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INTRODUCTION
Cardiovascular disease (CVD) is a leading cause of global mortality and is respon-
sible for approximately 17 million deaths annually (1). In an effort to reduce this
number, the World Heart and Stroke Forum (WHSF) Guidelines Task Force of the
World Heart Federation (WHF) recommended that every country develop its own
policy on CVD prevention. Although the causes of CVD are common to all parts of the
world, the approaches to its prevention will differ between countries for cultural, social,
medical, and economic reasons. As stated in a World Health Organization (WHO)
report from 2002, “Epidemiological theory indicates that, compared with intensive
individual treatment of high-risk patients, small improvements in the overall distri-
bution of risk in a population will yield larger gains in disease reduction when the
underlying conditions that confer risk are widespread in the population”; therefore,
national policy should be developed combining the expertise of governmental, public
health, and professional clinical groups.
A number of tools for estimating the risk of coronary heart disease (CHD) have been
created including risk-score charts, risk-assessment algorithms, and computer software
programs. Many were based on Framingham Heart Study data and others, such as
the European Guidelines Systematic Coronary Risk Evaluation (SCORE) system were
modified based on results from the second European Action on Secondary Prevention
through Intervention to Reduce Events (EUROASPIRE II) (2). The guidelines that
describe these tools are widely available from medical societies such as the American
Heart Association (AHA), European Society of Cardiology (ESC), the Canadian
Medical Society (CMS), and the Joint British Societies (JBS). Published guidelines
from these sites focus on three strategies (3):
1. A population strategy for altering lifestyle and environmental risk factors as well as
social and economic contributions to CHD.
2. A high-risk strategy first to identify those at high risk and then to treat this population.
3. A secondary prevention strategy for those with established coronary artery
disease (CAD).
The guidelines agree that risk factors for CHD are multiplicative and that drug
therapy must be initiated once a risk threshold is met; however, the guidelines differ
on how to measure CV risk and what threshold is best before initiating treatment for
dyslipidemia (4). For example, in a study of 100 German men and women, Broedl
et al. (4) demonstrated how widely several guidelines differ in the identification and
quantification of coronary risk as well as when to initiate lipid-lowering drug therapy.
This chapter will review and compare guidelines for the management of dyslipidemia
and prevention of CVD from Europe, Canada, and the United Kingdom.
Risk Assessment
The 2003 Canadian Update recommend routine screening for all men over age 40
and all women who are postmenopausal or are over age 50. Also, anyone with diabetes,
hypertension, abdominal obesity, smoking history, strong family history of premature
CVD, manifestations of hyperlipidemia, or evidence of symptomatic or asymptomatic
atherosclerosis should be routinely screened (5). The new guidelines attempted to
Chapter 3 / International Guidelines for Dyslipidemia Management 39
standardize CV risk assessment across North America using the Framingham Heart
Study model for estimating the 10-year risk of CVD in men and women without
diabetes mellitus or clinical evidence of CVD (Fig. 1). The Framingham CV risk
equations were first published by Grundy and colleagues in 1999, and the NCEP
ATP III Guidelines (6) adapted the equations based on the estimated 10-year risk
of “hard cardiac endpoints” including death from CAD and non-fatal myocardial
infarction (MI). Using the revised Framingham risk-stratification algorithm as described
in the NCEP ATP III Guidelines (6), the 10-year absolute risk is calculated, and
the patient is placed into one of three risk categories. Patients at high (≥20% or a
history of diabetes mellitus or other atherosclerotic disease), moderate (11–19%), or
low ≤10% risk have established target goals to guide lipid-lowering drug therapy
(Table 1). The Canadian Guidelines were further simplified by using two treatment
targets [low-density lipoprotein cholesterol (LDL-C) and the total cholesterol to high-
density lipoprotein cholesterol ratio (TC: HDL-C)], and both targets must be met. One
advantage of this approach is for patients with low HDL levels where more aggressive
LDL-C lowering and/or HDL-C raising may be necessary to achieve both targets. To
achieve a TC: HDL-C target of <40, the LDL-C must often be lowered to <75 mg/dL
in those patients with low HDL-C (7). Clinical trials have demonstrated that patients
with low HDL-C have a significantly higher residual risk of events on statin therapy.
The ratio has also been shown to be a better epidemiologic predictor of CV events than
LDL-C and also appears to significantly improve event prediction on statin therapy
(14). The Working Group has published the following recommendations to achieve
the TC: HDL-C of <40.
Lifestyle Therapy
For patients with hypertriglyceridemia, dietary therapy and exercise regimens are
intensified with the focus on weight loss and the restriction of refined carbohydrates
and alcohol. For patients with low HDL-C levels, increased activity (aerobic exercise),
increased intake of monounsaturated fats, and moderate alcohol intake [only with
normal triglycerides (TGs)] combined with weight loss are recommended.
Combination Therapy
In patients with combined dyslipidemia and low HDL-C levels, the combination of a
statin with niacin is recommended. If a patient is not a candidate for niacin therapy, the
group recommends substituting a fibrate. Also, the addition of fish oil in combination
with a statin may be beneficial in patients with moderate hypertriglyceridemia.
Specific topics addressed in the 2003 Guidelines include the management of patients
that are at high risk of CAD and are already at target for LDL-C (100 mg/dL), the
management of patients who have combined dyslipidemia and low HDL-C levels, and
the non-invasive assessment of CVD and other risk factors. Factors such as metabolic
syndrome, apolipoprotein B, lipoprotein (a), homocysteine, and C-reactive protein are
discussed as they relate to their influence on risk assessment.
Metabolic Syndrome
The Working Group defined metabolic syndrome in qualitative terms that included
abdominal obesity, insulin resistance, elevated plasma TG levels, low HDL-C levels,
and high blood pressure (Table 2). The Working Group used waist circumference
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20–34 –9 –7
35–39 –4 –3
40–44 0 0
45–49 3 3
50–54 6 6
55–59 8 8
60–64 10 10
65–69 11 12
70–74 12 14
75–79 13 16
Total Points
Cholestral
Age 20–39 Age 40–49 Age 50–59 Age 60–69 Age 70–79
Men Women Men Women Men Women Men Women Men Women
>160 0 0 0 0 0 0 0 0 0 0
160–199 4 4 3 3 2 2 1 1 0 1
200–239 7 8 5 6 3 4 1 2 0 1
240–279 9 11 6 8 4 5 2 3 1 2
≥280 11 13 8 10 5 7 3 4 1 2
Non-Smoker 0 0 0 0 0 0 0 0 0 0
Smoker 8 9 5 7 3 4 1 2 1 1
≥60 –1 –1
50–59 0 0
40–49 1 1
<40 2 2
Fig. 1. (Continued).
Chapter 3 / International Guidelines for Dyslipidemia Management 41
<120 0 0 0 0
120–129 0 1 1 3
130–139 1 2 2 4
140–159 1 3 2 5
≥160 2 4 3 6
Total Points: ———–. Check next table to determine 10-year CHD risk.
Men Women
Total Points 10-year risk (%) Total Points 10-year risk (%)
13 12 20 11
14 16 21 14
15 20 22 17
16 25 23 22
≥17 ≥30 24 27
≥25 ≥30
10-year risk:———–%
Fig. 1. Modified Framingham Score: estimate of 10-year coronary heart disease (CHD) risk.
Reproduced with permission (6).
values as established by the NCEP ATP III Guidelines of 102 cm for men and 88 cm
for women as the cut-off values. The guidelines also review the role of visceral fat as
being the most strongly related to insulin resistance and dyslipidemia (5).
Apolipoprotein B
The Canadian Guidelines discuss the advantages of measuring apolipoprotein B
especially in patients with moderate hypertriglyceridemia and metabolic syndrome.
Advantages also include being able to measure a non-fasting blood sample. According
to Genest, (5) Canadian population values for apolipoprotein B have been established,
apolipoprotein B measurement has been standardized, and most Canadian labora-
tories have the equipment and expertise to measure it. In the Canadian population,
an apolipoprotein B level of 0.9 g/L is around the 20th percentile, 1.05 g/L the 50th
percentile, and 1.2 g/L the 75th percentile.
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Table 1
Risk Categories and Target Lipid Levels
Target level
Risk category LDL-C (mmol/L) TC: HDL-C
Table 2
Clinical Identification of the Metabolic Syndrome
Abdominal obesity
Men Waist circumference >102 cm
Women Waist circumference >88 cm
TG level 1.7 mmol/L
HDL-C level
Men <10 mmol/L
Women <13 mmol/L
Blood pressure 130/85 mmHg
Fasting glucose level 6.2–7.0 mmol/L
Lipoprotein (a)
The Canadian Guidelines suggest that the measurement of lipoprotein (a) although
not a routine measurement may be useful in determining CV risk in patients with
moderate risk and a family history of early CVD. A lipoprotein level >30 mg/dL in a
patient with a TC: HDL-C >55 or other risk factors may indicate the need for earlier
and more intensive therapy to lower the LDL-C level (5).
Homocysteine
Randomized controlled trials studying the effects of lowering homocysteine levels
on CV endpoints are finishing. The position of the Working Group, the Canadian
Cardiovascular Society, the AHA, and the Heart and Stroke Foundation of Canada is
that there is currently insufficient evidence to warrant homocysteine screening until
the results of these trials are known. The group does recommend however that there
may be a specific indication for treatment with folic acid and vitamin B12 in patient’s
undergoing percutaneous coronary revascularization (8–10). They also suggest the
Chapter 3 / International Guidelines for Dyslipidemia Management 43
treatment of patients with homocysteine levels >10 mol/L using folic acid and
vitamins B12 and B6 may be warranted in high-risk patients with renal or CVD (5).
In the preparation of these guidelines, the Task Force recognized that these inter-
ventions are targeted at populations of highest risk. Therefore, the guidelines suggest
the following priorities for CVD prevention in clinical practice:
1. patients with established CHD, PVD, and cerebrovascular atherosclerotic disease;
2. asymptomatic patients with
a. multiple risk factors,
b. markedly raised levels of a single risk factor, and
c. type 2 diabetes mellitus;
3. close relatives of patients with early onset CVD and asymptomatic individuals at
particularly high risk; and
4. other individuals encountered in routine clinical practice (3).
Risk Assessment
As in the Canadian and NCEP ATP III Guidelines, the Third Task Force uses
a CVD risk-stratification method to guide therapeutic intervention in the European
community (Fig. 2). Total risk is estimated using the SCORE system for patients
without known vascular disease. SCORE is derived from a large data set of European
subjects (EUROASPIRE II) and was designed to predict fatal atherosclerotic endpoints
(e.g., fatal CVD events) over a 10-year period (3).
Systematic Coronary Risk Evaluation integrated several modifiable and non-
modifiable risk factors including gender, age, smoking, systolic blood pressure, and
either TC or HDL-C ratio. Advantages of the SCORE system include the ability to
produce risk charts tailored to specific European countries where reliable national
mortality data are available, the ability to project estimated CVD risk to age 60,
and the ability to estimate relative risk by comparing one risk cell against that of a
non-smoking healthy person of the same age/gender (3). Two risk-stratification charts
are available, one for high-risk European countries and one for low-risk European
countries. The low-risk chart is used in Belgium, France, Greece, Italy, Luxembourg,
Spain, Switzerland, and Portugal. The high-risk chart is used in all other European
countries. Patients who score ≥5% are candidates for intensive risk-factor intervention.
In addition to SCORE, the SCORECARD system software program provides infor-
mation on how total risk can be reduced by specific interventions such as lifestyle
modification and drug therapy.
Management of CVD Risk Factors
Behavioral Risk Factors
Behavioral risk factors including diet, activity, and smoking are addressed in the
new guidelines, which also suggest that recent surveys identified a significant gap
between the recommendations provided and the advice given out by physicians in
routine clinical practice (3). ESC guideline recommendations in these areas closely
follow evidence-based practice guidelines as outlined in all guidelines referenced in
this chapter; therefore, these will not be reviewed.
Lipid Management
Prior to the initiation of any therapies, secondary causes of dyslipidemia are ruled
out including alcohol, diabetes, hypothyroidism, liver/kidney disease, and concurrent
drug therapy. Using the recommendations from the SCORE chart, TC and LDL-C
goals are used to guide the decision process and, in general, should be kept <190
Chapter 3 / International Guidelines for Dyslipidemia Management 45
Fig. 2. CVD risk-stratification method to guide therapeutic intervention in the European Community,
the SCORE chart. Reproduced with permission (3).
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and 115 mg/dL, respectively. Although no treatment goals are defined for TGs and
HDL-C, these values are used as risk markers of increased CVD risk. An HDL-C of
<40 mg/dL in men and <46 mg/dL in women along with TG of >150 mg/dL increase
the patients’ risk score. In those asymptomatic patients with high multifactorial risk
as defined in the SCORE chart, the guidelines recommend a further reduction of TC
to <175 mg/dL and LDL-C to <100 mg/dL using lipid-lowering drug therapy. In
asymptomatic patients with a risk score of <5%, the risk assessment is repeated at
5-year intervals. If the risk score is ≥5%, the full lipid panel analysis is completed
and interventions are prescribed (including intensive dietary changes exclusive of drug
therapies) until the value for LDL-C falls <190 mg/dL and TC falls <155 mg/dL
and the total CVD risk falls <5%. The patient is then monitored at yearly intervals.
If, however, the total risk remains ≥5%, drug therapy is begun. The goals in this
population are TC <175 mg/dL and LDL-C <100 mg/dL.
Diabetes
In general, treatment goals for patients with diabetes are more extensive and are
represented in Table 3.
Metabolic Syndrome
The European Guidelines use the definition of metabolic syndrome as defined in the
NCEP ATP III Guidelines. Although the guidelines suggest that patients with metabolic
syndrome are usually at high risk of CVD, no specific guidelines exist beyond those
described by the SCORE assessment guidelines.
The European Guidelines also suggest the following in the prevention of CHD in
clinical practice:
Aspirin or other platelet-modifying drug therapy in virtually all patients with
diagnosed CVD;
Beta-blockers following MI or in patients with left ventricular dysfunction related
to CHD;
Table 3
Diabetic Treatment Goals
Goal
HbA1C ≤61%
Venous plasma glucose
Fasting/pre-prandial ≤60 mmol/L
<110 mg/dL
Self-monitored blood glucose
Fasting/pre-prandial 4.0–5.0 mmol / L
79–90 mg / dL
Postprandial 4.0–7.5 mmol / L
70–135 mg/dL
Blood pressure <130/80 mmHg
TC <45 175 mmol/L mg/dL
LDL-C <25 100 mmol/L mg/dL
of developing CVD over the next 10 years is sufficient to consider drug therapy. In
patients with existing CVD, the target range for TC is <40 mmol/L or a 25% reduction
(whichever is lower) and for LDL-C <20 mmol/L or a 30% reduction (whichever
is lower).
Cardioprotective Therapy
In addition to the lipid-lowering target ranges, all patients with existing CVD should
be considered for cardioprotective therapies that include
Aspirin 75 mg daily,
Blood pressure-lowering therapy as outlined by the British Hypertension Society,
Beta-blockers following MI,
Angiotensin-converting enzyme inhibitors for patients with symptoms of heart failure
at the time of MI or those with persistent LVD (ejection fraction <40%),
Fig. 3. (Continued).
Chapter 3 / International Guidelines for Dyslipidemia Management 49
Consider ACE inhibitor for those with normal LV function if blood pressure targets
not achieved,
Use angiotensin II receptor blockers if ACE inhibitor intolerant,
Calcium channel inhibitors in patients with coronary disease when blood pressure
targets have not been achieved, and
Anticoagulant therapy for those with CVD patients at high risk for systemic
embolization.
Table 4
Guidelines for Asymptomatic People at High Risk of Developing Cardiovascular
Disease (CVD)
BP, blood pressure; LDL-C, low-density lipoprotein cholesterol; TC, total cholesterol.
Reproduced with permission (12).
Chapter 3 / International Guidelines for Dyslipidemia Management 51
Table 5
Guideline Comparisons
Diabetes Mellitus
The guidelines discuss optimal targets for the following:
HbA1C <65%,
Fasting plasma glucose ≤60 mmol/L,
Blood pressure <130/80,
TC <4 mmol/L or 25% decrease, and
LDL-C <20 mmol/L or 30% decrease.
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CONCLUSION
Table 5 summarizes the similarities and differences of the guidelines reviewed.
Notable differences remain in whether to utilize the TC: HDL-C or continue to use
LDL-C as the primary marker for cholesterol management; yet, all describe what the
ideal parameters should be and when to consider initiating drug therapy. Some prefer
to include patients with diabetes in the same stratification system as non-diabetics. The
Joint European Guidelines are now unique in their use of EUROASPIRE II data versus
Framingham Heart Study data. As the population ages and more countries become
industrialized, the guidelines and stratification systems will be modified to reflect the
changing demographics and will incorporate the latest research data.
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Chapter 3 / International Guidelines for Dyslipidemia Management 53