What is the pathophysiology and management of stroke in adults over 65 with a history of ischemic or hemorrhagic stroke, including treatment options such as antiplatelet therapy with aspirin (acetylsalicylic acid), statins, anticoagulation with warfarin, apixaban, or rivaroxaban, and interventions like carotid endarterectomy or thrombolytic agents like tissue plasminogen activator (tPA)?

Pathophysiology and Management of Stroke in Adults Over 65

Pathophysiology of Ischemic Stroke

Ischemic stroke results from arterial occlusion leading to cerebral hypoperfusion, with distinct mechanisms determining treatment approach. 1

Mechanisms of Ischemic Stroke

• Large artery atherosclerosis accounts for approximately 20-25% of ischemic strokes, caused by atherosclerotic plaque rupture with subsequent thrombosis or artery-to-artery embolism 1
• Cardioembolic stroke represents 20-25% of cases, most commonly from intracardiac thrombi secondary to atrial fibrillation or myocardial infarction 1
• Lacunar infarcts comprise 15-20% of ischemic strokes, resulting from small vessel occlusion due to lipohyalinosis from chronic hypertension 1
• Cryptogenic strokes account for approximately 30% of cases with unknown or less common etiologies 1

Pathophysiological Cascade

• Arterial occlusion triggers an ischemic cascade beginning with energy failure and loss of ionic homeostasis 1
• Cytotoxic edema develops from astrocytic ischemia, leading to brain swelling that can cause mass effect and herniation 1
• Hemorrhagic transformation occurs when reperfusion of damaged blood-brain barrier allows extravasation of blood into infarcted tissue 2
• Neurological deterioration in the acute phase results from progressive stroke (33%), brain swelling (33%), recurrent ischemia (11%), or parenchymal hemorrhage (10%) 1

Pathophysiology of Hemorrhagic Stroke

• Primary intracerebral hemorrhage typically results from rupture of small penetrating arteries damaged by chronic hypertension, amyloid angiopathy in elderly patients, or vascular malformations 1
• Hemorrhagic transformation of ischemic stroke follows the Heidelberg Classification: HI1 (small petechiae at infarct margins), HI2 (confluent petechiae without mass effect), PH1 (blood clot ≤30% of infarct with mild mass effect), and PH2 (larger hemorrhages) 2

Acute Management of Ischemic Stroke

Thrombolytic Therapy

Intravenous tissue plasminogen activator (tPA) remains the cornerstone of acute ischemic stroke treatment for eligible patients, with the goal of early reperfusion to minimize neurologic impairment and disability. 1

• tPA administration should target restoration of cerebral perfusion within the therapeutic window to achieve favorable functional outcome (modified Rankin Scale score ≤1) 1
• Mechanical thrombectomy provides an alternative reperfusion strategy through endovascular clot removal, targeting functional independence (mRS ≤2) 1
• Aspirin 160-325 mg should be administered within 48 hours of symptom onset to reduce stroke mortality and morbidity, provided the patient has not received tPA 1

Management of Patients on NOACs

• Patients taking NOACs (dabigatran, rivaroxaban, apixaban) who present with acute ischemic stroke may receive tPA, though current guidelines urge caution 3
• Idarucizumab reversal for dabigatran-treated patients before tPA administration was associated with more favorable outcomes (79.1% versus 39.2%) and lower symptomatic intracranial hemorrhage rates (4.5% versus 7.4%) in observational data 3
• Laboratory testing with sensitive assays (thrombin time, diluted thrombin time, or anti-Xa) is rarely performed but should be considered when feasible 3

Acute Anticoagulation

Immediate anticoagulation with unfractionated heparin or low molecular weight heparins is NOT recommended for acute ischemic stroke, as bleeding risks outweigh benefits. 1

• Dose-adjusted unfractionated heparin is not recommended for reducing morbidity, mortality, or early recurrent stroke because evidence indicates it is not efficacious and may increase bleeding complications 1
• High-dose LMWH/heparinoids have not been associated with benefit or harm and are therefore not recommended 1
• Subcutaneous unfractionated heparin reduces early recurrent ischemic stroke but this benefit is negated by concomitant increase in hemorrhage 1
• No specific stroke subtype (cardioembolic, large vessel atherosclerotic, vertebrobasilar, or "progressing" stroke) benefits from immediate IV heparin or high-dose LMWH based on available data 1

Secondary Prevention: Noncardioembolic Stroke

For patients with noncardioembolic ischemic stroke or TIA, long-term single antiplatelet therapy with clopidogrel 75 mg daily or aspirin/extended-release dipyridamole 25/200 mg twice daily is recommended over aspirin alone. 1

Antiplatelet Therapy Selection

• Clopidogrel 75 mg once daily or aspirin/extended-release dipyridamole 25/200 mg twice daily are preferred over aspirin 75-100 mg once daily for superior stroke prevention 1
• Aspirin 75-100 mg once daily remains acceptable when other agents are not tolerated or available 1
• Cilostazol 100 mg twice daily is an alternative option, though less preferred than clopidogrel or aspirin/dipyridamole 1
• Combination clopidogrel plus aspirin is NOT recommended for long-term secondary prevention due to increased bleeding risk without additional benefit 1
• Oral anticoagulants are NOT recommended for noncardioembolic stroke as they provide no advantage over antiplatelet therapy 1

Short-Term Dual Antiplatelet Therapy

• DAPT with aspirin and clopidogrel for 21-30 days is more effective than single antiplatelet therapy in patients with minor acute non-cardioembolic stroke or high-risk TIA 4
• Confirm absence of hemorrhagic transformation on neuroimaging before initiating DAPT 2
• Prolonged DAPT beyond 90 days increases bleeding risks without additional benefit in most patients 4
• DAPT for 90 days followed by aspirin monotherapy is appropriate for patients with large vessel intracranial atherosclerotic disease 4

Secondary Prevention: Cardioembolic Stroke (Atrial Fibrillation)

For patients with ischemic stroke or TIA and atrial fibrillation, oral anticoagulation is strongly recommended over antiplatelet therapy alone, with direct oral anticoagulants preferred over warfarin. 1

Anticoagulant Selection

• Dabigatran 150 mg twice daily is preferred over warfarin (target INR 2.0-3.0) for stroke prevention in atrial fibrillation 1
• Rivaroxaban and apixaban are also effective alternatives to warfarin with decreased bleeding risks, including lower intracranial hemorrhage rates 5, 6
• DOACs offer advantages over warfarin including no INR monitoring, no dietary restrictions, and limited drug-drug interactions 4, 5
• Warfarin remains appropriate when DOACs are contraindicated or unavailable, targeting INR 2.0-3.0 1, 7
• Aspirin plus clopidogrel should be used only for patients unsuitable for or refusing oral anticoagulation 1

Timing of Anticoagulation Initiation

Oral anticoagulation should generally be initiated within 1-2 weeks after stroke onset, with timing adjusted based on infarct size and hemorrhagic transformation risk. 1

• Earlier anticoagulation (within 1 week) can be considered for patients with small infarct burden and no evidence of hemorrhage on brain imaging 1
• Delayed anticoagulation (beyond 2 weeks) should be considered for patients with extensive infarct burden or significant hemorrhagic transformation 1
• Bridge with aspirin until anticoagulation reaches therapeutic level 1

Special Considerations for DOACs

• Dabigatran is contraindicated in patients with severe renal impairment (creatinine clearance ≤30 mL/min) as it is primarily renally excreted 1
• Dose adjustment is required for all DOACs in patients with varying degrees of renal impairment 8

Management After Hemorrhagic Transformation

For patients with hemorrhagic transformation of ischemic stroke, antiplatelet therapy timing depends on the grade of bleeding using the Heidelberg Classification. 2

Algorithm for Antiplatelet Reinitiation

• For HI1 (small petechiae): Initiate antiplatelet therapy within 24-48 hours after confirming no progression on follow-up imaging 2
• For HI2, PH1, PH2 (higher-grade bleeds): Discontinue all antiplatelets for at least 1-2 weeks, then restart after 7-10 days if no hemorrhage expansion 2
• Start with aspirin 160-325 mg as initial loading dose for HI1, then continue standard antiplatelet regimen based on stroke etiology 1, 2
• Begin with single antiplatelet agent (typically aspirin) rather than DAPT for higher-grade hemorrhagic transformation 2
• Avoid immediate reinstitution of antiplatelet therapy in higher-grade hemorrhagic transformation to prevent rebleeding 2
• Avoid prolonged delays in antiplatelet therapy for minor hemorrhagic transformations (HI1) as this increases risk of recurrent ischemic events 2

Anticoagulation After Hemorrhagic Transformation

• For patients with atrial fibrillation and hemorrhagic transformation: Initiate oral anticoagulation more than 3 days after stroke for mild stroke, more than 6-8 days for moderate stroke, and more than 12-14 days for severe stroke after excluding hemorrhagic transformation 2
• Risk factors supporting delayed restart (7-14 days) include advanced age, uncontrolled hypertension, and microbleeds on MRI suggesting cerebral amyloid angiopathy 2

Management After Primary Intracerebral Hemorrhage

For patients with history of primary intracerebral hemorrhage, long-term antithrombotic therapy is generally NOT recommended for stroke prevention. 1

Exceptions to Antithrombotic Avoidance

• Patients at relatively low risk of recurrent ICH (deep hemorrhages) AND relatively high risk of thromboembolic events (>7% per year, such as mechanical heart valves or CHADS₂ score ≥4 points) may benefit from antithrombotic therapy 1
• Balance thromboembolism risk against recurrent hemorrhage risk on an individual basis 1

Venous Thromboembolism Prophylaxis

For hospitalized stroke patients with restricted mobility, prophylactic-dose low molecular weight heparin is recommended over unfractionated heparin for DVT prevention. 1

Ischemic Stroke Patients

• Prophylactic-dose LMWH is preferred over prophylactic-dose unfractionated heparin 1
• Subcutaneous heparin or LMWH may be used for DVT prophylaxis, recognizing that benefit in reducing pulmonary embolism has not been demonstrated 1
• Aspirin is a potential intervention for DVT prevention but is less effective than anticoagulants 1
• Intermittent external compression devices are recommended for patients who cannot receive anticoagulants 1

Hemorrhagic Stroke Patients

• Prophylactic-dose subcutaneous heparin (UFH or LMWH) started between days 2-4 or intermittent pneumatic compression devices are recommended over no prophylaxis 1
• Prophylactic-dose LMWH is preferred over prophylactic-dose UFH 1
• Elastic compression stockings are NOT recommended 1
• Patients preferring to avoid rebleeding risk with heparin should favor mechanical prophylaxis with intermittent pneumatic compression devices 1

Surgical Interventions

Carotid Endarterectomy

• Symptomatic patients with anterior circulation TIAs or minor completed strokes and carotid stenosis >70% benefit from carotid endarterectomy when performed in low-risk settings (perioperative stroke and death rate <6%) 1
• Patients with <30% stenosis have worse outcomes with carotid endarterectomy and should not undergo the procedure 1
• Evidence is less clear for patients with 30-70% stenosis or asymptomatic patients with high-grade stenosis 1

Risk Factor Management

All stroke patients require aggressive management of modifiable risk factors including hypertension, diabetes, hyperlipidemia, and smoking cessation. 1

Statin Therapy

• Statins should be initiated for treatment of hyperlipidemia as part of comprehensive secondary stroke prevention 1
• Lifestyle modifications including smoking cessation and dietary changes are essential components of stroke prevention 1

Blood Pressure Management

• Hypertension control is critical for preventing both ischemic and hemorrhagic stroke recurrence, particularly for lacunar stroke prevention 1

Common Pitfalls to Avoid

• Do not use immediate IV anticoagulation for acute ischemic stroke outside of specific clinical trial settings, as bleeding risks outweigh benefits 1
• Do not assume cardioembolic stroke requires immediate anticoagulation; early recurrent cardioembolic stroke risk is low and may be outweighed by bleeding risk 1
• Do not continue DAPT beyond 21-30 days in minor stroke/high-risk TIA patients without large vessel atherosclerosis, as bleeding risk increases without additional benefit 4
• Do not initiate DAPT before confirming absence of hemorrhagic transformation on neuroimaging 2
• Do not delay antiplatelet therapy for minor hemorrhagic transformations (HI1) beyond 48 hours, as this increases recurrent ischemic event risk 2
• Do not use combination clopidogrel plus aspirin for long-term secondary prevention in noncardioembolic stroke 1
• Do not prescribe dabigatran to patients with severe renal impairment (creatinine clearance ≤30 mL/min) 1
• Do not restart antithrombotic therapy immediately after primary intracerebral hemorrhage unless thromboembolism risk is exceptionally high (>7% per year) 1