Measurement of C-Reactive Protein for the Targeting of Statin Therapy in the Primary Prevention of Acute Coronary Events

Abstract

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.
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.
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=0.80).
Statin therapy may be effective in the primary prevention of coronary events among subjects with relatively low lipid levels but with elevated levels of C-reactive protein.

Full text

The New England
Journal
of
Medicine
Copyright © 2001 by the Massachusetts Medical Society
VOLUME 344
J
UNE
28, 2001
NUMBER 26
N Engl J Med, Vol. 344, No. 26
·
June 28, 2001
·
www.nejm.org
·
1959
MEASUREMENT OF C-REACTIVE PROTEIN FOR THE TARGETING OF STATIN
THERAPY IN THE PRIMARY PREVENTION OF ACUTE CORONARY EVENTS
P
AUL
M. R
IDKER
, M.D., M.P.H., N
ADER
R
IFAI
, P
H
.D., M
ICHAEL
C
LEARFIELD
, D.O., J
OHN
R. D
OWNS
, M.D.,
S
TEPHEN
E. W
EIS
, D.O., J. S
HAWN
M
ILES
, M.D.,
AND
A
NTONIO
M. G
OTTO
, J
R
., M.D., D.P
HIL
.,
FOR
THE
A
IR
F
ORCE
/T
EXAS
C
ORONARY
A
THEROSCLEROSIS
P
REVENTION
S
TUDY
I
NVESTIGATORS
A
BSTRACT
Background
Elevated levels of C-reactive protein,
even in the absence of hyperlipidemia, are associated
with an increased risk of coronary events. Statin ther-
apy reduces the level of C-reactive protein independ-
ently 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 meas-
ured at base line and after one year in 5742 partici-
pants in a five-year randomized trial of lovastatin for
the primary prevention of acute coronary events.
Results
The rates of coronary events increased sig-
nificantly 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 lip-
oprotein (HDL) cholesterol was higher than the median
ratio, regardless of the level of C-reactive protein (num-
ber 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 pro-
tein level higher than the median (number needed to
treat, 43; P=0.02). In contrast, lovastatin was ineffec-
tive 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. (N Engl J Med 2001;344:1959-65.)
Copyright © 2001 Massachusetts Medical Society.
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@par tners.org.
OTH the Air Force/Texas Coronary Athero-
sclerosis Prevention Study (AFCAPS/Tex-
CAPS) and the West of Scotland Coronary
Prevention Study demonstrated that inhib-
itors of hydroxymethylglutaryl coenzyme A (HMG-
CoA) reductase (statins) reduce the risk of first coro-
nary events.
1,2
However, the use of statins for primary
prevention has not been widely adopted, in part be-
cause 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
A method of distinguishing high-risk from low-
risk patients might make possible better targeting of
statin therapy for primary prevention.
4
For example,
restricting statin use to those with overt hyperlipide-
mia improves the cost effectiveness of the therapy,
5
and
the current guidelines of the National Cholesterol
Education Program recommend that statins be pre-
scribed for primary prevention when low-density lip-
oprotein (LDL) cholesterol levels exceed 160 mg per
deciliter (4.14 mmol per liter).
6
Unfortunately, half
of all coronary events occur in persons without overt
hyperlipidemia.
7
Thus, lipid screening alone may fail to
identify all high-risk subgroups that are likely to ben-
efit 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 cardiovascu-
lar disease in apparently healthy persons, particularly
when lipid levels are low.
8-12
Furthermore, statin ther-
apy has been shown to reduce C-reactive protein lev-
els independently of its effect on cholesterol,
13,14
and
B

1960
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N Engl J Med, Vol. 344, No. 26
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June 28, 2001
·
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The New England Journal of Medicine
statins may have antiinflammatory properties.
15
Al-
though the addition of an evaluation of C-reactive
protein levels to standard lipid screening has been
shown to improve risk prediction in the primary pre-
vention of acute coronary events,
9,16
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-con-
trolled trial of lovastatin in the primary prevention
of acute coronary events in persons with average lev-
els of total cholesterol and below-average levels of
high-density lipoprotein (HDL) cholesterol.
1
METHODS
AFCAPS/TexCAPS was a primary-prevention trial of lovastat-
in, 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.
1,17
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 un-
controlled hypertension, secondary hyperlipidemia, diabetes requir-
ing 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 dur-
ing 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 cor-
onary events, which were prospectively defined as fatal or nonfatal
myocardial infarction, unstable angina, or sudden death from car-
diac causes. As we previously reported,
1
assignment to the lovastat-
in group was associated with a rate of reaching this primary clin-
ical 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 pro-
tein in blood obtained at the time of randomization and at one
year.
18
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 suc-
cessful 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 cho-
lesterol (5.96) among these 5742 participants were virtually identi-
cal 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 pro-
tein and the risk of acute coronar y events. Adjusted risk estimates
were obtained from analyses that also controlled for age, sex, smok-
ing status, hypertension, parental history with respect to coronary
disease, and lipid levels.
19
Spearman correlation coefficients were used to evaluate poten-
tial relations between C-reactive protein levels and lipid levels at
study entr y 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 associ-
ated 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 choles-
terol 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 be-
low-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 val-
ues in this study was similar to that reported in pre-
vious studies of primary prevention.
8-11
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 associ-
ation between base-line C-reactive protein levels and
base-line lipid levels; the Spearman correlation coef-
ficients for the relations between C-reactive protein
levels and total, LDL, and HDL cholesterol and tri-
glyceride levels and the ratio of total to HDL cho-
lesterol 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 as-
signed 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 analy-
ses, the risk of acute coronary events increased by 21
percent with each increasing quartile of base-line
C-reactive protein levels (95 percent confidence in-

C-REACTIVE PROTEIN FOR TARGETING STATIN THERAPY FOR PRIMARY PREVENTION OF ACUTE CORONARY EVENTS
N Engl J Med, Vol. 344, No. 26
·
June 28, 2001
·
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·
1961
terval, 4 to 41 percent). In similar analyses with con-
trol for age, sex, smoking status, hypertension, pa-
rental 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 per-
cent) was almost identical in magnitude to that as-
sociated with an increase of 1.0 in the ratio of total
to HDL cholesterol (18 percent; 95 percent confi-
dence interval, 5 to 33 percent).
Lovastatin therapy was associated with a statisti-
cally significant 14.8 percent reduction in the medi-
an 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 median level of C-reactive protein (median per-
centage change, 0.0; 95 percent confidence interval,
0.0 to 5.3 percent), although there were more par-
ticipants 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 par-
ticipants in the lovastatin group, the Spearman cor-
relation coefficients for the relation between the per-
centage change in C-reactive protein level and the
percentage change in total, LDL, and HDL choles-
terol 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.
Table 2 presents the results of efficacy analyses for
lovastatin in subgroups of participants delineated ac-
cording to LDL cholesterol and C-reactive protein
levels. As expected, given the overall findings of the
trial, lovastatin was clinically effective among partic-
ipants with LDL cholesterol levels higher than the
median, regardless of their C-reactive protein levels
(relative risk of acute coronary events, 0.53; 95 per-
cent confidence interval, 0.37 to 0.77; number need-
ed to treat, 42; P=0.001). However, lovastatin was
also clinically effective among those with LDL cho-
lesterol 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 lova-
statin, lipids, and C-reactive protein indicated bor-
derline statistical significance (P=0.06).
We evaluated the robustness of these analyses by
stratifying the study cohort on the basis of the me-
dian base-line ratio of total to HDL cholesterol, rath-
er than on the basis of the base-line LDL cholesterol
level, and the results were nearly identical (Table 3).
Specifically, lovastatin was highly effective among par-
ticipants with a base-line ratio of total to HDL cho-
lesterol 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 me-
dian who also had a C-reactive protein level lower
*Data are shown for the 5719 study participants who provided both base-line and one-year blood
samples and who were free of any acute coronary event during the first year of follow-up. Confidence
intervals (CIs) of the medians are nonparametric.
†P<0.001 for the comparison with the lovastatin group.
T
ABLE
1.
M
EDIAN
C-R
EACTIVE
P
ROTEIN
L
EVELS
AT
B
ASE
L
INE
AND
AFTER
O
NE
Y
EAR
OF
T
HERAPY
IN
THE
L
OVASTATIN
AND
P
LACEBO
G
ROUPS
.*
T
REATMENT
M
EDIAN
C-R
EACTIVE
P
ROTEIN
L
EVEL
M
EDIAN
C
HANGE
M
EDIAN
P
ERCENT
C
HANGE
BASE
LINE ONE
YEAR
mg/dl (95% CI) % (95% CI)
Lovastatin
(n=2885)
0.16
(0.15 to 0.17)
0.13
(0.12 to 0.14)
¡0.02
(¡0.02 to ¡0.01)
¡14.8
(¡17.4 to ¡12.5)
Placebo
(n=2834)
0.15
(0.15 to 0.16)
0.16
(0.16 to 0.17)
0.0
(0.00 to 0.01)
0.0
(0.0 to 5.3)†

1962
·
N Engl J Med, Vol. 344, No. 26
·
June 28, 2001
·
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The New England Journal of Medicine
*The rates of events and the numbers needed to treat to prevent one event were calculated on the basis of five patient-
years at risk. CI denotes confidence interval.
T
ABLE
2.
N
UMBERS
OF
A
CUTE
C
ORONARY
E
VENTS
, R
ATES
OF
E
VENTS
, R
ELATIVE
R
ISKS
,
AND
N
UMBERS
N
EEDED
TO
T
REAT
WITH
L
OVASTATIN
TO
P
REVENT
O
NE EVENT, ACCORDING TO BASE-LINE LEVELS
OF LDL CHOLESTEROL AND C-REACTIVE PROTEIN.*
SUBGROUP LOVASTATIN GROUP PLACEBO GROUP
RELATIVE RISK
OF ACUTE
CORONARY
EVENTS (95% CI)
NO. NEEDED
TO TREAT
NO. OF
EVENTS/
NO. OF
PARTICIPANTS
RATE OF
EVENTS
NO. OF
EVENTS/
NO. OF
PARTICIPANTS
RATE OF
EVENTS
LDL <median 41/1444 0.027 54/1432 0.036 0.74 (0.49–1.11) 113
LDL >median 44/1450 0.029 77/1416 0.053 0.53 (0.37–0.77) 42
LDL <median, C-reactive
protein <median
19/726 0.025 17/722 0.022 1.08 (0.56–2.08) —
LDL <median, C-reactive
protein >median
22/718 0.029 37/710 0.051 0.58 (0.34–0.98) 48
LDL >median, C-reactive
protein <median
15/709 0.020 37/711 0.050 0.38 (0.21–0.70) 33
LDL >median, C-reactive
protein >median
29/741 0.038 40/705 0.055 0.68 (0.42–1.10) 58
*The rates of events and the numbers needed to treat to prevent one event were calculated on the basis of five patient-
years at risk. CI denotes confidence interval.
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.*
SUBGROUP LOVASTATIN GROUP PLACEBO GROUP
RELATIVE RISK
OF ACUTE
CORONARY
EVENTS (95% CI)
NO. NEEDED
TO TREAT
NO. OF
EVENTS/
NO. OF
PARTICIPANTS
RATE OF
EVENTS
NO. OF
EVENTS/
NO. OF
PARTICIPANTS
RATE OF
EVENTS
Cholesterol ratio <median 36/1412 0.024 55/1459 0.036 0.63 (0.41–0.95) 86
Cholesterol ratio >median 49/1482 0.032 76/1389 0.053 0.59 (0.41–0.85) 47
Cholesterol ratio <median,
C-reactive protein
<median
19/762 0.024 20/763 0.025 0.88 (0.47–1.67) 983
Cholesterol ratio <median,
C-reactive protein
>median
17/650 0.025 35/696 0.050 0.47 (0.27–0.85) 43
Cholesterol ratio >median,
C-reactive protein
<median
15/673 0.021 34/670 0.050 0.42 (0.23–0.77) 35
Cholesterol ratio >median,
C-reactive protein
>median
34/809 0.041 42/719 0.057 0.72 (0.46–1.13) 62

C-REACTIVE PROTEIN FOR TARGETING STATIN THERAPY FOR PRIMARY PREVENTION OF ACUTE CORONARY EVENTS
N Engl J Med, Vol. 344, No. 26 ·June 28, 2001 ·www.nejm.org ·1963
than the median (number needed to treat, 983; P=
0.87) (Table 3).
The rates of events among the participants in the
placebo group who had lipid levels lower than the me-
dian and C-reactive protein levels higher than the
median were just as high as the rates of events among
those with overt hyperlipidemia (Tables 2 and 3).
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 (Fig. 1).
In these data, the observed efficacy of lovastatin
in preventing acute coronary events was not statisti-
cally significant among the participants with lipid lev-
els and C-reactive protein levels that were both high-
er than the median (Fig. 1). 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 ev-
idence of any statistically significant difference be-
tween 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 medi-
an but C-reactive protein levels lower than the me-
dian; these data suggest that any small differences
between the results in these subgroups probably rep-
resent the effects of chance. Finally, because the rates
of events were high among participants with lipid lev-
els and C-reactive protein levels that were both high-
er than the median, the number needed to treat in
these subgroups was well below the number consid-
ered the threshold for justifying treatment for pri-
mary 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 statis-
tically significant (Tables 2 and 3).
DISCUSSION
Among the participants in AFCAPS/TexCAPS,
base-line C-reactive protein levels were an independ-
ent predictor of first acute coronary events. Further-
more, lovastatin appeared to be highly effective in
reducing the risk of acute coronary events in partic-
ipants with elevated C-reactive protein levels but no
hyperlipidemia. Indeed, among participants with ei-
ther 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 with-
out hyperlipidemia and suggest that evaluation of
the C-reactive protein level may provide a method
for the appropriate targeting of statin therapy for pri-
mary prevention.20 Finally, lovastatin significantly re-
duced 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-reac-
tive 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 clin-
ical coronary outcomes. Thus, as in our earlier stud-
ies,8,9,16 the current data are consistent with the hy-
pothesis that the addition of an evaluation of the
C-reactive protein level to the standard lipid evalua-
tion may provide an improved method of identifying
persons at high risk.
Second, in this double-blind trial, the use of lova-
statin 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 oc-
curred 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 lev-
els over a five-year period.13 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 lev-
els. Together, these clinical data provide evidence of
nonlipid effects of this class of agents13-15 and suggest
that statins may lead to the stabilization of plaque in
part through antiinflammatory mechanisms.21-23
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 impli-
cations for the use of HMG-CoA reductase inhibi-
tors 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 num-
ber needed to treat to prevent one event and im-
proves the cost effectiveness of these agents.5,6 How-
ever, as the current data suggest, lovastatin may be
highly effective among persons with average and be-
low-average LDL cholesterol levels who have C-reac-
tive 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-reac-
tive 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

1964 ·N Engl J Med, Vol. 344, No. 26 ·June 28, 2001 ·www.nejm.org
The New England Journal of Medicine
in risk associated with higher levels of C-reactive pro-
tein is somewhat smaller than that observed in pre-
vious studies.8-11 Several aspects of the design of our
study probably account for this difference. For exam-
ple, obese persons and diabetic patients requiring in-
sulin were excluded from the study. Since these groups
have elevated C-reactive protein levels and are at in-
creased risk for cardiovascular disease,24 their exclu-
sion would tend to lead to underestimation of the
predictive value of the C-reactive protein level. Sim-
ilarly, because C-reactive protein and lipid levels ap-
pear additive in their ability to predict the risk of car-
diovascular disease,9,16 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 par-
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).
LDL <median,
C-reactive protein <median
(n=1448)
A
B
LDL <median,
C-reactive protein >median
(n=1428)
LDL >median,
C-reactive protein <median
(n=1420)
LDL >median,
C-reactive protein >median
(n=1446)
LDL >median,
any C-reactive protein
(n=2866)
0.0 2.50.5 1.0 1.5 2.0
Lovastatin Superior Placebo Superior
Cholesterol ratio <median,
C-reactive protein <median
(n=1525)
Cholesterol ratio <median,
C-reactive protein >median
(n=1346)
Cholesterol ratio >median,
C-reactive protein <median
(n=1343)
Cholesterol ratio >median,
C-reactive protein >median
(n=1528)
Cholesterol ratio >median,
any C-reactive protein
(n=2871)
0.0 2.50.5 1.0 1.5 2.0
Lovastatin Superior Placebo Superior

C-REACTIVE PROTEIN FOR TARGETING STATIN THERAPY FOR PRIMARY PREVENTION OF ACUTE CORONARY EVENTS
N Engl J Med, Vol. 344, No. 26 ·June 28, 2001 ·www.nejm.org ·1965
ticipants 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 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 These issues would
not, however, affect the validity of observations made
in the context of this study with regard to statin ther-
apy and C-reactive protein, since the participants were
assigned to treatment groups in a double-blind man-
ner, without knowledge of C-reactive protein values.
From a clinical perspective, it is important to rec-
ognize that half of all heart attacks occur among
persons without overt hyperlipidemia7 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 In a recent
study of patients with a history of myocardial infarc-
tion, randomized use of statin therapy reduced the
risk of recurrent coronary events associated with el-
evated levels of C-reactive protein.26 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 hy-
perlipidemia. Thus, these hypothesis-generating clin-
ical studies, together with the recognition that, bio-
logically, atherosclerosis is in part an inflammatory
disease21 and that the lowering of lipid levels may
represent an antiinflammatory process,22 appear to
provide a rationale for considering wider use of stat-
ins 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 sig-
nificance (P=0.06). Thus, randomized trials of stat-
in therapy among persons without overt hyperlipi-
demia 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 Insti-
tute (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.
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Copyright © 2001 Massachusetts Medical Society.