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J. David Schnatz, M.D.
Director, Lipid Education Service
Saint Francis Hospital and Medical Center
114 Woodland Street, Hartford, CT 06105
Telephone: (860) 714-5555
November/December 2001
C-Reactive Protein (CRP) is an acute phase reactant in the bloodstream and
the level rises 100 fold or more in response to severe infection or inflammatory
condition. With the use of a new high sensitivity CRP assay (HSCRP), subtle,
but definite changes within the normal range can be detected. The following
comments will show that, in the absence of infections or recognized inflammatory
conditions, HSCRP can detect levels of CRP that are predictive of future coronary
events related to coronary artery disease (CAD), and offer the potential for
monitoring efforts at primary prevention.
In 1997, Ridker and colleagues reported on 543 healthy men participating in
the Physicians Health Study (PHS) in whom myocardial infarction (MI), stroke
or venous thrombosis developed, subsequently (1). These were paired with 543
men who remained healthy without an event (controls). Assays were done on plasma,
frozen and stored at -80�C. Those who subsequently developed an MI or stroke
had significantly higher baseline HSCRP, 1.51 vs 1.13 mg/L (p<0.001) for
MI and 1.38 vs 1.13 mg/L (p=0.02) for stroke. Those in the highest quartile
for HSCRP, compared with the lowest quartile, had three times the risk of MI
and twice the risk of ischemic stroke. No correlation was seen between HSCRP
and venous thrombosis. Aspirin lowered the risk of MI and stroke in the highest
quartile, and this appeared related to the baseline HSCRP level.
In 1998, Ridker and colleagues demonstrated that HSCRP adds to the value of
CHOL and HDL in predicting the risk of a first MI (2). Using frozen plasma from
617 in the PHS, they showed that, in an average follow-up of nine years, HSCRP,
CHOL and CHOL/HDL ratio were each associated with significant risk of future
MI, relative risks (RR); 1.38, 1.62 and 1.59, respectively (p<0.001 for each).
In multivariate analysis, they showed that the adjusted relative risk for an
elevated HSCRP and CHOL, combined, was 5.2 (p<0.0001) in contrast to 1.4
for elevated HSCRP and 2.1 for elevated CHOL alone.
Post-HOC analysis of the CARE Study (3, 4) suggested that Pravastatin can lower
HSCRP. The recently published Pravastatin inflammation/CRP evaluation (PRINCE)
Study was a prospective study designed to show if Pravastatin lowered HSCRP
in a community based prospective trial (5). Thus, 1702 persons (44% women) with
no prior cardiovascular disease were randomized, double blind, to 40mg of Pravastatin
(n=865) or placebo (n=837), and 1182 with known cardiovascular disease were
given 40mg of Pravastatin. In the primary prevention arm of the study, Pravastatin
decreased HSCRP 0.02 mg/dl or 16.9% (p<0.001) at 24 weeks, compared to no
change in placebo. Similar reductions were seen in the secondary prevention
arm. The authors concluded that "These data provide evidence that statins
may have anti-inflammatory effects in addition to lipid-lowering effects."
Since HSCRP represents a marker of inflammation that correlates with CAD events
and future MI, and since Pravastatin lowers HSCRP, it has been speculated that
statin treatment may have anti-inflammatory as well as a lipid lowering effect
in reducing the incidence of recurrent coronary events. In retrospective analysis
of the CARE Study, Ridker and colleagues have shown that, after an MI, the presence
of an elevated HSCRP is associated with an increased risk of non fatal MI or
fatal coronary event (highest quintile of HSCRP was 75% higher risk of recurrent
events than the lowest quintile, p=0.02), and that Pravastatin eliminated this
increased risk (3). They also showed that in the placebo group, HSCRP increased
over five years of follow-up in contrast to the Pravastatin group where HSCRP
decreased, -17.4% (p=0.004) (4). Thus, these changes in HSCRP, brought about
by Pravastatin, correlated with the decrease in second coronary events.
In June 2001, Ridker and colleagues reported the HSCRP analysis on blood from
5742 participants (87% of the total) in the AFCAPS/TexCAPS primary prevention
trial, taken at the time of randomization and at one year. Lipid analyses were
performed on the same blood specimens (6). Lovastatin produced a 0.02 mg/dl
(14.8%) reduction in HSCRP (p<0.001), similar to previously reported reductions,
in contrast to placebo where there was no change. This effect was not related
to the effect of Lovastatin on lipids. The study cohort was divided into four
groups, based on LDL values less than or greater than the median of 149.1 mg/dl
and HSCRP values less than or greater than the median of 0.16 mg/dl. Regardless
of the HSCRP values, Lovastatin was effective in lowering risk, if the LDL was
>149.1 mg/dl. If the LDL was <149 mg/dl, Lovastatin was still effective
in lowering risk, if the HSCRP was >0.16 mg/dl. No effect was seen when both
LDL and HSCRP were below the median. Similar results were seen when the CHOL/HDL
ratio was used in place of LDL. These results confirmed "that C-reactive
protein can be used to determine the risk of acute coronary events" and
"may have implications for the use of HMG-CoA reductase inhibitors in primary
prevention" (6). Randomized trials with statin therapy in persons with
elevated HSCRP and no overt hyperlipidemia would resolve this question.
Ridker has shown that, considering lipoprotein(a), homocysteine and HSCRP,
HSCRP is the only one where the test is easy and reliable clinically, and the
prospective data show a decrease in future CAD events when lowered. Further,
the risk of an elevated HSCRP is additive to CHOL (7).
We are close to being able to add this assay to our armamentarium in predicting
cardiovascular risk and in doing something about it. However, for the clinician
interested in its use, a word of caution. Be sure the assay is high sensitivity
and reliable, measuring the same thing with the same precision as Ridker's assay.
Nine-high sensitivity assays were compared recently (8). Among these, the Dade
Behring assay was the one which Ridker demonstrated to correlate well with his
early research assays (7). At the time of publication, "only the Dade Behring
and Kamiya methods had been approved by the Food and Drug Administration (FDA)
for clinical use in the U.S. and only the Dade Behring assay had been approved
by the FDA for use in assessing the risk of cardiovascular and peripheral vascular
disease" (8).
The hope for enhanced primary prevention, using the HSCRP assay, is real. However,
we need to obtain further information on the adaptability and availability of
the high-sensitivity assay to the clinical laboratory, and the reproducibility
of primary prevention in prospective studies using the HSCRP assay.
References:
- NEJ Med 336:973, 1997
- Circulation 97:2007, 1998
- Circulation 98:839, 1998
- Circulation 100: 230, 1999
- JAMA 286:64, 2001
- NEJ Med 344: 1959, 2001
- Circulation 103: 1813, 2001
- Clinical Chemistry 47:418, 2001
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