STROKE AND TIA

• ACRONYMS AND DEFINITIONS

• AAN - American Academy of Neurology
• ABCD² score - Estimates risk of stroke after TIA (see ABCD² online calculator)
• AHA - American Heart Association
• AIS - Acute ischemic stroke
• ASA - American Stroke Association
• ASA-ERPD - Aspirin + dipyridamole (Aggrenox®)
• ASPECTS - Alberta Stroke Program Early CT Score
• aPTT - activated Partial Thromboplastin Time
• CAD - Coronary artery disease
• CTA - Computed tomography angiography
• CVD - Cardiovascular disease
• DAPT - Dual antiplatelet therapy (e.g. Aspirin + P2Y12 inhibitor)
• DBP - Diastolic blood pressure
• DVT - Deep vein thrombosis
• INR - International Normalized Ratio
• MCA - Middle cerebral artery
• Modified Rankin scale - see modified Rankin scale for more
• MRA - Magnetic resonance angiography
• NIHSS - National Institutes of Health stroke scale
• NNT/NNH - Number needed to treat/harm
• PFO - Patent Foramen Ovale
• PT - Prothrombin Time
• RCT - Randomized controlled trial
• SBP - Systolic blood pressure
• TIA - Transient ischemic attack

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• ISCHEMIC STROKE

• Ischemic strokes account for about 80% of all strokes. They occur when arteries in the brain become occluded through one of two mechanisms, thrombosis or embolism. Thrombotic occlusions happen when a blood clot forms at the site of atherosclerosis in the blood vessel wall. Embolic occlusions occur when a blood clot forms at another location in the body (e.g. heart) and then travels to the brain, where it lodges in a vessel.

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• HEMORRHAGIC STROKE

• Hemorrhagic stroke can be divided into 2 main types:
• Stroke with intracerebral hemorrhage - stroke where bleeding occurs into the brain tissue
• Stroke with subarachnoid hemorrhage - stroke where bleeding occurs into the subarachnoid space
• Meninges illustration


• Stroke with intracerebral hemorrhage (ICH)
• Stroke with intracerebral hemorrhage accounts for about 15% of all strokes. It occurs when weak blood vessels rupture and bleed into the brain tissue. If enough bleeding occurs, a hematoma can form that produces pressure and displaces the brain. Brain displacement can lead to death. Stroke with ICH has a high mortality rate, with up to 34% of patients dying within 3 months. ICH treatment is complicated and not covered here. Management guidelines from the AHA are available at the link below. [1,22]
• 2022 AHA intracerebral hemorrhage management guidelines


• Stroke with subarachnoid hemorrhage
• Stroke with subarachnoid hemorrhage accounts for 5% of all strokes. The most common cause is a ruptured aneurysm that bleeds into the subarachnoid space (see meninges illustration). Subarachnoid bleeding can lead to vasospasm, ischemia, seizures, and hydrocephalus. Therapy consists of managing the complications and treating the aneurysm to prevent rebleeding. Subarachnoid hemorrhage treatment is complicated and not covered here. Management guidelines from the AHA are available at the link below. [1]
• 2012 AHA subarachnoid hemorrhage management guidelines

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• LACUNAR INFARCT

• About 25% of ischemic strokes are lacunar infarcts. Lacunar infarcts occur in small arteries that penetrate deep areas of the brain (ex. basal ganglia, putamen, pons, thalamus, caudate, and internal capsule). The cause of lacunar infarcts is not completely understood; proposed theories include fibrinoid degeneration and embolism.
• Most lacunar infarcts have no symptoms and are only discovered incidentally on imaging for other reasons. Symptomatic infarcts often present as "pure syndromes," meaning they only cause weakness or sensory loss but not both. Higher cortical functions like language, facial recognition, vision, and purposeful movements are typically unaffected.
• Lacunar infarcts are best detected with MRI, where they are defined as infarcts ≤ 15 mm in diameter.
• Patients with lacunar infarcts are treated with antiplatelet therapy. [4]

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• CRYPTOGENIC STROKE

• Overview
• "Cryptogenic" means the cause of something is unknown. Cryptogenic strokes, also referred to as "strokes of undetermined source," are strokes that occur without an identifiable source of thrombosis or embolism. About 30% of strokes are considered cryptogenic.
• Common sources of embolisms and thromboses are heart disorders (e.g. atrial fibrillation), large vessel atherosclerosis (e.g. carotid stenosis), and small vessel atherosclerosis (vessels in the brain). If a stroke workup does not find any of these, the stroke may be labeled as cryptogenic.
• Two hypothesized etiologies of cryptogenic strokes are undiagnosed atrial fibrillation and a heart defect known as a patent foramen ovale (PFO). A PFO allows blood to pass between the left and right atrium; therefore, it could enable a venous embolism to become an arterial embolism, something referred to as a paradoxical embolism.
• Theoretically, anticoagulation could help prevent recurrent cryptogenic strokes if atrial fibrillation and/or paradoxical embolism are significant sources of these types of strokes. The two studies detailed below looked at the effects of anticoagulation in preventing stroke recurrence among patients with cryptogenic stroke. Patent foramen ovale closure has also been studied, and it is discussed here - patent foramen ovale.

• STUDY
  Dabigatran vs Aspirin for Secondary Prevention of Cryptogenic Stroke, NEJM (2019) [PubMed abstract]
• Design: Randomized, placebo-controlled trial (N=5390 | length = 19 months) in patients who had been diagnosed with cryptogenic stroke
• Treatment: Dabigatran 150 mg twice daily vs Aspirin 100 mg once daily
• Primary outcome: Efficacy - recurrent stroke | Safety - major bleeding
• Results:
• Recurrent stroke: Dabigatran - 6.6%, Aspirin - 7.7% (p=0.10)
• Major bleeding: Dabigatran - 1.7%, Aspirin - 1.4% (HR 1.19 95%CI [0.85 – 1.66])
• Findings: In patients with a recent history of embolic stroke of undetermined source, dabigatran was not superior to aspirin in preventing recurrent stroke. The incidence of major bleeding was not greater in the dabigatran group than in the aspirin group, but there were more clinically relevant nonmajor bleeding events in the dabigatran group.

• Summary
• The results of these studies are surprising given the fact that undiagnosed atrial fibrillation and paradoxical embolism are thought to be significant sources of cryptogenic strokes
• Patients with cryptogenic stroke should only be treated with antiplatelet therapy. See patent foramen ovale below for a discussion on PFO closure in cryptogenic stroke.

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• TRANSIENT ISCHEMIC ATTACK (TIA)

• Overview
• TIA is defined as transient stroke symptoms that resolve within 24 hours with no findings consistent with stroke on brain imaging. The majority of TIAs last minutes, likely occurring through the same mechanism as ischemic strokes, except that the occlusions are smaller and dissolve quickly, so that blood flow is rapidly restored.
• Like strokes, the risk of TIA increases with age, with an annual incidence of 0.087% between the ages of 55 - 64 and 0.37% at 75. The average age of first TIA is 73 years in women and 70 in men. [15,38]

• Stroke risk after TIA
• TIAs are a significant risk factor for impending stroke. In some studies, up to 12.8% of patients with a TIA suffered a stroke within a week of their TIA. Recent data suggests that improved risk factor management has caused the risk of stroke after TIA to decline. In a study that followed 14,059 participants in the Framingham Heart Study for 66 years, the 90-day risk of stroke after TIA in 1986 - 1999 was 11.1%, and it dropped to 5.9% in 2000 - 2017. [1,38]
• Several risk estimators have been developed that give an estimated stroke risk after TIA based on select patient variables. The ABCD² score uses 5 variables and gives stroke risk estimates for 2, 7, and 90 days. The Canadian TIA Score uses 13 variables and gives a 7-day risk of stroke or carotid revascularization. Links to each estimator are provided below. A study that compared the accuracy of the tools at predicting stroke found the Canadian TIA Score to be better than the ABCD². [PMID 33602669]
• ABCD² Score for TIA
• Canadian TIA Score

• Treatment
• TIAs are treated in the same way as minor strokes. See secondary prevention below.

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• RISK FACTORS FOR STROKE

• Overview
• Strokes are often a sequelae of atherosclerosis so the risk factors for stroke are the same as other diseases caused by atherosclerosis (e.g. coronary artery disease). Strokes are also caused by conditions that increase the risk of blood clot formation (e.g. atrial fibrillation, thrombophilia)


• Risk factors for stroke include:
• Previous stroke - see stroke recurrence below
• Age
• Male sex
• African-American race
• Family history of stroke
• Low birth weight (unclear why)
• Hypertension
• Cigarette smoking
• Diabetes
• High cholesterol or low HDL
• Atrial fibrillation
• Carotid stenosis
• Sickle cell disease
• Postmenopausal hormone therapy
• Oral contraceptive use
• Antipsychotics (e.g. risperidone, aripiprazole, olanzapine)
• Antidopaminergic antiemetics (e.g. metoclopramoide) [41]
• Migraine with aura [3]
• Recent cancer diagnosis [24]
• Noncardiac surgery [35]

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• DIAGNOSIS

• Ischemic stroke symptoms
• Stroke symptoms depend on the area of the brain that is affected. Most strokes occur in one of the five arterial systems listed below. See stroke symptom illustration for a description of symptoms associated with each system.
• Five arterial systems of the brain:
• Middle cerebral artery
• Anterior cerebral artery
• Posterior cerebral artery
• Vertebrobasilar system
• Lacunar infarcts (small penetrating arteries)

• Hemorrhagic stroke symptoms
• Hemorrhagic strokes present with neurologic deficits (stroke symptom illustration) that are accompanied by signs of brain bleeding (e.g. decreased level of consciousness, vomiting, headache, seizure).

• Physical exam
• Physical exam findings depend on the area of the brain affected (see stroke symptom illustration)

• Brain imaging
• Patients with acute, ongoing stroke symptoms
• All patients who present with stroke symptoms should have brain imaging. Non-contrast CT scan is typically performed first because it can be done rapidly in most emergency centers. Some centers may prefer MRI if they have the means to perform it quickly.
• Rapid brain imaging is critical to determine if the stroke is ischemic or hemorrhagic because ischemic strokes may be eligible for fibrinolysis, whereas hemorrhagic strokes are not
• CTA with CT perfusion or MRA with diffusion-weighted magnetic resonance imaging with or without MR perfusion is useful for selecting candidates for mechanical thrombectomy between 6 and 24 hours after last known well [5,36]
• Patients whose symptoms have resolved (including suspected TIA)
• Diffusion MRI with MRA for viewing the intracranial vasculature is preferred
• Noninvasive imaging of the cervical vessels (carotid arteries and vertebral arteries) should be performed. This may be done with MRA, CTA, or US. [5]

• Cardiac and carotid testing
• AHA recommendations for cardiac and carotid testing are provided below
• Cardiac testing
• Cardiac monitoring is recommended to screen for atrial fibrillation and other potentially serious cardiac arrhythmias that would necessitate emergency cardiac interventions. Cardiac monitoring should be performed for at least the first 24 hours.
• For prevention of recurrent stroke, the use of echocardiography is reasonable in some patients with AIS to provide additional information to guide selection of appropriate secondary stroke prevention.
• Echocardiography is reasonable in selected patients as part of a comprehensive evaluation to determine if they meet the eligibility criteria of the RCTs that investigated mechanical closure of PFO for prevention of recurrent stroke. [36]
• Cervical carotid arteries
• For patients with nondisabling (mRS score 0–2) AIS in the carotid territory who are candidates for CEA or stenting, noninvasive imaging of the cervical carotid arteries should be performed routinely within 24 hours of admission [36]

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• ACUTE TREATMENT | Blood pressure control

• Overview
• Blood pressure elevations are common during and after acute ischemic stroke. Extreme elevations can be detrimental to the heart, brain, and kidneys, while moderate elevations may be advantageous because they improve cerebral perfusion to ischemic tissue. The optimal blood pressure range after acute stroke has not been determined.
• The first two studies detailed below evaluated different blood pressure regimens in patients with ischemic stroke who did not receive fibrinolysis. The third study compared intensive blood pressure reduction to guideline-based therapy in patients treated with fibrinolysis. The fourth study compared lower blood pressure targets (SBP < 120) to higher ones (SBP 140 - 180) after thrombectomy.

• STUDY
  ENCHANTED2/MT - Intensive (SBP < 120) vs Standard (SBP 140 - 180) Blood Pressure Control After Mechanical Thrombectomy, Lancet (2022) [PubMed abstract]
• Design: Randomized, controlled trial (N=816 | length = 90 days) in patients with SBP ≥ 140 after successful thrombectomy for ischemic stroke
• Treatment: SBP target of < 120 (intensive group) vs SBP target of 140 - 180 (standard group)
• Primary outcome: Functional recovery, assessed according to the distribution in scores on the modified Rankin scale (range 0 [no symptoms] to 6 [death]) at 90 days
• Results:
• Mean SBP at 24 hours: Intensive - 121 mmHg, Standard - 139 mmHg
• Primary outcome: The likelihood of poor functional outcome was greater in the more intensive group than the standard group (common OR 1·37 [95% CI 1·07-1·76])
• Findings: Intensive control of systolic blood pressure to lower than 120 mm Hg should be avoided to prevent compromising the functional recovery of patients who have received endovascular thrombectomy for acute ischaemic stroke due to intracranial large-vessel occlusion.

• AHA recommendations for blood pressure control in acute ischemic stroke
• Patients eligible for fibrinolysis
• Blood pressure should be carefully lowered (see fibrinolysis)
• SBP lowered to < 185 mmHg
• DBP lowered to < 110 mmHg
• Patients who are not considered for fibrinolysis or thrombectomy
• In patients with acute ischemic stroke, early treatment of hypertension is indicated when required by comorbid conditions (eg, concomitant acute coronary event, acute heart failure, aortic dissection, postthrombolysis, sICH, or preeclampsia/eclampsia)
• In patients with BP ≥ 220/120 mmHg who did not receive IV alteplase or thrombectomy and have no comorbid conditions requiring acute antihypertensive treatment, the benefit of initiating or reinitiating treatment of hypertension within the first 48 to 72 hours is uncertain. It might be reasonable to lower BP by 15% during the first 24 hours after onset of stroke
• Starting or restarting antihypertensive therapy during hospitalization in patients with BP > 140/90 mmHg who are neurologically stable is safe and is reasonable to improve long-term BP control unless contraindicated [32,36]
• Many patients will have spontaneous declines in blood pressure in the first 24 hours following a stroke [5]
• After thrombectomy
• In patients who undergo mechanical thrombectomy, it is reasonable to maintain the BP at ≤ 180/105 mmHg during and for 24 hours after the procedure
• In patients who undergo mechanical thrombectomy with successful reperfusion, it might be reasonable to maintain BP at a level < 180/105 mmHg [36]

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• ACUTE TREATMENT | Fibrinolysis

• Overview
• Fibrinolysis is the dissolution of blood clots with medications (see blood clot dissolution illustration)
• Tissue plasminogen activator (t-PA) is a naturally occurring protein that enhances the conversion of plasminogen to plasmin. Plasmin is a proteolytic enzyme that lyses fibrin and dissolves blood clots. First-generation tissue plasminogen activators (e.g. streptokinase, urokinase) were not selective for plasminogen bound to fibrin and had higher bleeding rates. This led to the development of recombinant tissue plasminogen activators (rt-PA), which are selective for plasminogen bound to fibrin, making them more specific for blood clots. The most common rt-PA used for stroke treatment is alteplase (Activase®). Other rt-PAs are not currently approved for stroke treatment, although comparative studies have found tenecteplase to be as good, if not better, than alteplase. [PMID 29694815, PMID 35779553, PMID 36774935]

• Fibrinolysis trial
• Four trials that showed a benefit with fibrinolysis are detailed below. The trials vary by the inclusion criteria they used to enroll patients. The NINDS and ECASS trials used length of time since symptom onset to enroll patients. The WAKE-UP and EXTEND trials primarily used MRI perfusion imaging, which can show hypoperfused but salvageable regions of the brain, as enrollment criteria.
• NINDS - symptom onset < 3 hours
• ECASS - symptom onset 3 - 4.5 hours
• WAKE-UP - unknown symptom onset with favorable MRI findings
• EXTEND - symptom onset between 4.5 and 9 hours with favorable CT/MRI findings
• The inclusion/exclusion criteria from the NINDS and ECASS trials currently serve as the foundation for selecting patients for fibrinolysis
• Three other trials - ECASS, ECASS II, and ATLANTIS - did not find a benefit with fibrinolysis compared to placebo. These trials differed from the NINDS and ECASS III trials in that patients could be enrolled up to 6 hours after stroke onset and only 14% of patients were treated within 3 hours. [6]

• AHA/ASA 2019 fibrinolysis recommendations
• IV alteplase
• IV alteplase (0.9 mg/kg, maximum dose 90 mg over 60 minutes with initial 10% of dose given as bolus over 1 minute) is recommended for selected patients who may be treated within 3 hours of ischemic stroke symptom onset or patient last known well or at baseline state. See fibrinolysis criteria for a review of patient eligibility.
• IV alteplase (0.9 mg/kg, maximum dose 90 mg over 60 minutes with initial 10% of dose given as bolus over 1 minute) is also recommended for selected patients who can be treated within 3 and 4.5 hours of ischemic stroke symptom onset or patient last known well. See fibrinolysis criteria for a review of patient eligibility.
• IV alteplase (0.9 mg/kg, maximum dose 90 mg over 60 minutes with initial 10% of dose given as bolus over 1 minute) administered within 4.5 hours of stroke symptom recognition can be beneficial in patients with acute ischemic stroke who awake with stroke symptoms or have unclear time of onset > 4.5 hours from last known well or at baseline state and who have a diffusion-weighted MRI lesion smaller than one-third of the MCA territory and no visible signal change on FLAIR
• Mild stroke
• For otherwise eligible patients with mild but disabling stroke symptoms, IV alteplase is recommended for patients who can be treated within 3 hours of ischemic stroke symptom onset or patient last known well or at baseline state.
• For otherwise eligible patients with mild disabling stroke symptoms, IV alteplase may be reasonable for patients who can be treated within 3 and 4.5 hours of ischemic stroke symptom onset or patient last known well or at baseline state
• For otherwise eligible patients with mild nondisabling stroke symptoms (NIHSS score 0–5), IV alteplase is not recommended for patients who could be treated within 3 hours of ischemic stroke symptom onset or patient last known well or at baseline state.
• For otherwise eligible patients with mild nondisabling stroke symptoms (NIHSS 0–5), IV alteplase is not recommended for patients who could be treated within 3 and 4.5 hours of ischemic stroke symptom onset or patient last known well or at baseline state.
• STUDIES: A trial published in 2023 compared DAPT to fibrinolysis in 760 patients with acute minor nondisabling stroke (NIHSS ≤ 5) presenting within 4.5 hours of symptom onset. At 90 days, there was no significant difference in the proportion of patients with a modified Rankin score of 0 or 1 (DAPT 93.8%, Fibrinolysis 91.4%). [PMID 37367978]
• Bleeding risk
• Given the extremely low risk of unsuspected abnormal platelet counts or coagulation studies in a population, it is reasonable that urgent IV alteplase treatment not be delayed while waiting for hematologic or coagulation testing if there is no reason to suspect an abnormal test.
• In otherwise eligible patients who have had a previously demonstrated small number (1–10) of cerebral microbleeds^✝ on MRI, administration of IV alteplase is reasonable.
• In otherwise eligible patients who have had a previously demonstrated high burden of cerebral microbleeds^✝ (>10) on MRI, treatment with IV alteplase may be associated with an increased risk of symptomatic intracerebral hemorrhage, and the benefits of treatment are uncertain. Treatment may be reasonable if there is the potential for substantial benefit. [36]
• ^✝Cerebral microbleeds are small, chronic hemorrhagic foci (< 5 mm) that have been increasingly detected on MRIs as technology has advanced. The clinical significance of these hemorrhages is unknown.

• Summary
• Fibrinolysis improves the chance of a favorable outcome in ischemic stroke by 7 - 13%. After the onset of stroke symptoms, fibrinolysis should be initiated as soon as possible. The NINDS study found a benefit up to 3 hours after symptom onset and the ECASS trial showed a benefit up to 4.5 hours. The WAKE-UP and EXTEND trials showed a benefit beyond 4.5 hours in patients with favorable brain imaging.
• Fibrinolysis increases the risk of symptomatic intracranial hemorrhage by 4 - 6%. Intracranial hemorrhage can lead to death and severe disability.

• Reference [5]

Inclusion/exclusion criteria for IV alteplase in patients with acute ischemic stroke
Overview The AHA/ASA 2018 Guidelines for Management of Acute Ischemic Stroke contains a 4 page table that discusses all the eligibility requirements for Alteplase therapy. The table is available here - AHA/ASA 2018 Alteplase eligibility requirements (page e65) The criteria listed below are the main criteria that were used in the NINDS and ECASS III trials. The AHA guidelines have evolved over the years and the criteria published in 2018 differ from the criteria listed below in some instances.
Criteria for patients with ischemic stroke who are to be treated with rt-PA within 3 hours of symptom onset: Inclusion criteria Ischemic stroke causing measurable neurological deficit Onset of symptoms less than 3 hours before beginning treatment Age ≥ 18 years Exclusion criteria Significant head trauma or prior stroke in previous 3 months Symptoms suggestive of subarachnoid hemorrhage Arterial puncture at noncompressible site in previous 7 days History of previous intracranial hemorrhage Intracranial neoplasm, arteriovenous malformation, or aneurysm Recent intracranial or intraspinal surgery Elevated blood pressure (systolic > 185 mmHg or diastolic > 110 mmHg) In some patients, attempts may be made to lower blood pressure below this cutoff Active internal bleeding Acute bleeding diathesis, including but not limited to Platelet count < 100,000/mm³ Heparin received within 48 hours, resulting in abnormally elevated aPTT greater than the upper limit of normal Current use of anticoagulant with INR > 1.7 or PT > 15 seconds Current use of direct thrombin inhibitors or Factor Xa inhibitors with elevated sensitive laboratory tests (such as aPTT, INR, platelet count, and ECT; TT; or appropriate factor Xa activity assays) Blood glucose concentration < 50 mg/dl (2.7 mmol/L) CT demonstrates multilobar infarction (hypodensity > 1/3 cerebral hemisphere) Relative exclusion criteria Recent experience suggests that under some circumstances—with careful consideration and weighing of risk to benefit—patients may receive fibrinolytic therapy despite 1 or more relative contraindications. Consider risk to benefit of IV rtPA administration carefully if any of these relative contraindications are present: Only minor or rapidly improving stroke symptoms (clearing spontaneously) Pregnancy Seizure at onset with postictal residual neurological impairments Major surgery or serious trauma within previous 14 days Recent gastrointestinal or urinary tract hemorrhage (within previous 21 days) Recent acute myocardial infarction (within previous 3 months) [5]
Additional criteria for patients with ischemic stroke who are to be treated with rt-PA within 3 to 4.5 hours of symptom onset Inclusion criteria Diagnosis of ischemic stroke causing measurable neurological deficit Onset of symptoms within 3 to 4.5 hours before beginning treatment Relative exclusion criteria Age > 80 years Severe stroke (NIHSS > 25) Taking an oral anticoagulant regardless of INR History of both diabetes and prior ischemic stroke [5]

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• ACUTE TREATMENT | Mechanical thrombectomy

• Overview
• Endovascular treatment of stroke involves running a catheter through the arteries and positioning it close to the blood clot in the brain. The catheter can then be used to deliver devices (stents, mechanical extractors, etc.) and drugs (rt-PA) directly to the clot.
• Interventions that utilize retrievable stents have been shown to be beneficial in a number of studies (see trials below). Retrievable stents are wire meshes that are placed along the area of occlusion in the artery. The stent expands, and in doing so, becomes embedded in the clot. The stent is then retrieved (retracted) pulling the clot with it.
• After a number of successful trials, the AHA/ASA published guidelines for the use of retrievable stents in 2018

• Mechanical thrombectomy trials
• Thrombectomy with stent retrievers has been shown to be superior to usual care in the treatment of acute ischemic stroke
• The first study to show a clear benefit with stent retrievers was the MR CLEAN trial detailed below. After MR CLEAN, a handful of other studies also confirmed a benefit with these devices (see other thrombectomy trials < 6 hours below). Studies were then performed to test the devices in patients with stroke symptoms for > 6 hours (see thrombectomy trials > 6 hours after stroke onset below). These studies also found a benefit, and in 2018, the FDA approved the Trevo clot retrieval device to treat certain stroke patients up to 24 hours after symptom onset.

• Other thrombectomy trials < 6 hours after stroke onset
• In addition to the MR CLEAN trial above, the trials below also looked at thrombectomy in patients with stroke of < 6 hours onset
• EXTEND-IA Trial - Endovascular therapy for ischemic stroke with perfusion-imaging selection, NEJM (2015) [PubMed abstract]
• SWIFT PRIME Trial - Stent-retriever thrombectomy after intravenous t-PA vs t-PA alone in stroke, NEJM (2015) [PubMed abstract]

• Thrombectomy trials > 6 hours after stroke symptom onset
• REVASCAT Trial - Thrombectomy within 8 hours after symptom onset in ischemic stroke, NEJM (2015) [PubMed abstract]
• ESCAPE Trial - Randomized assessment of rapid endovascular treatment of ischemic stroke up to 12 hours after symptom onset, NEJM (2015) [PubMed abstract]
• DAWN Trial - Thrombectomy 6 to 24 hours after stroke with a mismatch between deficit and infarct, NEJM (2018) [PubMed abstract]
• DEFUSE 3 Trial - Thrombectomy for stroke at 6 to 16 hours with selection by perfusion imaging, NEJM (2018) [PubMed abstract]
• MR CLEAN LATE Trial - Endovascular treatment 6 - 24 Hours after symptom onset in ischemic stroke with collateral flow, Lancet (2023) [PubMed abstract]

• Thrombectomy with and without fibrinolysis
• In early thrombectomy trials, eligible patients were almost always given fibrinolysis before the procedure. A number of trials have now evaluated thrombectomy both with and without antecedent fibrinolysis. These trials have had mixed results (see links below).
• DIRECT SAFE Trial - Thrombectomy With or Without Fibrinolysis Within 4.5 hours of Stroke Onset, Lancet (2022) [PubMed abstract]
• SWIFT DIRECT Trial - Thrombectomy With or Without Alteplase in Acute Stroke, Lancet (2022) [PubMed abstract]
• MR CLEAN-NO Trial - Endovascular Treatment With or Without Antecedent Alteplase in Acute Stroke, NEJM (2021) [PubMed abstract]
• DEVT trial - Endovascular Treatment With or Without Antecedent Alteplase in Acute Stroke, JAMA (2021) [PubMed abstract]
• SKIP trial - Mechanical Thrombectomy With or Without Antecedent Alteplase in Acute Stroke, JAMA (2021) [PubMed abstract]
• DIRECT-MT Trial - Endovascular Thrombectomy With or Without Antecedent Alteplase in Acute Stroke, NEJM (2020) [PubMed abstract]

• Basilar artery thrombectomy
• Basilar artery thrombosis accounts for 10% of all ischemic strokes. Early thrombectomy trials mostly excluded patients with basilar artery occlusions. More recently, studies that have looked exclusively at basilar artery thrombectomy have been published.
• BAOCHE Study - Thrombectomy for Stroke Due to Basilar-Artery Occlusion 6 to 24 Hours After Onset, NEJM (2022) [PubMed abstract]
• ATTENTION Study - Thrombectomy for Stroke Due to Basilar-Artery Occlusion Within 12 Hours of Onset, NEJM (2022) [PubMed abstract]
• BASIC Study - Endovascular Therapy for Stroke Due to Basilar-Artery Occlusion Within 6 Hours of Onset, NEJM (2021) [PubMed abstract]

• Large infarct (ASPECTS value 3 - 5)
• ASPECTS is a scoring system that quantifies the size of a stroke based on CT findings. Scores range from 0 to 10, with lower values indicating larger infarcts (see ASPECTS calculator). Early thrombectomy trials excluded patients with ASPECTS scores of 5 or less, so current guidelines do not recommend endovascular therapy in these patients. After the benefits of thrombectomy were established, researchers performed studies (see below) in patients with larger infarcts (ASPECTS 3 - 5), where it was also found to improve outcomes.
• Endovascular Therapy Within 24 hours for Large Ischemic Stroke, NEJM (2023) [PubMed abstract]
• Thrombectomy Within 24 Hours of Large Ischemic Stroke, NEJM (2023) [PubMed abstract]
• Endovascular Therapy for Acute Stroke with a Large Ischemic Region, NEJM (2022) [PubMed abstract]

• AHA/ASA 2019 recommendations for mechanical thrombectomy
• Fibrinolysis and thrombectomy
• Patients eligible for IV alteplase should receive IV alteplase even if mechanical thrombectomy is being considered.
• In patients under consideration for mechanical thrombectomy, observation after IV alteplase to assess for clinical response should not be performed.
• NOTE: Three trials have now found that antecedent fibrinolysis does not improve thrombectomy outcomes in patients with acute stroke (see thrombectomy with and without fibrinolysis above)
• Patients should receive mechanical thrombectomy (stent retriever or direct aspiration) if they meet all the following criteria:
• Prestroke modified Rankin score of 0 to 1
• Causative occlusion of the internal carotid artery or middle cerebral artery (M1)
• Age ≥ 18 years
• NIHSS score ≥ 6
• ASPECTS score ≥ 6 (range from 0 to 10, with lower values indicating larger infarction)
• Treatment can be initiated (groin puncture) within 6 hours of symptom onset
• Other considerations
• Although the benefits are uncertain, the use of mechanical thrombectomy with stent retrievers may be reasonable for carefully selected patients with AIS in whom treatment can be initiated (groin puncture) within 6 hours of symptom onset and who have causative occlusion of the MCA segment 2 (M2) or MCA segment 3 (M3) portion of the MCAs.
• Although its benefits are uncertain, the use of mechanical thrombectomy with stent retrievers may be reasonable for patients with AIS in whom treatment can be initiated (groin puncture) within 6 hours of symptom onset and who have prestroke mRS score > 1, ASPECTS < 6, or NIHSS score < 6, and causative occlusion of the internal carotid artery (ICA) or proximal MCA (M1)
• Although the benefits are uncertain, the use of mechanical thrombectomy with stent retrievers may be reasonable for carefully selected patients with AIS in whom treatment can be initiated (groin puncture) within 6 hours of symptom onset and who have causative occlusion of the anterior cerebral arteries, vertebral arteries, basilar artery, or posterior cerebral arteries.
• In selected patients with AIS within 6 to 16 hours of last known normal who have large vessel occlusion in the anterior circulation and meet other DAWN or DEFUSE 3 eligibility criteria, mechanical thrombectomy is recommended
• In selected patients with AIS within 16 to 24 hours of last known normal who have large vessel occlusion in the anterior circulation and meet other DAWN eligibility criteria, mechanical thrombectomy is reasonable. [36]

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• ACUTE TREATMENT | Antiplatelet / anticoagulant therapy

• Antiplatelet therapy
• Administration of aspirin is recommended in patients with acute ischemic stroke within 24 to 48 hours after onset
• For those treated with IV alteplase, aspirin administration is generally delayed until 24 hours later but might be considered in the presence of concomitant conditions for which such treatment given in the absence of IV alteplase is known to provide substantial benefit or withholding such treatment is known to cause substantial risk. The dose of aspirin is typically 160 - 325 mg.
• In patients presenting with minor noncardioembolic ischemic stroke (NIHSS score ≤ 3) who did not receive IV alteplase, treatment with dual antiplatelet therapy (aspirin and clopidogrel) started within 24 hours after symptom onset and continued for 21 days is effective in reducing recurrent ischemic stroke for a period of up to 90 days from symptom onset. See dual antiplatelet therapy below.

• Anticoagulants
• Urgent anticoagulation, with the goal of preventing early recurrent stroke, halting neurological worsening, or improving outcomes after AIS, is not recommended for treatment of patients with AIS. [36]

• Atrial fibrillation
• Two recent studies compared early vs late anticoagulation after acute stroke in patients with atrial fibrillation
• The ELAN study (N=2013) published in 2023 compared early (within 48 hours after a minor or moderate stroke or on day 6 or 7 after a major stroke) to late (day 3 or 4 after a minor stroke, day 6 or 7 after a moderate stroke, or day 12, 13, or 14 after a major stroke) anticoagulation in patients with acute stroke and atrial fibrillation. At 30 days, the composite outcome of recurrent ischemic stroke, systemic embolism, major extracranial bleeding, symptomatic intracranial hemorrhage, or vascular death occurred in 2.9% of the early group and 4.1% of the late group (difference -1.18% 95%CI, [-2.84 to 0.47]). [PMID 37222476]
• The TIMING study (N=888) published in 2022 compared early (≤ 4 days after stroke) to delayed (5 - 10 days after stroke) initiation of non-vitamin K antagonist oral anticoagulants in patients with A fib and acute stroke. There was no significant difference in the composite outcome of recurrent ischemic stroke, symptomatic intracerebral hemorrhage, or all-cause mortality at 90 days (6.89% for early vs 8.68% for delayed). [PMID 36065821]

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• ACUTE TREATMENT | Early mobilization

• Overview
• Most stroke guidelines recommend early mobilization after a stroke; however, these same guidelines do not define what early mobilization is or how it should be instituted
• The AVERT trial, published in 2015, compared a protocol of early mobilization to usual care in over 2000 patients with acute stroke

• AHA/ASA early mobilization recommendations
• It is recommended that early rehabilitation for hospitalized stroke patients be provided in environments with organized, interprofessional stroke care
• High-dose, very early mobilization within 24 hours of stroke onset should not be performed because it can reduce the odds of a favorable outcome at 3 months.

• Summary
• The AVERT study found that early mobilization actually led to worse outcomes in stroke patients. The results are counterintuitive and go against most current guidelines.
• The absolute difference between groups was small (4%), but the large study size led to significant results. In a secondary analysis, there was no significant difference in overall Rankin scores between groups.
• The ideal time to initiate mobilization after stroke is unknown, and likely varies by patient population. Given the available information, providers may want to encourage earlier mobilization in healthier patients with less severe strokes. Sicker patients with more severe strokes should probably be eased into mobilization.

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• ACUTE TREATMENT | Hemorrhagic stroke

• Significant hemorrhagic strokes (intracerebral and subarachnoid) are a serious condition with a high mortality rate
• Treatment and management of hemorrhagic stroke is complicated and beyond the scope of our review
• See hemorrhagic stroke above for a brief review of these conditions

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• OTHER TREATMENTS

• Aspiration thrombectomy
• Aspiration thrombectomy involves running a large-bore catheter to the position of the thrombus and aspirating it
• Most successful thrombectomy trials have used stent retrievers. There have now been several trials that have compared aspiration thrombectomy to stent retrievers. The ASTER trial [PMID 28763550 ] and the COMPASS trial [PMID 30860055 ] both found aspiration thrombectomy to be equivalent to stent retrievers for functional outcomes, although in both studies, the aspiration group required stent retrievers as second-line treatment in a portion of patients (COMPASS 21%, ASTER 33%).
• AHA/ASA recommendations
• The use of mechanical thrombectomy devices other than stent retrievers as first-line devices for mechanical thrombectomy may be reasonable in some circumstances, but stent retrievers remain the first choice [32]

• Intracranial angioplasty and stenting
• A handful of studies have looked at angioplasty and stenting for severe intracranial artery stenosis (70 - 99%). These studies have generally found no benefit or harm.
• The SAMMPRIS trial (N=452) compared angioplasty + stenting to medical therapy in patients with 70 - 99% stenosis of a major intracerebral artery. The trial was stopped early when angioplasty + stenting was found to have worse outcomes compared to medical therapy alone. [PMID 21899409, PMID 24168957]. The VISSIT trial (N=112) was also stopped early when balloon-expandable stent + medical therapy was found to be worse than medical therapy alone. [PMID 25803346] A third trial (N=358) published in 2022 found no difference between medical therapy + stenting compared to medical therapy alone. [PMID 35943472]
• The AHA guidelines from 2013 state that the usefulness of intracranial angioplasty and stent placement is not well established, and it should only be used in the setting of clinical trials. [5]

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• SECONDARY PREVENTION | Antiplatelet therapy

• Overview
• For patients without an indication for anticoagulation (e.g. atrial fibrillation), lifelong antiplatelet therapy is recommended in all patients who have experienced a stroke or TIA
• Studies comparing different antiplatelet regimens are detailed below. A study that compared warfarin to aspirin is also summarized.

• AHA/ASA recommendations
• Patients with an indication for anticoagulation
• Patients with an indication for anticoagulation (ex. atrial fibrillation, venous thromboembolism, mechanical heart valve) should receive anticoagulation alone
• Patients with an indication for anticoagulation who cannot receive anticoagulation should receive aspirin alone
• Patients who do not have an indication for anticoagulation (one of the following):
• Aspirin 50 - 325 mg once daily (first-line)
• Aspirin + dipyridamole 25/200 (Aggrenox®) twice a day (second-line)
• Clopidogrel 75 mg once daily (third-line) [29]
• In patients presenting with minor stroke, treatment for 21 days with dual antiplatelet therapy (aspirin and clopidogrel) begun within 24 hours can be beneficial for early secondary stroke prevention for a period of up to 90 days from symptom onset (see dual antiplatelet therapy below) [32]

• Summary
• Aspirin, clopidogrel, and aspirin + dipyridamole (Aggrenox®) all appear to be equally effective for the secondary prevention of stroke
• There is no proven benefit of chronic dual antiplatelet therapy, but recent studies have shown that short-term dual antiplatelet therapy may be beneficial in patients with minor strokes (see dual antiplatelet therapy below)
• In the SOCRATES trial, ticagrelor was not significantly better than aspirin for the primary outcome (p=0.07), but it was superior for preventing all strokes (p=0.03). The study was short, lasting only 90 days.
• The WARSS trial found that warfarin was no better than aspirin in preventing death or stroke in patients with a history of noncardioembolic ischemic stroke. Warfarin had a trend toward greater risk of major hemorrhage.
• In another warfarin trial, 569 patients with 50 - 99% stenosis of a major intracranial artery were randomly assigned to warfarin (INR 2 - 3) or aspirin (1300 mg a day). Patients were enrolled within 90 days of suffering a noncardioembolic TIA or stroke. The primary endpoint was a composite of ischemic stroke, brain hemorrhage, or death from vascular cause. The trial was stopped after 1.8 years when the warfarin group was found to have a significantly higher incidence of death (9.7% vs 4.3%, p=0.02) [PMID 15800226]
• Antiplatelet agents are safer than anticoagulants in patients with a history of noncardioembolic ischemic stroke

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• SECONDARY PREVENTION | Short-term dual antiplatelet therapy (DAPT)

• Overview
• Long-term dual antiplatelet therapy has not been found to be superior to single agent therapy for the secondary prevention of stroke
• Four studies have looked at the effects of short-term dual antiplatelet therapy (≤ 90 days) after ischemic stroke or TIA. Those studies are detailed below.

• AHA/ASA recommendations
• The AHA/ASA 2018 stroke treatment guidelines state the following about short-term dual antiplatelet therapy: "In patients presenting with minor stroke, treatment for 21 days with dual antiplatelet therapy (aspirin and clopidogrel) begun within 24 hours can be beneficial for early secondary stroke prevention for a period of up to 90 days from symptom onset." [32]

• Summary
• The CHANCE study found that 21 days of DAPT with clopidogrel was beneficial in preventing recurrent stroke in high-risk individuals. The POINT trial did not show a clear benefit of 90 days of DAPT. In the THALES trial, 30 days of DAPT with ticagrelor lowered the risk of stroke, increased the risk of severe bleeding, and had no effect on mortality or disability. In the TARDIS trial, clopidogrel + Aggrenox was found to be harmful when compared to either agent alone.
• The CHANCE trial was performed in China where risk factor control (ex. hypertension, diabetes) is often suboptimal compared to developed nations. Also, Asians tend to be poor CYP2C19 metabolizers which means clopidogrel is not as active in this population. These factors along with the shorter duration of dual therapy likely led to the lower bleeding risk seen in the trial.
• In summary, DAPT with clopidogrel for 21 days may be beneficial after minor stroke or TIA. The benefits of other regimens or longer periods of treatment are less clear.

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• SECONDARY PREVENTION | Blood pressure control

• AHA/ASA blood pressure recommendations
• Blood pressure treatment should be resumed or initiated several days after a stroke or TIA
• Ideal blood pressure goals for the secondary prevention of stroke have not been determined
• It is reasonable to treat patients to a BP goal of < 140/90 mmHg
• For patients with a lacunar stroke, a SBP target of < 130 mmHg might be reasonable
• The optimal drug regimen is uncertain, but diuretics or the combination of diuretics and ACE inhibitors may be useful. Drug regimens should be tailored to the individual patient. [29]
• For blood pressure recommendations in acute stroke see BP recommendations in acute stroke above

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• SECONDARY PREVENTION | Statin therapy

• AHA/ASA statin recommendations for secondary prevention of stroke
• Intensive statin therapy is indicated in patients with ischemic stroke or TIA thought to be of atherosclerotic origin
• Statins should be given regardless of LDL level
• Patients who also have coronary artery disease should be treated according to the AHA 2013 cholesterol guidelines [29]
• See statins in stroke prevention for more

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• SECONDARY PREVENTION | Anticoagulation + antiplatelet therapy

• In certain cases, patients with a history of stroke or TIA may have indications for both anticoagulation and antiplatelet therapy. For example, a patient with a history of a DVT and ischemic stroke would have indications for both antiplatelet therapy (stroke) and anticoagulation (DVT prevention).
• Whether these patients should receive both antiplatelet therapy and anticoagulation is a matter of debate. The AHA 2014 guidelines state that "the usefulness of adding antiplatelet therapy to anticoagulation is uncertain" [29]
• A study published in 2019 compared rivaroxaban to rivaroxaban + antiplatelet therapy in patients with A fib and stable CAD. The study found that rivaroxaban monotherapy was superior to combination therapy (see antiplatelet + anticoagulant therapy for more). These results may help guide decision making in patients with a history of ischemic stroke.

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• PRIMARY PREVENTION | Risk factor modification

• Modifiable risk factors for stroke include:
• Carotid stenosis
• Atrial fibrillation
• Cigarette smoking
• Diabetes
• Hypertension
• High cholesterol
• Heavy alcohol use
• Physical inactivity
• Oral contraceptives (have been associated with increased risk of stroke)
• Postmenopausal hormone therapy (should be stopped in women who have suffered stroke or TIA)
• Hypercoagulable disorders

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• PRIMARY PREVENTION | Aspirin

• Overview
• A number of studies have looked at the use of aspirin in the primary prevention of stroke
• In general, these studies have found no significant effect of aspirin in preventing strokes [3,11,12]
• The Women's Health Study detailed below was an enormous study that compared aspirin to placebo in the primary prevention of a number of outcomes

• Professional recommendations
• See primary prevention of CVD with aspirin

• Summary
• For the most part, aspirin has not been found to have an overall beneficial effect in the primary prevention of strokes
• The Women's Health Study was an enormous study that found a slight decrease in stroke risk with aspirin (absolute risk reduction 0.2%, NNT - 500) at a cost of more GI bleeding (absolute risk increase - 0.8%, NNH - 125)
• A more recent smaller study that enrolled patients at high risk for vascular disease found no significant effect of aspirin in preventing strokes (see AAA study)
• If aspirin has an overall benefit in the primary prevention of strokes, the effect is likely very small and limited to people at very high risk

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• RECURRENT STROKE

• Recurrent stroke risk
• In studies, stroke recurrence rates vary greatly depending on the population being studied and the time period in which the study was performed
• Stroke recurrence rates from a Danish registry study that followed patients with first-time ischemic stroke (N=105,397) or intracerebral hemorrhage (N=13,350) from 2004 - 2018 are presented in the table below

• Patients were followed from 2004 - 2018
• Reference [40]

Risk of recurrent stroke after first-time ischemic stroke (N=105,397)
Time since first-stroke	Recurrent stroke
1 year	4%
5 years	10%
10 years	13%
Risk of recurrent stroke after first-time intracerebral hemorrhage (N=13,350)
Time since first-stroke	Recurrent stroke
1 year	3%
5 years	8%
10 years	12%

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• STROKE WHILE TAKING ANTIPLATELET THERAPY

• Overview
• When patients experience a stroke while taking aspirin or other antiplatelet therapies, the question arises as to whether therapy should be changed


• AHA/ASA recommendations
• The AHA 2014 secondary stroke prevention guidelines state that there is no evidence increasing the dose of aspirin or changing antiplatelet therapy provides additional benefit. Long-term dual antiplatelet therapy is not recommended. [29]


• Summary
• There is no good evidence that switching to a different antiplatelet therapy after a stroke is beneficial. Intensive risk factor control (e.g. blood pressure, diabetes) is likely to be most effective.

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• PATENT FORAMEN OVALE (PFO)

• Overview
• Patent Foramen Ovale (PFO) is a congenital heart defect that causes a hole between the left and right atrium. It is one of the most common heart defects with an estimated prevalence of 20 - 26% in the general population.
• In theory, a PFO could allow a blood clot to travel from the venous system to the arterial system by providing a route for the clot to bypass the lungs. Once the blood clot reaches the arterial system, it can cause a stroke. Another proposed mechanism by which PFOs may be associated with greater stroke risk is through in situ thrombus formation within the PFO.
• In some studies, PFOs have been found more frequently in patients who have suffered a cryptogenic stroke. This has led researchers to study the effects of PFO closure on stroke risk. Three studies published in 2012 - 2013 (CLOSURE (2012), RESPECT (2013), PC Trial (2013)) compared PFO closure to medical therapy in patients with a history of cryptogenic stroke or TIA. In all 3 studies, PFO closure was not significantly better than medical therapy. The RESPECT trial had the best results with a trend towards lower recurrent stroke risk in the PFO closure group (p=0.08).
• Despite the lackluster trial results, the FDA approved the Amplatzer PFO Occluder for secondary stroke prevention in 2017. The Amplatzer PFO Occluder was studied in the RESPECT Trial and the PC Trial.
• In 2017, two more PFO closure studies were published. Contrary to the previous studies, these studies did find PFO closure to be superior to medical therapy. One of the trials, the REDUCE trial, is detailed below. The other trial can be found here - CLOSE Trial (2017) [2,39]

• AHA/ASA 2014 recommendations for secondary prevention in patients with PFO
• It is unknown if anticoagulation is superior to antiplatelet therapy. Antiplatelet therapy is recommended in patients who do not have an indication for anticoagulation.
• If a venous source of embolism is identified, anticoagulation is indicated. If anticoagulation is contraindicated, then an inferior vena cava filter is reasonable.
• For patients with a cryptogenic ischemic stroke or TIA without evidence of DVT, PFO closure is not recommended
• For patients with a cryptogenic ischemic stroke or TIA with evidence of DVT, PFO closure by a transcatheter device might be considered depending on the risk of recurrent DVT [29]

• AAN 2020 practice advisory on PFO and secondary stroke prevention
• In patients being considered for PFO closure, clinicians should ensure that an appropriately thorough evaluation has been performed to rule out alternative mechanisms of stroke
• In patients with a higher risk alternative mechanism of stroke identified, clinicians should not routinely recommend PFO closure
• Clinicians should counsel patients that having a PFO is common; that it occurs in about 1 in 4 adults in the general population; that it is difficult to determine with certainty whether their PFO caused their stroke; and that PFO closure probably reduces recurrent stroke risk in select patients
• In patients younger than 60 years with a PFO and embolic-appearing infarct and no other mechanism of stroke identified, clinicians may recommend closure following a discussion of potential benefits (absolute recurrent stroke risk reduction of 3.4% at 5 years) and risks (periprocedural complication rate of 3.9% and increased absolute rate of non-periprocedural atrial fibrillation of 0.33% per year)
• In patients who opt to receive medical therapy alone without PFO closure, clinicians may recommend an antiplatelet medication such as aspirin or anticoagulation [37]

• Summary
• Previous studies did not find a clear benefit with PFO closure where the most recent studies did. In their discussion, the authors of the REDUCE trial note that discontinuation of antiplatelet therapy after PFO closure was allowed in the previous trials while antiplatelet therapy was continued in the later trials. This may account for the differing outcomes.
• It's important to note that PFO closure conferred a 6% risk of new-onset A fib/A flutter. This means patients who underwent PFO closure lowered their stroke risk by about 5% while increasing their A fib risk by 6%. The long-term net effect of this trade-off is unclear.

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