Primary prevention

Established measures for primary prevention of stroke include physical activity; avoidance of obesity; appropriate diet; treatment of hypertension, hypercholesterolemia, and diabetes; and abstinence from smoking, illegal drug use, and heavy drinking.[98][99]

Further preventive measures may be appropriate in particular patient groups.

Prevention of further stroke in a patient with transient ischemic attack (TIA) is classed as secondary prevention.

Anticoagulation and atrial appendage closure for people with atrial fibrillation

Compared with antiplatelet therapy, adjusted-dose warfarin and related oral anticoagulants reduce the risk of stroke, disabling stroke, and other major vascular events by about one third in people with nonvalvular atrial fibrillation.[100] The benefits of anticoagulation therapy should be weighed against the risk of hemorrhage, particularly intracranial hemorrhage, for each patient.

In patients with nonvalvular atrial fibrillation, direct oral anticoagulants (DOACs) such as dabigatran, rivaroxaban, apixaban, and edoxaban are as effective as warfarin in preventing stroke and carry a smaller risk of intracranial bleeding.[101]

In patients with atrial fibrillation, surgical left atrial appendage closure may be beneficial in reducing the risk of stroke. Of patients with nonvalvular atrial fibrillation who have a stroke, the left atrial appendage is the location of identified thrombus 90% of the time.[102] In a randomized trial of 2379 patients with atrial fibrillation, ischemic stroke or systemic embolism at 3.8 years occurred in 4.8% of the occlusion of the left atrial appendage group compared with 7.0% of the no occlusion group.[103] Most of these patients (75%) continued to receive ongoing antithrombotic therapy. The Food and Drug Administration (FDA) has approved one device for atrial appendage closure. However, the efficacy of left atrial appendage closure compared with DOACs is unknown.[102] In patients at high bleeding risk from oral anticoagulation, left atrial appendage closure can reduce the long-term risk of bleeding with an ischemic stroke risk comparable to that of anticoagulation with a vitamin K antagonist (e.g. warfarin).[102]

Treatment of hyperlipidemia

Use of the cholesterol-lowering agent ezetimibe is associated with reduced stroke risk.[104][105]

There is a strong evidence base for the benefits of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors (e.g., evolocumab, alirocumab), and that they reduce low-density lipoprotein (LDL)-cholesterol (LDL-C).[106] BMJ: PCSK9 inhibitors and ezetimibe for the reduction of cardiovascular events Opens in new window​ Evolocumab reduced lipids and cardiovascular events in patients with hyperlipidemia compared with standard therapy.[107][108] Evolocumab has been approved by the FDA and the European Medicines Agency for the reduction of LDL-C in patients unable to reach LDL-C goals with the maximum tolerated dose of a statin, or alone or in combination with other lipid-lowering therapies in patients who are statin-intolerant or for whom a statin is contraindicated.

Alirocumab significantly reduced LDL levels in patients with heterozygous familial hypercholesterolemia receiving statin therapy at the maximum tolerated dose.[109] In one multicenter, randomized, double-blind, placebo-controlled trial of patients who had a previous acute coronary syndrome and who were receiving high-intensity statin therapy, the risk of recurrent ischemic cardiovascular events was lower among those who received alirocumab than among those who received placebo.[110]

Antiplatelet therapy

Patients without preexisting atherosclerotic cardiovascular disease (CVD): guidelines vary based on patients’ age and bleeding risk. ACC/AHA guidelines state that low-dose aspirin might be considered for primary prevention of atherosclerotic CVD in adults ages 40-70 years who are at higher risk of atherosclerotic CVD but not at increased bleeding risk.[111] The US Preventive Services Task Force (USPSTF) recommends that the decision to initiate low-dose aspirin use for the primary prevention of CVD in adults aged 40-59 years who have a 10% or greater 10-year CVD risk should be an individual one.[112] Evidence indicates that the net benefit of aspirin use in this group is small. Those who are not at increased risk for bleeding and are willing to take low-dose aspirin daily are more likely to benefit.[112] The risk-benefit ratio differs in older patients. AHA guidelines state low-dose aspirin should not be given routinely for primary prevention of atherosclerotic CVD to adults over 70 years, or to adults of any age who are at increased bleeding risk.[111][113][114][115] The USPSTF recommends against initiating low-dose aspirin use for the primary prevention of CVD in adults 60 years or older.[112]

Patients with preexisting coronary artery disease or peripheral artery disease: In one large randomized controlled trial, patients with preexisting coronary artery disease or peripheral artery disease were given aspirin, rivaroxaban, or rivaroxaban plus aspirin. During a mean follow-up of 23 months, fewer patients had strokes in the rivaroxaban plus aspirin group than in the aspirin group (83 [0.9% per year] vs. 142 [1.6% per year]). Ischemic/uncertain strokes were reduced by nearly half (68 [0.7% per year] vs. 132 [1.4% per year]), and fatal and disabling strokes were also decreased by the combination (32 [0.3% per year] vs. 55 [0.6% per year]). Therefore, low-dose rivaroxaban plus aspirin appears to offer significant primary and secondary stroke prevention in this population.[116]

Secondary prevention

The American Heart Association/American Stroke Association (AHA/ASA) have published recommendations for the secondary prevention of ischemic stroke.[102] 

Secondary prevention measures should be started for all patients as soon as possible after the diagnosis is confirmed.

Patients should be advised on lifestyle measures including recommendations to:[102] 

  • Exercise regularly

  • Maintain a healthy diet

  • Manage weight

  • Reduce alcohol consumption

  • Stop smoking.

See Management approach for more detail on the recommendations below.

Anticoagulation for stroke patients with atrial fibrillation (AF)

  • The AHA/ASA guidelines recommend starting oral anticoagulation 4-14 days after stroke symptom onset.[119]

  • In patients with nonvalvular AF and stroke or TIA, oral anticoagulation is recommended to reduce the risk of recurrent stroke, regardless of whether the AF pattern is paroxysmal, persistent, or permanent.[102] 

  • Direct-acting oral anticoagulants (DOACs) such as apixaban, dabigatran, edoxaban, or rivaroxaban are recommended over warfarin in patients with stroke or TIA and AF who do not have moderate to severe mitral stenosis or a mechanical heart valve.[102] 

  • The international normalized ratio (INR) range for patients on warfarin is 2.0 to 3.0.[102][186] A validated scoring system should be used to assess the bleeding risk of the patient; if high, the patient should be followed up more closely.[187][276] See New-onset atrial fibrillation.

  • See Management approach for more information.

Antiplatelet therapy for patients with stroke without AF

  • For patients with noncardioembolic ischemic stroke or TIA, aspirin, clopidogrel, or the combination of aspirin and extended-release dipyridamole is indicated for secondary prevention of ischemic stroke.[102]

    • In patients with recent minor (NIHSS score ≤3) noncardioembolic ischemic stroke or high-risk TIA (ABCD2 score ≥4), guidelines from the AHA/ASA recommend that dual antiplatelet therapy should be initiated early (ideally within 12-24 hours of symptom onset and at least within 7 days of onset) and continued for 21-90 days, followed by single antiplatelet therapy, to reduce the risk of recurrent ischemic stroke.[102]

  • Ticagrelor is approved by the Food and Drug Administration to reduce the risk of stroke in patients with acute ischemic stroke or high-risk TIA. Ticagrelor reversibly binds and inhibits the P2Y12 receptor on platelets. The THALES trial of 11,016 patients (none of whom received thrombolysis or thrombectomy or required anticoagulation) demonstrated that compared with aspirin alone, dual treatment with ticagrelor and aspirin reduced the risk of disabling stroke or death within 30 days (4.0% vs. 4.7%).[166] Severe bleeding was more frequent with ticagrelor plus aspirin than with aspirin alone (0.5% vs. 0.1%), including intracranial hemorrhage (0.4% vs. 0.1%).[166] In Europe, an application to the European Medicines Agency (EMA) to change the marketing authorization of ticagrelor to include the prevention of stroke in adults who have had a mild to moderate ischemic stroke or high-risk TIA was withdrawn in December 2021. Based on trial data and the company’s response to their questions, the EMA expressed concern that the benefits of short-term treatment with ticagrelor plus aspirin in preventing stroke in these patients did not clearly outweigh the risks of fatal and nonfatal bleeding.

Stroke or TIA with stenosis of a major intracranial artery

  • In patients with a stroke or TIA caused by 50% to 99% stenosis of a major intracranial artery, aspirin is recommended in preference to warfarin to reduce the risk of recurrent ischemic stroke and vascular death.[24][102]

  • In patients with recent stroke or TIA (within 30 days) attributable to severe stenosis (70% to 99%) of a major intracranial artery, the addition of clopidogrel to aspirin for up to 90 days is recommended to further reduce recurrent stroke risk in patients who have low risk of hemorrhagic transformation.[24][102]

  • In patients with recent (within 24 hours) minor stroke or high-risk TIA and concomitant ipsilateral >30% stenosis of a major intracranial artery, the addition of ticagrelor to aspirin for up to 30 days might be considered to further reduce recurrent stroke risk.[102]

  • In patients with stroke or TIA attributable to 50% to 99% stenosis of a major intracranial artery, the addition of cilostazol to aspirin or clopidogrel might be considered to reduce recurrent stroke risk.[102]

Carotid artery endarterectomy (CEA) and carotid artery stenting (CAS)

  • In patients with symptomatic carotid stenosis (i.e., TIA or nondisabling stroke) within the past 6 months and ipsilateral severe (70% to 99%) carotid artery stenosis, CEA is recommended to reduce the risk of future stroke, provided that perioperative morbidity and mortality risk is estimated to be <6%.[102]

  • In patients younger than 68 years and with symptomatic carotid stenosis (i.e., TIA or nondisabling stroke), CAS is preferred over CEA if the degree of stenosis is between 50% and 69% (as determined by digital subtraction angiography). This is appropriate only if perioperative risk of morbidity and mortality is <6%. CEA or CAS is beneficial for patients with 70% to 99% stenosis without near-occlusion. No evidence of benefit has been found in patients with a stenosis of <50% or near-occlusion.[45][46][189]

  • In patients older than 68 years and with recent TIA or ischemic stroke and ipsilateral moderate (50% to 69%) carotid stenosis (as documented by catheter-based imaging or noninvasive imaging), CEA is recommended to reduce the risk of future stroke, provided the perioperative morbidity and mortality risk is <6%. Patient-specific factors such as age, sex, and comorbidities will also affect the suitability of CEA.[102]

Patent foramen ovale

  • PFO closure (with antiplatelet therapy), antiplatelet therapy alone, or anticoagulants alone are options for the secondary prevention of stroke in patients with cryptogenic ischemic stroke secondary to PFO.[192] Antiplatelet options include aspirin or clopidogrel.[193]

  • The approach chosen depends on the risk of paradoxical embolism, age, patient preference, and vascular risk factors.

Medications used in secondary prevention should be reviewed. Some patients may have been started on these drugs at diagnosis.

Antiplatelet therapy

  • For patients with noncardioembolic ischemic stroke or TIA, guidelines from the AHA/ASA recommend aspirin, clopidogrel, or the combination of aspirin plus extended-release dipyridamole for secondary prevention of ischemic stroke.[102] In patients with recent minor (NIHSS score ≤3) noncardioembolic ischemic stroke or high-risk TIA (ABCD2 score ≥4), the AHA/ASA recommend that dual antiplatelet therapy should be initiated early (ideally within 12-24 hours of symptom onset and at least within 7 days of onset) and continued for 21-90 days, followed by single antiplatelet therapy, to reduce the risk of recurrent ischemic stroke.[102][119][162][163]

  • In 2020, the Food and Drug Administration (FDA) in the US approved the dual antiplatelet regimen of aspirin and ticagrelor to reduce the risk for stroke in patients with acute ischemic stroke with a NIHSS score of ≤5 or high-risk TIA. In Europe, an application to the European Medicines Agency (EMA) to change the marketing authorization of ticagrelor to include the prevention of stroke in adults who have had mild to moderate ischemic stroke or high-risk TIA was withdrawn in December 2021. Based on trial data and the company’s response to their questions, the EMA expressed concern that the benefits of short-term treatment with ticagrelor plus aspirin in preventing stroke in these patients did not clearly outweigh the risks of fatal and nonfatal bleeding

Antihypertensives

  • One systematic review found that blood pressure lowering treatment reduced the risk of recurrent stroke in people with stroke or TIA. Evidence was derived primarily from trials studying an ACE inhibitor or a diuretic.[277] In patients with hypertension who experience a stroke or TIA, treatment with a thiazide diuretic, ACE inhibitor, or angiotensin-II receptor antagonist is useful for lowering blood pressure and reducing recurrent stroke risk.[102] An office blood pressure goal of <130/80 mmHg is recommended for most patients to reduce the risk of recurrent stroke and vascular events. Drug regimens should be individualized to take into account patient comorbidities, agent pharmacological class, and patient preference.[102]

  • The American Academy of Neurology recommends a long-term blood pressure target of <140/90 mm Hg in patients with symptomatic intracranial atherosclerotic arterial stenosis.[24] Drug regimens should be individualized to take into account patient comorbidities, agent pharmacological class, and patient preference.[24][102]​​[278]

Anticoagulants

  • Should be started in people with stroke and paroxysmal, persistent, or permanent atrial fibrillation or atrial flutter once intracranial bleeding and other contraindications (such as uncontrolled hypertension) are excluded.

Lipid-lowering treatments

Statin therapy with intensive lipid-lowering effects is recommended for patients with ischemic stroke or TIA, to lower the risk of stroke and cardiovascular events.[102][206] The rate of recurrent cardiovascular events or stroke is lower in patients whose LDL is controlled to <70 mg/dL compared with those with LDL between 90 and 110 mg/dL.[24][207] Monitoring of liver enzymes is recommended for patients taking statins. Caution should be exercised when prescribing high-intensity statin to patients with a history of intracerebral hemorrhage.

  • In patients with ischemic stroke with no known coronary heart disease, no major cardiac sources of embolism, and LDL cholesterol (LDL-C) >100 mg/dL, atorvastatin is indicated to reduce risk of stroke recurrence.[102]

  • In patients with ischemic stroke or TIA and atherosclerotic disease (intracranial, carotid, aortic, or coronary), lipid-lowering therapy with a statin and also ezetimibe, if needed, to a goal LDL-C of <70 mg/dL is recommended to reduce the risk of major cardiovascular events.[102]

  • In patients with ischemic stroke who are very high risk (defined as stroke plus another major atherosclerotic CVD or stroke plus multiple high-risk conditions), are taking maximally tolerated statin and ezetimibe therapy and still have an LDL-C >70 mg/dL, it is reasonable to treat with proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor therapy to prevent atherosclerotic CVD events.[102] BMJ: PCSK9 inhibitors and ezetimibe for the reduction of cardiovascular events Opens in new window​

  • In patients with stroke or TIA and hyperlipidemia, adherence to changes in lifestyle and the effects of LDL-C-lowering medication should be assessed by measurement of fasting lipids and appropriate safety indicators 4-12 weeks after statin initiation or dose adjustment and every 3-12 months thereafter, based on need to assess adherence or safety.[102]

  • In patients with ischemic stroke or TIA, with fasting triglycerides 135 to 499 mg/dL and LDL-C of 41 to 100 mg/dL, on moderate- or high-intensity statin therapy, with HbA1c <10%, and with no history of pancreatitis, atrial fibrillation, or severe heart failure, treatment with icosapent ethyl is reasonable to reduce risk of recurrent stroke.[102][279]

  • In patients with severe hypertriglyceridemia (i.e., fasting triglycerides ≥500 mg/dL [≥5.7 mmol/L]), it is reasonable to identify and address causes of hypertriglyceridemia and, if triglycerides are persistently elevated or increasing, to further reduce triglycerides in order to lower the risk of atherosclerotic CVD events by implementation of a very low-fat diet, avoidance of refined carbohydrates and alcohol, consumption of omega-3 fatty acids, and, if necessary to prevent acute pancreatitis, fibrate therapy.[102]

Additional secondary prevention measures may be necessary depending on stroke risk factors and associated diseases discovered during investigations for the cause of stroke.[102][280]

Sleep studies should be considered for stroke patients because sleep apnea is common among this subgroup. In patients with an ischemic stroke or TIA and obstructive sleep apnea, treatment with positive airway pressure (e.g., continuous positive airway pressure [CPAP]) may be beneficial for improved sleep apnea, blood pressure, sleepiness, and other apnea-related outcomes.[102]

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