Residency · Residency · Emergency Medicine

Acute Ischemic Stroke: Thrombolytics and Thrombectomy

Epidemiology and Pathophysiology

Overview

Stroke is the fifth leading cause of death in the United States and the leading cause of long-term disability. Approximately 87 percent of strokes are ischemic, 10 percent are intracerebral hemorrhage, and 3 percent are subarachnoid hemorrhage. The ischemic penumbra concept is central to acute stroke management: a core of irreversibly infarcted tissue is surrounded by at-risk but salvageable tissue that can be rescued with timely reperfusion. Time is brain — approximately 1.9 million neurons die per minute of untreated large vessel occlusion.

Stroke Subtypes

Large vessel atherosclerosis involves the carotid, vertebral, and intracranial arteries. Cardioembolic stroke most commonly arises from atrial fibrillation but can also result from valvular disease or left ventricular thrombus. Small vessel (lacunar) strokes result from lipohyalinosis of perforating arteries and present as pure motor, pure sensory, or ataxic hemiparesis syndromes. Other causes include dissection, hypercoagulable states, and vasculitis. Cryptogenic strokes — those with no identified cause despite workup — account for up to 25 percent of cases.

ED Evaluation

Rapid Assessment

The last known well (LKW) time is the critical data point for treatment decisions — not the time of symptom discovery. Prehospital stroke scales such as the Cincinnati (FAST), LAMS, and RACE scales are designed for EMS triage. The NIHSS (National Institutes of Health Stroke Scale) provides a standardized severity assessment that guides treatment decisions: a score of 0 indicates no deficit, 1 to 4 is a minor stroke, 5 to 15 is moderate, 16 to 20 is moderate-severe, and 21 to 42 is severe. Glucose must be checked immediately because hypoglycemia is a common stroke mimic. The door-to-CT time target is less than 20 minutes.

Imaging

Non-Contrast CT Head

Non-contrast CT is the first-line imaging study, primarily to exclude hemorrhage. Early ischemic changes include loss of gray-white differentiation, sulcal effacement, and the hyperdense vessel sign. The ASPECTS (Alberta Stroke Program Early CT Score) is a 10-point scale assessing the MCA territory, where a score below 6 has historically been associated with poor outcome, though newer trials have challenged this threshold.

CT Angiography (CTA)

CTA identifies large vessel occlusion (LVO), which is essential for determining thrombectomy candidacy. It should be obtained concurrently with the non-contrast CT and must not be delayed for creatinine results — the risk of contrast-induced nephropathy is vastly overstated and should never delay CTA in the setting of acute stroke.

CT Perfusion (CTP)

CT perfusion defines the ischemic core versus the penumbra using cerebral blood flow and Tmax maps. It is particularly important for extended window cases (6 to 24 hours), where mismatch between the core infarct and the at-risk tissue determines eligibility for thrombectomy. CTP was used in both the DAWN and DEFUSE-3 trials to select patients for late-window intervention.

MRI

Diffusion-weighted imaging (DWI) is the most sensitive sequence for acute ischemia but is not typically obtained acutely in most EDs due to time constraints. MRI with DWI/FLAIR mismatch can help identify patients with unknown time of onset, such as wake-up strokes.

Intravenous Thrombolysis

Alteplase (tPA)

The standard dose of alteplase is 0.9 mg/kg (maximum 90 mg), with 10 percent given as a bolus and the remainder infused over 60 minutes. The time window extends to 4.5 hours from last known well. The number needed to treat is approximately 10 at 3 hours and approximately 20 at 4.5 hours. The NINDS trial established benefit within 3 hours, and ECASS III extended the window to 4.5 hours with additional exclusion criteria.

Tenecteplase

Tenecteplase is increasingly used as an alternative to alteplase. It is administered as a single IV bolus at 0.25 mg/kg, making it easier to administer with simpler logistics and faster administration compared to the alteplase infusion. Trials including AcT-TRACE and EXTEND-IA TNK suggest non-inferiority or superiority to alteplase for large vessel occlusion. Many stroke centers have already transitioned to tenecteplase, and the AHA/ASA 2024 guidelines now include it as an option.

Inclusion Criteria (Standard 0-3 Hour Window)

Inclusion criteria for the standard window include a clinical diagnosis of ischemic stroke with a measurable neurologic deficit, onset or last known well time within 3 hours, age 18 years or older, and CT without hemorrhage.

Extended Window (3-4.5 Hours) — Additional Exclusions

Additional exclusions for the extended window include age over 80 (though this is increasingly considered relative in current practice), NIHSS greater than 25, a history of both prior stroke and diabetes, and use of oral anticoagulants regardless of INR.

Absolute Contraindications

Absolute contraindications to thrombolysis include intracranial hemorrhage on CT, active internal bleeding, platelet count below 100,000, INR greater than 1.7 or PT greater than 15 seconds, heparin use within 48 hours with an elevated aPTT, recent intracranial or spinal surgery (within 3 months), history of intracranial hemorrhage, and acute aortic dissection.

Post-tPA Management

After thrombolysis, the patient requires ICU or stroke unit monitoring. Antiplatelets and anticoagulants are avoided for 24 hours. Blood pressure is maintained below 180/105 mmHg for 24 hours. A repeat non-contrast CT is obtained at 24 hours before starting antiplatelets. Monitoring for angioedema is important — orolingual angioedema occurs in 2 to 5 percent of cases, often contralateral to the ischemic hemisphere, and is treated with epinephrine and antihistamines, with intubation considered if there is airway compromise.

Endovascular Thrombectomy

Standard Window (0-6 Hours)

The landmark trials — MR CLEAN, ESCAPE, EXTEND-IA, SWIFT PRIME, and REVASCAT — provided overwhelming evidence for thrombectomy in large vessel occlusion within 6 hours. The number needed to treat is approximately 2.6, making thrombectomy one of the most powerful treatment effects in all of medicine. Eligible patients have a large vessel occlusion (ICA, M1, and sometimes M2 MCA or basilar), NIHSS of 6 or greater, ASPECTS of 6 or greater, and pre-stroke modified Rankin Scale of 0 to 1.

Extended Window (6-24 Hours)

The DAWN trial demonstrated benefit from 6 to 24 hours using clinical-core mismatch (NIHSS versus core infarct volume on CTP or MRI). The DEFUSE-3 trial showed benefit from 6 to 16 hours using perfusion mismatch (penumbra-to-core ratio). Both trials demonstrated dramatic benefit of thrombectomy in carefully selected patients. The key is patient selection through advanced imaging with CT perfusion or MRI perfusion.

Large Vessel Occlusion Detection

Screening scales such as LAMS, RACE, and VAN help EMS identify large vessel occlusion for routing to thrombectomy-capable centers. CTA remains the definitive test. Common LVO sites include the terminal ICA, M1 MCA, and basilar artery. Evidence for M2 and posterior circulation thrombectomy is growing but less robust.

Basilar Artery Occlusion

The ATTENTION and BAOCHE trials demonstrated benefit from thrombectomy for basilar artery occlusion within 24 hours. The natural history without treatment is devastating. Presentation includes altered consciousness, bilateral motor findings, cranial nerve palsies, and locked-in syndrome.

Blood Pressure Management

Pre-Thrombolysis

If tPA is to be administered, blood pressure must be below 185/110 mmHg before administration. Agents include labetalol 10 to 20 mg IV, nicardipine infusion starting at 5 mg/hr (titrated up to 15 mg/hr), and clevidipine.

Post-Thrombolysis

Blood pressure is maintained below 180/105 mmHg for 24 hours after thrombolysis.

No Thrombolysis

When thrombolytics are not given, permissive hypertension up to 220/120 mmHg is allowed to maintain perfusion to the ischemic penumbra. Treatment is indicated if blood pressure exceeds 220/120 or if end-organ damage is present.

Stroke Mimics

Common stroke mimics include hypoglycemia (which is why glucose should always be checked first), seizure with postictal Todd's paralysis, complex migraine with aura, conversion disorder or functional neurologic disorder, and intracranial mass lesions. The rate of mimics receiving tPA is 1 to 3 percent, and this is generally safe with a very low complication rate in mimics.

<image>A CT perfusion imaging panel showing three maps of the brain in a patient with an acute MCA territory stroke. Map 1: Cerebral blood flow (CBF) showing a small area of markedly reduced flow (ischemic core) in the left MCA territory. Map 2: Tmax map showing a much larger area with Tmax greater than 6 seconds representing the ischemic penumbra (at-risk tissue). Map 3: A summary mismatch map with the core in red and the penumbra in green, demonstrating a favorable mismatch ratio (large penumbra relative to small core), indicating the patient is a candidate for thrombectomy in the extended window.</image>

<image>A timeline infographic showing the key stroke treatment windows. At 0 hours: symptom onset, door-to-CT target less than 20 minutes, door-to-needle target less than 45 minutes. At 3 hours: standard tPA window closes (NINDS). At 4.5 hours: extended tPA window closes (ECASS III). At 6 hours: standard thrombectomy window closes (MR CLEAN, ESCAPE, etc.). At 16 hours: DEFUSE-3 extended thrombectomy window (with perfusion imaging selection). At 24 hours: DAWN trial extended thrombectomy window (with clinical-core mismatch). Below the timeline, key trials are listed at their respective time points with the qualifying imaging criteria.</image>

<image>A diagram showing the NIH Stroke Scale assessment components with scoring. Items include: level of consciousness (0-3), LOC questions (0-2), LOC commands (0-2), best gaze (0-2), visual fields (0-3), facial palsy (0-3), motor arm right and left (0-4 each), motor leg right and left (0-4 each), limb ataxia (0-2), sensory (0-2), best language (0-3), dysarthria (0-2), and extinction/inattention (0-2). Total possible score is 42.</image>

Clinical Pearls

Last known well time, not the time of symptom discovery, determines the treatment window. CTA must not be delayed for creatinine — the risk of contrast nephropathy is far outweighed by the benefit of identifying a large vessel occlusion. Thrombectomy for LVO has a number needed to treat of approximately 2.6, making it one of the most effective treatments in all of medicine. Tenecteplase is a single IV bolus and is increasingly replacing alteplase because of its simpler logistics and elimination of the need for an infusion pump. Extended-window thrombectomy (6 to 24 hours) requires advanced imaging with CT perfusion or MRI to select patients with favorable mismatch profiles. Permissive hypertension up to 220/120 is appropriate for ischemic stroke when thrombolytics are not being given. Hypoglycemia is the most important stroke mimic to exclude immediately, and a fingerstick glucose should always be obtained. Orolingual angioedema post-tPA occurs in 2 to 5 percent of patients and can compromise the airway, so intubation equipment should be readily available.

References

• National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. NEJM. 1995;333:1581-1588.
• Hacke W, et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke (ECASS III). NEJM. 2008;359:1317-1329.
• Goyal M, et al. Endovascular thrombectomy after large-vessel ischaemic stroke: a meta-analysis (HERMES). Lancet. 2016;387:1723-1731.
• Nogueira RG, et al. Thrombectomy 6 to 24 hours after stroke with a mismatch between deficit and infarct (DAWN). NEJM. 2018;378:11-21.
• Albers GW, et al. Thrombectomy for stroke at 6 to 16 hours with selection by perfusion imaging (DEFUSE-3). NEJM. 2018;378:708-718.
• Campbell BCV, et al. Tenecteplase versus alteplase before thrombectomy for ischemic stroke (EXTEND-IA TNK). NEJM. 2018;378:1573-1582.

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