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 https://www.uptodate.com/contents/overview-of-secondary-prevention-of-ischemic-stroke/print 12/36 7/6/23, 12:50 PM Overview of secondary prevention of ischemic stroke - UpToDate 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 https://www.uptodate.com/contents/overview-of-secondary-prevention-of-ischemic-stroke/print 13/36 7/6/23, 12:50 PM Overview of secondary prevention of ischemic stroke - UpToDate 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, salt restriction, and primary (essential) 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 "Approach to treating alcohol use disorder" and "Brief intervention for unhealthy alcohol and other drug use: Efficacy, adverse effects, and administration" and "Alcohol use disorder: Psychosocial treatment".) 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'.) https://www.uptodate.com/contents/overview-of-secondary-prevention-of-ischemic-stroke/print 14/36 7/6/23, 12:50 PM Overview of secondary prevention of ischemic stroke - UpToDate 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 "Clinical assessment of substance use disorders".) 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'.) https://www.uptodate.com/contents/overview-of-secondary-prevention-of-ischemic-stroke/print 15/36 7/6/23, 12:50 PM Overview of secondary prevention of ischemic stroke - UpToDate 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".) https://www.uptodate.com/contents/overview-of-secondary-prevention-of-ischemic-stroke/print 16/36 7/6/23, 12:50 PM Overview of secondary prevention of ischemic stroke - UpToDate 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." th th The Basics patient education pieces are written in plain language, at the 5 to 6 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 th th sophisticated, and more detailed. These articles are written at the 10 to 12 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)") https://www.uptodate.com/contents/overview-of-secondary-prevention-of-ischemic-stroke/print 17/36 7/6/23, 12:51 PM Overview of secondary prevention of ischemic stroke - UpToDate 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. https://www.uptodate.com/contents/overview-of-secondary-prevention-of-ischemic-stroke/print 18/36 7/6/23, 12:51 PM Overview of secondary prevention of ischemic stroke - UpToDate 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. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Harmsen P, Lappas G, Rosengren A, Wilhelmsen L. Long-term risk factors for stroke: twenty- eight years of follow-up of 7457 middle-aged men in G teborg, Sweden. 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Treatment of "other" causes of stroke. In: Stroke: Pathophsyiology, Diagnosis, an d Management, 4th ed, Mohr JP, Choi DW, Grotta JC, et al (Eds), Churchill Livingstone, Philad elphia 2004. p.1059. Topic 1120 Version 65.0 https://www.uptodate.com/contents/overview-of-secondary-prevention-of-ischemic-stroke/print 25/36 7/6/23, 12:51 PM Overview of secondary prevention of ischemic stroke - UpToDate GRAPHICS Known cardiovascular disease and similar risk Patients with the following are at high risk for a second (or first) cardiovascular disease event: Coronary heart disease Myocardial infarction Angina Coronary revascularization Cerebrovascular disease Stroke Transient ischemic attack Peripheral arterial disease Multiple risk factors that confer a 10-year risk of CVD >20% 2 Chronic kidney disease with estimated GFR <45 mL/min per 1.73 m * CVD: cardiovascular disease; GFR: glomerular filtration rate. Statin doses may require adjustment in patients with chronic kidney disease. Graphic 91576 Version 3.0 https://www.uptodate.com/contents/overview-of-secondary-prevention-of-ischemic-stroke/print 26/36 7/6/23, 12:51 PM Overview of secondary prevention of ischemic stroke - UpToDate Antithrombotic therapy according to cause of acute ischemic stroke This algorithm is intended to provide basic guidance regarding the immediate use of antithrombotic therapy with an acute ischemic stroke. For further details, including scoring of the NIHSS and suggested dosing regim antithrombotic agents, refer to the relevant UpToDate topic reviews. https://www.uptodate.com/contents/overview-of-secondary-prevention-of-ischemic-stroke/print 27/36 7/6/23, 12:51 PM Overview of secondary prevention of ischemic stroke - UpToDate HTN: hypertension; SBP: systolic blood pressure; DBP: diastolic blood pressure; ICA: internal carotid artery; C endarterectomy; OA: oral anticoagulation; CAS: carotid artery stenting; DAPT: dual antiplatelet therapy (eg, a clopidogrel, or aspirin and ticagrelor); NIHSS: National Institutes of Health Stroke Scale; CT: computed tomog magnetic resonance imaging. Brain and neurovascular imaging, cardiac evaluation, and (for select patients) other laboratory tests. Indications for long-term oral anticoagulation include atrial fibrillation, ventricular thrombus, mechanical h treatment of venous thromboembolism. "Large" infarcts are defined as those that involve more than one-third of the middle cerebral artery territor one-half of the posterior cerebral artery territory based upon neuroimaging with CT or MRI. Though less relia infarct size can also be defined clinically (eg, NIHSS score >15). Long-term aspirin therapy is alternative (though less effective) if OA contraindicated or refused. Direct oral anticoagulant agents have a more rapid anticoagulant effect than warfarin, a factor that may inf choice of agent and timing of OA initiation. Some experts prefer DAPT, based upon observational evidence. Long-term single-agent antiplatelet therapy for secondary stroke prevention with aspirin, clopidogrel, or as release dipyridamole. Graphic 131701 Version 2.0 https://www.uptodate.com/contents/overview-of-secondary-prevention-of-ischemic-stroke/print 28/36 7/6/23, 12:51 PM Overview of secondary prevention of ischemic stroke - UpToDate Immediate antithrombotic treatment of transient ischemic attack (TIA) This algorithm is intended to provide basic guidance regarding the use of immediate use of antithrombotic therapy for patients with a TIA. For further details, including suggested dosing regimens of antiplatelet and anticoagulant agents, refer to the relevant UpToDate topic reviews. 2 ABCD : age, blood pressure, clinical features, duration of symptoms, and diabetes; DAPT: dual antiplatelet therapy (eg, aspirin and clopidogrel, or aspirin and ticagrelor); BP: blood pressure; SBP: systolic blood pressure; DBP: diastolic blood pressure. Indications for long-term oral anticoagulation include embolism prevention for patients with atrial fibrillation, ventricular thrombus, mechanical heart valve, and treatment of venous thromboembolism. Graphic 131692 Version 1.0 https://www.uptodate.com/contents/overview-of-secondary-prevention-of-ischemic-stroke/print 29/36 7/6/23, 12:51 PM Overview of secondary prevention of ischemic stroke - UpToDate Immediate antithrombotic treatment of acute ischemic stroke This algorithm is intended to provide basic guidance regarding the immediated use of antithrombotic therapy for patients with an acute ischemic stroke. For further details, including scoring of the NIHSS and suggested dosing regimens of antithrombotic agents, refer to the relevant UpToDate topic reviews.