Dyslp
Dyslp
Dyslp
ESC/EAS
GUIDELINES
doi:10.1093/eurheartj/ehw272
* Corresponding authors: Alberico L. Catapano, Department of Pharmacological and Biomolecular Sciences, University of Milan, Via Balzaretti
9, 20133 Milan, and Multimedica IRCCS (MI) Italy. Tel: +39 02 5031 8401, Fax: +39 02 5031 8386, E-mail: alberico.catapano@unimi.it; Ian
Graham, Cardiology Department, Hermitage Medical Clinic, Old Lucan Road, Dublin 20, Dublin, Ireland. Tel: +353 1 6459715, Fax: +353 1
6459714, E-mail: ian@grahams.net
ESC Committee for Practice Guidelines (CPG) and National Cardiac Society Reviewers can be found in the Appendix.
ESC entities having participated in the development of this document:
Associations: Acute Cardiovascular Care Association (ACCA), European Association for Cardiovascular Prevention & Rehabilitation (EACPR),
European Association of Cardiovas- cular Imaging (EACVI), European Association of Percutaneous Cardiovascular Interventions (EAPCI), Heart
Failure Association (HFA)
Councils: Council on Cardiovascular Nursing and Allied Professions, Council for Cardiology Practice, Council on Cardiovascular Primary Care,
Council on Hypertension
Working Groups: Atherosclerosis & Vascular Biology, Cardiovascular Pharmacotherapy, Coronary Pathophysiology & Microcirculation, Ecardiology, Myocardial and Pericardial Diseases, Peripheral Circulation, Thrombosis.
The content of these European Society of Cardiology (ESC) and European Atherosclerosis Society Guidelines has been published for personal
and educational use only. No commercial use is authorized. No part of the ESC Guidelines may be translated or reproduced in any form without
D
o
w
nl
oa
de
d
fr
o
m
htt
p:/
/e
ur
he
art
j.o
xf
or
dj
ou
rn
als
.or
g/
by
gu
est
on
O
written permission from the ESC. Permission can be obtained upon submission of a written request to Oxford University Press, the publisher
of the European Heart Journal and the party authorized to handle such permissions on behalf of the ESC (journals.permissions@oup.com).
Disclaimer. The ESC Guidelines represent the views of the ESC and were produced after careful consideration of the scientific and medical
knowledge and the evidence available at the time of their publication. The ESC is not responsible in the event of any contradiction,
discrepancy and/or ambiguity between the ESC Guidelines and any other official recom- mendations or guidelines issued by the relevant public
health authorities, in particular in relation to good use of healthcare or therapeutic strategies. Health professionals are encour- aged to take
the ESC Guidelines fully into account when exercising their clinical judgment, as well as in the determination and the implementation of
preventive, diagnostic or therapeutic medical strategies; however, the ESC Guidelines do not override, in any way whatsoever, the individual
responsibility of health professionals to make appropriate and accurate decisions in consideration of each patients health condition and in
consultation with that patient and, where appropriate and/or necessary, the patients caregiver. Nor do the ESC Guidelines exempt health
professionals from taking into full and careful consideration the relevant official updated recommendations or guidelines issued by the
competent public health authorities in order to manage each patients case in light of the scientifically accepted data pursuant to their
respective ethical and professional obligations. It is also the health professionals responsibility to verify the applicable rules and regulations
relating to drugs and medical devices at the time of prescription.
& 2016 European Society of Cardiology and European Atherosclerosis Association. All rights reserved. For permissions please email:
journals.permissions@oup.com.
Page 2 of
72
ESC/EAS
Guidelines
Franc ois Gueyffier (France), Goran Krstacic (Croatia), Maddalena Lettino (Italy), Christos
Lionis (Greece), Gregory Y. H. Lip (UK), Pedro Marques-Vidal (Switzerland), Davor Milicic
(Croatia), Juan Pedro-Botet (Spain), Massimo F. Piepoli (Italy), Angelos G. Rigopoulos
(Germany), Frank Ruschitzka (Switzerland), Jose Tun o n (Spain), Arnold von Eckardstein
(Switzerland), Michal Vrablik (Czech Republic), Thomas W. Weiss (Austria), Bryan Williams
(UK), Stephan Windecker (Switzerland), and Reuven Zimlichman (Israel)
The disclosure forms of the authors and reviewers are available on the ESC website
www.escardio.org/guidelines.
-- -- --- -- -- --- -- --- -- -- --- -- -- --- -- -- --- -- -- --- -- -- --- -- --- -- -- --- -- -- --- - -- -- -- -- --- -
apolipoprotein B lipoprotein remnants total cardiovascular risk treatment, lifestyle treatment, drugs treatment, adherence
Table of Contents
List of abbreviations...................................................... 3
Preamble........................................................................ 5
1. What is cardiovascular disease prevention?.............6
1.1 Definition and rationale....................................... 6
1.2 Development of the Joint Task Force guidelines. .6
1.3 Cost-effectiveness of prevention......................... 7
2. Total cardiovascular risk........................................... 8
2.1 Total cardiovascular risk estimation.................... 8
2.1.1
Rationale for assessing total cardiovascular
disease
risk........................................................................8
2.1.2.............How to use the risk estimation charts
12
2.2 Risk levels......................................................... 13
2.2.1.................Risk- based intervention strategies
13
3. Evaluation of laboratory lipid and apolipoprotein
parameters . 14 3.1 Fasting or non-fasting?..........16
3.2 Intra-individual variation................................... 16
3.3 Lipid and lipoprotein analyses........................... 16
3.3.1..............................................Total cholesterol
16
3.3.2.................Low-density lipoprotein cholesterol
16
3.3.3.........Non-high-density lipoprotein cholesterol
17
3.3.4................High-density lipoprotein cholesterol
18
3.3.5....................................................Triglycerides
18
3.3.6...............................................Apolipoproteins
18
3.3.7..................................................Lipoprotein(a)
19
3.3.8..................................Lipoprotein particle size
19
3.3.9......................................................Genotyping
19
4. Treatment targets................................................... 20
5. Lifestyle modifications to improve the plasma lipid
profile . . . 21
5.1 The influence of lifestyle on total cholesterol and
low- density lipoprotein cholesterol levels.........23
D
o
w
nl
oa
de
d
fr
o
m
htt
p:/
/e
ur
he
art
j.o
xf
or
dj
ou
rn
als
.or
g/
by
gu
est
on
O
ESC/EAS
Guidelines
5.4.5..........................................................Smoking
25
5.5 Dietary supplements and functional foods for the
treatment of dyslipidaemias...................................25
5.5.1....................................................Phytosterols
26
5.5.2..........................Monacolin and red yeast rice
26
5.5.3....................................................Dietary fibre
26
5.5.4......................................................Soy protein
26
5.5.5...............................Policosanol and berberine
26
5.5.6.............................n-3 unsaturated fatty acids
26
5.6 Other features of a healthy diet contributing to
cardiovascular disease prevention.................... 26
6. Drugs for treatment of hypercholesterolaemia.......27
6.1 Statins............................................................... 27
6.1.1.......................................Mechanism of action
27
6.1.2Efficacy of cardiovascular disease prevention
in clinical studies.........................................27
6.1.3................................Adverse effects of statins
29
6.1.4.....................................................Interactions
30
6.2 Bile acid sequestrants....................................... 30
6.2.1.......................................Mechanism of action
30
Page 3 of
72
7.4 Statins...........................................................33
7.5 Fibrates.........................................................33
7.5.1........................................Mechanism of action
33
7.5.2...................................Efficacy in clinical trials
33
7.5.3.....................Adverse effects and interactions
34
7.6 Nicotinic acid................................................34
7.6.1........................................Mechanism of action
34
7.6.2...................................Efficacy in clinical trials
34
7.7 n-3 fatty acids...............................................34
7.7.1........................................Mechanism of action
34
7.7.2...................................Efficacy in clinical trials
34
7.7.3...................................Safety and interactions
35
8. Drugs affecting high-density lipoprotein cholesterol
(Table 20)
35
8.1 Statins...........................................................35
8.2 Fibrates.........................................................35
8.3 Nicotinic acid................................................35
8.4 Cholesteryl ester transfer protein inhibitors......36
8.5 Future perspectives......................................36
9. Management of dyslipidaemia in different clinical
settings...................................................................36
9.1 Familial dyslipidaemias.................................36
9.1.1.................Familial combined hyperlipidaemia
36
9.1.2.......................Familial hypercholesterolaemia
36
9.1.2.1 Heterozygous familial
hypercholesterolaemia . . 36
9.1.2.2 Homozygous familial
hypercholesterolaemia . . . 38
9.1.2.3Familial hypercholesterolaemia in children
38
9.1.3....................Familial dysbetalipoproteinaemia
38
9.1.4........Genetic causes of hypertriglyceridaemia
38
9.1.4.1....Action to prevent acute pancreatitis in
severe hypertriglyceridaemia................39
9.1.5
Other genetic disorders of lipoprotein
metabolism
(Table 23)............................................................39
9.2 Children........................................................40
9.3 Women..........................................................40
9.3.1..........................................Primary prevention
40
9.3.2.....................................Secondary prevention
40
9.3.3........................Non-statin lipid-lowering drugs
40
9.3.4............................................Hormone therapy
40
9.4 Older persons................................................40
9.4.1..........................................Primary prevention
41
9.4.2.....................................Secondary prevention
41
9.14..................................................Mental disorders
49
10........Monitoring of lipids and enzymes in patients on
lipid-lowering therapy (Table 36)............................51
11.
Strategies to encourage adoption of healthy
lifestyle changes
and adherence to lipid-modifying therapies................51
11.1Achieving and adhering to healthy lifestyle
changes . . . 51
11.2Adhering to medications..................................54
12....To do and not to do messages from the Guidelines
57
13....................................................................Appendix
...............................................................................58
14..................................................................References
...............................................................................59
List of abbreviations
ABI
ankle-brachial index
ACC
American College of Cardiology
ACCELERATE Assessment of Clinical Effects of
Cholesteryl Ester Transfer Protein Inhibition with
Evacetrapib in Patients at a High-Risk
for Vascular Outcomes
ACCORD
Action to Control Cardiovascular
Risk in Diabetes
ACS
acute coronary syndrome
AFCAPS
/
TEXCAP
S
AHA
AIM-HIGH
Atherothrombosis Intervention in
Metabolic
Syndrome
with
Low
HDL/High Triglycerides: Impact on
Global Health Outcomes
alanine aminotransferase
apolipoprotein
ALT
Apo
D
o
w
nl
oa
de
d
fr
o
m
htt
p:/
/e
ur
he
art
j.o
xf
or
dj
ou
rn
als
.or
g/
by
gu
est
on
O
ART
ASSIGN
antiretroviral treatment
CV risk estimation model from the
Scottish
Intercollegiate Guidelines Network
ASTRONOMER Aortic Stenosis Progression
Observation:
Measuring Effects of
Rosuvastatin
AURORA
A study to evaluate the Use of
Rosuvastatin
in
subjects On Regular
haemodialysis: an
Assessment of survival and cardiovascular
events
BIP
Bezafibrate Infarction Prevention study
BMI
body mass index
CABG
coronary artery bypass graft surgery
CAC
coronary artery calcium
CAD
coronary artery disease
CARE
Cholesterol and Recurrent Events
CETP
cholesteryl ester transfer protein
CHD
coronary heart disease
CIMT
carotid intima-media thickness
CK
creatine kinase
CKD
chronic kidney disease
CTT
Cholesterol Treatment Trialists
CV
cardiovascular
CVD
cardiovascular disease
CYP
cytochrome P450
4D
Die Deutsche Diabetes Dialyse
DASH
Dietary Approaches to Stop
Hypertension
DGAT-2
diacylglycerol acyltransferase-2
DHA
docosahexaenoic acid
DLCN
Dutch Lipid Clinic Network
EAS
European Atherosclerosis Society
EMA
European Medicines Agency
EPA
eicosapentaenoic acid
ER
extended release
ESC
European Society of Cardiology
ESRD
end-stage renal disease
EU
European Union
FACE-BD
Fondamental Academic Centers of
Expertise
in
Bipolar Disorders
FATS
Familial Atherosclerosis Treatment
Study
FCH
familial combined hyperlipidaemia
FDA
US Food and Drug Administration
FDC
fixed-dose combination
FH
familial hypercholesterolaemia
FIELD
Fenofibrate Intervention and Event
Lowering
Diabetes in
FOCUS
Fixed-Dose Combination Drug for
Secondary
Cardiovascular Prevention
GFR
glomerular filtration rate
GISSI
Gruppo Italiano per lo Studio della
Sopravvivenza nellInfarto Miocardico
GP
general practitioner
GWAS
genome-wide association studies
HAART
highly active antiretroviral treatment
HATS
HDL-Atherosclerosis Treatment Study
HbA1C
glycated haemoglobin
HeFH
heterozygous familial
hypercholesterolaemia
HDL-C
high-density lipoprotein cholesterol
HF
HHS
HIV
HMG-CoA
HPS
HPS2-THRIVE
HoFH
HTG
HR
hs-CRP
ICD
IDEAL
IDL
ILLUMINATE
IMPROVE-IT
JUPITER
KDIGO
LAL
LCAT
LDL-C
LDLR
LEAD
LIPID
LPL
Lp
MetS
MI
MTP
MUFA
NICE
NNRTI
NNT
NPC1L1
NSTE-ACS
NYHA
PAD
PCI
PCSK9
PPAR-a
PROCAM
PROSPER
PUFA
RAAS
RCT
REACH
REDUCE-IT
heart failure
Helsinki Heart Study
human immunodeficiency virus
hydroxymethylglutaryl-coenzyme A
Heart Protection Study
Heart Protection Study 2 Treatment
of
to HDL
Reduce the Incidence of Vascular
Events
homozygous familial
hypercholesterolaemia
hypertriglyceridaemia
hazard ratio
high-sensitivity C-reactive protein
International Classification of
Diseases
Incremental Decrease In End-points
Through
Aggressive Lipid-lowering Trial
intermediate-density lipoproteins
Investigation of Lipid Level
Management
Understand its to
Impact in
Atherosclerotic
Events
Improved Reduction
of Outcomes:
Vytorin
Efficacy International Trial
Justification for the Use of Statins in
Prevention:
an Intervention Trial Evaluating
Rosuvastatin
Kidney Disease: Improving Global
Outcomes
lysosomal acid lipase
lecithin cholesterol acyltransferase
low-density lipoprotein cholesterol
low-density lipoprotein receptor
lower extremities arterial disease
Long-Term Intervention with
Pravastatin
in Ischemic Disease
lipoprotein lipase
lipoprotein
metabolic syndrome
myocardial infarction
microsomal triglyceride transfer
protein
monounsaturated fatty acid
National Institute for Health and
Care
Excellence
non-nucleoside reverse transcriptase
inhibitor
number needed to treat
Niemann-Pick C1-like protein 1
non-ST elevation acute coronary
syndrome
New York Heart Association
peripheral arterial disease
percutaneous coronary intervention
proprotein convertase subtilisin/kexin
type
9
peroxisome
proliferator-activated
receptor-a Cardiovascular Munster
Prospective
Study
Prospective Study of Pravastatin in
the
RiskElderly at
polyunsaturated fatty acid
renin angiotensin aldosterone
system
randomized controlled trial
Reduction of Atherothrombosis for
Continued
Health
Reduction of Cardiovascular Events
with
EPA-Intervention Trial
D
o
w
nl
oa
de
d
fr
o
m
htt
p:/
/e
ur
he
art
j.o
xf
or
dj
ou
rn
als
.or
g/
by
gu
est
on
O
REVEAL
RR
RYR
4S
Scandinavian Simvastatin Survival
Study SALTIRE Scottish Aortic Stenosis and Lipid
Lowering
Trial, Impact on Regression
SAGE
SCORE
SEAS
Stenosis
SFA
SHARP
SLE
SPARCL
STEMI
STRENGTH
TIA
TC
T2DM
TG
triglyceride
TNT
TRL
triglyceride-rich lipoprotein
ULN
UMPIRE
VLDL
WHO
VA-HIT
Preamble
Guidelines summarize and evaluate all available
evidence on a par- ticular issue at the time of the
writing process, with the aim of as- sisting health
professionals in selecting the best management
strategies for an individual patient with a given
condition, taking into account the impact on
outcome as well as the risk benefit ra- tio of
particular
diagnostic
or
therapeutic
means.
Guidelines and recommendations should help health
professionals to make deci- sions in their daily
practice. However, the final decisions concern- ing
an individual patient must be made by the
responsible health professional(s) in consultation
with the patient and caregiver as appropriate.
A great number of guidelines have been issued in
recent years by the European Society of Cardiology
D
o
w
nl
oa
de
d
fr
o
m
htt
p:/
/e
ur
he
art
j.o
xf
or
dj
ou
rn
als
.or
g/
by
gu
est
on
O
Committee is also responsible for the endorsement process of these Guidelines. The ESC
Guidelines undergo extensive review by the CPG
and external experts, and in this case by EASappointed experts. After appropriate revisions the
Guidelines are approved by all the experts involved
in the Task Force. The finalized document is
approved by the CPG and EAS for publication in the
European Heart Journal and in Atheroscler- osis. The
Guidelines
were
developed
after
careful
consideration of the scientific and medical
knowledge and the evidence available at the time of
their dating.
The task of developing ESC and EAS Guidelines
covers not only integration of the most recent
research, but also the cre- ation of educational tools
and
implementation
programmes
for
the
recommendations. To implement the guidelines,
condensed pocket guideline versions, summary
slides, booklets with essen- tial messages, summary
cards for non-specialists and an electron- ic version
for digital applications (smartphones, etc.) are
produced. These versions are abridged and thus, if
needed, one should always refer to the full text
version, which is freely available on the ESC website.
The National Societies of the ESC are encouraged to
endorse, translate and implement all ESC Guidelines.
Implementation programmes are needed be- cause
it has been shown that the outcome of disease may
be fa- vourably influenced by the thorough
application of clinical recommendations.
Surveys and registries are needed to verify that
real-life daily prac- tice is in keeping with what is
recommended in the guidelines, thus
1.What is cardiovascular
disease prevention?
1.1 Definition and rationale
Cardiovascular disease (CVD) kills .4 million
people in Europe each year. It kills more women [2.2
million (55%)] than men [1.8 mil- lion (45%)],
although cardiovascular (CV) deaths before the age
of 65 years are more common in men (490 000 vs.
1
Suggested wording
to use
Is recommended/is
indicated
Should be considered
May be considered
Is not recommended
the
D
o
w
nl
oa
de
d
fr
o
m
htt
p:/
/e
ur
he
art
j.o
xf
or
dj
ou
rn
als
.or
g/
by
gu
est
on
O
Table 2
Level of
evidence
A
Level of
evidence
B
Level of
evidence
C
3,4
guidelines,
which
can
be
found
at
http://www.escardio.org/
Guidelines-&Education/Clinical-Practice-Guidelines/Guidelinesdevelopment/Writing-ESC-Guidelines.
Recommendations are graded in classes (Table 1)
and in levels of evidence (Table 2).
This document has been developed for healthcare
professionals to facilitate informed communication
with individuals about their CV risk and the benefits
of adopting and sustaining a healthy lifestyle and of
early modification of their CV risk. In addition, the
guidelines provide tools for healthcare professionals
to promote up-to-date intervention strategies and
integrate these strategies into national or regional
prevention frameworks and to translate them into
local- ly delivered healthcare services, in line with
the recommendations
of the World Health Organization (WHO) Global
5
Status Report on Noncommunicable Diseases 2010.
6
A lifetime approach to CV risk is considered. This
implies that apart from improving lifestyle habits
and reducing risk factor levels in patients with
established CVD and in those at increased risk of
developing CVD, healthy people of all ages should
be encouraged to adopt or sustain a healthy
lifestyle.
Healthcare
professionals
play
an
important role in achieving this in their clinical
practice.
Key messages
relatively scarce.
Cost-effectiveness results
strongly de- pend on parameters such as the target
populations age, the overall
population risk of CVD and the cost of
interventions. Hence, results obtained in one
country might not be valid in another. Furthermore,
aClass
of recommendation.
changes
such as the introduction of generic drugs
bLevel
of evidence.
12
can considerably
change cost-effectiveness. In
supporting recommendations.
general, lifestyle changes may be more cost
effective at the population level than drug
treatments (Table 3).
cReference(s)
D
o
w
nl
oa
de
d
fr
o
m
htt
p:/
/e
ur
he
art
j.o
xf
or
dj
ou
rn
als
.or
g/
by
gu
est
on
O
26,27
Recommendation
Measures aimed at
implementing healthy
lifestyles are more costeffective than drug
interventions at the
Class
Level
IIa
Ref
cost effective.
Import- antly, a sizable portion of
patients on hypolipidaemic or antihypertensive
drug treatment fail to take their treatment ad28,29
equately or to reach their therapeutic goals,
with
30
clinical and economic consequences. Reinforcing
measures aimed at improv- ing adherence to
31,32
treatment is cost effective.
It has been suggested that the prescription to the
whole popula- tion older than 55 years of age of a
single pill containing a combin- ation of CV drugs
(the polypill) could prevent as much as 80% of CVD
33
34
events and be cost effective. Part of the costeffectiveness of the polypill is due to improvement in
adherence to treatment, but which combination of
drugs is most cost effective in which target
35
population remains to be assessed.
Considerable evidence has quantified the relative
efforts and costs in relation to health impact. The
efforts may be depicted in the health impact
pyramid (Figure 1), where interventions with the
broadest impact on populations represent the base
and interven- tions with considerable individual
36
IncreasingIncreasing
populationindividual
impacteffort needed
Counseling and education
Clinical interventions
Long-lasting protective interventions
Changing the context to make individuals'default decisions healthy
Socioeconomic factors
39
Box 2
9,10
Gaps in evidence
risk
D
o
w
nl
oa
de
d
fr
o
m
htt
p:/
/e
ur
he
art
j.o
xf
or
dj
ou
rn
als
.or
g/
by
gu
est
on
O
documented CVD
type 1 or type 2 diabetes
very high levels of individual risk factors
chronic kidney disease (CKD) (refer to section
9.9)
are automatically at very high or high total CV risk.
No risk estima- tion models are needed for them;
they all need active management of all risk factors.
(2) For all other people, the use of a risk estimation
system such as SCORE is recommended to
estimate total CV risk since many people have
several risk factors that, in combination, may
result in unexpectedly high levels of total CV risk.
The SCORE system estimates the 10-year
cumulative risk of a first fatal atherosclerotic event,
whether heart attack, stroke or other occlusive
arterial disease, including sudden cardiac death.
Risk esti- mates have been produced as charts for
high- and low-risk regions in Europe (Figures 2 and
3). All International Classification of Diseases (ICD)
codes that are related to deaths from vascular origin
caused by atherosclerosis are included. Some other
systems estimate CAD risk only.
The reasons for retaining a system that estimates
fatal as opposed to total fatal + non-fatal events are
that non-fatal events are de- pendent on definition,
developments in diagnostic tests and meth- ods of
ascertainment, all of which can vary, resulting in
very
Figure 2 SCORE chart: 10-year risk of fatal cardiovascular disease (CVD) in populations at high CVD risk based on
the following risk factors: age, gender, smoking, systolic blood pressure, and total cholesterol. To convert the risk
of fatal CVD to risk of total (fatal + nonfatal) hard CVD, multiply by 3 in men and 4 in women, and slightly less in
old people. Note: the SCORE chart is for use in people without overt CVD, diabetes, chronic kidney disease,
familial hypercholesterolaemia or very high levels of individual risk factors because such people are already at
high-risk and need intensive risk factor advice.
D
o
w
nl
oa
de
d
fr
o
m
htt
p:/
/e
ur
he
art
j.o
xf
or
dj
ou
rn
als
.or
g/
by
gu
est
on
O
ESC/EAS
Guidelines
Page 11 of
72
Figure 3 SCORE chart: 10-year risk of fatal cardiovascular disease (CVD) in populations at low CVD risk based on
the following risk factors: age, gender, smoking, systolic blood pressure, and total cholesterol. To convert the risk
of fatal CVD to risk of total (fatal + non-fatal) hard CVD, multiply by 3 in men and 4 in women, and slightly less in
old people. Note: the SCORE chart is for use in people without overt CVD, diabetes, chronic kidney disease,
Page 10 of
72
ESC/EAS
Guidelines
familial hypercholesterolaemia, or very high levels of individual risk factors because such people are already at
high-risk and need intensive risk factor advice.
D
o
w
nl
oa
de
d
fr
o
m
htt
p:/
/e
ur
he
art
j.o
xf
or
dj
ou
rn
als
.or
g/
by
gu
est
on
O
D
o
w
nl
oa
de
d
fr
o
m
reliable endpoint of total CVD events. Risk age can
Figure 4 Relative risk chart for 10-year cardiovascular mortality. Please note
shows RELATIVE
not absolute
risk. The risks htt
are
be that
usedthis
in chart
any population
regardless
of baseline
p:/
systolic blood pressure. Therefore, the goals that are
/e
risk
or
secular
changes
in
mortality,
and
therefore
proposed in this document reflect this concept.
ur
avoids the need for recalibration. At preA particular problem relates to young people with
he
sent,
risk
age
is
recommended
for
helping
to
art
high levels of risk factors; a low absolute risk may
communicate about risk, especially to younger
j.o
conceal a very high relative risk requiring intensive
xf
people
with
a
low
absolute
risk
but
a
high
relative
lifestyle advice. To motivate young people not to
or
risk.
It
is
not
currently
recommended
to
base
delay changing their unhealthy lifestyle, an estimate
dj
treatment decisions on risk age.
ou
of their relative risk, illustrating that lifestyle
rn
Lifetime risk is another approach to illustrating
changes can reduce relative risk sub- stantially, may
als
the
impact
of
risk
factors
that
may
be
useful
in
be helpful (Figure 4).
.or
53
younger people. The greater the
g/
Another approach to this problem in young people
by
is to use CV risk age. The risk age of a person with
gu
several CV risk factors is the age of a person with
est
on
the same level of risk but with ideal levels of risk
O
factors. Thus a high-risk 40-year-old may have a risk
CV endpoint used,
which bypasses the dilemma
of whether to use a risk es- timation system based
on CVD mortality or on the more attractive but less
Page 12 of
72
ESC/EAS
Guidelines
D
o
w
nl
oa
de
d
fr
o
m
htt
p:/
/e
ur
he
art
j.o
xf
or
dj
ou
rn
als
.or
g/
by
gu
est
on
O
57
ESC/EAS
Guidelines
Page 13 of
72
gho/data/node.main.A865CARDIOVASCULAR?
lang=en): 450/ 100 000 for men or 350/100 000
for women (Albania, Algeria, Armenia, Azerbaijan,
Belarus, Bulgaria, Egypt, Georgia, Kazakhstan,
Kyrgyzstan, Latvia, FYR Macedonia, Republic of
Moldova, Russian Federation, Syrian Arab Republic,
Tajikistan, Turkmenistan, Ukraine and Uzbekistan).
The remaining high-risk countries are Bosnia and
Herzegovina, Croatia, Estonia, Hungary, Lithuania,
Montenegro, Morocco, Poland, Romania, Serbia,
Slovakia, Tunisia and Turkey. Note that several
countries have undertaken national recalibrations
D
o
w
nl
oa
de
d
fr
o
m
htt
p:/
/e
ur
he
art
j.o
xf
or
dj
ou
rn
als
.or di
Figure 6 Risk function without high-density lipoprotein-cholesterol (HDL-C) for women in populations at high cardiovascular
g/
examples of the corresponding estimated risk when different levels of HDL-C are included.
by
gu
est
Box
4
Qualifiers
Box 3 How to use the risk estimation charts
on
O
To estimate a persons 10-year risk of CVD death, find
the table for his/ her gender, smoking status, and age.
Within the table find the cell nearest to the persons
blood pressure and TC. Risk estimates will need to be
adjusted upwards as the person approaches the next
Risk is initially assessed on the level of TC and
systolic blood pressure before treatment, if known.
The longer the treatment and the more effective it
is, the greater the reduction in risk, but in general it
will not be more than about one-third of the baseline
risk. For example, for a person on antihypertensive
drug treatment in whom the pre-treatment blood
pressure is not known, if the total CV SCORE risk is
Low-risk persons should be offered advice to
maintain their low-risk status.While no threshold is
universally applicable, the intensity of advice should
increase with increasing risk.
The charts may be used to give some indication of
the effects of reducing risk factors, given that there
will be a time lag before the risk reduces and that
the results of randomized controlled trials in general
give better estimates of benefits. In general, those
who stop smoking rapidly halve their cumulative risk.
D
o
w
nl
oa
de
d
fr
o
m
htt
p:/
/e
ur
he
art
j.o
xf
or
dj
ou
rn
als
.or
Figure 7 Risk function without high-density lipoprotein-cholesterol (HDL-C) for men in populations at high cardiovascular diseas
g/
examples of the corresponding estimated risk when different levels of HDL-C are included.
by
gu
est
on
O
ability.
Subjects in need of reclassification are those
belonging to the intermediate CV risk group.
Therefore the use of methods to detect
D
o
w
nl
oa
de
d
fr
o
m
htt
p:/
/e
ur
he
art
j.o
xf
or
dj
ou
rn
als
.or
g/
by
gu
est
on
O
High-risk
Risk categories
Moderaterisk
Low-risk
Subjects with:
Markedly elevated single risk
factors, in particular cholesterol >8
mmol/L (>310 mg/dL) (e.g. in familial
hypercholesterolaemia) or
BP 180/110 mmHg.
Most other people with DM
(some young people with type 1
diabetes may be at low or
moderate risk).
Moderate CKD (GFR 3059
mL/min/1.73 m2).
SCORE is 1% and <5% for 10-year
risk of fatal CVD.
SCORE <1% for 10-year risk of fatal
CVD.
Table 5 Intervention strategies as a function of total cardiovascular risk and low-density lipoprotein cholesterol level
Total CV risk
(SCORE)
<70 mg/dL
<1
Class
/Levelb
I/C
/Levelb
/Levelb
No lipid
intervention
IIa/A
10 or
very high-risk
Class
/Levelb
Lifestyle
intervention,
consider drugc
IIa/A
2.6 to <4.0
4.0 to <4.9
190 mg/dL
4.9 mmol/L
I/C
I/C
I/C
Lifestyle
intervention,
consider drug if
uncontrolled
IIa/A
Lifestyle
intervention,
consider drug if
uncontrolled
IIa/A
Lifestyle
intervention,
consider drug if
uncontrolled
I/A
Lifestyle
intervention,
consider drug if
uncontrolled
IIa/A
Lifestyle
Lifestyle
Lifestyle
intervention and
intervention and
intervention and
concomitant drug concomitant drug concomitant drug
intervention
intervention
intervention
IIa/A
I/A
I/A
I/C
I/C
155 to <190
mg/dL
Lifestyle
intervention,
consider drug if
uncontrolled
IIa/A
No lipid
intervention
No lipid
intervention
5 to
<10, or
high-risk
Class
1.8 to <2.6
No lipid
intervention
1 to <5
Class
70 to <100
mg/dL
<1.8 mmol/L
LDL-C
levels
100 to <155
mg/dL
No lipid
intervention
No lipid
intervention
No lipid
intervention
Lifestyle
Lifestyle
Lifestyle
Lifestyle
intervention and
intervention and
intervention and
intervention and
concomitant drug concomitant drug concomitant drug concomitant drug
intervention
intervention
intervention
intervention
IIa/A
I/A
I/A
I/A
CV cardiovascular; LDL-C low-density lipoprotein cholesterol; SCORE Systematic Coronary Risk Estimation.
aClass of recommendation.
bLevel of evidence.
cIn patients with myocardial infarction, statin therapy should be considered irrespective of total cholesterol levels
3.Evaluation
of laboratory lipid and apolipoprotein
Table 6 Recommendations for risk estimation
parameters
Recommendations
Total risk estimation using a risk
estimation system such as SCORE
is recommended for asymptomatic
adults >40 years of age without
evidence of CVD, diabetes, CKD
or familial hypercholesterolaemia.
High and very high-risk individuals
can be detected on the basis of
documented CVD, diabetes
mellitus, moderate to severe renal
disease, very high levels of
individual risk factors, familial
hypercholesterolaemia or a high
SCORE risk and are a high priority
Class
Level
D
o
w
nl
oa
de
d
fr
o
m
htt
p:/
/e
ur
he
art
j.o
xf
or
dj
ou
rn
als
.or
g/
by
gu
est
on
O
Recommendations
TC is to be used for the estimation
of total CV risk by means of the
SCORE system.
LDL-C is recommended to be used
as the primary lipid analysis for
screening, risk estimation,
diagnosis and management. HDL-C
is a strong independent risk factor
and is recommended to be used
in the HeartScore algorithm.
TG adds information on risk and is
indicated for risk estimation.
Class
Level
D
o
w
nl
oa
de
d
fr
o
m
htt
p:/
/e
ur
he
art
j.o
xf
or
dj
ou
rn
als
.or
g/
by
gu
est
on
O
of evidence.
Recommendations
Class
Level
It is recommended to analyse
HDL-C before treatment.
IIa
IIa
IIb
with
normal
lipid
levels.
However,
in
hypertriglyceridaemia (HTG) these methods have
73 76
estimation.
It should be emphasized, however,
that the risk may be underestimated in patients with
diabetes, be- cause in one study, patients with
diabetes had up to 0.6 mmol/L low- er LDL-C in nonfasting samples.
77
Furthermore, to characterize
D
o
w
nl
oa
de
d
fr
o
m
htt
p:/
/e
ur
he
art
j.o
xf
or
dj
ou
rn
als
.or
g/
by
gu
est
on
O
83
level.
Most available assays are of high quality,
but the method used should be evaluated against
the available reference methods and controlled in
international quality programmes. It should also be
considered that HTG might interfere with the direct
HDL-C assays.
72
3.3.5 Triglycerides
TGs are determined by accurate enzymatic
techniques. A rare error occurs in patients with
hyperglycerolaemia, where falsely very high values
for TGs are detected.
High TG levels are often associated with low HDL-C
and high le- vels of small dense LDL particles. In a
number of meta-analyses, TGs has been shown to
96,97
be an independent risk factor.
Furthermore,
recent genetic data support the contention that
elevated TG levels are a direct cause of CV
76,88
disease.
Recent studies suggest that non-fasting TGs may
carry informa- tion regarding remnant lipoproteins
76,86,98,99
associated with increased risk.
For general
screening and risk evaluation, non-fasting TGs can
be used.
3.3.6 Apolipoproteins
From a technical point of view, there are advantages
in the deter- mination of apoB and apoA1. Good
immunochemical methods are available and easily
run in conventional autoanalysers. The ana- lytical
performance is good and the assays do not require
fasting conditions and are not sensitive to markedly
elevated TG levels.
Apolipoprotein B. ApoB is the major apolipoprotein
of the athero- genic lipoprotein families (VLDL, IDL
and LDL). ApoB is a good es- timate of the number
of these particles in plasma. This might be of special
importance in the case of high concentrations of
small dense LDL. Several prospective studies have
shown that apoB is equal to LDL-C and non-HDL-C in
risk prediction. ApoB has not been eval- uated as a
primary treatment target in clinical trials, but several
post
hoc analyses of clinical trials suggest that apoB may
be not only a risk marker, but also a treatment
100
target.
A major disadvantage of apoB is that it is
not included in algorithms for calculation of global
risk, and it has not been a predefined treatment
target in controlled trials. Recent data from a meta83,90
analysis
indicate that apoB does not provide any
benefit beyond non-HDL-C or traditional lipid ra101
tios.
Likewise, apoB provided no benefit beyond
traditional lipid markers in people with diabetes in
the Fenofibrate Intervention and Event Lowering in
102
Diabetes (FIELD) study.
In contrast, in another
meta-analysis of LDL-C, non-HDL-C and apoB, the
103
latter was su- perior as a marker of CV risk.
ApoB
(50 mg/dL).
Including Lp(a) in risk evaluation has
113,114
been shown to give a correct reclassifica- tion
and should be considered in patients on the
borderline be- tween high and moderate risk.
Individuals with:
3.3.7 Lipoprotein(a)
Lp(a) has been found in several studies to be an
additional independ- ent risk marker; indeed, genetic
data show it to be causal in the patho- physiology of
109
Premature CVD
Familial hypercholesterolaemia
D
o
w
nl
oa
de
d
fr
o
m
Reduction of Lp(a) has been shown with several
htt
of the emerging lipid-lowering drugs. Proprotein
p:/
/e
convertase subtilisin/ kexin type 9 (PCSK9)
ur
inhibitors and nicotinic acid reduce Lp(a) by
115 117
he
art
~30
An effect on CVD events targeting Lp(a)
j.o
%.
has not been
xf
shown. Antisense drugs targeting the Lp(a) gene
or
reduce the circulatdj
ing levels of this protein by up to 80%. A reasonable
ou
rn
option for pa- tients at risk with high Lp(a) is an
Individuals who should be considered for lipoprotein(a) screening
als
intensified treatment of the modifiable risk factors,
.or
including LDL-C.
g/
by
gu
est
3.3.8 Lipoprotein particle size
on
Lipoproteins are heterogeneous, and evidence
O
Page 20 of
72
ESC/EAS
Guidelines
118
4.Treatment targets
In both the 2011 EAS/ESC guidelines for the
125
3.3.9 Genotyping
Several genes have been associated with CVD.
Large GWASs have been published for coronary
heart disease (CHD), as well as for as- sociated
biomarkers and risk factors. At present, the use of
genotyp- ing for risk estimation is not recommended
since known risk loci account for only a small
management
of
dyslipidaemias
and
the
American Heart Association/Ameri- can College of
Cardiology (AHA/ACC) guidelines on the treat- ment
of blood cholesterol to reduce atherosclerotic CV risk
71
61
III
103
D
o
w
nl
oa
de
d
fr
o
m
htt
p:/
/e
ur
he
art
j.o
xf
or
dj
ou
rn
als
.or
g/
by
gu
est
on
O
ESC/EAS
Guidelines
Page 21 of
72
D
o
w
nl
oa
de
d
fr
o
m
htt
p:/
/e
ur
he
art
Non-HDL-C secondary targets are <2.6,
j.o
Recommendations
Class
Level
Ref c
3.4 and
a
b
xf
3.8 mmol/L (100, 130 and 145 mg/dL)
In patients at VERY HIGH
or
for very high-, high- and moderate-risk
d
HDL-C: no target, but >1.0 mmol/L (40 mg/dL)
CV risk , an LDL-C goal of
dj
in men and
<1.8 mmol/L
61,
ou
>1.2 mmol/L (48 mg/dL) in women indicates
62,
(70 mg/dL) or a reduction
I
B
rn
TG: no target but <1.7 mmol/L (150
65,
als
of at least 50% if the
mg/dL) indicates lower risk and higher
.or
68,
baseline LDL-Ce is between
levels indicate a need to look for other
g/
69,
1.8 and 3.5 mmol/L
risk factors.
by
128
Diabet HbA1c: <7% (<53 mmol/mol).
(70 and 135
In patients at HIGH CV
gu
es
d
BMI body mass index; HbA1C glycated haemoglobin; HDL-C high-density
risk , an LDL-C goal of
est
lipoprotein-cholesterol; LDL-C low-density lipoprotein-cholesterol; TG
<2.6 mmol/L
on
triglycerides.
(100 mg/dL), or a
I
B
65, 129
O
aThe BP target can be lower in some patients with type 2 diabetes127 and in some high-risk patients without diabetes who can tolerate multiple antihypertensive drugs.
reduction of at least 50% if
bThe term baseline LDL-C refers to the level in a subject not taking any lipid
the baseline LDL-Ce is
lowering medication.
between 2.6 and 5.2
mmol/L
In subjects at LOW or
MODERATE riskd an LDL-C
IIa
C
goal of <3.0 mmol/L (<115
mg/dL)
should
be
Page 22 of
72
ESC/EAS
Guidelines
5.Lifestyle modifications to
improve the plasma lipid
profile
The role of nutrition in the prevention of CVD has
132 134
Referenc
es
+++
136, 139
+++
136, 137
++
140, 141
++
142, 143
++
144146
++
147, 148
149
150
+/-
151
+++
147, 148
D
o
w
nl
oa
de
d
fr
o
m
htt
p:/
/e
ur
he
art
j.o
xf
or
dj
ou
rn
als
.or
g/
by
gu
est
on
O
152, 153
++
150, 154
++
148, 155
++
156, 157
++
158, 159
136, 137
+++
136, 160
+++
150, 161
++
147, 148
++
148, 162
++
B
152
HDL-C high-density lipoprotein-cholesterol; LDL-C low-density lipoprotein-cholesterol; TC total cholesterol; TG triglycerides.
continued
The magnitude of the
effect
(+++
marked
effects,
++
less
pronounced
effects,
+
small
effects,
not
effective)
and
the
level
of
evidence refer to the impact o
Quit smoking
+
B
163
ESC/EAS
Guidelines
Page 23 of
72
+/-
164
+/-
158, 159
D
o
w
nl
oa
de
Saturated fatty acids (SFAs) are the dietary factor
d
133
with the greatest impact on LDL-C levels (0.020.04
fr
contrib- ute to CVD prevention.
They are
mmol/L or 0.81.6 mg/dL of LDL-C increase for every
o
characterized by high con- sumption of fruits,
m
additional 1% energy coming from satu- rated
vegetables and wholegrain cereal products;
htt
165
fat).
Stearic acid, in contrast to other SFAs (lauric,
p:/
frequent intake of legumes, nuts, fish, poultry and
myristic and palmitic), does not increase TC levels.
/e
low fat dairy pro- ducts and limited intake of sweets,
ur
Trans
unsaturated
fatty
acids
can
be
found
in
limited
sugar-sweetened drinks and red meat. The DASH
he
amounts (usually ,5% of total fat) in
diet and the Mediterranean diet derive a large proart
dairy products and in meats from ruminants.
j.o
portion of dietary fat from non-tropical vegetable oil
xf
Partially hydrogenated fatty acids of industrial
rather than from animal sources; the most relevant
or
origin represent the major source of trans fatty acids
difference between them is the emphasis on extra
dj
in the diet; the average consumption of trans fatty
ou
virgin olive oil given in the Mediterranean diet. This
acids ranges from 0.2% to 6.5% of the total energy
rn
latter dietary pattern has been proven in RCTs to be
166
als
intake
in
different
populations.
Quantitatively,
ef.or
dietary trans fatty acids have a similar elevating
g/
fective in reducing CV diseases in primary and
by
effect on LDL-C to that of SFAs; however, while SFAs
137 ,138
secondary preven- tion.
In particular, the
gu
137
in- crease HDL-C levels, trans fats decrease them.
est
PREDIMED
trial,
a
multicentre
randomized
If 1% of the diet- ary energy derived from SFAs is
on
intervention study conducted in Spain, evaluated the
Table 13 Dietary recommendations to lower low-density lipoprotein-cholesterol
replaced by n-6 and
polyunsaturated
improve the overall
fatty acids
lipoprotein
(PUFAs),
profile O
To be preferred
Cereals
Vegetables
Legumes
Whole grains
Raw and cooked
Lentils,vegetables
beans, fava
beans, peas,
chickpeas, soybean
To be used with
moderation
Refined bread,
rice and pasta,
biscuits, corn flakes
Potatoes
Fruit
Sweets and
sweeteners
Meat and fish
Dairy food and eggs
Cooking fat and
dressings
Nuts/seeds
Cooking procedures
Grilling, boiling,
steaming
candies
Lean cuts of
beef, lamb,
pork or veal,
seafood,
shellfish
Low-fat milk,
low-fat
cheese
and other milk
products,
eggs
Olive
oil, non-tropical
vegetable oils, soft
margarines, salad dressing,
mayonnaise,
ketchup
All, unsalted
(except
coconut)
Stir-frying, roasting
variability
among
individuals.
Dietary
carbohydrate is neutral on LDL-C; therefore,
carbohydrate-rich
foods represent one of the possible options to
replace saturated fat in the diet. However, the major
drawback of their excessive con- sumption is
represented by untoward effects on plasma TGs and
165
on HDL-C levels.
Dietary fibre (particularly of the
soluble type), which is present in legumes, fruits,
vegetables, and wholegrain cer- eals (oats, barley),
has a direct hypocholesterolaemic effect. Therefore, carbohydrate foods rich in fibre represent a
good dietary substitute for saturated fat in order to
maximize the effects of the diet on LDL-C levels and
to minimize the untoward effects of a high
140
carbohydrate
diet
on
other
lipoproteins.
Conversely, re- fined carbohydrate foods and
beverages should not be recom- mended to replace
saturated fat since they may contribute to elevated
plasma TGs and lower HDL-C levels.
Body weight reduction also influences TC and LDLC, but the magnitude of the effect is rather small; in
grossly obese subjects, a decrease in LDL-C
concentration of ~0.2 mmol/L (8 mg/dL) is observed for every 10 kg of weight loss; the reduction
of LDL-C is greater if weight loss is achieved with a
147,148
150,169
ercise.
However, the beneficial effects of
weight reduction and physical exercise on the CV
risk profile go beyond LDL-C re- duction and involve
not only other lipoprotein classes but also other risk
factors.
In Table 13, lifestyle interventions to lower TC and
LDL-C are summarized. Given the cultural diversity
of the European popula- tions, they should be
translated into practical behaviours, taking into
account local habits and socio-economic factors.
171
an increase in TG concentrations.
The greater
and more rapid this perturbation, the more pronounced are the metabolic consequences. Most
detrimental ef- fects of a high carbohydrate diet
5.3
could be minimized if carbohydrate digestion and
absorption were slowed down. The glycaemic index
permits identification, among carbohydrate-rich
foods, of those with fast and slow absorption. In
particular,
the detrimental effects of a high carbohydrate diet on
TGs occur mainly when refined carbohydrate-rich
foods are consumed, while they are much less
prominent if the diet is based largely on fibre-rich,
low glycaemic index foods. This applies particularly to
people with diabetes or with metabolic syndrome
(MetS).173,174
Habitual
consumption
of
significant
amounts
(.10% energy) of
dietary fructose contributes to TG elevations,
particularly in people with HTG. These effects are
dose dependent; with a habitual fruc- tose
consumption between 15 and 20% of the total energy
intake, plasma TG increases as much as 30 40%.
Sucrose, a disaccharide- containing glucose and
fructose, represents an important source of fructose
158,175
in the diet.
Weight reduction improves insulin sensitivity and
decreases TG levels. In many studies the reduction of
TG levels due to weight re- duction is between 20
30%; this effect is usually preserved as long as weight
is not regained. Regular physical exercise reduces
plasma TG levels over and above the effect of weight
150,169,176
reduction.
Alcohol intake has a major impact
on TG levels. While in indivi- duals with HTG even a
small amount of alcohol can induce a further
elevation of TG concentrations, in the general
population alcohol
exerts detrimental effects on TG levels only if the
152,177
intake is excessive.
carbohydrates.
Moderate alcohol consumption
is as- sociated with increased HDL-C levels as
compared with abstainers, with a dose-response
relationship. Weight reduction has a beneficial
influence on HDL-C levels: a 0.01 mmol/L (0.4
mg/dL) increase is observed for every kilogram
decrease in body weight when weight
reduction has stabilized. Aerobic physical activity
corresponding to a total energy expenditure of 1500
2200 kcal/week, such as 25 30 km of brisk
walking per week (or any equivalent activity), may
mg/dL).
Smoking cessation may also contribute to
HDL-C elevation, pro- vided that weight gain is
prevented; this is often observed soon after quitting
163
smoking.
in the long run, this advice should be incorporated into structured, intensive lifestyle
education pro- grammes. In order to facilitate the
maintenance of body weight close to the target,
it is always appropriate to advise people with
dyslipidaemia to engage in regular physical
150
169
D
o
w
nl
oa
de
d
fr
o
m
htt
p:/
/e
ur
he
art
j.o
xf
or
dj
ou
rn
als
.or
g/
by
gu
est
on
O
Caucasians (Europids)
South Asians, Chinese,
Japanese
South and Central
Americans
Sub-Saharan Africans
Eastern Mediterranean
and Middle East (Arabic
populations)
165
158,159
142
5.4.4 Alcohol
Moderate alcohol consumption [up to 20 g/day (2
units) for men and 10 g/day (1 unit) for women] is
acceptable for those who drink alcoholic beverages,
provided that TG levels are not elevated.
5.4.5 Smoking
Smoking cessation has clear benefits on the overall
CV risk, and spe- cifically on HDL-C, but special
attention should be paid in order to prevent weight
163
gain in people who stop smoking.
5.5 Dietary
supplements
and
functional
foods
for
the
treatment of dyslipidaemias
Innovative nutritional strategies
to improve
dyslipidaemias have been developed. They are
based on either changing some risky dietary
components or encouraging the consumption of
specifically targeted healthy functional foods
and/or dietary supplements; these so-called
nutraceuticals can be used either as alternatives or
184
and TG levels.
Although the effect of plant sterol
con- sumption on TC levels has been clearly
shown, no studies have been performed yet on the
subsequent effect on CVD. However, the meta131
D
o
w
nl
oa
de
d
fr
o
m
htt
p:/
/e
ur
he
art
j.o
xf
or
dj
ou
rn
als
.or
g/
by
gu
est
on
O
146
~2.510 mg monacolin K.
Nutraceuticals containing
purified
RYR may be considered in people with elevated
plasma choles- terol concentrations who do not
qualify for treatment with statins in view of their
global CV risk.
metabolism.
Pharmacological doses of n-3 fatty
acids (2 3 g/day) reduce TG levels up to 30%, but a
higher dosage may
increase LDL-C. Alfa-linolenic acid (a medium chain
n-3 fatty acid present in chestnuts, some vegetables
and some seed oils) is less ef- fective on TG levels.
Long chain n-3 PUFAs also reduce the post- prandial
156,172
lipaemic response.
meals.
Dietary choices inspired by this model
should be recommended for both primary and
secondary prevention of CVD.
One of the important features of this type of diet is
represented by the consumption of large amounts of
fruits and vegetables of dif- ferent types providing a
sufficient amount and variety of minerals, vitamins
and antioxidants, particularly polyphenols. New
evidence is accumulating on the possible beneficial
effects of these com- pounds, which are also
present in olive oil, red wine, coffee, tea and cocoa,
on subclinical inflammation and endothelial function,
as well as their beneficial influence on plasma TGs at
fasting and par- ticularly in the postprandial period.
As for the consumption of fish, at least two
portions per week are recommended to the general
population for the prevention of CVD, together with
the regular consumption of other food sources of n-3
PUFAs (nuts, soy and flaxseed oil). For secondary
D
o
w
nl
oa
de
d
fr
o
m
htt
p:/
/e
ur
he
art
j.o
xf
or
dj
ou
rn
als
.or
g/
by
gu
est
on
O
Box 9 Summary of lifestyle measures and healthy food choices for managing total cardiovascular risk
6.1 Statins
6.1.1 Mechanism of action
Statins reduce the synthesis of cholesterol in the
liver by competi- tively inhibiting HMG-CoA
reductase activity. The reduction in intracellular
cholesterol concentration induces an increased
expres- sion of LDLR on the surface of the
hepatocytes, which results in in- creased uptake of
LDL-C from the blood and a decreased plasma
concentration of LDL-C and other apoB-containing
lipoproteins, including TG-rich particles.
The degree of LDL-C reduction is dose dependent
and
varies
between
the
different
statins
(supplementary Figure A and supple- mentary Table
191
A).
There is also considerable interindividual
variation in LDL-C reduction with the same dose of
61
drug. Poor response to statin treatment in clinical
studies is to some extent caused by poor
compliance, but may also be explained by a genetic
background involving variations in genes of both
70
LDL %
60
50
40
30
20
0
A10 A2010
A40 A80 F20 F40 F80 L10 L20 L40 L80 P10 P20 P40 S10 S20 S40 S80 R5 R10 R20 R40 P1 P2 P4
ATOR
FLUVA
LOVAPRAVA
SIMVA
ROSU
PITA
D
o
w
nl
oa
de
d
fr
o
m
htt
p:/
Supplementary Table A Percentage reduction of low-density lipoprotein cholesterol (LDL-C) requested to achieve goals as a function
/e
ur
he
Starting LDLReduction to reach LDL-C goal, %
art
C
j.o
mmol/L
~mg/dL
<1.8 mmol/L
<2.6 mmol/L
<3 mmol/L
xf
(~70 mg/dL)
(~100 mg/dL)
(~115 mg/dL)
or
>6.2
>240
>70
>60
>55
dj
ou
5.26.2
200240
65
50
40
rn
70
60
55
als
4.45.2
170200
60
40
30
.or
65
50
45
3.94.4
150170
55
35
25
g/
60
40
30
by
3.43.9
130150
45
25
10
gu
55
35
25
2.93.4
110130
35
10
<10
est
45
25
on
2.32.9
90110
22
<10
O
35
1.82.3
7090
<22
cholesterol metabolism and of statin uptake and6.1.2 Efficacy of cardiovascular disease prevention in
192,193
clinical studies
metabolism
in
the
liver.
Furthermore,
Statins are among the most studied drugs in CVD
conditions
causing
high
cholesterol
(e.g.
prevention, and dealing with single studies is beyond the
hypothyroidism) should be considered. Indeed,
scope of the present guide- lines. A number of large-scale
interindivi- dual variations in statin response warrant
trials have demonstrated that statins substantially reduce
monitoring of individual response on initiation of
CV morbidity and mortality in both primary and
therapy.
64 66,68,129,194 200
and in subgroups.
In the large
Cholesterol Treatment Trialists (CTT) analysis data,
.170 000 participants and 26 RCTs with statins
64
were included. A 10% proportional reduction in allcause mortality and 20% proportional reduction in
CAD death per 1.0 mmol/L (40 mg/dL) LDL-C
reduction was reported. The risk of major coronary
events was reduced by 23% and the risk
of stroke was reduced by 17% per 1 mmol/L (40 mg/dL) LDL-C
D
o
w
nl
oa
de
d
fr
o
m
htt
p:/
/e
ur
he
art
j.o
xf
or
dj
ou
rn
als
.or
g/
by
gu
est
on
O
209
considered.
Several studies have shown a
considerable LDL-C lowering effect of alternative
dosing such as every other day or twice a week with
57,220
atorvastatin or rosuvastatin.
Although no clinical
endpoint trials are avail- able, this treatment should
be considered in high-risk patients who do not
tolerate daily doses of statin treatment.
Liver. The activity of alanine aminotransferase
(ALT) in plasma is commonly used to assess
hepatocellular damage. Mild elevation of ALT occurs
in 0.5 2.0% of patients on statin treatment, more
Page 30 of
72
ESC/EAS
Guidelines
insulin resistance.
Overall, the absolute reduction
in the risk of CVD in high-risk pa- tients outweighs
the possible adverse effects of a small increase in
the incidence of diabetes.
Kidney. The effect of statin treatment on renal
function is still being debated. A recent Cochrane
analysis could not find support for bene- ficial effects
on renal function based on studies where creatinine
clear- ance was available, and no deleterious effects
228
were observed.
An increased frequency of
proteinuria has been reported for all statins, but has
been analysed in more detail for rosuvastatin,
probably due to the high frequency of proteinuria
observed with a higher dose (80 mg). With a dose of
80 mg, a frequency of 12% was reported. With the
approved doses up to 40 mg, the frequency is much
lower
and in line with the frequency for other statins. The
proteinuria induced by statins is of tubular origin and
is supposed to be due to reduced tubular
229
reabsorption and not to glomerular dysfunction.
In
experi- mental systems, reduced pinocytosis has been
shown in renal cells. The statin-induced reduced
pinocytosis is directly related to the inhibition of
230
cholesterol synthesis.
In clinical trials the frequency
of proteinuria is in general low and in most cases is
231
not higher than for placebo.
6.1.4 Interactions
A number of important drug interactions with statins
have been de- scribed that may increase the risk of
adverse effects. Inhibitors and inducers of enzymatic
D
o
w
nl
oa
de
d
fr
o
m
htt
p:/
/e
ur
he
art
j.o
xf
or
dj
ou
rn
als
.or
g/
by
gu
est
on
O
ESC/EAS
Guidelines
Page 31 of
72
239
241
D
o
w
nl
oa
de
d
fr
o
m
htt
p:/
/e
ur
he
art
j.o
xf
or
dj
ou
rn
als
.or
g/
by
gu
est
on
O
PRECISE-IVUS study,
IMPROVE-IT supports the
proposal that ezetimibe should be used as second-line
therapy in association with statins when the
therapeutic goal is not achieved at the maximal
tolerated statin dose or in patients intolerant of
statins or with contraindications to these drugs.
Page 32 of
72
ESC/EAS
Guidelines
reported on HDL-C or plasma TGs. However, the TG6.6.1 Statins and cholesterol absorption inhibitors
effect must be reconfirmed in populations with
The combination of statins and ezetimibe is
higher starting plasma TG levels. Given the
discussed above (see section 6.3.2).
mechanism of action, these drugs are effective at
redu- cing LDL-C in all patients with the capability of6.6.2 Statins and bile acid sequestrants
expressing LDLRs in the liver. Therefore this
The combination of a statin and cholestyramine,
pharmacological approach is effective in the vast
colestipol or cole- sevelam could be useful in
majority of patients, including those with
achieving LDL-C goals. On average, the addition of
heterozygous FH (HeFH) and, albeit to a lower level,
a bile acid sequestrant to a statin reduces LDL-C by
those with homozygous FH (HoFH) with residual
an additional 10 20%. However, there are no
LDLR expression. Receptor-deficient HoFH
published clinical out- come trials with either
responds poorly to the therapy.
conventional bile acid sequestrants or colesevelam in combination with other drugs. The
People at very high total CV risk, people with HeFH
combination has been
(and some with HoFH) on maximally tolerated doses
of first- and second-line therapy and/or in apheresis
and who are statin intolerant with per- sistent high
levels of LDL-C are reasonable candidates for the
use of these drugs.
6.4.3 Adverse effects and interactions
Anti-PCSK9 Mabs are injected subcutaneously,
usually every other week, at doses up to 150 mg.
The potential for interaction with or- ally absorbed
drugs is absent, as they will not interfere with
pharma- cokinetics or pharmacodynamics. AntiPCSK9 Mabs do not modulate pathways involved in
biotransformation or drug uptake/ extrusion from
cells. Among the most frequently reported side effects are itching at the site of injection and flu-like
symptoms. In
some studies an increase of patient-reported
neurocognitive effects was described. This finding
250
requires further scrutiny.
251
252
laropiprant,
showed no beneficial effect, but rather
an increased frequency of serious adverse effects,
no medication containing nicotinic acid is currently
approved in Europe. For the role of niacin in
hypertriglyceridaemia, see section 7.6.
Recommendations
Prescribe statin up to the
highest recommended
dose or highest
tolerable dose to reach
In the case of statin
intolerance, ezetimibe or
bile acid sequestrants, or
these combined, should
be considered.
If the goal is not
reached, statin
combination with a
cholesterol absorption
inhibitor should be
If the goal is not
reached, statin
combination with a bile
acid sequestrant may be
In patients at very highrisk, with persistent high
LDL-C despite treatment
with maximal tolerated
statin dose, in
combination with
ezetimibe or in patients
with statin intolerance, a
Class
Level
IIa
IIa
IIb
IIb
Ref
62, 64,
68
239,
256,
257
63
115,
116
D
o
w
nl
oa
de
d
fr
o
m
htt
p:/
/e
ur
he
art
j.o
xf
or
dj
ou
rn
als
.or
g/
by
gu
est
on
O
ESC/EAS
Guidelines
Page 33 of
72
Table 17
Genetic predisposition
Obesity
Type 2 diabetes
Alcohol consumption
Diet high in simple carbohydrates
Renal disease
Hypothyroidism
Pregnancy (physiological triglyceride concentrations
double during the third trimester)
Paraproteinaemia and autoimmune disorders such as
systemic lupus erythematosus
Multiple medications including:
Corticosteroids
Oestrogens, especially those taken orally
Tamoxifen
Antihypertensives: adrenergic beta-blocking
agents (to a different degree), thiazides
Isotretinoin
Bile acid-binding resins
Ciclosporin
7.2
Definition
hypertriglyceridaemia
of
D
o
w
nl
oa
de
d
fr
o
m
htt
p:/
/e
ur
he
art
j.o
xf
or
dj
ou
rn
als
.or
g/
by
gu
est
on
O
67,259
recommendations.
According to the EAS
consensus docu- ment, mild to moderate HTG is
defined as TGs .1.7 mmol/L (150 mg/dL) and ,
10 mmol/L (880 mg/dL); TGs .10 mmol/L is defined
260
as severe HTG.
Age/gender, race/ethnicity and
lifestyle
are modulating factors at the population level for
serum TGs. In the Copenhagen general population
~27% had TGs .1.7 mmol/
75
IIa
IIb
IIb
261,
262
263,
264
261
264
7.4 Statins
Recommendations
Class
a
Level
b
Ref
7.5 Fibrates
7.5.1 Mechanism of action
Fibrates are agonists of peroxisome proliferatoractivated
receptor-a
(PPAR-a),
acting
via
transcription factors regulating vari- ous steps in
lipid and lipoprotein metabolism. By interacting with
PPAR-a, fibrates recruit different cofactors and
regulate gene ex- pression. As a consequence,
fibrates have good efficacy in lowering fasting TG
levels as well as post-prandial TGs and TG-rich
lipopro- tein (TRL) remnant particles. The HDL-C
raising effects of fibrates are modest.
263
D
o
w
nl
oa
de
d
fr
o
m
htt
p:/
/e
ur
he
art
j.o
xf
or
dj
ou
rn
als
.or
g/
by
gu
est
on
O
group.
The risk of my- opathy has been reported to
be 5.5-fold greater with fibrate use as a monotherapy
compared with statin use. The risk of myopathy is
greater in patients with CKD, and it varies with
different fibrates and statins used in combination. This
is explained by the pharma- cological interaction
between different fibrates and glucuronida- tion of
statins. Gemfibrozil inhibits the metabolism of statins
via
the glucuronidation pathway, which leads to highly
increased plas- ma concentrations of statins. As
fenofibrate does not share the same pharmacokinetic
pathways as gemfibrozil, the risk of myop- athy is
273
much less with this combination therapy.
As a class, fibrates have been reported to raise both
serum cre- atinine and homocysteine in both shortterm and long-term studies. The increase of serum
creatinine by fibrate therapy seems to be fully
reversible when the drug is stopped. Data from metaanalyses sug- gest that a reduction of calculated
glomerular filtration rate (GFR) does not reflect any
274
276
Nicotinic acid
7.6.1 Mechanism of action
Nicotinic acid has been reported to decrease fatty
acid influx to the liver and the secretion of VLDL by
the liver. This effect appears to be mediated in part
by the action on hormone-sensitive lipase in the
adipose tissue. Nicotinic acid has key action sites in
both liver and adipose tissue. In the liver, nicotinic
acid inhibits diacylglycerol acyltransferase-2 (DGAT2), resulting in decreased secretion of VLDL
particles from the liver, which is also reflected in
277
35%.
The favourable effect on angiographic
measures has been reported in the Familial
Atherosclerosis Treatment Study (FATS) and in the
279
HDL-Atherosclerosis Treatment Study (HATS).
Two large randomized clinical trials [the
Atherothrombosis Inter- vention in Metabolic
Syndrome with Low HDL/High Triglycerides: Impact
on Global Health Outcomes (AIM-HIGH) and the
Heart
Table 19 Summar
combinations for th
251,252
lipid management.
Further- more, there was an
increased frequency of severe adverse effects in the
niacin groups. Since the EMA suspended ER nicotinic
acid/lar- opiprant, this therapeutic option is
unavailable in Europe.
TG triglycer
289
D
o
w
nl
oa
de
d
fr
o
m
htt
p:/
/e
ur
he
art
j.o
xf
or
dj
ou
rn
als
.or
g/
by
gu
est
on
O
Recommendations
Statins and fibrates raise
HDL-C with a similar
magnitude and these
drugs may be considered.
The efficacy of fibrates to
increase HDL-C may be
attenuated in people with
type 2 diabetes.
Class
Level
IIb
IIb
8.1 Statins
Statins produce modest elevations in HDL-C. In a
291
meta-analysis
of several intervention studies in
dyslipidaemic patients, elevations in HDL-C varied
with dose among the respective statins; such elevations were typically in the range of 5 10%. As a
result of the marked reductions in atherogenic apoBcontaining lipoproteins by statins, it is difficult to
assess the extent to which the effect on HDL-C
levels might contribute to the overall observed
reductions in CV risk con- sistently seen in statin
intervention trials. Despite such an effect, however,
the elevated CV risk associated specifically with
low HDL-C levels was only partially corrected by
statin treatment in
292
the Treatment to New Targets (TNT) trial.
8.2 Fibrates
As a class, fibrates differ in their potential to
modulate the athero- genic lipid profile by
concomitantly lowering TG levels (up to 50%) and by
raising those of HDL-C (up to 10 15% in short-term
stud- ies). However, the HDL-raising effect has been
markedly less (~5%) in the long-term intervention
261,262
trials in people with type 2 dia- betes
; such
differences appear to reflect distinctions in their
relative binding affinities for PPARs, and notably for
PPAR-a.
293
func- tions.
Itsefficacy in clinical trials and
adverse effects and drug interactions are
described in section 7.6.
D
o
w
nl
oa
de
d
fr
o
m
htt
p:/
/e
ur
he
art
j.o
xf
or
dj
ou
rn
als
.or
g/
by
gu
est
on
O
9.Management
dyslipidaemia in
clinical settings
of
different
Criteria
1) Family history
First-degree relative with known premature
(men: <55 years; women: <60 years) coronary
or vascular disease, or
Tendinous xanthomata
4) LDL-C levels
LDL-C 8.5 mmol/L (325 mg/dL)
5) DNA analysis
8
297
worldwide.
Only a minor fraction of these are
identified and properly treated. The risk of CHD
among individuals with def- inite or probable HeFH is
estimated to be increased at least 10-fold. FH is a
monogenic disease caused by loss of function
mutations in the LDLR or apoB genes or a gain of
function mutation in the PCSK9
gene; 95% of FH is caused by mutations in LDLR.
More than a thou- sand different mutations have
been identified in LDLR causing FH. The different
mutations cause reduced function or complete loss
of function. Complete loss of receptor function is
associated with more severe disease. A total of 4
5% of FH is caused by mutations in apoB causing
reduced binding to LDLR and ~1% is caused by
mutations in PCSK9 causing increased catabolism of
LDLR.
The diagnosis of FH is in most cases based on the
clinical picture. Different criteria for the diagnosis have
been developed. The com- monly used criteria from the
Dutch Lipid Clinic Network (DLCN) are shown in Table 21.
Other criteria are the Simon Broome register or the WHO
299,300
2) Clinical history
criteria.
The clinical diagnosis of HeFH is based on family
history of hyper- cholesterolaemia or premature CHD,
clinical history of the patient regarding CVD and clinical
signs. Finally, the diagnosis can be verified by showing
causative mutations in the three pathogenic genes. However, in most studies the frequency of detectable
mutations in pa- tients with a clinically definite or
probable HeFH is only 60 70%. This suggests that a
considerable fraction of patients with FH have either a
polygenic cause of the disease or that other genes, not
yet identified, are involved.
Genetic testing
and
cascade screening.
Probands
(index cases) should be identified
according to the following criteria:
plasma cholesterol 8 mmol/L (310 mg/dL) in an
adult or adult family member (or .95th
percentile by age and gender for country),
premature CHD in the subject or a family member,
tendon xanthomas in the subject or a family
member or
sudden premature cardiac death in a family
member
The most effective way to identify new cases is to
undertake cascade screening of family members of
D
o
w
nl
oa
de
d
fr
o
m
htt
p:/
/e
ur
he
art
j.o
xf
or
dj
ou
rn
als
.or
g/
by
gu
est
on
O
9.1.2.2
Homozygous
familial
hypercholesterolaemia
Homozygous FH (HoFH) is a rare and lifethreatening disease. The clinical picture is
characterized by extensive xanthomas, marked
premature and progressive CVD and total cholesterol
.13 mmol/L
(500 mg/dL). Most patients develop CAD and aortic
stenosis before the age of 20 years and die before 30
years of age. The frequency of HoFH is estimated to
be 1/160 000 1/300 000. The early identifica- tion
of these children and prompt referral to a specialized
clinic is cru- cial. The patients should be treated with
available cholesterol- lowering drugs and, when
available, with lipoprotein apheresis. For a more
detailed discussion of HoFH, including the role of
PCSK9
inhibitors and the microsomal triglyceride transfer
protein (MTP) in- hibitor lomitapide, see the EAS
Table 22 Recommendations for the detection and
302
consensus paper on HoFH.
treatment of patients with heterozygous familial hypercholesterolaemia
9.1.2.3
Familial
hypercholesterolaemia
in
children
FH is diagnosed in children based on phenotypic
criteria including ele- vated LDL-C plus a family history
of elevated LDL-C, premature CAD and/or positive
303
Recommendations
Class
Level
FH is recommended to be suspected
in patients with CHD before the
age of 55 years for men and 60
years for women, in subjects with
relatives with premature fatal or
I
C
non-fatal CVD, in subjects with
relatives having tendon
xanthomas, and in subjects with
severely elevated LDL-C [in adults
>5 mmol/L
Diagnosis is recommended to be
I
C
confirmed with clinical criteria
and, when available, with DNA
analysis.
Family cascade screening is
recommended to be performed
I
C
when an index case of FH is
diagnosed.
FH patients are recommended to
be treated with intense-dose statin,
I
C
often in combination with
ezetimibe.
Treatment should be considered to
aim at reaching an LDL-C <2.6
mmol/L (100 mg/dL) or in the
presence of CVD <1.8 mmol/L
IIa
C
(70 mg/dL). If targets cannot
be reached, maximal reduction
of LDL-C should be considered
using appropriate drug
Treatment with a PCSK9 antibody
should be considered in FH
patients with CVD or with other
IIa
C
factors putting them at very highrisk for CHD, such as other CV risk
factors, family history, high Lp(a) or
In children, testing is recommended
I
C
from age
5
years,
or
earlier
if
homozygous
FH
is
CHD coronary
CVD
cardiovascular disease; FH familial
Childrenheart
with disease;
FH should
beeducated
hypercholesterolaemia;
LDL-C
low-density
lipoprotein-cholesterol; Lp(a)
to adopt a proper
diet
and treated
lipoprotein(a).
with
statin
from
810
years
of
age.
IIa
C
aClass of recommendation.
Targets for treatment should be LDLbLevel of evidence.
C <3.5 mmol/L (135 mg/dL) at
genetic testing.
Testing during childhood is optimal
to discriminate between FH and non-FH using
LDL-C. LDL-C
5 mmol/L (190 mg/dL) is most probably FH. In
children witha family history of high cholesterol or
premature CHD, the cut-off point may be put at 4.0
mmol/L (160 mg/dL). If a parent has a known genetic
defect, the diagnostic level for the child is 3.5 mmol/L
(130 mg/dL). Although placebo-controlled trials are
missing in children, there are observational studies
suggesting that early treatment can reduce LDL-C
burden, improve endothelial function, substantially
attenuate development of atherosclerosis and
303
D
o
w
nl
oa
de
d
fr
o
m
htt
p:/
/e
ur
he
art
j.o
xf
or
dj
ou
rn
als
.or
g/
by
gu
est
on
O
genetic variants.
Moderate elevation of TG levels
(between 2.0 10.0 mmol/L) is caused by the
polygenic effect of multiple genes influencing both
VLDL production and removal. In CVD prevention,
polygenic moderate TG elevation is to be considered. Monogenic severe HTG causes pancreatitis and
lipid deposits. Thus far, mutations in six genes (LPL,
apoC2, apoA5, LMF1, GPIHBP1 and GPD1) with
monogenic effect have been recognized to lead to severe elevation of serum TGs due to disruption of the
chylomicron re- moval pathways. These mutations
are inherited as an autosomal recessive trait and are
rare. A profound defect in the catabolism of chylomicrons and VLDL results in chylomicronaemia and
TG levels
.11.2 mmol/L (1000 mg/dL), with turbid and milky
serum. Severe
HTG is seen in patients who are homozygous or
compound heterozy- gous for mutations of the
enzyme lipoprotein lipase (LPL) and in the other
genes linked to catabolism of TG-rich lipoproteins.
Recently, gene therapy for LPL deficiency has been
Disorde
Prevalence
Gene(s)
D
o
w
nl
oa
de
d
fr
o
m
htt
p:/
/e
ur
he
art
j.o
xf
or
dj
ou
rn
als
.or
g/
by
gu
est
on
O
Effect on lipoproteins
r
apo apolipoprotein; FCH familial combined
hyperlipidaemia; HeFH heterozygous familial hypercholesterolaemia; HoFH homozygous familial hypercholesterolaem
HDL-C high-density lipoprotein-cholesterol; IDL intermediate-density lipoprotein; LCAT lecithin cholesterol acyltransferase; LDL-C low-density lipoproteincholeste
HeFH
1 in 200250
HoFH
FCH
Familial dysbetalipoproteinaemia
1 in 100/200
1 in 5000
LDL
R
APO
BLDL
R
APO
USF1 +Bmodifying
genes
APO E
LDL-C
LDL-C
chylomicron
remnants (VLDL)
chylomicrons
and
1 in 106
LPL
APO
C2
ABCA1
1 in 106
LCAT
HDL-C
1 in 106
Tangier disease
(analphalipoproteinaemia)
Familial LCAT deficiency
VLDL-C
HDL-C
Page 40 of
72
ESC/EAS
Guidelines
309
9.2 Children
Only children with FH should be considered for lipidlowering drug treatment. In other cases of
dyslipidaemia in children, focus should be on diet
and treatment of underlying metabolic disorders.
HoFH patients should be treated with lipid-lowering
drugs as early as pos- sible, and the same is true for
HeFH patents with extremely high LDL-C, i.e. 400
310
9.3 Women
Among several studies that have evaluated the
impact of lipid-lowering therapy on primary and
secondary prevention of CAD, only a few have
included women, usually in small numbers, and the
results have often not been separately reported by
312
gen- der.
The most recent CTT meta-analysis,
however, indicates a similar relative benefit in men
and women.
65
ESC/EAS
Guidelines
demonstrated.
The
meta-analysis
of
Walsh
and
314
Pignone
reported a 26% reduction of CV mortality, a
29% reduction of MI and a 20% re- duction of total CAD
events in a cohort of 8272 females with previous CVD
mainly treated with statins. The CTT meta-analysis also
indicates that the benefit overall is similar in men and
65
women.
Therefore, sec- ondary prevention of CV
events in women should routinely include a statinbased lipid-lowering regimen, with the same
recommendations and therapeutic goals that are
applied to men.
9.3.3 Non-statin lipid-lowering drugs
No definitive evidence of cardioprotective effects was
63
115,116
Page 41 of
72
80 89 years old.
However, although a relative
risk reduction is seen in the oldest subjects, the
increased frequency of CAD means that the absolute
number of cases associated with cholesterol is
highest in this group. Evidence for treatment in this
group, particularly for those .80 85 years of age,
is limited, and clinical judgement should
guide decisions in the very old.
mg.
The ator- vastatin group had a lower allcause mortality (HR 0.33) and a non- significant
trend towards reduction in major CAD events.
Subgroup analyses in randomized trials have
been performed for several studies. In the
Scandinavian Simvastatin Survival Study (4S) trial,
patients .65 years of age had a similar relative
332
risk reduction as younger patients.
In the Heart
Protection Study (HPS), 20 536 individuals were
allocated to simvastatin or placebo. After 5 years
the relative risk reduction was 18% for coronary
death and 25%
for coronary events. The reduction was similar in age
groups
included.
Statin treat- ment reduced MI (RR 0.61)
and stroke (RR 0.76). The reduction in all-cause
mortality was not significant (RR 0.94). In the Air
Force/Texas Coronary Atherosclerosis Prevention
(AFCAPS-TEX- CAP) study, risk reduction was similar
above and below the median age (57 years for men
328
329
330
Recommendations
Treatment with statins is
recommended for older
adults with established CVD
in the same way as for
younger patients.
Since older people often
have co-morbidities and
have altered
pharmacokinetics, lipidlowering
medication should be
started at a lower dose
and then titrated with
caution to achieve target
Statin therapy should be
considered in older adults
free from CVD,
particularly in the
presence of hypertension,
Class
Level
IIa
IIa
Ref
334,
337
62, 64,
65
D
o
w
nl
oa
de
d
fr
o
m
htt
p:/
/e
ur
he
art
j.o
xf
or
dj
ou
rn
als
.or
g/
by
gu
est
on
O
333
(LIPID),
Cholesterol
and
Recurrent
Events
335
336
(CARE)
and TNT trials.
From data in the LIPID
trial the authors calculated that per 1000 persons
treated, 45 deaths and 47 major coronary events
would be prevented in the older group over 6 years
compared with 22 deaths and 32 major coronary
events in younger patients over the same time period.
In a CTT meta-analysis, rate ratios for the effects of
statins on ma- jor vascular events were 0.78, 0.78 and
0.84 in age groups ,65, 65 75 and .75 years,
64
respectively.
Results from an MI registry study in
Sweden demonstrate that statin treatment is
associated with low- er CV mortality in very old postMI patients without (which is important to stress)
337
increasing the risk of cancer.
9.4.3 Adverse effects, interactions and adherence
The safety and adverse effects of statins are a matter
of special concern in older adults because they often
Page 42 of
72
ESC/EAS
Guidelines
9.5 Diabetes
syndrome
and
metabolic
MetS.
Importantly, diabetes confers excess
mortality risk following ACS despite modern therapies,
highlighting the poor prognosis of coronary patients
345
with T2DM and the need for intensive therapy.
Even more frequent are conditions predisposing to
diabetes, such as the so-called metabolic syndrome.
The term MetS refers to the clustering of different
cardiometabolic risk factors: central obesity, raised
serum TGs, reduced HDL-C, glucose intolerance and
346,347
particles.
components
are at
not
isolated
apoB <100These
mg/dL is
desirable in those
high-risk,
andmalities
<2.6 mmol/L
(<100
mg/dL)
and to
<80
mg/dL,
abnorbut are
closely
linked
each
other.
in those at very high-risk.
Bothrespectively,
LDL waist
and
HDL particles
showof TG
variable
Increased
circumference
and elevation
seems to be achanges
simple tool
to capture
the high-risk in their
compositional
that
are reflected
subjects with MetS.
functions.
Notably
apoCIIIis levels
aremajor
increased
in
Atherogenic
dyslipidaemia
one of the
risk
factors for CVD in people with type 2 diabetes.
subjects
with T2DM.
Together, TRL remnants,
small dense LDL and small dense HDL comprise the
atherogenic
lipid
profile,
which
is
also
characterized by an increase in apoB concentration
due to an in- creased number of apoB-containing
particles. Importantly, TRLs,
350
D
o
w
nl
oa
de
d
fr
o
m
htt
p:/
/e
ur
he
art
j.o
xf
or
dj
ou
rn
als
.or
g/
by
gu
est
on
O
Page 43 of
72
ESC/EAS
Guidelines
CVD outcomes.
The FIELD trial failed to
reduce significantly the primary endpoint of CAD
events (CAD death or non-fatal MI). CVD events were
reduced significantly by 11%. In a post hoc analysis of
the FIELD study, fenofibrate reduced CVD events by
27% in those with elevated TGs
Table 26
Recommendations
In all patients with type I diabetes and in the presence of microalbuminuria and/or renal
disease, LDL-C lowering (at least 50%) with statins as the first choice is recommended
irrespective of the baseline LDL-C concentration.
In patients with type 2 diabetes and CVD or CKD, and in those without CVD who are >40
years of age with one or more other CVD risk factors or markers of target organ damage, the
recommended goal for LDL-C is <1.8 mmol/L (<70 mg/dL) and the secondary goal for nonHDL-C is <2.6 mmol/L (<100 mg/dL) and for apoB is <80 mg/dL.
In all patients with type 2 diabetes and no additional risk factors and/or evidence of target
organ damage, LDL-C <2.6 mmol/L (<100 mg/dL) is the primary goal. Non-HDL-C <3.4 mmol/L
(<130 mg/dL) and apoB <100 mg/dL are the secondary goals.
Class
Level
Ref
64,
357
62, 64
62, 64
apoB apolipoprotein B; CKD chronic kidney disease; CVD cardiovascular disease; HDL-C high-density lipoprotein-cholesterol; LDL-C low-density
lipoproteincholesterol; MetS metabolic syndrome; TG triglycerides.
aClass of recommendation.
bLevel of evidence.
cReference(s) supporting recommendations.
percutaneous coronary
intervention
358
360
D
o
w
nl
oa
de
d
fr
o
m
htt
p:/
/e
ur
he
art
j.o
xf
or
dj
ou
rn
als
.or
g/
by
gu
est
on
O
362
evidence A).
High-dose statin pretreatment or
loading before pri- mary or delayed PCI for ST
elevation MI (STEMI) requires further study. Statin
pretreatment is also effective in reducing the risk of
contrast-induced acute kidney injury after coronary
367
angiography or intervention.
Recommendations for lipid-lowering therapy in
patients with ACS and patients undergoing PCI
are shown in Table 27.
Table 27 Recommendations for lipid-lowering therapy in patients with acute coronary syndrome and patients
undergoing percutaneous coronary intervention
Recommendations
Class
Level
It is recommended to initiate or continue high dose statins early after admission in all ACS
patients without contra- indication or history of intolerance, regardless of initial LDL-C values.
If the LDL-C target is not reached with the highest tolerable statin dose, ezetimibe should be
considered in combination with statins in post-ACS patients.
IIa
If the LDL-C target is not reached with the highest tolerable statin dose and/or ezetimibe,
PCSK9 inhibitors may be considered on top of lipid-lowering therapy; or alone or in
combination with ezetimibe in statin intolerant patients or in whom a statin is contra-indicated.
IIb
Ref
64,
358
360
63
115,
116
D
o
w
nl
oa
de
d
fr
o
m
htt
p:/
/e
ur
he
art
j.o
xf
or
dj
ou
rn
als
.or
g/
by
gu
est
on
O
Lipids should be re-evaluated 46 weeks after ACS to determine whether target levels of LDL-C
<1.8 mmol/L
IIa
C
(<70 mg/dL) or a reduction of at least 50% if the baseline is between 1.8 and 3.5 mmol/L (70
and 135 mg/dL) have been reached and whether there are any safety issues. The therapy dose
Routine short pretreatment or loading (on the background of chronic therapy) with high-dose
IIa
A
363
statins before PCI should be considered in elective PCI or in NSTE-ACS.
ACS acute coronary syndrome; LDL-C low-density lipoprotein-cholesterol; NSTE-ACS non-ST elevation acute coronary syndrome; PCI percutaneous
coronary
365
9.7 Heart
failure
diseases
and
valvular
hospitalizations
and a marked reduction of LDLC and hs-CRP in patients with mainly systolic heart
failure. In any case, there is no evidence for harm in
patients on statin treat- ment after the occurrence of
HF, and therefore there is no need for
discontinuation if patients are already on this
medication. n-3 PUFAs may have a small benefit. In
the GISSI-HF RCT, a significant effect on primary
endpoints (all-cause death and hospitalization for
general population.
The immune system is
believed to be involved in the pathogenesis of
atherosclerosis. Inflammatory components of the immune
response as well as autoimmune elements (e.g.
autoantibodies, autoantigens and auto- reactive
lymphocytes) are involved in these processes. These
dis- eases are characterized by inflammatory
vasculitis and endothelial dysfunction. Therefore
particular attention should be paid to con- ventional
CVD risk factor treatment, including dyslipidaemia,
in these patients. Statins are effective in reducing
disease
activity,
CV
events
and
mortality
(particularly in primary prevention) in this set- ting,
while their discontinuation increases MI and
recommended in patients
of evidence.
withsupporting
aortic valvular
recommendations.
cReference(s)
III
377,
378
D
o
w
nl
oa
de
d
fr
o
m
htt
p:/
/e
ur
he
art
j.o
xf
or
dj
ou
rn
als
.or
g/
by
gu
est
on
O
of CVD.
The results from AURORA (A study to
evaluate the Use of Rosuvastatin in subjects On
Regular haemodialysis: an Assess- ment of survival
and cardiovascular events), involving 2776 patients
on haemodialysis, show that rosuvastatin lowered
LDL-C as ex- pected but had no significant effect on
396
228
III
IIa
IIb
388
392
393,
394,
397
395,
396
399
management in CKD.
In line with this, but with a
focus on those patients at high or very high risk for
developing CVD, recommenda- tions are summarized
in Table 30.
9.10 Transplantation
Recommendations
Class
a
Level
b
Ref
(Table 31)
Table
Recommendations
for lipid in
management
in
Lipid30abnormalities
are common
patients who
patients
with moderate
to severe
kidney disease
have undergone
solid
organ chronic
transplantation
and
predispose patients to the develop- ment of both
atherosclerotic disease and transplant arterial
vasculo- pathy, resulting in major vascular events.
Common general causes of dyslipidaemia in these
patients are diabetes, obesity, MetS and CKD.
403
404
LDL-C.
No outcome data are avail- able for this
drug, which should generally be reserved for secondline use. Care is required with the use of fibrates, as
they can decrease ci- closporin levels and have the
potential to cause myopathy. Extreme
caution is required if fibrate therapy is planned in
combination with a statin. Cholestyramine is not
effective as monotherapy in heart transplant patients
and has the potential to reduce absorption of immunosuppressants,
minimized
by
separate
administration.
pa- tients
and renal transplant patients,
the
amounts of out- come data are not extensive. A
recent systematic review demonstrated a strong
trend towards reduced CVD events and mor- tality
403
Recommendations
Class
a
Level
b
Ref
Global CV risk
management strategies
I
C
have to be developed in
transplant patients.
Statins should be
considered as the firstline agents in transplant
patients. Initiation should
IIa
B
402
be at low doses with
careful up-titration and
with caution regarding
potential
In patients who are
intolerant of statins or
those with significant
dyslipidaemia and high
residual risk despite a
maximally tolerated
IIb
C
CV cardiovascular;
high-density
lipoprotein-cholesterol;
statin dose, HDL
alternative
or
LDL low-density
additionallipoprotein-cholesterol.
therapy may be
aClass of recommendation.
considered: ezetimibe for
bLevel of evidence.
whose where high LDL-C is
cReference(s) supporting recommendations.
the principal abnormality;
409
D
o
w
nl
oa
de
d
fr
o
m
htt
p:/
/e
ur
he
art
j.o
xf
or
dj
ou
rn
als
.or
g/
by
gu
est
on
O
IIa
419
420
Table 32 Recommendations for lipid-lowering drugs in patients with peripheral arterial disease (including carotid artery disease)
Recommendations
PAD is a very-high-risk
condition and lipid-lowering
therapy (mostly statins) is
recommended in these
patients.
Class
Level
Ref
407,
421
D
o
w
nl
oa
de
d
fr
o
m
htt
p:/
/e
ur
he
art
j.o
xf
or
dj
ou
rn
als
.or
g/
by
gu
est
on
O
Class
Level
Ref
64,
65,
422,
426
63
65,
422,
426
422,
428
death.
Statin pre- treatment at TIA onset was
associated with reduced recurrent early stroke risk
in patients with carotid stenosis in a pooled data
analysis, supporting an as-early-as-possible initiation
429
422
D
o
w
nl
oa
de
d
fr
o
m
htt
p:/
/e
ur
he
art
j.o
xf
or
dj
ou
rn
als
.or
g/
by
gu
est
on
O
Recommendation
Lipid lowering therapy (mostly
statins) should be considered in
HIV patients with dyslipidaemia
to achieve the LDL-C goal as
defined for high-risk subjects
Class
a
IIa
Level
437
other.
All this explains the higher prevalence of
obesity, MetS, diabetes and dyslipidaemia in
438
population.
In patients with bipolar disorder there
was a re- duction in life expectancy of 12 14
440
years.
Among 654 patients with bipolar disorder in
the Fondamental Advanced Centers of Ex- pertise in
Disorders (FACE-BD)
18.5%
met the
HIV Bipolar
human immunodeficiency
virus; LDL-Ccohort,
low-density
lipoproteincholesterol.
aClass of recommendation.
cri- teria for MetS; only 11% and 28% of the
bLevel of evidence.
patients with hypercholesterolaemia and high
fasting glycaemia, respectively, were treated for
441
these conditions.
Patients with the aforementioned psychiatric diseases are in general less
compliant with chronic drug treatments and
therefore have their CV risk factors less well
controlled.
CVD accounts for much of the excess mortality in
442
psychiatric pa- tients.
CVD develops more than a
decade earlier in patients with bipolar disorders than
443
in controls.
Therefore it could be recom- mended
to start primary prevention earlier rather than later
in these patients. This is well summarized in a
position paper of the European
Page 50 of
72
ESC/EAS
Guidelines
Lipid-Lowering Treatment
Selector
Fibrates
153
490
43
37
Atorvastati
n
%
%
%
%
Fluvastati
n
Lovastati
n
81%
50% 44
Pravastati
n
%
48
Rosuvastat 213 48% 8% 107
in %
%
%
68
Simvastati
n
%
Bezafibrat
e
Clofibrate
Fenofibrat
e
Gemfibrozi
l
Ezetimibe
41%
Colour Legend
No clinically significant interaction expected. These drugs should not be coadministered.
Potential interaction which may require a dosage adjustment or close monitoring.
Potential interaction predicted to be of weak intensity (<2 fold AUC or <50% AUC). No a priori dosage adjustment is recommended.
Text Legend
Potential increased exposure of the lipid-lowering drug
Psychiatric Association supported by the European
Potential decreased exposure of the lipid-lowering drug
No signficant for
effect
Association
the Study of Diabetes and by the
444 increased exposure of HIV drug
Potential
ESC.
Potential decreased exposure of HIV drug
Numbers refer to increased or decreased AUC of the lipid-lowering drug as observed in drug-drug interaction studies.
antipsychotics
; however, in only a limited number
Recommendations
of these patients are preventive actions ta- ken both
Supplementary figure B HIV-drug interaction database of the University
of Liverpool.
Major psychiatric
disorders are
in regard to lifestyle and to the use of
modifiers
for estimating total CV
cardioprotective drugs. The odds of the use of statins
risk.
The management of total CV risk
was
approximately
halved
in
patients
with
446
in patients with a psychiatric
schizophrenia compared with controls.
disorder is not different from
Unfortunately, no RCTs with hard CV outcome
what is recommended in
measures have so far been conducted in patients
patients at high/very high CV
In patients with psychiatric
with these major mental dis- eases. It is reasonable
disorders particular attention has
to be paid to adherence to lifestyle
to expect that the favourable metabolic ef- fects of
CV cardiovascular.
changes and compliance with drug
treatment that have been demonstrated result in
aClass of recommendation.
445
bLevel
treatment.
of
evidence.
supporting recommendations.
cReference(s)
Class
Level
D
o
w
nl
oa
de
d
fr
o
m
htt
p:/
/e
ur
he
art
j.o
xf
or
dj
ou
rn
als
.or
g/
by
gu
est
on
O
ESC/EAS
Guidelines
Page 51 of
72
10.
Monitoring of
lipids and enzymes in
patients on
lipid-lowering therapy
36)
(Table
therapy.
ALT is recommended 8 12 weeks
after the start of lipid-lowering ther- apy or dose
change, but routine control of ALT during treatment
is not recommended and should be performed, if
indicated, based on clinical observations. In patients
whose liver function tests rise above three times the
ULN, explanations such as alco- hol ingestion or nonalcoholic fatty liver disease should be sought and
the levels monitored. If levels remain elevated then
lipid-lowering therapy should be stopped, but may
be cautiously reintroduced under monitoring after
levels have returned to normal.
There is no predictive value of routine repeat CK
testing for rhabdomyolysis since the level can
D
o
w
nl
oa
de
d
fr
o
m
htt
p:/
/e
ur
he
art
j.o
xf
or
dj
ou
rn
als
.or
g/
by
gu
est
on
O
11.
Strategies to
encourage adoption of
healthy lifestyle
changes and
adherence to lipidmodifying therapies
11.1
Achieving and adhering to
healthy lifestyle changes
clinical practice.
No smoking, healthy eating and being physically
active are the foundations of preventive cardiology
because of their favourable im- pact on CV risk,
including modification of the lipid profile. Healthy
lifestyle habits will also enhance effectiveness and
reduce the need for drug therapy.
Helping patients to change to healthier lifestyle
habits is most ef- fectively achieved through formal
programmes of preventive care, possibly because of
the intensive follow-up and multidisciplinary ex447
Page 52 of
72
ESC/EAS
Guidelines
Table 36 Summary of recommendations for monitoring lipids and enzymes in patients on lipidlowering therapy
Testing lipids
How often should lipids be tested?
Before starting lipid-lowering drug treatment, at least two measurements should be made, with an interval of 112
weeks, with the exception of conditions where concomitant drug treatment is suggested such as ACS and very high-risk
patients.
How often should a patients lipids be tested after starting lipid-lowering treatment?
8 (4) weeks after starting treatment.
8 (4) weeks after adjustment of treatment until within the target range.
How often should lipids be tested once a patient has reached the target or optimal lipid level?
Annually (unless there is adherence problems or other specific reasons for more frequent reviews).
Monitoring liver and muscle enzymes
How often should liver enzymes (ALT) be routinely measured in patients on lipid-lowering drugs?
Before treatment.
Once 812 weeks after starting a drug treatment or after dose increase.
Routine control of ALT thereafter is not recommended during lipid-lowering treatment.
What if liver enzymes become elevated in a person taking lipid-lowering drugs?
If ALT <3x ULN:
Continue therapy.
Recheck liver enzymes in 46 weeks.
If value rises to 3x ULN
Stop lipid-lowering therapy or reduce dose and recheck liver enzymes within 46 weeks.
Cautious reintroduction of therapy may be considered after ALT has returned to normal.
If ALT remains elevated check for the other reasons.
How often should CK be measured in patients taking lipid-lowering drugs?
Pre-treatment
Before starting therapy.
If baseline CK is 4x ULN, do not start drug therapy; recheck.
Monitoring:
Routine monitoring of CK is not necessary.
Check CK if patient develops myalgia.
Be alert regarding myopathy and CK elevation in patients at risk such as: elderly patients, concomitant interfering therapy,
multiple medications, liver or renal disease or sport athletes.
What if CK becomes elevated in a person taking lipid-lowering drugs?
Re-evaluate indication for statin treatment.
If 4 x ULN:
If CK >10x ULN: stop treatment, check renal function and monitor CK every 2 weeks.
If CK <10x ULN: if no symptoms, continue lipid-lowering therapy while monitoring CK.
If CK <10x ULN: if symptoms present, stop statin and monitor normalization of CK, before re-challenge with a lower statin
dose.
Consider the possibility of transient CK elevation for other reasons such as exertion.
Consider myopathy if CK remains elevated.
Consider combination therapy or an alternative drug.
If <4 x ULN:
If no muscle symptoms, continue statin (patient should be alerted to report symptoms; check CK).
If muscle symptoms, monitor symptoms and CK regularly.
If symptoms persist, stop statin and re-evaluate symptoms after 6 weeks; re-evaluate indication for statin treatment.
Consider re-challenge with the same or another statin.
Consider low-dose statin, alternate day or once/twice weekly dosing regimen or combination therapy.
For details on CK elevation and treatment of muscular symptoms during statin treatment see algorithm in supplementary
ACS acute coronary syndrome; ALT alanine aminotransferase; CK creatine kinase; ULN upper limit of normal.
D
o
w
nl
oa
de
d
fr
o
m
htt
p:/
/e
ur
he
art
j.o
xf
or
dj
ou
rn
als
.or
g/
by
gu
est
on
O
ESC/EAS
Guidelines
449
Page 53 of
72
CK 4 X ULN +/rhabdomyolisis
24 weeks washout of
Symptoms
improve:
second statin at
usual or starting
Symptoms
persist:
statin re-
Symptomfree:
continue
Symptoms re-
1) Low-dose third
efficacious
(potent)a statin;
2) Efficaciousa statin
with alternate day or
once/twice weekly
Low-dose second
efficaciousa
statin;
2) Efficaciousa statin
with alternate day or
once/twice weekly
1)
Ezetimi
B + fibrate (not
A+
If still not at goal: consider additional (future) novel therapies: PCSK9 monoclonal antibody
D
o
w
nl
oa
de
d
fr
o
m
htt
p:/
/e
ur
he
art
j.o
xf
or
dj
ou
rn
als
.or
g/
by
gu
est
on
O
CETP = cholesteryl ester transfer protein; CK = creatine kinase; LDL-C= low-density lipoprotein cholesterol; PCKS9 = propotein
onvertase subtilisin/kesin type 9; ULN = upper limit of the normal range.
a
Efficacious statin such as atorvastatin or rosuvastatin.
*Reiner Z et al. (2011).
Web Figure C Algorithm for treatment of muscular symptoms during statin treatment.
211
with
the
additional
controversy
generated
by
464,465
Abramson et al.
regarding their analysis of the
adverse effects of statins, which was subsequently
corrected, it is not surprising that GPs, in particular,
have a certain degree of reluctance to proceed with
the NICE strat- egy. If there is a lack of local
consensus on the prescription of statins in primary
prevention, then GPs may be less inclined to
prescribe them, let alone encourage patients to
adhere to their statin therapy, even in the face of
minor adverse effects.
Various empirical models of health behaviour and
behaviour change theory have been shown to
predict adherence, including the Theory of Planned
466
467
Behaviour
and the Health Belief Model.
Studies
that investigated adherence to medications in longterm conditions identified factors such as high
susceptibility, severity of the condition, strong
intentions and high self-efficacy as being
associated with good adherence, while poor
lifestyle habits and low perceived behavioural
468,469
470
de-
471
11.2
Adhering to medications
fie
d
world.
Not surprisingly, this non- adherence
has an impact on healthcare costs, morbidity,
457 461
physicians
in relation to the recent up- dated
recommendation from NICE to offer atorvastatin 20
mg for the primary prevention of CVD to people
who have an estimated
D
o
w
nl
oa
de
d
fr
o
m
htt
p:/
/e
ur
he
art
j.o
xf
or
dj
ou
rn
als
.or
g/
by
gu
est
on
O
recruits to an RCT.
The most commonly reported
reasons in- cluded general concerns about the
medication, wanting to try life- style measures first
and fear of adverse effects; however, a significant
proportion reported financial hardship, a lack of
understanding of why they needed to take the medication
and what the medication was for (indicating a need
to address the patient pro- fessional relationship
and poor health literacy). Health literacy is de- fined
as the degree to which individuals have the
capacity to obtain, process and understand basic
health info and services needed to make
appropriate
health
decisions
(http://nnlm.gov/outreach/ consumer/hlthlit.html).
Poor health literacy is of particular concern in
475
476
Lisinopri
l
Blood
20
20 mg
Simvasta
tin
Night/Bedti
Cholester
4
0
40 mg
Diabet
Metformi
n
50
0
50
0
500 mg
Gabapent
in
Nerve
30
0
300 mg
1 pill
Aspirin
EC
81 mg
Hear
30
0
30
0
D
o
w
nl
oa
de
d
fr
o
m
htt
p:/
/e
ur
he
art
j.o
xf
or
dj
ou
rn
als
.or
g/
by
gu
est
on
O
479
D
o
w
nl
oa
de
d
fr
o
m
htt
p:/
/e
ur
he
art
j.o
xf
or
dj
ou
rn
als
.or
g/
by
gu
est
on
O
482
484
adherence
drew on the support of allied
professionals such as nurses and pharmacists to
deliver com- plex interventions, which may include
telephone follow-up, interim appointments and
monitoring of repeat prescriptions. The reviewed
interventions may be difficult to replicate in
everyday clinical care
due to the cost and the availability of personnel.
Drawing on the support of non-professional people
within the social context of the patient, such as
spouses, other family members, caregivers or other
key figures, as well as lay groups in the community,
may prove to be a cost-effective way to improve
adherence.
Box 12 lists a number of tips to use when
prescribing multiple medications to patients in order
to help them adhere.
Box 12 Tips to aid adherence to multiple drug therapies
Recommendations
Class
Level
TG adds information about risk, and is indicated for diagnosis and choice of treatment.
Recommendations for lipid analyses as treatment targets in the prevention of cardiovascular disease
LDL-C is recommended as the primary target for treatment.
III
The ratios apoB/apoA1 and non-HDL-C/HDL-C are not recommended as targets for treatment.
III
In patients at VERY HIGH CV riskc, an LDL-C goal of <1.8 mmol/L (70 mg/dL), or a reduction of at least
50% if the baseline LDL-Cd is between 1.8 and 3.5 mmol/L (70 and 135 mg/dL) is recommended.
In patients at HIGH CV riskc, an LDL-C goal of <2.6 mmol/L (100 mg/dL), or a reduction of at least
50% if the baseline LDL-Cd is between 2.6 and 5.2 mmol/L (100 and 200 mg/dL) is recommended.
Prescribe statin up to the highest recommended dose or highest tolerable dose to reach the goal.
Recommendations for the detection and treatment of patients with heterozygous familial
hypercholesterolaemia
FH is recommended to be suspected in patients with CHD before the age of 55 years for men and 60
years for women, in subjects with relatives with premature fatal or non-fatal CVD, in subjects with
relatives having tendon xanthomas, and in subjects with severely elevated LDL-C [in adults >5
mmol/L (190 mg/dL), in children >4 mmol/L (150 mg/dL)].
Family cascade screening is recommended to be performed when an index case of FH is diagnosed.
FH patients are recommended to be treated with intense-dose statin, often in combination with
ezetimibe.
In children, testing is recommended from age 5 years, or earlier if homozygous FH is suspected.
Recommendations for the treatment of dyslipidaemia in older adults
Treatment with statins is recommended for older adults with established CVD in the same way as for
younger patients.
Recommendations for the treatment of dyslipidaemia in diabetes
In all patients with type I diabetes and in the presence of microalbuminuria and/or renal disease,
I
LDL-C lowering (at least 50%) with statins as the first choice is recommended irrespective of the
baseline LDL-C concentration.
In patients with type 2 diabetes and CVD or CKD, and in those without CVD who are >40 years of
age with one or more other CVD risk factors or markers of target organ damage, the recommended
I
goal for LDL-C is <1.8 mmol/L (< 70 mg/dL) and
the secondary goal for non-HDL-C is <2.6 mmol/L (< 100 mg/dL) and for apoB is <80 mg/dL.
In all patients with type 2 diabetes and no additional risk factors and/or evidence of target organ
I
damage, LDL-C <2.6 mmol/L (<100 mg/dL) is the primary goal. Non-HDL-C <3.4 mmol/L (<130
mg/dL) and apoB <100 mg/dL are the secondary goals.
Recommendation for lipid-lowering therapy in patients with acute coronary syndrome and patients
undergoing percutaneous coronary intervention
It is recommended to initiate or continue high dose statins early after admission in all ACS patients
without contra-indication or history of intolerance, regardless of initial LDL-C values.
C
B
B
D
o
w
nl
oa
de
d
fr
o
m
htt
p:/
/e
ur
he
art
j.o
xf
or
dj
ou
rn
als
.or
g/
by
gu
est
on
O
continued
To do or not to
do lipid guidelines (continued)
Recommendations
aClass
bLevel
Class
Level
Cholesterol lowering therapy with statins is not recommended (but is not harmful either) in patients
with heart failure in the absence of other indications for their use.
III
Cholesterol-lowering treatment is not recommended in patients with aortic valvular stenosis without
CAD in the absence of other indications for their use.
III
III
Recommendations for lipid management in patients with moderate to severe chronic kidney disease
Patients with stage 35 CKD have to be considered at high or very high CV risk.
of recommendation.
of evidence.
13. Appendix
ESC Committee for Practice Guidelines (CPG): Jose
Luis Zamorano (Chairperson) (Spain), Victor Aboyans
(France), Stephan Achenbach (Germany), Stefan
Agewall (Norway), Lina Badimon (Spain), Gonzalo
Baro n-Esquivias (Spain), Helmut Baumgartner
(Germany), Jeroen J. Bax (The Netherlands), Hector
Bueno (Spain), Scipione Carerj (Italy), Veronica Dean
(France), etin Erol (Turkey), Donna Fitzsimons (UK),
Oliver Gaemperli (Switzerland), Paulus Kirchhof
(UK/Germany), Philippe Kolh (Belgium), Patrizio
Lancellot- ti (Belgium), Gregory Y. H. Lip (UK), Petros
Nihoyannopoulos (UK), Massimo F. Piepoli (Italy),
Piotr Ponikowski (Poland), Marco Roffi (Switzerland),
Adam Torbicki (Poland), Anto nio Vaz Carneiro
(Portugal), Stephan Windecker (Switzerland).
ESC National Cardiac Societies actively involved
in the re- view process of the 2016 ESC/EAS
Guidelines for the management of dyslipidaemias:
Armenia: Armenian Cardiologists Association,
Parounak
H. Zelveian; Austria: Austrian Society of Cardiology,
Peter Siostr- zonek; Azerbaijan: Azerbaijan Society of
Cardiology,
Firdovsi
Ibrahimov;
Belarus:
Belorussian Scientific Society of Cardiologists,
Volha Sujayeva; Belgium: Belgian Society of
Cardiology, Marc
J. Claeys; Bosnia and Herzegovina: Association of
Cardiologists of Bosnia and Herzegovina, Belma
Pojskic; Bulgaria: Bulgarian
D
o
w
nl
oa
de
d
fr
o
m
htt
p:/
/e
ur
he
art
j.o
xf
or
dj
ou
rn
als
.or
g/
by
gu
est
on
O
14.References
1. Townsend N, Nichols M, Scarborough P, Rayner M.
Cardiovascular disease in Europeepidemiological update
2015. Eur Heart J 2015;36:2696 705.
2. Cooney MT, Dudina A, Whincup P, Capewell S, Menotti A,
Jousilahti P, Njlstad I, Oganov R, Thomsen T, Tverdal A, Wedel
H, Wilhelmsen L, Graham I. Re- evaluating the Rose approach:
comparative benefits of the population and high- risk
preventive strategies. Eur J Cardiovasc Prev Rehabil
2009;16:541 549.
3. Liu K, Daviglus ML, Loria CM, Colangelo LA, Spring B, Moller
AC, Lloyd-Jones DM. Healthy lifestyle through young adulthood
and the presence of low cardiovascular disease risk profile in
middle age: the Coronary Artery Risk Development in (Young)
Adults (CARDIA) study. Circulation 2012;125: 996 1004.
4. Ezzati M, Lopez AD, Rodgers A, Murray CJL. Comparative
quantification of health risks: global and regional burden of
disease attributable to selected major risk fac- tors. Geneva:
World Health Organization, 2004.
5. World Health Organization. Global status report on
noncommunicable diseases 2010. Geneva: World Health
Organization, 2011.
6. Perk J, De Backer G, Gohlke H, Graham I, Reiner Z, Verschuren
M, Albus C, Benlian P, Boysen G, Cifkova R, Deaton C, Ebrahim
S, Fisher M, Germano G, Hobbs R, Hoes A, Karadeniz S,
Mezzani A, Prescott E, Ryden L, Scherer M, Syvanne M,
Scholte op Reimer WJ, Vrints C, Wood D, Zamorano JL, Zannad F.
European Guidelines on cardiovascular disease prevention in
clinical practice (version 2012). The Fifth Joint Task Force of the
European Society of Cardiology and Other Societies on
Cardiovascular Disease Prevention in Clinical Practice
(constituted by representatives of nine societies and by invited
experts). Eur Heart J 2012;33:1635 1701.
7. Mistry H, Morris S, Dyer M, Kotseva K, Wood D, Buxton M. Costeffectiveness of a European preventive cardiology programme
in primary care: a Markov model- ling approach. BMJ Open
2012 Oct 11;2. pii: e001029.
8. Nichols M, Townsend N, Luengo-Fernandez R, Leal J, Gray A,
Scarborough P, Rayner M. European Cardiovascular Disease
Statistics, 2012. Brussels: European Heart Network, 2012.
9. Heidenreich PA, Trogdon JG, Khavjou OA, Butler J, Dracup K,
Ezekowitz MD, Finkelstein EA, Hong Y, Johnston SC, Khera A,
Lloyd-Jones DM, Nelson SA, Nichol G, Orenstein D, Wilson PW,
Woo YJ. Forecasting the future of cardiovas- cular disease in the
United States: a policy statement from the American Heart
Association. Circulation 2011;123:933 944.
10.
McConnachie A, Walker A, Robertson M, Marchbank L,
Peacock J, Packard CJ, Cobbe SM, Ford I. Long-term impact on
healthcare resource utilization of statin treatment, and its cost
effectiveness in the primary prevention of cardiovascular
disease: a record linkage study. Eur Heart J 2014;35:290 298.
11.
Ward S, Lloyd Jones M, Pandor A, Holmes M, Ara R, Ryan
A, Yeo W, Payne N. A systematic review and economic
evaluation of statins for the prevention of coron- ary events.
Health Technol Assess 2007;11:1 160, iii iv.
12.
Plans-Rubio P. The cost effectiveness of statin therapies
in Spain in 2010, after the introduction of generics and
reference prices. Am J Cardiovasc Drugs 2010;10: 369 382.
13.
Bjorck L, Rosengren A, Bennett K, Lappas G, Capewell S.
Modelling the decreasing coronary heart disease mortality in
Sweden between 1986 and 2002. Eur Heart J 2009;30:1046
1056.
14.
Aspelund T, Gudnason V, Magnusdottir BT, Andersen K,
Sigurdsson G, Thorsson B, Steingrimsdottir L, Critchley J,
Bennett K, OFlaherty M, Capewell S. Analysing the large
decline in coronary heart disease mortality in
D
o
w
nl
oa
de
d
fr
o
m
htt
p:/
/e
ur
he
art
j.o
xf
or
dj
ou
rn
als
.or
g/
by
gu
est
on
O
Page 60 of
72
36.
Frieden TR. A framework for public health action: the health
impact pyramid.
Am J Public Health 2010;100:590 595.
37.
Brown MT, Bussell JK. Medication adherence: WHO cares?
Mayo Clin Proc 2011;
86:304 314.
38.
National Institute for Health and Care Excellence. NICE Public
Health Guidance
25. June 2010. https://www.nice.org.uk/guidance/ph25.
39.
Capewell S, Ford ES, Croft JB, Critchley JA, Greenlund KJ,
Labarthe DR. Cardio- vascular risk factor trends and potential
for reducing coronary heart disease mor- tality in the United
States of America. Bull World Health Org 2010;88:120 130.
40.
Mozaffarian D, Capewell S. United Nations dietary policies
to prevent cardiovas- cular disease. BMJ 2011;343:d5747.
41.
DAgostino RB Sr, Vasan RS, Pencina MJ, Wolf PA, Cobain
M, Massaro JM, Kannel WB. General cardiovascular risk profile
for use in primary care: the Framingham Heart Study.
Circulation 2008;117:743 753.
42.
Conroy RM, Pyorala K, Fitzgerald AP, Sans S, Menotti A, De
Backer G, De Bacquer D, Ducimetie` re P, Jousilahti P, Keil
U, Njlstad I, Oganov RG, Thomsen T, Tunstall-Pedoe H,
Tverdal A, Wedel H, Whincup P, Wilhelmsen L, Graham IM.
Estimation of ten-year risk of fatal cardiovascular disease in
Europe: the SCORE project. Eur Heart J 2003;24:987 1003.
43.
Woodward M, Brindle P, Tunstall-Pedoe H. Adding social
deprivation and family history to cardiovascular risk
assessment: the ASSIGN score from the Scottish Heart Health
Extended Cohort (SHHEC). Heart 2007;93:172 176.
44.
Hippisley-Cox J, Coupland C, Vinogradova Y, Robson J,
Minhas R, Sheikh A, Brindle P. Predicting cardiovascular risk in
England and Wales: prospective deriv- ation and validation of
QRISK2. BMJ 2008;336:1475 1482.
45.
Assmann G, Cullen P, Schulte H. Simple scoring scheme for
calculating the risk of acute coronary events based on the 10year follow-up of the prospective cardio- vascular Munster
(PROCAM) study. Circulation 2002;105:310 315.
46.
Ridker PM, Paynter NP, Rifai N, Gaziano JM, Cook NR. Creactive protein and parental history improve global
cardiovascular risk prediction: the Reynolds Risk Score for
men. Circulation 2008;118:2243 2251.
47.
Ridker PM, Buring JE, Rifai N, Cook NR. Development and
validation of improved algorithms for the assessment of global
cardiovascular risk in women: the Reynolds Risk Score. JAMA
2007;297:611 619.
48.
Ferrario M, Chiodini P, Chambless LE, Cesana G, Vanuzzo D,
Panico S, Sega R, Pilotto L, Palmieri L, Giampaoli S. Prediction
of coronary events in a low incidence population. Assessing
accuracy of the CUORE Cohort Study prediction equation. Int J
Epidemiol 2005;34:413 421.
49.
Goff DC Jr, Lloyd-Jones DM, Bennett G, Coady S, DAgostino
RB, Gibbons R, Greenland P, Lackland DT, Levy D, ODonnell CJ,
Robinson JG, Schwartz JS, Shero ST, Smith SC Jr, Sorlie P, Stone
NJ, Wilson PW, Jordan HS, Nevo L, Wnek J, Anderson JL,
Halperin JL, Albert NM, Bozkurt B, Brindis RG, Curtis LH,
DeMets D, Hochman JS, Kovacs RJ, Ohman EM, Pressler SJ,
Sellke FW, Shen WK, Smith SC Jr, Tomaselli GF. 2013 ACC/AHA
guideline on the assessment of cardiovascular risk: a report
of the American College of Cardiology/American Heart
Association Task Force on Practice Guidelines. Circulation
2014;129(25 Suppl 2):S49 S73.
50.
Hajifathalian K, Ueda P, Lu Y, Woodward M, Ahmadvand A,
Aguilar-Salinas CA, Azizi F, Cifkova R, Di Cesare M, Eriksen L,
Farzadfar F, Ikeda N, Khalili D, Khang YH, Lanska V, Leo nMun oz L, Magliano D, Msyamboza KP, Oh K, RodrguezArtalejo F, Rojas-Martinez R, Shaw JE, Stevens GA, Tolstrup J,
Zhou B, Salomon JA, Ezzati M, Danaei G. A novel risk score to
predict cardiovas- cular disease risk in national populations
(Globorisk): a pooled analysis of pro- spective cohorts and
health examination surveys. Lancet Diabetes Endocrinol
2015;3:339 355.
51.
Cooney MT, Dudina AL, Graham IM. Value and limitations
of existing scores for the assessment of cardiovascular risk: a
review for clinicians. J Am Coll Cardiol 2009; 54:1209 1227.
52.
Cooney MT, Dudina A, DAgostino R, Graham IM.
Cardiovascular risk-estimation systems in primary prevention:
do they differ? Do they make a difference? Can we see the
future? Circulation 2010;122:300 310.
ESC/EAS
Guidelines
53.
Lloyd-Jones DM, Leip EP, Larson MG, DAgostino RB,
Beiser A, Wilson PW, Wolf PA, Levy D. Prediction of lifetime
risk for cardiovascular disease by risk factor burden at 50
years of age. Circulation 2006;113:791 798.
54.
Cooney MT, Selmer R, Lindman A, Tverdal A, Menotti A,
Thomsen T, DeBacker G, De Bacquer D, Tell GS, Njolstad I,
Graham IM. Cardiovascular risk estimation in older persons:
SCORE O.P. Eur J Prev Cardiol 2016;23: 1093 1103.
55.
Cooney MT, Dudina A, De Bacquer D, Wilhelmsen L, Sans
S, Menotti A, De Backer G, Jousilahti P, Keil U, Thomsen T,
Whincup P, Graham IM. HDL choles- terol protects against
cardiovascular disease in both genders, at all ages and at all
levels of risk. Atherosclerosis 2009;206:611 616.
56.
Cooney MT, Dudina A, De Bacquer D, Fitzgerald A,
Conroy R, Sans S, Menotti A, De Backer G, Jousilahti P, Keil U,
Thomsen T, Whincup P, Graham I. How much
D
o
w
nl
oa
de
d
fr
o
m
htt
p:/
/e
ur
he
art
j.o
xf
or
dj
ou
rn
als
.or
g/
by
gu
est
on
O
ESC/EAS
Guidelines
Page 61 of
72
Tershakovec AM, Musliner TA, Braunwald E, Califf RM. Ezetimibe
added to statin therapy after acute coronary syndromes. N
Engl J Med 2015;372:2387 2397.
64.
Cholesterol Treatment Trialists (CTT) Collaboration, Baigent
C, Blackwell L, Emberson J, Holland LE, Reith C, Bhala N, Peto
R, Barnes EH, Keech A, Simes J, Collins R. Efficacy and safety of
more intensive lowering of LDL cholesterol: a meta-analysis of
data from 170,000 participants in 26 randomised trials. Lancet
2010;376:1670 1681.
65.
Cholesterol Treatment Trialists (CTT) Collaboration, Fulcher
J, OConnell R, Voysey M, Emberson J, Blackwell L, Mihaylova B,
Simes J, Collins R, Kirby A, Colhoun H, Braunwald E, La Rosa J,
Pedersen TR, Tonkin A, Davis B, Sleight P, Franzosi MG, Baigent
C, Keech A. Efficacy and safety of LDL-lowering therapy among
men and women: meta-analysis of individual data from
174,000 partici- pants in 27 randomised trials. Lancet
2015;385:1397 1405.
66.
Cholesterol Treatment Trialists (CTT) Collaborators,
Mihaylova B, Emberson J, Blackwell L, Keech A, Simes J, Barnes
EH, Voysey M, Gray A, Collins R, Baigent C. The effects of
lowering LDL cholesterol with statin therapy in people at low
risk of vascular disease: meta-analysis of individual data from
27 randomised trials. Lancet 2012;380:581 590.
67.
Hegele RA, Ginsberg HN, Chapman MJ, Nordestgaard BG,
Kuivenhoven JA, Averna M, Bore n J, Bruckert E, Catapano
AL, Descamps OS, Hovingh GK, Humphries SE, Kovanen PT,
Masana L, Pajukanta P, Parhofer KG, Raal FJ, Ray KK, Santos
RD, Stalenhoef AF, Stroes E, Taskinen MR, Tybjrg-Hansen A,
Watts
GF,
Wiklund
O.
The
polygenic
nature
of
hypertriglyceridaemia: implica- tions for definition, diagnosis,
and management. Lancet Diabetes Endocrinol 2014; 2:655
666.
68.
Mills EJ, Rachlis B, Wu P, Devereaux PJ, Arora P, Perri D.
Primary prevention of cardiovascular mortality and events
with statin treatments: a network meta-analysis involving
more than 65,000 patients. J Am Coll Cardiol 2008;52: 1769
1781.
69.
Pedersen TR, Faergeman O, Kastelein JJ, Olsson AG,
Tikkanen MJ, Holme I, Larsen ML, Bendiksen FS, Lindahl C,
Szarek M, Tsai J. High-dose atorvastatin vs usual-dose
simvastatin for secondary prevention after myocardial
infarction: the IDEAL study: a randomized controlled trial. JAMA
2005;294:2437 2445.
70.
SPRINT Research Group, Wright JT Jr, Williamson JD,
Whelton PK, Snyder JK, Sink KM, Rocco MV, Reboussin DM,
Rahman M, Oparil S, Lewis CE, Kimmel PL, Johnson KC, Goff
DC Jr, Fine LJ, Cutler JA, Cushman WC,
D
o
w
nl
oa
de
d
fr
o
m
htt
p:/
/e
ur
he
art
j.o
xf
or
dj
ou
rn
als
.or
g/
by
gu
est
on
O
85.
Robinson JG, Wang S, Jacobson TA. Meta-analysis of
comparison of effectiveness of lowering apolipoprotein B versus
low-density
lipoprotein
cholesterol
and
nonhigh-density
lipoprotein cholesterol for cardiovascular risk reduction in randomized trials. Am J Cardiol 2012;110:1468 1476.
86.
Varbo A, Benn M, Tybjaerg-Hansen A, Jorgensen AB, FrikkeSchmidt R, Nordestgaard BG. Remnant cholesterol as a causal
risk factor for ischemic heart disease. J Am Coll Cardiol
2013;61:427 436.
87.
Triglyceride Coronary Disease Genetics, Consortium and
Emerging Risk Factors Collaboration, Sarwar N, Sandhu MS,
Ricketts SL, Butterworth AS, Di Angelantonio E, Boekholdt SM,
Ouwehand W, Watkins H, Samani NJ, Saleheen D, Lawlor D, Reilly
MP, Hingorani AD, Talmud PJ, Danesh J. Triglyceride- mediated
pathways and coronary disease: collaborative analysis of 101
studies. Lancet 2010;375:1634 1639.
88.
Do R, Willer CJ, Schmidt EM, Sengupta S, Gao C, Peloso GM,
Gustafsson S, Kanoni S, Ganna A, Chen J, Buchkovich ML, Mora
S, Beckmann JS, Bragg-Gresham JL, Chang HY, Demirkan A, Den
Hertog HM, Donnelly LA, Ehret GB, Esko T, Feitosa MF, Ferreira T,
Fischer K, Fontanillas P, Fraser RM, Freitag DF, Gurdasani D,
Heikkila K, Hyppo nen E, Isaacs A, Jackson AU, Johansson
A, Johnson T, Kaakinen M, Kettunen J, Kleber ME, Li X, Luan J,
Lyytikainen LP, Magnusson PK, Mangino M, Mihailov E,
Montasser ME, Mu ller-Nurasyid M, Nolte IM, OConnell
JR, Palmer CD, Perola M, Petersen AK, Sanna S, Saxena R,
Service SK, Shah S, Shungin D, Sidore C, Song C, Strawbridge RJ,
Surakka I, Tanaka T, Teslovich TM, Thorleifsson G, Van den Herik
EG, Voight BF, Volcik KA, Waite LL, Wong A, Wu Y, Zhang W,
Absher D, Asiki G, Barroso I, Been LF, Bolton JL, Bonnycastle LL,
Brambilla P, Burnett MS, Cesana G, Dimitriou M, Doney AS, Do
ring A, Elliott P, Epstein SE, Eyjolfsson GI, Gigante B, Goodarzi
MO, Grallert H, Gravito ML, Groves CJ, Hallmans G, Hartikainen
AL, Hayward C, Hernandez D, Hicks AA, Holm H, Hung YJ, Illig T,
Jones MR, Kaleebu P, Kastelein JJ, Khaw KT, Kim E, Klopp N,
Komulainen P, Kumari M, Langenberg C, Lehtimaki T, Lin SY,
Lindstro m J, Loos RJ, Mach F, McArdle WL, Meisinger C, Mitchell
BD, Mu ller G, Nagaraja R, Narisu N, Nieminen TV, Nsubuga RN,
Olafsson I, Ong KK, Palotie A, Papamarkou T, Pomilla C, Pouta A,
Rader DJ, Reilly MP, Ridker PM, Rivadeneira F, Rudan I,
Ruokonen A, Samani N, Scharnagl H, Seeley J, Silander K,
Stancakova A, Stirrups K, Swift AJ, Tiret L, Uitterlinden AG,
van Pelt LJ, Vedantam S, Wainwright N, Wijmenga C, Wild SH,
Willemsen G, Wilsgaard T, Wilson JF, Young EH, Zhao JH, Adair LS,
Arveiler D, Assimes TL, Bandinelli S, Bennett F, Bochud M,
Page 62 of
72
91.
Haase CL, Tybjrg-Hansen A, Grande P, Frikke-Schmidt R.
Genetically
elevated
apolipoprotein
A-I,
high-density
lipoprotein cholesterol levels, and risk of ische- mic heart
disease. J Clin Endocrinol Metab 2010;95:E500 510.
92.
Voight BF, Peloso GM, Orho-Melander M, Frikke-Schmidt R,
Barbalic M, Jensen MK, Hindy G, Ho lm H, Ding EL, Johnson T,
Schunkert H, Samani NJ, Clarke R, Hopewell JC, Thompson JF,
Li M, Thorleifsson G, Newton-Cheh C, Musunuru K, Pirruccello
JP, Saleheen D, Chen L, Stewart A, Schillert A, Thorsteinsdottir
U, Thorgeirsson G, Anand S, Engert JC, Morgan T, Spertus J,
Stoll M, Berger K, Martinelli N, Girelli D, McKeown PP,
Patterson CC, Epstein SE, Devaney J, Burnett MS, Mooser V,
Ripatti S, Surakka I, Nieminen MS, Sinisalo J, Lokki ML, Perola
M, Havulinna A, de Faire U, Gigante B, Ingelsson E, Zeller T,
Wild P, de Bakker PI, Klungel OH, Maitland-van der Zee AH,
Peters BJ, de Boer A, Grobbee DE, Kamphuisen PW, Deneer VH,
Elbers CC, Onland-Moret NC, Hofker MH, Wijmenga C,
Verschuren WM, Boer JM, van der Schouw YT, Rasheed A,
Frossard P, Demissie S, Willer C, Do R, Ordovas JM, Abecasis
GR, Boehnke M, Mohlke KL, Daly MJ, Guiducci C, Burtt NP, Surti
A, Gonzalez E, Purcell S, Gabriel S, Marrugat J, Peden J,
Erdmann J, Diemert P, Willenborg C, Ko nig IR, Fischer M,
Hengstenberg C, Ziegler A, Buysschaert I, Lambrechts D, Van
de Werf F, Fox KA, El Mokhtari NE, Rubin D, Schrezenmeir J,
Schreiber S, Schafer A, Danesh J, Blankenberg S, Roberts
R, McPherson R, Watkins H, Hall AS, Overvad K, Rimm E,
Boerwinkle E, Tybjaerg-Hansen A, Cupples LA, Reilly MP,
Melander O, Mannucci PM, Ardissino D, Siscovick D, Elosua R,
Stefansson K, ODonnell CJ, Salomaa V, Rader DJ, Peltonen L,
Schwartz SM, Altshuler D, Kathiresan S. Plasma HDL
cholesterol and risk of myocardial infarction: a Mendel- ian
randomisation study. Lancet 2012;380:572 580.
93.
Khera AV, Cuchel M, de la Llera-Moya M, Rodrigues A,
Burke MF, Jafri K, French BC, Phillips JA, Mucksavage ML,
Wilensky RL, Mohler ER, Rothblat GH, Rader DJ. Cholesterol
efflux capacity, high-density lipoprotein function, and atherosclerosis. N Engl J Med 2011;364:127 135.
94.
Li XM, Tang WH, Mosior MK, Huang Y, Wu Y, Matter W, Gao
V, Schmitt D, Didonato JA, Fisher EA, Smith JD, Hazen SL.
Paradoxical association of enhanced cholesterol efflux with
increased incident cardiovascular risks. Arterioscler Thromb
Vasc Biol 2013;33:1696 1705.
95.
Rohatgi A, Khera A, Berry JD, Givens EG, Ayers CR, Wedin
KE, Neeland IJ, Yuhanna IS, Rader DR, de Lemos JA, Shaul PW.
HDL cholesterol efflux capacity and incident cardiovascular
events. N Engl J Med 2014;371:2383 2393.
96.
Sarwar N, Danesh J, Eiriksdottir G, Sigurdsson G,
Wareham N, Bingham S, Boekholdt SM, Khaw KT, Gudnason V.
Triglycerides and the risk of coronary heart disease: 10,158
incident cases among 262,525 participants in 29 Western
prospective studies. Circulation 2007;115:450 458.
97.
Hokanson JE, Austin MA. Plasma triglyceride level is a risk
factor for cardiovascu- lar disease independent of high-density
lipoprotein cholesterol level: a meta-analysis of populationbased prospective studies. J Cardiovasc Risk 1996;3: 213
219.
98.
Bansal S, Buring JE, Rifai N, Mora S, Sacks FM, Ridker PM.
Fasting compared with nonfasting triglycerides and risk of
cardiovascular events in women. JAMA 2007; 298:309 316.
99.
Nordestgaard BG, Benn M, Schnohr P, Tybjaerg-Hansen A.
Nonfasting triglycer- ides and risk of myocardial infarction,
ischemic heart disease, and death in men and women. JAMA
2007;298:299 308.
100. Charlton-Menys V, Betteridge DJ, Colhoun H, Fuller J, France
M, Hitman GA, Livingstone SJ, Neil HA, Newman CB, Szarek M,
DeMicco DA, Durrington PN. Targets of statin therapy: LDL
cholesterol, non-HDL cholesterol, and apolipopro- tein B in type
2 diabetes in the Collaborative Atorvastatin Diabetes Study
(CARDS). Clin Chem 2009;55:473 480.
101. Ingelsson E, Schaefer EJ, Contois JH, McNamara JR,
Sullivan L, Keyes MJ, Pencina MJ, Schoonmaker C, Wilson PW,
DAgostino RB, Vasan RS. Clinical utility of different lipid
measures for prediction of coronary heart disease in men and
women. JAMA 2007;298:776 785.
102. Taskinen MR, Barter PJ, Ehnholm C, Sullivan DR, Mann K,
Simes J, Best JD, Hamwood S, Keech AC. Ability of traditional
lipid ratios and apolipoprotein ratios to predict cardiovascular
risk in people with type 2 diabetes. Diabetologia 2010;53: 1846
1855.
ESC/EAS
Guidelines
103. Sniderman AD, Williams K, Contois JH, Monroe HM,
McQueen MJ, de Graaf J, Furberg CD. A meta-analysis of lowdensity lipoprotein cholesterol, non-high-density lipoprotein
cholesterol, and apolipoprotein B as markers of cardiovascular risk. Circ Cardiovasc Qual Outcomes 2011;4:337
345.
104. Onat A, Hergenc G, Sansoy V, Fobker M, Ceyhan K,
Toprak S, Assmann G. Apo- lipoprotein C-III, a strong
discriminant of coronary risk in men and a determinant of the
metabolic syndrome in both genders. Atherosclerosis
2003;168:81 89.
105. Sacks FM, Alaupovic P, Moye LA, Cole TG, Sussex B,
Stampfer MJ, Pfeffer MA, Braunwald E. VLDL, apolipoproteins
B, CIII, and E, and risk of recurrent coronary events in the
Cholesterol and Recurrent Events (CARE) trial. Circulation
2000;102: 1886 1892.
D
o
w
nl
oa
de
d
fr
o
m
htt
p:/
/e
ur
he
art
j.o
xf
or
dj
ou
rn
als
.or
g/
by
gu
est
on
O
ESC/EAS
Guidelines
Page 63 of
72
15-year outcomes in the Bruneck Study. J Am Coll
prospective
Cardiol 2014;64:851 860.
114. Kamstrup PR, Tybjaerg-Hansen A, Nordestgaard BG.
Extreme lipoprotein(a) le- vels and improved cardiovascular
risk prediction. J Am Coll Cardiol 2013;61: 1146 1156.
115. Robinson JG, Farnier M, Krempf M, Bergeron J, Luc G,
Averna M, Stroes ES, Langslet G, Raal FJ, El Shahawy M, Koren
MJ, Lepor NE, Lorenzato C, Pordy R, Chaudhari U, Kastelein JJ.
Efficacy and safety of alirocumab in reducing lipids and
cardiovascular events. N Engl J Med 2015;372:1489 1499.
116. Sabatine MS, Giugliano RP, Wiviott SD, Raal FJ, Blom DJ,
Robinson J, Ballantyne CM, Somaratne R, Legg J, Wasserman
SM, Scott R, Koren MJ, Stein EA. Efficacy and safety of
evolocumab in reducing lipids and cardiovascular events. N
Engl J Med 2015;727:1500 1509.
117. Seed M, OConnor B, Perombelon N, ODonnell M, Reaveley
D, Knight BL. The effect of nicotinic acid and acipimox on
lipoprotein(a) concentration and turn- over. Atherosclerosis
1993;101:61 68.
118. Packard CJ. Small dense low-density lipoprotein and its role
as an independent predictor of cardiovascular disease. Curr
Opin Lipidol 2006;17:412 417.
119. Mora S, Szklo M, Otvos JD, Greenland P, Psaty BM, Goff DC
Jr, OLeary DH, Saad MF, Tsai MY, Sharrett AR. LDL particle
subclasses, LDL particle size, and ca- rotid atherosclerosis in
the Multi-Ethnic Study of Atherosclerosis (MESA). Atherosclerosis 2007;192:211 217.
120. Whitfield JB. Genetic insights into cardiometabolic risk
factors. Clin Biochem Rev
2014;35:15 36.
121. Nordestgaard BG, Chapman MJ, Humphries SE, Ginsberg
HN, Masana L, Descamps OS, Wiklund O, Hegele RA, Raal FJ,
Defesche JC, Wiegman A, Santos RD, Watts GF, Parhofer KG,
Hovingh GK, Kovanen PT, Boileau C, Averna M, Bore n J,
Bruckert E, Catapano AL, Kuivenhoven JA, Pajukanta P, Ray K,
Stalenhoef AF, Stroes E, Taskinen MR, Tybjrg-Hansen A.
Familial hyper- cholesterolaemia is underdiagnosed and
undertreated in the general population: guidance for clinicians
to prevent coronary heart disease: consensus statement of the
European Atherosclerosis Society. Eur Heart J 2013;34:3478
3490a.
122. Futema M, Shah S, Cooper JA, Li K, Whittall RA, Sharifi M,
Goldberg O, Drogari E, Mollaki V, Wiegman A, Defesche J,
DAgostino MN, DAngelo A, Rubba P, Fortunato G, WalusMiarka M, Hegele RA, Aderayo Bamimore M, Durst R,
Leitersdorf E, Mulder MT, Roeters van Lennep JE, Sijbrands EJ,
Whittaker JC, Talmud PJ, Humphries SE. Refinement of variant
selection for the LDL cholesterol
D
o
w
nl
oa
de
d
fr
o
m
htt
p:/
/e
ur
he
art
j.o
xf
or
dj
ou
rn
als
.or
g/
by
gu
est
on
O
D
o
w
nl
oa
de
d
fr
o
m
htt
p:/
/e
ur
he
art
j.o
xf
or
dj
ou
rn
als
.or
g/
by
gu
est
on
O
D
o
w
nl
oa
de
d
fr
o
m
htt
p:/
/e
ur
he
art
j.o
xf
or
dj
ou
rn
als
.or
g/
by
gu
est
on
O
227. Waters DD, Ho JE, Boekholdt SM, DeMicco DA, Kastelein JJ,
Messig M, Breazna A, Pedersen TR. Cardiovascular event
reduction versus new-onset diabetes during atorvastatin therapy:
effect of baseline risk factors for diabetes. J Am Coll Cardiol
2013;61:148 152.
228. Palmer SC, Navaneethan SD, Craig JC, Perkovic V, Johnson
DW, Nigwekar SU, Hegbrant J, Strippoli GF. HMG CoA reductase
inhibitors (statins) for kidney trans- plant recipients. Cochrane
Database Syst Rev 2014;1:CD005019.
229. Vidt DG. Statins and proteinuria. Curr Atheroscler Rep
2005;7:351 357.
230. Sidaway JE, Davidson RG, McTaggart F, Orton TC, Scott RC,
Smith GJ, Brunskill NJ. Inhibitors of 3-hydroxy-3-methylglutarylCoA reductase reduce receptor-mediated endocytosis in opossum
kidney cells. J Am Soc Nephrol 2004; 15:2258 2265.
231. Davidson MH. Rosuvastatin safety: lessons from the FDA
review and post- approval surveillance. Expert Opin Drug Saf
2004;3:547 557.
232. Egan A, Colman E. Weighing the benefits of high-dose
simvastatin against the risk of myopathy. N Engl J Med
2011;365:285 287.
233. Wiklund O, Pirazzi C, Romeo S. Monitoring of lipids, enzymes,
and creatine kinase in patients on lipid-lowering drug therapy.
Curr Cardiol Rep 2013;15:397.
234. Holoshitz N, Alsheikh-Ali AA, Karas RH. Relative safety of
gemfibrozil and fenofi- brate in the absence of concomitant
cerivastatin use. Am J Cardiol 2008;101: 95 97.
235. Franssen R, Vergeer M, Stroes ES, Kastelein JJ. Combination
statin-fibrate therapy: safety aspects. Diabetes Obes Metab
2009;11:89 94.
236. Guyton JR, Bays HE. Safety considerations with niacin
therapy. Am J Cardiol 2007; 99(6A):22C 31C.
237. Cziraky MJ, Willey VJ, McKenney JM, Kamat SA, Fisher MD,
Guyton JR, Jacobson TA, Davidson MH. Statin safety: an
assessment using an administrative claims database. Am J
Cardiol 2006;97(8A):61C 68C.
238. Ooi CP, Loke SC. Colesevelam for type 2 diabetes mellitus: an
abridged Cochrane review. Diabet Med 2014;31:2 14.
239. The Lipid Research Clinics Coronary Primary Prevention
Trial
results. I. Reduction in incidence of coronary heart
disease. JAMA 1984;251: 351 364.
240. Pre-entry characteristics of participants in the Lipid Research
Clinics Coronary Primary Prevention Trial. J Chronic Dis
1983;36:467 479.
241. The Lipid Research Clinics Coronary Primary Prevention Trial.
Results of 6 years of post-trial follow-up. The Lipid Research
Clinics Investigators. Arch Intern Med 1992;152:1399 1410.
D
o
w
nl
oa
de
d
fr
o
m
htt
p:/
/e
ur
he
art
j.o
xf
or
dj
ou
rn
als
.or
g/
by
gu
est
on
O
D
o
w
nl
oa
de
d
fr
o
m
htt
p:/
/e
ur
he
art
j.o
xf
or
dj
ou
rn
als
.or
g/
by
gu
est
on
O
316. Spitzer WO, Faith JM, MacRae KD. Myocardial infarction and
third generation oral contraceptives: aggregation of recent
studies. Human Reprod 2002;17: 2307 2314.
317. Shufelt CL, Bairey Merz CN. Contraceptive hormone use
and cardiovascular dis- ease. J Am Coll Cardiol 2009;53:221
231.
318. Manson JE, Hsia J, Johnson KC, Rossouw JE, Assaf AR, Lasser
NL, Trevisan M, Black HR, Heckbert SR, Detrano R, Strickland
OL, Wong ND, Crouse JR, Stein E, Cushman M. Estrogen plus
progestin and the risk of coronary heart dis- ease. N Engl J Med
2003;349:523 534.
319. Rosengren A. Better treatment and improved prognosis in
elderly patients with AMI: but do registers tell the whole truth?
Eur Heart J 2012;33:562 563.
320. Gale CP, Cattle BA, Woolston A, Baxter PD, West TH, Simms
AD, Blaxill J, Greenwood DC, Fox KA, West RM. Resolving
inequalities in care? Reduced mor- tality in the elderly after
acute coronary syndromes. The Myocardial Ischaemia National
Audit Project 2003 2010. Eur Heart J 2012;33:630 639.
321. Prospective Studies Collaboration, Lewington S, Whitlock
G, Clarke R, Sherliker P, Emberson J, Halsey J, Qizilibash N, Peto
R, Collins R. Blood choles- terol and vascular mortality by age,
sex, and blood pressure: a meta-analysis of individual data
from 61 prospective studies with 55,000 vascular deaths.
Lancet 2007;370:1829 1839.
322. Prevention of coronary heart disease in clinical practice.
Recommendations of the Second Joint Task Force of European
and other societies on coronary prevention. Eur Heart J
1998;19:1434 1503.
323. Berry JD, Dyer A, Cai X, Garside DB, Ning H, Thomas A,
Greenland P, Van Horn L, Tracy RP, Lloyd-Jones DM. Lifetime
risks of cardiovascular disease. N Engl J Med 2012;366:321
329.
324. Giang KW, Bjo rck L, Novak M, Lappas G, Wilhelmsen L,
Toren K, Rosengren A. Stroke and coronary heart disease:
predictive power of standard risk factors into old agelongterm cumulative risk study among men in Gothenburg,
Sweden. Eur Heart J 2013;34:1068 1074.
325. Wilhelmsen L, Svardsudd K, Eriksson H, Rosengren A,
Hansson PO, Welin C, Oden A, Welin L. Factors associated with
reaching 90 years of age: a study of men born in 1913 in
Gothenburg, Sweden. J Intern Med 2011;269:441 451.
326. Reiner Z. Primary prevention of cardiovascular disease with
statins in the elderly.
Curr Atheroscler Rep 2014;16:420.
327. Savarese G, Gotto AM Jr, Paolillo S, DAmore C, Losco T,
Musella F, Scala O, Marciano C, Ruggiero D, Marsico F, De Luca
G, Trimarco B, Perrone-Filardi P. Benefits of statins in elderly
subjects without established cardiovascular disease: a metaanalysis. J Am Coll Cardiol 2013;62:2090 2099.
328. Downs JR, Clearfield M, Weis S, Whitney E, Shapiro DR,
Beere PA, Langendorfer A, Stein EA, Kruyer W, Gotto AM Jr.
Primary prevention of acute coronary events with lovastatin in
men and women with average cholesterol le- vels: results of
AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis
Prevention Study. JAMA 1998;279:1615 1622.
329. Glynn RJ, Koenig W, Nordestgaard BG, Shepherd J, Ridker
PM. Rosuvastatin for primary prevention in older persons with
elevated C-reactive protein and low to average low-density
lipoprotein cholesterol levels: exploratory analysis of a randomized trial. Ann Intern Med 2010;152:488 496, W174.
330. Shepherd J, Blauw GJ, Murphy MB, Bollen EL, Buckley BM,
Cobbe SM, Ford I, Gaw A, Hyland M, Jukema JW, Kamper AM,
Macfarlane PW, Meinders AE, Norrie J, Packard CJ, Perry IJ,
Stott DJ, Sweeney BJ, Twomey C, Westendorp RG. Pravastatin
in elderly individuals at risk of vascular disease (PROSPER): a
randomised controlled trial. Lancet 2002;360:1623 1630.
331. Deedwania P, Stone PH, Bairey Merz CN, Cosin-Aguilar J,
Koylan N, Luo D, Ouyang P, Piotrowicz R, Schenck-Gustafsson
K, Sellier P, Stein JH, Thompson PL, Tzivoni D. Effects of
intensive versus moderate lipid-lowering therapy
on
myocardial ischemia in older patients with coronary heart
disease: re- sults of the Study Assessing Goals in the Elderly
(SAGE). Circulation 2007;115: 700 707.
332. Miettinen TA, Pyo rala K, Olsson AG, Musliner TA, Cook TJ,
Faergeman O, Berg K, Pedersen T, Kjekshus J. Cholesterollowering therapy in women and elderly pa- tients with
myocardial infarction or angina pectoris: findings from the
D
o
w
nl
oa
de
d
fr
o
m
htt
p:/
/e
ur
he
art
j.o
xf
or
dj
ou
rn
als
.or
g/
by
gu
est
on
O
336. Wenger NK, Lewis SJ, Herrington DM, Bittner V, Welty FK.
Outcomes of using high- or low-dose atorvastatin in patients 65
years of age or older with stable cor- onary heart disease. Ann
Intern Med 2007;147:1 9.
337. Gransbo K, Melander O, Wallentin L, Lindback J,
Stenestrand U, Carlsson J, Nilsson J. Cardiovascular and cancer
mortality in very elderly post-myocardial in- farction patients
receiving statin treatment. J Am Coll Cardiol 2010;55:1362
1369.
338. Zimmet PZ, Magliano DJ, Herman WH, Shaw JE. Diabetes: a
21st century chal- lenge. Lancet Diabetes Endocrinol 2014;2:56
64.
339. Emerging Risk Factors Collaboration, Seshasai SR, Kaptoge S,
Thompson A, Di Angelantonio E, Gao P, Sarwar N, Whincup PH,
Mukamal KJ, Gillum RF, Holme I, Njlstad I, Fletcher A, Nilsson P,
Lewington S, Collins R, Gudnason V, Thompson SG, Sattar N,
Selvin E, Hu FB, Danesh J. Diabetes mellitus, fasting glu- cose,
and risk of cause-specific death. N Engl J Med 2011;364:829
841.
340. Gregg EW, Li Y, Wang J, Burrows NR, Ali MK, Rolka D,
Williams DE, Geiss L. Changes in diabetes-related complications
in the United States, 1990 2010. N Engl J Med 2014;370:1514
1523.
341. Emerging Risk Factors Collaboration, Sarwar N, Gao P,
Seshasai SR, Gobin R, Kaptoge S, Di Angelantonio E, Ingelsson E,
Lawlor DA, Selvin E, Stampfer M, Stehouwer CD, Lewington S,
Pennells L, Thompson A, Sattar N, White IR, Ray KK, Danesh J.
Diabetes mellitus, fasting blood glucose concentration, and risk
of vascular disease: a collaborative meta-analysis of 102
prospective studies. Lancet 2010;375:2215 2222.
342. Sattar N. Revisiting the links between glycaemia, diabetes
and cardiovascular dis- ease. Diabetologia 2013;56:686 695.
343. Liu J, Grundy SM, Wang W, Smith SC Jr, Vega GL, Wu Z, Zeng
Z, Wang W, Zhao D. Ten-year risk of cardiovascular incidence
related to diabetes, predia- betes, and the metabolic syndrome.
Am Heart J 2007;153:552 558.
344. Despres JP. Body fat distribution and risk of cardiovascular
disease: an update.
Circulation 2012;126:1301 1313.
345. Donahoe SM, Stewart GC, McCabe CH, Mohanavelu S,
Murphy SA, Cannon CP, Antman EM. Diabetes and mortality
following acute coronary syndromes. JAMA 2007; 298:765 775.
346. Tchernof A, Despres JP. Pathophysiology of human visceral
obesity: an update.
Physiol Rev 2013;93:359 404.
347. van Vliet-Ostaptchouk JV, Nuotio ML, Slagter SN, Doiron D,
Fischer K, Foco L, Gaye A, Go gele M, Heier M, Hiekkalinna T,
Joensuu A, Newby C, Pang C, Partinen E, Reischl E,
Schwienbacher C, Tammesoo ML, Swertz MA, Burton P, Ferretti V,
D
o
w
nl
oa
de
d
fr
o
m
htt
p:/
/e
ur
he
art
j.o
xf
or
dj
ou
rn
als
.or
g/
by
gu
est
on
O
Page 70 of
72
randomized controlled trials involving 21,295 participants.
Pharmacol Res 2013;72: 35 44.
395. Wanner C, Krane V, Marz W, Olschewski M, Mann JF, Ruf G,
Ritz E. Atorvastatin in patients with type 2 diabetes mellitus
undergoing hemodialysis. N Engl J Med 2005; 353:238 248.
396. Fellstro m BC, Jardine AG, Schmieder RE, Holdaas H,
Bannister K, Beutler J, Chae DW, Chevaile A, Cobbe SM, Gro
nhagen-Riska C, De Lima JJ, Lins R, Mayer G, McMahon AW,
Parving HH, Remuzzi G, Samuelsson O, Sonkodi S, Sci D, Su
leymanlar G, Tsakiris D, Tesar V, Todorov V, Wiecek A, Wuthrich
RP, Gottlow M, Johnsson E, Zannad F. Rosuvastatin and
cardiovascular events in pa- tients undergoing hemodialysis. N
Engl J Med 2009;360:1395 1407.
397. Baigent C, Landray MJ, Reith C, Emberson J, Wheeler DC,
Tomson C, Wanner C, Krane V, Cass A, Craig J, Neal B, Jiang L,
Hooi LS, Levin A, Agodoa L, Gaziano M, Kasiske B, Walker R,
Massy
ZA,
Feldt-Rasmussen
B,
Krairittichai
U,
Ophascharoensuk V, Fellstro m B, Holdaas H, Tesar V, Wiecek
A, Grobbee D, de Zeeuw D, Gro nhagen-Riska C, Dasgupta
T, Lewis D, Herrington W, Mafham M, Majoni W, Wallendszus
K, Grimm R, Pedersen T, Tobert J, Armitage J, Baxter A, Bray C,
Chen Y, Chen Z, Hill M, Knott C, Parish S, Simpson D, Sleight P,
Young A, Collins R. The effects of lowering LDL cholesterol with
simvastatin plus ezetimibe in patients with chronic kidney
disease (Study of Heart and Renal Protection): a randomised
placebo-controlled trial. Lancet 2011; 377:2181 2192.
398. Erickson KF, Japa S, Owens DK, Chertow GM, Garber AM,
Goldhaber-Fiebert JD. Cost-effectiveness of statins for primary
cardiovascular prevention in chronic kid- ney disease. J Am Coll
Cardiol 2013;61:1250 1258.
399. Tonelli M, Wanner C, Kidney Disease: Improving Global
Outcomes Lipid Guide- line Development Work Group
Members. Lipid management in chronic kidney disease:
synopsis of the Kidney Disease: Improving Global Outcomes
2013 clinical practice guideline. Ann Intern Med 2014;160:182.
400. Kobashigawa JA, Katznelson S, Laks H, Johnson JA, Yeatman
L, Wang XM, Chia D, Terasaki PI, Sabad A, Cogert GA. Effect of
pravastatin on outcomes after cardiac transplantation. N Engl J
Med 1995;333:621 627.
401. Wenke K, Meiser B, Thiery J, Nagel D, von Scheidt W,
Steinbeck G, Seidel D, Reichart B. Simvastatin reduces graft
vessel disease and mortality after heart trans- plantation: a
four-year randomized trial. Circulation 1997;96:1398 1402.
402. Page RL 2nd, Miller GG, Lindenfeld J. Drug therapy in the
heart transplant recipi- ent: part IV: drug-drug interactions.
Circulation 2005;111:230 229.
403. Navaneethan SD, Perkovic V, Johnson DW, Nigwekar SU,
Craig JC, Strippoli GF. HMG CoA reductase inhibitors (statins)
for kidney transplant recipients. Cochrane Database Syst Rev
2009;2:CD005019.
404. Shaw SM, Chaggar P, Ritchie J, Shah MK, Baynes AC,
ONeill N, Fildes JE, Yonan N, Williams SG. The efficacy and
tolerability of ezetimibe in cardiac transplant reci- pients taking
cyclosporin. Transplantation 2009;87:771 775.
405. European Stroke Organisation, Tendera M, Aboyans V,
Bartelink ML, Baumgartner I, Cle ment D, Collet JP,
Cremonesi A, De Carlo M, Erbel R, Fowkes FG, Heras M,
Kownator S, Minar E, Ostergren J, Poldermans D, Riambau V,
Roffi M, Ro ther J, Sievert H, van Sambeek M, Zeller T. ESC
Guidelines on the diagnosis and treatment of peripheral artery
diseases: document covering atherosclerotic disease of
extracranial carotid and vertebral, mesenteric, renal, upper
and lower extremity arteries: the Task Force on the Diagnosis
and Treat- ment of Peripheral Artery Diseases of the European
Society of Cardiology (ESC). Eur Heart J 2011;32:2851 2906.
406. McDermott MM, Mandapat AL, Moates A, Albay M, Chiou E,
Celic L, Greenland P. Knowledge and attitudes regarding
cardiovascular disease risk and prevention in patients with
coronary or peripheral arterial disease. Arch Intern Med
2003;163: 2157 2162.
407. Aung PP, Maxwell HG, Jepson RG, Price JF, Leng GC. Lipidlowering for peripheral arterial disease of the lower limb.
Cochrane Database Syst Rev 2007;4: CD000123.
408. Kumbhani DJ, Steg PG, Cannon CP, Eagle KA, Smith SC Jr,
Goto S, Ohman EM, Elbez Y, Sritara P, Baumgartner I, Banerjee
S, Creager MA, Bhatt DL. Statin therapy and long-term adverse
limb outcomes in patients with peripheral artery disease:
ESC/EAS
Guidelines
insights from the REACH registry. Eur Heart J 2014;35:2864
2872.
409. Westin GG, Armstrong EJ, Bang H, Yeo KK, Anderson D,
Dawson DL, Pevec WC, Amsterdam EA, Laird JR. Association
between statin medications and mortality, major adverse
cardiovascular event, and amputation-free survival in
patients with critical limb ischemia. J Am Coll Cardiol
2014;63:682 690.
410. Amarenco P, Labreuche J, Lavallee P, Touboul PJ. Statins
in stroke prevention and carotid atherosclerosis: systematic
review and up-to-date meta-analysis. Stroke 2004;35:2902
2909.
411. Huang Y, Li W, Dong L, Li R, Wu Y. Effect of statin therapy
on the progression of common carotid artery intima-media
thickness: an updated systematic review and meta-analysis
of randomized controlled trials. J Atheroscler Thromb
2013;20: 108 121.
D
o
w
nl
oa
de
d
fr
o
m
htt
p:/
/e
ur
he
art
j.o
xf
or
dj
ou
rn
als
.or
g/
by
gu
est
on
O
ESC/EAS
Guidelines
Page 71 of
72
equivalent among both men and women: results from a nationwide study. Eur J Prev Cardiol 2015;22:317 325.
422. Amarenco P, Labreuche J. Lipid management in the
prevention of stroke: review and updated meta-analysis of
statins for stroke prevention. Lancet Neurol 2009;8: 453 463.
423. McKinney JS, Kostis WJ. Statin therapy and the risk of
intracerebral hemorrhage: a meta-analysis of 31 randomized
controlled trials. Stroke 2012;43:2149 2156.
424. Sever PS, Dahlo f B, Poulter NR, Wedel H, Beevers G,
Caulfield M, Collins R, Kjeldsen SE, Kristinsson A, McInnes GT,
Mehlsen J, Nieminen M, OBrien E, Ostergren J. Prevention of
coronary and stroke events with atorvastatin in hyper- tensive
patients who have average or lower-than-average cholesterol
concentra- tions, in the Anglo-Scandinavian Cardiac Outcomes
Trial--Lipid Lowering Arm (ASCOT-LLA): a multicentre
randomised controlled trial. Lancet 2003;361: 1149 1158.
425. Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto AM Jr,
Kastelein JJ, Koenig W, Libby P, Lorenzatti AJ, MacFadyen JG,
Nordestgaard BG, Shepherd J, Willerson JT, Glynn RJ.
Rosuvastatin to prevent vascular events in men and wo- men
with elevated C-reactive protein. N Engl J Med 2008;359:2195
2207.
426. Byington RP, Davis BR, Plehn JF, White HD, Baker J, Cobbe
SM, Shepherd J. Re- duction of stroke events with pravastatin:
the Prospective Pravastatin Pooling (PPP) Project. Circulation
2001;103:387 392.
427. Heart Protection Study Collaborative Group, Bulbulia R,
Bowman L, Wallendszus K, Parish S, Armitage J, Peto R, Collins
R. Effects on 11-year mortality and morbidity of lowering LDL
cholesterol with simvastatin for about 5 years in 20,536 highrisk individuals: a randomised controlled trial. Lancet
2011;378: 2013 2020.
428. Amarenco P, Bogousslavsky J, Callahan A 3rd, Goldstein
LB, Hennerici M, Rudolph AE, Sillesen H, Simunovic L, Szarek
M, Welch KM, Zivin JA. High-dose atorvastatin after stroke or
transient ischemic attack. N Engl J Med 2006;355: 549 559.
429. Merwick A , Albers GW, Arsava EM, Ay H, Calvet D, Coutts
SB, Cucchiara BL,
Demchuk AM, Giles MF, Mas JL, Olivot JM, Purroy F, Rothwell PM,
Saver JL, Sharma VK, Tsivgoulis G, Kelly PJ. Reduction in early
stroke risk in carotid stenosis with transient ischemic attack
associated with statin treatment. Stroke 2013;44: 2814 2820.
430. Riddler SA, Smit E, Cole SR, Li R, Chmiel JS, Dobs A, Palella
F, Visscher B, Evans R, Kingsley LA. Impact of HIV infection and
HAART on serum lipids in men. JAMA 2003;289:2978 2982.
D
o
w
nl
oa
de
d
fr
o
m
htt
p:/
/e
ur
he
art
j.o
xf
or
dj
ou
rn
als
.or
g/
by
gu
est
on
O
453. McGinnis BD, Olson KL, Delate TM, Stolcpart RS. Statin
adherence and mortality in patients enrolled in a secondary
prevention program. Am J Manag Care 2009;15: 689 695.
454. Huser MA, Evans TS, Berger V. Medication adherence trends
with statins. Adv Ther
2005;22:163 171.
455. Bosworth HB, Granger BB, Mendys P, Brindis R, Burkholder R,
Czajkowski SM, Daniel JG, Ekman I, Ho M, Johnson M, Kimmel
SE, Liu LZ, Musaus J, Shrank WH, Whalley Buono E, Weiss K,
Granger CB. Medication adherence: a call for action. Am Heart J
2011;162:412 424.
456. Hinchcliffe A. Patient Adherence to Treatment with Statins for
the Prevention of Cardio- vascular Disease. Cardiff: Public Health
Wales NHS Trust, 2011.
457. Blackburn DF, Dobson RT, Blackburn JL, Wilson TW, Stang
MR, Semchuk WM. Adherence to statins, beta-blockers and
angiotensin-converting enzyme inhibi- tors following a first
cardiovascular event: a retrospective cohort study. Can J Cardiol
2005;21:485 488.
458. Wei L, Wang J, Thompson P, Wong S, Struthers AD,
MacDonald TM. Adherence to statin treatment and readmission of
patients after myocardial infarction: a six year follow up study.
Heart 2002;88:229 233.
459. Corrao G, Conti V, Merlino L, Catapano AL, Mancia G. Results
of a retrospective database analysis of adherence to statin
therapy and risk of nonfatal ischemic heart disease in daily
clinical practice in Italy. Clin Ther 2010;32:300 310.
460. Aubert RE, Yao J, Xia F, Garavaglia SB. Is there a relationship
between early statin compliance and a reduction in healthcare
utilization? Am J Manag Care 2010;16: 459 466.
461. Sokol MC, McGuigan KA, Verbrugge RR, Epstein RS. Impact of
medication ad- herence on hospitalization risk and healthcare
cost. Med Care 2005;43: 521 530.
462. Naderi SH, Bestwick JP, Wald DS. Adherence to drugs that
prevent cardiovascular disease: meta-analysis on 376,162
patients. Am J Med 2012;125:882 887.e1.
463. Wise J. Open letter raises concerns about NICE guidance on
statins. BMJ 2014;
348:g3937.
464. Abramson JD, Rosenberg HG, Jewell N, Wright JM. Should
people at low risk of cardiovascular disease take a statin? BMJ
2013;347:f6123.
465. Huffman M, Taylor F, Ebrahim S. Huffman and colleagues
response to Abramson and colleagues article on statins in low
risk people. BMJ 2014;348:g1520.
466. Ajzen I. The Theory of Planned Behaviour. Organ Behav Hum
Decis Process 1991;
50:179 211.
467. Becker MH. The Health Belief Model and personal health
behaviour. Health Educ Monogr 1974;2:324 508.
468. Rich A, Brandes K, Mullan B, Hagger MS. Theory of planned
behavior and adher- ence in chronic illness: a meta-analysis. J
Behav Med 2015;38:673 688.
469. Kamran A, Sadeghieh Ahari S, Biria M, Malepour A, Heydari
H. Determinants of patients adherence to hypertension
medications: application of health belief model among rural
patients. Ann Med Health Sci Res 2014;4:922 927.
470. Jackson C, Eliasson L, Barber N, Weinman J. Applying COMB to medication ad- herence. Eur Health Psychol 2014;16:7
17.
471. Michie S, van Stralen MM, West R. The behaviour change
wheel: a new method for characterising and designing
behaviour change interventions. Implement Sci 2011; 6:42.
472. Mann DM, Woodward M, Muntner P, Falzon L, Kronish I.
Predictors of nonadher- ence to statins: a systematic review
and meta-analysis. Ann Pharmacother 2010;44: 1410 1421.
473. Latry P, Molimard M, Dedieu B, Couffinhal T, Begaud B,
Martin-Latry K. Adher- ence with statins in a real-life setting is
better when associated cardiovascular risk factors increase: a
cohort study. BMC Cardiovascular Disorders 2011;11:46.
474. Lewey J, Shrank WH, Bowry AD, Kilabuk E, Brennan TA,
Choudhry NK. Gender and racial disparities in adherence to
statin therapy: a meta-analysis. Am Heart J 2013;165:665
678.e1.
475. Harrison TN, Derose SF, Cheetham TC, Chiu V,
Vansomphone SS, Green K, Tunceli K, Scott RD, Marrett E,
Reynolds K. Primary nonadherence to statin ther- apy: patients
perceptions. Am J Manag Care 2013;19:e133 e139.
476. DeWalt DA, Broucksou KA, Hawk V, Brach C, Hink A, Rudd
R, Callahan L. Devel- oping and testing the health literacy
universal precautions toolkit. Nurs Outlook 2011;59:85 94.
477. Rubak S, Sandbaek A, Lauritzen T, Christensen B.
Motivational interviewing: a sys- tematic review and metaanalysis. Br J Gen Pract 2005;55:305 312.
478. Bandura A. Self-Efficacy: The Exercise of Control. New York:
Freeman, 1997.
479. Schedlbauer A, Davies P, Fahey T. Interventions to improve
adherence to lipid lowering medication. Cochrane Database
Syst Rev 2010;3:CD004371.
480. Nieuwlaat R, Wilczynski N, Navarro T, Hobson N, Jeffery R,
Keepanasseril A, Agoritsas T, Mistry N, Iorio A, Jack S,
Sivaramalingam B, Iserman E, Mustafa RA, Jedraszewski D,
Cotoi C, Haynes RB. Interventions for enhancing medication adherence. Cochrane Database Syst Rev 2014;11:CD000011.
481. Martin SS, Sperling LS, Blaha MJ, Wilson PW, Gluckman TJ,
Blumenthal RS, Stone NJ. Clinician-patient risk discussion for
atherosclerotic cardiovascular
Page 72 of
72
disease prevention: importance to implementation of the 2013
ACC/AHA Guidelines. J Am Coll Cardiol 2015;65:1361 1368.
482. Thom S, Poulter N, Field J, Patel A, Prabhakaran D, Stanton
A, Grobbee DE, Bots ML, Reddy KS, Cidambi R, Bompoint S,
Billot L, Rodgers A. Effects of a fixed-dose combination strategy
on adherence and risk factors in patients with or at high risk of
CVD: the UMPIRE randomized clinical trial. JAMA 2013;310:918
929.
483. Castellano JM, Sanz G, Penalvo JL, Bansilal S, FernandezOrtiz A, Alvarez L, Guzman L, Linares JC, Garca F, DAniello F,
Arnaiz JA, Varea S, Martnez F, Lorenzatti A, Imaz I, SanchezGo mez LM, Roncaglioni MC, Baviera M, Smith SC Jr, Taubert K,
Pocock S, Brotons C, Farkouh ME, Fuster V. A polypill strategy to
improve adherence: results from the FOCUS project. J Am Coll
Cardiol 2014;64:20712082.
484. Ryan R, Santesso N, Lowe D, Hill S, Grimshaw J, Prictor M,
Kaufman C, Cowie G, Taylor M. Interventions to improve
safe and effective medicines use by
ESC/EAS
Guidelines
consumers: an overview of systematic reviews. Cochrane
Database Syst Rev
2014;4:CD007768.
485. Piepoli MF, Hoes AW, Agewall S, Albus C, Brotons C,
Catapano AL, Cooney MT, Corra` U, Cosyns B, Deaton C,
Graham I, Hall MS, Hobbs FD, Lchen ML, Lo llgen H,
Marques-Vidal P, Perk J, Prescott E, Redon J, Richter DJ, Sattar
N, Smulders Y, Tiberi M, van der Worp HB, van Dis I, Verschuren
WM; Authors/ Task Force Members. 2016 European Guidelines
on cardiovascular disease prevention in clinical practice: The
Sixth Joint Task Force of the European So- ciety of Cardiology
and Other Societies on Cardiovascular Disease Prevention in
Clinical Practice (constituted by representatives of 10 societies
and by invited experts) Developed with the special contribution
of the European Association for Cardiovascular Prevention &
Rehabilitation (EACPR). Eur Heart J. 2016;37: 2315 2381.
D
o
w
nl
oa
de
d
fr
o
m
htt
p:/
/e
ur
he
art
j.o
xf
or
dj
ou
rn
als
.or
g/
by
gu
est
on
O