Off-label use of intravenous thrombolysis for acute ischemic stroke: a critical appraisal of randomized and real-world evidence

Abstract

Intravenous thrombolysis (IVT) represents the only systemic reperfusion therapy able to reverse neurological deficit in patients with acute ischemic stroke (AIS). Despite its effectiveness in patients with or without large vessel occlusion, it can be offered only to a minority of them, because of the short therapeutic window and additional contraindications derived from stringent but arbitrary inclusion and exclusion criteria used in landmark randomized controlled clinical trials. Many absolute or relative contraindications lead to disparities between the official drug label and guidelines or expert recommendations. Based on recent advances in neuroimaging and evidence from cohort studies, off-label use of IVT is increasingly incorporated into the daily practice of many stroke centers. They relate to extension of therapeutic time windows, and expansion of indications in co-existing conditions originally listed in exclusion criteria, such as use of alternative thrombolytic agents, pre-treatment with antiplatelets, anticoagulants or low molecular weight heparins. In this narrative review, we summarize recent randomized and real-world data on the safety and efficacy of off-label use of IVT for AIS. We also make some practical recommendations to stroke physicians regarding the off-label use of thrombolytic agents in complex and uncommon presentations of AIS or other conditions mimicking acute cerebral ischemia. Finally, we provide guidance on the risks and benefits of IVT in numerous AIS subgroups, where equipoise exists and guidelines and treatment practices vary.

Keywords: alteplase; contraindications; intracranial bleeding; intravenous thrombolysis; ischemic stroke; large vessel occlusion; off-label; tenecteplase; therapeutic window.

Figure 1.

A 64-year-old man fell asleep without symptoms and woke up 5 h and 30 min later, with right-sided hemiparesis. He was admitted to the hospital 30 min later, with a National Institute of Health Stroke Scale score of 5 points. Urgent brain magnetic resonance imaging (MRI) revealed a left center semioval area of high signal intensity on Diffusion-Weighted-Imaging (DWI) sequences (Panels A and B), but no corresponding hyperintensity on Fluid-Attenuated Inversion Recovery (FLAIR) MRI sequences (Panels C and D), a finding consistent with DWI/FLAIR mismatch. The patient fulfilled the WAKE-UP trial criteria and received, 6 h and 15 min from last known to be well and 75 min after symptom discovery, intravenous thrombolysis with 0.9 mg/kg dose of alteplase. Full recovery of the neurological deficits was noticed at patient’s discharge. Follow-up brain MRI (FLAIR sequences) at 3 months was negative for a corresponding ischemic infarct (Panels E and F).

Figure 2.

An 81-year-old woman with a history of non-coagulated paroxysmal atrial fibrillation presented to the emergency department 5 h after the acute development of expressive aphasia with mild facial droop and right upper limb drift (National Institute of Health Stroke Scale score of 4 points). MR-Perfusion study (RAPID software, IschemaView, Menlo Park, CA) disclosed the absence of ischemic core (cerebral blood flow <30%), and identified a critically hypoperfused (Tmax > 6 s) area of 16 mL (Panel A). Susceptibility-weighted imaging (SWI) brain magnetic resonance imaging (MRI) showed a left middle cerebral artery (MCA)-M2 segment thrombus (red arrow, Panel B), and transcranial duplex sonography (TCS) detected a sub-occlusive waveform corresponding to a Thrombolysis In Brain Ischemia (TIBI) grade III, in the left M2-MCA (Panel C). In accordance with the EXTEND trial eligibility criteria, the patient received intravenous thrombolysis with alteplase (0.9 mg/kg) at 6 h following symptom onset. Immediately after the 1-h infusion of alteplase, a complete resolution of the patient’s symptoms was noted. TCS disclosed restoration of a normal waveform within the left M2-MCA (TIBI grade V), (Panel D), and follow-up diffusion-weighted imaging (DWI) brain MRI showed small acute ischemic lesions within the left MCA territory (Panel E). MRI-SWI confirmed the complete resolution of the left M2-MCA thrombus (red arrow, Panel F).

Figure 3.

An 89-year-old man presented within 1 h of symptom onset with severe AIS [National Institute of Health Stroke Scale (NIHSS) score of 18 points] due to tandem (right internal carotid artery and middle cerebral artery) arterial occlusion. CT-Perfusion study (RAPID software, IschemaView, Menlo Park, CA) showed a critically hypoperfused area within the right middle cerebral artery territory of 113 mL (Tmax > 6 s), and an ischemic core volume of 29 mL (Cerebral Blood Flow <30%), with a mismatch difference of 84 mL (Panel A). However, 75 mL of the total 113 mL of the hypoperfused tissue showed Tmax values >10 s, resulting in a hypoperfusion index of 0.7 that indicates the presence of an extensive and severely hypoperfused cerebral volume (Panel B). The patient received intravenous thrombolysis and was transferred to the angiography suite, where significant extravasation of contrast was detected in the right hemisphere that corresponded to the formation of a large parenchymal hematoma type II and intraventricular hemorrhage confirmed on brain CT (Panel C). Substantial neurological deterioration was documented during the first 24 h following tPA bolus (NIHSS score 26).

Figure 4.

A 68-year-old woman was admitted to a primary stroke center within 4 h of acute onset of aphasia and right hemiparesis [National Institute of Health Stroke Scale (NIHSS) score of 7 points]. The patient received intravenous alteplase (0.9 mg/kg). During the infusion, she developed two episodes of generalized tonic-clonic seizures. A second urgent brain CT scan did not reveal brain hemorrhage. The patient was transferred to a comprehensive stroke center. Diffusion-weighted-imaging brain MRI sequences showed a left temporo-parietal acute ischemic lesion (red arrow, Panel A). Fluid-attenuated inversion recovery brain MRI sequences revealed extensive left temporo-parietal vasogenic edema that was attributed to a hyperperfusion syndrome with clinical epileptic seizures, an uncommon complication following successful recanalization with intravenous thrombolysis (Panels B–E).

Figure 5.

A 36-year-old woman with history of migraine presented in the Emergency Room with acute left homonymous hemianopsia (National Institute of Health Stroke Scale score of 2 points) within the time window of intravenous thrombolysis (onset-to-door time: 59 min). The patient had a history of PFO (patent foramen ovale) closure 12 days ago due to chronic migraine. She was receiving aspirin 100 mg qd following PFO closure and was also taking nimesulide 100 mg bid during the past 5 days. Brain CT (Panels A–C) disclosed sulcal effacement in right frontal and parietal lobes and loss of gray–white matter differentiation in the right hemisphere. The suspicion of isodense subdural hematoma was raised and intravenous thrombolysis was averted. Brain MRI was performed the following day and disclosed the presence of a right occipital subdural lesion that was hyperintense on axial T1 (Panel D) and axial T2 (Panel E) sequences. These findings confirmed the diagnosis of subacute subdural hematoma. Sulcal effacement in right frontal and parietal lobes was also noted on brain MRI (Panel F).

Figure 6.

A 63-year-old man presented 3.5 h after the acute onset of severe aphasia and right hemiplegia with left gaze deviation [National Institute of Health Stroke Scale (NIHSS) score of 18]. Admission troponin levels were increased (0.56 ng/mL, positive >0.1 ng/mL) and the electrocardiogram showed ST elevations in leads V1 to V4 (Panel A), consistent with anterior wall acute myocardial infarction (MI). Brain CT-Angiography and Perfusion study (RAPID software, IschemaView, Menlo Park, CA) revealed a distal left middle cerebral artery (MCA) M1-segment sub-occlusion (red arrow, Panel B), and a critically hypoperfused cerebral area (Penumbra, Tmax >6 s) of 45 mL, without detectable ischemic core (Panel C). The patient received intravenous alteplase (0.9 mg/kg) 4 h after symptom onset, bridged with mechanical thrombectomy with complete recanalization 5.5 h after symptom onset. Brain MRI showed an acute left MCA infarct (Panel D and E). A few hours later, troponin levels increased dramatically (120 ng/mL) and later decreased to normal ranges within the next few days, whereas ST elevations subsided (Panel F). These findings were consistent with recanalization of the anterior coronary artery that was verified later with coronary angiography. The patient was discharge with a NIHSS score of 5 points.

Figure 7.

An 85-year-old woman, with a history of degenerative mitral valve disease and a recent diagnosis of melanoma, presented with fever and reduced level of consciousness. Admission inflammatory markers (C-reactive protein and erythrocyte sedimentation rate) were increased. Urgent diffusion-weighted-imaging brain MRI sequences showed multiple small embolic-type acute infarcts in different arterial distributions including left middle cerebral artery, left anterior cerebral artery and right anterior cerebral artery (Panels A–C). Susceptibility-weighted imaging MRI showed multiple periventricular and subcortical cerebral microbleeds (Panels D and E, arrows). Echocardiography revealed valve vegetations and blood cultures were positive for Staphylococcus aureus, establishing the diagnosis of infective endocarditis due to contamination of the skin lesion (melanoma), which is an absolute contraindication for intravenous thrombolysis.

Figure 8.

A 53-year-old man presented with acute onset of dysarthria and right arm weakness (National Institute of Health Stroke Scale score of 4 points). Carotid ultrasound examination disclosed double lumen appearance within the right common carotid artery (Panel A), with opposite flow directions within each lumen, (Panels B and C). Double lumen appearance was also evident in the right subclavian artery (Panel D). The patient suffered an aortic arch dissection that extended into the innominate, right CCA, and right subclavian arteries. The decision was made to withhold IVT.