Prabhakaran, Shyam MD, MS; Chong, Ji Y. MD
Risk factors for stroke include those that are nonmodifiable and those that are modifiable. Studies suggest that 90% of strokes can be explained by modifiable risk factors, and 80% of recurrent strokes can be prevented with optimal risk factor control and/or elimination.1,2 Furthermore, on a population level, reductions in the burden of these conditions and adherence to medical treatment regimens have been associated with declines in stroke incidence.3
This review focuses on modifiable medical and behavioral risk factors (Table 2-1) commonly encountered by the neurologist after ischemic stroke or TIA. Evidence-based tools and strategies for risk factor management will be addressed.
Table 2-1 Modifiable...Image Tools
MEDICAL RISK FACTORS
Hypertension is the single most important modifiable risk factor for both hemorrhagic and ischemic stroke. One-third of adults in the United States have hypertension, defined as blood pressure (BP) 140/90 mm Hg or greater, and another 30% may have prehypertension, defined as BP between 120 and 139 mm Hg (systolic) and 80 and 89 mm Hg (diastolic).4 Studies have consistently shown a linear relationship between BP and stroke risk such that no threshold exists where risk could not be further reduced. In prospective studies, every 10–mm Hg reduction in BP is associated with a 33% lowering of stroke risk in primary prevention.5
The benefits of antihypertensive therapy on secondary stroke prevention are clear, with a 25% relative-risk reduction in patients with and without preexisting hypertension.6,7 Therefore, if BP lowering is reasonable and safe, it should be considered in every stroke patient. Even among patients with intracranial stenosis (Case 2-1), a condition that may be associated with cerebral hypoperfusion, elevated BP in the postacute phase was associated with recurrent stroke.8 In the recent Secondary Prevention of Small Subcortical Strokes (SPS3) trial, a lower systolic BP target (less than 130 mm Hg) was associated with a decrease in recurrent stroke (hazard ratio [HR] 0.81, P=.08) with a significant reduction in hemorrhagic stroke events in patients with lacunar stroke (HR 0.37, P=.03).9 However, a recent post hoc analysis of the Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) trial found that very low systolic BP (less than 120 mm Hg) after recent stroke was associated with increased risk of recurrent stroke compared with those with normal BP defined as 120 to 139 mm Hg.10 These data suggest that a goal BP of approximately 120 to 140 mm Hg (systolic) and 80 to 90 mm Hg (diastolic) may be ideal.
Whether specific classes of antihypertensive therapy are superior to others is debated, although specific subpopulations may preferentially benefit from certain drug classes (Table 2-2). Current guidelines support any antihypertensive agent in patients with stroke, although diuretics with or without angiotensin-converting enzyme inhibitors (ACE-I) may be reasonable evidence-based, first-line approaches (Figure 2-1). In most patients, goal BP lowering should strive for a 10–mm Hg and 5–mm Hg reduction in systolic BP and diastolic BP, respectively, from baseline even in nonhypertensive patients, and less than 140/90 mm Hg in hypertensive patients (less than 130/80 mm Hg in patients with diabetes mellitus and chronic kidney disease).11 Although very recently published guidelines12 liberalized these goals and recommended initiation of antihypertensive therapy at a higher threshold (> 150/90 mm Hg in patients older than 60 years without kidney disease or diabetes mellitus, and > 140/90 mm Hg in those with either condition), these recommendations were made for primary prevention and not specifically for patients with stroke (ie, secondary prevention). In addition to lifestyle modification and nonpharmacologic approaches, patient education—including explaining the specific medications, doses, risks, and importance of adherence—is paramount.
Table 2-2 Antihypert...Image Tools
Figure 2-1. Algorith...Image Tools
A 73-year-old woman with hypertension presented with transient arm weakness and expressive aphasia. She reported taking metoprolol for hypertension at home, but initial blood pressure (BP) in the emergency department was 176/99 mm Hg. Diagnostic imaging revealed left subcortical acute infarcts. Magnetic resonance angiography demonstrated a left middle cerebral artery flow gap consistent with high-grade stenosis. Aspirin 325 mg/d was started, and metoprolol was halved for 24 hours, after which it was resumed at the prior dose and then increased slowly to achieve BP of 135/80 mm Hg. At a follow-up 1 month later, she was doing well without recurrent stroke or TIA but had not resumed BP medications. BP was 210/105 mm Hg in the clinic.
Comment. Given the negative effects of hypertension on stroke (and other vascular) risk, it is recommended that gradual BP lowering be initiated as soon as neurologic stability is confirmed (ie, no changes in examination in the first 24 hours). While acute management of BP in acute stroke remains controversial, it is generally safe to begin lowering BP gradually (15% daily) after the first 24 hours and monitoring for symptom recurrence even while in the hospital. The long-term goal would be less than 140/90 mm Hg with careful titration of combination drug therapy. Frequent BP measurements and follow-up are advised until goals are achieved.
Approximately one-quarter of adults in the United States have elevated cholesterol levels.4 While associations between lipids and stroke risk are less clear compared with coronary or peripheral vascular disease, this is mostly attributed to the heterogeneity of stroke (eg, hemorrhagic stroke, nonatherosclerotic subtypes of ischemic stroke). A large meta-analysis found that low-density lipoprotein (LDL) cholesterol level, non–high-density lipoprotein (HDL) cholesterol level, and very low-density lipoprotein level (but not HDL cholesterol and triglyceride levels) were associated with ischemic stroke.
LDL-cholesterol level lowering is the primary goal of dyslipidemia management following stroke, primarily through use of statins. A meta-analysis of statins in primary or secondary prevention of stroke found that for each 1 mmol/L (or approximately 39 mg/dL) reduction in LDL cholesterol level, a 21% relative reduction in stroke risk was achieved.13 The Stroke Prevention by Aggressive Reduction of Cholesterol Levels (SPARCL) trial randomized patients with stroke or TIA within 6 months who had LDL-cholesterol levels between 100 mg/dL and 190 mg/dL, and without evident coronary artery disease to atorvastatin 80 mg daily or placebo. The study observed a modest but significant reduction in stroke risk at 5 years in favor of atorvastatin (2.2% absolute and 16% relative risk reductions).14 Those patients who achieved a 50% reduction in LDL-cholesterol level had the most benefit (38% relative reduction in stroke risk) followed by those who achieved an LDL-cholesterol level of less than 70 mg/dL (28% relative risk reduction).15 Although potency varies by statin drug, with rosuvastatin and atorvastatin considered the most potent (capable of achieving greater than 50% LDL-cholesterol level lowering at medium to high doses), choice of statin may be determined by other factors, including costs and patient tolerance.
The Adult Treatment Panel (ATP) III National Cholesterol Education Program (NCEP) has recommended that patients with atherosclerosis such as carotid artery disease be placed into the high-risk category, where the goal LDL is less than 100 mg/dL.16 The most recent American Heart Association (AHA) guidelines on secondary stroke prevention recommend even stricter goals: LDL lowering by 50% or more or an absolute LDL-cholesterol level goal of less than 70 mg/dL.17 These should apply to stroke or TIA patients with evidence of atherosclerosis (ie, large or small artery disease), those with an LDL-cholesterol level greater than 100 mg/dL, or those who have had coronary heart disease or its equivalents (Class I, Level of Evidence B). Although data on monitoring patients with an LDL-cholesterol level on statin therapy are limited, the ATP-III recommends checking LDL-cholesterol levels approximately 6 weeks after initiation and every 6 weeks until targets are achieved; thereafter, measurements every 6 to 12 months is reasonable. Monitoring for side effects such as myalgia and liver dysfunction should occur when symptoms or signs are reported or discovered. The AHA recently updated their recommendations for cholesterol management.18 While no longer targeting specific LDL goals, guidelines continue to emphasize high-dose statin therapy for those with clinical cardiovascular disease like atherothrombotic stroke and reserve moderate intensity statin therapy in patients over age 75 or intolerant of high-dose statin therapy.
For low HDL-cholesterol levels (less than 40 mg/dL), niacin may be a reasonable treatment option in stroke prevention despite the lack of clear benefit in cardiovascular risk reduction. While triglyceride levels may be a risk factor for ischemic stroke, particularly large artery atherosclerosis subtypes, studies of fibrate medications in stroke prevention have not yielded positive results. Other lipoproteins may be important treatment targets, although evidence for clinical utility of this treatment is less compelling. Triglycerides, lipoprotein A, lipoprotein phospholipase A2 (LpPLA2), and apolipoproteins are considered risk factors for cardiovascular disease. Elevated levels may be markers of stroke risk, but it is unclear whether treatment to attain normal levels (eg, dietary modification, niacin, fibrates, and statins) reduces risk.
Although a meta-analysis of statin trials concluded that there was no elevated risk of intracerebral hemorrhage (ICH) among patients taking statins,19 the SPARCL trial found an increased risk (absolute difference 0.9%) of ICH among stroke patients treated with atorvastatin 80 mg daily compared with placebo (Case 2-2). Those with prior lobar hemorrhage, who have higher rates of recurrent spontaneous ICH than those with deep hemorrhage, may be particularly at risk on statin therapy.20
A 67-year-old man with diabetes mellitus, coronary artery disease, and hyperlipidemia presented with left-sided neglect and hemianopsia. Brain imaging showed a right parietal ischemic stroke with petechial hemorrhagic transformation. Evaluation revealed right internal carotid artery stenosis of 80%. Fasting LDL-cholesterol level on admission was 137 mg/dL. Right carotid endarterectomy was performed with good technical results on hospital day 7. He was discharged on aspirin 325 mg daily and lisinopril 20 mg daily. Despite concerns about hemorrhagic stroke risk, the patient was started on atorvastatin 80 mg daily to achieve goal LDL-cholesterol level of less than 70 mg/dL. He presented to the clinic at 3 months after stroke for follow-up, at which time laboratory assessment showed that his LDL level was 65 mg/dL.
Comment. While the Stroke Prevention by Aggressive Reduction of Cholesterol Levels (SPARCL) trial showed a small risk of hemorrhagic stroke among stroke patients started on atorvastatin, this patient’s atherosclerotic disease (both carotid and coronary artery disease) and diabetes mellitus place him at the highest risk for ischemic vascular events. The absolute risk of hemorrhage in patients taking statins is small and would be outweighed by the potential benefits in this case.
New guidelines define diabetes mellitus as a hemoglobin A1c (HgA1c) greater than 6.5%.21 It is estimated that 19 million adults in the United States have diabetes mellitus, but nearly 90 million may have prediabetes and insulin resistance, a number that is expected to climb.4 Diabetes mellitus is a risk factor for recurrent, particularly lacunar, stroke.22 Despite the benefits of glycemic control on microvascular complications of diabetes mellitus, trials of aggressive glycemic lowering for secondary prevention of macrovascular events (including stroke) have failed to show benefit, especially when targets for HgA1c are less than 6.5%.23 Given this result, glycemic control should aim for HgA1c of less than 7% using diet, exercise, and medications such as oral hypoglycemic drugs and insulin.17 Aggressive targets for BP (less than 130/80 mm Hg) and lipid-lowering (LDL-cholesterol level of less than 70 mg/dL) in patients with diabetes mellitus are associated with decreased stroke risk.24,25
Obstructive Sleep Apnea
The relationship between obstructive sleep apnea (OSA) and stroke is complex. OSA has been associated with several physiologic changes, including BP, cardiac structure, and atrial fibrillation, all of which may contribute to an increased risk of stroke. Several prospective studies have found sleep-disordered breathing to be an independent risk factor for stroke. The odds ratio for incident stroke was 2.24 in a meta-analysis,26 and risk seems to correlate with severity of OSA.27 OSA may also develop as a result of stroke, and poststroke OSA may increase morbidity and mortality after a stroke.26,28,29 Complicating the relationship between OSA and stroke further are the shared risk factors between these conditions, eg, obesity and hypertension. Further studies are needed to further unravel these associations. Randomized clinical trials using continuous positive pressure ventilation among stroke survivors are especially needed to evaluate this treatment option to lower recurrent stroke rates and reduce mortality.30 For now, screening for OSA among stroke patients and its treatment once diagnosed seem appropriate.
Insulin Resistance, Metabolic Syndrome, and Homocysteine
In addition to hypertension, diabetes mellitus, and dyslipidemia, other atherosclerotic risk factors have been evaluated as potential targets for intervention. Insulin resistance may be a risk factor for stroke. Metabolic syndrome, a condition related to insulin resistance, is defined as three or more of the following factors: elevated triglyceride level, low HDL-cholesterol (HDL-C) level, elevated fasting glucose level, high BP, and high waist circumference or abdominal obesity. Metabolic syndrome appears to be a risk factor for stroke separate from its component parts. Hyperhomocysteinemia has also been consistently associated with atherosclerotic disease. Despite epidemiologic associations between these conditions and incident stroke, currently no compelling clinical trial data show that treatment of these conditions lowers recurrent stroke risk. Despite the lack of benefit in clinical trials, it is reasonable to treat hyperhomocysteinemia with vitamin B6, vitamin B12, and folic acid replacement in patients with atherosclerotic ischemic stroke.
Despite strong evidence to support these medical strategies for recurrent stroke risk reduction, medication adherence is a significant problem and has implications for long-term outcomes. Adherence to antihypertensive medications after stroke is close to 90% at 1 year31 but declines to approximately 75% by 2 years.32 In studies of statin use after stroke, 76.3% of patients remained on statin therapy at 1 year, and the number decreased further to 56.1% at 2 years.31,32 Continuation of all discharge secondary stroke prevention medications was only 66% at 1 year.31 Adherence has been associated with lower risk of vascular events.33 Effective means of maintaining medication adherence can be elusive, and few randomized trials of interventions to improve compliance are available. Patients should receive education on their medications and have adequate follow-up.
BEHAVIORAL RISK FACTORS
Several behavioral factors, including smoking, physical inactivity, diet, obesity, and alcohol use, affect stroke risk. In addition, some interventional studies support lifestyle modification strategies in primary prevention, although limited studies in secondary stroke prevention have been done.
Cigarette smoking is a well-established risk factor for stroke and has a strong association with atherothrombotic stroke. In the Framingham study, investigators found the relative risk of stroke in smokers, after adjusting for age and hypertension, was 2.3 in men and 3.1 in women. A significant dose-response relationship was found with double the risk of stroke in heavy smokers compared with light smokers. After 5 years of smoking cessation, stroke risk returned to nonsmoker levels.34
Because of the dose-response relationship between smoking and stroke risk, it is plausible that secondhand smoke, especially at high levels of exposure, also increases stroke risk. One study of Chinese women who never smoked found that those exposed to more than 20 cigarettes a day of passive smoke had nearly a twofold increased risk of ischemic stroke compared with women not exposed to passive smoke.35 Smoking cessation should be recommended for secondary stroke prevention, and environmental smoke should also be avoided. Physician counseling alone has a modest but definite benefit; it has been associated with higher quit rates (up to 7.5%) compared with spontaneous quit rates (3% to 5%). Group counseling and support groups are associated with higher quit rates of up to 20%.36 Beyond counseling, first-line medications for smoking cessation include nicotine replacement, such as gum or patch. Other treatments include bupropion and varenicline; both appear efficacious. Combination therapy with nicotine replacement and bupropion is US Food and Drug Administration–approved and may be superior to either alone.36
Many studies have evaluated the effects of different dietary components on cardiovascular outcomes. In a Cochrane meta-analysis of randomized trials of reduced dietary fat, a 14% reduction in cardiovascular events was noted in patients who adhered to a reduced-fat or modified-fat diet. Subgroup analysis suggested that modifying fat (reducing saturated fat) rather than reducing total fat contributed to this risk reduction.37
Another dietary component that has been attributed to increased stroke risk is sodium, because of its association with hypertension. Meta-analyses of sodium reduction trials have demonstrated that decreased sodium intake to 1800 mg per day was associated with a 2–mm Hg reduction in systolic BP and 1–mm Hg reduction in diastolic BP in nonhypertensive patients and a 5–mm Hg (systolic BP) and 2.7–mm Hg (diastolic BP) drop in hypertensive patients. These small changes in BP can still translate into a significant public health impact. Therefore, the AHA recommends less than 1500 mg per day of dietary sodium.38
Other dietary studies have examined several components of diet together. The Dietary Approaches to Stop Hypertension (DASH) diet encourages high fruit and vegetable, low-fat dairy, low animal protein, and high plant protein intake.39 In one study, higher DASH adherence was associated with lower risk of stroke; after adjusting for confounders, the relative risk (RR) for stroke was 0.82 comparing the top versus bottom quintiles of the DASH score.
Several studies have suggested the Mediterranean diet as beneficial in cardiovascular health. The Mediterranean diet encourages fresh fruits and vegetables, fish, legumes, white meat instead of red meat, and wine. A study of more than 7000 subjects compared the Mediterranean diet with a low-fat diet in cardiovascular outcomes.40 This study randomized patients with diabetes mellitus or multiple other risk factors to the Mediterranean diet supplemented with either nuts or olive oil, or a low-fat diet. This trial was stopped after an interim analysis because a significant difference occurred in the composite outcome of stroke, myocardial infarction, and cardiovascular death with the Mediterranean diet (HR 0.70) and for the secondary end point of stroke alone (HR 0.61) compared with controls. Overlap occurred between the DASH and Mediterranean diets (Table 2-3). Despite no studies of these diets in secondary stroke prevention, they may be considered in stroke patients.
Table 2-3 Comparison...Image Tools
Several studies have been done on alcohol consumption and stroke risk. One case-control study of an older, multiethnic population suggested that moderate alcohol consumption (up to two drinks per day) was associated with lower stroke risk. An increased risk was found in the group consuming more than seven drinks per day.41 A meta-analysis of observational studies of alcohol and stroke risk also found a J-shaped curve for ischemic stroke risk with the lowest relative risk for ischemic stroke in the group drinking less than one drink (RR 0.8) or one to two drinks per day (RR 0.7) compared with abstainers.42 Because of concerns about abuse and alcoholism, patients who do not drink alcohol should not be encouraged to start and those who drink excessively should be advised to moderate their intake.
A meta-analysis including more than 2 million subjects assessed the relationship between normal weight (body mass index [BMI] <25 kg/m2), overweight status (BMI 25 kg/m2 to 29.9 kg/m2), and obesity (BMI >30 kg/m2) and the risk of stroke. It concluded that the RR for ischemic stroke was 1.64 in obese versus healthy subjects and 1.22 in overweight versus healthy subjects.43
While BMI is the most commonly used assessment of obesity, other measures of obesity may be relevant in evaluating stroke risk. Studies of waist-hip ratio, waist-height ratio, and waist circumference suggest abdominal obesity is a risk factor for stroke, and these measurements may be better than BMI for stroke risk assessment.44
Weight loss can lead to improvements in BP and metabolic profile. However, no completed randomized trials have evaluated weight loss in preventing vascular events or in secondary stroke prevention, although maintenance of BMI within 18.5 kg/m2 to 25 kg/m2 is reasonable.
In the Northern Manhattan Study, moderate to heavy-intensity physical activity versus inactivity was protective for ischemic stroke in men (adjusted HR 0.65 [0.44 to 0.98]). A protective effect of light activity was not observed in women.45 Other studies have found that light activity (eg, walking) reduced cardiovascular events, including stroke, in women.46 The AHA recommends 30 minutes of moderate activity 5 days a week or 25 minutes of vigorous activity 3 days a week.
Taken together, adherence to a healthy lifestyle could have a significant effect on global stroke incidence. Data from the Health Professionals Follow-up Study and the Nurses’ Health Study assessed a low-risk lifestyle defined as not smoking, BMI less than 25 kg/m2, 30 minutes or more per day of moderate activity, modest alcohol consumption (men 5 g/d to 30 g/d, women 5 g/d to 15 g/d), and healthy diet. A significant lowering of ischemic stroke risk was observed with a healthier lifestyle score; half of the strokes in this population can be attributed to unhealthy lifestyles.47 Patient education on stroke prevention should include a discussion of healthy lifestyle behaviors (Case 2-3).
A 54-year-old man who had been diagnosed with a right occipital stroke after having visual symptoms presented for outpatient follow-up. He had no prior history of hypertension, diabetes mellitus, or high cholesterol. He admitted to smoking several cigarettes a day since age 9 and consumed three to four alcoholic drinks every day. His blood pressure (BP) was 140/80 mm Hg, weight 77 kg (170 lbs), and height 1.75 m (5 ft, 9 in). He had a left upper-quadrant visual field cut; otherwise, neurologic examination was normal. His HDL-cholesterol level was 80 mg/dL and LDL-cholesterol level was 115 mg/dL. His glucose and hemoglobin A1c levels were normal. His homocysteine level was 24.8 µmol/L. He had been placed on aspirin but refused to take a statin.
Comment. This patient has behavioral risk factors of cigarette smoking and heavy alcohol use. He also has a body mass index of 25.1, placing him in the overweight category. His BP is elevated, as is his homocysteine level. An optimal secondary stroke prevention strategy for him includes several medication and behavioral modifications. Compliance with his aspirin therapy was reinforced. His BP was elevated and a low-dose diuretic was started. He was advised to quit smoking and was referred to a smoking cessation clinic. He was counseled to decrease his alcohol intake to 2 or fewer drinks per day. Given his chronic alcohol use and elevated homocysteine level, he was advised to take a daily multivitamin that included folate and B vitamins. He was willing to change his diet to low fat and low sodium. He was provided with educational materials that described a diet of fresh fruits and vegetables, lean meats, low-fat dairy products, fish, whole grains, and legumes.
Most risk factors for stroke are modifiable. Secondary stroke prevention strategies should include treatment of hypertension, diabetes mellitus, and high cholesterol with medications and lifestyle modification. Lifestyle modification after stroke includes adherence to medications, smoking cessation, limiting alcohol intake, maintaining a normal weight, adhering to a healthy diet, and engaging in regular physical activity. These interventions taken together can have a significant effect on reducing recurrent stroke risk.
* Studies suggest that 90% of strokes can be explained by modifiable risk factors, and 80% of recurrent strokes can be prevented with optimal risk factor control and/or elimination.
* Goal blood pressure (BP) lowering should strive for a 10–mm Hg and 5–mm Hg reduction in systolic BP and diastolic BP, respectively, from baseline even in nonhypertensive patients, and less than 140/90 mm Hg in hypertensive patients (less than 130/80 mm Hg in patients with diabetes mellitus and chronic kidney disease).
* The most recent American Heart Association guidelines recommend strict goals of low-density lipoprotein (LDL) cholesterol level lowering by 50% or more or an absolute LDL goal level of less than 70 mg/dL.
* While the risk of intracerebral hemorrhage may not be increased in patients without prior stroke, patients with prior lobar hemorrhage, who have higher rates of recurrent spontaneous intracerebral hemorrhage than those with deep hemorrhage, may be particularly at risk on statin therapy.
* Glycemic control should aim for hemoglobin A1c of less than 7% using diet, exercise, and medications such as oral hypoglycemic drugs and insulin.
* Despite the lack of benefit in clinical trials, it is reasonable to treat hyperhomocysteinemia (greater than 15 μmol/L), if present, with vitamin B6, vitamin B12, and folic acid replacement in patients with atherosclerotic ischemic stroke.
* Effective means of maintaining medication adherence can be elusive, and few randomized trials of interventions to improve compliance are available. Patients should receive education on their medications and have adequate follow-up.
* Cigarette smoking is a well-established risk factor for stroke and has a strong association with atherothrombotic stroke.
* Meta-analyses of sodium reduction trials have demonstrated that decreased sodium intake to 1800 mg per day was associated with a 2–mm Hg reduction in systolic BP and 1–mm Hg reduction in diastolic BP in nonhypertensive patients and a 5–mm Hg (systolic BP) and 2.7–mm Hg (diastolic BP) drop in hypertensive patients.
* Several studies have suggested the Mediterranean diet as beneficial in cardiovascular health. The Mediterranean diet encourages fresh fruits and vegetables, fish, legumes, white meat instead of red meat, and wine.
* No completed randomized trials have evaluated weight loss in preventing vascular events or in secondary stroke prevention, although maintenance of body mass index within 18.5 kg/m2 to 25 kg/m2 is reasonable.
* Adherence to a healthy lifestyle could have a significant effect on global stroke incidence.
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