The New England Journal of Medicine

Original Article
Volume 344:1959-1965

June 28, 2001

Number 26
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 ABSTRACT
Background Elevated levels of C-reactive protein, even in the absence of
hyperlipidemia, are associated with an increased risk of coronary events.
Statin therapy reduces the level of C-reactive protein independently of its
effect on lipid levels. We hypothesized that statins might prevent coronary
events in persons with elevated C-reactive protein levels who did not have
overt hyperlipidemia.
Methods The level of C-reactive protein was measured at base line and after
one year in 5742 participants in a five-year randomized trial of lovastatin
for the primary prevention of acute coronary events.
Results The rates of coronary events increased significantly with increases
in the base-line levels of C-reactive protein. Lovastatin therapy reduced
the C-reactive protein level by 14.8 percent (P<0.001), an effect not
explained by lovastatin-induced changes in the lipid profile. As expected,
lovastatin was effective in preventing coronary events in participants whose
base-line ratio of total cholesterol to high-density lipoprotein (HDL)
cholesterol was higher than the median ratio, regardless of the level of
C-reactive protein (number needed to treat for five years to prevent 1
event, 47; P=0.005). However, lovastatin was also effective among those with
a ratio of total to HDL cholesterol that was lower than the median and a
C-reactive protein level higher than the median (number needed to treat, 43;
P=0.02). In contrast, lovastatin was ineffective among participants with a
ratio of total to HDL cholesterol and a C-reactive protein level that were
both lower than the median (number needed to treat, 983; P=0.87).
Conclusions Statin therapy may be effective in the primary prevention of
coronary events among persons with relatively low lipid levels but with
elevated levels of C-reactive protein.
  _____

Both the Air Force/Texas Coronary Atherosclerosis Prevention Study
(AFCAPS/TexCAPS) and the West of Scotland Coronary Prevention Study
demonstrated that inhibitors of hydroxymethylglutaryl coenzyme A (HMG-CoA)
reductase (statins) reduce the risk of first coronary events. 1
<http://content.nejm.org/cgi/content/full/344/26/#R1> , 2
<http://content.nejm.org/cgi/content/full/344/26/#R2>  However, the use of
statins for primary prevention has not been widely adopted, in part because
the number of persons who need to be treated to prevent one clinical event
is relatively large and the cost of this approach is substantial. 3
<http://content.nejm.org/cgi/content/full/344/26/#R3>
A method of distinguishing high-risk from low-risk patients might make
possible better targeting of statin therapy for primary prevention. 4
<http://content.nejm.org/cgi/content/full/344/26/#R4>  For example,
restricting statin use to those with overt hyperlipidemia improves the cost
effectiveness of the therapy, 5
<http://content.nejm.org/cgi/content/full/344/26/#R5>  and the current
guidelines of the National Cholesterol Education Program recommend that
statins be prescribed for primary prevention when low-density lipoprotein
(LDL) cholesterol levels exceed 160 mg per deciliter (4.14 mmol per liter).
6 <http://content.nejm.org/cgi/content/full/344/26/#R6>  Unfortunately, half
of all coronary events occur in persons without overt hyperlipidemia. 7
<http://content.nejm.org/cgi/content/full/344/26/#R7>  Thus, lipid screening
alone may fail to identify all high-risk subgroups that are likely to
benefit from statin therapy.
Several studies suggest that measurement of the inflammatory marker
C-reactive protein may provide a useful method of assessing the risk of
cardiovascular disease in apparently healthy persons, particularly when
lipid levels are low. 8
<http://content.nejm.org/cgi/content/full/344/26/#R8> , 9
<http://content.nejm.org/cgi/content/full/344/26/#R9> , 10
<http://content.nejm.org/cgi/content/full/344/26/#R10> , 11
<http://content.nejm.org/cgi/content/full/344/26/#R11> , 12
<http://content.nejm.org/cgi/content/full/344/26/#R12>  Furthermore, statin
therapy has been shown to reduce C-reactive protein levels independently of
its effect on cholesterol, 13
<http://content.nejm.org/cgi/content/full/344/26/#R13> , 14
<http://content.nejm.org/cgi/content/full/344/26/#R14>  and statins may have
antiinflammatory properties. 15
<http://content.nejm.org/cgi/content/full/344/26/#R15>  Although the
addition of an evaluation of C-reactive protein levels to standard lipid
screening has been shown to improve risk prediction in the primary
prevention of acute coronary events, 9
<http://content.nejm.org/cgi/content/full/344/26/#R9> , 16
<http://content.nejm.org/cgi/content/full/344/26/#R16>  there are no data
demonstrating that C-reactive protein screening can identify subgroups of
patients who are more or less likely to benefit from statin therapy.
To address this issue, we measured the level of C-reactive protein both at
base line and after one year of follow-up among 5742 of the 6605
participants enrolled in a randomized, double-blind, placebo-controlled
trial of lovastatin in the primary prevention of acute coronary events in
persons with average levels of total cholesterol and below-average levels of
high-density lipoprotein (HDL) cholesterol. 1
<http://content.nejm.org/cgi/content/full/344/26/#R1>
Methods
AFCAPS/TexCAPS was a primary-prevention trial of lovastatin, conducted
between 1990 and 1998, that included 6605 men and women at two sites in
Texas, the Lackland Air Force Base and the University of North Texas Health
Science Center. 1 <http://content.nejm.org/cgi/content/full/344/26/#R1> , 17
<http://content.nejm.org/cgi/content/full/344/26/#R17>  Men 45 to 73 years
old and postmenopausal women 55 to 73 years old who had average levels of
total and LDL cholesterol and below-average levels of HDL cholesterol were
eligible. Persons with uncontrolled hypertension, secondary hyperlipidemia,
diabetes requiring insulin, or a body mass 50 percent greater than desirable
were excluded.
Participants who provided written informed consent, met all the entrance
criteria, and completed a 12-week run-in period during which they followed
the American Heart Association Step I diet were randomly assigned to receive
either lovastatin (20 mg per day) or matching placebo. The dose of
lovastatin was increased in a double-blind manner to 40 mg of lovastatin per
day if the LDL cholesterol level was higher than 110 mg per deciliter (2.84
mmol per liter) at the three-month visit. We conducted follow-up for an
average of 5.2 years to monitor the occurrence of first acute coronary
events, which were prospectively defined as fatal or nonfatal myocardial
infarction, unstable angina, or sudden death from cardiac causes. As we
previously reported, 1 <http://content.nejm.org/cgi/content/full/344/26/#R1>
assignment to the lovastatin group was associated with a rate of reaching
this primary clinical end point that was 37 percent lower than that in the
placebo group (relative risk, 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 protein in blood obtained at the
time of randomization and at one year. 18
<http://content.nejm.org/cgi/content/full/344/26/#R18>  Lipid levels were
measured in a laboratory accredited by the Lipid Standardization Program of
the Centers for Disease Control and Prevention. In total, 5742 of the 6605
participants (87 percent) had blood available for analysis and underwent
successful evaluation for high-sensitivity C-reactive protein and lipid
levels. The median LDL cholesterol level (149.1 mg per deciliter [3.86 mmol
per liter]) and the median ratio of total to HDL cholesterol (5.96) among
these 5742 participants were virtually identical to the median level and
ratio (149.3 mg per deciliter [3.86 mmol per liter] and 5.98, respectively)
in the study cohort as a whole.
Statistical Analysis
After the study cohort had been divided into quartiles on the basis of
C-reactive protein levels, Cox regression analysis was used to test for an
association between base-line levels of C-reactive protein and the risk of
acute coronary events. Adjusted risk estimates were obtained from analyses
that also controlled for age, sex, smoking status, hypertension, parental
history with respect to coronary disease, and lipid levels. 19
<http://content.nejm.org/cgi/content/full/344/26/#R19>
Spearman correlation coefficients were used to evaluate potential relations
between C-reactive protein levels and lipid levels at study entry and
between the change in C-reactive protein levels and the change in lipid
values by the end of one year of therapy. The percentage change in
C-reactive protein levels that was associated with the use of lovastatin was
also computed and compared with the percentage change in C-reactive protein
levels among those assigned to the placebo group.
To evaluate the efficacy of lovastatin as compared with placebo in subgroups
defined according to base-line levels of lipids and C-reactive protein, we
divided the study cohort into four groups of approximately equal size: those
with an LDL cholesterol level lower than the median (less than 149.1 mg per
deciliter) and a C-reactive protein level lower than the median (less than
0.16 mg per deciliter) (1448 participants); those with an LDL cholesterol
level lower than the median and a C-reactive protein level higher than the
median (1428 participants); those with an LDL cholesterol level higher than
the median and a C-reactive protein level lower than the median (1420
participants); and those with an LDL cholesterol level higher than the
median and a C-reactive protein level higher than the median (1446
participants). We then computed the reductions in relative risk associated
with lovastatin as compared with placebo in each of these four groups, as
well as the number of persons who would have to be treated for five years to
prevent one acute coronary event.
To determine whether any observed effects within these groups were sensitive
to the choice of lipid variable and to address the fact that the
AFCAPS/TexCAPS trial enrolled participants with below-average HDL
cholesterol levels, we repeated these analyses 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 this study was
similar to that reported in previous studies of primary prevention. 8
<http://content.nejm.org/cgi/content/full/344/26/#R8> , 9
<http://content.nejm.org/cgi/content/full/344/26/#R9> , 10
<http://content.nejm.org/cgi/content/full/344/26/#R10> , 11
<http://content.nejm.org/cgi/content/full/344/26/#R11>  The mean and median
levels of C-reactive protein were 0.31 and 0.16 mg per deciliter,
respectively, and the ranges of C-reactive protein levels in the four
quartiles were less than 0.08 mg per deciliter, 0.08 to less than 0.16 mg
per deciliter, 0.16 to 0.35 mg per deciliter, and greater than 0.35 mg per
deciliter.
Our data provided minimal evidence of an association between base-line
C-reactive protein levels and base-line lipid levels; the Spearman
correlation coefficients for the relations between C-reactive protein levels
and total, LDL, and HDL cholesterol and triglyceride levels and the ratio of
total to HDL cholesterol were 0.069, 0.012, –0.058, 0.129, and 0.092,
respectively. Thus, less than 2 percent of the variance in base-line
C-reactive protein levels was determined by lipid factors.
Overall, the rates of coronary events increased with the base-line levels of
C-reactive protein, so that the relative risks of coronary events in
participants assigned to the placebo group as 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-line levels of C-reactive protein (P=0.01). In unadjusted
analyses, the risk of acute coronary events increased by 21 percent with
each increasing quartile of base-line C-reactive protein levels (95 percent
confidence interval, 4 to 41 percent). In similar analyses with control for
age, sex, smoking status, hypertension, parental history with respect to
coronary disease, and lipid levels, the increase in risk associated with a
one-quartile increase in the C-reactive protein level (17 percent; 95
percent confidence interval, 3 to 33 percent) was almost identical in
magnitude to that associated with an increase of 1.0 in the ratio of total
to HDL cholesterol (18 percent; 95 percent confidence interval, 5 to 33
percent).
Lovastatin therapy was associated with a statistically significant 14.8
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
<http://content.nejm.org/cgi/content/full/344/26/#T1> ). By contrast,
assignment to the placebo group had no effect on the median level of
C-reactive protein (median percentage change, 0.0; 95 percent confidence
interval, 0.0 to 5.3 percent), although there were more participants with an
increase in C-reactive protein levels than with a decrease. Thus, the
difference between the lovastatin group and the placebo group in terms of
the change in C-reactive protein levels over time was significant (P<0.001).
This effect of lovastatin on the level of C-reactive protein was not related
to the effect of lovastatin on lipid levels; among the participants in the
lovastatin group, the Spearman correlation coefficients for the relation
between the percentage change in C-reactive protein level and the percentage
change in total, LDL, and HDL cholesterol and triglyceride levels and the
ratio of total to HDL cholesterol were –0.001, 0.014, –0.079, –0.013, and
0.061, respectively. Thus, virtually none of the observed variance in the
effect of lovastatin on C-reactive protein levels could be explained by
lovastatin-induced changes in lipid fractions.


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Table 1. Median C-Reactive Protein Levels at Base Line and after One Year of
Therapy in the Lovastatin and Placebo Groups.

Table 2 <http://content.nejm.org/cgi/content/full/344/26/#T2>  presents the
results of efficacy analyses for lovastatin in subgroups of participants
delineated according to LDL cholesterol and C-reactive protein levels. As
expected, given the overall findings of the trial, lovastatin was clinically
effective among participants with LDL cholesterol levels higher than the
median, regardless of their C-reactive protein levels (relative risk of
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 LDL cholesterol levels lower than the
median and C-reactive protein levels higher than the median (relative risk,
0.58; 95 percent confidence interval, 0.34 to 0.98; number needed to treat,
48; P=0.04). In contrast, among the participants with LDL cholesterol and
C-reactive protein levels that were both lower than the median, the point
estimate did not indicate that lovastatin reduced the risk of acute coronary
events (relative risk, 1.08; 95 percent confidence interval, 0.56 to 2.08;
P=0.74). In these analyses, formal testing for a multiplicative interaction
among lovastatin, lipids, and C-reactive protein indicated borderline
statistical significance (P=0.06).


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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 stratifying the study
cohort on the basis of the median base-line ratio of total to HDL
cholesterol, rather than on the basis of the base-line LDL cholesterol
level, and the results were nearly identical ( Table 3
<http://content.nejm.org/cgi/content/full/344/26/#T3> ). Specifically,
lovastatin was highly effective among participants with a base-line ratio of
total to HDL cholesterol that was higher than the median (number needed to
treat, 47; P=0.005). However, lovastatin was also highly effective among
those with a ratio of total to HDL cholesterol lower than the median and a
C-reactive protein level higher than the median (number needed to treat, 43;
P=0.02). In contrast, lovastatin was far less effective among those with a
ratio of total to HDL cholesterol lower than the median who also had a
C-reactive protein level lower than the median (number needed to treat, 983;
P=0.87) ( Table 3 <http://content.nejm.org/cgi/content/full/344/26/#T3> ).


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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 group who had
lipid levels lower than the median and C-reactive protein levels higher than
the median were just as high as the rates of events among those with overt
hyperlipidemia ( Table 2
<http://content.nejm.org/cgi/content/full/344/26/#T2>  and Table 3
<http://content.nejm.org/cgi/content/full/344/26/#T3> ). Moreover,
lovastatin was clinically effective in reducing the risk of acute coronary
events among participants with lipid levels lower than the median and
C-reactive protein levels higher than the median, but not among those with
lipid levels and C-reactive protein levels that were both lower than the
median ( Figure 1 <http://content.nejm.org/cgi/content/full/344/26/#F1> ).


  <http://content.nejm.org/cgi/content/full/344/26/1959/F1>
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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 preventing acute
coronary events was not statistically significant among the participants
with lipid levels and C-reactive protein levels that were both higher than
the median ( Figure 1
<http://content.nejm.org/cgi/content/full/344/26/#F1> ). However, in each of
the two subgroups defined according to these criteria, the point estimates
of effect indicate an overall net benefit with lovastatin. Furthermore,
there was no evidence of any statistically significant difference between
the efficacy of lovastatin among the participants with lipid levels and
C-reactive protein levels that were both higher than the median and its
efficacy among those with lipid levels higher than the median but C-reactive
protein levels lower than the median; these data suggest that any small
differences between the results in these subgroups probably represent the
effects of chance. Finally, because the rates of events were high among
participants with lipid levels and C-reactive protein levels that were both
higher than the median, the number needed to treat in these subgroups was
well below the number considered the threshold for justifying treatment for
primary prevention. Indeed, the number needed to treat among participants
with lipid levels and C-reactive protein levels that were both higher than
the median was of similar magnitude to that found in subgroups in which the
efficacy of lovastatin was clearly statistically significant ( Table 2
<http://content.nejm.org/cgi/content/full/344/26/#T2>  and Table 3
<http://content.nejm.org/cgi/content/full/344/26/#T3> ).
Discussion
Among the participants in AFCAPS/TexCAPS, base-line C-reactive protein
levels were an independent predictor of first acute coronary events.
Furthermore, lovastatin appeared to be highly effective in reducing the risk
of acute coronary events in participants with elevated C-reactive protein
levels but no hyperlipidemia. Indeed, among participants with either an LDL
cholesterol level or a ratio of total to HDL cholesterol that was lower than
the median but a C-reactive protein level higher than the median, the number
needed to treat with lovastatin to prevent one clinical event was virtually
identical to that among participants with lipid levels higher than the
median. These analyses thus raise the possibility that statin therapy may be
clinically effective in persons without hyperlipidemia and suggest that
evaluation of the C-reactive protein level may provide a method for the
appropriate targeting of statin therapy for primary prevention. 20
<http://content.nejm.org/cgi/content/full/344/26/#R20>  Finally, lovastatin
significantly reduced C-reactive protein levels independently of its effect
on lipids.
The results of this study have several implications. First, the current data
confirm in a large population of apparently healthy men and women that
C-reactive protein can be used to determine the risk of acute coronary
events. The effect of the C-reactive protein level on risk was independent
of all other factors, including lipid levels, known to predict clinical
coronary outcomes. Thus, as in our earlier studies, 8
<http://content.nejm.org/cgi/content/full/344/26/#R8> , 9
<http://content.nejm.org/cgi/content/full/344/26/#R9> , 16
<http://content.nejm.org/cgi/content/full/344/26/#R16>  the current data are
consistent with the hypothesis that the addition of an evaluation of the
C-reactive protein level to the standard lipid evaluation may provide an
improved method of identifying persons at high risk.
Second, in this double-blind trial, the use of lovastatin resulted in a 14.8
percent reduction in median C-reactive protein levels after one year
(P<0.001), whereas no change in C-reactive protein levels occurred in
participants in the placebo group. Thus, the current data also confirm the
findings of the Cholesterol and Recurrent Events (CARE) trial, in which
assignment to pravastatin therapy led to a 17.4 percent reduction in median
C-reactive protein levels over a five-year period. 13
<http://content.nejm.org/cgi/content/full/344/26/#R13>  As in the CARE
trial, the effect of lovastatin on C-reactive protein levels in our study
appeared to be unrelated to any effect of HMG-CoA reductase inhibition on
plasma lipid levels. Together, these clinical data provide evidence of
nonlipid effects of this class of agents 13
<http://content.nejm.org/cgi/content/full/344/26/#R13> , 14
<http://content.nejm.org/cgi/content/full/344/26/#R14> , 15
<http://content.nejm.org/cgi/content/full/344/26/#R15>  and suggest that
statins may lead to the stabilization of plaque in part through
antiinflammatory mechanisms. 21
<http://content.nejm.org/cgi/content/full/344/26/#R21> , 22
<http://content.nejm.org/cgi/content/full/344/26/#R22> , 23
<http://content.nejm.org/cgi/content/full/344/26/#R23>
Third, although our study is hypothesis-generating, the fact that lovastatin
was highly effective among participants without marked hyperlipidemia but
with elevated levels of C-reactive protein may have implications for the use
of HMG-CoA reductase inhibitors in primary prevention. As outlined in the
current guidelines of the National Cholesterol Education Program, strategies
to target statin therapy in primary prevention rely largely on LDL
cholesterol screening, an approach that results in a reduction in the number
needed to treat to prevent one event and improves the cost effectiveness of
these agents. 5 <http://content.nejm.org/cgi/content/full/344/26/#R5> , 6
<http://content.nejm.org/cgi/content/full/344/26/#R6>  However, as the
current data suggest, lovastatin may be highly effective among persons with
average and below-average LDL cholesterol levels who have C-reactive protein
levels higher than the median. Thus, if the number needed to treat is used
to estimate the effect of therapy in primary prevention, then C-reactive
protein screening might provide an additional method for targeting the use
of statins, particularly when lipid levels are normal or low.
In the current study, the magnitude of the increase in risk associated with
higher levels of C-reactive protein is somewhat smaller than that observed
in previous studies. 8 <http://content.nejm.org/cgi/content/full/344/26/#R8>
, 9 <http://content.nejm.org/cgi/content/full/344/26/#R9> , 10
<http://content.nejm.org/cgi/content/full/344/26/#R10> , 11
<http://content.nejm.org/cgi/content/full/344/26/#R11>  Several aspects of
the design of our study probably account for this difference. For example,
obese persons and diabetic patients requiring insulin were excluded from the
study. Since these groups have elevated C-reactive protein levels and are at
increased risk for cardiovascular disease, 24
<http://content.nejm.org/cgi/content/full/344/26/#R24>  their exclusion
would tend to lead to underestimation of the predictive value of the
C-reactive protein level. Similarly, because C-reactive protein and lipid
levels appear additive in their ability to predict the risk of
cardiovascular disease, 9
<http://content.nejm.org/cgi/content/full/344/26/#R9> , 16
<http://content.nejm.org/cgi/content/full/344/26/#R16>  the further
exclusion from the study of persons with severe hyperlipidemia would also
tend to reduce the predictive value of the C-reactive protein level.
Finally, nearly 20 percent of the participants in AFCAPS/TexCAPS were taking
aspirin, a drug that has also been shown to reduce the effect of C-reactive
protein on vascular risk. 8
<http://content.nejm.org/cgi/content/full/344/26/#R8>  For all of these
reasons, estimates of the risk associated with C-reactive protein derived
from data from our study cohort would be expected to be lower than those
found in unselected populations. 20
<http://content.nejm.org/cgi/content/full/344/26/#R20>  These issues would
not, however, affect the validity of observations made in the context of
this study with regard to statin therapy and C-reactive protein, since the
participants were assigned to treatment groups in a double-blind manner,
without knowledge of C-reactive protein values.
From a clinical perspective, it is important to recognize that half of all
heart attacks occur among persons without overt hyperlipidemia 7
<http://content.nejm.org/cgi/content/full/344/26/#R7>  and thus that novel
approaches to the determination of the risk of cardiovascular disease as
well as to intervention are needed to improve resource allocation in the
primary prevention of myocardial infarction. 25
<http://content.nejm.org/cgi/content/full/344/26/#R25>  In a recent study of
patients with a history of myocardial infarction, randomized use of statin
therapy reduced the risk of recurrent coronary events associated with
elevated levels of C-reactive protein. 26
<http://content.nejm.org/cgi/content/full/344/26/#R26>  In the current study
of primary prevention, statin therapy was found to reduce the risk of acute
coronary events associated with C-reactive protein, even in the absence of
hyperlipidemia. Thus, these hypothesis-generating clinical studies, together
with the recognition that, biologically, atherosclerosis is in part an
inflammatory disease 21
<http://content.nejm.org/cgi/content/full/344/26/#R21>  and that the
lowering of lipid levels may represent an antiinflammatory process, 22
<http://content.nejm.org/cgi/content/full/344/26/#R22>  appear to provide a
rationale for considering wider use of statins than is typically achieved in
current practice. Nonetheless, despite large differences in the number
needed to treat in this study, the absolute number of events that occurred
in each of the four subgroups of participants was small, and formal testing
for a multiplicative interaction among lovastatin, lipids, and C-reactive
protein indicated borderline statistical significance (P=0.06). Thus,
randomized trials of statin therapy among persons without overt
hyperlipidemia but with evidence of systemic inflammation are needed in
order to test these hypotheses directly.
Supported by grants from the National Heart, Lung, and Blood Institute
(HL58755) and the Leducq Foundation, Paris. Dr. Ridker is also the recipient
of an Established Investigator Award from the American Heart Association and
a Doris Duke Distinguished Clinical 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 filed for the use
of inflammatory markers in coronary artery disease. Drs. Gotto, Clearfield,
Downs, and Weis have either served as consultants to Merck (the manufacturer
of lovastatin) or received honorariums from Merck.
We are indebted to Ms. JoAnne Emerson and Mr. Thomas Cook for their
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 [log in to unmask] <mailto:[log in to unmask]> .
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Edward E. Rylander, M.D.
Diplomat American Board of Family Practice.
Diplomat American Board of Palliative Medicine.