Eligibility criteria for the treatment of acute ischemic stroke with intravenous thrombolysis (recombinant tissue plasminogen activator or tPA)

Inclusion criteria

Clinical diagnosis of ischemic stroke causing measurable neurologic deficit
Onset of symptoms <4.5 hours before beginning treatment; if the exact time of stroke onset is not known, it is defined as the last time the patient was known to be normal or at neurologic baseline
Age ≥18 years

Exclusion criteria

Patient history

Ischemic stroke or severe head trauma in the previous three months
Previous intracranial hemorrhage
Intra-axial intracranial neoplasm
Gastrointestinal malignancy
Gastrointestinal hemorrhage in the previous 21 days
Intracranial or intraspinal surgery within the prior three months

Clinical

Symptoms suggestive of subarachnoid hemorrhage
Persistent blood pressure elevation (systolic ≥185 mmHg or diastolic ≥110 mmHg)
Active internal bleeding
Presentation consistent with infective endocarditis
Stroke known or suspected to be associated with aortic arch dissection
Acute bleeding diathesis, including but not limited to conditions defined under 'Hematologic'

Hematologic

Platelet count <100,000/mm³*
Current anticoagulant use with an INR >1.7 or PT >15 seconds or aPTT >40 seconds*
Therapeutic doses of low molecular weight heparin received within 24 hours (eg, to treat VTE and ACS); this exclusion does not apply to prophylactic doses (eg, to prevent VTE)
Current use (ie, last dose within 48 hours in a patient with normal renal function) of a direct thrombin inhibitor or direct factor Xa inhibitor with evidence of anticoagulant effect by laboratory tests such as aPTT, INR, ECT, TT, or appropriate factor Xa activity assays

Head CT

Evidence of hemorrhage
Extensive regions of obvious hypodensity consistent with irreversible injury

Warnings^¶

Only minor and isolated neurologic signs or rapidly improving symptoms^Δ
Serum glucose <50 mg/dL (<2.8 mmol/L)^◊
Serious trauma in the previous 14 days^§
Major surgery in the previous 14 days^¥
History of gastrointestinal bleeding (remote) or genitourinary bleeding^‡
Seizure at the onset of stroke with postictal neurologic impairments^†
Pregnancy**
Arterial puncture at a noncompressible site in the previous seven days^¶¶
Large (≥10 mm), untreated, unruptured intracranial aneurysm^¶¶
Untreated intracranial vascular malformation^¶¶

Additional warnings for treatment from 3 to 4.5 hours from symptom onset^ΔΔ

Age >80 years
Oral anticoagulant use regardless of INR
Severe stroke (NIHSS score >25)
Combination of both previous ischemic stroke and diabetes mellitus

ACS: acute coronary syndrome; aPTT: activated partial thromboplastin time; ECT: ecarin clotting time; INR: international normalized ratio; PT: prothrombin time; NIHSS: National Institutes of Health Stroke Scale; tPA: tissue plasminogen activator (alteplase or tenecteplase); TT: thrombin time; VTE: venous thromboembolism.

* Although it is desirable to know the results of these tests, thrombolytic therapy should not be delayed while results are pending unless (1) there is clinical suspicion of a bleeding abnormality or thrombocytopenia, (2) the patient is currently on or has recently received anticoagulants (eg, heparin, warfarin, a direct thrombin inhibitor, or a direct factor Xa inhibitor), or (3) use of anticoagulants is not known. Otherwise, treatment with intravenous tPA can be started before availability of coagulation test results but should be discontinued if the INR, PT, or aPTT exceed the limits stated in the table, or if platelet count is <100,000 mm³.

¶ With careful consideration and weighting of risk-to-benefit, patients may receive intravenous thrombolysis despite one or more warnings.

Δ Patients who have a persistent neurologic deficit that is potentially disabling, despite improvement of any degree, should be treated with intravenous thrombolysis in the absence of other contraindications. Any of the following should be considered disabling deficits:

Complete hemianopia: ≥2 on NIHSS question 3, or
Severe aphasia: ≥2 on NIHSS question 9, or
Visual or sensory extinction: ≥1 on NIHSS question 11, or
Any weakness limiting sustained effort against gravity: ≥2 on NIHSS question 5 or 6, or
Any deficits that lead to a total NIHSS >5, or
Any remaining deficit considered potentially disabling in the view of the patient and the treating practitioner using clinical judgment

◊ Patients may be treated with intravenous thrombolysis if glucose level is subsequently normalized.

§ The potential risks of bleeding with tPA from injuries related to the trauma should be weighed against the anticipated benefits of reduced stroke-related neurologic deficits.

¥ The increased risk of surgical site bleeding with tPA should be weighed against the anticipated benefits of reduced stroke-related neurologic deficits.

‡ There is a low increased risk of new bleeding with tPA in the setting of past gastrointestinal or genitourinary bleeding. However, tPA administration within 21 days of gastrointestinal bleeding is not recommended.

† Intravenous thrombolysis is reasonable in patients with a seizure at stroke onset if evidence suggests that residual impairments are secondary to acute ischemic stroke and not to a postictal phenomenon.

** tPA can be given 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 administering tPA is uncertain for these relative exclusions.

ΔΔ Although these were exclusions in the trial showing benefit in the 3 to 4.5 hour window, intravenous tPA appears to be safe and may be beneficial for patients with these criteria, including patients taking oral anticoagulants with an INR <1.7.

Adapted from:

Hacke W, Kaste M, Bluhmki E, et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med 2008; 359:1317.
Del Zoppo GJ, Saver JL, Jauch EC, et al. Expansion of the time window for treatment of acute ischemic stroke with intravenous tissue plasminogen activator. A science advisory from the American Heart Association/American Stroke Association. Stroke 2009; 40:2945.
Re-examining Acute Eligibility for Thrombolysis (TREAT) Task Force:, Levine SR, Khatri P, et al. Review, historical context, and clarifications of the NINDS rt-PA stroke trials exclusion criteria: Part 1: rapidly improving stroke symptoms. Stroke 2013; 44:2500.
Demaerschalk BM, Kleindorfer DO, Adeoye OM, et al. Scientific rationale for the inclusion and exclusion criteria for intravenous alteplase in acute ischemic stroke: A statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2016; 47:581.
Powers WJ, Rabinstein AA, Ackerson T, et al. Guidelines for the Early Management of Patients With Acute Ischemic Stroke: 2019 Update to the 2018 Guidelines for the Early Management of Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke 2019; 50:e344.

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Eligibility criteria for the treatment of acute ischemic stroke with intravenous thrombolysis (recombinant tissue plasminogen activator or tPA)