Nephrol Dial Transplant (2004) 19: 761-765
Nephrol Dial Transplant Vol. 19 No. 4 © ERA-EDTA 2004; all rights reserved
Editorial Comment
Is there a need for novel cardiovascular risk factors?
Arnold von Eckardstein
Institute of Clinical Chemistry, University Hospital Zurich, Zurich, Switzerland
Correspondence and offprint requests to: A. von Eckardstein, Institute of Clinical Chemistry, University Hospital Zurich, Rämistrasse 100, CH-8091 Zurich, Switzerland. Email: arnold.voneckardstein{at}ikc.usz.ch
Keywords: coronary heart disease; C-reactive protein; fibrinogen; homocysteine; lipoprotein(a); microalbuminuria; risk factor
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Introduction
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Atherosclerosis is a multifactorial disease whose age of onset
and progression are strongly influenced by inborn and acquired
risk factors. Since the pioneering work of the Framingham study,
many prospective population and clinical studies have identified
a series of independent risk factors for myocardial infarction,
stroke and peripheral vascular disease, among which the pre-existence
of atherosclerotic vascular disease, age, male gender, a positive
family history of premature atherosclerotic disease, smoking,
diabetes mellitus, hypertension, hypercholesterolaemia, hypertriglyceridaemia
and low HDL cholesterol are considered as classical risk factors.
Moreover, several large randomized and prospective intervention
studies have demonstrated that smoking cessation as well as
anti-hypertensive and lipid-lowering drug therapies help to
reduce cardiovascular morbidity and mortality by
30% in both
secondary and primary prevention. Despite these advances, we
currently witness a controversy concerning the introduction
of novel risk factors into clinical practice, specifically lipoprotein(a)
[Lp(a)], C-reactive protein (CRP), fibrinogen, homocysteine
and microalbuminuria.
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Advances and limitations of classical risk factors and global risk estimation
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Two recent reports on the data analysis of more than 500 000
participants in 14 intervention trials and three observational
studies showed that 80–90% of patients who developed clinically
significant coronary heart disease had at least one of four
classical risk factors, namely hypercholesterolaemia (serum
cholesterol >240 mg/dl/6.22 mmol/l), hypertension (systolic
blood pressure >140 mm Hg and/or diastolic blood pressure
>90 mm Hg), diabetes mellitus or smoking [
1,
2]. However,
counting of risk factors has a low sensitivity and specificity
because it does not take into account the graded and dose-dependent
influence of risk factors and the overproportional effect of
risk factor interaction. In a given individual, the presence
of a single risk factor has a low positive predictive value.
In contrast, the presence of several moderately expressed risk
factors can produce a significant increase in cardiovascular
risk. Therefore, at present the most advanced strategy for coronary
risk assessment is to combine the information of several risk
factors in algorithms or scores. This procedure allows calculation
of an individual's absolute risk of experiencing a cardiovascular
event within the next 10 years. The best accepted and evaluated
algorithms are those derived from the US-American Framingham
study and the German PROCAM study [
3,
4]. Current international
guidelines base their recommendations for the indication of
hypolipidaemic or anti-hypertensive drug treatment in clinically
asymptomatic patients (‘primary prevention’) on
the estimation of global risk. An estimated global risk of >20%
per 10 years in an asymptomatic patient is considered to be
high. The affected patient is given advice to be treated as
aggressively as a symptomatic patient with vascular disease.
This implies lowering of LDL cholesterol below 100 mg/dl (2.6
mmol/l) and systolic blood pressure below 130 mm Hg. An estimated
risk ranging between 10 and 20% in 10 years is considered as
moderate, and treatment targets for LDL cholesterol and systolic
blood pressure are <130 mg/dl (<3.4 mmol/l) and 140 mm
Hg, respectively. An estimated risk <10% is considered as
low. In this case, drug treatment recommendations are not offered
to the majority of individuals [International Task Force for
Prevention of Coronary Heart Disease. Pocket Guide to Prevention
of Coronary heart disease.
http://www.chd-taskforce.de/guide.htm;
5,6].
Using the PROCAM algorithm, 7.5% of German men aged 35 to 65 years have a risk estimate of >20%, 15% a risk estimate of 10–20% and 72.5% a risk estimate of <10%. Each group accounts for about one-third of all coronary events that will occur during 10 years of follow up. Using the PROCAM algorithm, the finding of an estimated global risk above 20% in a 35- to 65-year-old asymptomatic German man has a positive predictive value of 32%. The finding of an estimated global risk of <10% has a negative predictive value of 97%. The intermediate risk of 10–20% has positive and negative predictive values of 14 and 86%, respectively (http://www.chd-taskforce.de/guide.htm). The Framingham algorithm has an even lower positive predictive value and, hence, overestimates cardiovascular risk in asymptomatic German middle-aged men [7].
The predictive values summarized above give rise to a conceptual misunderstanding by many scientists, physicians and patients, who believe that the assessment of classical risk factors leads to an underestimation of coronary risk in many individuals. The opposite is the case. The detection of the relatively small percentage of individuals, who will develop atherosclerotic vascular disease despite estimated low global risk, would require cost-intensive screening of large populations with a low case-finding probability. The more relevant problem is the high false-positive rate in individuals with a high or intermediate estimated global risk.
The use of neural network statistics rather than conventional Cox-proportional hazard statistics can improve the diagnostic efficacy of global risk estimation. However, this strategy does not provide freely accessible algorithms and scores, but requires the communication with a central data manager for the calculation of an individual's risk [8]. Moreover, even this approach does not eliminate the problem of false-positive risk assignment, so that there is still considerable need for improving global risk assessment.
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Requirements for novel risk factors
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The interest in improving cardiovascular risk assessment, resulting
from a better understanding of the pathogenesis of atherosclerosis
and identification of new targets for anti-atherosclerotic drug
therapy has always stimulated the search for novel risk factors.
Thousands of cross-sectional case-control studies have identified
hundreds of clinical, biochemical or genetic markers that showed
statistically significant associations with coronary heart disease,
stroke or peripheral vascular disease. Most of these associations
were either not reproducible in other studies or not independent
of classical risk factors. However, some of these emerging risk
factors turned out to be robust and independent. Currently there
is an intense discussion whether they should be introduced into
routine risk assessment. This especially concerns Lp(a), CRP,
fibrinogen, homocysteine and microalbuminuria.
Before these and other emerging risk factors are widely introduced into clinical routine, they must fulfil pre-defined criteria [5,9,10]. (i) The methods for their measurement must be precise, accurate, and internationally standardized so that the results are reliable and independent from the manufacturer and the laboratory. (ii) The analyte should be biologically stable so that single measurements within an individual are representative and no special pre-analytical requirements are to be fulfilled. (iii) Consensus must have been obtained on diagnostic cut-offs so that clinical decisions can be drawn in daily practice. (iv) The novel risk factor must interact with the classical risk factors so that they improve the diagnostic efficacy of global risk estimation, preferably as discussed before, in the high- and intermediate-risk groups. In addition or alternatively, they should be of special importance in subgroups of patients, e.g. in women or patients with diabetes mellitus or kidney disease, or in association with specific vascular diseases, e.g. stroke or peripheral vascular disease. (v) The assessment of the risk factor should have therapeutic implications that in the ideal case are specific. (vi) The marker should exhibit a good cost-benefit relationship by fulfilling the criteria listed before and by being measured by easy-to-use and inexpensive tests.
How do these criteria apply to the emerging risk factors most intensively discussed?
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Lipoprotein(a) [11]
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An international Lp(a) standard has become available only recently.
However, the use of this standard by different tests still give
discrepant results so that Lp(a) data of different laboratories
give discrepant results [
12]. By convention the majority of
laboratories agree on a cut-off of 30 mg/dl, above which cardiovascular
risk is considered as increased. Because of its strong genetic
determination, Lp(a) levels show little intraindividual variation.
However, renal insufficiency and proteinuria cause increases
in Lp(a) levels. Consequently, it is not the Lp(a) level but
the size polymorphism of its protein constituent, apolipoprotein(a),
which shows a significant association with coronary events in
patients with renal disease [
13]. In the asymptomatic male population,
Lp(a) interacts with traditional risk factors so that elevated
Lp(a) further increases the coronary risk of men with intermediate
and high global risk but not in men at low risk [
14]. Because
of the high risk of venous thromboembolism in patients with
renal insufficiency or nephrotic syndrome, it is also interesting
to note that Lp(a) further increases the risk of stroke and
venous thromboembolism in children and adolescents with genetic
thrombophilic risk factors [
15,
16]. Lp(a) levels are little
influenced by currently available drugs except sex steroids.
In
post hoc analyses of some intervention trials, individuals
with high Lp(a) levels were found to derive an excessive benefit
from statin or postmenopausal hormone replacement therapy. However,
this finding has not been reproduced in the analyses of other
large intervention trials [
17,
18].
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C-reactive protein [19]
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CRP levels can be measured with precise, accurate, standardized
and relatively inexpensive tests. A CRP level above 1 mg/l is
considered to indicate a moderate increase in risk and a CRP
level above 3 mg/l is considered as an indicator of high risk
[
20]. However, CRP levels are strongly influenced by acute and
chronic inflammation so that levels >10 mg/l must not be
used for cardiovascular risk assessment [
21]. In this case,
repeated blood samples for analysis must be taken after recovery
from the acute disease. As yet, only one published study performed
in women has assessed the interaction of CRP with global risk
estimates. In this study, elevated CRP levels further increased
the cardiovascular risk of women being at low risk as well as
at combined intermediate and high risk (i.e. >10% in 10 years
as estimated with the Framingham risk score) [
22]. In the data
from the Augsburg cohort of the MONICA study, (W. V. König,
unpublished data presented at the European Society of Cardiology
Congress in Vienna, 2003) found that CRP improves the diagnostic
efficacy in men with intermediate global risk but not in men
with high global risk. Post hoc analyses of intervention trials
indicate that men with elevated CRP have an overproportional
benefit from aspirin and statin therapy [
23,
24]. CRP-directed
statin intervention studies have been initiated.
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Fibrinogen [24]
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Fibrinogen measurements have not been internationally standardized.
The analyte requires citrate plasma as a special specimen. Like
CRP, fibrinogen is an acute phase reactant, which is not clinically
useful for cardiovascular risk assessment in patients with acute
disease. There is no international consensus on a diagnostic
cut-off although in the majority of studies 3.5 g/l has been
used. Fibrinogen was found to further increase the risk of men
with a high estimated cardiovascular risk as estimated with
the Framingham score [
25]. Likewise in the PROCAM study, fibrinogen
was found to further increase the risk of men with low and combined
intermediate and high risk (G. Assmann, H. Schulte, A. von Eckardstein,
unpublished data). Information on therapeutic interventions
based on elevated fibrinogen is not available.
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Homocysteine [26]
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Homocysteine can be measured by precise, accurate and standardized
assays. In healthy individuals, the analyte shows little intraindividual
variation. However, it is strongly influenced by renal function
and several drugs [
26]. Although the analyte does not require
special specimens, care has to be taken that serum or plasma
is quickly separated from cells, since erythrocytes produce
homocysteine so that prolonged full blood storage causes an
increase in homocysteine levels [
27]. Alternatively, fluoride
can be added for the inhibition of erythrocyte metabolism. So
far there is no consensus on cut-offs for homocysteine levels
so that they vary from 10 to 16 µmol/l. Despite its moderate
association with coronary risk, homocysteine was found to further
increase the risk of high-risk individuals such as those with
pre-existing coronary heart disease or those with a high estimated
Framingham score risk [
25]. Homocysteine is the only one of
the novel risk factors discussed here which is connected with
a specific therapeutic intervention, namely the application
of folate either alone or in combination with vitamins B6 and
B12 [
26]. In one study, treatment of patients undergoing coronary
angioplasty with this vitamin combination reduced restenosis
rates after 6 and 12 months of follow up. In contrast, the number
of fatal and non-fatal myocardial infarctions was not reduced
[
28,
29]. Surprisingly, however, the rates of restenosis as well
as clinical events were increased upon folate/vitamins B6 and
B12 treatment in another study of similar design [
9]. We therefore
urgently need the outcomes of several ongoing large intervention
trials assessing the clinical effects of homocysteine-lowering
vitamins to judge the clinical relevance of this marker.
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Microalbuminuria
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Microalbuminuria is a well-accepted marker for micro and macrovascular
damage in patients with diabetes mellitus or hypertension [
30,
31].
Therefore, and because of the proven benefit of treatment with
angiotensin-converting enzyme inhibitors or angiotensin II receptor
antagonists in patients with microalbuminuria, consensus guidelines
recommend the measurement of albuminuria in hypertensive or
diabetic patients [
30,
31]. More and more evidence is accumulating
that microalbuminuria is an important cardiovascular risk factor
even in the general population [
32]. It interacts with classical
risk factors. It has not yet been shown, however, whether and
how it further increases the risk within estimated global risk
categories [
33]. Another major drawback for the wider use of
microalbuminuria is the lack of agreement on the optimal specimen
and the large intraindividual variation because of the great
impact of fever, physical stress and menstrual bleeding on renal
albumin excretion. The gold standard specimen, the 24 h urine,
is neither practical nor well-accepted by patients. Albumin
concentrations in spot urine show a good correlation with 24
h albumin excretion if taken at a defined time point (second
morning urine). However, disagreement exists on whether the
albumin over creatinine ratio or absolute albumin concentration
should be determined. The former takes into consideration muscle
mass and needs the definition of age and sex specific cut-offs;
the latter is confounded by intraindividual variation in diuresis
[
34,
35].
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Conclusion
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The classical risk factors have a high negative predictive value
especially if combined in scores and algorithms the use of which
is currently advocated in international consensus guidelines
for primary prevention of cardiovascular disease. Because costs
are high relative to the small chance of finding cases, novel
risk factors should not be included in unselected population-wide
screening programs. However, the global risk estimates have
insufficient positive predictive value so that there is a clear
need for improving risk estimation in individuals at high and
intermediate risk. This appears to be 20–25% of the population.
These individuals are the proper target for any novel risk factor
(and non-invasive imaging method for the early detection of
clinically relevant atherosclerosis). As yet, all emerging risk
factors have to be investigated along these lines, before they
are introduced into clinical practice. Among the novel risk
factors currently under discussion, CRP has apparently been
evaluated best.
Several authors advocate the use of novel risk factors in patients with existing coronary heart disease who lack any classical risk factors [9]. However, in this secondary prevention setting, a novel risk factor is of limited usefulness if it does not lead to specific treatment. For example, so far it is not justified to make decisions concerning the use of statins or aspirin in patients with manifest atherosclerosis dependent on CRP or Lp(a) levels. In this setting, parameters connected with specific treatment decisions have a great potential. However, randomized intervention studies are needed to prove the relevance of these risk factors and the benefit of the intervention based on their results.
Conflict of interest statement. None declared.
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Introduction
Advances and limitations of...