REVIEW

European Heart Journal (2011) 32, 545555

doi:10.1093/eurheartj/ehq472

Frontiers in cardiovascular medicine

Primary prevention of stroke: blood pressure,

lipids, and heart failure
Matthias Endres 1,2*, Peter U. Heuschmann 2, Ulrich Laufs 3, and Antoine M. Hakim 4
1
Klinik und Hochschulambulanz fur Neurologie, ChariteUniversitatsmedizin Berlin, 10117 Berlin, Germany; 2Center for Stroke Research Berlin (CSB), Charite
Universitatsmedizin Berlin, Berlin, Germany; 3Klinik fur Innere Medizin III, Kardiologie, Angiologie und Internistische Intensivmedizin, Universitatsklinikum des Saarlandes, Homburg/
Saar, Germany; and 4Division of Neurology, University of Ottawa, Neuroscience Research, Ottawa Hospital Research Institute, Canadian Stroke Network, The Heart and Stroke
Foundation Centre for Stroke Recovery, Ottawa, Canada

Received 7 September 2010; revised 20 October 2010; accepted 2 December 2010; online publish-ahead-of-print 1 February 2011

----------------------------------------------------------------------------------------------------------------------------------------------------------Keywords

Hypertension Cholesterol Heart failure Triglycerides Polypill Adherence

Introduction
The global burden of stroke is substantial. Stroke is the second
leading cause of death, one of the leading causes of adult acquired disability worldwide, and hence a major contributor to health-care
costs.1 For example, in the UK, the direct and indirect societal
costs caused by stroke are about 8.9 billion pounds a year.2 Stroke
is a disease of the elderly. The median age at the onset of first
stroke in Europe is 73 years.3 It is anticipated that the absolute
number of stroke patients will increase substantially over the next
decades. The WHO estimates that the absolute number of first-ever
stroke patients in the European Union and selected European Fair
Trade Association countries will increase from 1.1 million in 2000
to 1.5 million in 2025 if incidence rates remain stable.4

consisting of different pathophysiological and aetiological subgroups (Figure 1). Stroke is a clinical diagnosis and is classified
according to the duration of clinical symptoms into transient
ischaemic attack or stroke.5 New tissue- instead of time-based
classification systems are challenging this traditional definition.6
The clinical entity stroke is further subdivided based on the
underlying pathology into ischaemic stroke (IS), primary intracranial haemorrhage, or subarachnoidal haemorrhage. IS can be classified according to the leading aetiological cause into large-artery
atherosclerosis, cardioembolism, small-artery occlusion, other
causes, and undetermined aetiology7 with new classification
systems proposed in the light of wider availability of advanced diagnostic facilities.8

Risk factors for stroke

Disease condition stroke
The pathophysiology of acute coronary vascular syndromes is
primarily related to plaque rupture followed by local thrombosis.
In contrast, stroke is a rather heterogeneous clinical syndrome

The main risk factors for ischaemic and haemorrhagic stroke,

respectively, are well known and can be differentiated into nonmodifiable (age, sex, genetic predisposition, ethnicity) and modifiable ones (smoking, hypertension, lifestyle factors, diabetes)9 with

* Corresponding author. Tel: +49 30 450 560 102, Fax: +49 30 450 560 932, Email: matthias.endres@charite.de
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2011. For permissions please email: journals.permissions@oup.com

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Stroke contributes significantly to morbidity, mortality, and disability worldwide. Despite the successes accomplished in the acute treatment and
rehabilitation of stroke, the global burden of this disease can only be tackled with co-ordinated approaches for primary prevention. Stroke is a
heterogeneous disease and the contribution of individual risk factors to its occurrence estimated by population attributable risk differs from
coronary heart disease. Here, we review evidence to demonstrate the prominent role of elevated blood pressure (BP) and heart disease on
risk of stroke, while the influence of lipids on stroke is less clear; we also demonstrate that stroke is an important complication of heart
failure. Current approaches to primary preventive action emphasize the need to target the absolute risk of cardiovascular diseases rather
than individual risk factors. Lifestyle interventions serve as a basis for primary prevention of cardiovascular diseases. It is estimated that 70%
of strokes are potentially preventable by lifestyle modification but prospective evidence is needed to support these hypotheses derived from
epidemiological studies. Different strategies for drug interventions in primary prevention are discussed, including the polypill strategy. Additional
measures are needed for the primary prevention of stroke which focus on BP, chronic heart failure, and possibly lipids.

546

M. Endres et al.

Figure 1 Clinical syndrome stroke.65

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variations in the impact of specific risk factors between haemorrhagic stroke and IS. For example, atrial fibrillation (AF) is a risk
factor for IS but not for haemorrhagic stroke.10 12 Most risk
factors contribute to both coronary heart disease (CHD) and IS.
However, the relative contribution of individual risk factors
differs substantially between the two disease conditions.13 Defining
the weight of risk factors by population attributable fractions (PAF)
(i.e. the proportion of a disease that could be theoretically prevented if a risk factor would be absent) reveals hypercholesterolaemia as the main risk factor for CHD14 17 and hypertension
for stroke18,19 (Figure 2). However, the estimation of PAF for a
specific risk factor is not trivial, especially if diseases are caused
by multiple risk factors not acting independently,20 and the estimates are dependent on the definition of the population at
risk.21 The four main modifiable risk factors diabetes, smoking,
hypertension, and hypercholesterolaemia explain less variance of
occurrence of stroke compared with the occurrence of myocardial
infarction [e.g. 55% of stroke events vs. 88% of myocardial infarction events in the European Prospective Investigation into Cancer
and Nutrition (EPIC) study were attributed to these four risk
factors].22
Minimizing the impact of stroke on society will thus require
effective strategies for reducing its incidence in the general population. Here, we review current strategies for the main modifiable
risk factors: blood pressure (BP), lipids, and heart disease.

Figure 2 Percentage population attributable risk of main modifiable risk factors for acute myocardial infarction and stroke
(ischaemic and haemorrhagic stroke combined) based on the
estimates from the INTERHEART study and the INTERSTROKE
study.14,19 Population attributable risk (PAR) is estimating the
proportion of a disease that can theoretically be attributed to a
specific risk factor; estimates derived from the INTERHEART
study14 and the INTERSTROKE study.19

sub-Saharan Africa, although overall hypertension prevalence is

up to 15%, middle-income urban dwellers can have prevalence
rates as high as 32%.

Blood pressure

Blood pressure and stroke

High BP is a common phenomenon in the population. Its prevalence varies according to geography and ethnic background. At
the 140/90 mmHg threshold, the prevalence of hypertension is
28% in North America and 44% in six European countries.23 In

Hypertension has been identified as a major risk factor for stroke.

The INTERSTROKE study, which evaluated the contribution of
various risk factors to the burden of stroke worldwide, concluded
that hypertension provided 34.6% of the PAF for stroke19

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Primary prevention of stroke

(Figure 2). If in addition to patient-reported history of hypertension

a BP higher than 160/90 mmHg was measured, PAF for stroke due
to hypertension increased to 52%. Ezzati et al. 24 previously attributed 70 76% of strokes occurring in 14 subregions of the world to
a limited number of risk factors, with hypertension as the biggest
driver of stroke risk.
More recently, it has also been recognized that hypertension is
also a risk factor for reduced cognitive function. In a large observational study of a healthy population, an increase of 10 mmHg in
diastolic BP (DBP) was associated with 7% higher odds of cognitive
impairment.25 This is similar to the conclusion that a 1 mmHg rise
in systolic BP (SBP) in midlife was associated with a 1% increase in
risk of cognitive decline later in life.26 In addition to a direct association with dementia, hypertension also aggravates Alzheimers
disease, and the presence of a single lacune at autopsy, even
when asymptomatic, increased the probability of dementia by a
factor of 18 in the Nun Study.27

Blood pressure lowering in primary

stroke prevention

Lipids
Cholesterol and stroke
Total blood cholesterol levels are a prominent risk factor for cardiovascular disease.38 The association of cholesterol and stroke,
however, is much less clear: surprisingly, epidemiological studies
found no consistent relationship between cholesterol levels and
overall stroke risk.39 For example, neither the Framingham Study
nor the Honolulu Heart Study found an association between
cholesterol levels and cerebrovascular disease. The Prospective
Studies Collaboration has brought together evidence from 61 individual prospective studies and analysed the data of 55 000 vascular
deaths.38 There was no clear relationship between blood cholesterol and stroke (except in people aged 40 60 years and with
normal or high-normal BP). In many of the individual studies, no
differentiation between stroke subtypes was performed. For
example, many strokes were not verified by brain imaging and,
hence, could not even be differentiated into haemorrhagic stroke
vs. IS. Indeed, the MRFIT study in 350 000 men which examined
the link between cholesterol and fatal stroke (and differentiated
haemorrhagic stroke from IS) showed a J-shaped relationship
between total cholesterol levels and stroke mortality (Figure 3).40
This could be explained by an association of higher cholesterol
with IS and, vice versa, between lower cholesterol and haemorrhagic stroke10at least in patients with co-morbid high BP.40 Similarly, in the Prospective Studies Collaboration in individuals with

Conclusions: blood pressure and primary

prevention of stroke
Despite the overwhelming evidence that hypertension is a major
cause of damage particularly to the brain and that the brain
benefits the most from BP lowering, there are no randomized clinical trials that provide a BP target for effective prevention of first
strokes.36 This can only be answered by a new study that attempts
to define a target. The challenges of designing such a trial have

Figure 3 Cholesterol and stroke subtype stratified for the

history of prior myocardial infarction (MI) based on estimates
from the MRFIT study.40

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INTERSTROKE and INTERHEART report that hypertension provided 34.6 and 17.9% of the PAF for stroke and myocardial infarction, respectively (Figure 2).28 This is supported by a
population-based study from France showing that individuals with
stroke were more likely to be hypertensive than those with myocardial infarcts.29 At standard doses, drugs that lower BP also
reduce stroke incidence more than they reduce myocardial
infarcts.30 In the ACCORD study, where almost 5000 participants
with type 2 diabetes were assigned to target SBPs of ,120 or
,140 mmHg and were followed 4.7 years for vascular events,
stroke was the only outcome with a significantly lower incidence
in the intensive therapy group.31 Thus, the brain is the organ
most benefited when BP is reduced.
Several authors have estimated the extent of protection that
results when BP is lowered. Girerd and Giral32 concluded that
each 2 mmHg reduction in SBP was associated with a 25%
reduction in stroke events. More recently, Beckett et al. 33
showed that in patients 80 years of age or older, treatment
which lowered mean SBP and DBP by 15.0/6.1 mmHg resulted in
a 39% reduction in the rate of fatal strokes at 2 years of treatment.
Jones et al. 34 estimated that a 3544% reduction in the incidence
of new strokes can be achieved by lowering BP. Finally, Sokol
et al. 35 concluded from their review of the effect of BP management on the incidence of primary and secondary strokes that prolonged reduction in DBP of 5, 7.5, and 10 mmHg would lower
stroke rates by at least 34, 46, and 56%, regardless of the starting
BP level.

recently been described.37 Nonetheless, the SBP Intervention

Trial (SPRINT) launched recently by NIH, with a target SBP
of ,120 mmHg, should go a long way to filling this gap. In
the meantime, it is clear that improving the management of
hypertension at the population level will result in optimum brain
protection. Law et al. suggest that in people aged 6069 with a
DBP of 90 mmHg, three drugs at half standard dose reduced the
risk of stroke by 62%, whereas one drug at standard dose had
half this effect. In addition, they advocate lowering BP in the
population broadly rather than measuring it in everyone and
treating it in some.30

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Lipid lowering in primary stroke

prevention
Earlier intervention trials with non-statin cholesterol-lowering
drugs (including fibrates) failed to show a reduction of stroke
risk, which stands in contrast to the fact that these drugs
lowered cardiovascular risk (along with cholesterol levels).50 In
contrast, results from randomized trials have demonstrated that
treatment with HMG-CoA reductase inhibitors (i.e. statins),
which lower total and LDL cholesterol, not only reduces the incidence of ischaemic heart disease but also of IS.51,52 As a rule of
thumb, the reduction in LDL cholesterol by 1.5 mmol/L reduces
IS risk by about a third.51,52 Statins were also protective in populations at high vascular risk but without documented CHD, such
as in the ASCOT-LLA or CARDS (primary diabetic population)
cohorts.
So far, however, the protective results of statins on stroke risk
are limited to patients at high risk for stroke (i.e. with CHD or
other additional risk factors) and it remains unclear whether
statin treatment is effective for stroke prevention in the general
population without CHD. Data on the elderly, moreover, are
very limited: in the PROSPER trial, pravastatin had no effect on
stroke (while it reduced the combined vascular endpoint by
15%).53 For secondary stroke prevention, both the SPARCL trial
and a subgroup of the HPS trial demonstrated a significant
reduction of secondary cerebrovascular events in stroke patients

even without additional CHD.54,55 Consequently, statin therapy

has become a pillar of treatment in addition to aspirin and BP
medication.
Of note, reduction in IS risk by statins may be associated with a
small increase in haemorrhagic stroke as suggested by two secondary prevention trials, SPARCL and HPS.55,56 Statins might therefore
not be indicated for patients with haemorrhagic strokes. Further
studies of how exactly lipids, cholesterol, and lipoprotein particles
contribute to stroke risk invite further research.
Presently, the mechanism of stroke protection by statins is not
entirely clear. Cholesterol-independent pleiotropic effects may
contribute to it: statins reduce inflammation, are anti-atherogenic,
lower BP, stabilize plaques, are anti-thrombotic, improve fibrinolysis, and decrease platelet activation. They also have immunomodulatory effects, increase the number of circulating endothelial
progenitor cells, and improve endothelium function.57 In addition,
statins have neuroprotective properties, reduce ischaemic lesion
size in animal stroke models, and may therefore also improve
stroke outcome.57 However, the relative contribution of LDL
cholesterol lowering vs. other pleiotropic statin actions on the
reduction of stroke risk cannot be easily differentiated since essentially all pleiotropic effects of statins are also dependent on
HMG-CoA reductase inhibition. Thus, these effects go hand in
hand with any effect on LDL cholesterol levels, are dosedependent, and correspond with the potency of a given statin
drug. In other words, LDL cholesterol may as well serve as a biomarker for pleiotropic statin effects. It is therefore not surprising
that there is a linear association between reduction in LDL cholesterol concentration and stroke incidence among the major statin
trials.46
Recently, the JUPITER trial tested the hypothesis whether individuals with elevated inflammatory biomarkers but without hyperlipidaemia benefit from high-dose statin treatment. In fact,
high-sensitivity C-reactive protein levels were demonstrated to
be associated with the risk of IS, although its relevance is still
unclear.58 Rovastatin reduced major cardiovascular events including death from cardiovascular causes in apparently healthy men
and women with average LDL cholesterol and elevated highsensitivity C-reactive protein.59 Stroke reduction by rosuvastatin
treatment was also significant, but the absolute rate was low and
the number needed to treat consequently rather high (i.e.
286!).59 The JUPITER study has already evoked intensive
debate.60 However, its relevance for (primary) stroke prevention
is limited by the low number of stroke events and the fact that it
included individuals without a specific condition placing them at
risk for stroke.61

Conclusions: lipids and primary

prevention of stroke
Present guidelines recommend the regular measurement of blood
cholesterol levels. The National Cholesterol Education Program III
provided guidelines for the management of patients without previous cerebrovascular events with elevated non-HDL cholesterol
levels and additional risk factors.62 It is unclear whether lowering
lipids is effective in the primary prevention of stroke in the
general population (without CHD or additional vascular risk

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SBP .145 mmHg, total cholesterol was negatively related to haemorrhagic and total stroke mortality.38 Another caveat of the
meta-analyses is the fact that often only fatal strokes were analysed.41 Taken together, the relationship between cholesterol
and total stroke is weak but it seems likely that cholesterol is
associated with increased risk at least in the subgroup of atherothrombotic strokes.
Only few studies addressed the association of elevated LDL
cholesterol levels and IS, and they did not yield consistent findings.42 In contrast, high HDL levels are associated with reduced
stroke risk, and vice versa, low HDL is associated with increased
stroke risk.36,43,44 Also, the ratio of total cholesterol to HDL
cholesterol (or the LDL/HDL cholesterol) ratio may be more predictive. This is also supported by the INTERSTROKE study which
showed that the ratio of apolipoprotein B to A1 was predictive for
stroke risk.14 Overall, the population attributable risk of low HDL
cholesterol is estimated to be 10%.45
The role of triglyceride levels for stroke risk is also unclear.
Some studies and meta-analyses report an association between triglyceride levels and IS,46 but several studies found no relationship
between fasting triglyceride levels and IS risk (as was demonstrated
for cardiovascular disease). In contrast, non-fasting triglyceride
levels may be a better prediction for stroke (and cardiovascular)
risk.46,47 Recently, a cohort study also found an association of nonfasting triglyceride levels and IS in women.48 Triglyceride levels
vary considerably, making risk prediction difficult, and the lack of
standardization may explain some of the contradictory results.
The ongoing Berlin Cream & Sugar Study will employ an oral triglyceride tolerance test with standardized conditions to predict the
risk of further strokes.41

M. Endres et al.

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Primary prevention of stroke

factors). High-risk individuals should be treated with a statin and

lifestyle measures even with normal LDL cholesterol.45,63 In
future, the effects on stroke risk of aggressive LDL cholesterol lowering with treatment goals below 1.8 mmol/L (i.e. below 70 mg/dL)
will need to be established. Also, there is as yet no evidence that
ezitimibestatin combinations (which may offer superior lipidmodifying effects) may provide any additional benefit over statin
monotherapy. Future and ongoing studies need to test whether
HDL-raising drugs such as nicotinic acid (niacin) or cholesteryl
ester transfer protein inhibitors may be beneficial in addition to
statins and the proven baseline therapy of weight control, physical
activity, and smoking cessation.45 The role of triglycerides as Lp(a)
remains unclear and further research is needed to address risk prediction and optimal treatment. In particular, the effects of
triglyceride-lowering therapy alone or in combination with statins
and the effects of treatments to raise HDL cholesterol concentrations await further studies.

Heart failure

Table 1 Echocardiographic findings and risk of future

embolic events83
High risk

Low risk

Atrial fibrillation

Mitral valve prolapse

Mitral valve stenosis

Mechanical prosthetic valves

Mitral valve calcification

Patent foramen ovale

................................................................................

Recent myocardial infarction

Atrial septal aneurysm

Left ventricular thrombus/left

atrial thrombus

Regional wall movement

disturbances of the LV

Atrial myxoma
Infectious endocarditis

Calcifying aortic valve stenosis

Mitral valve strands

Dilative cardiomyopathy

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Cardiac diseases including valve disease and chronic heart failure

(CHF) represent a risk factor for IS64 (Table 1). Approximately
25% of all ISs are due to cardiac embolism.65 Up to 10 24% of
the patients with IS have CHF, and in 9% of ISs, CHF is the likely
cause.66 69 For CHF, a meta-analysis calculated that 18 per 1000
persons suffered a stroke during the first year after the diagnosis
and increased to 47 at 5 years.70 The overall relative risk of
stroke in CHF increases approximately two to three folds compared with patients without CHF. In addition, CHF represents an
independent predictor for the severity of cerebral ischaemia and
associated poor outcome.71 A recent analysis showed that the
odds ratio of in-hospital mortality rate for stroke patients with
CHF was more than doubled than for those without CHF.
Stroke patients with CHF also stayed longer in the hospital.67
The stroke risk in patients with CHF increases further with age,
concomitant arterial hypertension, and AF.
Recent imaging studies suggest that the incidence of silent cerebral ischaemia in CHF patients may be high (up to 40% of the
CHF population).72 Silent cerebral ischaemia, losses in grey
matter, and decreased cerebral perfusion may significantly

contribute to cognitive impairments that are reported in many

CHF patients (25 80%)73,74 A recent analysis of the Framingham
study looked at 1504 participants without prior stroke or dementia
showed that the cardiac index correlated with brain volume and
information processing speed75 (Table 2). Further research is
needed to characterize the underlying mechanism(s) for this
association, which is largely unknown, and to develop strategies
for specific prevention.
It seems likely that CHF-related strokes are primarily embolic.
The risk of embolism correlates with the degree of left ventricular
(LV) dysfunction. Specifically, an ejection fraction ,30% is associated with an increased risk of embolism.76 Chronic heart failure is
associated with an activation of thrombus formation likely
mediated by the renin angiotensin system, endothelial dysfunction, increased blood velocity, and dysregulation of mediators
(e.g. thrombin, plasminogen, and others).77 The main cause for
emboli in patients with CHF is AF.78 The prevalence of AF in
CHF is 1017% and it increases with LV dilatation and
New York Heart Association (NYHA) stage.79 The degree of LV
dysfunction is associated with embolic events and can be used to
stratify stroke risk in patients with AF (Table 3). Chronic heart
failure is therefore an important factor for the assessment of
stroke risk. For example, CHF is included in the CHADS2 score
to assess stroke risk in AF patients.80 An assessment of the individual co-morbidities using the CHADS2 score can help to make individual recommendations. For individuals with a CHADS2 score of
0 treatment with aspirin is sufficient, for a CHADS2 of 1 aspirin or
anticoagulation can be used and all patients with a CHADS2 .1
clearly benefit from anticoagulation.
Intracavitary thrombi are a source of embolism and occur in LVs
impaired by myocardial infraction, valve disease, or CHF. The
danger of intra-atrial thrombus formation exists particularly in
patients with AF (see above). In patients with a ventricular thrombus and additional risk factors (e.g. LV dysfunction or hypertension), anticoagulation for at least 6 months is indicated.81
Intra-atrial thrombi can only be detected or excluded with sufficient diagnostic reliability by the use of transoesophageal echocardiography (TEE). In contrast, both LV function and LV thrombi
(especially in the apex cordis) are better assessed by transthoracic
echocardiography than by TEE.81 83 Lack of atrial thrombi does
not exclude cardiogenic stroke.
Because of the increased risk of intermittent and of asymptomatic AF in CHF and the increased risk of stroke in patients
with CHF in sinus rhythm, the question arises whether all patients
with impaired LV function or LV aneurysms would benefit from
anticoagulation. However, all published studies that tested the
effect of oral anticoagulation in patients with CHF in sinus
rhythm, including the WATCH trial,84 were not able to demonstrate an advantage of anticoagulation with regard to mortality.
Anticoagulation is effective in patients with CHF and AF, but LV
dysfunction by itself does not represent an indication for anticoagulation treatment.
In addition to the causal relationship between CHF and IS, these
two disease entities represent manifestations of similar underlying
risk factors. In CHF patients in sinus rhythm, older age, hypertension, and diabetes are associated with increased incidence of
stroke.85 Arterial hypertension is a main risk factor for stroke

550

Table 2

M. Endres et al.

Change in total brain volume as a function of a 1 SD change in cardiac index75

Cardiac indexa

Total sample (n 5 1504)

P-value

Without prevalent CVD (n 5 1392)

P-value

...............................................................................................................................................................................
0.30 + 0.14

0.03

0.33 + 0.14

0.02

Tertile 1 (low)
Tertile 2 (mid)

20.36 + 0.17
20.35 + 0.17

0.04
0.04

20.41 + 0.17
20.34 + 0.17

0.02
0.04

Tertile 3 (high)

Reference

Reference

Continuous

Cardiac index is the cardiac output divided by the body surface area.

and CHF and represents one of the most important targets for
prevention. Indeed, the recent Hypertension in the Very Elderly
Trial (HYVET) showed that BP control in patients .80 years of
age reduced both stroke and heart failure events as well as mortality.33 Blood pressure control is the basis of the prevention of
CHF and stroke.13

Table 3 Estimation of stroke risk in patients with

atrial fibrillation based on echocardiographic findings118
Finding

Risk/
year

................................................................................

Primary stroke prevention

Atrial fibrillation + normal echographic finding

Atrial fibrillation + enlarged left atrium

1.5%
8.8%

Atrial fibrillation + left ventricular dysfunction

12.6%
20.0%

General principles of primary prevention

Atrial fibrillation + enlarged atrium + left ventricular

dysfunction

Implementing primary prevention in the

population
Lifestyle interventions serve as a basis for primary prevention. It
has been proposed that 70% of stroke and over 80% of CHD
might be preventable through lifestyle modifications (e.g. not
smoking, healthy diet, body mass index ,25 kg/m2, regular physical activity, and moderate alcohol consumption).93 This estimation

is in line with observations from prospective cohort studies which

report that a healthy life style (as defined above) is associated with
an 82% decrease in CHD risk in women.94 In addition, a substantial
decrease in relative risk of stroke in people with the healthiest lifestyle compared with an unhealthy lifestyle is observed in previous
cohort studies95 97 (Figure 4). Until now, evidence from clinical
trials is missing to confirm the data produced by these observational studies. Population strategies targeting economic and social
determinants for changing lifestyle behaviour in the population
require political action and need different partners at the local,
national, and international levels. Examples for policy actions to
put prevention into practice at the population level are provided
by the recently published NICE public health guidance Prevention
of cardiovascular disease at population level.98 Currently,
however, it is unclear how lifestyle changes can be successfully
achieved in healthy individuals.
Observational studies may also generate new pathophysiological
hypotheses about stroke occurrence. For example, individuals with
acute infection99 or with increased homocystein levels100 have a
higher stroke risk and might be suitable for population-wide interventions, e.g. via immunization or vitamin supplementation,
respectively. However, large primary prevention trials on the
potential reduction of stroke risk are lacking and homocystein lowering with vitamins B6, B12, and folic acid failed in clinical trials in
patients with a history of vascular diseases101 or stroke.102
In individuals at high risk for vascular diseases, drug intervention
by health-care professionals in clinical practice is often necessary in
addition to lifestyle recommendations. There are different strategies for identifying high-risk individuals. Often an opportunistic
screening is undertaken for this purpose, e.g. by risk charts that
are restricted to patients requesting a screening or to patients considered eligible by health practitioners. However, the use of the

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For primary prevention of stroke, two complementary approaches

can be differentiated: the population and the high-risk strategy.86,87
The population approach aims to change levels of risk factors in
the entire population towards a more favourable distribution.
These include environmental or lifestyle factors (such as diet, physical activity, smoking, and obesity) as well as their social and economic determinants.88 For example, the North Karelia Project
aiming at risk factor level reduction by population-wide chronic
disease prevention and health promotion interventions shows an
80% decline in coronary mortality over 35 years.89 In contrast,
the high-risk strategy aims at identifying currently asymptomatic
individuals at high risk of future vascular disease to reduce their
individual risk.86 The decision to take preventive action in asymptomatic high-risk individuals should be based on absolute risk
rules.13 This means that absolute levels of multiple risk factors
are taken into account rather than a specific risk factor unless it
is markedly increased.13,90 Risk charts are available for estimating
the probability of future vascular disease (absolute risk). They
contain relative risks of factors derived from cohort studies and
baseline risks reflecting cultural, socio-economic, and psycho-social
characteristics of a given population.90 Currently, global risk scores
(e.g. SCORE91), which estimate total cardiovascular risk rather
than incidence of single endpoints, are recommended for the
identification of high-risk individuals.13 To provide accurate identification, these risk charts should also be adapted to the baseline
risk of the population.92

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Primary prevention of stroke

charts might not be fully understood by physicians,103 leading to

only modest changes in prescription behaviour.104 There is also
an ongoing debate about mass screening programmes for identifying high-risk individuals in whole or pre-defined populations.105
Other approaches proposing targeted screening of potential highrisk groups such as a pre-stratification of potentially high-risk
people based on routine available data which then undergo a
more detailed screening programme.106
Another approach was proposed by Wald and Law107 as a
population-wide drug intervention from a given age without
screening or identification of individual risk. This polypill strategy
proposes to reduce simultaneously four major cardiovascular risk
factors: cholesterol, BP, homocystein/low-folate, and platelet function by drugs including a statin, three blood-lowering drugs in low
dosage, folic acid, and aspirin. The authors proposed treatment for
everybody older than 55 years or with a history of previous cardiovascular disease, regardless of pre-treatment risk factor levels and
without monitoring of the effect. Currently, evidence from clinical
trials to assess the overall benefit as well as potential adverse
effects is lacking. It needs to be established whether different

Drug adherence
Another important aspect in ensuring effectiveness of drug treatment in primary prevention is drug adherence. Increasing
numbers of elderly patients require polypharmacy for chronic diseases. Non-adherence to medication is common and is associated
with adverse treatment outcome. Reduced adherence is an indicator of higher morbidity, adverse events, and costs. Adherence
to medical therapy correlates with reduced morbidity and survival.
Average non-adherence rates are between 20 and 50% in patients
with chronic diseases.112 Adherence to medication can be effectively improved by specific measures such as counselling of
patient and care-giver, reduction of the number of single daily
doses, and provision of supporting medication management such
as blister packs.113 An important factor for medication adherence
is the number of pills taken daily. Increasing numbers of single
doses are directly associated with dramatically decreasing adherence.114 Fixed combinations, e.g. in the treatment of hypertension,
can contribute to the reduction of the number of single doses and
therefore also improve drug adherence.115,116 The polypill concept
introduced above offers the different drug substances in a single
formulation. In an analysis of .11 900 patients on fixed-dose combination, the relative risk of non-adherence was reduced by 26%
compared with patients on free-drug component regimens.115
Adherence can be improved using a single pill in comparison
with the drugs being taken separately; however, other ways of providing combination therapy, e.g. in unit doses, may maintain the
freedom of treatment. Speculation is justified that the impact of
implementing comprehensive measures to improve adherence
such as continuous counselling and individualized multidose adherence aids may be more important than our current focus on the
development of new drugs.117 However, clinical trials in primary
prevention are needed to test the effects of measures to
improve adherence on clinical endpoints in high-risk individuals.

Implications for future management

A substantial portion of the risk factors for stroke and CHD is
identical
(albeit
with
different
contributions).
Thus,

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Figure 4 Relative risk of first stroke by participants with most

healthy lifestyle habits compared with participants with unhealthy
lifestyle in previous cohort studies. Nurses Health Study
(Women): adjusted hazard ratio (aHR) for total stroke comparing
women with five low-risk lifestyle factors [not smoking, body
mass index (BMI) , 25 kg/m2, 30 min daily moderate activity,
modest alcohol consumption scoring within the top 40% of a
healthy diet score] with women who had none of these
factors;95 Health Professionals Follow-up Study (Men): aHR for
total stroke comparing men with five low-risk lifestyle factors
(not smoking, BMI , 25 kg/m2, 30 min daily moderate activity,
modest alcohol consumption scoring within the top 40% of a
healthy diet score) with men who had none of these factors;95
EPIC Potsdam (Men and Women): participants with four
healthy lifestyle factors (never smoking, BMI , 30 kg/m2,
3.5 h weakly physical activity, adhering to healthy dietary principles) or more compared with participants with zero healthy
factors;97 Womens Health Study (Women): aHR for total
stroke comparing women with healthy lifestyle according to a
health index (17 20 health index points based on smoking,
alcohol consumption, exercise, BMI, and diet) compared with
women with no healthy lifestyle (0 4 health index points).96

medications when combined in a single pill still exert their

expected mechanism of action. For example, a polypill containing
low doses of hydrochlorothiazide, atenolol, ramipril, simvastatin,
and aspirin was compared with the individual drugs given separately in a randomized trial in primary prevention in India. This polypill was well tolerated and non-inferior to its individual
components in lowering BP and heart rate. It substantially
lowered LDL cholesterol and urinary 11-dehydrothromboxane
B2, but to a degree that was slightly less effective than simvastatin
or ASA alone.108 However, there is no clear consensus as to which
kinds and doses of substances should be combined for optimal prevention.109 Drug registration of fixed combinations represents a
challenge and, in the case of adverse events, it is difficult to identify
the responsible component(s). Another important limitation is the
reduced flexibility in choice of drug substances and individual
doses. However, all currently proposed strategies for primary prevention based on modelling approaches. The cost effectiveness or
real population benefits of these strategies are in debate and the
outputs of clinical trials are expected.110,111

552

Funding
This work was supported by the European Unions Seventh Framework Programme grant agreement no. 202213 (European Stroke
Network, M.E. and U.L.) and no. 223153 (EIS, P.U.H), the
German Ministry of Research and Education (Center for Stroke
Research Berlin grant number 01 EO 0801, M.E. and P.U.H), the
Volkswagen Foundation, and the Deutsche Forschungsgemeinschaft (M.E.).
Conflict of interest: M.E. has received grant support from
Astra-Zeneca and Sanofi-aventis, has participated in advisory
board meetings of Boehringer Ingelheim and Sanofi-aventis, and
has received honoraria from Novartis, Pfizer, Bayer, Astra-Zeneca,
Boehringer Ingelheim, Sanofi-aventis, Trommsdorff, Berlin-Chemie,
GlaxoSmithKline, and BristolMyers-Squibb. P.U.H. received an
unrestricted research grant from the German Stroke Foundation.
U.L. has received honoraria from Astra-Zeneca, Boehringer
Ingelheim, Daiichi-Sankyo, Essex, MSD, Roche, Sanofi-aventis,
Servier, Takeda, and Trommsdorff.

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recommendations for primary prevention of vascular diseases in

general should also serve as a basis for the primary prevention
of stroke. For example, the existing European guidelines for cardiovascular disease prevention in clinical practice commissioned by
the Joint Task Force, including, for example, representatives from
the European Society of Cardiology and the European Stroke
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The question arises as to what additional implications for
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research questions outlined above, a number of areas can be identified that need to be addressed in future clinical studies. For
example, subjects with rare disease conditions but with particular
high risk of stroke need to be identified and might require more
aggressive primary preventive treatment (e.g. patients with CHF
and intracavitary thrombi). Stroke-specific risk factors such as AF
or carotid stenosis require specific action for stroke prevention,
and tailor-made guidance is necessary. The effects of aggressive
LDL cholesterol lowering in primary stroke prevention needs to
be established and it is necessary to test whether HDL-raising
drugs may be beneficial (in addition to statins and lifestyle factor
interventions in high-risk individuals). The role of triglycerides in
primary stroke prevention needs to be established and further
research is needed to address the aspect of risk prediction and
potential treatment. It is currently unclear whether individuals at
high absolute vascular risk but with normal BP levels will
benefit from BP lowering medication. Because of the outmost
importance of BP levels for the brain, it needs to be established
whether a specific BP target for effective prevention of first
strokes should also apply to existing recommendations for
primary prevention of cardiovascular diseases.

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