REVIEW

Frontiers in cardiovascular medicine

Primary prevention of stroke: blood pressure,lipids, and heart failureMatthias Endres1,2*, Peter U. Heuschmann2, Ulrich Laufs3, and Antoine M. Hakim4

1Klinik und Hochschulambulanz fur Neurologie, Charite—Universitatsmedizin 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 StrokeFoundation 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

Stroke contributes significantly to morbidity, mortality, and disability worldwide. Despite the successes accomplished in the acute treatment andrehabilitation of stroke, the global burden of this disease can only be tackled with co-ordinated approaches for primary prevention. Stroke is aheterogeneous disease and the contribution of individual risk factors to its occurrence estimated by population attributable risk differs fromcoronary heart disease. Here, we review evidence to demonstrate the prominent role of elevated blood pressure (BP) and heart disease onrisk of stroke, while the influence of lipids on stroke is less clear; we also demonstrate that stroke is an important complication of heartfailure. Current approaches to primary preventive action emphasize the need to target the absolute risk of cardiovascular diseases ratherthan 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 fromepidemiological studies. Different strategies for drug interventions in primary prevention are discussed, including the polypill strategy. Additionalmeasures are needed for the primary prevention of stroke which focus on BP, chronic heart failure, and possibly lipids.- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -Keywords Hypertension † Cholesterol † Heart failure † Triglycerides † Polypill † Adherence

IntroductionThe global burden of stroke is substantial. Stroke is the secondleading cause of death, one of the leading causes of adult acquired dis-ability worldwide, and hence a major contributor to health-carecosts.1 For example, in the UK, the direct and indirect societalcosts caused by stroke are about 8.9 billion pounds a year.2 Strokeis a disease of the elderly. The median age at the onset of firststroke in Europe is 73 years.3 It is anticipated that the absolutenumber of stroke patients will increase substantially over the nextdecades. The WHO estimates that the absolute number of first-everstroke patients in the European Union and selected European FairTrade Association countries will increase from 1.1 million in 2000to 1.5 million in 2025 if incidence rates remain stable.4

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

consisting of different pathophysiological and aetiological sub-groups (Figure 1). Stroke is a clinical diagnosis and is classifiedaccording to the duration of clinical symptoms into transientischaemic attack or stroke.5 New tissue- instead of time-basedclassification systems are challenging this traditional definition.6

The clinical entity ‘stroke’ is further subdivided based on theunderlying pathology into ischaemic stroke (IS), primary intracra-nial haemorrhage, or subarachnoidal haemorrhage. IS can be classi-fied according to the leading aetiological cause into large-arteryatherosclerosis, cardioembolism, small-artery occlusion, othercauses, and undetermined aetiology7 with new classificationsystems proposed in the light of wider availability of advanced diag-nostic facilities.8

Risk factors for strokeThe main risk factors for ischaemic and haemorrhagic stroke,respectively, are well known and can be differentiated into non-modifiable (age, sex, genetic predisposition, ethnicity) and modifi-able 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

European Heart Journal (2011) 32, 545–555doi:10.1093/eurheartj/ehq472

by guest on July 9, 2015D

ownloaded from

variations in the impact of specific risk factors between haemor-rhagic stroke and IS. For example, atrial fibrillation (AF) is a riskfactor for IS but not for haemorrhagic stroke.10 –12 Most riskfactors contribute to both coronary heart disease (CHD) and IS.However, the relative contribution of individual risk factorsdiffers substantially between the two disease conditions.13 Definingthe weight of risk factors by population attributable fractions (PAF)(i.e. the proportion of a disease that could be theoretically pre-vented if a risk factor would be absent) reveals hypercholestero-laemia as the main risk factor for CHD14–17 and hypertensionfor stroke18,19 (Figure 2). However, the estimation of PAF for aspecific risk factor is not trivial, especially if diseases are causedby multiple risk factors not acting independently,20 and the esti-mates are dependent on the definition of the population atrisk.21 The four main modifiable risk factors diabetes, smoking,hypertension, and hypercholesterolaemia explain less variance ofoccurrence of stroke compared with the occurrence of myocardialinfarction [e.g. 55% of stroke events vs. 88% of myocardial infarc-tion events in the European Prospective Investigation into Cancerand Nutrition (EPIC) study were attributed to these four riskfactors].22

Minimizing the impact of stroke on society will thus requireeffective strategies for reducing its incidence in the general popu-lation. Here, we review current strategies for the main modifiablerisk factors: blood pressure (BP), lipids, and heart disease.

Blood pressureHigh BP is a common phenomenon in the population. Its preva-lence varies according to geography and ethnic background. Atthe 140/90 mmHg threshold, the prevalence of hypertension is28% in North America and 44% in six European countries.23 In

sub-Saharan Africa, although overall hypertension prevalence isup to 15%, middle-income urban dwellers can have prevalencerates as high as 32%.

Blood pressure and strokeHypertension has been identified as a major risk factor for stroke.The INTERSTROKE study, which evaluated the contribution ofvarious risk factors to the burden of stroke worldwide, concludedthat hypertension provided 34.6% of the PAF for stroke19

Figure 1 Clinical syndrome stroke.65

Figure 2 Percentage population attributable risk of main mod-ifiable risk factors for acute myocardial infarction and stroke(ischaemic and haemorrhagic stroke combined) based on theestimates from the INTERHEART study and the INTERSTROKEstudy.14,19 Population attributable risk (PAR) is estimating theproportion of a disease that can theoretically be attributed to aspecific risk factor; estimates derived from the INTERHEARTstudy14 and the INTERSTROKE study.19

M. Endres et al.546

by guest on July 9, 2015D

ownloaded from

(Figure 2). If in addition to patient-reported history of hypertensiona BP higher than 160/90 mmHg was measured, PAF for stroke dueto hypertension increased to 52%. Ezzati et al.24 previously attrib-uted 70–76% of strokes occurring in 14 subregions of the world toa limited number of risk factors, with hypertension as the biggestdriver of stroke risk.

More recently, it has also been recognized that hypertension isalso a risk factor for reduced cognitive function. In a large observa-tional study of a healthy population, an increase of 10 mmHg indiastolic BP (DBP) was associated with 7% higher odds of cognitiveimpairment.25 This is similar to the conclusion that a 1 mmHg risein systolic BP (SBP) in midlife was associated with a 1% increase inrisk of cognitive decline later in life.26 In addition to a direct associ-ation with dementia, hypertension also aggravates Alzheimer’sdisease, and the presence of a single lacune at autopsy, evenwhen asymptomatic, increased the probability of dementia by afactor of 18 in the Nun Study.27

Blood pressure lowering in primarystroke preventionINTERSTROKE and INTERHEART report that hypertension pro-vided 34.6 and 17.9% of the PAF for stroke and myocardial infarc-tion, respectively (Figure 2).28 This is supported by apopulation-based study from France showing that individuals withstroke were more likely to be hypertensive than those with myo-cardial infarcts.29 At standard doses, drugs that lower BP alsoreduce stroke incidence more than they reduce myocardialinfarcts.30 In the ACCORD study, where almost 5000 participantswith 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 incidencein the intensive therapy group.31 Thus, the brain is the organmost benefited when BP is reduced.

Several authors have estimated the extent of protection thatresults when BP is lowered. Girerd and Giral32 concluded thateach 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, treatmentwhich lowered mean SBP and DBP by 15.0/6.1 mmHg resulted ina 39% reduction in the rate of fatal strokes at 2 years of treatment.Jones et al.34 estimated that a 35–44% reduction in the incidenceof new strokes can be achieved by lowering BP. Finally, Sokolet al.35 concluded from their review of the effect of BP manage-ment on the incidence of primary and secondary strokes that pro-longed reduction in DBP of 5, 7.5, and 10 mmHg would lowerstroke rates by at least 34, 46, and 56%, regardless of the startingBP level.

Conclusions: blood pressure and primaryprevention of strokeDespite the overwhelming evidence that hypertension is a majorcause of damage particularly to the brain and that the brainbenefits the most from BP lowering, there are no randomized clini-cal trials that provide a BP target for effective prevention of firststrokes.36 This can only be answered by a new study that attemptsto define a target. The challenges of designing such a trial have

recently been described.37 Nonetheless, the SBP InterventionTrial (SPRINT) launched recently by NIH, with a target SBPof ,120 mmHg, should go a long way to filling this gap. Inthe meantime, it is clear that improving the management ofhypertension at the population level will result in optimum brainprotection. Law et al. suggest that in people aged 60–69 with aDBP of 90 mmHg, three drugs at half standard dose reduced therisk of stroke by 62%, whereas one drug at standard dose hadhalf this effect. In addition, they advocate lowering BP in thepopulation broadly rather than ‘measuring it in everyone andtreating it in some’.30

Lipids

Cholesterol and strokeTotal blood cholesterol levels are a prominent risk factor for car-diovascular disease.38 The association of cholesterol and stroke,however, is much less clear: surprisingly, epidemiological studiesfound no consistent relationship between cholesterol levels andoverall stroke risk.39 For example, neither the Framingham Studynor the Honolulu Heart Study found an association betweencholesterol levels and cerebrovascular disease. The ProspectiveStudies Collaboration has brought together evidence from 61 indi-vidual prospective studies and analysed the data of 55 000 vasculardeaths.38 There was no clear relationship between blood choles-terol and stroke (except in people aged 40–60 years and withnormal or high-normal BP). In many of the individual studies, nodifferentiation between stroke subtypes was performed. Forexample, many strokes were not verified by brain imaging and,hence, could not even be differentiated into haemorrhagic strokevs. IS. Indeed, the MRFIT study in 350 000 men which examinedthe link between cholesterol and fatal stroke (and differentiatedhaemorrhagic stroke from IS) showed a J-shaped relationshipbetween total cholesterol levels and stroke mortality (Figure 3).40

This could be explained by an association of higher cholesterolwith IS and, vice versa, between lower cholesterol and haemorrha-gic stroke10—at least in patients with co-morbid high BP.40 Simi-larly, in the Prospective Studies Collaboration in individuals with

Figure 3 Cholesterol and stroke subtype stratified for thehistory of prior myocardial infarction (MI) based on estimatesfrom the MRFIT study.40

Primary prevention of stroke 547

by guest on July 9, 2015D

ownloaded from

SBP .145 mmHg, total cholesterol was negatively related to hae-morrhagic and total stroke mortality.38 Another caveat of themeta-analyses is the fact that often only fatal strokes were ana-lysed.41 Taken together, the relationship between cholesteroland total stroke is weak but it seems likely that cholesterol isassociated with increased risk at least in the subgroup of athero-thrombotic strokes.

Only few studies addressed the association of elevated LDLcholesterol levels and IS, and they did not yield consistent find-ings.42 In contrast, high HDL levels are associated with reducedstroke risk, and vice versa, low HDL is associated with increasedstroke risk.36,43,44 Also, the ratio of total cholesterol to HDLcholesterol (or the LDL/HDL cholesterol) ratio may be more pre-dictive. This is also supported by the INTERSTROKE study whichshowed that the ratio of apolipoprotein B to A1 was predictive forstroke risk.14 Overall, the population attributable risk of low HDLcholesterol 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 tri-glyceride levels and IS,46 but several studies found no relationshipbetween fasting triglyceride levels and IS risk (as was demonstratedfor cardiovascular disease). In contrast, non-fasting triglyceridelevels may be a better prediction for stroke (and cardiovascular)risk.46,47 Recently, a cohort study also found an association of non-fasting triglyceride levels and IS in women.48 Triglyceride levelsvary considerably, making risk prediction difficult, and the lack ofstandardization may explain some of the contradictory results.The ongoing Berlin Cream & Sugar Study will employ an oral trigly-ceride tolerance test with standardized conditions to predict therisk of further strokes.41

Lipid lowering in primary strokepreventionEarlier intervention trials with non-statin cholesterol-loweringdrugs (including fibrates) failed to show a reduction of strokerisk, which stands in contrast to the fact that these drugslowered cardiovascular risk (along with cholesterol levels).50 Incontrast, results from randomized trials have demonstrated thattreatment with HMG-CoA reductase inhibitors (i.e. statins),which lower total and LDL cholesterol, not only reduces the inci-dence of ischaemic heart disease but also of IS.51,52 As a rule ofthumb, the reduction in LDL cholesterol by 1.5 mmol/L reducesIS risk by about a third.51,52 Statins were also protective in popu-lations at high vascular risk but without documented CHD, suchas in the ASCOT-LLA or CARDS (primary diabetic population)cohorts.

So far, however, the protective results of statins on stroke riskare limited to patients at high risk for stroke (i.e. with CHD orother additional risk factors) and it remains unclear whetherstatin treatment is effective for stroke prevention in the generalpopulation without CHD. Data on the elderly, moreover, arevery limited: in the PROSPER trial, pravastatin had no effect onstroke (while it reduced the combined vascular endpoint by15%).53 For secondary stroke prevention, both the SPARCL trialand a subgroup of the HPS trial demonstrated a significantreduction of secondary cerebrovascular events in stroke patients

even without additional CHD.54,55 Consequently, statin therapyhas become a pillar of treatment in addition to aspirin and BPmedication.

Of note, reduction in IS risk by statins may be associated with asmall increase in haemorrhagic stroke as suggested by two second-ary prevention trials, SPARCL and HPS.55,56 Statins might thereforenot be indicated for patients with haemorrhagic strokes. Furtherstudies of how exactly lipids, cholesterol, and lipoprotein particlescontribute to stroke risk invite further research.

Presently, the mechanism of stroke protection by statins is notentirely clear. Cholesterol-independent pleiotropic effects maycontribute to it: statins reduce inflammation, are anti-atherogenic,lower BP, stabilize plaques, are anti-thrombotic, improve fibrinoly-sis, and decrease platelet activation. They also have immuno-modulatory effects, increase the number of circulating endothelialprogenitor cells, and improve endothelium function.57 In addition,statins have neuroprotective properties, reduce ischaemic lesionsize in animal stroke models, and may therefore also improvestroke outcome.57 However, the relative contribution of LDLcholesterol lowering vs. other pleiotropic statin actions on thereduction of stroke risk cannot be easily differentiated since essen-tially all pleiotropic effects of statins are also dependent onHMG-CoA reductase inhibition. Thus, these effects go hand inhand with any effect on LDL cholesterol levels, are dose-dependent, and correspond with the potency of a given statindrug. In other words, LDL cholesterol may as well serve as a bio-marker for pleiotropic statin effects. It is therefore not surprisingthat there is a linear association between reduction in LDL choles-terol concentration and stroke incidence among the major statintrials.46

Recently, the JUPITER trial tested the hypothesis whether indi-viduals with elevated inflammatory biomarkers but without hyper-lipidaemia benefit from high-dose statin treatment. In fact,high-sensitivity C-reactive protein levels were demonstrated tobe associated with the risk of IS, although its relevance is stillunclear.58 Rovastatin reduced major cardiovascular events includ-ing death from cardiovascular causes in apparently healthy menand women with average LDL cholesterol and elevated high-sensitivity C-reactive protein.59 Stroke reduction by rosuvastatintreatment was also significant, but the absolute rate was low andthe number needed to treat consequently rather high (i.e.286!).59 The JUPITER study has already evoked intensivedebate.60 However, its relevance for (primary) stroke preventionis limited by the low number of stroke events and the fact that itincluded individuals without a specific condition placing them atrisk for stroke.61

Conclusions: lipids and primaryprevention of strokePresent guidelines recommend the regular measurement of bloodcholesterol levels. The National Cholesterol Education Program IIIprovided guidelines for the management of patients without pre-vious cerebrovascular events with elevated non-HDL cholesterollevels and additional risk factors.62 It is unclear whether loweringlipids is effective in the primary prevention of stroke in thegeneral population (without CHD or additional vascular risk

M. Endres et al.548

by guest on July 9, 2015D

ownloaded from

factors). High-risk individuals should be treated with a statin andlifestyle measures even with normal LDL cholesterol.45,63 Infuture, the effects on stroke risk of aggressive LDL cholesterol low-ering 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 thatezitimibe–statin combinations (which may offer superior lipid-modifying effects) may provide any additional benefit over statinmonotherapy. Future and ongoing studies need to test whetherHDL-raising drugs such as nicotinic acid (niacin) or cholesterylester transfer protein inhibitors may be beneficial in addition tostatins and the proven baseline therapy of weight control, physicalactivity, and smoking cessation.45 The role of triglycerides as Lp(a)remains unclear and further research is needed to address risk pre-diction and optimal treatment. In particular, the effects oftriglyceride-lowering therapy alone or in combination with statinsand the effects of treatments to raise HDL cholesterol concen-trations await further studies.

Heart failureCardiac diseases including valve disease and chronic heart failure(CHF) represent a risk factor for IS64 (Table 1). Approximately25% of all ISs are due to cardiac embolism.65 Up to 10–24% ofthe patients with IS have CHF, and in 9% of ISs, CHF is the likelycause.66– 69 For CHF, a meta-analysis calculated that 18 per 1000persons suffered a stroke during the first year after the diagnosisand increased to 47 at 5 years.70 The overall relative risk ofstroke in CHF increases approximately two to three folds com-pared with patients without CHF. In addition, CHF represents anindependent predictor for the severity of cerebral ischaemia andassociated poor outcome.71 A recent analysis showed that theodds ratio of in-hospital mortality rate for stroke patients withCHF 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 cer-ebral ischaemia in CHF patients may be high (up to 40% of theCHF population).72 Silent cerebral ischaemia, losses in greymatter, and decreased cerebral perfusion may significantly

contribute to cognitive impairments that are reported in manyCHF patients (25–80%)73,74 A recent analysis of the Framinghamstudy looked at 1504 participants without prior stroke or dementiashowed that the cardiac index correlated with brain volume andinformation processing speed75 (Table 2). Further research isneeded to characterize the underlying mechanism(s) for thisassociation, which is largely unknown, and to develop strategiesfor 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 associ-ated with an increased risk of embolism.76 Chronic heart failure isassociated with an activation of thrombus formation likelymediated by the renin–angiotensin system, endothelial dysfunc-tion, increased blood velocity, and dysregulation of mediators(e.g. thrombin, plasminogen, and others).77 The main cause foremboli in patients with CHF is AF.78 The prevalence of AF inCHF is 10–17% and it increases with LV dilatation andNew York Heart Association (NYHA) stage.79 The degree of LVdysfunction is associated with embolic events and can be used tostratify stroke risk in patients with AF (Table 3). Chronic heartfailure is therefore an important factor for the assessment ofstroke risk. For example, CHF is included in the CHADS2 scoreto assess stroke risk in AF patients.80 An assessment of the individ-ual co-morbidities using the CHADS2 score can help to make indi-vidual recommendations. For individuals with a CHADS2 score of0 treatment with aspirin is sufficient, for a CHADS2 of 1 aspirin oranticoagulation can be used and all patients with a CHADS2 .1clearly benefit from anticoagulation.

Intracavitary thrombi are a source of embolism and occur in LVsimpaired by myocardial infraction, valve disease, or CHF. Thedanger of intra-atrial thrombus formation exists particularly inpatients with AF (see above). In patients with a ventricular throm-bus and additional risk factors (e.g. LV dysfunction or hyperten-sion), anticoagulation for at least 6 months is indicated.81

Intra-atrial thrombi can only be detected or excluded with suffi-cient diagnostic reliability by the use of transoesophageal echocar-diography (TEE). In contrast, both LV function and LV thrombi(especially in the apex cordis) are better assessed by transthoracicechocardiography than by TEE.81– 83 Lack of atrial thrombi doesnot exclude cardiogenic stroke.

Because of the increased risk of intermittent and of asympto-matic AF in CHF and the increased risk of stroke in patientswith CHF in sinus rhythm, the question arises whether all patientswith impaired LV function or LV aneurysms would benefit fromanticoagulation. However, all published studies that tested theeffect of oral anticoagulation in patients with CHF in sinusrhythm, including the WATCH trial,84 were not able to demon-strate an advantage of anticoagulation with regard to mortality.Anticoagulation is effective in patients with CHF and AF, but LVdysfunction by itself does not represent an indication for anticoa-gulation treatment.

In addition to the causal relationship between CHF and IS, thesetwo disease entities represent manifestations of similar underlyingrisk factors. In CHF patients in sinus rhythm, older age, hyperten-sion, and diabetes are associated with increased incidence ofstroke.85 Arterial hypertension is a main risk factor for stroke

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

Table 1 Echocardiographic findings and risk of futureembolic events83

High risk Low risk

Atrial fibrillation Mitral valve prolapse

Mitral valve stenosis Mitral valve calcification

Mechanical prosthetic valves Patent foramen ovale

Recent myocardial infarction Atrial septal aneurysm

Left ventricular thrombus/leftatrial thrombus

Regional wall movementdisturbances of the LV

Atrial myxoma Calcifying aortic valve stenosis

Infectious endocarditis Mitral valve strands

Dilative cardiomyopathy

Primary prevention of stroke 549

by guest on July 9, 2015D

ownloaded from

and CHF and represents one of the most important targets forprevention. Indeed, the recent Hypertension in the Very ElderlyTrial (HYVET) showed that BP control in patients .80 years ofage reduced both stroke and heart failure events as well as mor-tality.33 Blood pressure control is the basis of the prevention ofCHF and stroke.13

Primary stroke prevention

General principles of primary preventionFor primary prevention of stroke, two complementary approachescan be differentiated: the population and the high-risk strategy.86,87

The population approach aims to change levels of risk factors inthe entire population towards a more favourable distribution.These include environmental or lifestyle factors (such as diet, phys-ical activity, smoking, and obesity) as well as their social and econ-omic determinants.88 For example, the North Karelia Projectaiming at risk factor level reduction by population-wide chronicdisease prevention and health promotion interventions shows an80% decline in coronary mortality over 35 years.89 In contrast,the high-risk strategy aims at identifying currently asymptomaticindividuals at high risk of future vascular disease to reduce theirindividual risk.86 The decision to take preventive action in asymp-tomatic high-risk individuals should be based on ‘absolute riskrules’.13 This means that absolute levels of multiple risk factorsare taken into account rather than a specific risk factor unless itis markedly increased.13,90 Risk charts are available for estimatingthe probability of future vascular disease (absolute risk). Theycontain relative risks of factors derived from cohort studies andbaseline risks reflecting cultural, socio-economic, and psycho-socialcharacteristics of a given population.90 Currently, global risk scores(e.g. SCORE91), which estimate total cardiovascular risk ratherthan incidence of single endpoints, are recommended for theidentification of high-risk individuals.13 To provide accurate identi-fication, these risk charts should also be adapted to the baselinerisk of the population.92

Implementing primary prevention in thepopulationLifestyle interventions serve as a basis for primary prevention. Ithas been proposed that 70% of stroke and over 80% of CHDmight be preventable through lifestyle modifications (e.g. notsmoking, healthy diet, body mass index ,25 kg/m2, regular phys-ical activity, and moderate alcohol consumption).93 This estimation

is in line with observations from prospective cohort studies whichreport that a healthy life style (as defined above) is associated withan 82% decrease in CHD risk in women.94 In addition, a substantialdecrease in relative risk of stroke in people with the healthiest life-style compared with an unhealthy lifestyle is observed in previouscohort studies95–97 (Figure 4). Until now, evidence from clinicaltrials is missing to confirm the data produced by these observa-tional studies. Population strategies targeting economic and socialdeterminants for changing lifestyle behaviour in the populationrequire political action and need different partners at the local,national, and international levels. Examples for policy actions toput prevention into practice at the population level are providedby the recently published NICE public health guidance ‘Preventionof cardiovascular disease at population level’.98 Currently,however, it is unclear how lifestyle changes can be successfullyachieved in healthy individuals.

Observational studies may also generate new pathophysiologicalhypotheses about stroke occurrence. For example, individuals withacute infection99 or with increased homocystein levels100 have ahigher stroke risk and might be suitable for population-wide inter-ventions, e.g. via immunization or vitamin supplementation,respectively. However, large primary prevention trials on thepotential reduction of stroke risk are lacking and homocystein low-ering with vitamins B6, B12, and folic acid failed in clinical trials inpatients with a history of vascular diseases101 or stroke.102

In individuals at high risk for vascular diseases, drug interventionby health-care professionals in clinical practice is often necessary inaddition to lifestyle recommendations. There are different strat-egies for identifying high-risk individuals. Often an opportunisticscreening is undertaken for this purpose, e.g. by risk charts thatare restricted to patients requesting a screening or to patients con-sidered eligible by health practitioners. However, the use of the

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

Table 2 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

Continuous 0.30 + 0.14 0.03 0.33 + 0.14 0.02

Tertile 1 (low) 20.36 + 0.17 0.04 20.41 + 0.17 0.02

Tertile 2 (mid) 20.35 + 0.17 0.04 20.34 + 0.17 0.04

Tertile 3 (high) Reference — Reference —

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

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

Table 3 Estimation of stroke risk in patients withatrial fibrillation based on echocardiographic findings118

Finding Risk/year

Atrial fibrillation + normal echographic finding 1.5%

Atrial fibrillation + enlarged left atrium 8.8%

Atrial fibrillation + left ventricular dysfunction 12.6%

Atrial fibrillation + enlarged atrium + left ventriculardysfunction

20.0%

M. Endres et al.550

by guest on July 9, 2015D

ownloaded from

charts might not be fully understood by physicians,103 leading toonly modest changes in prescription behaviour.104 There is alsoan ongoing debate about mass screening programmes for identify-ing high-risk individuals in whole or pre-defined populations.105

Other approaches proposing targeted screening of potential high-risk groups such as a pre-stratification of potentially high-riskpeople based on routine available data which then undergo amore detailed screening programme.106

Another approach was proposed by Wald and Law107 as apopulation-wide drug intervention from a given age withoutscreening or identification of individual risk. This ‘polypill’ strategyproposes to reduce simultaneously four major cardiovascular riskfactors: cholesterol, BP, homocystein/low-folate, and platelet func-tion by drugs including a statin, three blood-lowering drugs in lowdosage, folic acid, and aspirin. The authors proposed treatment foreverybody older than 55 years or with a history of previous cardi-ovascular disease, regardless of pre-treatment risk factor levels andwithout monitoring of the effect. Currently, evidence from clinicaltrials to assess the overall benefit as well as potential adverseeffects is lacking. It needs to be established whether different

medications when combined in a single pill still exert theirexpected mechanism of action. For example, a polypill containinglow doses of hydrochlorothiazide, atenolol, ramipril, simvastatin,and aspirin was compared with the individual drugs given separ-ately in a randomized trial in primary prevention in India. This poly-pill was well tolerated and non-inferior to its individualcomponents in lowering BP and heart rate. It substantiallylowered LDL cholesterol and urinary 11-dehydrothromboxaneB2, but to a degree that was slightly less effective than simvastatinor ASA alone.108 However, there is no clear consensus as to whichkinds and doses of substances should be combined for optimal pre-vention.109 Drug registration of fixed combinations represents achallenge and, in the case of adverse events, it is difficult to identifythe responsible component(s). Another important limitation is thereduced flexibility in choice of drug substances and individualdoses. However, all currently proposed strategies for primary pre-vention based on modelling approaches. The cost effectiveness orreal population benefits of these strategies are in debate and theoutputs of clinical trials are expected.110,111

Drug adherenceAnother important aspect in ensuring effectiveness of drug treat-ment in primary prevention is drug adherence. Increasingnumbers of elderly patients require polypharmacy for chronic dis-eases. Non-adherence to medication is common and is associatedwith adverse treatment outcome. Reduced adherence is an indi-cator of higher morbidity, adverse events, and costs. Adherenceto medical therapy correlates with reduced morbidity and survival.Average non-adherence rates are between 20 and 50% in patientswith chronic diseases.112 Adherence to medication can be effec-tively improved by specific measures such as counselling ofpatient and care-giver, reduction of the number of single dailydoses, and provision of supporting medication management suchas blister packs.113 An important factor for medication adherenceis the number of pills taken daily. Increasing numbers of singledoses are directly associated with dramatically decreasing adher-ence.114 Fixed combinations, e.g. in the treatment of hypertension,can contribute to the reduction of the number of single doses andtherefore also improve drug adherence.115,116 The polypill conceptintroduced above offers the different drug substances in a singleformulation. In an analysis of .11 900 patients on fixed-dose com-bination, 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 comparisonwith the drugs being taken separately; however, other ways of pro-viding combination therapy, e.g. in unit doses, may maintain thefreedom of treatment. Speculation is justified that the impact ofimplementing comprehensive measures to improve adherencesuch as continuous counselling and individualized multidose adher-ence aids may be more important than our current focus on thedevelopment of new drugs.117 However, clinical trials in primaryprevention are needed to test the effects of measures toimprove adherence on clinical endpoints in high-risk individuals.

Implications for future managementA substantial portion of the risk factors for stroke and CHD isidentical (albeit with different contributions). Thus,

Figure 4 Relative risk of first stroke by participants with mosthealthy lifestyle habits compared with participants with unhealthylifestyle in previous cohort studies. Nurses Health Study(Women): adjusted hazard ratio (aHR) for total stroke comparingwomen with five low-risk lifestyle factors [not smoking, bodymass index (BMI) , 25 kg/m2, ≥30 min daily moderate activity,modest alcohol consumption scoring within the top 40% of ahealthy diet score] with women who had none of thesefactors;95 Health Professionals Follow-up Study (Men): aHR fortotal 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 ahealthy diet score) with men who had none of these factors;95

EPIC Potsdam (Men and Women): participants with fourhealthy lifestyle factors (never smoking, BMI , 30 kg/m2,≥3.5 h weakly physical activity, adhering to healthy dietary prin-ciples) or more compared with participants with zero healthyfactors;97 Women’s Health Study (Women): aHR for totalstroke comparing women with healthy lifestyle according to ahealth index (17–20 health index points based on smoking,alcohol consumption, exercise, BMI, and diet) compared withwomen with no healthy lifestyle (0–4 health index points).96

Primary prevention of stroke 551

by guest on July 9, 2015D

ownloaded from

recommendations for primary prevention of vascular diseases ingeneral should also serve as a basis for the primary preventionof stroke. For example, the existing European guidelines for cardi-ovascular disease prevention in clinical practice commissioned bythe Joint Task Force, including, for example, representatives fromthe European Society of Cardiology and the European StrokeInitiative,87 shifted from recommendations for primary preventionof stroke or CHD towards general preventive recommendationsfor all cardiovascular disease.13,86

The question arises as to what additional implications forprimary prevention of stroke are needed. On the basis of theresearch questions outlined above, a number of areas can be ident-ified that need to be addressed in future clinical studies. Forexample, subjects with rare disease conditions but with particularhigh risk of stroke need to be identified and might require moreaggressive primary preventive treatment (e.g. patients with CHFand intracavitary thrombi). Stroke-specific risk factors such as AFor carotid stenosis require specific action for stroke prevention,and tailor-made guidance is necessary. The effects of aggressiveLDL cholesterol lowering in primary stroke prevention needs tobe established and it is necessary to test whether HDL-raisingdrugs may be beneficial (in addition to statins and lifestyle factorinterventions in high-risk individuals). The role of triglycerides inprimary stroke prevention needs to be established and furtherresearch is needed to address the aspect of risk prediction andpotential treatment. It is currently unclear whether individuals athigh absolute vascular risk but with ‘normal’ BP levels willbenefit from BP lowering medication. Because of the outmostimportance of BP levels for the brain, it needs to be establishedwhether a specific BP target for effective prevention of firststrokes should also apply to existing recommendations forprimary prevention of cardiovascular diseases.

FundingThis work was supported by the European Union’s Seventh Frame-work Programme grant agreement no. 202213 (European StrokeNetwork, M.E. and U.L.) and no. 223153 (EIS, P.U.H), theGerman Ministry of Research and Education (Center for StrokeResearch Berlin grant number 01 EO 0801, M.E. and P.U.H), theVolkswagen Foundation, and the Deutsche Forschungsge-meinschaft (M.E.).

Conflict of interest: M.E. has received grant support fromAstra-Zeneca and Sanofi-aventis, has participated in advisoryboard meetings of Boehringer Ingelheim and Sanofi-aventis, andhas received honoraria from Novartis, Pfizer, Bayer, Astra-Zeneca,Boehringer Ingelheim, Sanofi-aventis, Trommsdorff, Berlin-Chemie,GlaxoSmithKline, and Bristol–Myers-Squibb. P.U.H. received anunrestricted research grant from the German Stroke Foundation.U.L. has received honoraria from Astra-Zeneca, BoehringerIngelheim, Daiichi-Sankyo, Essex, MSD, Roche, Sanofi-aventis,Servier, Takeda, and Trommsdorff.

References1. Johnston SC, Mendis S, Mathers CD. Global variation in stroke burden and mor-

tality: estimates from monitoring, surveillance, and modelling. Lancet Neurol2009;8:345–354.

2. Saka O, McGuire A, Wolfe C. Cost of stroke in the United Kingdom. Age Ageing2009;38:27–32.

3. Incidence of stroke in Europe at the beginning of the 21st century. Stroke 2009;40:1557–1563.

4. Truelsen T, Piechowski-Jozwiak B, Bonita R, Mathers C, Bogousslavsky J,Boysen G. Stroke incidence and prevalence in Europe: a review of availabledata. Eur J Neurol 2006;13:581.

5. Hatano S. Experience from a multicentre stroke register: a preliminary report.Bull World Health Organ 1976;54:541.

6. Amarenco P, Bogousslavsky J, Caplan LR, Donnan GA, Hennerici MG. Classifi-cation of stroke subtypes. Cerebrovasc Dis 2009;27:493–501.

7. Adams HP Jr, Bendixen BH, Kappelle LJ, Biller J, Love BB, Gordon DL, Marsh EEIII. Classification of subtype of acute ischemic stroke. Definitions for use in amulticenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment.Stroke 1993;24:35.

8. Amarenco P, Bogousslavsky J, Caplan LR, Donnan GA, Hennerici MG. Newapproach to stroke subtyping: the A-S-C-O (phenotypic) classification ofstroke. Cerebrovasc Dis 2009;27:502–508.

9. Sacco RL, Benjamin EJ, Broderick JP, Dyken M, Easton JD, Feinberg WM,Goldstein LB, Gorelick PB, Howard G, Kittner SJ, Manolio TA, Whisnant JP,Wolf PA. Risk factors. Stroke 1997;28:1507.

10. Law MR, Wald NJ, Rudnicka AR. Quantifying effect of statins on low density lipo-protein cholesterol, ischaemic heart disease, and stroke: systematic review andmeta-analysis. BMJ 2003;326:1423.

11. Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factorfor stroke: the Framingham Study. Stroke 1991;22:983.

12. Rothwell PM. Carotid artery disease and the risk of ischaemic stroke and coron-ary vascular events. Cerebrovasc Dis 2000;10(Suppl. 5):21–33.

13. Graham I, Atar D, Borch-Johnsen K, Boysen G, Burell G, Cifkova R,Dallongeville J, De Backer G, Ebrahim S, Gjelsvik B, Herrmann-Lingen C,Hoes A, Humphries S, Knapton M, Perk J, Priori SG, Pyorala K, Reiner Z,Ruilope L, Sans-Menendez S, Op Reimer WS, Weissberg P, Wood D,Yarnell J, Zamorano JL, Walma E, Fitzgerald T, Cooney MT, Dudina A,Vahanian A, Camm J, De Caterina R, Dean V, Dickstein K, Funck-Brentano C,Filippatos G, Hellemans I, Kristensen SD, McGregor K, Sechtem U, Silber S,Tendera M, Widimsky P, Altiner A, Bonora E, Durrington PN, Fagard R,Giampaoli S, Hemingway H, Hakansson J, Kjeldsen SE, Larsen L, Mancia G,Manolis AJ, Orth-Gomer K, Pedersen T, Rayner M, Ryden L, Sammut M,Schneiderman N, Stalenhoef AF, Tokgozoglu L, Wiklund O, Zampelas A. Euro-pean guidelines on cardiovascular disease prevention in clinical practice: full text.Fourth Joint Task Force of the European Society of Cardiology and othersocieties on cardiovascular disease prevention in clinical practice (constitutedby representatives of nine societies and by invited experts). Eur J CardiovascPrev Rehabil 2007;14(Suppl. 2):S1–S113.

14. Yusuf S, Hawken S, Ounpuu S, Dans T, Avezum A, Lanas F, McQueen M,Budaj A, Pais P, Varigos J, Lisheng L. Effect of potentially modifiable riskfactors associated with myocardial infarction in 52 countries (the INTERHEARTstudy): case–control study. Lancet 2004;364:937.

15. Singh-Manoux A, Nabi H, Shipley M, Gueguen A, Sabia S, Dugravot A,Marmot M, Kivimaki M. The role of conventional risk factors in explainingsocial inequalities in coronary heart disease: the relative and absoluteapproaches to risk. Epidemiology 2008;19:599–605.

16. Grau M, Subirana I, Elosua R, Fito M, Covas MI, Sala J, Masia R, Ramos R,Solanas P, Cordon F, Nieto FJ, Marrugat J. Why should population attributablefractions be periodically recalculated? An example from cardiovascular risk esti-mation in southern Europe. Prev Med 2010;51:78–84.

17. Nilsson PM, Nilsson JA, Berglund G. Population-attributable risk of coronaryheart disease risk factors during long-term follow-up: the Malmo PreventiveProject. J Intern Med 2006;260:134–141.

18. Lloyd-Jones D, Adams RJ, Brown TM, Carnethon M, Dai S, De Simone G,Ferguson TB, Ford E, Furie K, Gillespie C, Go A, Greenlund K, Haase N,Hailpern S, Ho PM, Howard V, Kissela B, Kittner S, Lackland D, Lisabeth L,Marelli A, McDermott MM, Meigs J, Mozaffarian D, Mussolino M, Nichol G,Roger VL, Rosamond W, Sacco R, Sorlie P, Thom T, Wasserthiel-Smoller S,Wong ND, Wylie-Rosett J. Heart disease and stroke statistics—2010update: a report from the American Heart Association. Circulation 2010;121:e46–e215.

19. O’Donnell MJ, Xavier D, Liu L, Zhang H, Chin SL, Rao-Melacini P, Rangarajan S,Islam S, Pais P, McQueen MJ, Mondo C, Damasceno A, Lopez-Jaramillo P,Hankey GJ, Dans AL, Yusoff K, Truelsen T, Diener HC, Sacco RL,Ryglewicz D, Czlonkowska A, Weimar C, Wang X, Yusuf S. Risk factors forischaemic and intracerebral haemorrhagic stroke in 22 countries (the INTER-STROKE study): a case–control study. Lancet 2010;376:112–123.

20. Rowe AK, Powell KE, Flanders WD. Why population attributable fractions cansum to more than one. Am J Prev Med 2004;26:243–249.

M. Endres et al.552

by guest on July 9, 2015D

ownloaded from

21. Emberson JR, Whincup PH, Morris RW, Walker M. Re-assessing the contri-bution of serum total cholesterol, blood pressure and cigarette smoking tothe aetiology of coronary heart disease: impact of regression dilution bias. EurHeart J 2003;24:1719–1726.

22. Pischon T, Mohlig M, Hoffmann K, Spranger J, Weikert C, Willich SN, Pfeiffer AF,Boeing H. Comparison of relative and attributable risk of myocardial infarctionand stroke according to C-reactive protein and low-density lipoprotein choles-terol levels. Eur J Epidemiol 2007;22:429–438.

23. Wolf-Maier K, Cooper RS, Banegas JR, Giampaoli S, Hense HW, Joffres M,Kastarinen M, Poulter N, Primatesta P, Rodriguez-Artalejo F, Stegmayr B,Thamm M, Tuomilehto J, Vanuzzo D, Vescio F. Hypertension prevalence andblood pressure levels in 6 European countries, Canada, and the United States.JAMA 2003;289:2363–2369.

24. Ezzati M, Vander Hoorn S, Rodgers A, Lopez AD, Mathers CD, Murray CJL. Esti-mates of global and regional potential health gains from reducing multiple majorrisk factors. Lancet 2003;362:271.

25. Tsivgoulis G, Alexandrov AV, Wadley VG, Unverzagt FW, Go RC, Moy CS,Kissela B, Howard G. Association of higher diastolic blood pressure levelswith cognitive impairment. Neurology 2009;73:589–595.

26. Launer LJ, Masaki K, Petrovitch H, Foley D, Havlik RJ. The association betweenmidlife blood pressure levels and late-life cognitive function. The Honolulu-AsiaAging Study. JAMA 1995;274:1846–1851.

27. Snowdon DA, Greiner LH, Mortimer JA, Riley KP, Greiner PA, Markesbery WR.Brain infarction and the clinical expression of Alzheimer disease. The Nun Study.JAMA 1997;277:813–817.

28. Tu JV. Reducing the global burden of stroke: INTERSTROKE. Lancet 2010;376:74–75.

29. Gentil A, Bejot Y, Lorgis L, Durier J, Zeller M, Osseby GV, Dentan G, Beer JC,Moreau T, Giroud M, Cottin Y. Comparative epidemiology of stroke and acutemyocardial infarction: the Dijon Vascular project (Diva). J Neurol Neurosurg Psy-chiatry 2009;80:1006–1011.

30. Law MR, Morris JK, Wald NJ. Use of blood pressure lowering drugs in the pre-vention of cardiovascular disease: meta-analysis of 147 randomised trials in thecontext of expectations from prospective epidemiological studies. BMJ 2009;338:b1665.

31. Cushman WC, Evans GW, Byington RP, Goff DC Jr, Grimm RH Jr, Cutler JA,Simons-Morton DG, Basile JN, Corson MA, Probstfield JL, Katz L,Peterson KA, Friedewald WT, Buse JB, Bigger JT, Gerstein HC, Ismail-Beigi F.Effects of intensive blood-pressure control in type 2 diabetes mellitus. N EnglJ Med 2010;362:1575–1585.

32. Girerd X, Giral P. Risk stratification for the prevention of cardiovascular compli-cations of hypertension. Curr Med Res Opin 2004;20:1137–1142.

33. Beckett NS, Peters R, Fletcher AE, Staessen JA, Liu L, Dumitrascu D,Stoyanovsky V, Antikainen RL, Nikitin Y, Anderson C, Belhani A, Forette F,Rajkumar C, Thijs L, Banya W, Bulpitt CJ. Treatment of hypertension in patients80 years of age or older. N Engl J Med 2008;358:1887–1898.

34. Jones C, Simpson SH, Mitchell D, Haggarty S, Campbell N, Then K,Lewanczuk RZ, Sebaldt RJ, Farrell B, Dolovitch L, Kaczorowski J,Chambers LW. Enhancing hypertension awareness and management in theelderly: lessons learned from the Airdrie Community Hypertension Awarenessand Management Program (A-CHAMP). Can J Cardiol 2008;24:561–567.

35. Sokol SI, Kapoor JR, Foody JM. Blood pressure reduction in the primary and sec-ondary prevention of stroke. Curr Vasc Pharmacol 2006;4:155–160.

36. Sacco RL, Benson RT, Kargman DE, Boden-Albala B, Tuck C, Lin IF, Cheng JF,Paik MC, Shea S, Berglund L. High-density lipoprotein cholesterol and ischemicstroke in the elderly: the Northern Manhattan Stroke Study. JAMA 2001;285:2729–2735.

37. Gorelick PB. Challenges of designing trials for the primary prevention of stroke.Stroke 2009;40(Suppl. 3):S82–S84.

38. Lewington S, Whitlock G, Clarke R, Sherliker P, Emberson J, Halsey J,Qizilbash N, Peto R, Collins R. Blood cholesterol and vascular mortality byage, sex, and blood pressure: a meta-analysis of individual data from 61 prospec-tive studies with 55,000 vascular deaths. Lancet 2007;370:1829–1839.

39. Cholesterol, diastolic blood pressure, and stroke: 13,000 strokes in 450,000people in 45 prospective cohorts. Prospective studies collaboration. Lancet1995;346:1647–1653.

40. Iso H, Jacobs DR Jr, Wentworth D, Neaton JD, Cohen JD. Serum cholesterollevels and six-year mortality from stroke in 350,977 men screened for the mul-tiple risk factor intervention trial. N Engl J Med 1989;320:904–910.

41. Ebinger M, Heuschmann PU, Jungehuelsing GJ, Werner C, Laufs U, Endres M.The Berlin ‘Cream&Sugar’ Study: the prognostic impact of an oral triglyceridetolerance test in patients after acute ischaemic stroke. Int J Stroke 2010;5:126–130.

42. Shahar E, Chambless LE, Rosamond WD, Boland LL, Ballantyne CM,McGovern PG, Sharrett AR. Plasma lipid profile and incident ischemic stroke:

the Atherosclerosis Risk in Communities (ARIC) study. Stroke 2003;34:623–631.

43. Wannamethee SG, Shaper AG, Ebrahim S. HDL-cholesterol, total cholesterol,and the risk of stroke in middle-aged British men. Stroke 2000;31:1882–1888.

44. Amarenco P, Labreuche J, Touboul PJ. High-density lipoprotein-cholesterol andrisk of stroke and carotid atherosclerosis: a systematic review. Atherosclerosis2008;196:489–496.

45. Goldstein LB, Adams R, Alberts MJ, Appel LJ, Brass LM, Bushnell CD,Culebras A, DeGraba TJ, Gorelick PB, Guyton JR, Hart RG, Howard G,Kelly-Hayes M, Nixon JV, Sacco RL. Primary prevention of ischemic stroke: aguideline from the American Heart Association/American Stroke AssociationStroke Council: cosponsored by the Atherosclerotic Peripheral VascularDisease Interdisciplinary Working Group; Cardiovascular Nursing Council;Clinical Cardiology Council; Nutrition, Physical Activity, and MetabolismCouncil; and the Quality of Care and Outcomes Research InterdisciplinaryWorking Group. Circulation 2006;113:e873.

46. Amarenco P, Labreuche J. Lipid management in the prevention of stroke: reviewand updated meta-analysis of statins for stroke prevention. Lancet Neurol 2009;8:453–463.

47. Nordestgaard BG, Benn M, Schnohr P, Tybjaerg-Hansen A. Nonfasting triglycer-ides and risk of myocardial infarction, ischemic heart disease, and death in menand women. JAMA 2007;298:299–308.

48. Bansal S, Buring JE, Rifai N, Mora S, Sacks FM, Ridker PM. Fasting compared withnonfasting triglycerides and risk of cardiovascular events in women. JAMA 2007;298:309–316.

49. Freiberg JJ, Tybjaerg-Hansen A, Jensen JS, Nordestgaard BG. Nonfasting trigly-cerides and risk of ischemic stroke in the general population. JAMA 2008;300:2142–2152.

50. Atkins D, Psaty BM, Koepsell TD, Longstreth WT Jr, Larson EB. Cholesterolreduction and the risk for stroke in men. A meta-analysis of randomized, con-trolled trials. Ann Intern Med 1993;119:136–145.

51. O’Regan C, Wu P, Arora P, Perri D, Mills EJ. Statin therapy in stroke prevention:a meta-analysis involving 121,000 patients. Am J Med 2008;121:24–33.

52. Baigent C, Keech A, Kearney PM, Blackwell L, Buck G, Pollicino C, Kirby A,Sourjina T, Peto R, Collins R, Simes R. Efficacy and safety of cholesterol-loweringtreatment: prospective meta-analysis of data from 90,056 participants in 14 ran-domised trials of statins. Lancet 2005;366:1267–1278.

53. Shepherd J, Blauw GJ, Murphy MB, Bollen EL, Buckley BM, Cobbe SM, Ford I,Gaw A, Hyland M, Jukema JW, Kamper AM, Macfarlane PW, Meinders AE,Norrie J, Packard CJ, Perry IJ, Stott DJ, Sweeney BJ, Twomey C,Westendorp RG. Pravastatin in elderly individuals at risk of vascular disease(PROSPER): a randomised controlled trial. Lancet 2002;360:1623–1630.

54. Collins R, Armitage J, Parish S, Sleight P, Peto R. Effects of cholesterol-loweringwith simvastatin on stroke and other major vascular events in 20536 people withcerebrovascular disease or other high-risk conditions. Lancet 2004;363:757–767.

55. Amarenco P, Bogousslavsky J, Callahan A 3rd, Goldstein LB, Hennerici M,Rudolph AE, Sillesen H, Simunovic L, Szarek M, Welch KM, Zivin JA. High-doseatorvastatin after stroke or transient ischemic attack. N Engl J Med 2006;355:549–559.

56. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet2002;360:7–22.

57. Endres M. Statins and stroke. J Cereb Blood Flow Metab 2005;25:1093–1110.58. Kaptoge S, Di Angelantonio E, Lowe G, Pepys MB, Thompson SG, Collins R,

Danesh J. C-reactive protein concentration and risk of coronary heart disease,stroke, and mortality: an individual participant meta-analysis. Lancet 2010;375:132–140.

59. Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto AM Jr, Kastelein JJ,Koenig W, Libby P, Lorenzatti AJ, MacFadyen JG, Nordestgaard BG,Shepherd J, Willerson JT, Glynn RJ. Rosuvastatin to prevent vascular events inmen and women with elevated C-reactive protein. N Engl J Med 2008;359:2195–2207.

60. de Lorgeril M, Salen P, Abramson J, Dodin S, Hamazaki T, Kostucki W,Okuyama H, Pavy B, Rabaeus M. Cholesterol lowering, cardiovascular diseases,and the rosuvastatin-JUPITER controversy: a critical reappraisal. Arch Intern Med2010;170:1032–1036.

61. Goldstein LB. JUPITER and the world of stroke medicine. Lancet Neurol 2009;8:129–131.

62. Grundy SM, Cleeman JI, Merz CN, Brewer HB Jr, Clark LT, Hunninghake DB,Pasternak RC, Smith SC Jr, Stone NJ. Implications of recent clinical trials forthe National Cholesterol Education Program Adult Treatment Panel III guide-lines. Circulation 2004;110:227–239.

63. Guidelines for management of ischaemic stroke and transient ischaemic attack2008. Cerebrovasc Dis 2008;25:457.

Primary prevention of stroke 552a

by guest on July 9, 2015D

ownloaded from

64. Wolf PA, Kannel WB, McNamara PM. Occult impaired cardiac function, conges-tive heart failure, and risk of thrombotic stroke: the Framingham Study. Neurology1970;20:373.

65. Kolominsky-Rabas PL, Weber M, Gefeller O, Neundoerfer B, Heuschmann PU.Epidemiologyof ischemic stroke subtypes according to TOAST criteria - Incidence,recurrence, and long-term survival in ischemic stroke subtypes: a population-basedstudy. Stroke 2001;32:2735.

66. Appelros P, Nydevik I, Viitanen M. Poor outcome after first-ever stroke: predic-tors for death, dependency, and recurrent stroke within the first year. Stroke2003;34:122–126.

67. Divani AA, Vazquez G, Asadollahi M, Qureshi AI, Pullicino P. Nationwide fre-quency and association of heart failure on stroke outcomes in the UnitedStates. J Card Fail 2009;15:11–16.

68. Hays AG, Sacco RL, Rundek T, Sciacca RR, Jin Z, Liu R, Homma S, Di Tullio MR.Left ventricular systolic dysfunction and the risk of ischemic stroke in a multieth-nic population. Stroke 2006;37:1715–1719.

69. Pullicino P, Homma S. Stroke in heart failure: atrial fibrillation revisited? J StrokeCerebrovasc Dis 2010;19:1–2.

70. Witt BJ, Gami AS, Ballman KV, Brown RD Jr, Meverden RA, Jacobsen SJ,Roger VL. The incidence of ischemic stroke in chronic heart failure: ameta-analysis. J Card Fail 2007;13:489–96.

71. Appelros P, Nydevik I, Seiger A, Terent A. Predictors of severe stroke: influenceof preexisting dementia and cardiac disorders. Stroke 2002;33:2357–2362.

72. Kozdag G, Ciftci E, Ural D, Sahin T, Selekler M, Agacdiken A, Demirci A,Komsuoglu S, Komsuoglu B. Silent cerebral infarction in chronic heart failure:ischemic and nonischemic dilated cardiomyopathy. Vasc Health Risk Manag2008;4:463–469.

73. Vogels RL, Scheltens P, Schroeder-Tanka JM, Weinstein HC. Cognitive impair-ment in heart failure: a systematic review of the literature. Eur J Heart Fail2007;9:440–449.

74. Vogels RL, van der Flier WM, van Harten B, Gouw AA, Scheltens P,Schroeder-Tanka JM, Weinstein HC. Brain magnetic resonance imaging abnorm-alities in patients with heart failure. Eur J Heart Fail 2007;9:1003–1009.

75. Jefferson AL, Himali JJ, Beiser AS, Au R, Massaro JM, Seshadri S, Gona P,Salton CJ, Decarli C, O’Donnell CJ, Benjamin EJ, Wolf PA, Manning WJ.Cardiac index is associated with brain aging. The Framingham Heart Study. Cir-culation 2010;122:690–697.

76. Pullicino PM, Halperin JL, Thompson JL. Stroke in patients with heart failure andreduced left ventricular ejection fraction. Neurology 2000;54:288–294.

77. Jug B, Vene N, Salobir BG, Sebestjen M, Sabovic M, Keber I. Procoagulant state inheart failure with preserved left ventricular ejection fraction. Int Heart J 2009;50:591–600.

78. Hohnloser SH, Pajitnev D, Pogue J, Healey JS, Pfeffer MA, Yusuf S, Connolly SJ.Incidence of stroke in paroxysmal versus sustained atrial fibrillation in patientstaking oral anticoagulation or combined antiplatelet therapy: an ACTIVE W Sub-study. J Am Coll Cardiol 2007;50:2156–2161.

79. Maisel WH, Stevenson LW. Atrial fibrillation in heart failure: epidemiology,pathophysiology, and rationale for therapy. Am J Cardiol 2003;91:2D–8D.

80. Gage BF, Waterman AD, Shannon W, Boechler M, Rich MW, Radford MJ. Vali-dation of clinical classification schemes for predicting stroke: results from theNational Registry of Atrial Fibrillation. JAMA 2001;285:2864–2870.

81. Laufs U, Hoppe UC, Rosenkranz S, Kirchhof P, Bohm M, Diener HC, Endres M,Grond M, Hacke W, Meinertz T, Ringelstein EB, Rother J, Dichgans M. Cardio-logical evaluation after cerebral ischaemia: Consensus statement of the WorkingGroup Heart and Brain of the German Cardiac Society-Cardiovascular Research(DGK) and the German Stroke Society (DSG). Clin Res Cardiol 2010;99:609–625.

82. Cheitlin MD, Armstrong WF, Aurigemma GP, Beller GA, Bierman FZ, Davis JL,Douglas PS, Faxon DP, Gillam LD, Kimball TR, Kussmaul WG, Pearlman AS,Philbrick JT, Rakowski H, Thys DM. ACC/AHA/ASE 2003 guideline update forthe clinical application of echocardiography—summary article: a report of theAmerican College of Cardiology/American Heart Association Task Force onPractice Guidelines (ACC/AHA/ASE Committee to Update the 1997 Guidelinesfor the Clinical Application of Echocardiography). J Am Coll Cardiol 2003;42:954–970.

83. Flemming KD, Brown RD Jr, Petty GW, Huston J 3rd, Kallmes DF, Piepgras DG.Evaluation and management of transient ischemic attack and minor cerebralinfarction. Mayo Clin Proc 2004;79:1071–1086.

84. Massie BM, Collins JF, Ammon SE, Armstrong PW, Cleland JG, Ezekowitz M,Jafri SM, Krol WF, O’Connor CM, Schulman KA, Teo K, Warren SR. Random-ized trial of warfarin, aspirin, and clopidogrel in patients with chronic heartfailure: the Warfarin and Antiplatelet Therapy in Chronic Heart Failure(WATCH) trial. Circulation 2009;119:1616–1624.

85. Mujib M, Giamouzis G, Agha SA, Aban I, Sathiakumar N, Ekundayo OJ,Zamrini E, Allman RM, Butler J, Ahmed A. Epidemiology of stroke in chronic

heart failure patients with normal sinus rhythm: Findings from the DIG strokesub-study. Int J Cardiol 2010;144:389–393.

86. De Backer G, Ambrosioni E, Borch-Johnsen K, Brotons C, Cifkova R,Dallongeville J, Ebrahim S, Faergeman O, Graham I, Mancia G, Cats VM,Orth-Gomer K, Perk J, Pyorala K, Rodicio JL, Sans S, Sansoy V, Sechtem U,Silber S, Thomsen T, Wood D. European guidelines on cardiovascular diseaseprevention in clinical practice—Third Joint Task Force of European and otherSocieties on Cardiovascular Disease Prevention in Clinical Practice. Eur Heart J2003;24:1601.

87. Graham I, Atar D, Borch-Johnsen K, Boysen G, Burell G, Cifkova R, Dallongeville J,De BG, Ebrahim S, Gjelsvik B, Herrmann-Lingen C, Hoes A, Humphries S,Knapton M, Perk J, Priori SG, Pyorala K, Reiner Z, Ruilope L, Sans-Menendez S,Op Reimer WS, Weissberg P, Wood D, Yarnell J, Zamorano JL, Walma E,Fitzgerald T, Cooney MT, Dudina A, Vahanian A, Camm J, De CR, Dean V,Dickstein K, Funck-Brentano C, Filippatos G, Hellemans I, Kristensen SD,McGregor K, Sechtem U, Silber S, Tendera M, Widimsky P, Zamorano JL,Altiner A, Bonora E, Durrington PN, Fagard R, Giampaoli S, Hemingway H,Hakansson J, Kjeldsen SE, Larsen L, Mancia G, Manolis AJ, Orth-Gomer K,Pedersen T, Rayner M, Ryden L, Sammut M, Schneiderman N, Stalenhoef AF,Tokgozoglu L, Wiklund O, Zampelas A. European guidelines on cardiovasculardisease prevention in clinical practice: full text. Fourth Joint Task Force of the Euro-pean Society of Cardiology and other societies on cardiovascular disease preven-tion in clinical practice (constituted by representatives of nine societies and byinvited experts). Eur J Cardiovasc Prev Rehabil 2007;14(Suppl. 2):S1.

88. Lopez AD, Mathers CD, Ezzati M, Jamison DT, Murray CJ. Global and regionalburden of disease and risk factors, 2001: systematic analysis of population healthdata. Lancet 2006;367:1747.

89. Vartiainen E, Laatikainen T, Peltonen M, Juolevi A, Mannisto S, Sundvall J,Jousilahti P, Salomaa V, Valsta L, Puska P. Thirty-five-year trends in cardiovascularrisk factors in Finland. Int J Epidemiol 2010;39:504–518.

90. Jackson R. Guidelines on preventing cardiovascular disease in clinical practice.BMJ 2000;320:659–661.

91. Conroy RM, Pyorala K, Fitzgerald AP, Sans S, Menotti A, De Backer G, DeBacquer D, Ducimetiere P, Jousilahti P, Keil U, Njolstad I, Oganov RG,Thomsen T, Tunstall-Pedoe H, Tverdal A, Wedel H, Whincup P,Wilhelmsen L, Graham IM. Estimation of ten-year risk of fatal cardiovasculardisease in Europe: the SCORE project. Eur Heart J 2003;24:987.

92. Hense HW. Risk factor scoring for coronary heart disease—prediction algor-ithms need regular updating. Br Med J 2003;327:1238.

93. Willett WC. Balancing life-style and genomics research for disease prevention.Science 2002;296:695–698.

94. Stampfer MJ, Hu FB, Manson JE, Rimm EB, Willett WC. Primary prevention ofcoronary heart disease in women through diet and lifestyle. N Engl J Med2000;343:16–22.

95. Chiuve SE, Rexrode KM, Spiegelman D, Logroscino G, Manson JE, Rimm EB.Primary prevention of stroke by healthy lifestyle. Circulation 2008;118:947–954.

96. Kurth T, Moore SC, Gaziano JM, Kase CS, Stampfer MJ, Berger K, Buring JE.Healthy lifestyle and the risk of stroke in women. Arch Intern Med 2006;166:1403–1409.

97. Ford ES, Bergmann MM, Kroger J, Schienkiewitz A, Weikert C, Boeing H.Healthy living is the best revenge: findings from the European Prospective Inves-tigation Into Cancer and Nutrition-Potsdam study. Arch Intern Med 2009;169:1355–1362.

98. 25 Nphg. Prevention of Cardiovascular Disease at Population Level. London: NationalInstitute for Health and Clinical Excellence; 2010.

99. Smeeth L, Thomas SL, Hall AJ, Hubbard R, Farrington P, Vallance P. Risk of myo-cardial infarction and stroke after acute infection or vaccination. N Engl J Med2004;351:2611.

100. Casas JP, Bautista LE, Smeeth L, Sharma P, Hingorani AD. Homocysteine andstroke: evidence on a causal link from mendelian randomisation. Lancet 2005;365:224.

101. Lonn E, Yusuf S, Arnold MJ, Sheridan P, Pogue J, Micks M, McQueen MJ,Probstfield J, Fodor G, Held C, Genest J Jr. Homocysteine lowering withfolic acid and B vitamins in vascular disease. N Engl J Med 2006;354:1567–577.

102. B vitamins in patients with recent transient ischaemic attack or stroke in theVITAmins TO Prevent Stroke (VITATOPS) trial: a randomised, double-blind,parallel, placebo-controlled trial. Lancet Neurol 2010;9:855–865.

103. Muller-Riemenschneider F, Holmberg C, Rieckmann N, Kliems H, Rufer V,Muller-Nordhorn J, Willich SN. Barriers to routine risk-score use for healthyprimary care patients: survey and qualitative study. Arch Intern Med 2010;170:719–724.

104. Sheridan SL, Crespo E. Does the routine use of global coronary heart diseaserisk scores translate into clinical benefits or harms? A systematic review ofthe literature. BMC Health Serv Res 2008;8:60.

M. Endres et al.552b

by guest on July 9, 2015D

ownloaded from

105. UK National Screening Committee. Handbook for Vascular Risk Assessment, RiskReduction and Risk Management. 2008. Available at: http://www.library.nhs.uk/HealthManagement/ViewResource.aspx?resID=282009.

106. Chamnan P, Simmons RK, Khaw KT, Wareham NJ, Griffin SJ. Estimating thepopulation impact of screening strategies for identifying and treating people athigh risk of cardiovascular disease: modelling study. BMJ 2010;340:c1693.

107. Wald NJ, Law MR. A strategy to reduce cardiovascular disease by more than80%. BMJ 2003;326:1419.

108. Yusuf S, Pais P, Afzal R, Xavier D, Teo K, Eikelboom J, Sigamani A, Mohan V,Gupta R, Thomas N. Effects of a polypill (Polycap) on risk factors in middle-agedindividuals without cardiovascular disease (TIPS): a phase II, double-blind, ran-domised trial. Lancet 2009;373:1341–1351.

109. Reddy KS. The preventive polypill—much promise, insufficient evidence. N Engl JMed 2007;356:212.

110. Capewell S. Will screening individuals at high risk of cardiovascular eventsdeliver large benefits? No. BMJ 2008;337:a1395.

111. Jackson R, Wells S, Rodgers A. Will screening individuals at high risk of cardio-vascular events deliver large benefits? Yes. BMJ 2008;337:a1371.

112. Laufs U, Rettig-Ewen V, Bohm M. Strategies to improve drug adherence. EurHeart J 2010; doi:10.1093/eurheartj/ehq297. Published online ahead of print 21August 2010.

113. Lee JK, Grace KA, Taylor AJ. Effect of a pharmacy care program onmedication adherence and persistence, blood pressure, and low-densitylipoprotein cholesterol: a randomized controlled trial. JAMA 2006;296:2563–2571.

114. Claxton AJ, Cramer J, Pierce C. A systematic review of the associationsbetween dose regimens and medication compliance. Clin Ther 2001;23:1296–1310.

115. Gaziano TA, Opie LH, Weinstein MC. Cardiovascular disease prevention with amultidrug regimen in the developing world: a cost-effectiveness analysis. Lancet2006;368:679–686.

116. Bangalore S, Kamalakkannan G, Parkar S, Messerli FH. Fixed-dose combi-nations improve medication compliance: a meta-analysis. Am J Med 2007;120:713–719.

117. Granger BB, Swedberg K, Ekman I, Granger CB, Olofsson B, McMurray JJ,Yusuf S, Michelson EL, Pfeffer MA. Adherence to candesartan and placeboand outcomes in chronic heart failure in the CHARM programme: double-blind,randomised, controlled clinical trial. Lancet 2005;366:2005–2011.

118. Predictors of thromboembolism in atrial fibrillation: II. Echocardiographic fea-tures of patients at risk. The Stroke Prevention in Atrial Fibrillation Investigators.Ann Intern Med 1992;116:6–12.

Primary prevention of stroke 552c

by guest on July 9, 2015D

ownloaded from