Buscar en
Neurología (English Edition)
Toda la web
Inicio Neurología (English Edition) Guidelines for the preventive treatment of ischaemic stroke and TIA (I). Update ...
Journal Information
Vol. 27. Issue 9.
Pages 560-574 (November - December 2012)
Vol. 27. Issue 9.
Pages 560-574 (November - December 2012)
Review article
Full text access
Guidelines for the preventive treatment of ischaemic stroke and TIA (I). Update on risk factors and life style
Guía para el tratamiento preventivo del ictus isquémico y AIT (I). Actuación sobre los factores de riesgo y estilo de vida
B. Fuentes??
Corresponding author

Corresponding author.
, J. Gállego, A. Gil-Nuñez, A. Morales, F. Purroy, J. Roquer, T. Segura, J. Tejada, A. Lago, E. Díez-Tejedor, por el Comité ad hoc del Grupo de Estudio de Enfermedades Cerebrovasculares de la SEN: , M. Alonso de Leciñana, J. Álvarez-Sabin, J. Arenillas, S. Calleja, I. Casado, M. Castellanos, J. Castillo, A. Dávalos, F. Díaz-Otero, J.A. Egido, J.C. López-Fernández, M. Freijo, A. García Pastor, F. Gilo, P. Irimia, J. Maestre, J. Masjuan, J. Martí-Fábregas, P. Martínez-Sánchez, E. Martínez-Vila, C. Molina, F. Nombela, M. Ribó, M. Rodríguez-Yañez, F. Rubio, J. Serena, P. Simal, J. Vivancos
Article information
Full Text
Download PDF
Tables (2)
Table 1. Levels of evidence and recommendation grades. Based on the classification drawn up by the Centre for Evidence Based Medicine (CEBM).1
Table 2. Modification of risk factors for stroke. Levels of evidence and recommendation grades.
Show moreShow less

To update the ad hoc Committee of the Cerebrovascular Diseases Study Group of The Spanish Neurological Society guidelines on prevention of ischaemic stroke (IS) and transient ischaemic attack (TIA).


We reviewed available evidence on risk factors and means of modifying them to prevent IS and TIA. Levels of evidence and recommendation grades are based on the classification of the Centre for Evidence-Based Medicine.


This first section summarises the recommendations for action on the following factors: blood pressure, diabetes, lipids, tobacco and alcohol consumption, diet and physical activity, cardio-embolic diseases, asymptomatic carotid stenosis, hormone replacement therapy (HRT) and contraceptives, hyperhomocysteinemia, prothrombotic states and sleep apnea syndrome.


Changes in lifestyle and pharmacological treatment for hypertension, diabetes mellitus and dyslipidemia, according to criteria of primary and secondary prevention, are recommended for preventing IS.

Ischaemic stroke
Transient ischaemic attack

Actualizar las guías terapéuticas del Comité ad hoc del Grupo de Estudio de Enfermedades Cerebrovasculares de la SEN en el tratamiento preventivo de ictus isquémico (II) y ataque isquémico transitorio (AIT).


Revisión de evidencias disponibles sobre los factores de riesgo y la oportunidad de su modificación para prevenir el ictus isquémico y AIT. Los niveles de evidencia y grados de recomendación se han basado en la clasificación del Centro de Medicina Basada en la Evidencia.


En esta primera parte se resumen las recomendaciones sobre la actuación sobre los siguientes factores: presión arterial, DM, lípidos plasmáticos, consumo de tabaco y alcohol, dieta y actividad física, cardiopatías embolígenas, estenosis carotídea asintomática, terapia hormonal sustitutiva y anticonceptivos, hiperhomocisteinemía, estados protrombóticos y síndrome de apnea del sueño.


La modificación de los estilos de vida y el tratamiento farmacológico de la hipertensión arterial, diabetes méllitus y dislipemia según criterios de prevención primaria y secundaria se recomiendan en la prevención de ictus isquémico.

Palabras clave:
Guías de práctica clínica
Prevención de ictus
Ataque isquémico transitorio
Full Text

In Spain, cerebrovascular diseases are the leading cause of death in women, the third most frequent in men,1 and the most common cause of disability. The measures we describe here are designed to prevent both first-ever ischaemic strokes (IS) and future episodes in patients who have already suffered a stroke. We will also list measures intended to reduce overall vascular risk in these patients2; given the length of this chapter, we decided to publish it in 2 parts. Firstly, we will review the risk factors for IS and any modifications to those factors which may be appropriate. Secondly, we will specify different preventive treatments according to the stroke subtype. Recommendations for each section are shown in tables for better readability. Levels of evidence and recommendation grades are based on the classification system proposed by the Centre for Evidence Based Medicine at the University of Oxford3 (Table 1). Following current criteria, we included transient ischaemic attack (TIA) in the definition of IS, which also improves readability. Therefore, all recommendations included in these clinical practice guidelines are directed at preventing focal cerebral ischaemia in general, without distinguishing between cerebral infarction and TIA.

Table 1.

Levels of evidence and recommendation grades. Based on the classification drawn up by the Centre for Evidence Based Medicine (CEBM).1

Level of evidence  Type of study on which classification is based  Recommendation grades
1a  Systematic review of randomised clinical trials (with homogeneity)  B (extrapolation)    D (inconclusive studies) 
1b  Randomised clinical trial with narrow confidence interval  B (extrapolation)    D (inconclusive studies) 
2a  Systematic review of cohort studies (with homogeneity)    C (extrapolation)  D (inconclusive studies) 
2b  Individual cohort study (including low quality randomised clinical trials, e.g. those with a follow-up level below 80%)    C (extrapolation)  D (inconclusive studies) 
3a  Systematic reviews of case–control studies (with homogeneity)    C (extrapolation)  D (inconclusive studies) 
3b  Case–control studies    C (extrapolation)  D (inconclusive studies) 
Case series or cohort studies or low quality case–control studies      D (inconclusive studies) 
Experts’ opinion without explicit critical appraisal or based on physiology or pathophysiology       
Action on risk factors (Table 2)Antihypertensive drugs and blood pressure

Epidemiological studies and clinical trials have illustrated the relationship between blood pressure and stroke.4–8 Lifestyle changes (decreasing tobacco and alcohol consumption, losing weight, engaging in moderate physical activity, decreasing salt consumption, and increasing fruit and vegetable intake) are useful for reducing blood pressure levels.9 It has been shown that reduction in risk of stroke is proportional to a patient's decrease in blood pressure.10,11 Studies of different antihypertensive drugs present similar results with regard to reduction in vascular episodes. The most recent Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure indicates which levels of blood pressure are considered high and which treatments are the most appropriate in each situation.7

Table 2.

Modification of risk factors for stroke. Levels of evidence and recommendation grades.

Risk factor    Recommendation grade and level of evidence 
High blood pressure  Primary prevention   
  - Measure blood pressure regularly; apply lifestyle changes aimed at decreasing blood pressure (smoking cessation and moderate alcohol consumption, weight loss, moderate physical activity, lower salt consumption, and higher consumption of fruits and vegetables).  Level of evidence 1a; recommendation grade A 
  - Antihypertensive treatment to maintain blood pressure levels <140/90. Maintaining levels <130/80 is recommended in patients with DM, kidney disease, or heart failure  Level of evidence 1a; recommendation grade A 
  Secondary prevention   
  - Begin antihypertensive treatment in patients with stroke/TIA after the acute phase  Level of evidence 1a; recommendation grade A 
  - Start treatment in patients with either high or normal blood pressure  Level of evidence 1a; recommendation grade B 
  - The treatment objective is BP <130/80mmHg (ideal level <120/80), with target BP adapted to conditions (absence of ischaemic heart disease or bilateral carotid stenosis without revascularisation)  Level of evidence 1b; recommendation grade B 
  - The optimal antihypertensive treatment has not been clearly identified due to limitations of the studies that have been carried out. Available data support treatment with ACE inhibitors+diuretics, diuretics alone, or ARBs  Level of evidence 1b; recommendation grade A 
Diabetes mellitus  Primary prevention   
  - Maintain BP <130/80 in diabetic patients  Level of evidence 1a; recommendation grade A 
  - Prescription of statins as a stroke prevention method, especially in patients with other vascular risk factors  Level of evidence 1b; recommendation grade A 
  Secondary prevention   
  - Control glycaemic levels and maintain HbA1c levels below 7%  Level of evidence 1a; recommendation grade A 
Dyslipidaemia  Primary prevention   
  - Treatment with statins is appropriate for stroke prevention in adults with ischaemic heart disease, diabetes mellitus, or high vascular risk  Level of evidence 1a; recommendation grade A 
  Secondary prevention   
  - All patients with TIA or cerebral infarction caused by atherothrombosis or small vessel disease should be treated with atorvastatin at 80mg/day  Level of evidence 1b; recommendation grade A 
  - Most of the patients with TIA or cerebral infarction of other aetiologies should be treated with statins due to the vascular high risk or the associated vascular diseases requiring this treatment (ischaemic heart disease, peripheral artery disease, FM, or HBP)  Level of evidence 1b; recommendation grade B 
  Treatment onset level for LDL is ≥100mg/dl, although treatment at lower levels may be optimal  Level of evidence 1b; recommendation grade B 
  - The therapeutic objective is < 100mg/dl, or < 70mg/dl in patients with atherosclerosis  Level of evidence 1b; recommendation grade B 
Tobacco  - Avoiding or giving up smoking is recommended  Level of evidence 2a; recommendation grade B 
  - Avoid passive exposure to tobacco  Level of evidence 3b; recommendation grade B 
  - Use of smokeless tobacco products is not recommended  Level of evidence 2a; recommendation grade B 
  - Use of counselling, nicotine replacement therapy, and smoking cessation drugs may be appropriate.  Level of evidence 2b; recommendation grade B 
Alcohol  - Men should not exceed 2 alcohol units daily; women should not exceed 1 alcohol unit daily  Level of evidence 2a; recommendation grade B 
Asymptomatic carotid stenosis  - Carotid revascularisation may be recommended in selected patients (men younger than 75 with carotid stenosis of between 70% and 99% and expected survival of at least 5 years) with high risk of stroke, provided that perioperative risk lower than 3% is guaranteed  Level of evidence 1a; recommendation grade A 
Hormone replacement therapy  - Not recommended for primary or secondary prevention of stroke in menopausal women  Level of evidence 1a; recommendation grade A 
Hormonal contraception  - The risk of stroke associated with the use of low-dose oral contraceptives in women without risk factors is low  Level of evidence 2a; recommendation grade B 
  - Use of oral contraceptives is not recommended in women with congenital thrombophilia  Level of evidence 2a; recommendation grade B 
  - Use of oral contraceptives is not recommended in smokers with history of migraine, thrombotic episodes, HBP, or DM  Level of evidence 4; recommendation grade C 
Hyperhomocysteinaemia  Primary prevention   
  - Although vitamin supplements reduce homocysteine levels, this decrease does not have a significant impact on vascular risk  Level of evidence 1a; recommendation grade A 
  Secondary prevention   
  - Use of folic acid, vitamin B6, and vitamin B12 supplements in patients with a history of stroke is safe, but these supplements do not reduce risk of new vascular episodes  Level of evidence 1a; recommendation grade A 
Thrombophilias  Primary prevention   
  - Available data are insufficient to support specific therapeutic recommendations in adult patients with inherited or acquired thrombophilias   
  Secondary prevention   
  - In patients with ischaemic stroke and inherited thrombophilia, doctors should check for deep venous thrombosis, which requires short- or long-term anticoagulant treatment depending on clinical and haematological factors  Level of evidence 1a; recommendation grade A 
  - Antithrombotic treatment (antiplatelet or anticoagulant agents) is recommended in the absence of venous thrombosis  Level of evidence 2a; recommendation grade C 
  - Aspirin and low-intensity anticoagulation may be considered as preventive treatment in patients testing positive for antiphospholipid antibodies who have suffered a first-ever ischaemic stroke  Level of evidence 2b; recommendation grade B 

BP, blood pressure.

Studies of different antihypertensive agents used in secondary IS prevention have yielded inconsistent results.12 Beta blockers have not been shown to deliver significant benefits.13–15 Results from diuretics have been contradictory16; a single study of indapamide at 2.5mg/day pointed to a positive effect.17 Using ACE inhibitors, such as ramipril at 10mg/day18 or combination therapy with perindopril (4mg/day) and indapamide (2.5mg/day), decreases the risk of stroke recurrence, even in patients without a history of HBP.19 Regarding results from ARBs, trials have shown that eprosartan performed better than nitrendipine20; telmisartan performed no better than a placebo21 and similarly to ramipril22; and combination therapy with telmisartan and ramipril was associated with a higher frequency of side effects and no significant benefits.22 Major vascular events decreased by an additional 15% with intensive antihypertensive treatments, regardless of the drug employed.23 Some studies show differing levels of IS risk reduction for different classes of antihypertensive drugs. This could be due to the fact that some antihypertensive drugs, such as ACE inhibitors or ARBs, may have an added pleiotropic effect as well as an antihypertensive effect.12,24,25

Diabetes mellitus

Patients with DM are more susceptible to developing arteriosclerosis and display a higher prevalence of HBP, obesity, and dyslipidaemia. The risk entailed by DM is considered equal to that entailed by coronary disease, which is why secondary prevention measures must be applied in these cases.26 The risk of IS is 2 to 6 times higher in diabetic patients,27 and 9.1% of recurrences are directly attributable to DM.28 Adjusting glycaemic control and normalising HbA1c are more effective for reducing the complications of microangiopathy, whereas the approach to stroke prevention should be more global and include strict blood pressure control29 and administration of statins.30 Results from studies of close glycaemic control are controversial, with the ACCORD study31 showing a possible negative effect on mortality rates. The ADVANCE study32 and Veterans Affairs Diabetes Trial33 showed that glycaemic control did not reduce risk of IS.33 Long-term follow-up in the DCCT and UKPDS trials suggests that maintaining HbA1c levels under or near 7% at the onset of DM is associated with a long-term reduction in macrovascular disease.34 In a subanalysis of the PROactive study,35 treatment with pioglitazone in patients with prior stroke was associated with a 47% decrease in risk of recurrence.36 Based on these results, it has been recommended for preventing secondary stroke in patients with DM.37 Nevertheless, the safety of glitazone treatment has recently been called into question.38 It is therefore advisable to wait for the results of the Insulin Resistance Intervention after Stroke (IRIS) study.39

Plasma lipids and lipid-lowering drugs

High levels of cholesterol increase risk of IS. The Asia-Pacific Cohort Studies Collaboration found a 25% higher risk of IS for each mmol/L (38.7mg/dL) increase in total cholesterol levels.40 The US Women's Pooling Project detected a similar risk increase in women aged 30 to 54.41 Several primary prevention studies have shown that statins are effective for reducing cholesterol levels and risk of stroke (by 27%–32%).42,43 Treatment with rosuvastatin decreases the risk of IS,44 even in patients with high levels of high-sensitivity C-reactive protein and no hyperlipidaemia. Earlier guidelines already recommended statin use for secondary prevention of stroke or TIA in most patients based on NCEP-ATP III criteria.45 According to the SPARCL study, 80mg/day of atorvastatin significantly decreases the risk of recurrence in patients with non-cardioembolic stroke or TIA, and those with other vascular complications such as ischaemic heart disease or revascularisation procedures.46 We detected an increase in haemorrhagic stroke frequency in the atorvastatin group, especially in cases with a history of haemorrhagic stroke at time of inclusion, men, elderly subjects, and patients with stage 2 HBP, without significant interactions in baseline and recent LDL cholesterol levels.47 Another exploratory study showed that decreases ≥50% with respect to baseline figures achieve the greatest reductions in risk of stroke and major coronary episodes without risk of cerebral haemorrhage.48 A meta-analysis of randomised clinical trials suggested that fibrates may play a role in patients with DM.49


Tobacco consumption is associated with increased risk of all stroke subtypes, especially atherothrombotic stroke50–55 and in young patients.56 Additionally, it has a synergistic effect through its link to other vascular risk factors, such as HBP, DM, use of oral contraceptives, or physical inactivity. Smoking cessation reduces the risk of stroke, coronary disease, peripheral vascular disease and death from vascular causes proportionally to the length of the period during which the subject stopped using tobacco.57–60 Passive smoking also entails a risk of cerebrovascular disease.61–63 Smokeless tobacco products are associated with increased risk of fatal stroke as well.64


Robust evidence shows that excessive consumption of alcohol is a risk factor for all types of stroke.65–70 However, whether or not light-to-moderate alcohol consumption is related to ischaemic or haemorrhagic stroke is a matter of debate.71,72 Risk of stroke with light (<12g/day) or moderate (between 12 and 24g/day) alcohol consumption is less than risk of stroke with total abstinence from alcohol. High levels of alcohol consumption (>60g/day) increases total risk of stroke and risk of both ischaemic and haemorrhagic stroke.69 We found a J-shaped relationship between the risk of coronary morbidity and mortality73 and IS,68–70 as well as a linear association for the risk of haemorrhagic stroke.65–67 Moderate red wine consumption is associated with lower vascular risk.73 There are not enough studies to establish a relationship between alcohol consumption and recurrent stroke.

Diet and physical activity

It has been shown that dietary habits are related to cerebrovascular risk.74–76 Low intakes of salt77 and fat78 along with regular consumption of fish,79 pulses, fibre, fruits, and vegetables80–82 are associated with lower vascular mortality rates and a significant decrease in risk of cerebrovascular diseases. Sedentary lifestyle is very prevalent in the general population.83 It is associated with cerebrovascular diseases84 and related to other factors such as HBP, hypercholesterolaemia, obesity, and DM.85,86 Physical activity increases HDL cholesterol, reduces LDL cholesterol and triglycerides, decreases blood pressure, fosters insulin homeostasis, helps in losing and maintaining weight, promotes good mental health, and is helpful in quitting smoking.86–90 Individuals who are physically active have a lower risk of ischaemic heart disease and stroke.84,87,91 This relationship is independent of age and sex, but it should be noted that data from patients older than 80 are limited.92 The benefits of exercise can be observed whether the activity is undertaken during work or leisure time.84 The general recommendation is at least 30minutes of moderate-intensity exercise, most days of the week.93

Asymptomatic carotid stenosis

Prevalence of asymptomatic carotid artery stenosis (≥50%) increases with age. The prevalence is 0.5% in individuals younger than 50 years and higher than 10% in men older than 80 years.94 After a 15-year follow-up period, 16.6% of patients may suffer an episode of stroke.95 There are 2 alternative strategies: medical treatment or revascularisation using an endarterectomy or endovascular treatment with angioplasty and stenting. Initial studies of endarterectomy96,97 indicated that this treatment was beneficial, since it reduced risk of stroke after 5 years of follow-up. Nevertheless, new developments in medical treatment have raised questions about the benefit of surgical techniques, which deliver a decrease in absolute risk of stroke of only 1% per year, according to several meta-analyses.98–100 According to the CREST study,101 there is a 2.5% risk of suffering periprocedural stroke during an angioplasty and a 1.4% risk during endarterectomy. Therefore, indiscriminate use of revascularisation treatment in asymptomatic patients does not seem justified provided that they receive appropriate medical treatment. Revascularisation is only recommended in selected cases according to factors such as age, comorbidity, life expectancy, and perioperative risk.102 Based on the above, revascularisation can be considered for 70% to 99% carotid stenosis in men younger than 75, provided that perioperative risk is <3% and expected post-operative survival is at least 5 years.37,103 Of all patients with asymptomatic carotid stenosis, those with the highest level of risk have a history of contralateral TIAs,104 silent cerebral infarcts ipsilateral to stenosis,105 stenosis progression,106 or microemboli detected using transcranial Doppler.107 The SPACE 2 trial will compare results from current medical treatment with anti-platelet and antihypertensive drugs and statins with results from endovascular therapy or open surgical revascularisation.

Heart disease

Heart disease is the second leading cause of IS. In addition, patients with cardioembolic stroke present a higher risk of death and of new vascular events over the long term than patients with IS of arterial origin (non-cardioembolic).108 Findings regarding risk of IS for different types of emboligenic heart disease are listed below. The second part of this guide will list specific recommendations for preventing IS.

Atrial fibrillation

Atrial fibrillation (AF) is the most frequent type of arrhythmia109 with a prevalence of 6% in patients older than 65. In patients older than 85, prevalence rises to 12%.110 AF is one of the main risk factors for stroke. It is estimated that 1 out of 6 strokes occur in patients with AF,111 which is the cause of nearly half of all cardioembolic ISs.112 AF is associated with an increase in IS risk by a factor of 3 to 4 after adjusting for other risk factors.113 In cases with associated rheumatic heart disease, risk of stroke is 17 times higher than in healthy controls.114 Several factors significantly increase risk of embolism: age >75 years, congestive heart failure (CHF), HBP, DM, history of thromboembolism, left ventricular dysfunction with left ventricular ejection fraction (LVEF) <35%, atrial size, presence of mitral annular calcification (MAC), presence of spontaneous echo contrast, and detection of a left atrial thrombus.39 Based on the above, researchers have designed IS risk stratification systems for patients with AF.115 The CHADS2 score116,117 is the most well-known and validated risk classification method. It factors in CHF (1 point), HBP (1 point), DM (1 point), age >75 years (1 point), and history of cardiovascular disease or systemic embolism (2 points). The recently validated CHA2-DS2-VASc score118 divides the study population into 2 age groups: 65–74 (1 point) and >75 (2 points). It also accounts for the following factors: vascular disease (prior AMI, peripheral artery disease, and complex aortic plaque) (1 point); and female sex (1 point). All other scores were the same as for CHADS2.

Mitral stenosis

Between 10% and 20% of patients with mitral stenosis present systemic embolism. In cases of rheumatic stenosis (the most frequent cause) and a history of prior embolism, the level of risk reaches 30% to 65%. Moreover, up to 40% of patients with mitral stenosis develop AF.119 They therefore have a higher risk of stroke and a poorer prognosis than those who maintain sinus rhythm.120 Regarding patients with mitral stenosis and no AF or prior embolism, treatment is controversial since there are no data supporting the prescription of oral anticoagulant therapy. It is true that these patients may experience episodes of paroxysmal AF which are difficult to detect. At present, experts agree that oral anticoagulant drugs should be prescribed for patients with severe mitral stenosis and dilation of the left atrium ≥55mm or spontaneous contrast in the echocardiographic study.119 One observational study comparing medical treatment, percutaneous balloon valvuloplasty, and valve replacement suggests that balloon commissurotomy is the most effective method for reducing the incidence of IS.121 MAC is an infrequent non-rheumatic cause of mitral stenosis, and it is associated with distal complex aortic atheroma.122,123 The relationship between MAC and the risk of stroke is unclear; some cohort studies observe an increased risk of ischaemic heart disease and vascular death but no increase in IS,124 while other studies do observe a significant increase of IS risk after adjusting for other risk factors.125

Mitral valve prolapse

Mitral valve prolapse (MVP), the most frequent valve anomaly in adults, is present in 2.5% of population. It is particularly prevalent in individuals with connective tissue diseases. It is considered innocuous since different population-based observational studies have not detected a higher risk of stroke in subjects with MVP.126

Ischaemic heart disease

AMI is associated with a 2% absolute risk of stroke during the first 30 days after the infarct. This is due to the presence of mural thrombi in the left ventricle (LV), most of which occur during the first 2 weeks following the previous AMI (12% incidence). The majority of these cases are characterised by extensive infarcts that reduce left ventricular function or provoke dyskinesia/apical akinesia, although AMIs at any location may cause thrombi to form. The incidence of early embolism is >22%, especially in cases of moving or protruding thrombi in the LV. It is estimated that 10% of these patients will suffer from IS if they are not treated. Risk increases in cases of left ventricular dilation, ventricular dyskinesia, ejection fraction <30%, or CHF.127–129


In dilated cardiomyopathy and other conditions with decreased LVEF, such as CHF, there is an increased risk of emboli due to stasis of blood in the LV. This risk is relatively low (1%–3% yearly) in cases of depressed LVEF and echocardiographic signs of intramural thrombi.128 Stable CHF (NYHA Class II and Class III) is associated with an absolute risk of stroke of 1% per year. The relative risk increases by 18% when there is a 5% decrease in the LVEF. With more severe conditions (NYHA Class IV), risk of stroke is 4% per year.128 Approximately 10% of patients with IS have a LVEF of ≤30%.130

Anomalies of the interatrial septum

Patent foramen ovale (PFO) is very prevalent in the general population (15%–25%), while atrial septal aneurysm (ASA) is less frequent (2.3%). The risk of stroke in patients with PFO is similar to that in the general population,131,132 but there seems to be a well-documented correlation between persistent PFO and cryptogenic stroke, especially in the younger population. This anomaly was detected in 35% to 50% of patients with cryptogenic IS vs only 4% to 10% of control subjects.133 According to the PFO-ASA study, risk of stroke recurrence in PFO patients treated with acetylsalicylic acid is low after 4 years of follow-up (2.3% vs 4.2% in patients without PFO), with a higher risk when PFO is associated with ASA.134 Subsequent studies did not detect any differences in risk of recurrence in patients with massive right-to-left shunt compared to patients without this anomaly.135 According to a recent meta-analysis, the risk of stroke recurrence in patients with PFO does not differ from that in patients with cryptogenic stroke and no PFO.136

Other risk factors for strokeHormone replacement therapy (HRT) and oral contraceptives

Initial observational studies with hormone replacement therapy137 along with subsequent published articles related to the Women's Health Initiative (WHI) showed that use of HRT favoured the onset of vascular episodes.138,139 Several meta-analyses have confirmed that HRT is associated with a 30% increase in risk of stroke.140,141 This risk is not age-related, and progesterone replacement in addition to oestrogen doubles the risk of venous thromboembolism.142 However, a systematic review showed that risk of stroke from use of low doses of oestrogens administered transdermally may be no higher than that associated with the oral route of administration. The review was unable to present any conclusions due to the presence of confounding factors.143 Other alternative therapies also entail cerebrovascular risks. For example, tibolone is associated with risk of stroke in postmenopausal women144,145 and raloxifene may increase risk of fatal stroke in at-risk women.146 HRT in postmenopausal women with prior stroke does not seem to present benefits and the treatment is associated with increased risk of stroke and stroke-related death.141,147–149

The relationship between oral contraceptives and risk of stroke is still a matter of debate. Recommendations are based on observational studies, since no randomised trials are available. Another systematic review found no association between oral contraceptives and stroke in cohort studies, while it did detect a significant increase in risk in case–control studies. This increase in risk was more evident for IS than for haemorrhagic stroke. Higher risk levels were observed in hospital-based populations than in community-based populations.150 A different systematic review showed increased risk of AMI or stroke associated with the use of first and second-generation oral contraceptives. The increase in risk was more evident for stroke.151 A systematic review showed that progesterone-only contraceptive use is not associated with an increased risk of stroke.152 Women older than 35 years who smoke and have HBP, DM, history of migraine, or history of thrombotic complications may be at increased risk.150,153–157 Certain congenital thrombophilias, such as Factor V Leiden, prothrombin G20210A, methylenetetrahydrofolate reductase (MTHFR) mutation, or hyperhomocysteinaemia, are associated with an increased risk of cerebral vein thrombosis.158,159


A meta-analysis and various systematic reviews have confirmed the association between homocysteine levels and stroke.160,161 The high risk thymidine–thymidine (TT) genotype is associated with a 21% increase in risk of ischaemic heart disease and an increase in risk of stroke that is not statistically significant.162 Several studies have analysed the efficacy of folic acid or vitamin B supplements. Although vitamin supplements reduced homocysteine levels, this decrease did not have any significant effect on vascular risk.163–165 A single systematic review described an 18% decrease in risk of stroke in a group taking folic acid supplements with or without B complex vitamins compared to a control group. Researchers have observed this effect mainly in trials lasting more than 36 months in countries in which cereals are supplemented with folic acid.166 According to a meta-analysis, patients with history of vascular disease show similar risks of vascular disease, coronary disease, stroke, or death whether they receive folic acid supplements or a placebo.167 The VISP and VITATOPS studies have shown that folic acid, vitamin B6 and vitamin B12 supplements are safe in patients with prior stroke, but they do not reduce risk of new vascular episodes.163,168 Nevertheless, some authors point to a probable benefit in patients with markedly higher or lower homocysteine levels.169 A systematic review has confirmed that there is not enough evidence to determine whether or not treatments affecting homocysteine levels can prevent stroke recurrence.170

Prothrombotic statesInherited thrombophilias

Observational studies have not demonstrated a clear association between inherited thrombophilias and IS in adults.171–175 One review even concluded that routine testing for factor V Leiden, prothrombin G20210A, protein C, protein S, and antithrombin III in IS was unproductive.176 Nevertheless, doctors can detect a hypercoagulable state in more than 40% of young patients with IS.177 A systematic review in a paediatric population (<18 years) concluded that all the thrombophilias which it evaluated (antithrombin III deficiency, protein C deficiency, protein S deficiency, factor V Leiden, prothrombin G20210A, thermolabile MTHFR polymorphism, and antiphospholipid antibodies) were associated with increased risk of suffering new IS or cerebral venous thrombosis. Patients with multiple defects had higher levels of risk.178 Two meta-analyses have researched the potential relationship between stroke and prothrombotic disorders. The first meta-analysis found significant associations between stroke and factor V Leiden, MTHFR C677T variant, and factor II G20210A mutation.179 The risk of suffering stroke in the general population with these polymorphisms is low. The second meta-analysis studied the association between prothrombotic factors and arterial thrombotic episodes. Researchers could not verify a significant association between stroke and factor V Leiden; they did find slight associations between stroke and factor II G20210A mutation and MTHFR C677T mutation. These findings were more evident in young subjects (<55 years).180 The relationship between cerebral venous disease and thrombophilias has been clearly demonstrated. For example, a review showed a significant relationship with cerebral venous thrombosis in patients with factor V Leiden, factor II G20210A mutation and MTHFR C677T mutation.158 The risk of suffering cerebral thrombosis is high in patients who take oral contraceptives and have factor V Leiden mutation, prothrombin G20210A mutation, or hyperhomocysteinaemia.159 Doctors still debate whether or not hypercoagulation studies should be carried out in patients with venous thrombosis. Additional studies are needed, and doctors should follow clinical criteria in these situations.181

Acquired thrombophilias

A retrospective study in patients with antiphospholipid antibodies revealed a 4.4% probability of developing IS.182 The presence of anticardiolipin antibodies was associated with an increase by a factor of 1.5 to 2.2 of risk of developing stroke in men,183 and a cohort study showed a similar relationship in women.184 Nevertheless, there have been no clinical trials in patients with antiphospholipid antibody syndrome and no prior thrombosis.185–187

Sleep apnoea

Sleep apnoea affects up to 24% of the adult male population.188 It has traditionally been associated with a risk of severe vascular episodes such as ischaemic heat disease, stroke,189 CHF,190 and sudden death.191 In population studies, sleep apnoea showed a slight association with CHF and ischaemic heart disease after adjusting for other risk factors.192 It showed a more marked association with risk of stroke.193–195

Conflicts of interest

The authors have no conflicts of interest to declare.

Appendix A

Ad hoc committee of the SEN Study Group for Cerebrovascular Diseases constituted to draw up clinical practice guidelines for stroke.

Coordinator: Exuperio Díez-Tejedor, Hospital Universitario La Paz, Madrid.

Drafting committee

Exuperio Díez-Tejedor (Coordinator), Hospital Universitario La Paz, Madrid; Blanca Fuentes (Secretary), Hospital Universitario La Paz, Madrid; María Alonso de Leciñana, Hospital Universitario Ramón y Cajal, Madrid; José Álvarez-Sabin, Hospital Universitari Vall d’Hebron, Barcelona; Juan Arenillas, Hospital Universitario Clínico de Valladolid; Sergio Calleja, Hospital Universitario Central de Asturias, Oviedo; Ignacio Casado, Hospital San Pedro, Cáceres; Mar Castellanos, Hospital Josep Trueta, Gerona; José Castillo, Hospital Clínico Universitario, Santiago de Compostela; Antonio Dávalos, Hospital Universitari Germans Trias i Pujol, Badalona Fernando Díaz-Otero, Hospital Universitario Gregorio Marañón, Madrid; Exuperio Díez-Tejedor, Hospital Universitario La Paz, Madrid; José Antonio Egido, Hospital Clínico Universitario San Carlos, Madrid; Juan Carlos Fernández, Hospital Universitario Dr. Negrín, Las Palmas; Mar Freijo, Hospital Universitario de Basurto, Bilbao; Blanca Fuentes, Hospital Universitario La Paz, Madrid; Jaime Gállego, Hospital General de Navarra, Pamplona; Andrés García Pastor, Hospital Universitario Gregorio Marañón, Madrid; Antonio Gil-Núñez, Hospital Universitario Gregorio Marañón, Madrid; Francisco Gilo, Hospital Universitario La Princesa, Madrid; Pablo Irimia, Clínica Universitaria de Navarra, Pamplona; Aida Lago, Hospital Universitario La Fe, Valencia; José Maestre, Hospital Universitario Virgen de las Nieves, Granada; Jaime Masjuan, Hospital Universitario Ramón y Cajal, Madrid; Joan Martí-Fábregas, Hospital de la Santa Creu i Sant Pau, Barcelona; Patricia Martínez-Sánchez, Hospital Universitario La Paz, Madrid; Eduardo Martínez-Vila, Clínica Universitaria de Navarra, Pamplona; Carlos Molina, Hospital Universitario Vall d’Hebron, Barcelona; Ana Morales, Hospital Universitario Virgen de la Arrixaca, Murcia; Florentino Nombela, Hospital Universitario La Princesa, Madrid; Francisco Purroy, Hospital Universitario Arnau de Vilanova, Lérida; Marc Ribó, Hospital Universitari Vall d’Hebron, Barcelona; Manuel Rodríguez-Yañez, Hospital Clínico Universitario, Santiago de Compostela; Jaime Roquer, Hospital del Mar, Barcelona; Francisco Rubio, Hospital Universitario de Bellvitge, Barcelona; Tomás Segura, Hospital Universitario de Albacete, Albacete; Joaquín Serena, Hospital Josep Trueta, Gerona; Patricia Simal, Hospital Clínico Universitario San Carlos, Madrid; Javier Tejada, Hospital Universitario de León, León; José Vivancos, Hospital Universitario La Princesa, Madrid.

Review and institutional committee

José Álvarez-Sabín, Hospital Universitario ValldHebron, Barcelona; José Castillo, Hospital Clínico Universitario, Santiago de Compostela; Exuperio Díez-Tejedor, Hospital Universitario La Paz, Madrid; Antonio Gil-Núñez, Hospital Universitario Gregorio Marañón, Madrid; José Larracoechea, Hospital de Cruces, Bilbao; Eduardo Martínez-Vila, Clínica Universitaria de Navarra, Pamplona; Jaime Masjuan, Hospital Universitario Ramón y Cajal, Madrid; Jorge Matías-Guiu, Hospital Clínico Universitario San Carlos, Madrid; Francisco Rubio, Hospital de Bellvitge, Barcelona.

Instituto Nacional de Estadística. Defunciones según causa de muerte 2006. Available from: http://www.ine.es/prensa/np490.pdf [accessed 29.07.11].
R.J. Adams, M.I. Chimowitz, J.S. Alpert, I.A. Awad, M.D. Cerqueria, P. Fayad, et al.
Coronary risk evaluation in patients with transient ischemic attack and ischemic stroke: a scientific statement for healthcare professionals from the Stroke Council and the Council on Clinical Cardiology of the American Heart Association/American Stroke Association.
Centre for Evidence Based Medicine. Available from: http://www.cebm.net/ [accessed 29.07.11].
S. Lewington, R. Clarke, N. Qizilbash, R. Peto, R. Collins, Prospective Studies Collaboration.
Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies.
Lancet, 360 (2002), pp. 1903-1913
C.M. Lawes, D.A. Bennett, V.L. Feigin, A. Rodgers.
Blood pressure and stroke: an overview of published reviews.
S.E. Kjeldsen, S. Julius, T. Hedner, L. Hansson.
Stroke is more common than myocardial infarction in hypertension: analysis based on 11 major randomized intervention trials.
Blood Press, 10 (2001), pp. 190-192
A.V. Chobanian, G.L. Bakris, H.R. Black, W.C. Cushman, L.A. Green, J.L. Izzo Jr., et al.
Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure.
Hypertension, 42 (2003), pp. 1206-1252
C.M. Lawes, S. Vander Hoorn, M.R. Law, P. Elliott, S. MacMahon, A. Rodgers.
Blood pressure and the global burden of disease 2000. Part II: estimates of attributable burden.
S. Ebrahim, A. Beswick, M. Burke, G. Davey Smith.
Multiple risk factor interventions for primary prevention of coronary heart disease.
Cochrane Database Syst Rev, 4 (2006), pp. CD001561
P. Rashid, J. Leonardi-Bee, P. Bath.
Blood pressure reduction and secondary prevention of stroke and other vascular events: a systematic review.
H. Zhang, L. Thijs, J.A. Staessen.
Blood pressure lowering for primary and secondary prevention of stroke.
Hypertension, 48 (2006), pp. 187-195
B. Fuentes, M.A. Ortega-Casarrubios, P. Martinez, E. Diez-Tejedor.
Action on vascular risk factors: importance of blood pressure and lipid lowering in stroke secondary prevention.
Cerebrovasc Dis, 24 (2007), pp. 96-106
The Dutch TIA Trial Study Group.
Trial of secondary prevention with atenolol after transient ischemic attack or nondisabling ischemic stroke.
Stroke, 24 (1993), pp. 543-548
S. Eriksson, B. Olofsson, P.O. Wester.
Atenolol in secondary prevention after stroke.
Cerebrovasc Dis, 5 (1995), pp. 21-25
C.S. Wiysonge, H. Bradley, B.M. Maysi, R. Maroney, A. Mbewu, L.H. Opie, et al.
Beta-blockers for hypertension.
Cochrane Database Syst Rev, 1 (2007), pp. CD002003
Hypertension-Stroke Cooperative Group.
Effect of antihypertensive treatment on stroke recurrence.
JAMA, 229 (1974), pp. 409-418
PATS Collaborating Group.
Post-stroke antihypertensive treatment study. A preliminary result. PATS Collaborating Group.
Chin Med J (Engl), 108 (1995), pp. 710-717
S. Yusuf, P. Sleight, J. Pogue, J. Bosch, R. Davies, G. Dagenais.
Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators.
N Engl J Med, 342 (2000), pp. 145-153
PROGRESS Collaborative Group.
Randomised trial of a perindopril-based blood-pressure-lowering regimen among 6,105 individuals with previous stroke or transient ischaemic attack.
Lancet, 358 (2001), pp. 1033-1041
J. Schrader, S. Luders, A. Kulschewski, F. Hammersen, K. Plate, J. Berger, et al.
Morbidity and mortality after stroke, eprosartan compared with nitrendipine for secondary prevention: principal results of a prospective randomized controlled study (MOSES).
S. Yusuf, H.C. Diener, R.L. Sacco, D. Cotton, S. Ounpuu, W.A. Lawton, et al.
Telmisartan to prevent recurrent stroke and cardiovascular events.
N Engl J Med, 359 (2008), pp. 1225-1237
S. Yusuf, K.K. Teo, J. Pogue, L. Dyal, I. Copland, ONTARGET Investigators.
Telmisartan, ramipril, or both in patients at high risk for vascular events.
N Engl J Med, 358 (2008), pp. 1547-1559
F. Turnbull, B. Neal, C. Algert, J. Chalmers, N. Chapman, J. Cutler, et al.
Effects of different blood pressure-lowering regimens on major cardiovascular events in individuals with and without diabetes mellitus: results of prospectively designed overviews of randomized trials.
Arch Intern Med, 165 (2005), pp. 1410-1419
A.C. Gil-Nunez, J. Vivancos-Mora.
Blood pressure as a risk factor for stroke and the impact of antihypertensive treatment.
Cerebrovasc Dis, 20 (2005), pp. 40-52
B. Fuentes, J. Fernandez-Dominguez, M.A. Ortega-Casarrubios, B. SanJose, P. Martinez-Sanchez, E. Diez-Tejedor.
Treatment with angiotensin receptor blockers before stroke could exert a favourable effect in acute cerebral infarction.
J Hypertens, 28 (2010), pp. 575-581
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults AT Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III).
JAMA, 285 (2001), pp. 2486-2497
T. Almdal, H. Scharling, J.S. Jensen, H. Vestergaard.
The independent effect of type 2 diabetes mellitus on ischemic heart disease, stroke, and death: a population-based study of 13,000 men and women with 20 years of follow-up.
Arch Intern Med, 164 (2004), pp. 1422-1426
T. Hillen, C. Coshall, K. Tilling, A.G. Rudd, R. McGovern, C.D. Wolfe, et al.
Cause of stroke recurrence is multifactorial: patterns, risk factors, and outcomes of stroke recurrence in the South London Stroke Register.
G. Mancia.
Optimal control of blood pressure in patients with diabetes reduces the incidence of macro and microvascular events.
J Hypertens Suppl, 25 (2007), pp. S7-S12
P.M. Kearney, L. Blackwell, R. Collins, A. Keech, J. Simes, Cholesterol Treatment Trialists’ (CTT) Collaborators,.
Efficacy of cholesterol-lowering therapy in 18,686 people with diabetes in 14 randomised trials of statins: a meta-analysis.
H.C. Gerstein, M.E. Miller, R.P. Byington, D.C. Goff Jr., J.T. Bigger, Action to Control Cardiovascular Risk in Diabetes Study Group.
Effects of intensive glucose lowering in type 2 diabetes.
N Engl J Med, 358 (2008), pp. 2545-2559
A. Patel, S. MacMahon, J. Chalmers, B. Neal, L. Billot, ADVANCE Collaborative Group.
Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes.
N Engl J Med, 358 (2008), pp. 2560-2572
W. Duckworth, C. Abraira, T. Moritz, D. Reda, N. Emanuele, P.D. Reaven, et al.
Glucose control and vascular complications in veterans with type 2 diabetes.
N Engl J Med, 360 (2009), pp. 129-139
American Diabetes Association.
Standards of medical care in diabetes-2011.
Diabetes Care, 34 (2011), pp. S11-S61
J.A. Dormandy, B. Charbonnel, D.J. Eckland, E. Erdmann, M. Massi-Benedetti, I.K. Moules, et al.
Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial.
Lancet, 366 (2005), pp. 1279-1289
R. Wilcox, M.G. Bousser, D.J. Betteridge, G. Schernthaner, V. Pirags, S. Kupfer, et al.
Effects of pioglitazone in patients with type 2 diabetes with or without previous stroke: results from PROactive (PROspective pioglitAzone Clinical Trial In macroVascular Events 04).
European Stroke Organisation (ESO) Executive Committee, ESO Writing Committee.
Guidelines for management of ischaemic stroke and transient ischaemic attack 2008.
Cerebrovasc Dis, 25 (2008), pp. 457-507
A.M. Lincoff, K. Wolski, S.J. Nicholls, S.E. Nissen.
Pioglitazone and risk of cardiovascular events in patients with type 2 diabetes mellitus: a meta-analysis of randomized trials.
JAMA, 298 (2007), pp. 1180-1188
K.L. Furie, S.E. Kasner, R.J. Adams, G.W. Albers, R.L. Bush, S.C. Fagan, et al.
Guidelines for the prevention of stroke in patients with stroke or transient ischemic attack: a guideline for healthcare professionals from the American heart association/American stroke association.
X. Zhang, A. Patel, H. Horibe, Z. Wu, F. Barzi, A. Rodgers, et al.
Cholesterol, coronary heart disease, and stroke in the Asia Pacific region.
Int J Epidemiol, 32 (2003), pp. 563-572
R.B. Horenstein, D.E. Smith, L. Mosca.
Cholesterol predicts stroke mortality in the Women's Pooling Project.
Stroke, 33 (2002), pp. 1863-1868
P.S. Sever, B. Dahlof, N.R. Poulter, H. Wedel, G. Beevers, M. Caulfield, et al.
Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial.
Lancet, 361 (2003), pp. 1149-1158
R. Collins, J. Armitage, S. Parish, P. Sleight, R. Peto, Heart Protection Study Collaborative Group.
Effects of cholesterol-lowering with simvastatin on stroke and other major vascular events in 20536 people with cerebrovascular disease or other high-risk conditions.
B.M. Everett, R.J. Glynn, J.G. MacFadyen, P.M. Ridker.
Rosuvastatin in the prevention of stroke among men and women with elevated levels of C-reactive protein: justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER).
Circulation, 121 (2010), pp. 143-150
National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III).
Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report.
Circulation, 106 (2002), pp. 3143-3421
P. Amarenco, J. Bogousslavsky, A. Callahan 3rd, L.B. Goldstein, M. Hennerici, A.E. Rudolph, et al.
High-dose atorvastatin after stroke or transient ischemic attack.
N Engl J Med, 355 (2006), pp. 549-559
L.B. Goldstein, P. Amarenco, M. Szarek, A. Callahan 3rd, M. Hennerici, H. Sillesen, et al.
Hemorrhagic stroke in the stroke prevention by aggressive reduction in cholesterol levels study.
P. Amarenco, L.B. Goldstein, M. Szarek, H. Sillesen, A.E. Rudolph, A. Callahan 3rd, et al.
Effects of intense low-density lipoprotein cholesterol reduction in patients with stroke or transient ischemic attack: the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial.
Stroke, 38 (2007), pp. 3198-3204
J. Costa, M. Borges, C. David, A. Vaz Carneiro.
Efficacy of lipid lowering drug treatment for diabetic and non-diabetic patients: meta-analysis of randomised controlled trials.
S.L. Paul, A.G. Thrift, G.A. Donnan.
Smoking as a crucial independent determinant of stroke.
Tob Induc Dis, 2 (2004), pp. 67-80
P.A. Wolf, R.B. D’Agostino, W.B. Kannel, R. Bonita, A.J. Belanger.
Cigarette smoking as a risk factor for stroke. The Framingham Study.
JAMA, 259 (1988), pp. 1025-1029
L.L. Haheim, I. Holme, I. Hjermann, P. Leren.
Smoking habits and risk of fatal stroke: 18 years follow up of the Oslo Study.
J Epidemiol Community Health, 50 (1996), pp. 621-624
R. Shinton, G. Beevers.
Meta-analysis of relation between cigarette smoking and stroke.
BMJ, 298 (1989), pp. 789-794
R. Bonita, R. Scragg, A. Stewart, R. Jackson, R. Beaglehole.
Cigarette smoking and risk of premature stroke in men and women.
Br Med J (Clin Res Ed), 293 (1986), pp. 6-8
T. Kurth, C.S. Kase, K. Berger, E.S. Schaeffner, J.E. Buring, J.M. Gaziano.
Smoking and the risk of hemorrhagic stroke in men.
V.M. Bhat, J.W. Cole, J.D. Sorkin, M.A. Wozniak, A.M. Malarcher, W.H. Giles, et al.
Dose–response relationship between cigarette smoking and risk of ischemic stroke in young women.
Stroke, 39 (2008), pp. 2439-2443
S.G. Wannamethee, A.G. Shaper, M. Walker.
Changes in physical activity, mortality, and incidence of coronary heart disease in older men.
Lancet, 351 (1998), pp. 1603-1608
K. Fagerstrom.
The epidemiology of smoking: health consequences and benefits of cessation.
Drugs, 62 (2002), pp. 1-9
A.S. Robbins, J.E. Manson, I.M. Lee, S. Satterfield, C.H. Hennekens.
Cigarette smoking and stroke in a cohort of U.S. male physicians.
Ann Intern Med, 120 (1994), pp. 458-462
J.A. Critchley, S. Capewell.
Mortality risk reduction associated with smoking cessation in patients with coronary heart disease: a systematic review.
JAMA, 290 (2003), pp. 86-97
R. Bonita, J. Duncan, T. Truelsen, R.T. Jackson, R. Beaglehole.
Passive smoking as well as active smoking increases the risk of acute stroke.
Tob Control, 8 (1999), pp. 156-160
R.X. You, A.G. Thrift, J.J. McNeil, S.M. Davis, G.A. Donnan.
Ischemic stroke risk and passive exposure to spouses’ cigarette smoking. Melbourne Stroke Risk Factor Study (MERFS) Group.
Am J Public Health, 89 (1999), pp. 572-575
C. García-Nunez, J. Saez, J.M. García-Nunez, J. Grau, J.M. Molto-Jorda, J. Matias-Guiu.
Passive smoking as a cerebrovascular risk factor.
Rev Neurol, 45 (2007), pp. 577-581
P. Boffetta, K. Straif.
Use of smokeless tobacco and risk of myocardial infarction and stroke: systematic review with meta-analysis.
BMJ, 339 (2009), pp. b3060
J.S. Gill, A.V. Zezulka, M.J. Shipley, S.K. Gill, D.G. Beevers.
Stroke and alcohol consumption.
N Engl J Med, 315 (1986), pp. 1041-1046
A.L. Klatsky, M.A. Armstrong, G.D. Friedman, S. Sidney.
Alcohol drinking and risk of hemorrhagic stroke.
Neuroepidemiology, 21 (2002), pp. 115-122
G. Mazzaglia, A.R. Britton, D.R. Altmann, L. Chenet.
Exploring the relationship between alcohol consumption and non-fatal or fatal stroke: a systematic review.
Addiction, 96 (2001), pp. 1743-1756
H. Iso, S. Baba, T. Mannami, S. Sasaki, K. Okada, M. Konishi, et al.
Alcohol consumption and risk of stroke among middle-aged men: the JPHC Study Cohort I.
K. Reynolds, B. Lewis, J.D. Nolen, G.L. Kinney, B. Sathya, J. He.
Alcohol consumption and risk of stroke: a meta-analysis.
JAMA, 289 (2003), pp. 579-588
K. Berger, U.A. Ajani, C.S. Kase, J.M. Gaziano, J.E. Buring, R.J. Glynn, et al.
Light-to-moderate alcohol consumption and risk of stroke among U.S. male physicians.
N Engl J Med, 341 (1999), pp. 1557-1564
J.H. O’Keefe, K.A. Bybee, C.J. Lavie.
Alcohol and cardiovascular health: the razor-sharp double-edged sword.
J Am Coll Cardiol, 50 (2007), pp. 1009-1014
J.R. Emberson, D.A. Bennett.
Effect of alcohol on risk of coronary heart disease and stroke: causality, bias, or a bit of both?.
Vasc Health Risk Manag, 2 (2006), pp. 239-249
A. Di Castelnuovo, S. Rotondo, L. Iacoviello, M.B. Donati, G. De Gaetano.
Meta-analysis of wine and beer consumption in relation to vascular risk.
Circulation, 105 (2002), pp. 2836-2844
F.M. Sacks, L.P. Svetkey, W.M. Vollmer, L.J. Appel, G.A. Bray, D. Harsha, et al.
Effects on blood pressure of reduced dietary sodium and the Dietary Approaches to Stop Hypertension (DASH) diet. DASH-Sodium Collaborative Research Group.
N Engl J Med, 344 (2001), pp. 3-10
L.J. Appel, F.M. Sacks, V.J. Carey, E. Obarzanek, J.F. Swain, E.R. Miller 3rd, et al.
Effects of protein, monounsaturated fat, and carbohydrate intake on blood pressure and serum lipids: results of the OmniHeart randomized trial.
JAMA, 294 (2005), pp. 2455-2464
R. Estruch, M.A. Martínez-González, D. Corella, J. Salas-Salvado, V. Ruiz-Gutiérrez, M.I. Covas, et al.
Effects of a Mediterranean-style diet on cardiovascular risk factors: a randomized trial.
Ann Intern Med, 145 (2006), pp. 1-11
P. Strazzullo, L. D’Elia, N.B. Kandala, F.P. Cappuccio.
Salt intake, stroke, and cardiovascular disease: meta-analysis of prospective studies.
BMJ, 339 (2009), pp. b4567
D. Mozaffarian, E.B. Rimm.
Fish intake, contaminants, and human health: evaluating the risks and the benefits.
JAMA, 296 (2006), pp. 1885-1899
K. He, Y. Song, M.L. Daviglus, K. Liu, L. Van Horn, A.R. Dyer, et al.
Fish consumption and incidence of stroke: a meta-analysis of cohort studies.
L. Dauchet, P. Amouyel, J. Dallongeville.
Fruit and vegetable consumption and risk of stroke: a meta-analysis of cohort studies.
C. Heidemann, M.B. Schulze, O.H. Franco, R.M. van Dam, C.S. Mantzoros, F.B. Hu.
Dietary patterns and risk of mortality from cardiovascular disease, cancer, and all causes in a prospective cohort of women.
Circulation, 118 (2008), pp. 230-237
M. Osler, B.L. Heitmann, L.U. Gerdes, L.M. Jorgensen, M. Schroll.
Dietary patterns and mortality in Danish men and women: a prospective observational study.
Br J Nutr, 85 (2001), pp. 219-225
M.S. Bernstein, A. Morabia, D. Sloutskis.
Definition and prevalence of sedentarism in an urban population.
Am J Public Health, 89 (1999), pp. 862-867
G.C. Wendel-Vos, A.J. Schuit, E.J. Feskens, H.C. Boshuizen, W.M. Verschuren, W.H. Saris, et al.
Physical activity and stroke. A meta-analysis of observational data.
Int J Epidemiol, 33 (2004), pp. 787-798
D. Mozaffarian, P.W. Wilson, W.B. Kannel.
Beyond established and novel risk factors: lifestyle risk factors for cardiovascular disease.
Circulation, 117 (2008), pp. 3031-3038
S. Mora, N. Cook, J.E. Buring, P.M. Ridker, I.M. Lee.
Physical activity and reduced risk of cardiovascular events: potential mediating mechanisms.
Circulation, 116 (2007), pp. 2110-2118
P.D. Thompson, D. Buchner, I.L. Pina, G.J. Balady, M.A. Williams, B.H. Marcus, et al.
Exercise and physical activity in the prevention and treatment of atherosclerotic cardiovascular disease: a statement from the Council on Clinical Cardiology (Subcommittee on Exercise, Rehabilitation, and Prevention) and the Council on Nutrition, Physical Activity, and Metabolism (Subcommittee on Physical Activity).
Circulation, 107 (2003), pp. 3109-3116
Y. Netz, M.J. Wu, B.J. Becker, G. Tenenbaum.
Physical activity and psychological well-being in advanced age: a meta-analysis of intervention studies.
Psychol Aging, 20 (2005), pp. 272-284
S.S. Bassuk, J.E. Manson.
Epidemiological evidence for the role of physical activity in reducing risk of type 2 diabetes and cardiovascular disease.
J Appl Physiol, 99 (2005), pp. 1193-1204
A.H. Taylor, M.H. Ussher, G. Faulkner.
The acute effects of exercise on cigarette cravings, withdrawal symptoms, affect and smoking behaviour: a systematic review.
Addiction, 102 (2007), pp. 534-543
C.D. Lee, A.R. Folsom, S.N. Blair.
Physical activity and stroke risk: a meta-analysis.
E.J. Shiroma, I.M. Lee.
Physical activity and cardiovascular health: lessons learned from epidemiological studies across age, gender, and race/ethnicity.
Circulation, 122 (2010), pp. 743-752
NIH Consensus Development Panel on Physical Activity and Cardiovascular Health.
Physical activity and cardiovascular health.
JAMA, 276 (1996), pp. 241-246
M. De Weerd, J.P. Greving, B. Hedblad, M.W. Lorenz, E.B. Mathiesen, D.H. O’Leary, et al.
Prevalence of asymptomatic carotid artery stenosis in the general population: an individual participant data meta-analysis.
Stroke, 41 (2010), pp. 1294-1297
Z.G. Nadareishvili, P.M. Rothwell, V. Beletsky, A. Pagniello, J.W. Norris.
Long-term risk of stroke and other vascular events in patients with asymptomatic carotid artery stenosis.
Arch Neurol, 59 (2002), pp. 1162-1166
A. Halliday, A. Mansfield, J. Marro, C. Peto, R. Peto, J. Potter, et al.
Prevention of disabling and fatal strokes by successful carotid endarterectomy in patients without recent neurological symptoms: randomised controlled trial.
Lancet, 363 (2004), pp. 1491-1502
Executive Committee for the Asymptomatic Carotid Atherosclerosis Study.
Endarterectomy for asymptomatic carotid artery stenosis.
JAMA, 273 (1995), pp. 1421-1428
L. Marquardt, O.C. Geraghty, Z. Mehta, P.M. Rothwell.
Low risk of ipsilateral stroke in patients with asymptomatic carotid stenosis on best medical treatment: a prospective, population-based study.
A.L. Abbott.
Medical (nonsurgical) intervention alone is now best for prevention of stroke associated with asymptomatic severe carotid stenosis: results of a systematic review and analysis.
Stroke, 40 (2009), pp. e573-e583
J.D. Spence, V. Coates, H. Li, A. Tamayo, C. Munoz, D.G. Hackam, et al.
Effects of intensive medical therapy on microemboli and cardiovascular risk in asymptomatic carotid stenosis.
Arch Neurol, 67 (2010), pp. 180-186
T.G. Brott, R.W. Hobson 2nd, G. Howard, G.S. Roubin, W.M. Clark, W. Brooks, et al.
Stenting versus endarterectomy for treatment of carotid-artery stenosis.
N Engl J Med, 363 (2010), pp. 11-23
T.G. Brott, J.L. Halperin, S. Abbara, J.M. Bacharach, J.D. Barr, R.L. Bush, et al.
TASA/ACCF/AHA/AANN/AANS/ACR/ASNR/CNS/SAIP/SCAI/SIR/SNIS/SVM/SVS Guideline on the Management of Patients With Extracranial Carotid and Vertebral Artery Disease: Executive Summary: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, and the American Stroke Association, American association of Neuroscience Nurses, American Association of Neurological Surgeons, American College of Radiology, American Society of Neuroradiology, Congress of Neurological Surgeons, Society of Atherosclerosis Imaging and Prevention, Society for Cardiovascular Angiography and Interventions, Society of Interventional Radiology, Society of NeuroInterventional Surgery, Society for Vascular Medicine, and Society for Vascular Surgery.
Stroke, 42 (2011), pp. e420-e463
C.D. Liapis, P.R. Bell, D. Mikhailidis, J. Sivenius, A. Nicolaides, J. Fernandes e Fernandes, et al.
ESVS guidelines. Invasive treatment for carotid stenosis: indications, techniques.
Eur J Vasc Endovasc Surg, 37 (2009), pp. 1-19
A.N. Nicolaides, S. Kakkos, M. Griffin, G. Geroulakos, E. Ioannidou.
Severity of asymptomatic carotid stenosis and risk of ipsilateral hemispheric ischaemic events: results from the ACSRS study. Nicolaides et al.: EJVES 2005; 30: 275–284.
Eur J Vasc Endovasc Surg, 31 (2006), pp. 336
S.K. Kakkos, M. Sabetai, T. Tegos, J. Stevens, D. Thomas, M. Griffin, et al.
Silent embolic infarcts on computed tomography brain scans and risk of ipsilateral hemispheric events in patients with asymptomatic internal carotid artery stenosis.
J Vasc Surg, 49 (2009), pp. 902-909
S. Sabeti, O. Schlager, M. Exner, W. Mlekusch, J. Amighi, P. Dick, et al.
Progression of carotid stenosis detected by duplex ultrasonography predicts adverse outcomes in cardiovascular high-risk patients.
Stroke, 38 (2007), pp. 2887-2894
H.S. Markus, A. King, M. Shipley, R. Topakian, M. Cullinane, S. Reihill, et al.
Asymptomatic embolisation for prediction of stroke in the Asymptomatic Carotid Emboli Study (ACES): a prospective observational study.
Lancet Neurol, 9 (2010), pp. 663-671
I. van Wijk, P.J. Koudstaal, L.J. Kappelle, J. van Gijn, J.W. Gorter, A. Algra, et al.
Long-term occurrence of death and cardiovascular events in patients with transient ischaemic attack or minor ischaemic stroke: comparison between arterial and cardiac source of the index event.
J Neurol Neurosurg Psychiatry, 79 (2008), pp. 895-899
A.S. Go, E.M. Hylek, K.A. Phillips, Y. Chang, L.E. Henault, J.V. Selby, et al.
Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study.
JAMA, 285 (2001), pp. 2370-2375
K. Lakshminarayan, C.A. Solid, A.J. Collins, D.C. Anderson, C.A. Herzog.
Atrial fibrillation and stroke in the general medicare population: a 10-year perspective (1992 to 2002).
R.G. Hart, J.L. Halperin.
Atrial fibrillation and thromboembolism: a decade of progress in stroke prevention.
Ann Intern Med, 131 (1999), pp. 688-695
R.L. Sacco, E.J. Benjamin, J.P. Broderick, M. Dyken, J.D. Easton, W.M. Feinberg, et al.
American Heart Association Prevention Conference. IV. Prevention and Rehabilitation of Stroke Risk factors.
Stroke, 28 (1997), pp. 1507-1517
P.A. Wolf, R.D. Abbott, W.B. Kannel.
Atrial fibrillation as an independent risk factor for stroke: the Framingham Study.
Stroke, 22 (1991), pp. 983-988
P.A. Wolf, T.R. Dawber, H.E. Thomas Jr., W.B. Kannel.
Epidemiologic assessment of chronic atrial fibrillation and risk of stroke: the Framingham study.
Neurology, 28 (1978), pp. 973-977
R.G. Hart, L.A. Pearce.
Current status of stroke risk stratification in patients with atrial fibrillation.
Stroke, 40 (2009), pp. 2607-2610
B.F. Gage, A.D. Waterman, W. Shannon, M. Boechler, M.W. Rich, M.J. Radford.
Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation.
JAMA, 285 (2001), pp. 2864-2870
S. Rietbrock, E. Heeley, J. Plumb, T. van Staa.
Chronic atrial fibrillation: Incidence, prevalence, and prediction of stroke using the Congestive heart failure. Hypertension, Age >75, Diabetes mellitus, and prior Stroke or transient ischemic attack (CHADS2) risk stratification scheme.
Am Heart J, 156 (2008), pp. 57-64
G.Y. Lip, R. Nieuwlaat, R. Pisters, D.A. Lane, H.J. Crijns.
Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: the Euro Heart Survey on atrial fibrillation.
Chest, 137 (2010), pp. 263-272
R.O. Bonow, B.A. Carabello, K. Chatterjee, A.C. De León Jr., D.P. Faxon, M.D. Freed, et al.
2008 focused update incorporated into the ACC/AHA 2006 guidelines for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to revise the 1998 guidelines for the management of patients with valvular heart disease). Endorsed by the Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons.
J Am Coll Cardiol, 52 (2008), pp. e1-e142
K.H. Olesen.
The natural history of 271 patients with mitral stenosis under medical treatment.
Br Heart J, 24 (1962), pp. 349-357
T.J. Liu, H.C. Lai, W.L. Lee, K.Y. Wang, H.J. Wei, C.T. Ting, et al.
Percutaneous balloon commissurotomy reduces incidence of ischemic cerebral stroke in patients with symptomatic rheumatic mitral stenosis.
Int J Cardiol, 123 (2008), pp. 189-190
M.G. Karas, S. Francescone, A.Z. Segal, R.B. Devereux, M.J. Roman, J.E. Liu, et al.
Relation between mitral annular calcium and complex aortic atheroma in patients with cerebral ischemia referred for transesophageal echocardiography.
Am J Cardiol, 99 (2007), pp. 1306-1311
R. Pujadas, A. Arboix, N. Anguera, J. Rafel, F. Sagues, R. Casanas.
Mitral annular calcification as a marker of complex aortic atheroma in patients with stroke of uncertain etiology.
Echocardiography, 25 (2008), pp. 124-132
S. Kohsaka, Z. Jin, T. Rundek, B. Boden-Albala, S. Homma, R.L. Sacco, et al.
Impact of mitral annular calcification on cardiovascular events in a multiethnic community: the Northern Manhattan Study.
JACC Cardiovasc Imaging, 1 (2008), pp. 617-623
J.R. Kizer, D.O. Wiebers, J.P. Whisnant, J.M. Galloway, T.K. Welty, E.T. Lee, et al.
Mitral annular calcification, aortic valve sclerosis, and incident stroke in adults free of clinical cardiovascular disease: the Strong Heart Study.
L.A. Freed, D. Levy, R.A. Levine, M.G. Larson, J.C. Evans, D.L. Fuller, et al.
Prevalence and clinical outcome of mitral-valve prolapse.
N Engl J Med, 341 (1999), pp. 1-7
N.U. Weir.
An update on cardioembolic stroke.
Postgrad Med J, 84 (2008), pp. 133-142
J. Hirsh, G. Guyatt, G.W. Albers, R. Harrington, H.J. Schunemann.
American College of Chest Physicians. Executive summary: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition).
Chest, 133 (2008), pp. 71S-109S
E.M. Antman, M. Hand, P.W. Armstrong, E.R. Bates, L.A. Green, L.K. Halasyamani, et al.
2007 Focused Update of the ACC/AHA 2004 Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines: developed in collaboration With the Canadian Cardiovascular Society endorsed by the American Academy of Family Physicians: 2007 Writing Group to Review New Evidence and Update the ACC/AHA 2004 Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction. Writing on Behalf of the 2004 Writing Committee.
Circulation, 117 (2008), pp. 296-329
R.C. Becker, T.W. Meade, P.B. Berger, M. Ezekowitz, C.M. O’Connor, D.A. Vorchheimer, et al.
The primary and secondary prevention of coronary artery disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition).
Chest, 133 (2008), pp. 776S-814S
M.R. Di Tullio, R.L. Sacco, R.R. Sciacca, Z. Jin, S. Homma.
Patent foramen ovale and the risk of ischemic stroke in a multiethnic population.
J Am Coll Cardiol, 49 (2007), pp. 797-802
I. Meissner, B.K. Khandheria, J.A. Heit, G.W. Petty, S.G. Sheps, G.L. Schwartz, et al.
Patent foramen ovale: innocent or guilty? Evidence from a prospective population-based study.
J Am Coll Cardiol, 47 (2006), pp. 440-445
J.R. Overell, I. Bone, K.R. Lees.
Interatrial septal abnormalities and stroke: a meta-analysis of case–control studies.
Neurology, 55 (2000), pp. 1172-1179
J.L. Mas, C. Arquizan, C. Lamy, M. Zuber, L. Cabanes, G. Derumeaux, et al.
Recurrent cerebrovascular events associated with patent foramen ovale, atrial septal aneurysm, or both.
N Engl J Med, 345 (2001), pp. 1740-1746
J. Serena, J. Marti-Fabregas, E. Santamarina, J.J. Rodríguez, M.J. Pérez-Ayuso, J. Masjuan, et al.
Recurrent stroke and massive right-to-left shunt: results from the prospective Spanish multicenter (CODICIA) study.
Stroke, 39 (2008), pp. 3131-3136
M.A. Almekhlafi, S.B. Wilton, D.M. Rabi, W.A. Ghali, D.L. Lorenzetti, M.D. Hill.
Recurrent cerebral ischemia in medically treated patent foramen ovale: a meta-analysis.
F. Grodstein, M.J. Stampfer, J.E. Manson, G.A. Colditz, W.C. Willett, B. Rosner, et al.
Postmenopausal estrogen and progestin use and the risk of cardiovascular disease.
N Engl J Med, 335 (1996), pp. 453-461
J.E. Rossouw, G.L. Anderson, R.L. Prentice, A.Z. LaCroix, C. Kooperberg, M.L. Stefanick, et al.
Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial.
JAMA, 288 (2002), pp. 321-333
S. Wassertheil-Smoller, S.L. Hendrix, M. Limacher, G. Heiss, C. Kooperberg, A. Baird, et al.
Effect of estrogen plus progestin on stroke in postmenopausal women: the Women's Health Initiative: a randomized trial.
JAMA, 289 (2003), pp. 2673-2684
J.E. Rossouw, R.L. Prentice, J.E. Manson, L. Wu, D. Barad, V.M. Barnabei, et al.
Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause.
JAMA, 297 (2007), pp. 1465-1477
S.R. Gabriel, L. Carmona, M. Roque, G.L. Sanchez, X. Bonfill.
Hormone replacement therapy for preventing cardiovascular disease in post-menopausal women.
Cochrane Database Syst Rev, 2 (2005), pp. CD002229
G.M. Sare, L.J. Gray, P.M. Bath.
Association between hormone replacement therapy and subsequent arterial and venous vascular events: a meta-analysis.
Eur Heart J, 29 (2008), pp. 2031-2041
C. Renoux, S. Dell’aniello, E. Garbe, S. Suissa.
Transdermal and oral hormone replacement therapy and the risk of stroke: a nested case–control study.
BMJ, 340 (2010), pp. c2519
N.R. De Melo, L.M. Pompei.
Tibolone reduces osteoporotic fracture risk and breast cancer risk, but increases the risk of stroke.
Gynecol Endocrinol, 26 (2010), pp. 73-75
H.D. Nelson, R. Fu, J.C. Griffin, P. Nygren, M.E. Smith, L. Humphrey.
Systematic review: comparative effectiveness of medications to reduce risk for primary breast cancer.
E. Barrett-Connor, D.A. Cox, J. Song, B. Mitlak, L. Mosca, D. Grady.
Raloxifene and risk for stroke based on the framingham stroke risk score.
Am J Med, 122 (2009), pp. 754-761
C.M. Viscoli, L.M. Brass, W.N. Kernan, P.M. Sarrel, S. Suissa, R.I. Horwitz.
A clinical trial of estrogen-replacement therapy after ischemic stroke.
N Engl J Med, 345 (2001), pp. 1243-1249
L.M. Brass.
Hormone replacement therapy and stroke: clinical trials review.
P.M. Bath, L.J. Gray.
Association between hormone replacement therapy and subsequent stroke: a meta-analysis.
W.S. Chan, J. Ray, E.K. Wai, S. Ginsburg, M.E. Hannah, P.N. Corey, et al.
Risk of stroke in women exposed to low-dose oral contraceptives: a critical evaluation of the evidence.
Arch Intern Med, 164 (2004), pp. 741-747
J.P. Baillargeon, D.K. McClish, P.A. Essah, J.E. Nestler.
Association between the current use of low-dose oral contraceptives and cardiovascular arterial disease: a meta-analysis.
J Clin Endocrinol Metab, 90 (2005), pp. 3863-3870
Z. Chakhtoura, M. Canonico, A. Gompel, J.C. Thalabard, P.Y. Scarabin, G. Plu-Bureau.
Progestogen-only contraceptives and the risk of stroke: a meta-analysis.
Stroke, 40 (2009), pp. 1059-1062
WHO Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception.
Ischaemic stroke and combined oral contraceptives: results of an international, multicentre, case–control study.
Lancet, 348 (1996), pp. 498-505
S.M. Schwartz, D.S. Siscovick, W.T. Longstreth Jr., B.M. Psaty, R.K. Beverly, T.E. Raghunathan, et al.
Use of low-dose oral contraceptives and stroke in young women.
Ann Intern Med, 127 (1997), pp. 596-603
W.J. Becker.
Use of oral contraceptives in patients with migraine.
Neurology, 53 (1999), pp. S19-S25
S. Siritho, A.G. Thrift, J.J. McNeil, R.X. You, S.M. Davis, G.A. Donnan, et al.
Risk of ischemic stroke among users of the oral contraceptive pill: The Melbourne Risk Factor Study (MERFS) Group.
O. Lidegaard.
Oral contraceptives pregnancy and the risk of cerebral thromboembolism: the influence of diabetes, hypertension, migraine and previous thrombotic disease.
Br J Obstet Gynaecol, 102 (1995), pp. 153-159
F. Dentali, M. Crowther, W. Ageno.
Thrombophilic abnormalities, oral contraceptives, and risk of cerebral vein thrombosis: a meta-analysis.
Blood, 107 (2006), pp. 2766-2773
I. Martinelli, T. Battaglioli, I. Burgo, S. Di Domenico, P.M. Mannucci.
Oral contraceptive use, thrombophilia and their interaction in young women with ischemic stroke.
Haematologica, 91 (2006), pp. 844-847
Homocysteine Studies Collaboration.
Homocysteine and risk of ischemic heart disease and stroke: a meta-analysis.
JAMA, 288 (2002), pp. 2015-2022
J.P. Casas, L.E. Bautista, L. Smeeth, P. Sharma, A.D. Hingorani.
Homocysteine and stroke: evidence on a causal link from mendelian randomisation.
D.S. Wald, M. Law, J.K. Morris.
Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis.
BMJ, 325 (2002), pp. 1202
J.F. Toole, M.R. Malinow, L.E. Chambless, J.D. Spence, L.C. Pettigrew, V.J. Howard, et al.
Lowering homocysteine in patients with ischemic stroke to prevent recurrent stroke, myocardial infarction, and death: the Vitamin Intervention for Stroke Prevention (VISP) randomized controlled trial.
JAMA, 291 (2004), pp. 565-575
E. Lonn, S. Yusuf, M.J. Arnold, P. Sheridan, J. Pogue, M. Micks, et al.
Homocysteine lowering with folic acid and B vitamins in vascular disease.
N Engl J Med, 354 (2006), pp. 1567-1577
K.H. Bonaa, I. Njolstad, P.M. Ueland, H. Schirmer, A. Tverdal, T. Steigen, et al.
Homocysteine lowering and cardiovascular events after acute myocardial infarction.
N Engl J Med, 354 (2006), pp. 1578-1588
X. Wang, X. Qin, H. Demirtas, J. Li, G. Mao, Y. Huo, et al.
Efficacy of folic acid supplementation in stroke prevention: a meta-analysis.
Lancet, 369 (2007), pp. 1876-1882
L.A. Bazzano, K. Reynolds, K.N. Holder, J. He.
Effect of folic acid supplementation on risk of cardiovascular diseases: a meta-analysis of randomized controlled trials.
JAMA, 296 (2006), pp. 2720-2726
VITATOPS Trial Study Group.
B vitamins in patients with recent transient ischaemic attack or stroke in the VITAmins TO Prevent Stroke (VITATOPS) trial: a randomised, double-blind, parallel, placebo-controlled trial.
Lancet Neurol, 9 (2010), pp. 855-865
J.D. Spence.
Homocysteine-lowering therapy: a role in stroke prevention?.
Lancet Neurol, 6 (2007), pp. 830-838
A.J. Marti-Carvajal, I. Sola, D. Lathyris, G. Salanti.
Homocysteine lowering interventions for preventing cardiovascular events.
Cochrane Database Syst Rev, 4 (2009), pp. CD006612
P.M. Ridker, C.H. Hennekens, K. Lindpaintner, M.J. Stampfer, P.R. Eisenberg, J.P. Miletich.
Mutation in the gene coding for coagulation factor V and the risk of myocardial infarction, stroke, and venous thrombosis in apparently healthy men.
N Engl J Med, 332 (1995), pp. 912-917
M. Cushman, F.R. Rosendaal, B.M. Psaty, E.F. Cook, J. Valliere, L.H. Kuller, et al.
Factor V Leiden is not a risk factor for arterial vascular disease in the elderly: results from the Cardiovascular Health Study.
Thromb Haemost, 79 (1998), pp. 912-915
W.M. Feinberg, L.A. Pearce, R.G. Hart, M. Cushman, E.S. Cornell, G.Y. Lip, et al.
Markers of thrombin and platelet activity in patients with atrial fibrillation: correlation with stroke among 1531 participants in the stroke prevention in atrial fibrillation III study.
Stroke, 30 (1999), pp. 2547-2553
K. Juul, A. Tybjaerg-Hansen, R. Steffensen, S. Kofoed, G. Jensen, B.G. Nordestgaard.
Factor V Leiden: The Copenhagen City Heart Study and 2 meta-analyses.
P.M. Ridker, C.H. Hennekens, J.P. Miletich.
G20210A mutation in prothrombin gene and risk of myocardial infarction, stroke, and venous thrombosis in a large cohort of US men.
Circulation, 99 (1999), pp. 999-1004
A. Rahemtullah, E.M. Van Cott.
Hypercoagulation testing in ischemic stroke.
Arch Pathol Lab Med, 131 (2007), pp. 890-901
M. Martínez-Martínez, R. Cazorla-Garcia, L.A. Rodríguez de Antonio, P. Martínez-Sánchez, B. Fuentes, E. Díez-Tejedor.
Hypercoagulability and ischemic stroke in young patients.
Neurologia, 25 (2010), pp. 343-348
G. Kenet, L.K. Lutkhoff, M. Albisetti, T. Bernard, M. Bonduel, L. Brandao, et al.
Impact of thrombophilia on risk of arterial ischemic stroke or cerebral sinovenous thrombosis in neonates and children: a systematic review and meta-analysis of observational studies.
Circulation, 121 (2010), pp. 1838-1847
J.P. Casas, A.D. Hingorani, L.E. Bautista, P. Sharma.
Meta-analysis of genetic studies in ischemic stroke: thirty-two genes involving approximately 18,000 cases and 58,000 controls.
Arch Neurol, 61 (2004), pp. 1652-1661
R.J. Kim, R.C. Becker.
Association between factor V Leiden, prothrombin G20210A, and methylenetetrahydrofolate reductase C677T mutations and events of the arterial circulatory system: a meta-analysis of published studies.
Am Heart J, 146 (2003), pp. 948-957
D. Cohn, F. Vansenne, C. De Borgie, S. Middeldorp.
Thrombophilia testing for prevention of recurrent venous thromboembolism.
Cochrane Database Syst Rev, 1 (2009), pp. CD007069
G. Finazzi, V. Brancaccio, M. Moia, N. Ciaverella, M.G. Mazzucconi, P.C. Schinco, et al.
Natural history and risk factors for thrombosis in 360 patients with antiphospholipid antibodies: a four-year prospective study from the Italian Registry.
Am J Med, 100 (1996), pp. 530-536
R.L. Brey, R.D. Abbott, J.D. Curb, D.S. Sharp, G.W. Ross, C.L. Stallworth, et al.
Beta(2)-glycoprotein 1-dependent anticardiolipin antibodies and risk of ischemic stroke and myocardial infarction: the honolulu heart program.
Stroke, 32 (2001), pp. 1701-1706
V. Janardhan, P.A. Wolf, C.S. Kase, J.M. Massaro, R.B. D’Agostino, C. Franzblau, et al.
Anticardiolipin antibodies and risk of ischemic stroke and transient ischemic attack: the Framingham cohort and offspring study.
W. Lim, M.A. Crowther, J.W. Eikelboom.
Management of antiphospholipid antibody syndrome: a systematic review.
JAMA, 295 (2006), pp. 1050-1057
R.L. Brey.
Management of the neurological manifestations of APS – what do the trials tell us?.
Thromb Res, 114 (2004), pp. 489-499
P.A. Gatenby.
Controversies in the antiphospholipid syndrome and stroke.
Thromb Res, 114 (2004), pp. 483-488
T. Young, M. Palta, J. Dempsey, J. Skatrud, S. Weber, S. Badr.
The occurrence of sleep-disordered breathing among middle-aged adults.
N Engl J Med, 328 (1993), pp. 1230-1235
J.M. Marín, S.J. Carrizo, E. Vicente, A.G. Agusti.
Long-term cardiovascular outcomes in men with obstructive sleep apnoea–hypopnoea with or without treatment with continuous positive airway pressure: an observational study.
Lancet, 365 (2005), pp. 1046-1053
S. Javaheri, T.J. Parker, J.D. Liming, W.S. Corbett, H. Nishiyama, L. Wexler, et al.
Sleep apnea in 81 ambulatory male patients with stable heart failure. Types and their prevalences, consequences, and presentations.
Circulation, 97 (1998), pp. 2154-2159
J.J. Goldberger, M.E. Cain, S.H. Hohnloser, A.H. Kadish, B.P. Knight, M.S. Lauer, et al.
American Heart Association/American College of Cardiology Foundation/Heart Rhythm Society scientific statement on noninvasive risk stratification techniques for identifying patients at risk for sudden cardiac death: a scientific statement from the American Heart Association Council on Clinical Cardiology Committee on Electrocardiography and Arrhythmias and Council on Epidemiology and Prevention.
Circulation, 118 (2008), pp. 1497-1518
D.J. Gottlieb, G. Yenokyan, A.B. Newman, G.T. O’Connor, N.M. Punjabi, S.F. Quan, et al.
Prospective study of obstructive sleep apnea and incident coronary heart disease and heart failure: the sleep heart health study.
Circulation, 122 (2010), pp. 352-360
S. Redline, G. Yenokyan, D.J. Gottlieb, E. Shahar, G.T. O’Connor, H.E. Resnick, et al.
Obstructive sleep apnea–hypopnea and incident stroke: the sleep heart health study.
Am J Respir Crit Care Med, 182 (2010), pp. 269-277
H.K. Yaggi, J. Concato, W.N. Kernan, J.H. Lichtman, L.M. Brass, V. Mohsenin.
Obstructive sleep apnea as a risk factor for stroke and death.
N Engl J Med, 353 (2005), pp. 2034-2041
M. Arzt, T. Young, L. Finn, J.B. Skatrud, T.D. Bradley.
Association of sleep-disordered breathing and the occurrence of stroke.
Am J Respir Crit Care Med, 172 (2005), pp. 1447-1451

The affiliations of the authors and committee members are listed in the appendix.

Please cite this article as: Fuentes B, et al. Guía para el tratamiento preventivo del ictus isquémico y AIT (I). Actuación sobre los factores de riesgo y estilo de vida. Neurología. 2012;27:560–74.

Copyright © 2011. Sociedad Española de Neurología
Article options
es en pt

¿Es usted profesional sanitario apto para prescribir o dispensar medicamentos?

Are you a health professional able to prescribe or dispense drugs?

Você é um profissional de saúde habilitado a prescrever ou dispensar medicamentos