Kardiovaskular 1
Kardiovaskular 1
Kardiovaskular 1
Cardiovascular
Disease
Guidelines for assessment
and management of
cardiovascular risk
WHO Library Cataloguing-in-Publication Data
All rights reserved. Publications of the World Health Organization can be obtained from
WHO Press, World Health Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland
(tel.: +41 22 791 3264; fax: +41 22 791 4857; e-mail: bookorders@who.int). Requests for per-
mission to reproduce or translate WHO publications – whether for sale or for noncommercial
distribution – should be addressed to WHO Press, at the above address (fax: +41 22 791 4806;
e-mail: permissions@who.int).
The designations employed and the presentation of the material in this publication do not imply
the expression of any opinion whatsoever on the part of the World Health Organization concern-
ing the legal status of any country, territory, city or area or of its authorities, or concerning the
delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border
lines for which there may not yet be full agreement.
The mention of specific companies or of certain manufacturers’ products does not imply that
they are endorsed or recommended by the World Health Organization in preference to others of
a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary
products are distinguished by initial capital letters.
All reasonable precautions have been taken by the World Health Organization to verify the
information contained in this publication. However, the published material is being distributed
without warranty of any kind, either expressed or implied. The responsibility for the interpreta-
tion and use of the material lies with the reader. In no event shall the World Health Organization
be liable for damages arising from its use.
Printed in
iii
2. Psychosocial factors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .38
3. Multiple risk factor interventions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .40
4. Blood pressure lowering . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .40
Targets for blood pressure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .41
Choice of initial drug therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .41
5. Lipid lowering . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .45
Benefits . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .45
Risks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .49
Monitoring of treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .50
6. Cost-effectiveness, feasibility and resource implications of antihypertensive
and statin therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .51
7. Control of glycaemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .52
8. Aspirin therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .53
Risks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .54
Balance of risks and benefits . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .54
9. Fixed-dose combinations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .55
10. Hormone therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .56
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .57
ANNEX 1. WHO Member States by subregion, classified according to mortality stratum . . . . . . .73
ANNEX 2. Proportion of the population in each risk category, by WHO subregion . . . . . . . . . . .75
ANNEX 3. Sample WHO/ISH risk prediction chart, for use where measurement of
cholesterol level is possible . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .79
ANNEX 4. Sample WHO/ISH risk prediction chart for use where measurement of
cholesterol level is not possible . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .81
ANNEX 5. Methods of development of WHO/ISH risk prediction charts . . . . . . . . . . . . . . . . . . .83
ANNEX 6. Guideline Development Committee. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .84
ANNEX 7. Peer reviewers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .85
v
vi Prevention of cardiovascular disease
Executive summary
Cardiovascular disease is a major cause of disability and premature death throughout the
world, and contributes substantially to the escalating costs of health care. The underlying
pathology is atherosclerosis, which develops over many years and is usually advanced by
the time symptoms occur, generally in middle age. Acute coronary and cerebrovascular
events frequently occur suddenly, and are often fatal before medical care can be given.
Modification of risk factors has been shown to reduce mortality and morbidity in people
with diagnosed or undiagnosed cardiovascular disease.
This publication provides guidance on reducing disability and premature deaths from
coronary heart disease, cerebrovascular disease and peripheral vascular disease in people
at high risk, who have not yet experienced a cardiovascular event. People with established
cardiovascular disease are at very high risk of recurrent events and are not the subject of
these guidelines. They have been addressed in previous WHO guidelines.a
Several forms of therapy can prevent coronary, cerebral and peripheral vascular events.
Decisions about whether to initiate specific preventive action, and with what degree of
intensity, should be guided by estimation of the risk of any such vascular event. The risk
prediction charts that accompany these guidelinesb allow treatment to be targeted accord-
ing to simple predictions of absolute cardiovascular risk.
Recommendations are made for management of major cardiovascular risk factors through
changes in lifestyle and prophylactic drug therapies. The guidelines provide a framework
for the development of national guidance on prevention of cardiovascular disease that
takes into account the particular political, economic, social and medical circumstances.
a World Health Organization. Prevention of recurrent heart attacks and strokes in low and middle income populations. Evidence-based
recommendations for policy makers and health professionals. Geneva, 2003 (http://www.who.int/bookorders ).
b Risk prediction charts for each WHO subregion (and country) are available with the pocket version of these guidelines.
Executive summary 1
Introduction
High baseline 1 590 000 0.1 2.2 64.0 33.8 35 800 290
risk (12.9) (0.0) (1.4) (40.6) (100.0)
Single risk 1 370 000 4.0 27.4 54.0 14.7 15 500 125
factor (11.1) (0.8) (15.1) (29.5) (37.5)
a Assuming 100% community effectiveness for the single risk factor and high baseline risk strategies, and a 2% total cholesterol
reduction for the Rose strategy.
* Source: ref. 4.
and Control of Noncommunicable Diseases (6), one of the major tasks for WHO and its Member
States is to scale up cost-effective, integrated approaches for prevention of CVD.
This document provides guidance to policy-makers and health care workers on how to target indi-
viduals at high risk of developing CVD, at all levels of the health system and in different resource
settings, using evidence-based and cost-effective preventive approaches. The objective is to reduce
the incidence of heart attacks, strokes, and renal failure associated with hypertension and diabetes,
as well as the need for amputation of limbs because of ischaemia, by reducing the cardiovascular
risk. The focus is prevention of disability and early deaths and improvement of quality of life. This
document should be considered as a framework, which can be adapted to suit different political,
economic, social, cultural and medical circumstances.
Introduction 3
Recommendations can be defined as weak when it is uncertain that their application will do more
good than harm or that the net benefits are worth the costs. In this guide, such recommendations
include the words “suggest” or “should probably”. In applying weak recommendations, clinicians
need to take into account each individual patient’s circumstances, preferences and values. Policy-
making related to weak recommendations requires substantial debate and the involvement of a
range of stakeholders.
/PTIMALDISTRIBUTION
0ERCENTOFPOPULATION
0RESENTDISTRIBUTION
(IGHRISK
0 5 10 15 20 25 30 35 40
10
YEARCARDIOVASCULARDISEASERISK
Figure 1
A combination of population-wide and high-risk strategies are required to reduce the cardiovascular
disease risk distribution of the population (to shift the cardiovascular risk distribution to the left)
source: ref. 11
MEN WOMEN
WHO SUBREGION Age group (years) Age group (years)
African Region: D 0.32% 1.98% 11.15% 13.30% 0.04% 1.10% 8.78% 24.45%
African Region: E 1.26% 1.87% 4.05% 3.84% 0.37% 1.34% 2.43% 3.93%
Region of the 0.85% 8.40% 31.77% 54.23% 0.24% 3.13% 14.38% 31.59%
Americas: A
Region of the 0.43% 5.42% 19.24% 23.25% 0.31% 4.23% 12.95% 25.28%
Americas: B
Region of the 0.08% 2.25% 5.62% 12.36% 0.28% 1.62% 4.36% 18.65%
Americas: D
Eastern Mediterranean 0.13% 4.53% 25.32% 36.64% 0.09% 5.98% 24.08% 49.01%
Region: B
Eastern Mediterranean 0.19% 4.65% 18.73% 38.46% 0.16% 2.60% 15.49% 39.91%
Region: D
European Region: A 0.15% 2.77% 16.13% 37.83% 0.05% 0.32% 2.79% 20.69%
European Region: B 0.88% 8.94% 28.12% 41.93% 0.46% 1.92% 10.79% 22.77%
European Region: C 1.31% 13.70% 40.29% 58.69% 0.50% 3.16% 22.48% 51.89%
South-East Asia 0.37% 4.13% 10.23% 13.54% 0.22% 2.02% 9.32% 13.29%
Region: B
South-East Asia 0.47% 5.12% 22.23% 31.39% 0.22% 3.31% 19.23% 29.75%
Region: D
Western Pacific 0.35% 2.63% 12.32% 26.41% 0.05% 0.61% 2.20% 8.92%
Region: A
Western Pacific 0.16% 3.78% 15.06% 21.63% 0.10% 1.99% 6.74% 15.28%
Region: B
in a Chinese population (48), but not in other populations. The European Guidelines on CVD pre-
vention use a new model for total risk estimation based on the SCORE (Systematic Coronary Risk
Evaluation) system (37). The risk charts based on the SCORE study are derived from a large dataset of
prospective European studies (37). The risk estimation is based on sex, age, smoking, systolic blood
pressure, and either total cholesterol (TC) or the ratio of total cholesterol to high-density lipoprotein
cholesterol (HDL-C). SCORE predicts only the likelihood of fatal CVD events, unlike the risk scores
based on the Framingham equations. The threshold for high risk is defined as a risk of death of 5% or
greater, instead of the composite fatal and non-fatal coronary endpoint of 20%.
The evidence that underpins the use of risk factor scoring and management comes from a range of
sources. There is now increasing evidence that cardiovascular risk factors are associated with clinical
Table 3
Effect of discounting and 30-day case-fatality on life years lost after a cardiovascular disease
event in men*
Age (years) Average life Average life 30-day case fatal- Average discounted
expectancy expectancy ity after a major life-years lost after a
(years) discounted at 3% CVD eventa (%) CVD event, attribut-
per year (years) able to 30-day case
fatality (years)
80 6·8 6·2 60 3·7
70 12 · 2 10 · 3 50 5·2
60 19 · 2 14 · 8 40 5·9
50 27 · 6 18 · 9 30 5·7
40 36 · 8 22 · 4 25 5·6
a Coronary heart disease case-fatality used as a proxy for cardiovascular disease case-fatality
(note that the model does not account for morbidity after a cardiovascular disease event).
* Source: ref. 50.
,OWRISK
'OALOFTREATMENT2EDUCTIONOFTOTALCARDIOVASCULARRISK
Figure 2
Intensity of interventions should be proportional to the total cardiovascular risk
Table 4
Causes, clinical features and laboratory tests for diagnosis of secondary hypertension
Cushing syndrome ◆ truncal obesity, rounded face, buffalo hump, thin skin, abdominal striae, etc.
◆ raised 24-hour urinary cortisol excretion
Physical examination
A full physical examination is essential, and should include careful measurement of blood pres-
sure, as described below. Other important elements of the physical examination include:
● measurement of height and weight, and calculation of body mass index (BMI) (weight in kilo-
grams divided by the square of height in meters); measurement of waist and hip circumference
for calculation of waist–hip ratio;
● examination of the cardiovascular system, particularly for heart size, evidence of heart failure,
evidence of disease in the carotid, renal and peripheral arteries, and physical signs suggestive of
coarctation of the aorta, particularly in young people with hypertension;
● examination for features of secondary hypertension (phaeochromocytoma, Cushing syndrome,
etc.) (Table 4);
● examination of the lungs for congestion ;
● examination of the abdomen for bruits, enlarged kidneys and other masses;
● examination of the optic fundi and of the central and peripheral nervous system for evidence of
cerebrovascular disease and complications of diabetes.
Table 5
Levels of evidence
reviews of randomized controlled trials control or cohort studies with a very low
(RCTs), or RCTs with a very low risk of risk of confounding, bias or chance, and
bias a high probability that the relationship is
causal
1+ Well conducted meta-analyses, systematic Well conducted case–control and cohort
reviews of RCTs, or RCTs with a low risk studies with a very low risk of confounding,
of bias bias or chance, and a high probability that
the relationship is causal
1− Meta-analyses, systematic reviews of RCTs, Case–control and cohort studies with a low
or RCTs with a high risk of bias risk of confounding, bias or chance and a
moderate probability that the relationship
is causal
2++ High quality systematic reviews of case– Case–control or cohort studies with a high
control or cohort studies. High quality risk of confounding, bias or chance and a
case control or cohort studies with a very significant risk that the relationship is not
low risk of confounding or bias and a high causal
probability that the relationship is causal
Pa r t 2
R e c om m e n dat i o n s
population and demonstrating overall consistency of results; or extrapolated evidence from
studies rated as 1++ or 1+.
C On balance of evidence, a pattern of care is recommended with caution.
A body of evidence, including studies rated as 2+, directly applicable to the target popu-
lation and demonstrating overall consistency of results; or extrapolated evidence from
studies rated as 2++.
D Evidence is inadequate, and a pattern of care is recommended by consensus.
Evidence is of level 3 or 4; or extrapolated evidence from studies rated as 2+.
✓ Recommended best practice based on the clinical experience of the guideline development
group
Pa r t 2
high risk of fatal or high risk of fatal or moderate risk of risk. Low risk does
nonfatal vascular nonfatal vascular fatal or nonfatal not mean “no” risk.
events. events. vascular events.
Conservative
Monitor risk profile Monitor risk profile Monitor risk profile management
every 3–6 months every 3–6 months every 6–12 months focusing on lifestyle
interventions is
suggestedb.
When resources are limited, individual counselling and provision of care may have to be
prioritized according to cardiovascular risk.
SMOKING CESSATION
continued …
a Excluding people with established coronary artery disease, cerebrovascular disease and peripheral vascular disease.
b Policy measures that create conducive environments for quitting tobacco, engaging in physical activity and consuming
healthy diets are necessary to promote behavioural change. They will benefit the whole population. For individuals in
low risk categories, they can have a health impact at lower cost, compared to individual counselling and therapeutic
approaches.
DIETARY CHANGES
All individuals should be strongly encouraged to reduce total fat and saturated fat intake (1+,
A). Total fat intake should be reduced to about 30% of calories, saturated fat intake should be
limited to less than 10% of calories and trans-fatty acids eliminated. Most dietary fat should be
polyunsaturated (up to 10% of calories) or monounsaturated (10–15% of calories). (1+, A)
All individuals should be strongly encouraged to reduce daily salt intake by at least one-third
R e c om m e n dat i o n s
and, if possible, to <5 g or 90 mmol per day. (1+, A)
All individuals should be encouraged to eat, at least 400 g a day, of a range fruits and vegetables,
as well as whole grains and pulses. (2+, A)
PHYSICAL ACTIVITY
All individuals should be strongly encouraged to take at least 30 minutes of moderate physical
activity (e.g. brisk walking) a day, through leisure time, daily tasks and work-related physical
activity. (1+, A)
WEIGHT CONTROL
All individuals who are overweight or obese should be encouraged to lose weight through a
combination of a reduced-energy diet (dietary advice) and increased physical activity. (1+, A)
ALCOHOL INTAKE
Individuals who take more than 3 units of alcoholc per day should be advised to reduce alcohol
consumption. (2++, B)
Pa r t 2
continued …
c One unit (drink) = half pint of beer/lager (5% alcohol), 100 ml of wine (10% alcohol), spirits 25 ml (40% alcohol)
ANTIHYPERTENSIVE DRUGS ✓
All individuals with blood pressure at or above 160/100 mm Hg, or lesser degree of raised
blood pressure with target organ damage should have drug treatment and specific lifestyle
advice to lower their blood pressure and risk of cardiovascular disease (2++, B).
continued …
d Evidence from two recent meta-analyses indicates that beta-blockers are inferior to calcium-channel blockers and ACE
inhibitors in reducing the frequency of hard endpoints. In addition, beta-blockers are less well tolerated than diuretics
(see Part III, section 4). Most of this evidence comes from trials where atenolol was the beta-blocker used.
e Reducing blood pressure by 10–15/5–8 mmHg with drug treatment reduces combined CVD mortality and morbidity by
about one-third, whatever the pretreatment absolute risk. However, applying this recommendation will lead to a large
proportion of the adult population receiving antihypertensive drugs. Even in some high-resource settings, current practice
is to recommend drugs for this group only if the blood pressure is at or above 160/100 mmHg.
All individuals with total cholesterol at or above 8 mmol/l (320 mg/dl), should be advised to
follow a lipid-lowering diet and given a statin to lower the risk of cardiovascular disease (2++, B).
R e c om m e n dat i o n s
be advised to follow persistently high lowering dietg
a lipid-lowering diet serum cholesterol
and given a statin. (> 5.0 mmol/l), and
(1++, A) or LDL-cholesterol
> 3.0 mmol/l, despite
Serum cholesterol a lipid-lowering diet,
should be reduced to should be given a
less than 5.0 mmol/l statin. (1+, A)
(LDL-cholesterol to
below 3.0 mmol/l),
or by 25% (30% for
LDL cholesterol)
which ever is greater.f
HYPOGLYCEMIC DRUGS ✓
Individuals with persistent fasting blood glucose > 6 mmol/l despite Recommendations as
diet control should be given metformin. (1+, A) for moderate risk, as
resources permit.
continued …
Pa r t 2
f Reducing cholesterol level by 20% (approximately 1 mmol/l) with statin treatment would be expected to yield a coronary
heart disease mortality benefit of 30%, whatever the pretreatment absolute risk. However, applying this to the general
population may not be cost effective. It will lead to a large proportion of the adult population receiving statins. Even in
some high-resource settings, current practice is to recommend drugs for this group only if serum cholesterol is above
8mmol/l (320 mg/dl).
g There are no clinical trials that have evaluated the absolute and relative benefits of cholesterol lowering to different
cholesterol targets in relation to clinical events.
ANTIPLATELET DRUGS ✓
Hormone replacement, vitamin B, C, E and folic acid supplements, are not recommended for
reduction of cardiovascular risk.
Pa r t 2
h Consider aspirin in areas where coronary heart disease rates exceed stroke rates.
✓ Best Practice point: Unless there are compelling indications to use a specific drug, the least expensive preparation of the
above classes of drugs should be used. Good quality generic preparations of medicines listed in WHO essential medicines
list are recommended.
1.1 Tobacco
Issues
● Does quitting use of tobacco products reduce cardiovascular risk?
● How can smokers be helped to stop smoking?
Evidence
There is a large body of evidence from prospective cohort studies regarding the beneficial effect of
smoking cessation on coronary heart disease mortality (116). However, the magnitude of the effect
and the time required to achieve beneficial results are unclear. Some studies suggest that, about
10 years after stopping smoking, coronary heart disease mortality risk is reduced to that of people
who have never smoked (109, 110, 117, 118). Other reports suggest that a much longer time is
required (119). It has also been shown that cigarette smokers who change to a pipe or cigar (119),
and those who continue to smoke but reduce the number of cigarettes, have a greater mortality
risk than those who quit smoking (112). A 50-year follow-up of British doctors demonstrated
that, among ex-smokers, the age of quitting has a major impact on survival prospects; those who
quit between 35 and 44 years of age had the same survival rates as those who had never smoked
(120). The benefits of giving up other forms of tobacco use are not clearly established (121–124).
General recommendations are therefore based on the evidence for cigarette smoking. Recent
evidence from the Interheart study (31) has highlighted the adverse effects of use of any tobacco
product and, importantly, the harm caused by even very low consumption (1–5 cigarettes a day).
The benefits of stopping smoking are evident; however, the most effective strategy to encourage
smoking cessation is not clearly established. All patients should be asked about their tobacco use
and, where relevant, given advice and counselling on quitting, as well as reinforcement at follow-up.
There is evidence that advice and counselling on smoking cessation, delivered by health profession-
als (such as physicians, nurses, psychologists, and health counsellors) are beneficial and effective
(125–130). Several systematic reviews have shown that one-time advice from physicians during
routine consultation results in 2% of smokers quitting for at least one year (127, 131).
Similarly, nicotine replacement therapy (132, 133) can increase the rate of smoking cessation. Nico-
tine may be administered as a nasal spray, skin patch or gum; no particular route of administration
seems to be superior to others.
Data from observational studies suggest that passive cigarette smoking produces a small increase
in cardiovascular risk (138–140). Whether reducing exposure to passive cigarette smoke reduces
cardiovascular risk has not been directly established.
The interventions described above targeted at individuals may be less effective if they are imple-
mented in populations exposed to widespread tobacco advertising, sponsorship of sporting
activities by the tobacco industry, low-cost tobacco products, and inadequate government tobacco
control policies. There is evidence that tobacco consumption decreases markedly as the price
of tobacco products increases. Bans on advertising of tobacco products in public places and on
sales of tobacco to young people are essential components of any primary prevention programme
addressing noncommunicable diseases (140).
1.2 Diet
Issue
Are there specific dietary changes that can reduce cardiovascular risk?
1.2.1 Effect on cardiovascular risk of saturated fat, unsaturated fat, trans-fatty acids
and cholesterol in the diet
The relationship between dietary fat and coronary heart disease has been extensively investi-
gated. Saturated fats as a whole have been shown to raise LDL-cholesterol levels (104, 141–145).
However, individual fatty acids within the group have different effects, with myristic and palmitic
acids having the greatest effect on LDL-cholesterol (146). Saturated fatty acids are not all equally
hypercholesterolaemic. The cholesterol-raising properties of saturated fats are attributed to lauric
acid (12:0), myristic acid (14:0), and palmitic acid (16:0). Stearic acid (18:0) and saturated fatty
acids with fewer than 12 carbon atoms are thought not to raise serum cholesterol concentrations
(146, 147). The effects of different saturated fatty acids on the distribution of cholesterol over the
various lipoproteins are not well known.
When substituted for saturated fatty acids in metabolic studies, n-6 polyunsaturated fatty acids
(which are abundant in soybean and sunflower oil) and monounsaturated fatty acids (which are
abundant in olive oil) lower total cholesterol, LDL cholesterol and triglyceride concentrations (145,
148). More research is needed to determine the appropriate mixture of unsaturated fatty acids that
will produce maximum effect on CVD risk.
Trans-fatty acids come from both animal and vegetable sources and are produced by partial hydro-
genation of unsaturated oils. Dietary intake of trans-fatty acids increases LDL-cholesterol and, at
high intakes, lowers HDL cholesterol (143–145, 149–151). Metabolic and epidemiological studies
have indicated that trans-fatty acids increase the risk of coronary heart disease (145, 152, 153).
1.2.5 Summary
Dietary intakes of fat, cholesterol, fruits and vegetables, fish and sodium are linked to cardiovascu-
lar risk. There is a considerable body of evidence regarding the nutritional background of athero-
sclerosis in general and CHD in particular. However, much of this evidence is from observational
studies, in which control for potential confounding factors, in particular socioeconomic position,
is often inadequate. The inferences that can be made from these studies are necessarily guarded.
A cardioprotective diet should consist of a variety of foods, and should aim to achieve four major
goals: a healthy overall diet, a healthy body weight, a desirable lipid profile, and a desirable blood
pressure. There is strong observational evidence that reducing intakes of total fat (to less than 30%
of calories), saturated fat (to less than 10% of calories), and salt (to less than 5 g or 90 mmol per
day), and increasing fruits and vegetables (to 400–500 g daily) are likely to be beneficial. Applying
these principles to develop diets that match individual preferences and local customs, and demon-
strating their effectiveness in reducing cardiovascular risk, are important priorities for research.
Evidence
It has been estimated that inadequate physical activity is responsible for about one-third of deaths
due to coronary heart disease and type 2 diabetes (191). There is evidence from observational
studies that leisure-time physical activity is associated with reduced cardiovascular risk and cardio-
vascular mortality in both men and women (192–194) and in middle-aged and older individuals
(195, 196).
Several meta-analyses have examined the association between physical activity and cardiovascular
disease (197–202). Berlin & Colditz (200) found a summary relative risk of death from coronary
heart disease of 1.9 (95% CI 1.6 to 2.2) for people with sedentary occupations compared with
those with active occupations. A meta-analysis of studies in women showed that physical activity
was associated with a reduced risk of overall cardiovascular disease, coronary heart disease and
stroke, in a dose–response fashion (197).
Physical activity improves endothelial function, which enhances vasodilatation and vasomotor
function in the blood vessels (199). In addition, physical activity contributes to weight loss,
glycaemic control (203, 204), improved blood pressure (205), lipid profile (206–208) and insulin
sensitivity (209). The possible beneficial effects of physical activity on cardiovascular risk may be
mediated, at least in part, through these effects on intermediate risk factors. Physical inactivity and
low physical fitness are independent predictors of mortality in people with type 2 diabetes (210).
Overall, the evidence points to the benefit of continued regular moderate physical activity,
which does not need to be strenuous or prolonged, and can include daily leisure activities, such
as walking or gardening (197). Taking up regular light or moderate physical activity in middle
or older age significantly reduces CVD and all-cause mortality, and improves the quality of life
(85, 86, 196–198, 211, 212).
Evidence
Obesity is a growing health problem in both developed and developing countries (2). Prospective
epidemiological studies have shown a relationship between overweight or obesity and cardiovas-
cular morbidity, CVD mortality and total mortality (215–221). Obesity is strongly related to major
cardiovascular risk factors, such as raised blood pressure, glucose intolerance, type 2 diabetes, and
dyslipidaemia (215, 218, 220, 222).
Meta-analyses of RCTs have shown that a weight-reducing diet, combined with exercise, produces
significant weight loss, reduces total cholesterol and LDL-cholesterol, increases HDL-cholesterol,
and improves control of blood pressure and diabetes (223, 224).
Weight loss programmes using dietary, physical activity, or behavioural interventions have been
shown to produce significant reductions in weight among people with pre-diabetes, and a signifi-
cant decrease in diabetes incidence (225). A meta-analysis of randomized controlled trials (226)
1.5 Alcohol
Issue
Does alcohol consumption reduce cardiovascular risk?
Evidence
Many studies have shown a U- or J-shaped association between mortality and alcohol consump-
tion, in which people who drink light or moderate amounts have a lower death rate than non-
drinkers, while those who drink large amounts have a higher death rate (232–240). People who
drink heavily have a high mortality from all causes and cardiovascular disease, including sudden
death and haemorrhagic stroke. In addition, they may suffer from psychological, social and other
medical problems related to high alcohol consumption (237–240).
2. Psychosocial factors
Issue
Are there specific psychosocial interventions that can reduce cardiovascular risk?
Evidence
Observational studies have indicated that some psychosocial factors, such as depression and
anxiety, lack of social support, social isolation, and stressful conditions at work, independently
In the MRFIT cohort study (248) greater depressive symptoms were associated with increased
mortality after 18 years of follow-up. Significantly higher risks of all-cause mortality (HR 1.15;
95% CI 1.03 to 1.28; P < 0.01), CVD mortality (HR 1.21; 95% CI 1.03 to 1.41; P < 0.05), and
stroke mortality (HR 2.03; 95% CI 1.20 to 3.44; P < 0.01) were found in the quintile with the
highest level of depressive symptoms compared with those in the lowest quintile.
More recent trials have cast doubt on the causal nature of the association between depression
and CHD. In a large randomized trial of psychological intervention after myocardial infarction,
no impact on recurrence or mortality was found (253). Another large trial that provided social
support and treatment for depression also found no impact (254). Depression has a negative
impact on quality of life (255, 256), and antidepressant therapy has been shown to significantly
improve quality of life and functioning in patients with recurrent depression who are hospitalized
with acute coronary syndromes (257, 258).
Kivimäki et al. (255), in a 25.6-year prospective cohort study in Finland, found that metal indus-
try employees with high job strain (a combination of high demands at work and low job control)
had a cardiovascular mortality risk 2.2 times that of their colleagues with low job strain (95% CI
1.2 to 4.2). This association between stressful conditions at work and CHD is supported by other
studies (250, 257).
There is also some evidence that social isolation and lack of quality social support are indepen-
dent risk factors for CHD onset and prognosis: the risks are increased 2–3-fold and 3–5-fold,
respectively, in both men and women (259). The association has been demonstrated in subjects
in different countries, and in various age groups (250, 259–262). While these findings provide
some support for a causal interpretation of the associations, it is quite possible that they represent
confounding or a form of reporting bias, as illustrated in a large Scottish cohort (263).
Well planned trials of interventions to reduce work stress and social isolation are required to
elucidate whether there is a true cause–effect relationship and, more importantly, whether inter-
vention reduces cardiovascular risk. In the meantime, physicians and health care providers should
consider the whole patient. Early detection, treatment and referral of patients with depression and
other emotional and behavioural problems are, in any case, important for reducing suffering and
improving the quality of life, independent of any effect on cardiovascular disease. Mobilizing social
support to avoid or solve social and work concerns is also a legitimate response to a patient’s
difficulties (258).
Evidence
A Cochrane systematic review has evaluated the effectiveness of multiple risk factor interven-
tions for the primary prevention of cardiovascular disease in adults from general populations,
occupational groups and high-risk groups (106). Eighteen randomized controlled trials involving
counselling and/or health education, with or without pharmacological treatment, which aimed
to affect more than one cardiovascular risk factor (smoking, diet, physical activity, blood pressure
and blood cholesterol) were included. Overall, modest reductions in smoking prevalence, systolic
blood pressure, diastolic blood pressure, and blood cholesterol were observed. The studies with
the highest baseline levels of smoking prevalence, diastolic blood pressure or cholesterol levels
demonstrated greater intervention-related reductions in these risk factors. The pooled effects of
the ten trials with clinical event endpoints showed no significant effect on total or cardiovascular
disease mortality; this is consistent with the extent of changes in risk factors. However, trials that
focused on participants with elevated blood pressure, and those that used drug treatment, demon-
strated significant reductions in coronary heart disease mortality and total mortality. Interventions
using personal or family counselling and education, with or without drug treatment, were more
effective in modifying risk factors and reducing mortality in people at high risk because of raised
blood pressure. These results argue in favour of multiple risk factor interventions for prevention
of cardiovascular disease in multifactorial high-risk groups. For the general low-risk population,
policy measures that create a conducive environment which facilitates behavioural change may
have a greater impact at lower cost than individual counselling and therapeutic approaches.
Evidence
Raised blood pressure is estimated to cause about 7 million premature deaths throughout the
world, and 4.5% of the disease burden (64 million disability-adjusted life years (DALYs)) (1–3).
It is a major risk factor for cerebrovascular disease, coronary heart disease, and cardiac and renal
failure. Treating raised blood pressure has been associated with a 35–40% reduction in the risk
of stroke and at least a 16% reduction in the risk of myocardial infarction (264). Raised blood
pressure often coexists with other cardiovascular risk factors, such as tobacco use, overweight or
obesity, dyslipidaemia and dysglycaemia, which increase the cardiovascular risk attributable to any
level of blood pressure. Worldwide, these coexisting risk factors are often inadequately addressed
in patients with raised blood pressure, with the result that, even if their blood pressure is lowered,
these people still have high cardiovascular morbidity and mortality rates (265–267).
Almost all clinical trials have confirmed the benefits of antihypertensive treatment at blood pres-
sure levels of 160 mmHg (systolic) and 100 mmHg (diastolic) and above, regardless of the pres-
Compelling indications
Compelling
Class of drug Reference and grade of Cautions
Condition contraindications
recommendation
ACE inhibitorsa, b Type 1 diabetic Lewis et al. (303) 1++, A Pregnancy
nephropathy
Bilateral renal
Non-diabetic Jafar et al. (304) 1++, A artery stenosis
nephropathy
Hyperkalaemia
Left ventricular SOLVD investigators (305)
dysfunction Flather et al. (306) 1++, A
ARBsb Type 2 diabetic Parving et al. (283) 1+, A Pregnancy
nephropathy Brenner et al. (282)
Lewis et al. (307) Bilateral renal
artery stenosis
Left ventricular Pitt et al. (308) 1+, A
hypertrophy Dahlof et al. (309) Hyperkalaemia
Lindholm et al. (290)
Heart failure in Granger et al. (310) 1+, A
ACE-inhibitor
intolerance
CCBs Elderly with Staessen et al. (311) 1+, A Congestive heart Following myo-
(dihydropyridine) isolated systolic failure cardial infarction
hypertension (short-acting
CCBs)
Black patients Cushman et al. (297) 1+, A
Diuretics Elderly with SHEP (312) 1+, A Gout
isolated systolic
hypertension
Black patients Radevski et al. (298) 1+, A
Beta-blockers Following myo- Teo et al. (313) 1++, A High-degree heart Heart failure
cardial infarction Freemantle et al. (314) block,
Yusuf et al. (315) Peripheral
Severe bradycardia vascular disease,
(< 50/min)
Diabetes (except
Obstructive with CHD)
airways disease
Raynaud
Alpha-blockers Benign prostatic Oesterling (299) Urinary Congestive heart
hypertrophy incontinence failure
Central Pregnancy Withdrawal syn-
alpha-agonist (methyldopa) drome (clonidine)
Hepatotoxicity
(methyldopa)
Peripheral When other Lindholm et al. (316) Depression
alpha-agonist medicines are
ineffective or Active peptic
not available or ulcer
affordable
a Type 2 diabetic nephropathy is possible indication for ACE inhibitors.
b Chronic renal disease and proteinuric renal disease are possible indications for ACE inhibitors and ARBs; however, they
should be used with caution, under close supervision and with specialist advice.
ACE inhibitors dry cough, renal dysfunction in patients with impaired renal function
5. Lipid lowering
Issue
Does treatment with statins reduce cardiovascular risk?
Evidence
Many studies have shown that the benefits of cholesterol-lowering therapy depend on the initial
level of cardiovascular risk: the higher the total risk, the greater the benefit. This is because the
relative reductions in risk as a consequence of lipid lowering are approximately the same at differ-
ent levels of cardiovascular risk.
The effectiveness of statins in patients with established atherosclerotic disease (principally coronary
artery disease) is well established. Primary prevention trials, on the other hand, are more limited;
however, the benefits seen in these trials, as demonstrated by meta-analyses, are consistent with the
overall results for all statin trials.
Benefits
The benefits of statins for primary prevention have been examined in several RCTs and subsequent
meta-analyses.
In the West of Scotland Coronary Prevention Study (WOSCOPS) (318), 6595 men aged
45–64 years, with no history of myocardial infarction and plasma total cholesterol concentrations
Risks
There is no evidence from the large studies that cholesterol-lowering therapy increases the risk of
death from other causes (333, 337, 338). Meta-analysis of data from statin trials has not shown
an excess of adverse symptoms, including muscle pain and various gastrointestinal symptoms,
in the treated group. The absolute risks of rhabdomyolysis and liver failure from hepatitis were
low. Rhabdomyolysis (indicated by serum creatine kinase ≥10 times the upper limit of normal)
was reported in 55 treated patients (0.17%) and 43 placebo patients (0.13%). The incidence of
rhabdomyolysis is estimated to be about one per million person–years of use. There were no cases
of liver failure in the trials. Hepatitis (indicated by alanine aminotransferase ≥3 times the upper
limit of normal) was reported in 449 treated patients (1.3%) and 383 placebo patients (1.1%).
From 1987 to 2000, the Food and Drug Administration in the USA recorded 30 cases of liver
failure attributable to statins – about one per million person-years of use (339, 340).
Data from randomized trials of cholesterol reduction and disease events have not provided evi-
dence that a low serum cholesterol concentration increases mortality from any cause, other than
possibly haemorrhagic stroke. Too few haemorrhagic strokes were observed in the randomized
trials to resolve the uncertainty related to this condition. Further, the risk of haemorrhagic stroke
affected only people with a very low cholesterol concentration and, even in this group, the risk
was outweighed by the benefits from the reduced risk of coronary heart disease.
In some trials, the possibility of an excess risk of cancer has been raised. In the Cholesterol
Treatment Trialists Collaboration meta-analysis, there was no evidence of an effect on cancer
deaths. There was also no evidence of an increased risk of developing cancer (RR 1.00; 95% CI
0.95 to 1.06; P = 0·9), no evidence of an excess incidence of cancers with increasing duration of
No therapy is completely free from adverse effects. Treatment of those most at risk will bring the
most benefit; treatment of patients not at high risk of cardiovascular disease may expose them
to adverse effects without much benefit. As the side-effects of liver and muscle damage are dose-
dependent (340), the high-dose statin regimens evaluated in some of the trials (344) will have a
worse side-effects profile when applied to patients treated in everyday clinical practice.
Nicotonic acid is an effective HDL raising agent. A meta-analysis of 53 trials using fibrates and
30 trials using niacin showed that each drug significantly lowered total cholesterol, LDL-C and
triglycerides and raised HDL-C (348) . Fibrates reduced the risk of major coronary events by 25%
and niacin by 27% (349).
Monitoring of treatment
Some guidelines recommend that treatment should aim to reduce total and LDL-cholesterol levels
below particular targets, e.g. total cholesterol to less than 5 mmol/l (190 mg/dl) or LDL-cholesterol
to less than 3 mmol/l (115 mg/dl) (350). However, recent studies have not found a cholesterol
level below which there is no benefit, suggesting that taking a trial-validated dose of a statin is
more important than aiming for a particular target cholesterol level (321). Thus, continued moni-
toring of blood lipids may not be necessary in settings with limited resources.
Primary prevention trials (320, 322, 323) have demonstrated that patients at highest total risk of
cardiovascular events obtain the greatest benefit from statin therapy. Treatment should therefore
be targeted at the group with highest total risk, rather than simply those with highest lipid levels.
The relative importance of resource considerations and patient preference will increase as the total
CVD risk decreases.
7. Control of glycaemia
Issue
Does control of glycaemia reduce cardiovascular risk in patients with diabetes?
Evidence
Cardiovascular disease accounts for about 60% of all mortality in people with diabetes. The risk
of cardiovascular events is 2–3 times higher in people with type 1 or type 2 diabetes (354, 355)
and the risk is disproportionately higher in women (354, 356). Patients with diabetes also have a
poorer prognosis after cardiovascular events compared with non-diabetics (357, 358).
Epidemiological evidence also suggests that the association between blood glucose and cardiovas-
cular disease begins before diabetes manifests itself (357–361). In a meta-analysis of non-diabetic
subjects, those with the highest blood glucose levels had a relative risk for cardiovascular disease
events of 1.26 compared with those with the lowest blood glucose. This suggests that cardiovas-
cular risk increases as glucose tolerance becomes impaired and then progresses to diabetes (362).
Further, abnormal glucose regulation tends to occur together with other known cardiovascular
risk factors, such as central obesity, elevated blood pressure, low HDL-cholesterol and high tri-
glyceride level (363, 364).
The Diabetes Control and Complications Trial (DCCT) (365), which included 1441 young adults
with type 1 diabetes, demonstrated that intensive treatment to ensure good glycaemic control
substantially reduced the risks of cardiovascular events, neuropathy, nephropathy and retinopathy.
However, the difference in the number of events in the two groups was not significant. Among
the more than 1300 volunteers who continued to participate in the DCCT follow-up study, those
who had received intensive treatment had 57% fewer serious cardiovascular events, such as heart
attacks and strokes, than those given conventional treatment (366).
The United Kingdom Prospective Diabetes Study (UKPDS) found that glycaemic control in people
with type 2 diabetes reduced the frequency of microvascular complications, such as blindness,
amputation, and end-stage renal disease (367). Each 1% increase in HbA1c level was associated
with a 14% increase in the incidence of fatal or nonfatal myocardial infarction (368). However,
intensive treatment of patients with newly diagnosed type 2 diabetes, with sulfonylureas or insulin,
resulted in a 16% reduction (P = 0.052) in the relative risk of myocardial infarction compared with
patients treated conventionally (367). The UKPDS concluded that there is a direct relationship
between level of glycaemia and the risk of complications of diabetes. There was no “threshold” of
glycaemia at which there was a significant change in risk for any of the clinical outcomes examined.
The rate of increase of microvascular disease with hyperglycaemia was greater than that of macro-
vascular disease. The UKPDS also showed that lowering the HbA1c level by an average of 0.9%,
for a median follow-up period of 10 years after diagnosis of type 2 diabetes, was associated with a
significant reduction in microvascular endpoints, retinopathy and nephropathy (367).
Metformin is safe and effective for treatment of type 2 diabetes, either as monotherapy or in com-
bination with other drugs. The role of the newer insulin secretagogues, the thiazolidinediones, is
still being evaluated in clinical trials. In most circumstances, metformin is the drug of choice for
initial therapy of obese patients with type 2 diabetes and mild to moderate hyperglycaemia (370).
For each patient the risk of hypoglycaemia must be considered when determining the target
HbA1c level, especially in people treated with insulin and those with type 1 diabetes. Health care
practitioners should be aware that more intensive glycaemic control increases the risk of hypo-
glycaemia. Treatment guidelines often set therapeutic goals at the level of lowest risk. However, it
is important to set targets appropriate to the individual and in consultation with him or her. It is
also important to recognize that adherence to medicines is much lower in real-life settings than in
clinical trials. The results of controlled trials are unlikely to be achieved in clinical practice unless
specific measures are taken to improve compliance with treatment.
In summary, good glycaemic control should be a key goal of treatment of diabetes, to delay the
onset and progression of microvascular and macrovascular disease. Treatment should aim to
achieve:
● a fasting blood glucose level of 4–7 mmol/l (72–126 mg/dl);
● an HbA1c level of 6.5% or less.
The first approach to controlling glycaemia should be through diet alone; if this is not sufficient,
oral medication should be given, followed by insulin if necessary. The decision on whether to give
statins to people with diabetes needs to be made if their CVD risk is estimated to be 20% or more
over 10 years (371).
8. Aspirin therapy
Issue
Does long-term treatment with aspirin reduce cardiovascular risk?
Evidence
Several RCTs (277, 372–377) and meta-analyses (377–379) have evaluated the role of aspirin
in the primary prevention of cardiovascular disease. Overall, the results of the randomized trials
indicated that, compared with placebo, aspirin was associated with a 32% reduction in myocardial
infarction (RR 0.68; 95% CI 0.54 to 0.86; P = 0.001) and a non-significant increase in the risk of
stroke. The numbers of women enrolled in most of these trials were too small to allow robust con-
clusions to be drawn about the role of aspirin in primary prevention for women. In the Women’s
Health study (376), women aged 45 years or older (n = 39 876) were randomly assigned to receive
low-dose aspirin therapy or placebo, and followed up for 10 years. Aspirin had no significant
effect on the risk of myocardial infarction. However, there was a 17% lower risk of stroke in the
Risks
Aspirin roughly doubles the risk of gastrointestinal haemorrhage. A review of observational studies
(380) suggested that the background risk of major gastrointestinal complications is about 1–2 per
1000 per year at age 60 years. The excess risks attributable to aspirin are therefore 1–2 per 1000
per year at age 60. Among unselected people under 60 years, therefore, the expected benefit in
terms of myocardial infarction (2 per 1000 per year avoided) does not exceed the expected risk
of a major gastrointestinal bleed. Further observational studies strongly suggested that the risk of
bleeding associated with aspirin increases substantially in older people, rising to 7 per1000 per
year at age 80; the balance of benefit and risk, therefore, needs to be clearly defined before aspirin
can recommended for all elderly people.
Estimates of the rate of excess haemorrhagic stroke associated with the use of aspirin in three
primary prevention trials were 0.20, 0.05, and 0.12 bleeding events per 1000 patients treated per
year (372-374). In Hypertension Optimal Treatment (HOT) trial and Primary Prevention Project
(PPP) (277, 375), approximately 0.03 and 0.12 bleeding events were caused per 1000 patients
treated per year, respectively. The meta-analysis of these studies (378) also found that aspirin was
associated with an increased risk of haemorrhagic stroke (summary odds ratio 1.4; 95% CI 0.9 to
2.0). Estimates of the beneficial and harmful effects of aspirin have been used to project the impact
of aspirin on populations of patients at different levels of 5-year risk for CHD. In 1000 patients
with a 5% (high) risk, aspirin would be expected to prevent 14 CHD events and cause 0–2 haem-
orrhagic strokes; in patients with a 3% (moderate) risk, aspirin would prevent 8 CHD events and
cause 0–2 haemorrhagic strokes; and in patients with a 1% (low) risk, aspirin would prevent
3 CHD events and cause 0–2 haemorrhagic strokes (381). A similar analysis using the same
primary prevention studies estimated comparable effects for haemorrhagic stroke, confirming that
the absolute excess risk of haemorrhagic stroke attributable to aspirin is small (around 0.1 per
1000 per year) (382).
The rationale for the components in a combination pill require scrutiny. While the efficacy of
aspirin in men is established, for example (387), the recently completed women’s health study
found no difference in all-cause mortality or fatal and non-fatal myocardial infarction between
groups of women given 100 mg of aspirin every other day or placebo (388). In addition, although
observational evidence favours a possible causal association between raised plasma homocysteine
concentrations and cardiovascular disease (389), there is growing evidence from RCTs that the
expected beneficial effects of folic acid may not be confirmed (390–392).
In reviewing the evidence supporting the use of combination therapy, a recent working group
report commented that: (a) the estimates of effect may have been exaggerated; (b) adherence to
treatment may be low in healthy populations; (c) new studies of efficacy, effectiveness and cost-
effectiveness are needed; and (d) social and behavioural issues related to population coverage,
adoption, and long-term maintenance need to be examined (393). In addition, the potentially
damaging effect of a mass-medication approach on population-wide public health measures for
tobacco control, healthy diets and physical activity need to be considered. Commentators are gen-
erally agreed on the need for further research on the combination pill, and for continued strong
engagement with public health programmes for cardiovascular disease prevention (394, 395).
A pill containing amlodipine and atorvastatin (in a range of dose combinations) has been licensed
by the Food and Drug Administration in the USA, and marketed at slightly less than the cost of
the two drugs separately since 2003.
Marketing a polypill directly to individuals without testing, thus avoiding the costs of clinical
consultation, risk factor measurement and scoring, and individualized prescription of treatments,
sounds tempting, but runs the risk of overtreating people who are at low cardiovascular risk and
undertreating people at substantial risk. Use of the polypill to treat people who have been classi-
fied according to their total cardiovascular risk does have attractions, as it would simplify selec-
tion of drugs and ensure predefined doses. Meta-analyses of RCTs have found limited evidence of
advantages of single-pill treatments over use of multiple drugs (396–399); thus, use of a combi-
nation pill to treat people at moderate levels of total cardiovascular risk might have advantages,
but further studies of adherence, side-effects and effectiveness are required. In summary, while a
combination pill has some promise as a means of targeted treatment, it raises major challenges that
would have to be addressed if it is to meet the claims made for it.
Evidence
On the basis of data from observational studies (400), hormone therapy has been used for pre-
vention of cardiovascular disease, osteoporosis and dementia. This practice has been called into
question following publication of the results of several randomized clinical trials, which showed
no coronary protection, and the Women’s Health Initiative (401), which indicated that long-term
use of estrogen plus progestin was associated with increased risks of cancer and cardiovascular
disease.
A Cochrane systematic review (402) of 15 randomized double-blind trials (involving 35 089 women
aged 41 to 91 years) examined the effect of long-term hormone replacement therapy on mortality,
heart disease, venous thromboembolism, stroke, transient ischaemic attacks, cancer, gallbladder
disease, fractures and quality of life. All were placebo-controlled trials, in which perimenopausal or
postmenopausal women were given estrogens, with or without progestogens, for at least one year.
The only statistically significant benefits of hormone therapy were decreased incidences of frac-
tures and colon cancer with long-term use. In relatively healthy women, combined continuous
hormone therapy significantly increased the risk of coronary events and venous thromboembolism
(after one year’s use), stroke (after 3 years), breast cancer (after 5 years) and gallbladder disease.
Long-term estrogen-only hormone therapy also significantly increased the risk of stroke and gall-
bladder disease. In relatively healthy women over 65 years taking continuous combined hormone
therapy, there was an increase in the incidence of dementia.
1. Preventing chronic disease: a vital investment. Geneva, World Health Organization, 2005.
2. The World Health Report 2002: reducing risks, promoting healthy life. Geneva, World Health Organization, 2002.
3. Lopez AD et al. Global and regional burden of disease and risk factors, 2001: systematic analysis of popula-
tion health data. Lancet. 2006;367(9524):1747–57.
4. Manuel DG et al. Revisiting Rose: strategies for reducing coronary heart disease. BMJ. 2006;332:659–662.
5. World Health Organization. Prevention of recurrent heart attacks and strokes in low and middle income popula-
tions. Evidence-based recommendations for policy makers and health professionals. Geneva, 2003.
6. Global strategy for the prevention and control of noncommunicable diseases. Report by the Director General.
Geneva, World Health Organization, 2000 (Document A53/14).
7. WHO Framework Convention on Tobacco Control. Geneva, World Health Organization, 2003.
8. World Health Assembly Resolution WHA57.17. Global strategy on diet, physical activity and health. Geneva,
World Health Organization, 2004.
9. Leeder S et al. A race against time: the challenge of cardiovascular disease in developing economies. New York, The
Center for Global Health and Economic Development, 2004.
10. Secondary prevention of non-communicable diseases in low- and middle-income countries through community-based
and health service interventions. Report of the Cambridge Meeting. World Health Organization and Wellcome
Trust, 2001.
11. Cardiovascular disease prevention. Translating evidence into action. Geneva, World Health Organization, 2005.
12. WHO CVD risk management package for low-and medium-resource settings. Geneva, World Health Organization,
2002.
13. Scottish Intercollegiate Guidelines Network. SIGN 50: A guideline developers’ handbook. Section 6: Forming
guideline recommendations. Scottish Intercollegiate Guidelines Network, 2004
14. Schunemann HJ et al., ATS Documents Development and Implementation Committee. An official ATS state-
ment: grading the quality of evidence and strength of recommendations in ATS guidelines and recommen-
dations. Am J Respir Crit Care Med. 2006;174(5):605ˆ–614.
15. Berenson Berenson GS et al. Risk factors in early life as predictors of adult heart disease: the Bogalusa Heart
Study. Am J Med Sci. 1989;298(3):141–151.
16. Zieske AW, Malcom GT, Strong JP. Natural history and risk factors of atherosclerosis in children and youth:
the PDAY study. Pediatr Pathol Mol Med. 2002;21(2):213–237.
17. Mendis S et al. for the Pathobiological Determinants of Atherosclerosis in Youth (PBDAY) Research group.
Atherosclerosis in children and young adults: An overview of the World Health Organization (WHO) and
International Society and Federation of Cardiology Study on Pathobiological Determinants of Atherosclerosis
in Youth study (1985–1995). Prevention and Control, 2005;1:3–15.
18. Tunstall-Pedoe H, ed. (for the WHO MONICA Project) MONICA Monograph and Multimedia Sourcebook.
World largest study of heart disease, stroke, risk factors and population trends. 1979–2002. Geneva, World Health
Organization, 2003.
19. Integrated management of cardiovascular risk: report of a WHO meeting. Geneva, World Health Organization,
2002.
20. Lewington S, Clarke R. Combined effects of systolic blood pressure and total cholesterol on cardiovascular
disease risk. Circulation. 2005;112:3373–3374.
21. Asia Pacific Cohort Studies Collaboration. Joint effects of systolic blood pressure and serum cholesterol on
cardiovascular disease in the Asia Pacific Region. Circulation. 2005;112:3384–3390.
22. Baigent C et al., Cholesterol Treatment Trialists’ (CTT) Collaborators. Efficacy and safety of cholesterol-
lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of
statins. Lancet. 2005;366(9493):1267–78 (Epub 2005 Sep 27).
23. Turnbull F. Blood pressure lowering treatment trialists’ collaboration. Effects of different blood-pressure-
lowering regimens on major cardiovascular events: results of prospectively-designed overviews of
randomised trials. Lancet. 2003;362(9395):1527–1535.
24. Sever PS et al., ASCOT investigators. Prevention of coronary and stroke events with atorvastatin in hyper-
tensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandi-
navian Cardiac Outcomes Trial – Lipid Lowering Arm (ASCOT–LLA): a multicentre randomised controlled
trial. Lancet. 2003;361(9364):1149–1158.
References 57
25. Lewington S et al., Prospective Studies Collaboration. Age-specific relevance of usual blood pressure to vas-
cular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet.
2002;360(9349):1903–1913.
26. Lawes CM et al., Asia Pacific Cohort Studies Collaboration. Blood pressure and cardiovascular disease in the
Asia Pacific region. J Hypertens. 2003;21(4):707–716.
27. LaRosa JC, He J, Vupputuri S. Effect of statins on risk of coronary disease: a meta-analysis of randomized
controlled trials. JAMA. 1999;282(24):2340–2346.
28. Wald NJ, Law MR. A strategy to reduce cardiovascular disease by more than 80%. BMJ. 2003 Jun
28;326(7404):1419. Erratum in: BMJ. 2003 Sep 13;327(7415):586. BMJ. 2006 Sep;60(9):823
29. MacMahon S, Rodgers A. The effects of blood pressure reduction in older patients: an overview of five
randomized controlled trials in elderly hypertensives. Clin Exp Hypertens. 1993;15(6):967–978.
30. Gaziano TA. Cardiovascular disease in the developing world and its cost-effective management. Circulation.
2005;112(23):3547–3553.
31. Yusuf S et al. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 coun-
tries (the INTERHEART study): case-control study. Lancet. 2004;364(9438):937–952.
32. Jackson R, Lynch J, Harper S. Preventing coronary heart disease. BMJ. 2006;332(7542):617–618.
33. WOSCOPS. West of Scotland Coronary Prevention Study: identification of high-risk groups and comparison
with other cardiovascular intervention trials. Lancet. 1996;348(9038):1339–1342.
34. UK Department of Health. Preventing CHD in high-risk patients. In: Coronary heart disease: National Service
Framework for Coronary Heart Disease – Modern standards and service models. Chapter 2. London 2000
(http://www.nhis.info/nhis_resources/chdchapter2).
35. Wilson PW et al. Prediction of coronary heart disease using risk factor categories. Circulation.
1998;97(18):1837–1847.
36. Assmann G, Cullen P, Schulte H. Simple scoring scheme for calculating the risk of acute coronary events
based on the 10-year follow-up of the prospective cardiovascular Munster (PROCAM) study. Circulation.
2002;105(3):310–315.
37. Conroy RM et al., SCORE Project Group. Estimation of ten-year risk of fatal cardiovascular disease in
Europe: the SCORE project. Eur Heart J. 2003;24(11):987–1003.
38. Ferrario M et al.. Prediction of coronary events in a low incidence population. Assessing accuracy of the
CUORE Cohort Study prediction equation. Int J Epidemiol. 2005;34(2):413–421.
39. Wallis EJ et al. Coronary and cardiovascular risk estimation for primary prevention: validation of the new
Sheffield table in the 1995 Scottish health survey population. BMJ. 2000;320:671–676.
40. Williams B et al., BHS guidelines working party, for the British Hypertension Society. British Hypertension
Society guidelines for hypertension management 2004 (BHS-IV): summary. BMJ. 2004;328(7440):634–640.
41. British Heart Foundation. Updated guidelines on CVD Risk assessment. Factfile 08/2004
(http://www.bhf.org.uk/professionals/index.asp?secID=15&secondlevel=471&thirdlevel=970&artID=5446).
42. McCormack JP, Levine M, Rango RE. Primary prevention of heart disease and stroke: a simplified approach
to estimating risk of events and making drug treatment decisions. Can Med Assoc J. 1997;157:422–428.
43. Jackson R. Updated New Zealand cardiovascular risk-benefit prediction guide. BMJ. 2000;320:709–710.
44. Wood D et al. Prevention of coronary heart disease in clinical practice: recommendations of the Second Joint
Task Force of European and other Societies on Coronary Prevention. Atherosclerosis. 1998;140(2):199–270.
45. D’Agostino RB Sr et al. CHD Risk Prediction Group. Validation of the Framingham coronary heart disease
prediction scores: results of a multiple ethnic groups investigation. JAMA. 2001;286(2):180–187.
46. Marrugat J et al. An adaptation of the Framingham coronary heart disease risk function to European Medi-
terranean areas. J Epidemiol Community Health. 2003;57(8):634–638.
47. Brindle P et al. Predictive accuracy of the Framingham coronary risk score in British men: prospective
cohort study. BMJ. 2003;327(7426):1267.
48. Liu J et al. Predictive value for the Chinese population of the Framingham CHD risk assessment tool com-
pared with the Chinese Multi-Provincial Cohort Study. JAMA. 2004;291(21):2591–2599.
49. Asia Pacific Cohort Studies Collaboration. Central obesity and risk of cardiovascular disease in the Asia
Pacific Region. Asia Pac J Clin Nutr. 2006;15(3):287–92.
50. Jackson R et al. Treatment with drugs to lower blood pressure and blood cholesterol based on an individual’s
absolute cardiovascular risk. Lancet. 2005;365(9457):434–441.
51. Reavan GM. Role of insulin resistance in human disease. Diabetes. 1988;37:1595–1607.
52. Meigs JB. Invited commentary: Insulin resistance syndrome? Syndrome X? Multiple metabolic syndrome?
A syndrome at all? Factor analysis reveals patterns in the fabric of correlated risk factors. Am J Epidemiol.
2000;152:908–911.
References 59
77. Rubins HB et al. Diabetes, plasma insulin, and cardiovascular disease: subgroup analysis from the
Department of Veterans Affairs high-density lipoprotein intervention trial (VA-HIT). Arch Intern Med.
2002;162:2597–2604.
78. Pyörälä K et al. Reduction of cardiovascular events by simvastatin in nondiabetic coronary heart disease
patients with and without the metabolic syndrome. Subgroup analysis of the Scandinavian Simvastatin Sur-
vival Study (4S). Diabetes Care. 2004;27:1735–1740.
79. Deedwania PC et al. Effects of rouvastatin, atrovastatin, and pravastatin on atherogenic dyslipidemia in
patients with characteristics of the metabolic syndrome. Am J Cardiol. 2005;95:360–366.
80. Stender S et al. on behalf of the MERCURY I study group. Comparison of rosuvastatin with atrovastatin,
simvastatin and pravastatin in achieving cholesterol goals and improving plasma lipids in hypercholester-
olaemic patients with or without the metabolic syndrome in the MERCURY I trial. Diabetes Obes Metab.
2005;7:430–438.
81. Shephered J, Betteridge J, Gaal LV on behalf of a European Consensus Panel. Nicotinic acid in the manage-
ment of dyslipideamia associated with diabetes and metabolic syndrome: a position paper developed by a
European Consensus Panel. Curr Med Res and Opin. 2005;21(5):665–682.
82. Orchard TJ. The impact of gender and general risk factors on the occurrence of atherosclerotic vascular
disease in non-insulin-dependent diabetes mellitus. Ann Med. 1996;28:323–333.
83. 1999 World Health Organization (WHO)/International Society of Hypertension (ISH) guidelines for the
management of hypertension. J Hypertens. 1999;17:151–183.
84. Affordable technology. Blood pressure measuring devices for low resource settings. Geneva, World Health
Organization, 2005
85. De Backer G et al.Third Joint Task Force of European and Other Societies on Cardiovascular Disease Pre-
vention in Clinical Practice. European guidelines on cardiovascular disease prevention in clinical practice.
Eur Heart J. 2003;24(17):1601–1610.
86. Diet, nutrition and the prevention of chronic diseases: Report of a joint WHO/FAO expert consultation. Geneva.
World Health Organization, 2003 (WHO Technical Report Series No. 916).
87. Pearson TA et al. AHA guidelines for primary prevention of cardiovascular disease and stroke: 2002 update.
Consensus panel guide to comprehensive risk reduction for adult patients without coronary or other ath-
erosclerotic vascular diseases. American Heart Association Science Advisory and Coordinating Committee.
Circulation. 2002;106(3):388–391.
88. Mosca L et al. American Heart Association. Evidence-based guidelines for cardiovascular disease prevention
in women. Circulation. 2004;109(5):672–693.
89. Ebrahim S, Smith GD. Lowering blood pressure: a systematic review of sustained effects of non-pharmaco-
logical interventions. J Public Health Med. 1998;20(4):441–448.
90. Stevens VJ et al. Trials for the Hypertension Prevention Research Group. Long-term weight loss and
changes in blood pressure: results of the Trials of Hypertension Prevention, phase II. Ann Intern Med.
2001;134(1):1–11.
91. Leiter LA et al.. Lifestyle modifications to prevent and control hypertension. 2. Recommendations on obesity
and weight loss. Canadian Hypertension Society, Canadian Coalition for High Blood Pressure Prevention
and Control, Laboratory Centre for Disease Control at Health Canada, Heart and Stroke Foundation of
Canada. CMAJ. 1999;160(9 Suppl):S7–12.
92. Neter JE et al. Influence of weight reduction on blood pressure: a meta-analysis of randomized controlled
trials. Hypertension. 2003;42(5):878–884 (Epub 2003 Sep 15).
93. Hagberg JM, Park JJ, Brown MD The role of exercise training in the treatment of hypertension: an update.
Sports Med. 2000;30(3):193–206.
94. Whelton SP et al. Effect of aerobic exercise on blood pressure: a meta-analysis of randomized, controlled
trials. Ann Intern Med. 2002;136(7):493–503.
95. Xin X et al. Effects of alcohol reduction on blood pressure: a meta-analysis of randomized controlled trials.
Hypertension. 2001;38(5):1112–1117.
96. Sacks FM et al. DASH-Sodium Collaborative Research Group. Effects on blood pressure of reduced dietary
sodium and the Dietary Approaches to Stop Hypertension (DASH) diet. N Engl J Med. 2001;344(1):3–10.
97. Cutler JA, Follmann D, Allender PS. Randomized trials of sodium reduction: an overview. Am J Clin Nutr.
1997;65(2 Suppl):643S–651S.
98. Whelton PK et al. Sodium reduction and weight loss in the treatment of hypertension in older persons: a
randomized controlled trial of nonpharmacologic interventions in the elderly (TONE). TONE Collaborative
Research Group. JAMA. 1998;279(11):839–846.
99. Whelton PK, He J. Potassium in preventing and treating high blood pressure. Semin Nephrol.
1999;19(5):494–499.
References 61
128. Stead LF, Lancaster T, Perera R. Telephone counselling for smoking cessation. Cochrane Database Syst Rev.
2003;(1):CD002850.
129. Lancaster T, Stead LF. Individual behavioural counselling for smoking cessation. Cochrane Database Syst
Rev. 2005;(2):CD001292.
130. Stead LF, Lancaster T. Group behaviour therapy programmes for smoking cessation. Cochrane Database Syst
Rev. 2005;(2):CD001007.
131. Ashenden R, Silagy C, Weller D. A systematic review of the effectiveness of promoting lifestyle change in
general practice. Fam Pract. 1997;14(2):160–176.
132. Silagy C et al.. Nicotine replacement therapy for smoking cessation. Cochrane Database Syst Rev. 2001;(3):
CD000146.
133. Silagy C et al. Nicotine replacement therapy for smoking cessation. Cochrane Database Syst Rev. 2004;(3):
CD000146.
134. Hughes JR, Stead LF, Lancaster T. Antidepressants for smoking cessation. Cochrane Database Syst Rev.
2004;(4):CD000031.Cochrane Database Syst Rev. 2000;(4):CD000031., 2002 and 2003
135. Hughes JR, Stead LF, Lancaster T. Antidepressants for smoking cessation. Cochrane Database Syst Rev.
;(1–3):CD000031., 2002 and 2003
136. Jorenby DE et al. A controlled trial of sustained-release bupropion, a nicotine patch, or both for smoking
cessation. N Engl J Med. 1999;340(9):685–691.
137. Wagena EJ, Knipschild P, Zeegers MP. Should nortriptyline be used as a first-line aid to help smokers quit?
Results from a systematic review and meta-analysis. Addiction. 2005;100(3):317–326.
138. Law MR, Morris JK, Wald NJ. Environmental tobacco smoke exposure and ischaemic heart disease: an
evaluation of the evidence. BMJ. 1997;315(7114):973–980.
139. He J et al. Passive smoking and the risk of coronary heart disease – a meta-analysis of epidemiologic studies.
N Engl J Med. 1999;340(12):920–926.
140. Levy DT et al. Increasing taxes to reduce smoking prevalence and smoking attributable mortality in Taiwan:
results from a tobacco policy simulation model. Tobacco Control. 2005;14(Suppl 1):45–50.
141. Grundy SM et al. Comparison of monounsaturated fatty acids and carbohydrates for reducing raised levels
of plasma cholesterol in man. Am J Clin Nutr. 1988;47(6):965–969.
142. Mensink RP, Katan MB. Effect of dietary fatty acids on serum lipids and lipoproteins. A meta-analysis of 27
trials. Arterioscler Thromb. 1992;12(8):911–919
143. Katan MB, Zock PL, Mensink RP. Trans fatty acids and their effects on lipoproteins in humans. Ann Rev Nutr.
1995;15:473–493.
144. Katan MB et al. Dietary trans fatty acids and their impact on plasma lipoproteins. Can J Cardiol.
1995;11(Suppl G):36G–38G.
145. Hu FB, Willett WC. Optimal diets for prevention of coronary heart disease. JAMA. 2002;288(20):2569–2578.
146. Mensink RP. Effects of the individual saturated fatty acids on serum lipids and lipoprotein concentrations.
Am J Clin Nutr. 1993;57(5 Suppl):711S–714S.
147. Howell WH et al. Plasma lipid and lipoprotein responses to dietary fat and cholesterol: a meta-analysis.
Am J Clin Nutr. 1997;65(6):1747–1764.
148. Kris-Etherton PM et al. High-monounsaturated fatty acid diets lower both plasma cholesterol and triacyl-
glycerol concentrations. Am J Clin Nutr. 1999;70(6):1009–1015.
149. Lichtenstein AH et al. Effects of different forms of dietary hydrogenated fats on serum lipoprotein cholesterol
levels. N Engl J Med. 1999;340(25):1933–1940.
150. Mensink RP, Katan MB. Effect of dietary trans fatty acids on high-density and low-density lipoprotein
cholesterol levels in healthy subjects. N Engl J Med. 1990;323(7):439–445.
151. Sundram K et al. Trans (elaidic) fatty acids adversely affect the lipoprotein profile relative to specific satu-
rated fatty acids in humans. J Nutr. 1997;127(3):514S–520S.
152. Pietinen P et al. Intake of fatty acids and risk of coronary heart disease in a cohort of Finnish men. The
Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. Am J Epidemiol. 1997;145(10):876–887.
153. Hu FB et al. Dietary fat intake and the risk of coronary heart disease in women. N Engl J Med.
1997;337(21):1491–1499.
154. Kasim-Karakas SE et al. Changes in plasma lipoproteins during low-fat, high-carbohydrate diets: effects of
energy intake. Am J Clin Nutr. 2000;71(6):1439–1447.
155. Laaksonen DE et al. Prediction of cardiovascular mortality in middle-aged men by dietary and serum lin-
oleic and polyunsaturated fatty acids. Arch Intern Med. 2005;165(2):193–199.
156. Mattson FH, Erickson BA, Kligman AM. Effect of dietary cholesterol on serum cholesterol in man. Am J Clin
Nutr. 1972;25(6):589–594.
References 63
185. Joshipura KJ et al. The effect of fruit and vegetable intake on risk for coronary heart disease. Ann Intern Med.
2001;134(12):1106–1114.
186. Hung HC et al. Fruit and vegetable intake and risk of major chronic disease. J Natl Cancer Inst.
2004;96(21):1577–1584.
187. Steffen LM et al. Associations of whole-grain, refined-grain, and fruit and vegetable consumption with risks
of all-cause mortality and incident coronary artery disease and ischemic stroke: the Atherosclerosis Risk in
Communities (ARIC) Study. Am J Clin Nutr. 2003;78(3):383–390.
188. Sauvaget C et al. Vegetable and fruit intake and stroke mortality in the Hiroshima/Nagasaki Life Span Study.
Stroke. 2003;34(10):2355–2360 (Epub 2003 Sep 18).
189. Pereira MA et al. Dietary fiber and risk of coronary heart disease: a pooled analysis of cohort studies. Arch
Intern Med. 2004;164(4):370–376.
190. Brunner E et al. Dietary advice for reducing cardiovascular risk. Cochrane.Database.Syst Rev. 2005;4:
CD002128.
191. Powell KE, Blair SN. The public health burdens of sedentary living habits: theoretical but realistic estimates.
Med Sci Sports Exerc. 1994;26(7):851–856.
192. Abbott RD et al. Physical activity in older middle-aged men and reduced risk of stroke: the Honolulu Heart
Program. Am J Epidemiol. 1994;139(9):881–893.
193. Gillum RF, Mussolino ME, Ingram DD. Physical activity and stroke incidence in women and men. The
NHANES I Epidemiologic Follow-up Study. Am J Epidemiol. 1996;143(9):860–869.
194. Manson JE et al. A prospective study of walking as compared with vigorous exercise in the prevention of
coronary heart disease in women. N Engl J Med. 1999;341(9):650–658.
195. Wannamethee SG, Shaper AG, Walker M. Changes in physical activity, mortality, and incidence of coronary
heart disease in older men. Lancet. 1998;351(9116):1603–1608.
196. Wannamethee SG, Shaper AG. Physical activity in the prevention of cardiovascular disease: an epidemiologi-
cal perspective. Sports Med. 2001;31(2):101–114.
197. Oguma Y, Shinoda-Tagawa T. Physical activity decreases cardiovascular disease risk in women: review and
meta-analysis. Am J Prev Med. 2004;26(5):407–418.
198. Wendel-Vos GC et al. Physical activity and stroke. A meta-analysis of observational data. Int J Epidemiol.
2004;33(4):787–798 (Epub 2004 May 27).
199. Lee CD, Folsom AR, Blair SN. Physical activity and stroke risk: a meta-analysis. Stroke. 2003;34(10):2475–
2481 (Epub 2003 Sep 18).
200. Berlin JA, Colditz GA. A meta-analysis of physical activity in the prevention of coronary heart disease. Am J
Epidemiol. 1990;132(4):612–628.
201. Cornelissen VA, Fagard RH. Effects of endurance training on blood pressure, blood pressure-regulating
mechanisms, and cardiovascular risk factors. Hypertension. 2005;46(4):667–675 (Epub 2005 Sep 12).
202. Cornelissen VA, Fagard RH. Effect of resistance training on resting blood pressure: a meta-analysis of ran-
domized controlled trials. J Hypertens. 2005;23(2):251–259.
203. Rogers MA. Acute effects of exercise on glucose tolerance in non-insulin-dependent diabetes. Med Sci Sports
Exerc. 1989;21(4):362–368.
204. Schneider SH et al. Ten-year experience with an exercise-based outpatient life-style modification program in
the treatment of diabetes mellitus. Diabetes Care. 1992;15(11):1800–1810.
205. Whelton SP et al. Effect of aerobic exercise on blood pressure: a meta-analysis of randomized, controlled
trials. Ann Intern Med. 2002;136(7):493–503.
206. Wei M et al. Changes in lipids associated with change in regular exercise in free-living men. J Clin Epidemiol.
1997;50(10):1137–1142.
207. Kelley GA, Kelley KS, Tran ZV. Walking and non-HDL-C in adults: a meta-analysis of randomized controlled
trials. Prev Cardiol. 2005;8(2):102–107.
208. Kelley GA, Kelley KS, Vu Tran Z. Aerobic exercise, lipids and lipoproteins in overweight and obese adults: a
meta-analysis of randomized controlled trials. Int J Obes Relat Metab Disord. 2005;29(8):881–893.
209. Gautier JF. [Physical activity and type 2 diabetes.] Rev Med Liege. 2005;60(5–6):395–401.
210. Wei M et al. Low cardiorespiratory fitness and physical inactivity as predictors of mortality in men with type
2 diabetes. Ann Intern Med. 2000;132(8):605–611.
211. Lee CD, Folsom AR, Blair SN. Physical activity and stroke risk: a meta-analysis. Stroke. 2003;34(10):2475–
2481 (Epub 2003 Sep 18).
212. Health Development Agency, Department of Health. The effectiveness of public health interventions for increas-
ing physical activity among adults. A review of reviews. A report from the Chief Medical Officer. London, 2004
(http://www.hda.nhs.uk/documents/physicalactivity_evidence_briefing.pdf).
References 65
244. Jackson R et al. Alcohol and ischaemic heart disease: probably no free lunch. Lancet.
2005;366(9501):1911–1912.
245. Goldberg IJ et al., Nutrition Committee, Council on Epidemiology and Prevention, Council on Cardio-
vascular Nursing of the American Heart Association. AHA Science Advisory: Wine and your heart: a
science advisory for healthcare professionals from the Nutrition Committee, Council on Epidemiology
and Prevention, and Council on Cardiovascular Nursing of the American Heart Association. Circulation.
2001;103(3):472–475.
246. Rugulies R. Depression as a predictor for coronary heart disease. a review and meta-analysis. Am J Prev Med.
2002;23(1):51–61.
247. Rosengren A et al., INTERHEART investigators. Association of psychosocial risk factors with risk of acute
myocardial infarction in 11119 cases and 13648 controls from 52 countries (the INTERHEART study): case-
control study. Lancet. 2004;364(9438):953–962.
248. Gump BB et al. for the MRFIT Research Group. Depressive symptoms and mortality in men. Stroke.
2005;36:98.
249. Rozanski A et al. The epidemiology, pathophysiology, and management of psychosocial risk factors in
cardiac practice: the emerging field of behavioral cardiology. J Am Coll Cardiol. 2005;45(5):637–651.
250. Hemingway H, Marmot M. Evidence based cardiology: psychosocial factors in the aetiology and prognosis
of coronary heart disease. Systematic review of prospective cohort studies. BMJ. 1999;318(7196):1460.
251. Rozanski A, Blumenthal JA, Kaplan J. Impact of psychological factors on the pathogenesis of cardiovascular
disease and implications for therapy. Circulation. 1999;99(16):2192–2217.
252. Lett HS et al. Depression as a risk factor for coronary artery disease: evidence, mechanisms, and treatment.
Psychosomatic Medicine. 2004;66:305–315.
253. Jones DA, West RR. Psychological rehabilitation after myocardial infarction: Multicentre randomised con-
trolled trial. British Medical Journal. 1996;313(7071):1517–1521.
254. Berkman LF et al., Enhancing Recovery in Coronary Heart Disease Patients Investigators (ENRICHD).
Effects of treating depression and low perceived social support on clinical events after myocardial infarc-
tion: the enhancing recovery in coronary heart disease patients (ENRICHD) randomized trial. JAMA.
2003;289:3106–3116.
255. Kivimäki M et al. Work stress and risk of cardiovascular mortality: prospective cohort study of industrial
employees. BMJ. 2002;325(7369):857.
256. Rumsfeld JS et al. History of depression, angina, and quality of life after acute coronary syndromes. Am
Heart J. 2003;145(3):493–499.
257. Peter R, Siegrist J. Psychosocial work environment and the risk of coronary heart disease. Int Arch Occup
Environ Health. 2000;73(Suppl):S41-S45.
258. Glassman AH et al. for the Sertraline Antidepressant Heart Attack Randomized Trial (SADHEART)
Group. Sertraline treatment of major depression in patients with acute MI or unstable angina. JAMA.
2002;288(6):701–709.
259. Bunker SJ et al. “Stress” and coronary heart disease: psychosocial risk factors. Med J Aust.
2003;178(6):272–276.
260. Eng PM et al. Social ties and change in social ties in relation to subsequent total and cause-specific mortality
and coronary heart disease incidence in men. Am J Epidem. 2002;155(8):700–709.
261. Hedblad B et al. Influence of social support on cardiac event rate in men with ischaemic type ST segment
depression during ambulatory 24-h long-term ECG recording. The prospective population study ‘Men born
in 1914’, Malmo, Sweden. Eur Heart J. 1992;13(4):433–139.
262. Orth-Gomer K, Rosengren A, Wilhelmsen L. Lack of social support and incidence of coronary heart disease
in middle-aged Swedish men. Psychosom Med. 1993;55(1):37–43.
263. Macleod J et al. Psychological stress and cardiovascular disease: empirical demonstration of bias in a pro-
spective observational study of Scottish men. BMJ. 2002;324(7348):1247–1251.
264. Collins R et al. Blood pressure, stroke, and coronary heart disease. Part 2: Short-term reductions in blood
pressure. Lancet. 1990;335:827–838.
265. Godley P et al. Opportunities for improving the quality of hypertension care in a managed care setting.
Am J Health Syst Pharm. 2001;58(18):1728–1733.
266. Klungel OH, Seidell JC, de Boer A. Overestimation of the prevalence of hypertension in the population.
J Hypertens. 1998;16(11):1702–1703.
267. Trilling JS, Froom J. The urgent need to improve hypertension care. Arch Fam Med. 2000;9(9):794–801.
268. Blood Pressure Lowering Treatment Trialists’ Collaboration. Effects of ACE inhibitors, calcium antagonists,
and other blood-pressure-lowering drugs. Lancet. 2000;355:1955–1964.
References 67
294. Bradley HA et al. How strong is the evidence for use of beta-blockers as first-line therapy for hypertension?
Systematic review and meta-analysis. J Hypertens. 2006;24(11):2131–2141.
295. Khan N, McAlister FA. Re-examining the efficacy of beta-blockers for the treatment of hypertension: a meta-
analysis. CMAJ. 2006;174(12):1737–1742.
296. Wiysonge C et al. Beta-blockers for hypertension. Cochrane Database Syst Rev. 2007;(1):CD002003.
297. Cushman WC et al. Regional and racial differences in response to antihypertensive medication use in a
randomized controlled trial of men with hypertension in the United States. Department of Veterans Affairs
Cooperative Study Group on Antihypertensive Agents. Arch Intern Med. 2000;160:825–831.
298. Radevski IV et al. Antihypertensive effect of low-dose hydrochlorothiazide alone or in combination with
quinapril in black patients with mild to moderate hypertension. J Clin Pharmacol. 2000;40:713–721.
299. Oesterling JE. Benign prostatic hyperplasia: Medical and minimally invasive treatment options. N Engl J
Med. 1995;332(2):99–105.
300. Kramer AB et al. Sodium intake modifies the negative prognostic value of renal damage prior to treatment
with ACE inhibitors on proteinuria induced by adriamycin. Nephron Physiol. 2006;103(1):43–52 (Epub
2005 Dec 12).
301. Losito A et al. Long-term follow-up of atherosclerotic renovascular disease. Beneficial effect of ACE inhibi-
tion. Nephrol Dial Transplant. 2005;20(8):1604–1609 (Epub 2005 May 3).
302. Nieminen MS et al., ESC Committee for Practice Guideline (CPG). Executive summary of the guidelines on
the diagnosis and treatment of acute heart failure: the Task Force on Acute Heart Failure of the European
Society of Cardiology. Eur Heart J. 2005;26(4):384–416.
303. Lewis EJ et al. The effect of angiotensin-converting enzyme inhibition on diabetic nephropathy. The Col-
laborative Study Group. N Engl J Med. 1993;329:1456–1462.
304. Jafar TH et al. Angiotensin-converting enzyme inhibitors and progression of nondiabetic renal disease. A
meta-analysis of patient-level data. Ann Intern Med. 2001;135:138–139.
305. The SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection
fractions and congestive heart failure. N Engl J Med. 1991;325:293–302.
306. Flather MD et al. Long-term ACE-inhibitor therapy in patients with heart failure or left-ventricular dysfunc-
tion. A systematic overview of data from individual patients. ACE-Inhibitor Myocardial Infarction Collabora-
tive Group. Lancet 2000; 355:1575–1581.
307. Lewis EJ et al. Renoprotective effect of the angiotensin-receptor antagonist Irbesartan in patients with
nephropathy due to type 2 diabetes. N Eng J Med. 2001;345(12):851–860.
308. Pitt B et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure.
Randomized Aldactone Evaluation Study Investigators. N Engl J Med. 1999;341:709–717.
309. Dahlof B et al. Cardiovascular morbidity and mortality in the Losartan Intervention for endpoint reduction
in hypertension study (LIFE). A randomized trial against Atenolol. Lancet. 2002;359:995–1003.
310. Granger CB, CHARM Investigators and Committees. Effects of candesartan in patients with chronic heart
failure and reduced left-ventricular systolic function intolerant to angiotensin-converting-enzyme inhibitors:
the CHARM-Alternative trial. Lancet. 2003;362(9386):772–776.
311. Staessen JA et al. Randomised double-blind comparison of placebo and active treatment for older patients
with isolated systolic hypertension. The Systolic Hypertension in Europe (Syst-Eur) Trial Investigators.
Lancet. 1997;350:757–764.
312. SHEP Cooperative Research Group. Prevention of stroke by antihypertensive drug treatment in older
persons with isolated systolic hypertension. Final results of the Systolic Hypertension in the Elderly Program
(SHEP). JAMA 1991; 265:3255–3264.
313. Teo KK, Yusuf S, Furberg CD. Effects of prophylactic antiarrhythmic drug therapy in acute myocardial
infarction. An overview of results from randomized controlled trials. JAMA. 1993;270(13):1589–1595.
314. Freemantle N et al. [beta] Blockade after myocardial infarction. Systematic review and regression analysis.
BMJ. 1999;318:1730–1737.
315. Yusuf S et al. Beta blockade during and after myocardial infarction: an overview of the randomized trials.
Prog Cardiovasc Dis. 1985;27(5):335–371.
316. Lindholm L et al. Cost-effectiveness analysis with defined budget: how to distribute resources for the pre-
vention of cardiovscular disease? Health Policy. 1999;48(3):155–170.
317. WHO Model Formulary. Geneva World Health Organization, 2004:290–304.
318. Shepherd J et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia.
West of Scotland Coronary Prevention Study Group. N Engl J Med. 1995;333(20):1301–1307.
319. Downs JR et al. Primary prevention of acute coronary events with lovastatin in men and women with
average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention
Study. JAMA. 1998;279(20):1615–1622.
References 69
343. Sacks FM et al. for the Cholesterol and Recurrent Events Trial Investigators. The effect of pravastatin on
coronary events after myocardial infarction in patients with average cholesterol levels. New Engl J Med.
1996;355:1001–1009.
344. Nissen SE et al. for the ASTEROID Investigators. Effect of very high-intensity statin therapy on regression of
coronary atherosclerosis. The ASTEROID Trial. JAMA. 2006;295(13):1556–1565
345. Frick MH et al . Helsinki Heart Study. Primary prevention trial with gemfibrozil in middle aged men with
dyslipidemia. N Engl J Med 1987;317 (20), 1237–1245
346. Secondary prevention by raising HDL cholesterol and reducing triglycerides in patients with coronary artery
disease. The Bezafibrate Infarction Prevention (BIP) Study. Circulation 2000;102(1):21–27
347. Rubins HB et al . Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels
of high density lipoprotein cholesterol. Veterans Affairs High-Density Lipoprotein Cholesterol Intervention
Trial Study Group. N Engl J Med 1999;34 1(6):410–408
348. Canner PL et al. Fifteen years mortality in Coronary Drug Project patients: longterm benefit with niacin.
J Am Coll Cardiol 1986;8(6):1245–1255
349. Birjm ohun RS et al. Efficacy and safety of high density lipoprotein cholesterol increasing compounds a
meta analysis of randomized controlled trials. J Am Coll Cardiol 2005;45:185–197
350. Third Joint Task Force of European and other Societies on Cardiovascular Disease Prevention in Clinical
Practice. European guidelines on cardiovascular disease prevention in clinical practice. European Journal of
Cardiovascular Prevention and Rehabilitation. 2003;10(Suppl 1):S1-S78.
351. Chen GJ et al. A cost minimization analysis of diuretic-based antihypertensive therapy reducing cardiovas-
cular events in older adults with isolated systolic hypertension. Cost Eff Resour Alloc. 2005;3(1):2.
352. National Institute for Health and Clinical Excellence. Statins for the prevention of cardiovascular events.
Technology Appraisal 94, 2006 (http://guidance.nice.org.uk/TA94).
353. Song SH, Brown PM. Coronary heart disease risk assessment in diabetes mellitus: comparison of
UKPDS risk engine with Framingham risk assessment function and its clinical implications. Diabet Med.
2004;21(3):238–245.
354. Eberly LE et al., Intervention Trial Research Group. Impact of incident diabetes and incident nonfatal
cardiovascular disease on 18-year mortality: the multiple risk factor intervention trial experience. Diabetes
Care. 2003;26:848–854.
355. Laing SP et al. Mortality from heart disease in a cohort of 23,000 patients with insulin-treated diabetes.
Diabetologia. 2003;46(6):760–765.
356. Manson JE et al. A prospective study of maturity-onset diabetes mellitus and risk of coronary heart disease
and stroke in women. Arch Intern Med. 1991;151(6):1141–1147.
357. Malmberg K et al. Impact of diabetes on long-term prognosis in patients with unstable angina and non-Q
wave myocardial infarction. Results of the OASIS (Organization to Assess Strategies for Ischemic Syn-
dromes) Registry. Circulation. 2000;102:1014–1019.
358. Shindler DM et al. for the SOLVD investigators. Diabetes mellitus, a predictor of morbidity and
mortality in the studies of left ventricular dysfunction (SOLVD) trials and registry. Am J Cardiol.
1996;77(11):1017–1020.
359. Khan SE. The relative contributions of insulin resistance and beta-cell dysfunction to the pathophysiology
of type 2 diabetes. Diabetologia, 2003;46(1):3–19.
360. Weyer C, Bogardus C, Pratley RE. Metabolic characteristics of individuals with impaired fasting glucose
and/or impaired glucose tolerance. Diabetes. 1999;48(11):2197–2203.
361. The DECODE Study Group on behalf of the European Diabetes Epidemiology Group. Is the current defini-
tion for diabetes relevant to mortality risk from all causes and cardiovascular and noncardiovascular disease?
Diabetes Care. 2003;26:688–696.
362. Levitan EB et al. Is nondiabetic hyperglycemia a risk factor for cardiovascular disease? A meta-analysis of
prospective studies. Arch Intern Med. 2004;164(19):2147–2155.
363. Lakka HM et al. The metabolic syndrome and total and cardiovascular disease mortality in middle-aged
men. JAMA. 2002;288:2709–2716.
364. Sattar N et al. Metabolic syndrome with and without C-reactive protein as a predictor of coronary heart
disease and diabetes in the West of Scotland Coronary Prevention Study. Circulation. 2000;108:414–419.
365. The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes
on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N
Engl J Med. 1993;329(14):977–986.
366. The Diabetes Control and Complications Trial/Epidmiology of Diabetes Interventions and Complications
(DCCT/EDIC) Study Research Group , Intensive diabetes treatment and cardiovascular disease in patients
with type 1 diabetes. N Engl J Med. 2005;353(25):2643–2653.
References 71
393. Combination Pharmacotherapy and Public Health Research Working Group. Combination pharmacother-
apy for cardiovascular disease. Ann Intern Med. 2005;143:593–599.
394. Mulrow C, Kussmaul W. The middle-aged and older American: wrong prototype for a preventive polypill?
Ann Intern Med. 2005;142:467–468.
395. Fahey T, Brindle P, Ebrahim S. The polypill and cardiovascular disease. BMJ. 2005;330:1035–1036.
396. Conner J, Rafter N, Rogers A. Do fixed-dose combination pills or unit-of-use packaging improve adherence?
A systematic review. Bull WHO. 2004;82:935–939.
397. Schroeder K, Fahey T, Ebrahim S. Interventions for improving adherence to treatment in patients with high
blood pressure in ambulatory settings. Cochrane Database of Systematic Reviews. 2004;(3): CD004804 (DOI:
10.1002/14651858.CD004804).
398. Schedlbauer A et al. Interventions to improve adherence to lipid lowering medication. Cochrane Database of
Systematic Reviews. 2004;(4):CD004371 (DOI: 10.1002/14651858.CD004371).
399. How can we improve adherence to blood pressure-lowering medication in ambulatory care? Systematic
review of randomized controlled trials. Arch Intern Med. 2004;164:722–732.
400. Stampfer MJ, Colditz GA. Estrogen replacement therapy and coronary heart disease: a quantitative assess-
ment of the epidemiologic evidence. Prev Med. 1991;20(1):47–63.
401. Writing Group for the Women’s Health Initiative Investigators. Risks and benefits of estrogen plus progestin
in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized con-
trolled trial. JAMA. 2002;288(3):321–333.
402. Farquhar CM et al., the Cochrane HT Study Group. Long term hormone therapy for perimenopausal and
postmenopausal women. Cochrane Database Syst Rev. 2005;(3):CD004143.
African Region
D Algeria, Angola, Benin, Burkina Faso, Cameroon, Cape Verde, Chad, Comoros, Equatorial
Guinea, Gabon, Gambia, Ghana, Guinea, Guinea-Bissau, Liberia, Madagascar, Mali,
Mauritania, Mauritius, Niger, Nigeria, Sao Tome and Principe, Senegal, Seychelles, Sierra
Leone, Togo
E Botswana, Burundi, Central African Republic, Congo, Côte d’Ivoire, Democratic Republic of
the Congo, Eritrea, Ethiopia, Kenya, Lesotho, Malawi, Mozambique, Namibia, Rwanda, South
Africa, Swaziland, Uganda, United Republic of Tanzania, Zambia, Zimbabwe
B Antigua and Barbuda, Argentina, Bahamas, Barbados, Belize, Brazil, Chile, Colombia, Costa
Rica, Dominica, Dominican Republic, El Salvador, Grenada, Guyana, Honduras, Jamaica,
Mexico, Panama, Paraguay, Saint Kitts and Nevis, Saint Lucia, Saint Vincent and the
Grenadines, Suriname, Trinidad and Tobago, Uruguay, Venezuela
B Bahrain, Iran (Islamic Republic of), Jordan, Kuwait, Lebanon, Libyan Arab Jamahiriya, Oman,
Qatar, Saudi Arabia, Syrian Arab Republic, Tunisia, United Arab Emirates
European Region
A Andorra, Austria, Belgium, Croatia, Cyprus, Czech Republic, Denmark, Finland, France,
Germany, Greece, Iceland, Ireland, Israel, Italy, Luxembourg, Malta, Monaco, Netherlands,
Norway, Portugal, San Marino, Slovenia, Spain, Sweden, Switzerland, United Kingdom
B Albania, Armenia, Azerbaijan, Bosnia and Herzegovina, Bulgaria, Georgia, Kyrgyzstan, Poland,
Romania, Serbia and Montenegro, Slovakia, Tajikistan, The Former Yugoslav Republic of Mace-
donia, Turkey, Turkmenistan, Uzbekistan
continued …
a Mortality strata: A: very low child mortality and very low adult mortality; B: low child mortality and low adult mortality;
C: low child mortality and high adult mortality; D: high child mortality and high adult mortality; E: high child mortality and
very high adult mortality.
ANNEX 1 73
Subregion WHO Member States
D Bangladesh, Bhutan, Democratic People’s Republic of Korea, India, Maldives, Myanmar, Nepal
Distribution of the population, by age and sex, according to 10-year total CVD risk,
in the 14 WHO subregions
MEN WOMEN
African Region: D
<10% 96.29% 86.26% 64.34% 42.57% <10% 98.06% 83.30% 63.72% 42.39%
10–19.9% 3.28% 7.53% 12.67% 29.35% 10–19.9% 1.57% 12.14% 6.63% 19.97%
20–29.9% 0.12% 4.23% 11.83% 14.78% 20–29.9% 0.33% 3.46% 20.87% 13.19%
30–39.9% 0.28% 1.45% 7.61% 8.96% 30–39.9% 0.01% 0.68% 5.94% 19.80%
≥40% 0.04% 0.53% 3.54% 4.34% ≥40% 0.03% 0.42% 2.84% 4.65%
African Region: E
<10% 96.05% 86.43% 73.26% 57.98% <10% 95.38% 83.33% 68.90% 56.83%
10–19.9% 1.24% 7.49% 15.53% 28.08% 10–19.9% 4.22% 11.93% 11.48% 18.42%
20–29.9% 1.45% 4.21% 7.18% 10.10% 20–29.9% 0.03% 3.39% 17.18% 20.83%
30–39.9% 0.75% 1.40% 2.77% 2.93% 30–39.9% 0.33% 0.98% 1.84% 2.31%
≥40% 0.51% 0.47% 1.28% 0.91% ≥40% 0.04% 0.36% 0.59% 1.62%
<10% 96.00% 69.27% 19.27% 3.15% <10% 98.18% 86.91% 50.09% 15.84%
10–19.9% 2.63% 17.18% 35.27% 18.76% 10–19.9% 1.18% 6.45% 27.03% 32.09%
20–29.9% 0.51% 5.14% 13.69% 23.86% 20–29.9% 0.40% 3.51% 8.50% 20.47%
30–39.9% 0.29% 2.95% 12.83% 20.31% 30–39.9% 0.05% 1.10% 5.69% 11.66%
≥40% 0.56% 5.45% 18.94% 33.92% ≥40% 0.19% 2.03% 8.69% 19.93%
ANNEX 2 75
MEN WOMEN
European Region: A
ANNEX 2 77
MEN WOMEN
<10% 97.99% 83.02% 35.97% 10.17% <10% 98.39% 84.58% 29.80% 6.64%
10–19.9% 1.30% 7.45% 27.48% 44.02% 10–19.9% 0.65% 8.72% 38.52% 40.66%
20–29.9% 0.25% 4.41% 14.32% 14.42% 20–29.9% 0.74% 3.39% 12.45% 22.95%
30–39.9% 0.23% 2.13% 9.48% 15.00% 30–39.9% 0.09% 0.28% 6.97% 14.25%
≥40% 0.24% 2.99% 12.75% 16.39% ≥40% 0.13% 3.03% 12.26% 15.50%
<10% 97.86% 83.88% 48.59% 15.61% <10% 99.10% 91.88% 73.60% 38.30%
10–19.9% 1.45% 7.22% 24.64% 36.44% 10–19.9% 0.64% 6.32% 20.06% 33.76%
20–29.9% 0.34% 6.27% 14.46% 21.54% 20–29.9% 0.21% 1.18% 4.14% 19.03%
30–39.9% 0.24% 1.61% 5.95% 9.92% 30–39.9% 0.03% 0.45% 1.53% 4.15%
≥40% 0.11% 1.02% 6.37% 16.49% ≥40% 0.02% 0.16% 0.67% 4.77%
<10% 98.92% 84.99% 49.54% 24.15% <10% 99.16% 91.39% 72.72% 48.11%
10–19.9% 0.52% 8.72% 25.37% 39.98% 10–19.9% 0.58% 4.33% 7.54% 26.53%
20–29.9% 0.40% 2.51% 10.03% 14.25% 20–29.9% 0.16% 2.29% 13.00% 10.08%
30–39.9% 0.08% 1.25% 5.46% 9.20% 30–39.9% 0.08% 1.14% 3.65% 11.39%
≥40% 0.08% 2.53% 9.60% 12.43% ≥40% 0.02% 0.85% 3.09% 3.89%
The chart below indicates total 10-year risk of a fatal or non-fatal cardiovascular event (myocar-
dial infarction or stroke), according to age, sex, blood pressure, presence or absence of diabetes,
smoking status, and cholesterol level, for the WHO Region of South-East Asia, subregion D.
0EOPLEWITHDIABETES 3YSTOLIC
!GE BLOODPRESSURE
YEARS -EN 7OMEN MM(G
.ON
SMOKER 3MOKER .ON
SMOKER 3MOKER
+EYTORISKLEVEL
¯
¯
¯
≥
0EOPLEWITHOUTDIABETES
#HOLESTEROLMMOLL
ANNEX 3 79
80 Prevention of cardiovascular disease
Annex 4
Sample WHO/ISH risk prediction chart for use where
measurement of cholesterol level is not possible
The chart below indicates total 10-year risk of a fatal or non-fatal cardiovascular event (myocardial
infarction or stroke), according to age, sex, blood pressure, presence or absence of diabetes, and
smoking status, for the WHO Eastern Mediterranean Region, subregion B.
3YSTOLIC
7ITHOUTDIABETES 7ITHDIABETES BLOOD
!GE PRESSURE
YEARS -EN 7OMEN -EN 7OMEN MM(G
.ON
.ON
.ON
.ON
3MOKER SMOKER 3MOKER SMOKER 3MOKER SMOKER 3MOKER SMOKER
180
160
70
140
120
180
160
60
140
120
180
160
50
140
120
180
160
40
140
120
+EYTORISKLEVEL
10
10¯19.9
20¯29.9
30¯39.9
≥40%
ANNEX 4 81
82 Prevention of cardiovascular disease
Annex 5
Methods of development of WHO/ISH risk
prediction charts
Several equations have been developed previously to predict individual absolute risk of a cardio-
vascular event over a specified time period.a, b Most of these equations have been derived from
Caucasian populations in developed countries and are not necessarily valid in other populations.
The Comparative Risk Assessment (CRA) Project,c conducted by the World Health Organization
and described in the 2002 World Health Report,d determined the burden of disease attributable to
selected major risk factors, including high blood pressure, high blood cholesterol, high body mass
index and smoking. This project involved the standardized collection and assessment of data on
risk factor prevalence and relative risk by WHO epidemiological subregion. The WHO/ISH risk
prediction charts (see Annexes 3 and 4) were based on these data.
A hypothetical cohort was created for each WHO subregion, consisting of 1 000 000 people for
each age and sex group, using Stata Statistical Software release 7.0.e The age groups used were
30–44, 45–59, 60–69, and 70–79 years. Individuals were assigned values for the following car-
diovascular risk factors: systolic blood pressure, total blood cholesterol, and smoking status (as a
yes/no variable), using the estimates of risk factor prevalence by WHO subregion from the CRA
Project. The risk factor values were assigned using log–normal distributions of the reported mean
and standard deviation for each risk factor. Correlations between risk factor distributions were
based on information from the Asia-Pacific cohort.
Estimates of relative risk per unit increase in continuous risk factors, i.e. per mmHg for systolic blood
pressure and per mmol/l for total cholesterol, as well as for the presence of smoking were determined
from the CRA project (largely from prospective cohort studiesc, f ). These relative risk estimates were
applied to the hypothetical cohort to determine the relative risk of each individual in the cohort.
Absolute risk of a cardiovascular event was determined by scaling individual relative risk to popula-
tion incidence rates of cardiovascular disease (ischaemic heart disease and stroke), estimated from
the Global Burden of Disease Study.g The probability of a cardiovascular event was extrapolated to a
10-year period. The mean absolute risk for various combinations of risk factor levels was then calcu-
lated and tabulated.
a D’Agostino RB et al. Primary and subsequent coronary risk appraisal: new results from The Framingham Study. Am Heart J.
2000;139:272–281.
b Conroy RM et al., SCORE project group. Estimation of ten-year risk of fatal cardiovascular disease in Europe: the SCORE
project. Eur Heart J. 2003;24(11):987–1003.
c Ezzati M et al., Comparative Risk Assessment Collaborating Group. Estimates of global and regional potential health gains
from reducing multiple major risk factors. Lancet. 2003;362(9380):271–280.
d The World Health Report 2002: reducing risks, promoting healthy life. Geneva, World Health Organization, 2002.
e StataCorp, College Station, Texas 77845.
f Ezzati, M., Lopez, A.D., Rodgers, A., Murray, C.J.L. Comparative Quantification of Health Risks: Global and Regional Burden of
Diseases Attributable to Selected Major Risk Factors. World Health Organization: Geneva, 2004
g Murray CJL, Lopez AD. The global burden of disease: a comprehensive assessment of mortality and disability from diseases, injuries
and risk factors in 1990 and projected to 2020. Cambridge, MA, Harvard University Press, 1996.
ANNEX 5 83
Annex 6
Guideline Development Committee*
Observers
Dr James Wright, University of British Columbia, Vancouver, BC, Canada
Dr Eugene Zhelenyakov, St Petersburg, Russian Federation
ANNEX 7 85
Dr Pekka Puska, National Public Health Institute, Helsinki, Finland
Dr Yacoob Seedat, Nelson R Mandela School of Medicine, Durban, South Africa
Dr Cesari R Sirtori, University of Milan, Milan, Italy
Dr Krisela Steyn, Medical Research Council, Capetown, South Africa
Dr Suh Il, Department of Preventive Medicine, Seoul, Republic of Korea
Dr Diego Vanuzzo, Centre for Cardiovascular Diseases, Udine, Italy
Dr A Wielgosz, Ottawa Hospital, Ontario, Canada
Dr Alberto Zanchetti, Centre for Clinical Physiology and Hypertension, Milan, Italy
Acknowledgements
Ms Melanie Bertram, University of Queensland, School of Population Health, Herston, Australia
assisted in the development of the risk prediction charts.