onary heart disease (CHD) risk, together with recent genetic findings, indicates that elevated Lp(a), like elevated LDL-
cholesterol, is causally related to premature CVD/CHD. The association is continuous without a threshold or depen-
dence on LDL- or non-HDL-cholesterol levels. Mechanistically, elevated Lp(a) levels may either induce a prothrom-
botic/anti-fibrinolytic effect as apolipoprotein(a) resembles both plasminogen and plasmin but has no fibrinolytic
activity, or may accelerate atherosclerosis because, like LDL, the Lp(a) particle is cholesterol-rich, or both. We
advise that Lp(a) be measured once, using an isoform-insensitive assay, in subjects at intermediate or high CVD/
CHD risk with premature CVD, familial hypercholesterolaemia, a family history of premature CVD and/or elevated
Lp(a), recurrent CVD despite statin treatment, ≥3% 10-year risk of fatal CVD according to European guidelines, and/
or ≥10% 10-year risk of fatal + non-fatal CHD according to US guidelines. As a secondary priority after LDL-choles-
terol reduction, we recommend a desirable level for Lp(a) ,80th percentile (less than ?50 mg/dL). Treatment
should primarily be niacin 1–3 g/day, as a meta-analysis of randomized, controlled intervention trials demonstrates
reduced CVD by niacin treatment. In extreme cases, LDL-apheresis is efficacious in removing Lp(a).
We recommend screening for elevated Lp(a) in those at intermediate or high CVD/CHD risk, a desirable level
,50 mg/dL as a function of global cardiovascular risk, and use of niacin for Lp(a) and CVD/CHD risk reduction.
- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -
Lipids † Hyperlipidemia † Prevention † Myocardial infarction † Stroke
Lipoprotein(a) as a cardiovascular risk factor:
Børge G. Nordestgaard1*, M. John Chapman2, Kausik Ray3, Jan Bore ´n4,
Felicita Andreotti5, Gerald F. Watts6, Henry Ginsberg7, Pierre Amarenco8,
Alberico Catapano9, Olivier S. Descamps10, Edward Fisher11, Petri T. Kovanen12,
Jan Albert Kuivenhoven13, Philippe Lesnik2, Luis Masana14, Zeljko Reiner15,
Marja-Riitta Taskinen16, Lale Tokgo ¨zoglu17, and Anne Tybjærg-Hansen18, for the
European Atherosclerosis Society Consensus Panel†
1Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, University of Copenhagen, DK-2730 Herlev, Denmark;2European Atherosclerosis Society,
INSERM UMR-S939, Pitie ´-Salpetriere University Hospital, Paris 75651, France;3St George’s University of London, London, UK;4University of Gothenburg, Sweden;5Catholic
University Medical School, Rome, Italy;6University of Western Australia, Perth, Australia;7Columbia University, New York, USA;8Bichat University Hospital, Paris, France;
9University of Milan, Italy;10Hopital de Jolimont, Haine Saint-Paul, Belgium;11New York University, New York, USA;12Wihuri Research Institute, Helsinki, Finland;13University of
Amsterdam, The Netherlands;14Universitat Rovira & Virgili, Reus, Spain;15University Hospital Center Zagreb, Croatia;16Biomedicum, Helsinki, Finland;17Hacettepe University,
Ankara, Turkey; and18Rigshospitalet, University of Copenhagen, Denmark
Received 11 June 2010; revised 17 August 2010; accepted 24 September 2010; online publish-ahead-of-print 21 October 2010
The aims of the study were, first, to critically evaluate lipoprotein(a) [Lp(a)] as a cardiovascular risk factor and,
second, to advise on screening for elevated plasma Lp(a), on desirable levels, and on therapeutic strategies.
The robust and specific association between elevated Lp(a) levels and increased cardiovascular disease (CVD)/cor-
* Correspondence author. Tel: +45 44883297, Fax: +45 44883311, Email: email@example.com (B.G.N.); Tel: +33 1 42177878, Email: firstname.lastname@example.org (M.J.C.)
†Writing Committee Members, Co-Chairs, and Consensus Panel members are listed in the Author contribution section.
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2010. For permissions please email: email@example.com
The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article
for non-commercial purposes provided that the original authorship is properly and fully attributed; the Journal, Learned Society and Oxford University Press are attributed as the
original place of publication with correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this
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The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.
European Heart Journal (2010) 31, 2844–2853
Lipoprotein(a) [Lp(a)] has been considered a cardiovascular risk
factor for many years.1Owing to incomplete scientific evidence,
screening for and treatment of high Lp(a) levels have to date
been performed principally by lipid specialists. However, during
the last few years, major advances have been achieved in under-
standing the causal role of elevated Lp(a) in premature cardiovas-
cular disease (CVD).2–4These new findings have prompted the
present critical appraisal of the evidence base in the form of a Con-
cholesterol-rich LDL particle with one molecule of apolipoprotein
B100 and an additional protein, apolipoprotein(a), attached via a
disulfide bond (Figure 1).1Elevated Lp(a) levels can potentially
increase the risk of CVD (i) via prothrombotic/anti-fibrinolytic
effects as apolipoprotein(a) possesses structural homology with
plasminogen and plasmin but has no fibrinolytic activity and (ii)
via accelerated atherogenesis as a result of intimal deposition of
Lp(a) cholesterol, or both.
Typical distributions of Lp(a) in Caucasians are shown in Figure 2:
plasma levels of Lp(a) are similar in men and women and are
Figure 1 Lipoprotein(a) consists of an LDL-like particle to which apolipoprotein(a) is covalently linked. The LDL-like moiety is composed of a
central core of cholesteryl esters (CE) and triglycerides (TG) surrounded by phospholipids (PL), free cholesterol (FC), and a single molecule of
apolipoprotein B (apoB). Apolipoprotein(a) contains 10 different types of plasminogen kringle 4-like repeats as well as regions homologous to
the kringle 5 and protease (P) regions of plasminogen. The kringle 4 type 2 domain (42) is present in multiply repeated copies from 2 to .40
that differ in number between apolipoprotein(a) isoforms.1Apolipoprotein(a) is linked to apolipoprotein B100 by a single disulfide bond invol-
ving an unpaired cysteine residue in kringle 4 type 9. Modified from Koschinsky and Marcovina.18
Figure 2 Typical distributions of lipoprotein(a) levels in the general population. These graphs are based on non-fasting fresh serum samples
from ?3000 men and 3000 women from the Copenhagen General Population Study collected from 2003 through 2004.2Green colour indi-
cates levels below the 80th percentile, whereas red colour indicates levels above the 80th percentile.
Lipoprotein(a) as a cardiovascular risk factor
skewed in the population with a tail towards the highest levels.
Levels are lowest in non-Hispanic Caucasians (e.g. median:
12 mg/dL; inter-quartile range: 5–32),5Chinese (11, 4–22), and
Japanese (13, 5–26), slightly higher in Hispanics (19, 8–43), and
even higher levels in Blacks (39, 19–69).1,5It is significant that
Lp(a) has been surrounded by controversy among clinicians for
more than 20 years, and the various conceptions and misconcep-
tions are summarized and explained in Supplementary material
online, Table S1.
The aim of the present Consensus Paper is to critically evaluate
the evidence base supporting the contention that Lp(a) constitutes
a significant cardiovascular risk factor. On the basis of the evidence,
the Consensus Panel provides recommendations on whom to
screen, desirable levels, and finally, how to treat elevated Lp(a)
levels. This is the first Consensus Statement on diagnosis, desirable
levels, and treatment of elevated Lp(a).
Findings from earlier prospective studies suggest that the relation
between Lp(a) concentration and the risk of CVD may involve a
threshold and that the association may be more marked among
individuals with elevated LDL cholesterol.6–8Individual studies,
however, are rarely sufficiently powered to assess the shape of
the relation or to make precise estimates of relative risk within
subgroups of the study populations such as among individuals
with high rather than low LDL cholesterol levels.
An early meta-analysis of 18 prospective studies of general
populations that was published before 2000, which reported on
a pooled analysis of 4000 coronary heart disease (CHD) cases,
suggested that the combined relative risk of CHD for individuals
in the top vs. bottom thirds of baseline Lp(a) concentrations was
1.7 (95% CI: 1.4–1.9).9An updated meta-analysis of 31 prospective
studies, involving a total of 9870 CHD cases, suggested that the
corresponding combined risk was more modest (relative risk:
1.5; 1.3–1.8).10Subgroups defined by other characteristics pre-
specified for investigation, notably study size, sample storage
characteristics, and Lp(a) assay isoform sensitivity, were not signifi-
Although the evidence from literature-based meta-analyses of
prospective studies suggests the potential importance of Lp(a) in
CHD, it does not provide sufficient detail to allow the assessment
of the relevance of this lipoprotein to CVD prevention and treat-
ment. For example, it is not possible to determine, from a
literature-based meta-analysis, whether Lp(a) is associated with
CHD throughout the concentration range (similar to blood
pressure and LDL cholesterol) or whether Lp(a) is particularly
atherothrombogenic in specific subgroups of individuals (such as
in those with high LDL cholesterol level). Re-analysis of individual
participant data from a comprehensive set of prospective epide-
miological studies (i.e. individual participant data meta-analysis)
can help overcome several of the limitations of individual studies
or literature-based meta-analyses of individual studies. However,
because some of the earlier studies had problems with the
correct measurement of Lp(a) in, for example, frozen samples,
the risk estimates reported below should be considered minimal
The largest epidemiological study to date on Lp(a) assessed indi-
vidual records of 126 634 participants in 36 prospective studies.3
Lipoprotein(a) concentration was weakly correlated with several
known risk factors: positively with total and non-HDL cholesterol,
apolipoprotein B100, and inversely with logetriglycerides. Lipopro-
tein(a) levels were 12% (95% CI: 8–16%) higher in women and
11% (4–17%) lower in people with diabetes. The regression
dilution ratio of logeLp(a), adjusted for age and sex, was 0.87
which was considerably higher than that for total cholesterol
(0.65), thereby suggesting that Lp(a) levels are remarkably stable
Associations of Lp(a) with CHD risk were broadly continuous in
shape and curvilinear, with no evidence of a threshold (Figure 3).3
Assuming a log-linear association, the relative risk for CHD per
3.5-fold (1 SD) higher Lp(a) level, adjusted for age and sex only,
was 1.16 and 1.13 (95% CI: 1.09–1.18) following further adjust-
ment for systolic blood pressure, smoking, history of diabetes,
and total cholesterol, suggesting that any association is only mini-
mally confounded by conventional risk factors (Figure 4). Impor-
tantly, Lp(a) levels may vary up to a 1000-fold between
individuals (Figure 2).1The relative risk for CHD did not vary sig-
nificantly by sex, non-HDL- or HDL cholesterol, triglycerides,
blood pressure, diabetes, or body mass index; in accordance, a
recent prospective study found that the Lp(a)/CHD risk associ-
ation did not depend on levels of other CVD risk factors, including
LDL cholesterol levels.11There was no convincing evidence of
major variations in relative risk in studies using isoform-sensitive
vs. -insensitive assays.3
In analyses adjusted for age and sex only, the association of elev-
ated Lp(a) levels with increased risk of ischaemic stroke was less
pronounced than that for CHD (Figure 3).3However, the relatively
weak association with ischaemic stroke may be due to heterogen-
eity of stroke aetiologies, that is, the association in atherothrombo-
tic stroke could be diluted by weaker or no association with other
stroke subtypes. Assuming a log-linear association with risk, the
age-and-sex-only-adjusted relative risk for ischaemic stroke was
1.11 per 3.5-fold higher than usual Lp(a) levels and was 1.10
(95% CI: 1.02–1.18) following further adjustment for traditional
risk factors (Figure 4). The adjusted relative risks per 3.5-fold
higher than usual Lp(a) levels was 1.06 (0.90–1.26) for haemorrha-
gic stroke, 1.01 (0.98–1.05) for nonvascular mortality, 1.00 (0.97–
1.04) for all cancer deaths, 1.03 (0.97–1.09) for smoking-related
cancer deaths, and 1.00 (0.95–1.06) for non-vascular deaths
other than cancer.
In summary, elevated Lp(a) levels associate robustly and specifi-
cally with increased CVD risk. The association is continuous in
shape without a threshold and does not depend on high levels
of LDL or non-HDL cholesterol, or on the levels or presence of
other cardiovascular risk factors.
tein(a) gene ideal for use in a Mendelian randomization study,12
examining whether lifelong, genetically elevated levels of plasma
Lp(a) cause CVD. By analogy, familial hypercholesterolaemia with
B.G. Nordestgaard et al.
mutations in the LDL receptor or apolipoprotein B genes have life-
long, genetically elevated LDL cholesterol levels and premature
CVD,13,14a fact that has helped establish that elevated LDL choles-
terol levels constitute a direct cause of atherosclerosis and CVD.
A Mendelian randomization study needs three pieces of data to
help provide evidence for a causal link between elevated plasma
Lp(a) levels and CVD.12First, elevated plasma Lp(a) levels should
be associated with increased CVD risk, as demonstrated in the
previous section on Lp(a) epidemiology. Secondly, genetic vari-
ation should exist in human populations that can explain a large
fraction of the variation in plasma Lp(a) levels: such genetic vari-
ation has been known for many years, most importantly the
kringle IV type 2 size polymorphism (Figure 1, 42), resulting in a
variable number from 2 to .40 number of a 5.6 kb repeat
Figure 3 Risk ratios of coronary heart disease, ischaemic stroke and non-vascular death by quantiles of usual lipoprotein(a) levels. CI, con-
fidence interval. Sizes of data markers are proportional to the inverse of the variance of the risk ratios. (A) Adjustment for age and sex only. (B)
Further adjustment for systolic blood pressure, smoking status, history of diabetes, body mass index, and total cholesterol. MI, myocardial infarc-
tion. Modified from The Emerging Risk Factors Collaboration.3
Lipoprotein(a) as a cardiovascular risk factor
associated inversely with plasma Lp(a) levels. Thus, the fewer the
repeats in the apolipoprotein(a) gene, the higher the plasma
levels of Lp(a), which has also been demonstrated in the past.1
Thirdly, such genetic variation should be linked directly with
CVD risk: previous smaller case–control studies (n , 2400)
have demonstrated an association of kringle IV type 2 genotype
[or the associated apolipoprotein(a) isoform size] with risk of
CVD, as reviewed previously.1,2
On the basis of the Copenhagen City Heart Study (CCHS), the
Copenhagen General PopulationStudy(CGPS), andthe
Copenhagen Ischemic Heart Disease Study (CIHDS) with 40 000
individuals genotyped for the kringle IV type 2 size polymorphism
in the apolipoprotein(a) gene, a large Mendelian randomization
study was published in 2009.2In the CCHS, multifactorially
adjusted hazard ratios for myocardial infarction for elevated lipo-
protein(a) levels were 1.2 (95% CI: 0.9–1.6) for the 22nd–66th
percentile, 1.6 (1.1–2.2) for the 67th–89th percentile, 1.9 (1.2–
3.0) for the 90th–95th percentile, and 2.6 (1.6–4.1) for levels
.95th percentile, respectively, vs. levels ,22nd percentile
(trend P , 0.001; Figure 5).2,11
Figure 4 Risk ratios for various vascular and non-vascular endpoints per 3.5-fold (i.e. 1 SD) higher than usual lipoprotein(a) levels adjusted for
cardiovascular risk factors. MI, myocardial infarction.aSubtotals do not add to the total number of coronary heart disease outcomes because
some studies did not subdivide outcomes into coronary death and non-fatal MI. RR, relative risk; CI, confidence interval. Modified from The
Emerging Risk Factors Collaboration.3
Figure 5 Risk of myocardial infarction by levels of lipoprotein(a) in the general population. Hazard ratios (HRs) are adjusted for cardiovas-
cular risk factors (multivariable) or for these factors as well as kringle IV type 2 (KIV-2) genotype. P-values are test for trend of hazard ratios
where lipoprotein(a) groups with increasing levels were coded 1, 2, 3, 4, and 5. Values are from the 1991–94 examination of the Copenhagen
City Heart Study with up to 16 years of follow-up (n ¼ 7524). CI, confidence interval. Modified from Kamstrup et al.2
B.G. Nordestgaard et al.
The number of kringle IV type 2 repeats (sum of repeats on both
alleles) ranged from 6 to 99 and explained 21 and 27% of all vari-
ation in plasma lipoprotein(a) levels in the CCHS and the CGPS,
respectively.2Mean lipoprotein(a) levels were 56, 31, 20, and
15 mg/dL for the first, second, third, and fourth quartiles of
kringle IV type 2 repeats in the CCHS, respectively (trend P ,
0.001; Figure 6); corresponding values in the CGPS were 60, 34,
22, and 19 mg/dL (trend P , 0.001).
In the CCHS, multifactorially adjusted hazard ratios for myocar-
dial infarction were 1.5 (1.2–1.9), 1.3 (1.0–1.6), and 1.1 (0.9–1.4)
for individuals in the first, second, and third vs. fourth quartile of
kringle IVtype2 repeats,
Figure 7).2Corresponding odds ratios were 1.3 (1.1–1.5), 1.1
(0.9–1.3), and 0.9 (0.8–1.1) in the CGPS (trend P ¼ 0.005), and
1.4 (1.1–1.7), 1.2 (1.0–1.6), and 1.3 (1.0–1.6) in the CIHDS
(trend P ¼ 0.01). The significant similar trend tests in three separ-
ate studies all point to increased CVD risk when the number of
kringles is low and thus plasma levels of Lp(a) elevated.2
Later in 2009, a further key paper on this topic including 8000
CHD cases and 8000 controls was published.4On the basis of
genotyping for 49 000 single-nucleotide polymorphisms (SNPs)
in 2100 candidate genes for CVD, 2 SNPs in linkage disequilibrium
with the kringle IV type 2 size polymorphism in the apolipopro-
tein(a) gene showed the highest of any association with CHD.
These two SNPs combined were found in one in six people and
together explained 36% of the variation in plasma Lp(a) levels.
The odds ratios for CHD were 1.51 (95% CI: 1.38–1.66) for
one variant and 2.57 (1.80–3.67) for two or more variants. Con-
sistent with these observations, a 2007 study tested 12 000 puta-
tive functional SNPs in many different genes and found that only
one, in the apolipoprotein(a) gene, was consistently associated
with severe coronary atherosclerosis.15Elevated Lp(a) is also an
independent CVD risk factor
Taken together, the robust and specific epidemiological associ-
ation between elevated plasma Lp(a) levels and increased risk of
respectively(trendP , 0.001;
inpatients with familial
CVD,3together with the two recent Mendelian randomization
studies,2,4support the contention that elevated Lp(a) levels, like
elevated LDL, is causally related to premature development of
atherosclerosis and CVD (Table 1).
It is believed that plasma concentrations of Lp(a) are determined
chiefly by rates of hepatic synthesis of apolipoprotein(a): although
the site of formation of Lp(a) has not been definitively identified,
evidence suggests that apolipoprotein(a) adducts extracellularly
and covalently to apolipoprotein B100-containing lipoproteins,
Apolipoprotein(a) genotype, which
determines both the synthetic rate and size of the apolipopro-
tein(a) moiety of Lp(a), alone accounts for 90% of plasma concen-
trations of Lp(a).17,19,20As hepatic secretion rates are lower
for large apolipoprotein(a) isoforms, and as most individuals are
heterozygous for two different isoforms, the smallest isoform
typically predominates in plasma. Lipoprotein(a) is thought to
be catabolized primarily by hepatic and renal pathways, but
these metabolic routes do not appear to govern plasma Lp(a)
underlying the atherothrombotic
potential of lipoprotein(a)
After transfer from plasma into the arterial intima, Lp(a) may be
more avidly retained than LDL as it binds to the extracellular
matrix not only through apolipoprotein(a), but also via its apolipo-
protein B component,21thereby contributing cholesterol to the
expanding atherosclerotic plaque. In vitro, Lp(a) binds to several
extracellular matrix proteins including fibrin22and defensins, a
family of 29–35 amino acid peptides that are released by neutro-
phils during inflammation and severe infection.23It is likely that
Figure 6 Mean lipoprotein(a) levels in the Copenhagen City Heart Study as a function of quartiles of apolipoprotein(a) KIV-2 repeats. P-value
is for the Cuzick non-parametric test for trend of mean lipoprotein(a) levels. Participants in the 1991–94 or 2001–03 examination were
included (n ¼ 9867). KIV-2, kringle IV type 2. Error bars indicate 95% confidence intervals. Modified from Kamstrup et al.2
Lipoprotein(a) as a cardiovascular risk factor
defensins, like lipoprotein lipase, provide a bridge between Lp(a)
and the extracellular matrix.
Transgenic mice expressing a mutant form of apolipoprotein(a)
with greatly reduced ability to bind to fibrin exhibited 20% less
atherosclerotic lesion area and less accumulation in the arterial
wall compared with transgenic mice expressing wild-type Lp(a).24
In addition, Lp(a) seems to be retained at sites of mechanical
injury;21fibrin deposition occurs preferentially at such sites.
Through its apolipoprotein(a) moiety, Lp(a) also interacts with
the b2-integrin Mac-1, thereby promoting the adhesion of mono-
cytes and their transendothelial migration.25In atherosclerotic cor-
onary arteries, Lp(a) was found to localize in close proximity to
Mac-1 on infiltrating mononuclear cells.
inflammatory-oxidized phospholipids26and is a preferential carrier
of oxidized phospholipids in human plasma. Lipoprotein(a) also con-
tains lipoprotein-associated phospholipase A2 (equally referred to as
Paf-acetylhydrolase), which may cleave oxidized fatty acids at the
shownto bind pro-
sn-2 position in oxidized phospholipids to yield short chain fatty
acids and lysolecithin.27
Apolipoprotein(a), a homologue of the fibrinolytic proenzyme
plasminogen, impairs fibrinolysis.28Indeed, Lp(a)/apolipoprotein(a)
can competitively inhibit tissue-type plasminogen activator-mediated
plasminogen activation on fibrin surfaces, although the mechanism of
inhibition by apolipoprotein(a) remains controversial. Essential to
fibrinclotlysisare anumberofplasmin-dependent,positive feedback
reactions that enhance the efficiency of plasminogen activation,
including the plasmin-mediated conversion of Glu-plasminogen to
Lys-plasminogen. It has been observed that the apolipoprotein(a)
component of Lp(a) inhibits the key positive feedback step involving
plasminogen.29Lipoprotein(a) may also enhance coagulation by inhi-
biting the function of tissue factor pathway inhibitor.30
Finally, small isoforms of apolipoprotein(a) have been observed
to possess elevated potency in inhibiting fibrinolysis and thereby
a recent meta-analysis
Figure 7 Risk of myocardial infarction by quartiles of apolipoprotein(a) KIV-2 repeats in the Copenhagen City Heart Study (CCHS), the
Copenhagen General Population Study (CGPS), and the Copenhagen Ischemic Heart Disease Study (CIHDS). P-values are test for trend of
risk estimates [hazard ratios (HRs) or odds ratios (ORs)] where kringle IV type 2 (KIV-2) groups with decreasing numbers of KIV-2 repeats
were coded 1, 2, 3, and 4. CI, confidence interval (shown as error bars). Modified from Kamstrup et al.2
B.G. Nordestgaard et al.
demonstrated a two-fold increase in the risk of CHD and ischae-
mic stroke in subjects with small apolipoprotein(a) phenotypes.32
Furthermore, prospective findings in the Bruneck study have
revealed a significant association specifically between small apoli-
poprotein(a) phenotypes and advanced atherosclerotic disease
involving a component of plaque thrombosis.33These data
suggest that the determination of apolipoprotein(a) phenotype/
genotype may provide clinicians with additional information by
which to evaluate Lp(a)/apolipoprotein(a)-associated athero-
Insummary,elevated Lp(a)levelsmaypromote atherosclerosisvia
Lp(a)-derived cholesterol entrapment in the intima, via inflammatory
phospholipids. The prothrombotic, anti-fibrinolytic actions of apoli-
poprotein(a) are expressed on the one hand as inhibition of fibrino-
lysis with enhancement of clot stabilization and on the other as
enhanced coagulation via the inhibition of tissue factor pathway
Several types of Lp(a) assays are currently available, some com-
mercially; prominent among them are sandwich enzyme-linked
immunosorbent assays (ELISAs), non-competitive ELISAs, latex
immunoassays, immunonephelometric assays, and immunoturbido-
metric and fluorescence assays.19In order for clinical laboratories
to provide clinicians with Lp(a) values which allow correct cardio-
vascular risk evaluation when Lp(a) is included in the estimate, the
following elements in standardization between Lp(a) assays are
(i) Inclusion of antibodies in assay kits whose immunoreactivity
with Lp(a) is apolipoprotein(a) isoform-insensitive and fully
characterized, and for which there is minor variation
between batches over time. In this regard, immunosorbent
assays are of considerable interest, as they allow the use of
polyclonal antibodies [anti-apolipoprotein(a) capture; anti-
apolipoprotein B100] and are isoform-insensitive.19,28
(ii) Availability of a robust secondary reference Lp(a) preparation
at an international level, which has received approval by
organizations such as the International Federation of Clinical
Chemistry and the World Health Organisation.
(iii) The widespread use of methodologies which are robust,
highly reproducible with inter- and intra-coefficient of vari-
ations ,10%, economically priced, and accurate.
(iv) A common resolve, based on the uniformity and widespread
availability of an approved and standardized Lp(a) assay, to
express Lp(a) concentrations as total Lp(a) protein; point
(ii) above is critical to this goal,
(v) Standardization of procedures for blood collection, plasma, or
serum isolation with a preferential use of fresh samples.34
(vi) Ranges and percentiles for Lp(a) protein levels established for
individual ethnicities given present knowledge of race-
dependent variation in Lp(a),1,5ultimately leading to race-
specific estimates of risk thresholds.
These factors will contribute significantly not only to the reliable
diagnosis and classification of subjects presenting with high
cholesterol and lipoprotein(a) levels in the fasting or
Desirable levels for low-density lipoprotein
Highest level of
trials of statin
trials of niacin
aAccording to the 2007 European guidelines.35
bThe 80th percentile roughly corresponds to 50 mg/dL in Caucasians (Figure 2).
cThe evidence is for the effect of niacin treatment, not specifically for Lp(a)
Human epidemiology Direct association in numerous studies
Mechanistic studiesMechanism clearly demonstrated: LDL accumulate in intima and
Animal modelsProatherogenic effect in numerous studies
elevated lipoprotein(a) each cause cardiovascular disease
Comparison of evidence supporting the contention that elevated low-density lipoprotein cholesterol and
Elevated LDL cholesterol Elevated Lp(a)
Direct association in numerous studies
Direct association in numerous studies, e.g. for kringle IV type 2
Mechanism similar to that for LDL cholesterol and/or
Proatherogenic effect in numerous studies
Niacin trials are favourable
Direct association in numerous studies, e.g. familial
Statin trials gave final proof of causality
Lipoprotein(a) as a cardiovascular risk factor
atherothrombotic risk due to elevation of Lp(a), but also to the
success of multicentre clinical trials designed to evaluate pharma-
cotherapeutic agents targeted to concomitantly reduce elevated
Lp(a) levels and CVD risk.
Whom to screen
We suggest that Lp(a) should be measured once in all subjects at
intermediate or high risk of CVD/CHD who present with:
(i) premature CVD,
(ii) familial hypercholesterolaemia,
(iii) a family history of premature CVD and/or elevated Lp(a),
(iv) recurrent CVD despite statin treatment,
(v) ≥3% 10-year risk of fatal CVD according to the European
(vi) ≥10% 10-year risk of fatal and/or non-fatal CHD according to
the US guidelines36
Repeat measurement is only necessary if treatment for high Lp(a)
levels is initiated in order to evaluate therapeutic response.
Scientific and clinical evidence favouring an interpretation of caus-
ality between elevated levels of a lipoprotein and increased CVD
risk constitutes a pre-requisite for selection of desirable levels.
For an interpretation of causality, five types of evidence should
each favour causality and all three types of human evidence (epide-
miology, genetics, and intervention trials) must concur (Table 1).37
For elevated LDL cholesterol levels, all five criteria are well docu-
mented and the consensus is causality. On the basis of the same
criteria, elevated Lp(a) levels probably are also causally related
to increased CVD risk (Table 1).
Recommendations proposing desirable levels should preferably
be based on evidence from a meta-analysis of randomized, con-
trolled intervention trials documenting benefit of treatment
(level Ia evidence). Desirable levels for LDL cholesterol levels
are based on such evidence from statin trials (Table 2).35,36For
Lp(a), the evidence is less clear; however, a meta-analysis of
randomized, controlled intervention trials documenting benefit
of niacin (¼nicotinic acid) treatment has recently been published38
For reduction of plasma Lp(a) as a secondary priority after
reduction in LDL and total cholesterol levels,35,36we recommend
a desirable level below the 80th percentile (less than ?50 mg/dL;
Table 2). As for LDL reduction,35,36treatment of high Lp(a) levels
in persons without CVD/CHD or diabetes is recommended for
those with intermediate or high absolute risk of CVD/CHD (see
Graham et al.35and Grundy et al.36and Figure 3 in Kamstrup
If statin treatment in a person with Lp(a) .50 mg/dl, but
without CVD or diabetes, reduces absolute risk for fatal CVD to
,3% or for fatal and/or non-fatal CHD to ,10%, there might
be no need for further treatment with niacin; however, in those
with premature CVD, familial hypercholesterolaemia, a family
history of premature CVD and elevated Lp(a), or recurrent CVD
despite statin treatment, niacin may still be justified despite
aggressive LDL cholesterol reduction with a statin.
Studies using niacin alone or in combination with, for example,
statins have shown cardiovascular benefit;38–43niacin reduces
Lp(a) levels by up to 30–40% in a dose-dependent manner and
in addition exerts other potential beneficial effects by reducing
LDL cholesterol, total cholesterol, triglycerides, and remnant
cholesterol and by raising HDL cholesterol.44In a meta-analysis
including 11 randomized controlled trials with 2682 patients in
the active group and 3934 in the control group, niacin 1–3 g/day
reduced major coronary events by 25% (95% CI: 13–35%),
stroke by 26% (8–41%), and any cardiovascular event by 27%
However, there have been no randomized, controlled interven-
tion trials with selective reduction in plasma lipoprotein(a) levels
aimed to reduce CVD: we urgently need trials demonstrating
that selective reduction of Lp(a) in those with Lp(a) above the
80th percentile will benefit clinically with reduced CVD. Until
such trials are published, reduction in Lp(a) should mainly be
achieved using niacin, as the use of niacin for CVD risk reduction
as described above is evidence-based. However, in addition to
lowering Lp(a), niacin lowers LDL cholesterol, total cholesterol,
triglycerides, and remnant cholesterol and concomitantly increases
HDL cholesterol levels. Therefore, the favourable effects of
niacin on CVD cannot be ascribed solely to Lp(a) reduction.
Nevertheless, these studies clearly demonstrate that the use of
niacin for reduction in Lp(a) to the suggested desirable levels
(Table 2) is safe and in all likelihood beneficial.
Compared with LDL, Lp(a) is relatively refractory to both life-
style and drug intervention.20,45The data on the effects of statins
and fibrates on Lp(a) are limited and highly variable.45,46Overall,
statins have, however, been shown to consistently and modestly
decrease elevated Lp(a) in patients with heterozygous familial
hypercholesterolaemia. Other agents reported to decrease Lp(a)
to a minor degree (,10%) include aspirin, L-carnitine, ascorbic
acid combined with
converting enzyme inhibitors, androgens, oestrogen, and its
replacements (e.g. tibolone), anti-estrogens (e.g. tamoxifen), and
thyroxine replacement in hypothyroid subjects.20,45,47
Larger studies of longer duration of Lp(a) lowering against back-
ground statin therapy in high-risk individuals including diabetics are
needed. In the FATS angiographic trial,48aggressive lowering of
LDL and apolipoprotein B abrogated the risk due to Lp(a) in patients
with established coronary disease. The ongoing AIM-HIGH (http
further evaluate this notion, although the niacin employed in these
trials is not selective for Lp(a) lowering as noted above.
It is clear that more detailed studies of the metabolism of Lp(a)
are required to aid in the design and development of selective and
potent therapies for lowering Lp(a). Given the critical role of Lp(a)
synthesis in determining the plasma concentration of Lp(a), target-
ing either the synthesis of apolipoprotein(a) and/or the formation
of Lp(a) would appear worthwhile.18,20Antisense oligonucleotide
L-lysine, calcium antagonists, angiotensin-
B.G. Nordestgaard et al.
and thyroid hormone analogue therapies directed at apolipopro-
tein(a) synthesis may hold particular promise for the future.49,50
Finally, in young or middle-aged patients with evidence of pro-
gressive coronary disease and markedly elevated plasma Lp(a),
serious consideration should be given to instituting LDL apheresis
which removes Lp(a) efficaciously;51however, this form of treat-
ment is prohibitively expensive and impractical for most patients
and most clinical centres.
Future needs in basic and clinical
research on lipoprotein(a) and
The Consensus Panel is convinced that further international effort
is required in different ethnicities to assess the atherothrombotic
risk due to the Lp(a) particle on the one hand and to apolipopro-
tein(a) on the other. The potential contribution of Lp(a)-associated
phospholipase A2, and equally of Lp(a)-associated oxidized phos-
pholipids, to the pathophysiological mechanisms underlying such
elevated risk remains indeterminate. Both cutting-edge basic
research, rigorously designed prospective studies and intervention
trials of selective Lp(a) lowering agents are required to attain these
goals. Furthermore, it is entirely appropriate that Lp(a), as a causal,
independent risk factor, should be integrated into existing treat-
ment algorithms. Finally, randomized, controlled intervention
trials with selective reduction in plasma lipoprotein(a) levels to
reduce CVD in both primary and secondary prevention settings
are urgently needed in order to define more precisely who to
treat and to what targets.
European Atherosclerosis Society (EAS) Consensus Panel:
Writing committee. B.G.N., M.J.C., K.R., J.B., F.A., G.F.W., H.G.
Co-chairs. M.J.C. and H.G. Members. P.A. (Bichat University
Hospital, Paris, France), F.A. (Catholic University Medical School,
Rome, Italy), J.B. (University of Gothenburg, Sweden), A.C.
(University of Milan, Italy), M.J.C. (INSERM, Paris, France), O.S.D.
(Hopital de Jolimont, Belgium), E.F. (New York University,
New York, USA), H.G. (Columbia University, New York, USA),
P.T.K.(Wihuri Research Institute,
(University of Amsterdam, The Netherlands), P.L. (INSERM,
Paris, France), L.M. (Universitat Rovira and Virgili, Reus, Spain),
B.G.N. (University of Copenhagen, Denmark), K.R. (St George’s
University of London, London, UK), Z.R. (University Hospital
Center Zagreb, Croatia), M.-R.T. (Biomedicum, Helsinki, Finland),
L.T. (Hacettepe University, Ankara, Turkey), A.T.-H. (University
of Copenhagen, Denmark), G.F.W. (University of Western
Australia, Perth, Australia).
The EAS Consensus Panel met twice in Paris organized and
chaired by M.J.C. and H.G. The first meeting critically reviewed
the literature, whereas the second meeting scrutinized the first
draft of the consensus paper. B.G.N., K.R., J.B., F.A., G.F.W., H.G.,
and M.J.C. each drafted sections and/or outline for the first
version, whereas the complete draft was written up by B.G.N.
and M.J.C. All committee members agreed to conception and
Helsinki, Finland), J.A.K.
design, contributed to interpretation of available data, all suggested
revisions for this document, and all members approved the final
document before submission.
Supplementary material is available at European Heart Journal
We thank Jane Stock for assistance with co-ordination of the
This work including Consensus Panel meetings were supported by
unrestricted educational grants to EAS from Merck, Kowa, Roche,
and AstraZeneca. These companies were not present at the
Consensus Panel meetings, had no role in the design or content of
the Consensus Statement, and had no right to approve or disapprove
of the final document. Funding to pay the Open Access publication
charges for this article was provided by funding from the European
Conflict of interest
Several of the Consensus Panel members have received lecture
honoraria, consultancy fees, and/or research funding from Pfizer
(B.G.N., M.J.C., K.R., H.G., J.B., F.A., G.W., L.T., Z.R., O.S.D.,
P.T.K.), Astra Zeneca (B.G.N., M.J.C., K.R., H.G., J.B., F.A., G.W.,
L.T., Z.R., O.S.D., E.F., L.M., P.T.K.), Merck (M.J.C., K.R., H.G., J.B.,
F.A., G.W., L.T., Z.R., O.S.D., E.F., M.-R.T., L.M., P.T.K.), Abbott
(B.G.N., K.R., H.G., G.W., L.T.), Boehringer Ingelheim (B.G.N.,
F.A., M.-R.T.), sanofi-aventis (B.G.N., K.R., J.B., G.W., L.T., O.S.D.,
M.-R.T.), Karo Bio (B.G.N.), Bayer (F.A.), Daiichi-Sankyo (F.A.,
K.R., L.T.), Bristol–Meyers Squibb (F.A., K.R., L.T.), Lilly (F.A.,
K.R., M.-R.T.), Solvay (K.R., L.T., Z.R., O.D.S.), Novartis (K.R., L.T.,
M.-R.T., L.M., M.J.C.), Menarini (K.R., L.T.), Takeda (E.F.), and
Kowa (L.M., M.J.C.).
1. Utermann G. Lipoprotein(a). In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The
Metabolic and Molecular Bases of Inherited Disease. 8th ed. New York: McGraw-Hill;
2. Kamstrup PR, Tybjaerg-Hansen A, Steffensen R, Nordestgaard BG. Genetically
elevated lipoprotein(a) and increased risk of myocardial infarction. JAMA 2009;
3. Erqou S, Kaptoge S, Perry PL, Di AE, Thompson A, White IR, Marcovina SM,
Collins R, Thompson SG, Danesh J. Lipoprotein(a) concentration and the risk
of coronary heart disease, stroke, and nonvascular mortality. JAMA 2009;302:
4. Clarke R, Peden JF, Hopewell JC, Kyriakou T, Goel A, Heath SC, Parish S,
Barlera S, Franzosi MG, Rust S, Bennett D, Silveira A, Malarstig A, Green FR,
Lathrop M, Gigante B, Leander K, de FU, Seedorf U, Hamsten A, Collins R,
Watkins H, Farrall M. Genetic variants associated with Lp(a) lipoprotein level
and coronary disease. N Engl J Med 2009;361:2518–2528.
5. Matthews KA, Sowers MF, Derby CA, Stein E, Miracle-McMahill H, Crawford SL,
Pasternak RC. Ethnic differences in cardiovascular risk factor burden among
middle-aged women: Study of Women’s Health Across the Nation (SWAN).
Am Heart J 2005;149:1066–1073.
6. Cantin B, Gagnon F, Moorjani S, Despres JP, Lamarche B, Lupien PJ, Dagenais GR.
Is lipoprotein(a) an independent risk factor for ischemic heart disease in men? The
Quebec Cardiovascular Study. J Am Coll Cardiol 1998;31:519–525.
Lipoprotein(a) as a cardiovascular risk factor
7. Luc G, Bard JM, Arveiler D, Ferrieres J, Evans A, Amouyel P, Fruchart JC,
Ducimetiere P. Lipoprotein (a) as a predictor of coronary heart disease: the
PRIME Study. Atherosclerosis 2002;163:377–384.
8. Suk DJ, Rifai N, Buring JE, Ridker PM. Lipoprotein(a), measured with an assay
independent of apolipoprotein(a) isoform size, and risk of future cardiovascular
events among initially healthy women. JAMA 2006;296:1363–1370.
9. Danesh J, Collins R, Peto R. Lipoprotein(a) and coronary heart disease.
Meta-analysis of prospective studies. Circulation 2000;102:1082–1085.
10. Bennet A, Di AE, Erqou S, Eiriksdottir G, Sigurdsson G, Woodward M, Rumley A,
Lowe GD, Danesh J, Gudnason V. Lipoprotein(a) levels and risk of future
coronary heart disease: large-scale prospective data. Arch Intern Med 2008;168:
11. Kamstrup PR, Benn M, Tybjaerg-Hansen A, Nordestgaard BG. Extreme lipopro-
tein(a) levels and risk of myocardial infarction in the general population: the
Copenhagen City Heart Study. Circulation 2008;117:176–184.
12. Smith GD, Ebrahim S. Mendelian randomization: prospects, potentials, and
limitations. Int J Epidemiol 2004;33:30–42.
13. Goldstein JL, Hobbs HH, Brown MS. Familial hypercholesterolemia. In:
Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular
Bases of Inherited Disease. 8th ed. New York: McGraw-Hill; 2001. p2863–2913.
14. Tybjaerg-Hansen A, Steffensen R, Meinertz H, Schnohr P, Nordestgaard BG.
Association of mutations in the apolipoprotein B gene with hypercholesterolemia
and the risk of ischemic heart disease. N Engl J Med 1998;338:1577–1584.
15. Luke MM, Kane JP, Liu DM, Rowland CM, Shiffman D, Cassano J, Catanese JJ,
Pullinger CR, Leong DU, Arellano AR, Tong CH, Movsesyan I, Naya-Vigne J,
Noordhof C, Feric NT, Malloy MJ, Topol EJ, Koschinsky ML, Devlin JJ, Ellis SG.
A polymorphism in the protease-like domain of apolipoprotein(a) is associated
with severe coronary artery disease. Arterioscler Thromb Vasc Biol 2007;27:
16. Holmes DT, Schick BA, Humphries KH, Frohlich J. Lipoprotein(a) is an
independent risk factor for cardiovascular disease in heterozygous familial
hypercholesterolemia. Clin Chem 2005;51:2067–2073.
17. Rader DJ, Cain W, Ikewaki K, Talley G, Zech LA, Usher D, Brewer HB Jr. The
inverse association of plasma lipoprotein(a) concentrations with apolipopro-
tein(a) isoform size is not due to differences in Lp(a) catabolism but to differences
in production rate. J Clin Invest 1994;93:2758–2763.
18. Koschinsky ML, Marcovina SM. Structure-function relationships in apolipopro-
tein(a): insights into lipoprotein(a) assembly and pathogenicity. Curr Opin Lipidol
19. Marcovina SM, Koschinsky ML, Albers JJ, Skarlatos S. Report of the National
Heart,Lung, andBlood Institute
Cardiovascular Disease: recent advances and future directions. Clin Chem 2003;
20. Koschinsky M, Marcovina SM. Lipoprotein(a). In: Ballantyne C, ed. Clinical Lipidol-
ogy: A Companion to Braunwauld’s Heart Disease. Philadelphia: Saunders Elsevier;
21. Nielsen LB. Atherogenecity of lipoprotein(a) and oxidized low density lipopro-
tein: insight from in vivo studies of arterial wall influx, degradation and efflux.
22. Lundstam U, Hurt-Camejo E, Olsson G, Sartipy P, Camejo G, Wiklund O.
Proteoglycans contribution to association of Lp(a) and LDL with smooth
muscle cell extracellular matrix. Arterioscler Thromb Vasc Biol 1999;19:
23. Bdeir K, Cane W, Canziani G, Chaiken I, Weisel J, Koschinsky ML, Lawn RM,
Bannerman PG, SachaisBS, Kuo
Raghunath PN, Ganz T, Higazi AA, Cines DB. Defensin promotes the binding
of lipoprotein(a) to vascular matrix. Blood 1999;94:2007–2019.
24. Boonmark NW, Lou XJ, Yang ZJ, Schwartz K, Zhang JL, Rubin EM, Lawn RM.
Modification of apolipoprotein(a) lysine binding site reduces atherosclerosis in
transgenic mice. J Clin Invest 1997;100:558–564.
25. Sotiriou SN, Orlova VV, Al-Fakhri N, Ihanus E, Economopoulou M, Isermann B,
Bdeir K, Nawroth PP, Preissner KT, Gahmberg CG, Koschinsky ML, Chavakis T.
Lipoprotein(a) in atherosclerotic plaques recruits inflammatory cells through
interaction with Mac-1 integrin. FASEB J 2006;20:559–561.
26. Tsimikas S, Brilakis ES, Miller ER, McConnell JP, Lennon RJ, Kornman KS,
Witztum JL, Berger PB. Oxidized phospholipids, Lp(a) lipoprotein, and coronary
artery disease. N Engl J Med 2005;353:46–57.
27. Tsimikas S, Tsironis LD, Tselepis AD. New insights into the role of
lipoprotein(a)-associated lipoprotein-associated phospholipase A2 in athero-
sclerosis and cardiovascular disease. Arterioscler Thromb Vasc Biol 2007;27:
28. Rouy D, Grailhe P, Nigon F, Chapman J, Angles-Cano E. Lipoprotein(a) impairs
generation of plasmin by fibrin-bound tissue-type plasminogen activator. In
vitro studies in a plasma milieu. Arterioscler Thromb 1991;11:629–638.
29. Feric NT, Boffa MB, Johnston SM, Koschinsky ML. Apolipoprotein(a) inhibits the
conversion of Glu-plasminogen to Lys-plasminogen: a novel mechanism for
lipoprotein(a)-mediated inhibition of plasminogen activation. J Thromb Haemost
30. Pan S, Kleppe LS, Witt TA, Mueske CS, Simari RD. The effect of vascular smooth
muscle cell-targeted expression of tissue factor pathway inhibitor in a murine
model of arterial thrombosis. Thromb Haemost 2004;92:495–502.
31. Hervio L, Chapman MJ, Thillet J, Loyau S, Angles-Cano E. Does apolipoprotein(a)
heterogeneity influence lipoprotein(a) effects on fibrinolysis? Blood 1993;82:
32. Erqou S, Thompson A, Di AE, Saleheen D, Kaptoge S, Marcovina S, Danesh J.
Apolipoprotein(a) isoforms and the risk of vascular disease: systematic review
of 40 studies involving 58,000 participants. J Am Coll Cardiol 2010;55:2160–2167.
33. KronenbergF,Kronenberg MF,
Oberhollenzer F, Egger G, Utermann G, Willeit J. Role of lipoprotein(a) and
apolipoprotein(a) phenotype in atherogenesis: prospective results from the
Bruneck study. Circulation 1999;100:1154–1160.
34. von Eckardstein A, Schulte H, Cullen P, Assmann G. Lipoprotein(a) further
increases the risk of coronary events in men with high global cardiovascular
risk. J Am Coll Cardiol 2001;37:434–439.
35. Graham I, Atar D, Borch-Johnsen K, Boysen G, Burell G, Cifkova R,
Dallongeville J, De BG, Ebrahim S, Gjelsvik B, Herrmann-Lingen C, Hoes A,
Humphries S, Knapton M, Perk J, Priori SG, Pyorala K, Reiner Z, Ruilope L,
Sans-Menendez S, Scholte op RW, Weissberg P, Wood D, Yarnell J,
Zamorano JL, Walma E, Fitzgerald T, Cooney MT, Dudina A, Vahanian A,
Camm J, De CR, Dean V, Dickstein K, Funck-Brentano C, Filippatos G,
Hellemans I, Kristensen SD, McGregor K, Sechtem U, Silber S, Tendera M,
Widimsky P, Zamorano JL, Hellemans I, Altiner A, Bonora E, Durrington PN,
Fagard R, Giampaoli S, Hemingway H, Hakansson J, Kjeldsen SE, Larsen ML,
Mancia G, Manolis AJ, Orth-Gomer K, Pedersen T, Rayner M, Ryden L,
Sammut M, Schneiderman N, Stalenhoef AF, Tokgozoglu L, Wiklund O,
Zampelas A. European guidelines on cardiovascular disease prevention in clinical
practice: executive summary. Eur Heart J 2007;28:2375–2414.
36. Grundy SM, Cleeman JI, Merz CN, Brewer HB Jr, Clark LT, Hunninghake DB,
Pasternak RC, Smith SC Jr, Stone NJ. Implications of recent clinical trials for
the National Cholesterol Education Program Adult Treatment Panel III guidelines.
Arterioscler Thromb Vasc Biol 2004;24:e149–e161.
37. Nordestgaard BG. Does elevated C-reactive protein cause human atherothrom-
bosis? Novel insights from genetics, intervention trials, and elsewhere. Curr Opin
38. Bruckert E, Labreuche J, Amarenco P. Meta-analysis of the effect of nicotinic acid
alone or in combination on cardiovascular events and atherosclerosis. Athero-
39. Carlson LA, Rosenhamer G. Reduction in mortality in the Stockholm Ischemic
Heart Disease Secondary Prevention Study by combined treatment with clofi-
brate and nicotinic acid. Acta Med Scand 1988;233:405–418.
40. Canner PL, Berge KG, Wenger NK, Stamler J, Friedman L, Prineas RJ,
Friedewald W. Fifteen year mortality in Coronary Drug Project patients: long-
term benefit with niacin. J Am Coll Cardiol 1986;8:1245–1255.
Blankenhorn DH. Beneficial effects of colestipol-niacin on coronary atherosclero-
sis. A 4-year follow-up. JAMA 1990;264:3013–3017.
42. Brown G, Albers JJ, Fisher LD, Schaefer SM, Lin JT, Kaplan C, Zhao XQ,
Bisson BD, Fitzpatrick VF, Dodge HT. Regression of coronary artery disease as
a result of intensive lipid-lowering therapy in men with high levels of apolipopro-
tein B. N Engl J Med 1990;323:1289–1298.
43. Taylor AJ, Villines TC, Stanek EJ, Devine PJ, Griffen L, Miller M, Weissman NJ,
Turco M. Extended-release niacin or ezetimibe and carotid intima-media thick-
ness. N Engl J Med 2009;361:2113–2122.
44. Chapman MJ, Redfern JS, McGovern ME, Giral P. Niacin and fibrates in athero-
genic dyslipidemia: pharmacotherapy to reduce cardiovascular risk. Pharmacol
45. Tziomalos K, Athyros VG, Wierzbicki AS, Mikhailidis DP. Lipoprotein a: where
are we now? Curr Opin Cardiol 2009;24:351–357.
46. Gonbert S, Malinsky S, Sposito AC, Laouenan H, Doucet C, Chapman MJ, Thillet J.
Atorvastatin lowers lipoprotein(a) but not apolipoprotein(a) fragment levels in
hypercholesterolemic subjects at high cardiovascular risk. Atherosclerosis 2002;
47. Suk DJ, Rifai N, Buring JE, Ridker PM. Lipoprotein(a), hormone replacement
therapy, and risk of future cardiovascular events. J Am Coll Cardiol 2008;52:
48. Maher VM, Brown BG, Marcovina SM, Hillger LA, Zhao XQ, Albers JJ. Effects of
lowering elevated LDL cholesterol on the cardiovascular risk of lipoprotein(a).
Kiechl S, TrenkwalderE,SanterP,
B.G. Nordestgaard et al.
49. Merki E, Graham MJ, Mullick AE, Miller ER, Crooke RM, Pitas RE, Witztum JL, Download full-text
Tsimikas S. Antisense oligonucleotide directed to human apolipoprotein B-100
reduces lipoprotein(a) levels and oxidized phospholipids on human apolipopro-
tein B-100 particles in lipoprotein(a) transgenic mice. Circulation 2008;118:
50. Ladenson PW, Kristensen JD, Ridgway EC, Olsson AG, Carlsson B, Klein I,
Baxter JD, Angelin B. Use of the thyroid hormone analogue eprotirome in statin-
treated dyslipidemia. N Engl J Med 2010;362:906–916.
51. Thompson GR. Recommendations for the use of LDL apheresis. Atherosclerosis
Lipoprotein(a) as a cardiovascular risk factor