Eligibility recommendations for IV alteplase in patients with acute ischemic stroke

Indications

Within 3 h*

IV alteplase (0.9 mg/kg, maximum dose 90 mg over 60 min with initial 10% of dose given as bolus over 1 min) is recommended for selected patients who may be treated within 3 h of ischemic stroke symptom onset or patient last known well or at baseline state. Physicians should review the criteria outlined in this table to determine patient eligibility.

Age

For otherwise medically eligible patients ≥18 y of age, IV alteplase administration within 3 h is equally recommended for patients <80 and >80 y of age.

Severity

For severe stroke symptoms, IV alteplase is indicated within 3 h from symptom onset of ischemic stroke. Despite increased risk of hemorrhagic transformation, there is still proven clinical benefit for patients with severe stroke symptoms.

For patients with mild but disabling stroke symptoms, IV alteplase is indicated within 3 h from symptom onset of ischemic stroke. There should be no exclusion for patients with mild but nonetheless disabling stroke symptoms, in the opinion of the treating physician, from treatment with IV alteplase because there is proven clinical benefit for those patients.

3–4.5 h*

IV alteplase (0.9 mg/kg, maximum dose 90 mg over 60 min with initial 10% of dose given as bolus over 1 min) is also recommended for selected patients who can be treated within 3 and 4.5 h of ischemic stroke symptom onset or patient last known well. Physicians should review the criteria outlined in this table to determine patient eligibility.

Age, Diabetes mellitus Prior stroke Severity, Oral AnticoagulantCs, Imaging

IV alteplase treatment in the 3- to 4.5-h time window is recommended for those patients ≤80 y of age, without a history of both diabetes mellitus and prior stroke, NIHSS score ≤25, not taking any OACs, and without imaging evidence of ischemic injury involving more than one third of the MCA territory.

Urgency

Treatment should be initiated as quickly as possible within the above listed time frames because time to treatment is strongly associated with outcomes.

BP

IV alteplase is recommended in patients whose BP can be lowered safely (to <185/110 mm Hg) with antihypertensive agents, with the physician assessing the stability of the BP before starting IV alteplase.

Blood glucose

IV alteplase is recommended in otherwise eligible patients with initial glucose levels >50 mg/dL.

CT

IV alteplase administration is recommended in the setting of early ischemic changes on NCCT of mild to moderate extent (other than frank hypodensity).

Prior antiplatelet therapy

IV alteplase is recommended for patients taking antiplatelet drug monotherapy before stroke on the basis of evidence that the benefit of alteplase outweighs a possible small increased risk of sICH.

IV alteplase is recommended for patients taking antiplatelet drug combination therapy (eg, aspirin and clopidogrel) before stroke on the basis of evidence that the benefit of alteplase outweighs a probable increased risk of sICH.

End-stage renal disease

In patients with end-stage renal disease on hemodialysis and normal aPTT, IV alteplase is recommended. However, those with elevated aPTT may have elevated risk for hemorrhagic complications.

Contraindications

Time of onset

IV alteplase is not recommended in ischemic stroke patients who have an unclear time and/or unwitnessed symptom onset and in whom the time last known to be at baseline state is >3 or 4.5 h.

IV alteplase is not recommended in ischemic stroke patients who awoke with stroke with time last known to be at baseline state >3 or 4.5 h.

CT

IV alteplase should not be administered to a patient whose CT reveals an acute intracranial hemorrhage.

There remains insufficient evidence to identify a threshold of hypoattenuation severity or extent that affects treatment response to alteplase. However, administering IV alteplase to patients whose CT brain imaging exhibits extensive regions of clear hypoattenuation is not recommended. These patients have a poor prognosis despite IV alteplase, and severe hypoattenuation defined as obvious hypodensity represents irreversible injury.

Ischemic stroke within 3 mo

Use of IV alteplase in patients presenting with AIS who have had a prior ischemic stroke within 3 mo may be harmful.

Severe head trauma within 3 mo

In AIS patients with recent severe head trauma (within 3 mo), IV alteplase is contraindicated.

Given the possibility of bleeding complications from the underlying severe head trauma, IV alteplase should not be administered in posttraumatic infarction that occurs during the acute in-hospital phase.

Intracranial/intraspinal surgery within 3 mo

For patients with AIS and a history of intracranial/spinal surgery within the prior 3 mo, IV alteplase is potentially harmful.

History of intracranial hemorrhage

IV alteplase administration in patients who have a history of intracranial hemorrhage is potentially harmful.

Subarachnoid hemorrhage

IV alteplase is contraindicated in patients presenting with symptoms and signs most consistent with an SAH.

GI malignancy or GI bleed within 21 d

Patients with a structural GI malignancy or recent bleeding event within 21 d of their stroke event should be considered high risk, and IV alteplase administration is potentially harmful.

Coagulopathy

The safety and efficacy of IV alteplase for acute stroke patients with platelets <100 000/mm3, INR >1.7, aPTT >40 s, or PT >15 s are unknown, and IV alteplase should not be administered.

(In patients without history of thrombocytopenia, treatment with IV alteplase can be initiated before availability of platelet count but should be discontinued if platelet count is <100 000/mm3. In patients without recent use of OACs or heparin, treatment with IV alteplase can be initiated before availability of coagulation test results but should be discontinued if INR is >1.7 or PT is abnormally elevated by local laboratory standards.)

LMWH

IV alteplase should not be administered to patients who have received a treatment dose of LMWH within the previous 24 h.

Thrombin inhibitors or factor Xa inhibitors

The use of IV alteplase in patients taking direct thrombin inhibitors or direct factor Xa inhibitors has not been firmly established but may be harmful. IV alteplase should not be administered to patients taking direct thrombin inhibitors or direct factor Xa inhibitors unless laboratory tests such as aPTT, INR, platelet count, ecarin clotting time, thrombin time, or appropriate direct factor Xa activity assays are normal or the patient has not received a dose of these agents for >48 h (assuming normal renal metabolizing function).

(Alteplase could be considered when appropriate laboratory tests such as aPTT, INR, ecarin clotting time, thrombin time, or direct factor Xa activity assays are normal or when the patient has not taken a dose of these ACs for >48 h and renal function is normal.)

Glycoprotein IIb/IIIa receptor inhibitors

Antiplatelet agents that inhibit the glycoprotein IIb/IIIa receptor should not be administered concurrently with IV alteplase outside a clinical trial.

Infective endocarditis

For patients with AIS and symptoms consistent with infective endocarditis, treatment with IV alteplase should not be administered because of the increased risk of intracranial hemorrhage.

Aortic arch dissection

IV alteplase in AIS known or suspected to be associated with aortic arch dissection is potentially harmful and should not be administered.

Intra-axial intracranial neoplasm

IV alteplase treatment for patients with AIS who harbor an intra-axial intracranial neoplasm is potentially harmful.

Additional recommendations for treatment with IV alteplase for patients with AIS

Extended 3- to 4.5-h window

For patients >80 y of age presenting in the 3- to 4.5-h window, IV alteplase is safe and can be as effective as in younger patients.

For patients taking warfarin and with an INR ≤1.7 who present in the 3- to 4.5-h window, IV alteplase appears safe and may be beneficial.

In AIS patients with prior stroke and diabetes mellitus presenting in the 3- to 4.5- h window, IV alteplase may be as effective as treatment in the 0- to 3-h window and may be a reasonable option.

Severity 0- to 3-h window

Within 3 h from symptom onset, treatment of patients with mild ischemic stroke symptoms that are judged as nondisabling may be considered. Treatment risks should be weighed against possible benefits; however, more study is needed to further define the risk- to-benefit ratio.

Severity 3- to 4.5-h window

For otherwise eligible patients with mild stroke presenting in the 3- to 4.5-h window, IV alteplase may be as effective as treatment in the 0- to 3-h window and may be a reasonable option. Treatment risks should be weighed against possible benefits.

The benefit of IV alteplase between 3 and 4.5 h from symptom onset for patients with very severe stroke symptoms (NIHSS > 25) is uncertain.

Preexisting disability

Preexisting disability does not seem to independently increase the risk of sICH after IV alteplase, but it may be associated with less neurological improvement and higher mortality. Thrombolytic therapy with IV alteplase for acute stroke patients with preexisting disability (mRS score ≥2) may be reasonable, but decisions should take into account relevant factors, including quality of life, social support, place of residence, need for a caregiver, patients’ and families’ preferences, and goals of care.

Patients with preexisting dementia may benefit from IV alteplase. Individual considerations such as life expectancy and premorbid level of function are important to determine whether alteplase may offer a clinically meaningful benefit.

Early improvement

IV alteplase treatment is reasonable for patients who present with moderate to severe ischemic stroke and demonstrate early improvement but remain moderately impaired and potentially disabled in the judgment of the examiner.

Seizure at onset

IV alteplase is reasonable in patients with a seizure at the time of onset of acute stroke if evidence suggests that residual impairments are secondary to stroke and not a postictal phenomenon.

Blood glucose

Treatment with IV alteplase in patients with AIS who present with initial glucose levels <50 or >400 mg/dL that are subsequently normalized and who are otherwise eligible may be reasonable.

Coagulopathy

The safety and efficacy of IV alteplase for acute stroke patients with a clinical history of potential bleeding diathesis or coagulopathy are unknown. IV alteplase may be considered on a case-by-case basis.

IV alteplase may be reasonable in patients who have a history of warfarin use and an INR ≤1.7 and/or a PT <15 s.

Dural puncture

IV alteplase may be considered for patients who present with AIS, even in instances when they may have undergone a lumbar dural puncture in the preceding 7 d.

Arterial puncture

The safety and efficacy of administering IV alteplase to acute stroke patients who have had an arterial puncture of a noncompressible blood vessel in the 7 d preceding stroke symptoms are uncertain.

Recent major trauma

In AIS patients with recent major trauma (within 14 d) not involving the head, IV alteplase may be carefully considered, with the risks of bleeding from injuries related to the trauma weighed against the severity and potential disability from the ischemic stroke.

Recent major surgery

Use of IV alteplase in carefully selected patients presenting with AIS who have undergone a major surgery in the preceding 14 d may be considered, but the potential increased risk of surgical-site hemorrhage should be weighed against the anticipated benefits of reduced stroke related neurological deficits.

GI and genitourinary bleeding

Reported literature details a low bleeding risk with IV alteplase administration in the setting of past GI/genitourinary bleeding. Administration of IV alteplase in this patient population may be reasonable.(Note: Alteplase administration within 21 d of a GI bleeding event is not recommended; see Contraindications.)

Menstruation

IV alteplase is probably indicated in women who are menstruating who present with AIS and do not have a history of menorrhagia. However, women should be warned that alteplase treatment could increase the degree of menstrual flow.

Because the potential benefits of IV alteplase probably outweigh the risks of serious bleeding in patients with recent or active history of menorrhagia without clinically significant anemia or hypotension, IV alteplase administration may be considered.

When there is a history of recent or active vaginal bleeding causing clinically significant anemia, then emergency consultation with a gynecologist is probably indicated before a decision about IV alteplase is made.

Extracranial cervical dissections

IV alteplase in AIS known or suspected to be associated with extracranial cervical arterial dissection is reasonably safe within 4.5 h and probably recommended.

Intracranial arterial dissection

IV alteplase usefulness and hemorrhagic risk in AIS known or suspected to be associated with intracranial arterial dissection remain unknown, uncertain, and not well established.

Unruptured intracranial aneurysm

For patients presenting with AIS who are known to harbor a small or moderate-sized (<10 mm) unruptured and unsecured intracranial aneurysm, administration of IV alteplase is reasonable and probably recommended.

Usefulness and risk of IV alteplase in patients with AIS who harbor a giant unruptured and unsecured intracranial aneurysm are not well established.

Intracranial vascular malformations

For patients presenting with AIS who are known to harbor an unruptured and untreated intracranial vascular malformation the usefulness and risks of administration of IV alteplase are not well established.

Because of the increased risk of ICH in this population of patients, IV alteplase may be considered in patients with stroke with severe neurological deficits and a high likelihood of morbidity and mortality to outweigh the anticipated risk of ICH secondary to thrombolysis.

CMBs

In otherwise eligible patients who have previously had a small number (1–10) of CMBs demonstrated on MRI, administration of IV alteplase is reasonable.

In otherwise eligible patients who have previously had a high burden of CMBs (>10) demonstrated on MRI, treatment with IV alteplase may be associated with an increased risk of sICH, and the benefits of treatment are uncertain. Treatment may be reasonable if there is the potential for substantial benefit.

Extra-axial intracranial neoplasms

IV alteplase treatment is probably recommended for patients with AIS who harbor an extra-axial intracranial neoplasm.

Acute MI

For patients presenting with concurrent AIS and acute MI, treatment with IV alteplase at the dose appropriate for cerebral ischemia, followed by percutaneous coronary angioplasty and stenting if indicated, is reasonable.

Recent MI

For patients presenting with AIS and a history of recent MI in the past 3 mo, treating the ischemic stroke with IV alteplase is reasonable if the recent MI was non-STEMI.

For patients presenting with AIS and a history of recent MI in the past 3 mo, treating the ischemic stroke with IV alteplase is reasonable if the recent MI was a STEMI involving the right or inferior myocardium.

For patients presenting with AIS and a history of recent MI in the past 3 mo, treating the ischemic stroke with IV alteplase may reasonable if the recent MI was a STEMI involving the left anterior myocardium.

Other cardiac diseases

For patients with major AIS likely to produce severe disability and acute pericarditis, treatment with IV alteplase may be reasonable; urgent consultation with a cardiologist is recommended in this situation.

For patients presenting with moderate AIS likely to produce mild disability and acute pericarditis, treatment with IV alteplase is of uncertain net benefit.

For patients with major AIS likely to produce severe disability and known left atrial or ventricular thrombus, treatment with IV alteplase may be reasonable.

For patients presenting with moderate AIS likely to produce mild disability and known left atrial or ventricular thrombus, treatment with IV alteplase is of uncertain net benefit.

For patients with major AIS likely to produce severe disability and cardiac myxoma, treatment with IV alteplase may be reasonable.

For patients presenting with major AIS likely to produce severe disability and papillary fibroelastoma, treatment with IV alteplase may be reasonable.

Procedural stroke

IV alteplase is reasonable for the treatment of AIS complications of cardiac or cerebral angiographic procedures, depending on the usual eligibility criteria.

Systemic malignancy

The safety and efficacy of alteplase in patients with current malignancy are not well established. Patients with systemic malignancy and reasonable (>6 mo) life expectancy may benefit from IV alteplase if other contraindications such as coagulation abnormalities, recent surgery, or systemic bleeding do not coexist.

Pregnancy

IV alteplase administration may be considered in pregnancy when the anticipated benefits of treating moderate or severe stroke outweigh the anticipated increased risks of uterine bleeding.

The safety and efficacy of IV alteplase in the early postpartum period (<14 d after delivery) have not been well established.

Ophthalmological conditions

Use of IV alteplase in patients presenting with AIS who have a history of diabetic hemorrhagic retinopathy or other hemorrhagic ophthalmic conditions is reasonable to recommend, but the potential increased risk of visual loss should be weighed against the anticipated benefits of reduced stroke-related neurological deficits.

Sickle cell disease

IV alteplase for adults presenting with an AIS with known sickle cell disease can be beneficial.

Illicit drug use

Treating clinicians should be aware that illicit drug use may be a contributing factor to incident stroke. IV alteplase is reasonable in instances of illicit drug use–associated AIS in patients with no other exclusions.

Stroke mimics

The risk of symptomatic intracranial hemorrhage in the stroke mimic population is quite low; thus, starting IV alteplase is probably recommended in preference over delaying treatment to pursue additional diagnostic studies.

Notes

AC = anticoagulants ACC = American College of Cardiology AIS = acute ischemic stroke AHA = American Heart Association aPTT = activated partial thromboplastin time BP = blood pressure CMB = cerebral microbleed CT = computed tomography GI = gastrointestinal ICH = intracerebral hemorrhage INR = international normalized ratio IV = intravenous LMWH = low-molecular-weight heparin LOE = level of evidence MCA = middle cerebral artery MI = myocardial infarction MRI = magnetic resonance imaging mRS = modified Rankin Scale NCCT = noncontrast computed tomography NIHSS = National Institutes of Health Stroke Scale OAC = oral anticoagulant PT = prothromboplastin time sICH = symptomatic intracerebral hemorrhage STEMI = ST-segment–elevation myocardial infarction.

Source: 2018 Guidelines for the Early Management of Patients With Acute Ischemic Stroke, Stroke. 2018 Mar;49(3):e46-e110