Overview of secondary prevention of ischemic stroke

INTRODUCTION — The management of treatable risk factors and common mechanisms of brain ischemia is important for reducing the risk of ischemic stroke. This topic will review the risk factors for stroke, with a focus on secondary prevention in patients who have a history of transient ischemic attack or ischemic stroke, or who have an elevated risk of ischemic stroke due to the presence of coronary heart disease or diabetes.

Risk factors for hemorrhagic stroke are reviewed elsewhere. (See "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis", section on 'Risk factors' and "Aneurysmal subarachnoid hemorrhage: Epidemiology, risk factors, and pathogenesis", section on 'Risk factors'.)

The role of primary prevention for cardiovascular disease, including stroke, is discussed separately. (See "Overview of primary prevention of cardiovascular disease".)

MAJOR RISK FACTORS — Control of atherosclerotic risk factors is important for the primary and secondary prevention of stroke. Control of risk factors also reduces the risk of coronary events, a common comorbidity in patients with cerebrovascular disease. (See "Overview of primary prevention of cardiovascular disease" and "Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk".)

●Modifiable risk factors – The major modifiable risk factors for stroke are the following [1-4]:

•Hypertension (see 'Hypertension' below)

•Dyslipidemia (see 'Dyslipidemia' below)

•Diabetes mellitus (see 'Diabetes mellitus' below)

•Smoking (see 'Smoking cessation' below)

•Physical inactivity (see 'Physical activity and exercise' below)

●Unmodifiable risk factors – Important but unmodifiable risk factors for stroke include the following [3,5-8]:

•Older age, particularly age >80 years [3]

•Race and ethnicity, with risk higher for Black than for White patients [8]

•Sex, with risk higher at most ages for men compared with women, except for ages 35 to 44 years and >85 years, where women have a similar or higher risk than men [9,10]

•Family history and genetic disorders, with a higher risk for monozygotic twins and those with genetic disorders (see "Pathophysiology of ischemic stroke", section on 'Monogenic disorders') such as sickle cell disease or cerebral autosomal dominant arteriopathy with subcortical infarctions and leukoencephalopathy [5-7]

●Stroke risk assessment – The risk of stroke is particularly increased in patients with two or more risk factors, as suggested by calculators for female (calculator 1) and male (calculator 2) patients, derived from the Framingham Study [11]. These risk factor assessment tools incorporate atrial fibrillation, a common cause of ischemic stroke, and the presence of coronary heart disease and other types of cardiovascular disease (table 1), which are markers of increased risk for subsequent cardiovascular and cerebrovascular events.

When all of these risk factors and stroke mechanisms are considered together, they account for 60 to 80 percent of the population-attributable risk of ischemic stroke [2].

●Treatment – Most patients with an ischemic stroke or transient ischemic attack should be treated with all available risk reduction strategies, including blood pressure reduction, low-density lipoprotein cholesterol lowering therapy, antithrombotic therapy, and lifestyle modification [12]; select patients with symptomatic carotid disease may benefit from revascularization. By some estimates, treatment of all major stroke risk factors, compared with no treatment, would reduce the risk of recurrent stroke by 80 percent [13].

Guidelines from the American Heart Association and American Stroke Association advocate a multidisciplinary, team-based approach to effectively manage these risk factors, with treatment tailored to the individual patient [12]. To promote health equity and reduce healthcare disparities, the approach should evaluate and address social determinants of health, including literacy level, language proficiency, medication affordability, food insecurity, housing needs, and transportation obstacles.

ANTITHROMBOTIC THERAPY — Antithrombotic therapy with antiplatelet or anticoagulant agents is an important part of secondary stroke prevention for patients with ischemic stroke or transient ischemic attack (TIA) (algorithm 1) [12].

●Noncardioembolic ischemic stroke or TIA – Antiplatelet agents are effective for the prevention of recurrent ischemic stroke in patients with a history of noncardioembolic ischemic stroke or TIA of atherothrombotic, lacunar (small vessel occlusive), or cryptogenic type. Aspirin (50 to 100 mg daily), clopidogrel (75 mg daily), and the combination of aspirin-extended-release dipyridamole (25 mg/200 mg twice a day) are all acceptable long-term options for preventing recurrent noncardioembolic ischemic stroke. (See "Long-term antithrombotic therapy for the secondary prevention of ischemic stroke".)

●Role of DAPT – Early, short-term dual antiplatelet therapy (DAPT), typically with aspirin plus clopidogrel, is beneficial for select patients with high-risk TIA or minor ischemic stroke and may be beneficial for patients with recently symptomatic intracranial large artery atherosclerosis, as outlined in the algorithms (algorithm 2 and algorithm 3). (See "Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack", section on 'Efficacy of DAPT'.)

●Dissection – For patients with ischemic neurologic symptoms caused by cervical artery dissection, antithrombotic therapy is indicated, but the choice between antiplatelet and anticoagulant therapy remains somewhat controversial. (See "Cerebral and cervical artery dissection: Treatment and prognosis", section on 'Choosing between antiplatelet and anticoagulation therapy'.)

●Cardiogenic embolism – Long-term anticoagulation with warfarin or a direct oral anticoagulant (dabigatran, apixaban, rivaroxaban, or edoxaban) is recommended as prevention for patients with chronic nonvalvular atrial fibrillation who have had an ischemic stroke or TIA. While the use of anticoagulant therapy is also associated with an increased risk of major bleeding, the benefit outweighs the risk in most patients. These issues are discussed elsewhere. (See "Atrial fibrillation in adults: Selection of candidates for anticoagulation" and "Atrial fibrillation in adults: Use of oral anticoagulants".)

In addition to atrial fibrillation, other potential cardiac sources of embolism for which anticoagulation therapy may be indicated for select patients include the following (see "Overview of secondary prevention for specific causes of ischemic stroke and transient ischemic attack", section on 'Cardiogenic embolism'):

•Mechanical heart valves and a subpopulation of high-risk patients with bioprosthetic valves (see "Antithrombotic therapy for mechanical heart valves")

•Left ventricular thrombus (see "Antithrombotic therapy in patients with heart failure", section on 'Left ventricular thrombus' and "Left ventricular thrombus after acute myocardial infarction", section on 'Prevention of embolic events')

•Dilated cardiomyopathy (see "Antithrombotic therapy in patients with heart failure")

•Rheumatic valve disease (see "Management and prevention of rheumatic heart disease", section on 'Management of carditis in acute rheumatic fever')

•Recent myocardial infarction in high-risk patients (see "Anticoagulant therapy in non-ST elevation acute coronary syndromes" and "Acute ST-elevation myocardial infarction: Management of anticoagulation" and "Acute coronary syndrome: Oral anticoagulation in medically treated patients")

HYPERTENSION

Hypertension and stroke risk — Hypertension, which promotes the formation of atherosclerotic lesions, is the single most important treatable risk factor for stroke [4]. Epidemiologic studies of treated and untreated patients reveal that there is a gradually increasing incidence of cardiovascular mortality as the blood pressure rises above 110/75 mmHg (figure 1A-B) [14,15]. Hypertension is associated with an increased likelihood of subclinical or silent stroke, which in turn has been linked with an elevated risk of vascular dementia and recurrent stroke [16-18]. In addition to hypertension defined by systolic and diastolic blood pressure, stroke risk may be associated with other blood pressure variables including mean blood pressure, pulse pressure, blood pressure variability, blood pressure instability, and nocturnal nondipping [19,20].

However, these observations alone do not prove a causal relationship, since increasing blood pressure could be a marker for other risk factors such as increasing body weight, dyslipidemia, glucose intolerance, and the metabolic syndrome. The best evidence supporting a causal role of increasing blood pressure in cardiovascular complications comes from studies that show outcome reduction in the risk of recurrent stroke with antihypertensive therapy. This evidence is reviewed elsewhere. (See "Antihypertensive therapy for secondary stroke prevention".)

Antihypertensive therapy — Treatment of hypertension is important for both prevention of recurrent stroke and prevention of other vascular events. We recommend antihypertensive therapy for patients with any type of ischemic stroke or transient ischemic attack (TIA) who have an established blood pressure that is above goal, as outlined in the table (table 2) for higher-risk populations, which includes all patients with ischemic stroke or TIA. Similarly, the 2021 American Heart Association/American Stroke Association (AHA/ASA) guidelines recommend an office measurement blood pressure goal of <130/80 mmHg for most patients to reduce the risk of recurrent stroke and vascular events [12].

Lifestyle modifications that have been associated with blood pressure reductions should be included as part of the antihypertensive regimen [12]. Important modifications include weight loss; salt restriction; a diet rich in fruits, vegetables, and low-fat dairy products; regular aerobic physical activity; and limited alcohol consumption. (See 'Lifestyle modification' below.)

The role of antihypertensive therapy in secondary stroke prevention is discussed in detail separately. (See "Antihypertensive therapy for secondary stroke prevention".)

The appropriate time to initiate or reinstate antihypertensive drug therapy in hypertensive patients who have had a stroke or TIA can vary according to several factors, including stroke mechanism (eg, whether the stroke was ischemic or hemorrhagic), neurologic stability, and comorbid medical problems. This issue is discussed in detail separately. (See "Antihypertensive therapy for secondary stroke prevention", section on 'When to initiate (or reinstate) antihypertensive therapy'.)

In patients with acute ischemic stroke (ie, the first hours and days after onset), it is important not to lower the blood pressure too quickly. The management of blood pressure in the setting of acute stroke is reviewed elsewhere. (See "Initial assessment and management of acute stroke", section on 'Blood pressure management'.)

DYSLIPIDEMIA

Lipids and stroke risk — Hyperlipidemia is a major risk factor for atherosclerotic cardiovascular disease (see "Overview of established risk factors for cardiovascular disease"). However, the relationship between the serum cholesterol concentration and stroke incidence appears to be more complex, in that cholesterol is an established risk factor for atherosclerosis, but the degree of risk varies for stroke subtypes [21].

Studies that have examined ischemic and hemorrhagic stroke types have generally found a weak but positive association of elevated cholesterol with ischemic stroke, particularly for large artery atherosclerotic and lacunar stroke subtypes, and an inverse association of cholesterol levels with hemorrhagic stroke [22]. Most [23-26] but not all [27,28] large observational studies have found that elevated cholesterol and low-density lipoprotein levels are associated with an increased risk of ischemic stroke [21]. The strong association between cholesterol and carotid atherosclerosis also supports the role of cholesterol in the pathogenesis of large artery ischemic stroke [29].

The relationship of cholesterol levels and statin therapy with intracerebral hemorrhage is discussed in greater detail separately. (See "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis", section on 'Other risk factors'.)

LDL-C lowering therapy — Statins, ezetimibe, and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have been shown to reduce the risk of major adverse cardiovascular events. Among these three, statins are the best studied and have proven efficacy for reducing the risk of recurrent ischemic stroke. The available evidence suggests that lipid lowering by other means (eg, fibrates, bile acid sequestrants, niacin, diet) has no significant impact on the secondary prevention of stroke or prevention of other cardiovascular events. (See "Low-density lipoprotein cholesterol lowering with drugs other than statins and PCSK9 inhibitors" and "Lipid management with diet or dietary supplements" and "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease".)

Therefore, it seems plausible that the protective effects of statins are not mediated by cholesterol lowering alone [30], but by pleiotropic (eg, anti-atherothrombotic, anti-inflammatory) properties [31,32]. (See "Mechanisms of benefit of lipid-lowering drugs in patients with coronary heart disease".)

Even patients with "average" serum cholesterol concentrations appear to benefit from statin therapy in terms of stroke reduction. This was demonstrated in the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial [33], in which the mean baseline low-density lipoprotein cholesterol (LDL-C) level was 133 mg/dL (3.4 mmol/L), and in the Heart Protection Study trial [34], in which the mean baseline LDL-C level was 131 mg/dL (3.4 mmol/L).

●Approach to LDL-C lowering

•High-risk patients – For high-risk patients (eg, those with atherosclerotic cardiovascular disease, including with transient ischemic attack [TIA] or ischemic stroke) who are able to tolerate statins, we begin LDL-C lowering with high-intensity statin therapy, independent of the baseline LDL-C, to reduce the risk of stroke and cardiovascular events [12,35]. We generally treat with atorvastatin 80 mg/day, since this was the agent and dose used in the SPARCL trial that showed a benefit for secondary ischemic stroke prevention. (See "Statins: Actions, side effects, and administration".)

While the entirety of the evidence does not clearly identify a threshold below which further LDL-C lowering leads to little benefit, we believe that efforts to lower the LDL-C to <70 mg/dL (1.8 mmol/L) should be made in most patients with cardiovascular disease. A similar approach is recommended for patients with other types of cardiovascular disease at high risk for a recurrent or initial cardiovascular event (table 1). (See "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease".)

•Statin intolerance – For patients who are intolerant of high-intensity statin therapy, the maximally tolerated dose of a statin can be used; alternatives are moderate-intensity statin therapy (eg, atorvastatin 10 to 20 mg daily, rosuvastatin 5 to 10 mg daily, simvastatin 20 to 40 mg daily, pravastatin 40 to 80 mg daily, lovastatin 40 mg daily, or fluvastatin 40 mg daily in two divided doses) or low-intensity statin therapy (eg, pravastatin 10 to 20 mg daily or lovastatin 20 mg daily). For patients whose LDL-C level remains ≥70 mg/dL (≥1.8 mmol/L) despite maximally tolerated statin therapy, adding ezetimibe or a PCSK9 inhibitor is reasonable [35].

For patients who are unable to tolerate any statin regimen, we treat with ezetimibe and consider adding a PCSK9 inhibitor if LDL-C remains ≥70 mg/dL (≥1.8 mmol/L) [35]. (See "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease" and "Low-density lipoprotein cholesterol lowering with drugs other than statins and PCSK9 inhibitors".)

•Monitoring – Fasting lipid levels should be measured 4 to 12 weeks after starting LDL-C lowering therapy and then every 3 to 12 months thereafter.

●Benefit of LDL-C lowering – Data from randomized controlled trials has established that LDL-C lowering, primarily with statins, reduces the risk of major cardiovascular events, including both initial and recurrent stroke, regardless of age, gender, or pretreatment blood lipid concentration. A systematic review of the literature up to July 2017 identified nine randomized controlled trials assessing statins in over 10,000 patients with ischemic stroke or TIA [36]. A network meta-analysis of these data showed that the risk of ischemic stroke was reduced with statin treatment versus no statin (7.6 versus 9.3 percent, OR 0.81, 95% CI 0.70-0.93; absolute risk reduction [ARR] 1.6 percent, 95% CI 0.6-2.6), as was the risk of cardiovascular events (22.8 versus 28 percent, OR 0.75, 95% CI 0.69-0.83; ARR 5.4 percent, 95% CI 3.6-6.8). The greatest benefit was observed with high-dose statin treatment (eg, atorvastatin 80 mg daily or simvastatin 40 mg daily).

The 2006 SPARCL trial was the first to show that statin treatment decreased the risk of recurrent ischemic stroke among patients with a history of stroke or TIA [33]. The trial enrolled 4731 ambulatory patients with no known coronary heart disease (CHD) who had a stroke or TIA within one to six months; patients were randomly assigned to treatment with either atorvastatin 80 mg/day or placebo. Patients were required to have a baseline LDL-C of 100 to 190 mg/dL (2.6 to 4.9 mmol/L). The mean baseline LDL-C level was 133 mg/dL (3.4 mmol/L). Patients with hemorrhagic stroke were included if they were deemed to be at risk for ischemic stroke or CHD. Patients were excluded if they had atrial fibrillation, other cardiac sources of embolism, or subarachnoid hemorrhage.

At a median follow-up of 4.9 years, atorvastatin led to a mean reduction in LDL-C of 56 mg/dL (1.4 mmol/L) and reduced fatal or nonfatal stroke (11.2 versus 13.1 percent, adjusted hazard ratio [HR] 0.84, 95% CI 0.71-0.99, ARR at five years 2.2 percent, 95% CI 0.2-4.2 percent) [33]. Atorvastatin also led to a reduction in all coronary events (5.2 versus 8.6 percent, HR 0.58, 95% CI 0.46-0.73) and all cardiovascular events (22.4 versus 29 percent, HR 0.74, 95% CI 0.66-0.83). There was no difference between the atorvastatin and placebo groups in overall mortality.

●The lower the LDL-C, the greater the benefit – In the Treat Stroke to Target (TST) trial, patients with a recent ischemic stroke or TIA were randomly assigned to a lower target LDL-C level of <70 mg/dL (1.8 mmol/L) or to a higher target LDL-C level of 90 to 110 mg/dL (2.3 to 2.8 mmol/L) [37]. The mean LDL-C level at baseline was 135 mg/dL (3.5 mmol/L). The LDL-C level was lowered by adjustment of the statin dose in most cases, with addition of ezetimibe in approximately 34 percent of patients in the lower-target group. The trial was stopped early due to lack of funding, with data for 2860 patients who were followed for a median 3.5 years. The mean achieved LDL-C level in the lower-target group was 65 mg/dL (1.7 mmol/L) and in the higher-target group was 96 mg/dL (2.5 mmol/L). The composite primary end point of major cardiovascular events (ie, ischemic stroke, myocardial infarction, new symptoms leading to urgent coronary or carotid revascularization, or cardiovascular death) was reduced in the lower-target LDL-C group compared with the higher-target group (8.5 versus 10.9 percent, adjusted HR 0.78, 95% CI 0.61-0.98, ARR 2.4 percent).

A 2022 meta-analysis identified 11 randomized trials (including the TST trial) that enrolled over 20,000 patients with stroke and compared more intensive versus less intensive LDL-C lowering statin-based therapies [38]. More intensive LDL-C lowering led to a reduced risk of recurrent stroke compared with less intensive LDL-C lowering (8.1 versus 9.3 percent; RR 0.88, 95% CI 0.80-0.96; number needed to treat, 90) and to a lower risk of major cardiovascular events (13.9 versus 16.7 percent; RR 0.83, 95% CI 0.78-0.89). The benefit of LDL-C lowering was similar among different LDL-C lowering strategies (statins versus no statins, more statins or ezetimibe versus less statins or ezetimibe, and PCSK9 inhibitors plus statins versus placebo plus statins).

●The benefit of more intensive LDL-C lowering may apply only to patients with atherosclerosis – In the 2022 meta-analysis, more intensive LDL-C versus less intensive LDL-C-lowering led to a reduced risk of recurrent stroke in trials with all patients having evidence of atherosclerosis (RR 0.79, 95% CI 0.69-0.91) but not in trials with most patients not having evidence of atherosclerosis (RR 0.95, 95% CI 0.85-1.07) [38].

●LDL-C lowering and hemorrhagic stroke – The 2022 meta-analysis found that more intensive versus less intensive LDL-C lowering led to a small increased risk of hemorrhagic stroke when patients with all types of stroke at entry were included (1.3 versus 0.9 percent; RR 1.46, 95% CI 1.11-1.91; number needed to harm 242) [38]. However, sensitivity tests restricting analysis to only patients with ischemic stroke as an entry event found that more intensive versus less intensive LDL-C lowering led to a nonsignificant increased risk of hemorrhagic stroke while maintaining a significant reduction in the risk of recurrent ischemic stroke. The relationship between statin therapy and hemorrhagic stroke is reviewed in greater detail separately. (See "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis", section on 'Other risk factors' and "Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis", section on 'Management of statins'.)

Lipoprotein(a) — Lipoprotein(a), also referred to as Lp(a), is a modest independent risk factor for atherosclerotic cardiovascular disease and cerebrovascular events. Note that LDL-C measurements include the cholesterol component of Lp(a). In an occasional patient, a substantial fraction of LDL-C may be carried in Lp(a) particles rather than in normal LDL. In these cases, treatment with a statin may lead to a lesser reduction in LDL-C than expected, as statins do not effectively reduce Lp(a) levels. However, there is only limited evidence that Lp(a) lowering reduces atherosclerotic cardiovascular disease risk, as discussed separately. (See "Lipoprotein(a)".)

Hypertriglyceridemia — Some [39-41], but not all [27,42,43] observational studies suggested that hypertriglyceridemia is a risk factor for ischemic stroke. Management involves lifestyle modification (eg, weight loss, smoking cessation, aerobic exercise, healthy diet, limited alcohol consumption), treatment of hypertension, glycemic control for patients with diabetes, and LDL-C lowering therapy (most LDL-C lowering medications also reduce triglyceride levels). (See "Hypertriglyceridemia in adults: Management", section on 'General measures'.)

For patients with high atherosclerotic cardiovascular disease risk (including those with atherosclerotic ischemic stroke or TIA) whose triglyceride levels remain >150 mg/dL after lifestyle interventions and optimal LDL-C lowering therapy, it is reasonable to treat with high-dose marine omega-3 fatty acid using icosapent ethyl, 2 g twice daily. This in general agreement with the AHA/ASA guideline recommendation for the treatment of hypertriglyceridemia [12].

The evidence regarding the efficacy and safety of omega-3 fatty acid therapy for cardiovascular outcomes is reviewed separately. (See "Hypertriglyceridemia in adults: Management", section on 'Marine omega-3 fatty acid effects'.)

DIABETES MELLITUS

Diabetes and stroke risk — Patients with diabetes mellitus have approximately twice the risk of ischemic stroke compared with those without diabetes [44-48]. In addition, the risk of stroke associated with diabetes is higher in women than in men [48]. Dyslipidemia, endothelial dysfunction, and platelet and coagulation abnormalities are among the risk factors that may promote the development of carotid atherosclerosis in diabetics. (See "Prevalence of and risk factors for coronary heart disease in patients with diabetes mellitus".)

However, there is no proven benefit of intensive glucose-lowering therapy for reducing macrovascular outcomes (eg, stroke and death) in patients with type 2 diabetes [12].

Impaired glucose tolerance may be a risk factor for ischemic stroke in patients with a history of transient ischemic attack (TIA) or minor ischemic stroke [49]. It may also be a risk factor for carotid atherosclerosis, as illustrated by studies in nondiabetics showing that elevated serum hemoglobin A1C is associated with an increased risk of carotid plaque development [50,51].

Glycemic control — For most patients with diabetes, a reasonable goal of therapy is a glycated hemoglobin (A1C) value of ≤7 percent [12]. Diet, exercise, oral hypoglycemic drugs, and insulin are proven methods to achieve glycemic control.

This recommendation is based on evidence that tight glucose control reduces microvascular complications. The available evidence has not demonstrated a consistent beneficial effect of intensive glucose-lowering therapy for macrovascular outcomes (eg, stroke and death) in patients with type 2 diabetes. Nevertheless, for patients with ischemic stroke or TIA, the 2021 American Heart Association/American Stroke Association (AHA/ASA) guidelines recommend screening for diabetes mellitus using A1C [12].

These issues are discussed in detail elsewhere:

●(See "Glycemic control and vascular complications in type 1 diabetes mellitus".)

●(See "Glycemic control and vascular complications in type 2 diabetes mellitus".)

●(See "Initial management of hyperglycemia in adults with type 2 diabetes mellitus".)

Metabolic syndrome — The metabolic syndrome, defined as the presence of three or more components that include high fasting glucose, hypertension, low serum high-density lipoprotein, elevated serum triglycerides, and abdominal obesity, is considered a prediabetic condition linked to increased risk of cardiovascular disease. (See "Metabolic syndrome (insulin resistance syndrome or syndrome X)".)

However, it is unclear if the metabolic syndrome is an independent risk factor for ischemic stroke beyond the sum of its individual components, and the available evidence is inconsistent. (See "Metabolic syndrome (insulin resistance syndrome or syndrome X)", section on 'A critical look at the metabolic syndrome'.)

Furthermore, the utility of the metabolic syndrome to predict stroke risk does not appear to improve upon more conventional assessments such as the Framingham Risk Score [52]. (See "Cardiovascular disease risk assessment for primary prevention: Risk calculators".)

Although the metabolic syndrome is not clearly established as an independent stroke risk factor, it is important to treat the underlying causes such as obesity and physical inactivity. Management should include counseling for lifestyle modification (diet, exercise, and weight loss) and appropriate treatment for individual components of the metabolic syndrome, particularly hypertension and dyslipidemia, which are also stroke risk factors. (See 'Hypertension' above and 'Dyslipidemia' above and "Metabolic syndrome (insulin resistance syndrome or syndrome X)", section on 'Therapy'.)

Treatment of insulin resistance — Pioglitazone treatment appears to reduce the risk of recurrent stroke and myocardial infarction in nondiabetic patients who have insulin resistance, though this benefit is partially offset by an increased risk of adverse effects such as bone fracture. These points are illustrated by the findings of the multicenter Insulin Resistance Intervention After Stroke (IRIS) trial, which randomly assigned over 3800 subjects with recent ischemic stroke or TIA and insulin resistance to treatment with pioglitazone (target dose 45 mg daily) or placebo [53]. The trial defined insulin resistance as a value of >3 on the homeostasis model assessment of insulin resistance (HOMA-IR) index, calculated as the level of fasting glucose (measured in mmol/L) times the level of fasting insulin (measured in microU/mL) divided by 22.5. Patients with diabetes, heart failure, or active liver disease were excluded.

After 4.8 years, the composite outcome of stroke or myocardial infarction in IRIS was significantly reduced in the pioglitazone group compared with the placebo group (9 versus 11.8 percent, hazard ratio [HR] 0.76, 95% CI 0.62-0.93); the absolute risk reduction with pioglitazone for the composite outcome was 2.8 percent [53]. Several adverse effects were significantly more common with pioglitazone compared with placebo, including bone fracture requiring surgery or hospitalization (5.1 versus 3.2 percent), edema (36 versus 25 percent), and weight gain exceeding 4.5 kg (52 versus 34 percent). There was no difference between groups in the incidence of heart failure (the pioglitazone dose was adjusted for symptoms such as new or worsening edema, shortness of breath, or excessive weight gain during the trial). However, there is good evidence from other studies that thiazolidinediones increase the risk of heart failure. (See "Thiazolidinediones in the treatment of type 2 diabetes mellitus", section on 'Fluid retention/heart failure'.)

Based upon the results of the IRIS trial [53], the number needed to treat (NNT) with pioglitazone to prevent one patient from developing stroke or myocardial infarction is 36, while the number needed to harm (NNH) to cause one patient to develop bone fracture requiring hospitalization is 53.

Given the benefit of pioglitazone in this setting, it is an option for carefully selected nondiabetic patients with insulin resistance who are willing to accept the risk of adverse events such as bone fracture and heart failure. Since there is no validated test for measuring insulin resistance in clinical practice, clinicians should emulate the IRIS methodology as closely as possible by calculating the HOMA-IR index using laboratories that adapt the IRIS trial assays for plasma insulin level.

LIFESTYLE MODIFICATION — A number of behavioral and lifestyle modifications may be beneficial for reducing the risk of ischemic stroke and cardiovascular disease [12,54]. These include smoking cessation, regular aerobic physical activity, salt restriction, a Mediterranean diet, limited alcohol consumption, and weight control. Our recommendations are in general agreement with the national guidelines [12].

Smoking cessation — All patients who are recent or current tobacco smokers should be counseled routinely to quit smoking. (See "Overview of smoking cessation management in adults".)

Cigarette smoking is associated with an increased risk for all stroke subtypes and has a strong, dose-response relationship for both ischemic stroke and subarachnoid hemorrhage [55-61]. In the Nurses' Health Study, smokers had a relative risk of stroke of 2.58 compared with never smokers [56]. Evaluation of former smokers found that the excess risk disappeared within two to four years after the cessation of smoking. In the Framingham Heart Study, the odds ratio for moderate carotid stenosis was 1.08 for each five pack-years of smoking [58].

Among 10,938 normotensive subjects in a prospective Swedish cohort study, approximately 39 percent of strokes were attributable to smoking [59].

There are no randomized controlled trials of smoking cessation compared with no intervention for stroke prevention. However, observational studies have shown that the elevated risk of stroke due to smoking declines after quitting and is eliminated by five years later [56,60,62]. Therefore, American Heart Association/American Stroke Association (AHA/ASA) guidelines recommend smoking cessation for patients with stroke or transient ischemic attack (TIA) who smoke tobacco, counseling with or without pharmacologic therapy to assist in quitting, and avoidance of environmental tobacco smoke [12]. (See "Overview of smoking cessation management in adults".)

Physical activity and exercise — Patients with ischemic stroke or TIA who are capable of regular exercise should engage in moderate-intensity physical exercise performed for a minimum of 10 minutes four times a week or vigorous-intensity exercise performed for a minimum of 20 minutes twice a week. Moderate-intensity exercise is defined as activity sufficient to break a sweat or noticeably raise the heart rate (eg, walking briskly, using an exercise bicycle) [12]. (See "The benefits and risks of aerobic exercise", section on 'Benefits of exercise'.)

Increasing evidence suggests that low physical activity and prolonged sitting increases the risk of cardiovascular disease, including stroke [4,63,64]. Additional support that physical inactivity is a risk factor for stroke comes from studies showing the benefit of increased physical activity and exercise for reducing the risk of cardiovascular events [65].

Diet — Emerging evidence suggests that dietary interventions, and in particular a Mediterranean diet (see "Healthy diet in adults", section on 'Mediterranean diet'), improves outcomes in patients with established cardiovascular disease [66]. Until further studies evaluate the magnitude of benefit of a Mediterranean diet, it is reasonable to advise all patients to adhere to its components.

●For patients with a history of stroke or TIA, we encourage patients to follow a Mediterranean-type diet that emphasizes the intake of vegetables, fruits, whole grains, low-fat dairy products, poultry, fish, legumes, nontropical vegetable oils, and nuts. It limits the intake of sweets, sugar-sweetened beverages, and red meats. Calories from saturated fat should be limited to 5 to 6 percent and calories from trans-fat should be reduced.

●For patients who would benefit from blood pressure lowering, a reduction in sodium intake of at least 1 g/day (or daily sodium intake of <2.5 g per day) is also suggested. (See "Salt intake and hypertension".)

These recommendations are consistent with the 2021 AHA/ASA guideline for stroke prevention in patients with stroke or TIA [12] and the 2013 AHA/American College of Cardiology (ACC) guideline on lifestyle management to reduce cardiovascular risk [67]. (See "Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk", section on 'Diet'.)

Supplementation with beta-carotene, vitamin E, and vitamin C, either alone or in combination with each other or other antioxidant vitamins does not appear to be effective in the primary or secondary prevention of cardiovascular disease. The data supporting these conclusions are reviewed elsewhere.

Alcohol and substance use — All patients with ischemic stroke or TIA who are heavy drinkers should eliminate or reduce their alcohol consumption because of the increased risk of stroke and high morbidity associated with alcoholism, despite the lack of clear evidence from clinical trials that reduction of alcohol intake decreases the risk of recurrent stroke [12]. (See "Cardiovascular benefits and risks of moderate alcohol consumption", section on 'Stroke risk' and "Screening for unhealthy use of alcohol and other drugs in primary care" and "Alcohol use disorder: Treatment overview" and "Brief intervention for unhealthy alcohol and other drug use: Efficacy, adverse effects, and administration" and "Alcohol use disorder: Psychosocial management".)

Alcohol affects the risk of stroke in different directions depending upon level of consumption, type of stroke, and possibly ethnicity. Light drinking (one to two drinks per day) is associated with a reduced risk of ischemic stroke, while heavy drinking is associated with an increased risk. (See "Cardiovascular benefits and risks of moderate alcohol consumption", section on 'Stroke risk'.)

The risk of stroke is increased with infective endocarditis related to intravenous drug use, and with the use of certain stimulants (eg, cocaine, amphetamine and its derivatives) [68,69]. The AHA/ASA guideline recommends counseling patients about these risks and offering services to manage substance use disorders [12]. (See "Substance use disorders: Clinical assessment".)

Obesity and weight reduction — Obesity is associated with an increased risk of cardiovascular disease, including ischemic stroke [12,70]. As with glycemic control, the available data do not show that weight reduction reduces the risk of recurrent stroke [12]. However, weight reduction for obese patients is potentially beneficial for improved control of other important parameters, including blood pressure, blood glucose, and serum lipid levels. Thus, the AHA/ASA guidelines for stroke prevention recommend screening all patients with stroke or TIA for obesity with measurement of body mass index, and recommend weight loss for patients who are overweight or obese [12]. Patients identified as candidates for weight loss should receive multidisciplinary team management and appropriate interventions, beginning with a combination of diet, exercise, and intensive behavioral intervention. These issues are reviewed in detail separately. (See "Obesity in adults: Overview of management".)

OTHER RISK FACTORS — In addition to the traditional stroke risk factors, myriad other risk factors and pathologic mechanisms are associated with ischemic stroke [71].

Sleep-related breathing disorders — Patients with obstructive sleep apnea appear to be at increased risk for stroke. It is unknown whether patients with central sleep apnea syndrome, including Cheyne-Stokes breathing, also have an increased risk. (See "Sleep-related breathing disorders and stroke", section on 'Sleep apnea as a risk factor for stroke'.)

Limited data suggest that the presence of sleep-related breathing disorders following a stroke may be a marker of a poorer long-term outcome. (See "Sleep-related breathing disorders and stroke", section on 'Complications'.)

Clinically significant sleep apnea is highly prevalent in patients with acute stroke. Clinical features that have been associated with an increased risk for sleep-disordered breathing in patients with stroke include obesity, systolic hypertension, nocturnal oxygen desaturations, and increased stroke severity. The diagnosis of a sleep-related breathing disorder in patients with stroke requires a high index of suspicion and formal sleep testing, since clinical features and questionnaires lack high predictive value in patients with stroke. (See "Sleep-related breathing disorders and stroke", section on 'Diagnosis'.)

Positive airway pressure therapy and behavioral modifications are the mainstays of treatment for patients diagnosed with sleep-related breathing disorders. These issues are reviewed elsewhere. (See "Sleep-related breathing disorders and stroke", section on 'Management'.)

Hypercoagulability — The approach to secondary stroke prevention for hypercoagulable states, including antiphospholipid syndrome, inherited thrombophilias, and cancer-related hypercoagulability, is reviewed separately. (See "Overview of secondary prevention for specific causes of ischemic stroke and transient ischemic attack", section on 'Hypercoagulable states'.)

Hyperhomocysteinemia — Increased serum homocysteine concentrations are associated with an increased risk of coronary and cerebrovascular disease, as discussed separately (see "Overview of homocysteine"). Elevated homocysteine appears to be associated with an increased risk of the large artery subtype of ischemic stroke, and possibly to the small artery subtype; it does not appear to be associated with cardioembolic or other stroke subtypes [72,73]. However, there is evidence from several clinical trials that treatment with homocysteine-reducing vitamins is not beneficial for secondary prevention of cardiovascular disease or stroke [12]. Thus, we do not routinely screen patients with ischemic stroke or transient ischemic attack for homocysteine levels or vitamin levels associated with homocysteine metabolism.

Head and neck radiotherapy — Head and neck radiotherapy for cancer treatment may lead to a delayed vasculopathy of large and small vessels mediated by endothelial damage, fibrosis, and accelerated atherosclerosis [74-76]. Radiotherapy-related occlusive disease is often diffuse and occurs in uncommon locations, in contrast to the typical focal lesions that develop at vessel bifurcations from atherosclerosis in the absence of radiation. Depending on the site and dose of radiation, the involved vessels may include the extracranial carotid and vertebral arteries and the intracranial circle of Willis vessels [74,77]. This process may lead to symptomatic carotid disease, moyamoya syndrome, and ischemic stroke. (See "Management of late complications of head and neck cancer and its treatment", section on 'Carotid artery injury' and "Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis", section on 'Associated conditions'.)

While data are limited, secondary prevention of stroke attributed to radiation-induced stenosis typically involves maximal medical therapy including an antiplatelet agent; revascularization with stenting may be appropriate for select patients with extracranial carotid involvement, whereas intracranial stenting is used as a last resort for intracranial large artery involvement, similar to patients with atherosclerotic intracranial large artery disease. Management should be multidisciplinary and tailored to the patient's anatomy and comorbidities. (See "Management of symptomatic carotid atherosclerotic disease" and "Intracranial large artery atherosclerosis: Treatment and prognosis".)

TREATMENT BY STROKE MECHANISM — Several important mechanisms of ischemic stroke are amenable to effective secondary prevention, including anticoagulation for atrial fibrillation, revascularization for internal carotid artery stenosis, and device closure for patent foramen ovale with paradoxical embolism. An overview of the treatment for specific causes of ischemic stroke and transient ischemic attack, including large and small artery disease, cardiogenic embolism, aortic atherosclerosis, and blood disorders, is presented separately. (See "Overview of secondary prevention for specific causes of ischemic stroke and transient ischemic attack".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Stroke in adults".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Stroke (The Basics)" and "Patient education: Medicines after an ischemic stroke (The Basics)" and "Patient education: Lowering the risk of having a stroke (The Basics)")

●Beyond the Basics topics (see "Patient education: Stroke symptoms and diagnosis (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Major risk factors – The major treatable stroke risk factors are hypertension, dyslipidemia, diabetes, smoking, and physical inactivity. Most patients with an ischemic stroke or transient ischemic attack (TIA) should be treated with all available risk reduction strategies, ideally by a multidisciplinary team, including antithrombotic therapy, blood pressure reduction, low-density lipoprotein (LDL)-lowering therapy, and lifestyle modification. (See 'Major risk factors' above.)

●Antithrombotic therapy – Nearly all patients with TIA or ischemic stroke of atherosclerotic origin should be treated with an antiplatelet agent (algorithm 2 and algorithm 3 and algorithm 1). Early short-term dual antiplatelet therapy (DAPT) is beneficial for select patients with high-risk TIA or minor ischemic stroke and may be beneficial for patients with recently symptomatic intracranial large artery atherosclerosis. The combination of aspirin-extended-release dipyridamole, clopidogrel alone, or aspirin alone are all acceptable options for long-term therapy.

Long-term oral anticoagulation should be used as prevention for patients with chronic nonvalvular atrial fibrillation who have had an ischemic stroke or TIA. (See 'Antithrombotic therapy' above.)

●Antihypertensive therapy – After the acute phase of stroke, antihypertensive therapy should be resumed in previously treated, neurologically stable patients with known hypertension for both prevention of recurrent stroke and prevention of other vascular events. In addition, antihypertensive therapy should be initiated in previously untreated, neurologically stable patients with stroke or TIA who have an established blood pressure that is above the goal blood pressure indicated in the table (table 2) for higher-risk populations, which includes all patients with ischemic stroke or TIA. (See 'Hypertension' above and "Antihypertensive therapy for secondary stroke prevention".)

●LDL-C lowering therapy – Detailed low-density lipoprotein cholesterol (LDL-C) lowering recommendations are provided separately. (See "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease".)

•High-intensity statin therapy – For patients with atherosclerotic cardiovascular disease, including TIA or ischemic stroke, we treat with high-intensity statin therapy (eg, atorvastatin 80 mg/day), independent of the baseline LDL-C, to lower the LDL-C to <70 mg/dL (1.8 mmol/L) in order to reduce the risk of stroke and cardiovascular events.

•Intolerance of high-intensity statin therapy – For patients who are intolerant of high-intensity statin therapy, the maximally tolerated dose of a statin therapy can be used.

•LDL-C above goal despite statin therapy – For patients whose LDL-C level remains ≥70 mg/dL (≥1.8 mmol/L) despite maximally tolerated statin therapy, adding ezetimibe or a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor is reasonable.

•Patients unable to tolerate statin therapy – For patients who are unable to tolerate any statin regimen, we treat with ezetimibe; we consider adding a PCSK9 inhibitor if LDL-C remains ≥70 mg/dL (≥1.8 mmol/L).

●Glycemic control – For most patients with diabetes, a reasonable goal of therapy is a glycated hemoglobin (A1C) value of ≤7 percent. Diet, exercise, oral hypoglycemic drugs, and insulin are proven methods to achieve glycemic control. (See 'Glycemic control' above.)

●Lifestyle modification – A number of behavioral and lifestyle modifications may be beneficial for reducing the risk of ischemic stroke and cardiovascular disease (see 'Lifestyle modification' above):

•Smoking cessation for tobacco smokers (see 'Smoking cessation' above)

•Eliminating or reducing alcohol consumption for heavy drinkers (see 'Alcohol and substance use' above)

•Regular exercise for patients who are capable of physical activity (see 'Physical activity and exercise' above)

•Healthy diet and salt restriction (see 'Diet' above)

•Weight reduction for obese patients (see 'Obesity and weight reduction' above)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Karen L Furie, MD, MPH, who contributed to an earlier version of this topic review.