Alteplase in early recurrent ischemic stroke: A case reevaluating the 3-month exclusion criteria for thrombolysis

Dear Editor,

Ischemic strokes are a leading cause of morbidity and mortality worldwide, affecting diverse patient populations.[1] The risk of recurrence is significant, with approximately 25% of patients experiencing a recurrent stroke within 5 years, and the highest risk occurring in the first 90 days after the initial event.[1] Τhrοmbolytic therapy, particularly intravenous alteplase, is the mainstay of treatment to optimize outcomes in acute ischemic Stroke.[1,2,3] However, the 2019 American Heart Association/American Stroke Association (AHA/ASA) guidelines exclude patients with ischemic stroke within the past 3 months from receiving thrombolysis due to concerns about increased bleeding risk.[3,4,5,6] Despite these restrictions, growing clinical experience with thrombolysis has sparked debate about extending alteplase use beyond established guidelines, particularly in patients with early recurrent ischemic strokes who have limited treatment options.[7,8] Current evidence regarding thrombolytic therapy for patients with early recurrent ischemic stroke within 3 months is limited, with only a few studies indicating that thrombolysis is safe and effective.[7,8,9] We encounter a successful case of repeated intravenous thrombolysis with alteplase in an 80-year-old male patient with recurrent ischemic stroke within 10 days after the index stroke.

An 80-year-old male, nonsmoker with a medical history of hypertension and diabetes, presented to our casualty department with complaints of sudden onset speech difficulty and left-sided weakness that had started 90 min earlier. Upon arrival, he was conscious, oriented, exhibiting left-sided hemiparesis, and dysarthria with a National Institutes of Health Stroke Scale (NIHSS) of 11. Brain magnetic resonance imaging (MRI) revealed diffusion-weighted (DW) restriction with apparent diffusion coefficient (ADC) hypointense signal changes in the right corona radiata [Figure 1]. Reperfusion therapy with alteplase (0.9 mg/kg) was administered 2 h and 30 min after symptom onset, resulting in a reduction of his NIHSS to 2 with marked improvement in muscle strength. Further assessment with carotid Doppler showed 30%–40% plaque stenosis at the origins of both internal carotid arteries, though MR angiography did not reveal any significant stenosis [Figure 1]. Comprehensive cardiac evaluations including transthoracic echocardiography, electrocardiogram, and holter monitoring results were normal. He was subsequently started on dual antiplatelet therapy and statins for secondary prevention. On day 10, a Digital subtraction angiogram (DSA) was performed to assess the cerebral vasculature status due to discrepancies between the results of the carotid color Doppler and MR angiogram. Immediately following the procedure, he developed right-sided hemiplegia and aphasia, with a NIHSS of 26. Manual compression was applied to the femoral puncture site, and an urgent brain MRI revealed DW/ADC restriction in the left basal ganglia and corona radiata region, consistent with a new ischemic stroke [Figure 2]. After discussing thrombolytic contraindications with his family, given the patient’s prior successful response to alteplase therapy and review of available evidence supporting thrombolysis in early recurrent ischemic stroke, we decided to proceed with alteplase therapy 45 min after symptom onset. After completion of the alteplase therapy (0.9 mg/kg), his speech and strength returned to normal with an NIHSS of 3. He developed a right-sided inguinoscrotal hematoma at the femoral puncture site, which was managed conservatively. No intracerebral or other significant major bleeding was observed. The following day, dual antiplatelet therapy was resumed, and he was discharged a week later with a modified Rankin Scale (mRS) score of 1. At his 3-month follow-up, his mRS score improved to 0, and he had an NIHSS score of 1.

Figure 1.

(a) Magnetic resonance imaging brain imaging reveals restricted diffusion in the right corona radiata, (b) Left carotid Doppler demonstrates plaque stenosis, (c) Right internal carotid arteries (ICA) Doppler shows plaque-induced stenosis, (d) Magnetic resonance angiography shows normal blood flow at bilateral ICAs origin

Figure 2.

(a) Diffusion-weighted (DW) sequence shows restricted diffusion in the left basal ganglia, (b) DW sequence shows restricted diffusion in the left corona radiata and prior changes in the right corona radiata

The primary goal of thrombolytic therapy for acute ischemic stroke is to restore perfusion to the regions of the brain that are ischemic but not yet infarcted.[1,7] Since the therapeutic benefit is time-sensitive, it is crucial to treat eligible patients as promptly as possible.[2,4] However, a history of recurrent ischemic stroke within the past 3 months has traditionally been considered an exclusion criterion, following criteria established by the original National Institute of Neurological Disorders and Stroke Alteplase trial in 1996. This exclusion appears to have been influenced by thrombolysis studies in acute myocardial infarction. The primary concern for excluding patients with recurrent ischemic stroke within 3 months is the potential for hemorrhage. Repeated thrombolysis could increase bleeding risk due to disrupted blood–brain barrier integrity in previously infarcted tissue. Inflammatory responses at the cellular level also lead to increased capillary permeability, further heightening the risk of hemorrhage.[10] The European Cooperative Acute Stroke Study-III, which extended the time window for alteplase administration, retained this exclusion criterion due to continued concerns regarding hemorrhage risk. Consequently, major guidelines, including the AHA/ASA stroke guidelines, upheld these exclusion criteria, emphasizing the risk of reperfusion injury and blood–brain barrier disruption in previously infarcted tissue. Although this recommendation was initially upheld in the Food and Drug Administration’s alteplase labeling, it was later removed in updated guidelines. In addition, the 2021 European Stroke Organization guidelines do not provide clear guidance on alteplase use in early recurrent stroke.[3,8,9] As a result, many patients with recurrent ischemic stroke are excluded from the benefits of alteplase therapy. While the recurrence rate for ischemic stroke within 90 days is lower with advances in medical management (estimated at 5.0%–7.5%), it remains significant.[1] Excluding these patients from thrombolytic therapy may impose a considerable burden on healthcare systems and negatively impact patient outcomes. Evidence from cardiology and pulmonary medicine demonstrates the safety and efficacy of repeated systemic thrombolysis in myocardial infarction and pulmonary embolism cases.[11] Similarly, although comparative studies are lacking, observational data on recurrent ischemic stroke cases show favorable outcomes in patients receiving alteplase therapy within 3 months of an initial event.[10,11,12]

Recent literature reviews, including a systematic analysis by Sarmiento et al., have challenged the exclusion of patients with recurrent stroke within 3 months, showing comparable rates of symptomatic intracranial hemorrhage (6.2%) to the initial alteplase trial.[12,13] A systematic review by Wen et al. covering 24 cases of repeated thrombolysis within 3 months, suggesting that recurrent alteplase therapy can be considered in patients with lower NIHSS scores and positive outcomes from previous thrombolysis.[10] Heldner et al. also advise against withholding thrombolysis based on recent stroke alone, while Karlinski et al. report that early repeat alteplase therapy does not worsen outcomes compared to initial thrombolysis.[4,8] Caplan has also argued that rigid time windows in stroke treatment may be outdated, advocating for a more individualized, benefit-risk approach. He proposes advanced imaging techniques can provide valuable insights to guide treatment decisions. Even in the absence of advanced imaging, he emphasizes that clinicians should weigh potential benefits against risks rather than relying solely on time-based exclusion criteria.[14] Despite the limited number of cases and outcome data, these findings collectively support the need for larger studies to clarify the safety and efficacy of early recurrent thrombolysis.

This report presents another successful application of intravenous thrombolysis in an early recurrent ischemic stroke, and demonstrates a favorable functional outcome, providing valuable insights into the possible guideline adaptations for select cases. In this case, the patient presented with a recurrent stroke only 10 days after initial thrombolysis for right corona radiata infarction, with substantial recovery following the first alteplase administration. While conservative management might typically be chosen in such cases, the decision to proceed with thrombolysis during the early recurrence was challenging and required careful consideration of the available evidence, particularly due to concerns over hemorrhagic transformation. After evaluating the patient’s stability postfirst thrombolysis and reviewing available literature suggesting the potential safety of repeated thrombolysis in ischemic stroke, alteplase was administered with favorable results. While a subcutaneous hematoma occurred at the femoral puncture site, no intracranial hemorrhage or neurological decline was observed. The rapid and favorable response to thrombolysis in our patient suggests that, in carefully selected cases, an approach extending beyond standard guidelines can be safe and effective. However, treatment decisions should be individualized, with careful consideration of the potential risks and benefits.

While a single case does not warrant changes to existing guidelines, it adds to the growing body of literature on alteplase use in early recurrent stroke and underscores the need for further research to refine treatment protocols. This case supports the potential for thrombolytic therapy in selected cases of early recurrent ischemic stroke, contributing to the ongoing discussion on expanding thrombolysis eligibility criteria. This case suggests that, in select cases, thrombolysis beyond conventional limits may offer clinical benefits, emphasizing the importance of future studies to establish clearer guidelines.

Author contributions

Concept and Design: RK. Analysis and interpretation: RK. Data collection: RK, DV, JS. Writing the article: RK, DV. Critical revision of article: RK, DV, JS.

Ethical policy and institutional review board statement

The study was performed in accordance with the Declaration of Helsinki.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given her consent for her images and other clinical information to be reported in the journal. The patient understands that name and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed.

Data availability statement

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.