JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY VOL. 67, NO.

6, 2016

ª 2016 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION ISSN 0735-1097/$36.00

PUBLISHED BY ELSEVIER http://dx.doi.org/10.1016/j.jacc.2015.11.037

THE PRESENT AND FUTURE

REVIEW TOPIC OF THE WEEK

A Test in Context
High-Sensitivity C-Reactive Protein

Paul M Ridker, MD, MPH

JACC JOURNAL CME

This article has been selected as the month’s JACC Journal CME activity,
available online at http://www.acc.org/jacc-journals-cme by selecting the
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Accreditation and Designation Statement
The American College of Cardiology Foundation (ACCF) is accredited by
the Accreditation Council for Continuing Medical Education (ACCME) to
provide continuing medical education for physicians.
(hsCRP) as a tool for risk prediction in both primary and secondary
prevention of atherosclerotic events; 2) communicate to colleagues
where hsCRP testing is appropriate and where hsCRP testing is not
warranted; 3) recognize that “residual inflammatory risk” poses as large a
clinical problem for atherosclerosis patients as does “residual cholesterol
risk”; and 4) describe to both colleagues and patients the rationale for
ongoing clinical trials that target vascular inflammation but have no
effects on LDL cholesterol.

The ACCF designates this Journal-based CME activity for a maximum of 1 CME Editor Disclosure: JACC CME Editor Ragavendra R. Baliga, MD, FACC,
AMA PRA Category 1 Credit(s). Physicians should only claim credit has reported that he has no financial relationships or interests to disclose.
commensurate with the extent of their participation in the activity.

Author Disclosures: Dr. Ridker is listed as a coinventor on patents held

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by the Brigham and Women’s Hospital that relate to the use of inflam-
matory biomarkers in cardiovascular disease and diabetes, which have
been licensed to AstraZeneca and Siemens; and has received investigator-
initiated research grants from Novartis, AstraZeneca, Pfizer, and the Na-
tional Heart, Lung, and Blood Institute that relate to the completed and
ongoing clinical trials described in this review.
Medium of Participation: Print (article only); online (article and quiz).
CME Term of Approval

CME Objective for This Article: After reading this article, the reader should Issue Date: February 16, 2016
be able to: 1) discuss the role of high-sensitivity C-reactive protein Expiration Date: February 15, 2017

Listen to this manuscript’s

audio summary by
JACC Editor-in-Chief
Dr. Valentin Fuster.
From the Center for Cardiovascular Disease Prevention, Brigham and Women’s Hospital, Harvard Medical School, Boston,
Massachusetts. Dr. Ridker is listed as a coinventor on patents held by the Brigham and Women’s Hospital that relate to the use of
inflammatory biomarkers in cardiovascular disease and diabetes, which have been licensed to AstraZeneca and Siemens; and has
received investigator-initiated research grants from Novartis, AstraZeneca, Pfizer, and the National Heart, Lung, and Blood
Institute that relate to the completed and ongoing clinical trials described in this review.

Manuscript received August 17, 2015; revised manuscript received November 3, 2015, accepted November 11, 2015.
JACC VOL. 67, NO. 6, 2016 Ridker 713
FEBRUARY 16, 2016:712–23 A Test in Context: hsCRP

A Test in Context
High-Sensitivity C-Reactive Protein

ABSTRACT

The inflammatory biomarker high-sensitivity C-reactive protein (hsCRP) adds prognostic information on cardiovascular
risk comparable to blood pressure or cholesterol. Values <1, 1 to 3, and >3 mg/l indicate lower, average, or higher
relative cardiovascular risk, respectively. Global risk algorithms that include hsCRP outperform those solely using
Framingham covariates. Although diet, exercise, and smoking cessation are first steps for patients with a proinflammatory
response, JUPITER (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin) trial
data demonstrate that statins reduce by 47% the rate of first myocardial infarction, stroke, or confirmed cardiovascular
death when given to patients with low-density lipoprotein-C levels of <130 mg/dl and hsCRP of >2 mg/l (hazard
ratio: 0.53; 95% confidence interval: 0.40 to 0.69; p < 0.00001). In current U.S. guidelines, hsCRP carries a class
IIb assessment and is most appropriate in primary prevention when clinical decisions to initiate statin therapy are
uncertain. Ongoing multinational trials are pursuing whether reducing inflammation will decrease vascular event rates.
(J Am Coll Cardiol 2016;67:712–23) © 2016 by the American College of Cardiology Foundation.

I nflammation is ubiquitous in the atherothrom-

botic process and interplay between adhesion mol-
ecules, cytokines, circulating mononuclear cells,
oxidized low-density lipoprotein cholesterol (LDL-C),
and the vascular endothelium contribute to the lifelong
risk of heart attack and stroke (1). These insights led to
the recognition that a substantial proportion of unex-
plained vascular disease relates to inflammatory mech-
anisms. The clinical expression of this discovery
has been use of the inflammatory biomarker high-
sensitivity C-reactive protein (hsCRP) to detect
elevated vascular risk in both primary and secondary
prevention settings. In current U.S. guidelines, hsCRP
carries a Class IIb recommendation and is most appro-
priate in primary prevention when clinical decisions
related to the initiation of statin therapy are uncertain.
This review describes the relationships of hsCRP with
incident vascular disease and diabetes, a suggested
approach to interpretation of hsCRP results, settings
where hsCRP testing is appropriate, and the interaction
between inflammation and lipid-lowering therapy.
Areas of controversy are then discussed, including
whether C-reactive protein (CRP) is only a biomarker of
disease or if it plays a causal role in atherothrombosis.
Finally, ongoing cardiovascular inflammation reduc-
tion trials—the ultimate test of the inflammatory hy-
pothesis of atherosclerosis—are described.
THE RELATIONSHIP OF hsCRP LEVELS
TO FUTURE VASCULAR RISK
Initially described as a critical component of the acute
phase response in the 1930s, CRP gained attention
among cardiovascular researchers following reports in
the mid-1990s that increased levels are associated with
unstable angina and acute coronary ischemia (2,3).
Whether this was a result or a cause of ischemia, how-
ever, could not be addressed in cross-sectional studies
or among those in the midst of an ischemic event. In
1997, data from the prospective Physicians’ Health
Study, in which elevated hsCRP levels were described
in healthy subjects many years in advance of first-ever
vascular events, resolved this critical issue (4). That
study additionally showed that low-grade systemic
inflammation, as defined by hsCRP, is stable across
long periods of time and that the anti-inflammatory
agent aspirin significantly modified the effects of
hsCRP on vascular risk. This latter observation would
usher in attempts to decrease inflammation as a target
for atherothrombotic protection.
The core findings made in male participants in the
Physicians’ Health Study would soon be confirmed in
women (5) and, later, in more than 50 epidemiological
studies worldwide. In a 2010 meta-analysis (6),
encompassing more than 160,000 subjects with 1.3
million person-years of follow-up and nearly 28,000
incident vascular events, each standard deviation
increase in log-normalized hsCRP was associated with
a multivariate-adjusted relative increase in risk of
1.37 for coronary heart disease (95% confidence in-
terval: 1.27 to 1.48) and 1.55 (95% confidence interval:
1.37 to 1.76) for cardiovascular mortality. The magni-
tude of these effects was at least as large as
those reported in the same study participants for
total cholesterol, high-density lipoprotein cholesterol
(HDL-C), and blood pressure (Figure 1).
714 Ridker JACC VOL. 67, NO. 6, 2016

A Test in Context: hsCRP FEBRUARY 16, 2016:712–23

ABBREVIATIONS High-sensitivity CRP relates more closely
AND ACRONYMS to the risks of plaque rupture and vascular
thrombosis than to the extent of underlying
ACC/AHA = American College
of Cardiology/American Heart
atherosclerotic burden. In terms of cardio-
Association vascular event-free survival, the risks asso-
CRP = C-reactive protein ciated with hsCRP are comparable with and
HDL-C = high-density independent of LDL-C (Figures 2A and 2B)
lipoprotein cholesterol (7). However, these effects are modest;
hsCRP = high-sensitivity addition of hsCRP testing to traditional fac-
C-reactive protein tors, such as age, smoking, and blood pres-
IL = interleukin sure, has only modest impact on the C-
LDL-C = low-density statistic (a measure of discrimination) and
lipoprotein cholesterol
on indexes of reclassification. Analyses from
the Framingham Heart Study, Women’s Health
Study, EPIC-Norfolk, and MESA (Multi Ethnic Study
of Atherosclerosis), reported net reclassification in-
dex values of 8% to 12%, but smaller effects were
seen elsewhere (8). For example, in the Emerging
Risk Factors Consortium and in a recent analysis
from Yeboah et al., addition of hsCRP only margin-
ally improved the C-statistic and net reclassification
index, less than would be accomplished with direct
plaque imaging (9,10).
THE RELATIONSHIP OF hsCRP TO THE
METABOLIC SYNDROME AND DIABETES
Adipose tissue is a major source of inflammatory
cytokines and the diabetes community considers
inflammation likely to play a causal role in the pro-
gression from insulin resistance to frank type 2 dia-
betes (11). Early epidemiological evidence linking
basal interleukin (IL)-6 and hsCRP levels in currently
healthy individuals to future development of dia-
betes played a major role in translation of this dis-
covery to practice (12,13). The hsCRP levels track with
the severity and number of underlying features of
metabolic syndrome, and predict vascular risk among
those already defined as having significant insulin
resistance. Partly for these reasons, ongoing trials of
inflammation inhibition are adjudicating incident
diabetes, as well as vascular events.

F I G U R E 1 Predictive Usefulness of hsCRP in Primary Prevention

Coronary Heart Disease All Vascular Deaths

3.0 3.0
2.5 2.5
Risk Ratio (95% CI)

2.0 2.0

1.5 1.5

1.0 1.0

0.5 1.0 2.0 4.0 8.0 0.5 1.0 2.0 4.0 8.0
hsCRP Concentration (mg/L) hsCRP Concentration (mg/L)

Risk Ratio (95% CI)

hsCRP 1.37 (1.27-1.48)

Systolic BP 1.35 (1.25-1.45)

Total cholesterol 1.16 (1.06-1.28)

Non-HDL-C 1.28 (1.16-1.40)

0.5 1.0 1.2 1.4 1.8

Risk Ratio (95% CI) per 1-SD Higher Usual Values

The relationship of hsCRP levels in healthy subjects to future risks of coronary heart disease and vascular deaths (top). The magnitude of cardiovascular risk
associated with a 1-standard deviation (SD) change in hsCRP is at least as great as that associated with a similar change in systolic blood pressure,
total cholesterol, or non–HDL-C (bottom). Data from Kaptoge et al. (6). BP ¼ blood pressure; CI ¼ confidence interval; hsCRP ¼ high-sensitivity C-reactive
protein; HDL-C ¼ high-density lipoprotein cholesterol.
JACC VOL. 67, NO. 6, 2016 Ridker 715
FEBRUARY 16, 2016:712–23 A Test in Context: hsCRP

STATIN THERAPY AND hsCRP: IMPACT OF

F I G U R E 2 Magnitude of Risk Associated With hsCRP Is Comparable With and
HARD ENDPOINT CLINICAL TRIALs Independent of LDL-C

High-sensitivity CRP has played a critical role in un-

A Quintiles of hsCRP Quintiles of LDL

1.00
1.00
derstanding statin therapy as a treatment with both
anti-inflammatory and lipid-lowering effects. In 1998,

CVD Event-Free Survival Probability

investigators in the Cholesterol and Recurrent Events

0.99
0.99
trial first observed that statins reduced hsCRP in an 1

LDL-independent manner and that that their benefit 1

2
in event reduction was greatest among those with 2

0.98
0.98
elevated hsCRP levels (14). In 2001, AFCAPS (Air 3
3
Force Coronary Arteriosclerosis Prevention Study)/
4
TexCAPS (Texas Coronary Atherosclerosis Prevention 4

0.97
0.97
Study) trial data raised the hypothesis that statin
therapy could reduce vascular event rates among 5
5

0.96
0.96
those with elevated hsCRP, even if LDL-C levels were
low (15). Then, between 2005 and 2006, analyses from 0 2 4 6 8 0 2 4 6 8
the PROVE-IT-TIMI 22 (Pravastatin or Atorvastatin Years of Follow-Up Years of Follow-Up
Evaluation and Infection Therapy–Thrombolysis In
Myocardial Infarction 22), REVERSAL (Reversal of B 1.00
Atherosclerosis with Aggressive Lipid Lowering), and
A-to-Z (Aggrastat-to-Zocor) trials would demonstrate hsCRP < 2 mg/L, LDL < 130 mg/dL
Probability of Event-Free Survival

that the best clinical outcomes after initiating statin
therapy accrued among those who reduced LDL-C
to <70 mg/dl and hsCRP to <2 mg/l, a concept
introduced into clinical practice as “dual targets”
for statin therapy (16–18).
Hypotheses relating statin therapy to hsCRP were
formally tested in the multinational JUPITER (Justifi-
cation for the Use of Statins in Prevention: an Inter-
vention Trial Evaluating Rosuvastatin) primary
prevention trial. In JUPITER, 17,802 apparently
healthy men and women with LDL-C levels of
<130 mg/dl (median, 108 mg/dl), who were at
increased cardiovascular risk due to hsCRP levels of
>2 mg/l, were allocated randomly to rosuvastatin
20 mg/day or placebo (19). Overall, random allocation
to rosuvastatin resulted in a 54% reduction in
myocardial infarction (p ¼ 0.0002), a 48% reduction in
stroke (p ¼ 0.002), a 47% reduction in the need for
arterial revascularization procedures (p < 0.0001), and
a 20% reduction in all-cause mortality (p ¼ 0.02)
(Figure 3). A 37% reduction in the primary trial
endpoint of all major vascular events was observed in
the subgroup with an hsCRP of >2 mg/l, but no other
major risk factors than age.
Within the JUPITER trial population, the magni-
tude of the absolute risk reduction attributable to
rosuvastatin increased with increasing baseline levels
of hsCRP. Of particular interest for the inflammation
hypothesis of thrombosis, rosuvastatin decreased
incident deep vein thrombosis and pulmonary em-
bolism by 43% (20). This was an important observa-
tion, because LDL-C has a minimal role in these
0.99
hsCRP < 2 mg/L, LDL > 130 mg/dL
0.98
hsCRP > 2 mg/L, LDL < 130 mg/dL
0.97
0.96 hsCRP > 2 mg/L, LDL > 130 mg/dL
0.00
0 2 4 6 8
Years of Follow-Up
(A) Increasing quintiles of both hsCRP and LDL-C predict vascular risk. (B) The highest-risk
patients in a primary prevention setting are those with both increased hsCRP and increased
LDL-C. Data from Ridker et al. (7). CVD ¼ cardiovascular disease; hsCRP ¼ high-sensitivity
C-reactive protein; LDL ¼ low-density lipoprotein; LDL-C ¼ low-density lipoprotein
cholesterol.
disorders, and there is no plaque to rupture in the
venous circulation. Overall in JUPITER, the number
needed to treat for the trial primary endpoint was
25, an effect size comparable with the use of statin
therapy in primary prevention among those with
overt hyperlipidemia. Some investigators have sug-
gested that coronary artery calcium might better
identify JUPITER-eligible participants who would
benefit from statin therapy, although no trial data
demonstrating this effect exist (21).
As observed in the earlier AFCAPS/TexCAPS,
REVERSAL, and PROVE-IT trials, those who achieved
very low levels of hsCRP and LDL-C had the greatest
clinical benefits (22). Most recently, the IMPROVE-IT
716 Ridker JACC VOL. 67, NO. 6, 2016

A Test in Context: hsCRP FEBRUARY 16, 2016:712–23

F I G U R E 3 The JUPITER Trial

Primary Endpoint Myocardial Infarction, Stroke, Cardiovascular Death

0.08

0.04
RR 0.56, 95% CI 0.46-0.69 RR 0.53, 95% CI 0.40-0.69
P<0.000001 P<0.00001 Placebo
Placebo
0.06
Cumulative Incidence

0.03
Cumulative Incidence
0.04

0.02
0.02

Rosuvastatin Rosuvastatin

0.01
0.00

0.00
0 1 2 3 4 0 1 2 3 4
Follow-Up (Years) Follow-Up (Years)

Revascularization or Hospitalization for Unstable Angina All Cause Mortality

0.04

0.00 0.01 0.02 0.03 0.04 0.05 0.06

RR 0.53, 95% CI 0.40-0.70 RR 0.79, 95% CI 0.65-0.96
P<0.00001 Placebo P=0.02
Placebo
0.03

Cumulative Incidence
Cumulative Incidence
0.02

Rosuvastatin
0.01

Rosuvastatin
0.00

0 1 2 3 4 0 1 2 3 4
Follow-Up (Years) Follow-Up (Years)

Primary results of the JUPITER trial, demonstrating the efficacy of statin therapy in reducing first major cardiovascular events among patients with low levels of LDL-C,
but increased levels of high-sensitivity C-reactive protein. Data from Ridker et al. (19). CI ¼ confidence interval; JUPITER ¼ Justification for the Use of Statins in
Prevention: an Intervention Trial Evaluating Rosuvastatin; RR ¼ relative risk.

investigators reported that addition of ezetimibe to of hsCRP when additional risk information may be
statin therapy reduced vascular event rates compared needed before the initiation of statin therapy. Cur-
with statin therapy alone (23). Of interest, the statin rent European Society of Cardiology guidelines also
plus ezetimibe arm of this trial not only had greater give hsCRP a Class IIb recommendation, stating that
reductions in LDL-C, but also had greater reductions hsCRP may be measured as part of refined risk
in hsCRP. Thus, the IMPROVE-IT data are also assessment in patients with unusual or moderate
consistent with the concepts of “dual targets” for cardiovascular risk profiles (25). Guidelines also note
vascular event reduction (24). As is also the case for that laboratories running hsCRP should report values
LDL-C, evaluations of on-treatment hsCRP cannot in milligrams per liter. If results are reported as mil-
exclude residual confounding. ligrams per deciliter, it is likely to be a “regular”
CRP test, rather than an hsCRP test. Although the
HOW SHOULD hsCRP TEST RESULTS “regular” CRP assay is adequate for monitoring major
BE INTERPRETED? infections, clinically evident inflammatory disorders,
and endocarditis, atherosclerotic risk assessment
On the basis of the evidence described earlier, current requires the increased sensitivity of the hsCRP test.
U.S. cardiovascular screening guidelines give hsCRP High-sensitivity CRP levels are related linearly
a Class IIb recommendation and suggest evaluation to vascular risk across a wide range of values.
JACC VOL. 67, NO. 6, 2016 Ridker 717
FEBRUARY 16, 2016:712–23 A Test in Context: hsCRP

CENTRAL I LLU ST RAT ION Clinical Interpretation of hsCRP for Cardiovascular Risk Prediction

Ridker, P.M. J Am Coll Cardiol. 2016; 67(6):712–23.

The relationship of inflammation to cardiovascular risk is linear across a wide range of hsCRP values. Blue bars represent crude relative risks; red bars
represent relative risks adjusted for traditional Framingham risk factors. Data from Ridker et al. (65). CV ¼ cardiovascular; hsCRP ¼ high-sensitivity
C-reactive protein.

Thus, interpretation of hsCRP results is straightfor-
ward: levels <1 mg/l are desirable and reflect a low
systemic inflammatory status and lower atheroscle-
rotic risk; levels between 1 and 3 mg/l indicate mod-
erate vascular risk; whereas levels >3 mg/l indicate
higher vascular risk when interpreted in the context
of other risk factors. Values of hsCRP that are
>10 mg/l may reflect a transient infectious process or
other acute phase response, and thus should be
repeated in 2 to 3 weeks (and the lower value, not the
average, used for risk prediction) (Central Illustration,
top). Persistently high values, however, are often
seen and do not necessarily represent false positive
results; such values can associate with considerably
elevated vascular risk (Central Illustration, bottom).
As noted, although the addition of hsCRP improves
risk reclassification, this effect is modest
comparison with direct tests for the presence of
atherosclerosis, such as coronary calcium testing.
Post-menopausal women who take estrogen-
containing oral hormone replacement therapy can
have increased hsCRP levels. By contrast, the use
of topical estrogens or selective estrogen-receptor
modulators does not have such an effect. If
women taking hormone replacement therapy are
excluded, levels are generally similar across sexes
and increase modestly with age. Median hsCRP
levels are greater in black patients than in Cauca-
sian or Hispanic patients, and are somewhat lower
among those of Asian origin. These trends reflect
the higher levels of risk in black patients and lower
levels of risk in Asian patients compared with age-
and smoking-matched Caucasian patients. The me-
in dian hsCRP level in the United States is close to
718 Ridker
A Test in Context: hsCRP
2 mg/l, and approximately 25% of the general pop-
ulation has levels exceeding 3 mg/l.
AREAS OF CONTROVERSY I: SPECIFICITY, REPRO-
DUCIBILITY, AND STABILITY OF hsCRP. There has
been concern that hsCRP measurement is not specific
for vascular disease. At 1 level, this criticism is valid
because increases in hsCRP also reflect metabolic
disorders, including insulin resistance and adiposity.
As noted, it is partly for these reasons that hsCRP
levels are also a predictor of risk for type 2 diabetes
and all-cause mortality. Because CRP is an acute
phase reactant, levels increase transiently during
major trauma and infection, and measurement should
be avoided in these situations. However, hsCRP levels
are neither a predictor of incident cancer nor of the
risk of developing major systemic inflammatory dis-
orders, such as rheumatoid arthritis or inflammatory
bowel disease.
From an epidemiological perspective, non-
specificity is a bias toward the null; thus, if anything,
the biological impact of inflammation on vascular risk
is underestimated (not overestimated) by this po-
tential limitation of hsCRP testing. The theoretical
potential for alternative inflammatory biomarkers,
such as lipoprotein-associated phospholipase A 2,
to have improved specificity compared with hsCRP
have not been borne out in clinical studies, and
trials of the lipoprotein-associated phospholipase A2
inhibitor darapladib failed to show event reduction.
A related area of controversy concerns the stability
of hsCRP levels over time. In early work, among 214
subjects with hsCRP measurements separated by
5 years, we found an age-adjusted partial correlation
of 0.60 (14). In the SEASONS (Seasonal variation in
blood cholesterol levels) study, where 5 measures of
hsCRP were made at 3-month intervals in 113 subjects,
an estimated intraclass correlation for hsCRP of 0.66
was reported (26), a value similar to that observed in
paired measures taken 1 year apart among 1,700
Japanese civil servants (log-normalized intraclass
correlation 0.6) (27). Somewhat lower intraclass cor-
relations of 0.54 and 0.59 have been reported in
population studies from the MONICA (Monitoring of
Trends and Determinants in Cardiovascular Disease)
Augsberg cohort and from the Reykjavik study,
respectively (28,29). In all of these analyses, the re-
ported measurement reliability estimates were com-
parable with that of total cholesterol and superior to
that of blood pressure. By contrast, in the MESA
cohort, the intraclass correlation for hsCRP (0.62)
was lower than that of total cholesterol (0.75) and
non-HDL-C (0.76) (30).
Perhaps the most comprehensive study of hsCRP
tracking over time was performed in the placebo arm
JACC VOL. 67, NO. 6, 2016
FEBRUARY 16, 2016:712–23
of the JUPITER trial, where 8,901 individuals had
annual hsCRP measurements over a 4-year period
(31). As anticipated, because all JUPITER partici-
pants were initially selected for high hsCRP levels,
the median hsCRP concentration showed modest
regression to the mean over time, decreasing from
3.8 mg/l at randomization to 3.4 mg/l at 4 years.
However, as in the smaller studies, tracking corre-
lations for hsCRP over time were comparable with
that of blood pressure and LDL-C, but lower than
that of HDL-C.
AREAS OF CONTROVERSY II: THE MARKER VERSUS
MEDIATOR DEBATE AND MENDELIAN RANDOMIZATION
STUDIES. There has been a long-standing controversy
regarding whether CRP is itself a causal factor in
atherothrombosis (32–34). Although several early in-
vestigations suggested that CRP had direct vascular
effects, it has been uncertain in retrospect whether
some (if not all) of these effects were due to endo-
toxin contamination or were secondary to the infu-
sion of bacterial recombinant CRP. In a recent study
in which highly purified pharmaceutical-grade hu-
man CRP was infused into healthy volunteers, no
systematic changes in heart rate, temperature, or
blood pressure were observed, nor did infusion lead
to any change in circulating cytokine levels indicative
of an acute phase response (35). My group collabo-
rated in a comparable study in which pretreatment
with an antisense oligonucleotide inhibitor of CRP
synthesis was shown to reduce endotoxin-induced
increases in CRP in a dose-dependent manner, but
this led to no alterations of other components of the
acute phase response (36). Taken together, these data
support the concept that pentameric CRP is predom-
inantly a biomarker of disease, rather than a causal
factor. Studies of monomeric CRP, which typically
does not circulate in plasma and thus cannot be
measured easily, are ongoing.
The neutral findings from the pentameric CRP
infusion and inhibition trials are also consistent with
data from Mendelian randomization studies that
confirm CRP to be a predictor of cardiovascular
events, but unlikely to itself be in the critical causal
pathway of disease expression (37–39). Importantly,
a risk marker need not be causal to be clinically
useful; clinicians routinely measure HDL-C to predict
vascular risk, despite similar null Mendelian ran-
domization studies and disappointing data from
completed trials of HDL raising. However, the neutral
data for CRP as a causal agent do emphasize the
importance of targeting upstream mediators of
inflammation as potential treatments for cardiovas-
cular disease, rather than targeting CRP, the
JACC VOL. 67, NO. 6, 2016 Ridker 719
FEBRUARY 16, 2016:712–23 A Test in Context: hsCRP

downstream biomarker (40). In this regard, Mende-
lian randomization studies focusing on
morphisms in IL-6 receptor pathways have shown
concordant lifelong decreases in hsCRP levels and in
vascular risk (41,42). Although beyond the scope of
this review, an emerging consensus in the vascular
biology community is that CRP levels are a surrogate
biomarker for upstream IL-1 b activity (43). Thus, as
described elsewhere in this paper, ongoing trials of
inflammation inhibition are focusing upstream, at the
level of IL-1 and IL-6.
AREAS OF CONTROVERSY III: IS hsCRP EVALUATION
COST EFFECTIVE? Physicians should not measure
biomarkers simply to predict risk or because they are
independent risk factors; rather, the clinical goal
should be to improve patients’ lives
cost-effective manner. In primary prevention, all
patients are recommended for diet, exercise, and
smoking cessation. Thus, when considering use of
any biomarker in this setting, clinicians should insist
that a fundamental critical question be answered: is
there clear evidence that those identified by the
biomarker will benefit from a therapy they otherwise
would not have received?
No imaging biomarker can answer this critical
question affirmatively, nor is there data to support
this contention for alternative biomarkers, such as
homocysteine, lipoprotein(a), lipoprotein-associated
phospholipase A 2, myeloperoxidase, or plasma tri-
glycerides. As noted earlier, no trials to date have
demonstrated that raising HDL-C (a powerful predic-
tor of risk levels) improves clinical outcomes. How-
ever, the JUPITER trial indicates that patients who
would not normally qualify for statin therapy will
Other cost analyses suggest that risk-based statin
poly- treatment without hsCRP testing could be more
cost effective than hsCRP screening; however, this
assumes that statins provide benefit among low-risk
patients with normal hsCRP levels, where trial data
do not currently exist (45). High-sensitivity CRP
screening is a simple blood test done at the time of
cholesterol evaluation, and (unlike coronary artery
calcium scanning) does not involve radiation exposure
or increase downstream testing due to incidental
imaging findings.
AREAS OF CONTROVERSY IV: THE REYNOLDS
RISK SCORE VERSUS THE AMERICAN COLLEGE
OF CARDIOLOGY/AMERICAN HEART ASSOCIATION
POOLED RISK SCORE. The Reynolds Risk Scores (46)
were developed to estimate 10-year vascular risk in
in a
contemporary cohorts of apparently healthy men and
women, incorporating data on traditional risk factors,
hsCRP, family history of premature atherosclerosis,
and, among diabetics, glycosylated hemoglobin (47).
In all direct comparisons to date, the Reynolds Risk
Score has outperformed traditional risk algorithms
that rely on the usual Framingham risk factors
in terms of model discrimination, calibration, and
reclassification. In a comparison conducted within
the large-scale prospective Women’s Health Initiative
Observational Study (which, importantly, was not
used to develop either the Reynolds or the Framing-
ham Risk Score), predicted 10-year risks varied
F I G U R E 4 Overestimation and Underestimation of Risk in a Comparison of Global Risk
Scores Performed in a Contemporary, Prospective, Multiethnic Population
+ 115%
120
100
Over-Estimation

have fewer heart attacks and strokes if they take + 78%

80
statins when hsCRP is increased, even if untreated
60 + 45%
LDL-C levels are low. Within the JUPITER trial, where
40 + 25%
all participants had an hsCRP of >2 mg/l, statin
Discordance (%)

20
therapy reduced vascular event rates by 40%, even in - 3%
0
the subgroup with native LDL-C <60 mg/dl. Thus,
-20 FRS FRS ATPIII RRS AHA
Under-Estimation

there is a proven treatment strategy that patients CHD CVD FRS ACC
otherwise would be very unlikely to receive, were it -40 CHD ASCVD
not for direct hsCRP testing. -60

Despite these efficacy data, the cost effectiveness of -80

hsCRP screening has been a third area of ongoing -100

controversy. In part, this stems from the use in
JUPITER of a currently branded statin, rosuvastatin.
However, studies using lovastatin, pravastatin, and
atorvastatin also show decreases in hsCRP that relate
directly to potency and dose. Several studies report the
cost effectiveness of a clinical strategy of hsCRP
screening, followed by targeted statin therapy,
particularly as statin therapy costs have declined (44).
-120
Of scores tested, the Reynolds Risk Score (RRS) showed the greatest ability to discriminate
between cases and controls and was the best calibrated with regard to matching predicted
and observed event rates. Data from DeFilippis et al. (49). ACC ¼ American College of
Cardiology; AHA ¼ American Heart Association; ASCVD ¼ atherosclerotic cardiovascular
disease; ATPIII ¼ Adult Treatment Panel III; CHD ¼ coronary heart disease; CVD ¼ car-
diovascular disease; FRS ¼ Framingham Risk Score.
720 Ridker JACC VOL. 67, NO. 6, 2016

A Test in Context: hsCRP FEBRUARY 16, 2016:712–23

widely between models, with a $10% risk being pre- event rates between 7.5% and 10%. The Reynolds Risk
dicted in 6%, 10%, and 41% of women using the Score, with a net underestimation of risk of just 3%,
ATP-III (Adult Treatment Panel III), Reynolds, and was the best-calibrated (Figure 4) (49). In this recent
Framingham cardiovascular disease models, respec- MESA analysis, the Reynolds Risk Score also had the
tively (48). In this head-to-head comparison, the highest C statistic of the scores compared (0.72),
Reynolds Risk Score was better calibrated and indicating better discrimination. Recalibration of the
showed improved discrimination compared with the ACC/AHA risk score, alternative use of hsCRP and the
Framingham-based scores, particularly among those Reynolds Risk Score, or the use of direct trial data
with a 10-year risk between 5% and 10%, the clinical have all been suggested as methods to improve clin-
group where decisions regarding initiation of statin ical application of risk scoring to preventive cardiol-
therapy are most complex. ogy and the prophylactic prescription of statin
Overestimation of risk using the newest American therapy.
College of Cardiology/American Heart Association
(ACC/AHA) risk prediction algorithm has been a MOVING FORWARD: WILL REDUCING
controversial issue for the clinical community, but VASCULAR INFLAMMATION REDUCE
can be avoided through use of the Reynolds Risk CARDIOVASCULAR EVENT RATES?
Score. In a 2015 analysis, 4,227 men and women, 50 to
74 years of age, who were free of cardiovascular Initial interventions for patients with elevated hsCRP
disease and followed over 10 years in the National should be diet, exercise, and smoking cessation. As
Institutes of Health-sponsored MESA trial, the described, evidence-based prescription of statins and
ACC/AHA Pooled Cohort risk score was directly aspirin can also be considered in primary prevention
compared with 3 prior Framingham-based scores and for those with increased hsCRP. However, because
with the Reynolds Risk Score. The risk prediction aspirin has primary antiplatelet effects and statins
models using Framingham covariates overestimated have primary lipid-lowering effects, these data do
observed risks by 25% to 115%, with the new not directly address whether inflammation reduction
ACC/AHA risk score overestimating observed risk by per se will reduce cardiovascular event rates. At
78%; the actual observed event rates were only 3% for this time, 2 major hard outcome trials of targeted
men and 5.1% for women among those predicted by anti-inflammatory therapy in high-risk secondary
the ACC/AHA risk score to have 10-year vascular prevention are ongoing and other trials are in the
planning stages.
With funding from the National Heart, Lung, and
F I G U R E 5 Completed and Ongoing Trials of LDL Reduction and
Blood Institute, CIRT (Cardiovascular Inflammation
Inflammation Inhibition
Reduction Trial) investigators are currently enrolling
Agent Event Reduction? LDL-Lowering? CRP-Lowering? post-myocardial infarction patients or those with
multivessel coronary disease into a randomized,
Statins Yes Yes Yes
double-blind, placebo-controlled trial of low-dose
Ezetimibe + Statin Yes Yes Yes methotrexate (target dose 20 mg weekly) (50).
Low-dose methotrexate is the cornerstone anti-
Evolocumab ?? Yes No inflammatory intervention for rheumatoid arthritis,
has few drug interactions, and has an acceptable
Alirocumab ?? Yes No
safety profile in older patients at risk for re-
Bococizumab ?? Yes No current coronary events. In addition to being an
upstream broad spectrum anti-inflammatory, clinical
Canakinumab ?? No Yes and biological support for CIRT comes from multiple
sources, including the nonrandomized observation
Low Dose MTX ?? No Yes
that low-dose methotrexate associates with
reduced vascular risk among those with rheumatoid
Trials of statins or statins plus ezetimibe are proved to lower vascular event rates and these and psoriatic arthritis (51), and laboratory evi-
agents reduce both LDL-C and hsCRP (top). Outcome trials of PCSK9 inhibitors, which dence in cholesterol-fed rabbits that methotrexate
reduce LDL-C with no anti-inflammatory effects, are ongoing (middle), as are trials of
pretreatment decreases biomarkers of endothelial
the anti-inflammatory agents methotrexate and canakinumab, which reduce hsCRP, but
activation, and the number and severity of athero-
have no effect on LDL-C (bottom). CRP ¼ C-reactive protein; LDL ¼ low-density lipo-
protein; MTX ¼ methotrexate; PCSK9 ¼ proprotein convertase subtilisin/kexin type 9; sclerotic lesions in the aorta (52). The CIRT trial’s Data
other abbreviations as in Figure 2. and Safety Monitoring Board recently reviewed the
initial 2,000 patients enrolled in the “vanguard
JACC VOL. 67, NO. 6, 2016 Ridker 721
FEBRUARY 16, 2016:712–23 A Test in Context: hsCRP

phase” and no safety issues were raised. CIRT is now
seeking new cardiovascular sites to complete the
planned full enrollment of 7,000 participants. Sites
interested in participating can obtain investigator
information at the CIRT website (53).
Whereas CIRT is testing a broad spectrum
anti-inflammatory agent, the Novartis-sponsored
CANTOS (Canakinumab Anti-Inflammatory Throm-
bosis Outcomes Study) trial (54,55) has enrolled
10,065 post-myocardial infarction patients into a
randomized, double-blind, placebo-controlled trial of
canakinumab, a narrow-spectrum human monoclonal
antibody that inhibits IL-1b . IL-1 is a critical driver of
the central IL-6 pathway that is likely to be causal for
atherosclerosis. Furthermore, IL-1 expression
increased by hypoxia (56), to and fro vascular flow
(57), and by cholesterol crystals through activation of
the NLRP3 inflammasome (58). In a phase 2 study of
canakinumab conducted among high vascular risk
patients with diabetes, canakinumab decreased the
inflammatory biomarkers fibrinogen, IL-6, and hsCRP
by 15%, 45%, and 50%, respectively (59). No effect
was seen for LDL-C. Thus, canakinumab provides a
targeted method to test the inflammatory hypothesis
of atherothrombosis without confounding effects on
hyperlipidemia. Like CIRT, in addition to the primary
endpoint of hard vascular events, CANTOS is also
tracking incident type 2 diabetes. In contrast with
CIRT, which is limiting enrollment to those with
diabetes or metabolic syndrome and a history of
atherosclerosis, CANTOS enrolled a post-myocardial
infarction population with persistently elevated
hsCRP levels >2 mg/l, despite aggressive care,
including high-dose statin therapy. CANTOS thus
uses a targeted biomarker approach, in which a
narrow-spectrum anti-inflammatory therapy is being
given to a high-risk group selected on the basis of
a persistent proinflammatory response.
Alternative anti-inflammatory strategies are also
under investigation for chronic atherosclerosis or
acute coronary syndrome. These include agents such
as colchicine (commonly given for pericarditis),
for which the nonblinded LoDoCo trial provided pro-
vocative preliminary data) (60); salsalate
anti-inflammatory agent shown to have efficacy in
diabetes) (61); anakinra (an IL-1 receptor antagonist)
(62); and mitogen-activated protein kinase inhibitors
(under investigation in the ongoing TIMI-60 trial of
acute ischemia) (63). Careful assessment of risks for
infection are needed in anti-inflammatory trials, and it
is important to recognize that prior studies of nonste-
roidal anti-inflammatory agents and tumor necrosis
factor inhibitors have not shown vascular protection.
The cardiovascular community is fortunate to be
in the midst of large-scale trials independently
testing the LDL and inflammation hypotheses (64).
To date, completed trials of statin therapy and
of ezetimibe added to statin therapy have shown
vascular event reduction, and both interventions
is lower LDL-C and hsCRP (Figure 5). Ongoing trials of
proprotein convertase subtilisin/kexin type 9 inhi-
bition (which markedly lowers LDL without anti-
inflammatory effects) are promising and will teach
us if reducing LDL alone, through a novel mecha-
nism that prolongs LDL receptor half-life, reduces
heart attack and stroke rates. The CIRT and CANTOS
trials will teach us if targeted anti-inflammatory
treatments that reduce hsCRP and IL-6 (but have
no impact on LDL-C) might also reduce cardiovas-
cular event rates.
If both sets of trials are positive, the cardiology
community will have learned that both pure LDL
reduction and pure inflammation inhibition reduce
vascular event rates. If so, proprotein convertase
subtilisin/kexin type 9 inhibitors will likely be
considered as adjunctive therapy to statins when LDL
levels remain high, and inflammation inhibitors will
be considered as adjunctive therapy to statins when
hsCRP levels remain high. This approach would
represent the thoughtful use of monoclonal anti-
bodies that target the underlying pathophysiology for
individual patients, the essence of “personalized
medicine.” All of these trials are scheduled to report
out in the next 3 to 5 years.
REPRINT REQUESTS AND CORRESPONDENCE: Dr.
Paul M Ridker, Center for Cardiovascular Disease Preven-
tion, Brigham and Women’s Hospital, 900 Common-
(an wealth Avenue, Boston, Massachusetts 02215. E-mail:
pridker@partners.org.

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KEY WORDS biomarkers, metabolic
syndrome, prevention, risk prediction
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