarction Associated with Each Increasing Quartile of Base-Line C-Reactive Protein Values, According to the Year of Study Follow-up.
Smokers had significantly higher median concentrations of C-reactiveprotein than nonsmokers (2.20 vs. 1.19 mg per liter, P<0.001).By matching patients and controls for smoking status, we minimizedthe potential for confounding by smoking. To assess for effectmodification, however, we repeated the analyses, limiting thecohort to nonsmokers. As Table 3 also shows, the relative riskof future myocardial infarction among nonsmokers increased significantlywith each increasing quartile of C-reactive protein (P for trend,<0.001). Similarly, the long-term effects of the concentrationof C-reactive protein on the risk of myocardial infarction werevirtually identical among nonsmokers (Table 4). Moreover, therelation between the concentration of C-reactive protein andmyocardial infarction was not significantly altered in analysesthat adjusted for body-mass index; the presence or absence ofdiabetes, hypertension, or a family history of premature coronaryartery disease; and the plasma concentrations of total cholesterol,HDL cholesterol, triglycerides, lipoprotein(a), t-PA antigen,d-dimer, fibrinogen, or homocysteine (Table 5).
Table 5. Relative Risk of Future Myocardial Infarction, According to Base-Line Plasma Concentrations of C-Reactive Protein, Adjusted for Lipid and Nonlipid Variables.
Finally, to assess whether the beneficial effect of aspirinon the risk of myocardial infarction varied according to thebase-line level of C-reactive protein, we repeated these analysesfor events occurring before January 25, 1988, the date whenrandomized aspirin treatment was terminated.
The risk of future myocardial infarction increased with eachincreasing quartile of C-reactive protein values for men randomlyassigned to either aspirin or placebo, and the rates of myocardialinfarction were lower in the aspirin group for all quartilesof C-reactive protein (Figure 2). However, the magnitude ofthe beneficial effect of aspirin in preventing myocardial infarctionwas directly related to base-line levels of C-reactive protein.Specifically, randomized aspirin assignment was associated witha large and statistically significant reduction in the riskof myocardial infarction among men with base-line levels ofC-reactive protein in the highest quartile (risk reduction,55.7 percent; P = 0.02). Among those with base-line levels ofC-reactive protein in the lowest quartile, however, the reductionin risk associated with aspirin was far smaller and no longerstatistically significant (risk reduction, 13.9 percent; P =0.77). These effects were linear across quartiles, so that theapparent benefit of aspirin diminished in magnitude with eachdecreasing quartile of inflammatory risk (Figure 2). This findingremained essentially unchanged after further adjustment forother coronary risk factors, and the interaction between assignmentto the aspirin group and base-line levels of C-reactive protein(treated as a log-transformed continuous variable) was statisticallysignificant (P = 0.048).
Figure 2. Relative Risk of a First Myocardial Infarction Associated with Base-Line Plasma Concentrations of C-Reactive Protein, Stratified According to Randomized Assignment to Aspirin or Placebo Therapy.
Analyses are limited to events occurring before the unblinding of the aspirin component of the Physicians' Health Study. The reduction in the risk of myocardial infarction associated with the use of aspirin was 13.9 percent in the first (lowest) quartile of C-reactive protein values, 33.4 percent in the second quartile, 46.3 percent in the third quartile, and 55.7 percent in the fourth (highest) quartile.
Discussion
These prospective data indicate that the base-line plasma concentrationof C-reactive protein in apparently healthy men can predictthe risk of first myocardial infarction and ischemic stroke.In addition, the risk of arterial thrombosis associated withthe level of C-reactive protein was stable over long periodsand was not modified by other factors, including smoking status,body-mass index, blood pressure, or the plasma concentrationof total or HDL cholesterol, triglyceride, lipoprotein(a), t-PAantigen, d-dimer, fibrinogen, or homocysteine. In contrast,the benefits of aspirin in reducing the risk of a first myocardialinfarction diminished significantly with decreasing concentrationsof C-reactive protein — an intriguing finding, since thissubstance has antiinflammatory as well as antiplatelet properties.Finally, there was no significant association for venous thromboembolism,suggesting that the relation of inflammation to vascular riskmay be limited to the arterial circulation.
Because blood samples were collected at base line, we can excludethe possibility that acute ischemia affected levels of C-reactiveprotein. Furthermore, the statistically significant associationsobserved were present among nonsmokers, indicating that theeffect of C-reactive protein on vascular risk is not simplythe result of cigarette smoking.11,12 Thus, our prospectivedata relating base-line levels of C-reactive protein to futurerisks of myocardial infarction and stroke among apparently healthymen greatly extend previous observations from studies of acutelyill patients,9 patients with symptomatic coronary disease,10or those at high risk partly because of cigarette smoking.11Moreover, in these data, the effects of C-reactive protein wereindependent of a large number of lipid-related and non–lipid-relatedrisk factors.
The mechanism that relates the level of C-reactive protein toatherothrombosis is unclear. Previous infection with Chlamydiapneumoniae, Helicobacter pylori, herpes simplex virus, or cytomegalovirusmay be a source of the chronic inflammation detected by C-reactiveprotein.21,22,23,24,25,26,27 It is also possible that C-reactiveprotein is a surrogate for interleukin-6,28 a cellular cytokineassociated with the recruitment of macrophages and monocytesinto atherosclerotic plaques.29 In addition, C-reactive proteincan induce monocytes to express tissue factor, a membrane glycoproteinimportant in initiating coagulation.30 Finally, it had beenhypothesized that bronchial inflammation due to smoking wasresponsible for associations seen in previous studies relatingC-reactive protein to vascular risk.11 In this regard, our observationthat the effect of C-reactive protein is present among nonsmokersmakes bronchial inflammation a less likely mechanism. Furthermore,the finding that the effects are stable over long periods suggeststhat short-term effects on clotting are unlikely.
Our data regarding the interrelation of C-reactive protein andaspirin merit careful consideration. In the Physicians' HealthStudy, aspirin reduced the risk of a first myocardial infarctionby 44 percent.13 The present findings indicate that the effectof aspirin in preventing a first myocardial infarction was greatestamong the men with the highest base-line C-reactive proteinconcentrations and that the benefit diminished significantlywith decreasing concentrations of this inflammatory marker.Thus, although the antiplatelet effects of aspirin may be modifiedby underlying inflammation, these data also suggest the possibilitythat the benefit of aspirin may have been due, at least in part,to antiinflammatory effects.31 Alternatively, patients withlarge inflammatory burdens may have a distinct vascular mechanismleading to thrombosis that is affected differently by aspirintherapy. For example, the protective effect of aspirin may differin the setting of plaque rupture as compared with focal endothelialerosion.32,33
The potential limitations of these data also merit consideration.First, our analyses are based on a single base-line determinationthat may not accurately reflect inflammatory status over longperiods. Furthermore, although coefficients of variation werelow, misclassification due to laboratory error cannot be ruledout. It is important to note, however, that neither of thesesources of variability can account for the observed associations,since any random misclassification would bias results towardthe null hypothesis. Since our study was limited to measuresof C-reactive protein, other prospective studies evaluatingspecific cytokines, cellular adhesion molecules, and chronicinfectious agents will be required to further elucidate therole of inflammation in the initiation and progression of atherosclerosis.
We draw four main conclusions from these data. First, amongapparently healthy men, the base-line level of inflammationas assessed by the plasma concentration of C-reactive proteinpredicts the risk of a first myocardial infarction and ischemicstroke, independently of other risk factors. Second, the base-lineconcentration of C-reactive protein is not associated with therisk of venous thrombosis, a vascular event generally not associatedwith atherosclerosis. Third, C-reactive protein is not simplya short-term marker of risk, as has previously been demonstratedin patients with unstable angina,9 but is also a long-term markerof risk, even for events occurring six or more years later.This observation suggests that the effects of inflammation areprobably mediated through a chronic process and excludes thepossibility that undetected acute illness at base line is responsiblefor the observed effects. Finally, the benefits of aspirin appearto be modified by underlying inflammation — an observationthat raises the possibility of antiinflammatory as well as antiplateleteffects of this agent. The latter observation also suggeststhe possibility that other antiinflammatory agents may havea role in preventing cardiovascular disease. Moreover, thesedata suggest that inflammatory markers such as C-reactive proteinmay provide a method of identifying people for whom aspirinis likely to be more or less effective — a hypothesisrequiring direct testing in randomized trials.
Supported by grants (HL-26490, HL-34595, HL-46696, CA-34944,CA-42182, and CA-40360) from the National Institutes of Health.Dr. Ridker is supported by a Clinician Scientist Award fromthe American Heart Association.
Source Information
From the Divisions of Preventive Medicine (P.M.R., C.H.H.) and Cardiovascular Disease (P.M.R.) and the Channing Laboratory (M.J.S.), Department of Medicine, Brigham and Women's Hospital; the Department of Ambulatory Care and Prevention, Harvard Medical School (C.H.H.); and the Departments of Epidemiology (M.J.S., C.H.H.) and Nutrition (M.J.S.), Harvard School of Public Health — all in Boston; and the Laboratory for Clinical Biochemistry Research, University of Vermont, Burlington (M.C., R.P.T.).
Address reprint requests to Dr. Ridker at the Division of Preventive Medicine, Brigham and Women's Hospital, 900 Commonwealth Ave. E., Boston, MA 02215-1204.
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A correction has been published: N Engl J Med 1997;337(5):356.
