Issues of Concern
Risk Factors
Risk factors important in stroke prevention can be divided into non-modifiable and modifiable risk factors. [3][4][5]
Non-modifiable risk factors include
Age (increased risk with increasing age)
Race and ethnicity (higher risk of strokes in Africans than whites)
Gender (higher risk for men, but this trend disappears beyond the mid-80s)
Family history (especially of cerebral arterial disease)
Genetic risk factors (for example, hypercoagulable states, sickle cell disease, cerebral amyloid angiopathy)
Modifiable risk factors
Hypertension
Diabetes mellitus
Obesity
Impaired lipid profile
Atrial fibrillation
Structural heart disease
Carotid artery stenosis
Lifestyle choices- Diet, Exercise, Smoking, Alcohol, etc.
In most cases, the patient has a combination of modifiable risk factors, i.e., hypertension, diabetes, high cholesterol.
Hypertension is a major risk factor for both ischemic and hemorrhagic stroke. Hypertension is an identified risk factor in up to 90% of all strokes, and it is estimated that up to 40% of all strokes can be prevented with good blood pressure control. Higher blood pressures are associated with a higher risk of stroke, even in the normotensive range. The term ‘prehypertension’ has been eliminated in the recent guidelines, and normal BP is considered to be less than 120/80 mm Hg. BP over 130/80 mm Hg should be treated in all symptomatic atherosclerotic cardiovascular disease (ASCVD) individuals and asymptomatic individuals with over 10% risk of 10-year ASCVD risk. For secondary prevention of stroke, antihypertensive treatment should be initiated for BP more than 140/90 mm Hg. Lower BP target (SBP < 130 mm Hg) is recommended only after lacunar stroke. Lifestyle modifications like salt restriction, weight loss, and regular exercise should be a part of comprehensive antihypertensive therapy. The choice of antihypertensive should be individualized based on patient demographics and comorbid conditions.[5][6][7]
Diabetes is a major risk factor for ischemic stroke, especially lacunar stroke and large artery stroke. The risk of stroke is tripled in patients with diabetes mellitus of duration over 10 years. Diabetes is a strong risk factor for ischemic stroke and is further associated with other stroke risk factors such as hypertension, abnormal lipid profile, and obesity. So far, there is no proven direct risk between diabetes and primary hemorrhagic stroke. Nevertheless, aggressive diabetic control is prudent. Lifestyle modifications and pharmacological treatment should be initiated for a target glycated hemoglobin of less than 6.5% (48 mmol), along with optimal lipid and blood pressure targets. Aspirin is recommended for diabetic patients with higher ASCVD risk for primary prevention of cardiovascular disease (CVD), although its role in primary stroke prevention is unclear. Metformin - the first-line medication for type 2 diabetes mellitus patients also has potential benefits for clinical atherosclerotic disease. Some other hypoglycemic agents like SGLT2 inhibitors- empagliflozin, canagliflozin, GLP-1 receptor agonist- liraglutide, thiazolidinedione- pioglitazone, have shown efficacy for reduction of carotid atherosclerosis, and when appropriate diabetic patients with atherosclerotic stroke should receive therapy with such agents. Existing guidelines for glycemic control and lipid and BP targets should be used in diabetic patients who have had a stroke or TIA.[5][8]
Dyslipidemia- Ischemic stroke risk is increased by high cholesterol levels, whereas low cholesterol levels may increase the risk of hemorrhagic stroke. [5] Statin treatment reduces the risk of stroke in patients with or at high risk of atherosclerotic disease and even in healthy individuals with LDL < 130 mg/dL and high sensitivity CRP levels > 2mg/L. Despite initial concerns, statin treatment does not increase the risk of hemorrhagic CVA. Estimating total cardiovascular risk is the first step in the medical management of dyslipidemia. Clinical ASCVD, including stroke and TIA, is the major determinant of an individual’s CVD risk. LDL targets are based on risk factors or 10-year risk of ASCVD. American college of endocrinology 2017 guidelines for management of dyslipidemia and prevention of cardiovascular disease recommend LDL target of < 55 mg/dL for extreme risk, < 70 mg/dL for very high risk, < 100 mg/dL for high and moderate risk and < 130 mg/dL for low-risk individuals. Fibrates are recommended for triglycerides >200 mg/dL and HDL < 40 mg/dL. Proprotein Convertase Subtilisin Kexin 9 (PCSK9) inhibitors are recommended for very high-risk individuals unable to reach LDL target of <140 mg/dL or < 100 mg/dL for those with multivessel or rapidly progressive atherosclerotic disease, despite statin therapy with or without ezetimibe therapy or because of inability to tolerate at least three statin medications.[5] A meta-analysis from Cholesterol Treatment Trialists' (CTT) Collaboration has shown that "in individuals with a 5-year risk of major vascular events lower than 10%, each one mmol/L reduction in LDL cholesterol produced an absolute reduction in major vascular events of about 11 per 1000 over 5 years."[9] For secondary prevention, SPARCL trial showed that the use of high-dose atorvastatin (80 mg) for cardioembolic stroke/TIA patients led to a 43% reduction in the risk of fatal recurrent stroke and a 26% reduction in any cardiovascular events. [10]
Smoking has been associated with a two to four-time increased risk of ischemic stroke and intracranial bleeds. It is one of the leading preventable risk factors for stroke. It takes two to four years after smoking cessation for the excess risk to go down. Smoking cessation options such as counseling, nicotine replacement therapy, or agents such as bupropion should be offered to all appropriate patients. Passive tobacco smoking should be avoided.[5][8]
Regular exercise (burning 2000 to 3000 calories per week) has been shown to reduce stroke risk by half.[8]
Obesity- The risk of ischemic stroke is increased by 22% for overweight individuals and by 64% in obese individuals as compared to normal-weight individuals.[5]
Diet- American heart association recommends a diet that has increased intake of fruits, vegetables, and whole grains and limited intake of sugar, saturated fat, trans-fat and red meat. Most Mediterranean diets advocate increased consumption of vegetables, whole grains, fruits, nuts, and olive oil. Moderate amounts of fish, poultry, and dairy products are allowed, whereas red meat is avoided. It is uncertain whether the health benefits are due to the consumption of the before mentioned food items or an under-consumption of red meats (and subsequently decreased intake of saturated fats). Absolute risk reduction is approximately three cardiovascular events per 1000 person-years treated (PREDIMED study).[5][8][11]
Alcohol- Chronic alcohol use and heavy drinking are risk factors for stroke. J-shaped association between alcohol and ischemic stroke risk has been suggested by most studies. There is a protective effect from light to moderate consumption (likely due to an increase in HDL and a decrease in platelet aggregation) and increased risk of stroke with heavy alcohol consumption (due to a hypercoagulable state, alcohol-induced hypertension, cardiomyopathy, and Afib). Stopping or reducing alcohol consumption is recommended for patients with ischemic stroke or TIA.[5][8]
Lower socioeconomic status, including low income, lower education level, is associated with an increased risk of stroke recurrence.[5][8]
Sleep disorders have been identified as a risk for stroke in some recent studies. It is a potentially modifiable risk factor. Proper screening and appropriate therapeutic intervention are recommended.[5][8][12]
Atrial fibrillation by itself is a risk factor for embolic stroke events - atrial fibrillation leads to about a 1.9% risk of stroke per year and is responsible for as many as one in six strokes, with a further risk depending on factors such as diabetes, hypertension, age group, previous strokes, heart failure, peripheral vascular disease, previous ischemic cardiac event and gender (higher for females). If all of these risk factors are present along with atrial fibrillation, the risk of embolic stroke is as high as 17% per year. Obviously, anticoagulation is recommended, but that leads to an increased bleeding risk. There are various tools (CHA2DS2VASc score, HAS-BLED score) that can help decide about treating atrial fibrillation with anticoagulation, balancing the benefit and harm of treatment.[8][13]. There is growing evidence that the new NOACs (Novel Oral Anticoagulants) are as effective, if not superior, to warfarin and possibly carry fewer bleeding risks. They are now considered first-line therapies for stroke risk reduction in an appropriately selected patient with nonvalvular AF.[14]
Data suggests that vitamin B therapy helps in small vessel brain injury (due to a reduction in Homocysteine) but not large artery disease or cardioembolic disease. B-vitamins have a role in primary stroke prevention and are associated with a reduction in primary stroke risk between 7% to 11% in high vascular risk patients (but no reduction in cardiac events is reported). VITATOPS study showed secondary prevention benefits: a reduction in small artery ischemic strokes from 17% to 14% after intervention, reduction in intracerebral hemorrhage from 18% to 12% after intervention, reduction in recurrent TIAs from 14% to 10% after intervention, and reduction in milder strokes from 22% to 18% after intervention.[15]
Antiplatelet therapy is preferred for primary and secondary prevention of atherosclerotic stroke prevention. Daily aspirin has been shown to be beneficial in primary prevention for ischemic cardiac disease, but the data is not so robust for primary prevention in strokes. The data for secondary prevention in ischemic strokes is much more convincing. A significant reduction in stroke recurrence within 2 weeks has been reported if aspirin is initiated within 48 hours of an ischemic stroke. Clopidogrel has shown better outcomes for patients with poly vascular disease and could be considered for secondary stroke prevention of atherosclerotic ischemic stroke patients already on aspirin. Dual antiplatelet therapy (aspirin and clopidogrel) has shown efficacy but has significantly more bleeding complications than aspirin alone. Increased mortality has been reported with long-term dual antiplatelet therapy after lacunar stroke. Ticagrelor plus aspirin reduced stroke recurrence in patients with ischemic stroke with symptomatic atherosclerotic stenosis of ipsilateral intra or extracranial stenosis as compared to aspirin alone. Antiplatelet therapy is recommended for primary and secondary prevention of stroke; however, it should be weighed against the risk of bleed, and treatment should always be individualized, taking into account all risk factors.[5][16][17][18]
Anticoagulation therapy - COMPASS trial published in 2017 compared three antiplatelet regimens- rivaroxaban (2.5 mg twice daily) plus aspirin (100 mg once daily), rivaroxaban (5 mg twice daily), and aspirin (100 mg once daily) in patients with stable atherosclerotic disease (peripheral, coronary, symptomatic carotid artery disease, >50% asymptomatic carotid disease) and found the combination treatment group had a significantly lower risk of major adverse cardiovascular events than with aspirin alone, but a significantly higher risk of major bleeding. Combination treatment is not yet added to guidelines, but there is a possibility that this could soon be part of treatment guidelines on secondary prevention of atherosclerotic stroke in select patients. Caution is recommended in patients with a high risk of bleeding.[5][19]
Structural Interventions Considered in Secondary Prevention
The structural cardiac disease can sometimes be corrected, though not all structural defect correction is beneficial for stroke prevention. Antiplatelet therapy is reasonable for patients with PFO and ischemic stroke or TIA. Data regarding the recommendation of PFO closure in patients with ischemic stroke is insufficient. Patent foramen ovale correction may be considered in very select patients (high risk on echo, multi-territory infarcts, absence of other significant predisposing risk factors, and recurrent strokes despite anticoagulation).[15]
In patients with symptomatic ICA stenosis of >70%, Carotid endarterectomy (CEA) or Carotid Artery Stenosis (CAS) is shown to be beneficial in the first two weeks after an ipsilateral stroke or TIA. CEA is preferred over CAS in older patients (>70 years). Studies have shown a higher procedural risk with CAS than CEA. Women have a less favorable benefit to risk ratio. Guidelines recommend intervention only if estimated perioperative mortality and morbidity risk is <6% for men and <4% for women. Guidelines recommend considering CEA in asymptomatic patients with over 70% ICA stenosis; if their perioperative risk is estimated to be less than 3%, CAS may be considered for high-risk patients. The benefit of carotid intervention for moderate symptomatic and asymptomatic ICA stenosis is unclear so far. There is no benefit in carotid endarterectomy if the carotid is 100% blocked.[5][8][20][21][22]
Stroke in Women
The lifetime risk of stroke and mortality due to stroke is higher in women than men. Some factors that contribute to an increased risk of stroke in women include pregnancy, oral contraceptive use (especially when combined with smoking), preeclampsia/eclampsia, gestational diabetes, migraine with aura, increased risk of atrial fibrillation, hormonal replacement therapy.[23]
Low-dose aspirin (from the 12th week of gestation until delivery) and calcium supplementation are recommended for women with hypertension before pregnancy or with a history of pregnancy-related hypertension to prevent preeclampsia risk. The risk of stroke is increased two folds and hypertension by four folds in women with preeclampsia.
OCPs may be harmful in women, especially in women with additional risk factors like smoking and a history of thromboembolic events. Aggressive risk factor modification is recommended in women using OCPs. Women should be screened for hypertension before starting hormonal contraception.[23]
