| Revised | For patients suitable for intravenous thrombolysis within 4.5 hours of onset, intravenous rt-PA treatment is recommended (0.9 mg/kg, maximum dose 90 mg, 10% of the total dose intravenous push over 1 min, and the rest intravenous drip within 60 min). | I | A |
| The ENCHANTED trial did not show non-inferiority of the low dose of rt-PA (0.6 mg/kg) in functional outcome recovery compared with the standard dose.48 A dose of 0.9 mg/kg intravenous rt-PA was used in most RCTs focused on the benefit of thrombolysis within 4.5 hours. For Chinese patients with AIS within 3–4.5 hours after symptom onset, the standard dose of rt-PA (0.9 mg/kg) for intravenous thrombolysis is recommended as effective and safe.49 The ECASS III trial found that intravenous rt-PA administered between 3 and 4.5 hours after the onset of symptoms significantly improved clinical outcomes in patients with AIS.38
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| Revised | For elderly patients with AIS (aged >80 years) with an onset <4.5 hours, intravenous rt-PA treatment is considered reasonable. | IIa | B |
| In clinical trials, intravenous rt-PA has been restricted to patients aged 18–80 years old. Systematic review revealed a similar benefit in patients >80 years, particularly when treated early.50 51 A higher proportion of mRS 0–1 (19.1% vs 13.1%, p=0.0109) and similar 90 days’ mortality (29.5% vs 30.2%, p=0.8382) were associated with intravenous rt-PA versus placebo.50
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| New recommendation | For patients with AIS occurring beyond 4.5 hours but with DWI lesions, less than one-third of the MCA territory or no visible lesions on FLAIR, intravenous rt-PA is beneficial. | IIa | B |
| New recommendation | Intravenous rt-PA is not recommended for patients with AIS within 4.5–9 hours based only on a NCCT. | III | B |
| In the WAKE-UP, MR WITNESS, EXTEND and EPITHET trials, patients with AIS within 4.5–9 hours of onset (including unknown time of onset and wake-up) had either CT+CTP or DWI+FLAIR for eligibility of intravenous rt-PA or not.9 17 19 Intravenous rt-PA-treated patients had improved outcomes. |
| New recommendation | For patients with AIS within 4.5–9 hours (including unknown time of onset), if the perfusion-core mismatch identified by CTP or MRP indicates the benefits from vascular recanalisation treatment, intravenous rt-PA treatment is recommended when IA MT is not planned or recommended. | I | A |
| The EXTEND and EPITHET trials showed a valuable use of multimodel CT or MRI to identify patients with AIS within 4.5–9 hours or unknown time of onset who would benefit from intravenous rt-PA.52 53
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| New recommendation | For patients who had a wake-up stroke, if DWI–FLAIR mismatch indicates the benefits from vascular recanalisation treatment, intravenous rt-PA treatment is recommended when IA MT is not planned or recommended. | IIa | B |
| For patients with wake-up AIS and treated based on the perfusion-core mismatch, both IA MT and intravenous rt-PA of an LVO improve functional outcomes without increasing the risk of death. The EXTEND trial used CTP or MRP, while the WAKE-UP trial used DWI–FLAIR mismatch to select patients for intravenous rt-PA.17 52
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| Unchanged | Treat hypoglycaemia (blood glucose <60 mg/dL) in patients with AIS. | I | C |
| Unchanged | Prolonged hyperglycaemia within 24 hours of hospitalisation is associated with adverse outcomes compared with normal blood glucose levels. It is recommended correcting hyperglycaemia and maintaining it between 140 and 180 mg/dL while closely monitoring it to prevent hypoglycaemia. | IIa | C |
| Revised | Patients with elevated blood pressure but otherwise suitable for intravenous rt-PA treatment should be cautious in lowering blood pressure before thrombolysis. The recommended goal of systolic blood pressure (SBP) is <185 mm Hg and diastolic blood pressure (DBP) is <110 mm Hg. | I | B |
| Increased blood pressure is associated with a higher risk of sICH after intravenous rt-PA treatment. The NINDS and ECASS trials excluded patients with baseline blood pressure >185/110 mm Hg.37 54 The IST-3 and ECASS III trials did not mention the restrictions on blood pressure.38 55 In an observational study, pretreatment blood pressure of SBP >185 mm Hg and/or DBP >110 mm Hg was independently associated with a higher risk of sICH (OR 2.59, 95% CI 1.07 to 6.25).56
|
| Revised | For patients who have not received intravenous thrombolysis but are planned for IA MT, it may be reasonable to maintain blood pressure ≤185/110 mm Hg before the procedure. | IIb | B |
| The REVASCAT, SWIFT PRIME, EXTEND-IA, TRACE, MR CLEAN and DAWN trials excluded patients with baseline blood pressure >185/110 mm Hg for bridging treatment.18 42 45–47 57 It is reasonable to control preoperative blood pressure below 185/110 mm Hg before IA MT. |
| Revised | During intravenous thrombolysis and within 24 hours after treatment, blood pressure should be maintained at <180/105 mm Hg. | I | B |
| The ENCHANTED trial compared controlling blood pressure to either >150 mm Hg and <185/110 mm Hg, or to 130–140 mm Hg within 72 hours after intravenous rt-PA. No significant difference in mRS was found at 90 days.58 However, another RCT with 626 patients who underwent thrombolysis showed a significant decrease in the risk of ICH and mortality if SBP was kept between 141 and 150 mm Hg, compared with those kept SBP between 151 and 185 mm Hg.59
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| New recommendation | The risk of using antithrombotic therapy within 24 hours after intravenous thrombolysis is still uncertain. | IIb | B |
| A prospective clinical registry study revealed that earlier initiation of antithrombotics was associated with a low risk of any haemorrhage (adjusted OR 0.56, 95% CI 0.35 to 0.89), or sICH (adjusted OR 0.85, 95% CI 0.35 to 2.10) or mRS 0–3 changes at 90 days (adjusted OR 1.09, 95% CI 0.75 to 1.59).60 In the post hoc analysis of the randomised ARTIS trial, early aspirin use after intravenous rt-PA increased the risk of sICH (OR 3.73, 95% CI 1.03 to 13.49) but not cerebral ischaemia (OR 1.14, 95% CI 0.44 to 3.00).61
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| New recommendation | Intravenous administration of aspirin should not be used within the first 90 min of initiating intravenous thrombolysis. | III | B |
| The ARTIS trial randomly assigned patients to 300 mg intravenous aspirin within 90 min after starting rt-PA therapy or to no additional treatment. Oral antiplatelet therapy was started 24 hours after intravenous rt-PA treatment. This trial was stopped early due to an excess of sICHs (4.3% vs 1.6%, absolute difference 2.8%, 95% CI 0.2% to 5.4%, p=0.04) and no benefit in outcome (54.0% vs 57.2%, absolute difference −3.2%, 95% CI −10.8% to 4.2%, crude relative risk 0.94, 95% CI 0.82 to 1.09, p=0.42) in the aspirin group.62
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| New recommendation | Patients with AIS occurring within <4.5 hours and presenting with multiple comorbidities, weakness or pre-stroke disabilities may also benefit from intravenous thrombolysis. | IIb | B |
| For patients with chronic kidney disease (CKD) or renal dysfunction and treated with intravenous rt-PA, two meta-analyses demonstrated a higher risk of sICH and poor functional outcome, mainly in patients with moderate-to-severe CKD.63 64 Another meta-analysis showed a neutral result.65 Patients diagnosed with cancer may also benefit from intravenous thrombolysis without increased risk of bleeding.66 Patients with pre-existing disabilities before intravenous rt-PA treatment, those with mRS scores 2 and ≥3 had similar favourable functional outcomes (34% vs 29%), despite higher mortality (48% vs 39%).67 Patients with pre-existing disabilities had a higher risk of mortality (33% vs 14%, OR 3.2, 95% CI 1.0 to 10.1) and poor function outcome (median mRS 3 vs 2, p=0.03), but little difference in a good NIHSS score at 24 hours or 3 months, and favourable outcomes at 3 months.68
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| New recommendation | For patients with AIS with mild and disabling symptoms within 4.5 hours of onset, intravenous thrombolysis is recommended. | IIa | B |
| Mild or rapidly improving strokes were not well studied in clinical trials. A post hoc analysis of the NINDS and IST-3 trials showed the benefit of rt-PA in patients with minor stroke compared with the control group.69 70 In the MINOR-STROKE trial, patients with M1 LVO and minor stroke symptoms benefited from bridging therapy, whereas patients with M2 LVO benefited from intravenous rt-PA alone.71 Data from the Austrian Stroke Unite Registry divided 35 113 patients into NIHSS 0–1 for non-disabling stroke and NIHSS 2–4 for mild deficit stroke.72 Intravenous rt-PA in NIHSS 0–1 group was associated with an early neurological deterioration (adjusted OR 8.84, 95% CI 6.61 to 11.83), increased risk of sICH (adjusted OR 9.32, 95% CI 4.53 to 19.15) and a lower rate of excellent outcome (mRS 0–1) at 90 days, whereas patients with NIHSS 2–5 had a higher rate of excellent outcomes (mRS 0–1), but initially neurological deterioration (adjusted OR 1.7, 95% CI 1.47 to 1.98) and sICH (adjusted OR 5.75, 95% CI 4.45 to 7.45). |
| New recommendation | For patients with AIS with mild non-disabling symptoms (NIHSS 0–5) within 4.5 hours, intravenous thrombolysis is not routinely recommended. | III | B |
| The PRISMS trial enrolled 313 patients who had minor non-disabling neurological deficits with an NIHSS score of 0–5. Favourable outcome was seen in 78.2% of patients in the intravenous rt-PA group vs 81.5% in the aspirin group (adjusted risk difference −1.1%, 95% CI −9.4% to 7.3%). About 3.2% of patients in the intravenous rt-PA group had sICH, but none in the aspirin group (risk difference 3.3%, 95% CI 0.8% to 7.4%).73 More evidence is needed, and the MaRISS trial is ongoing.74
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| Reworded | Intravenous thrombolysis is not suitable for patients who have used low molecular weight heparin (LMWH) within 24 hours, regardless of whether the dose is for prophylactic or therapeutic purposes. | III | B |
| Unchanged | During intravenous thrombolysis, physicians should be fully prepared to respond to adverse reactions such as haemorrhagic complications and vasogenic oedema. | I | B |
| Unchanged | The safety and efficacy of intravenous thrombolysis in patients with AIS with coagulation disorders have not been determined. | III | C |
| Reworded | Any delay in intravenous thrombolysis has a major impact on prognosis. The treatment should not be postponed to wait for symptoms to resolve spontaneously. | III | C |
| Reworded | Intravenous thrombolysis may benefit patients with AIS with a digestive tract or urinary bleeding history. | IIb | C |
| Reworded | Intravenous thrombolysis for patients with AIS may be considered within 14 days of surgery. However, careful consideration is required regarding the risk of surgical site bleeding and the benefits of thrombolysis. | IIb | C |
| Reworded | In patients with AIS with a history of major trauma (within 14 days, without affecting the head), intravenous thrombolysis can be carefully considered. The risk of wound haemorrhage versus the severity of stroke and subsequent disability should be taken into consideration. | IIb | C |
| Reworded | The safety and efficacy of intravenous thrombolysis in patients with AIS with a history of vascular perforation within 7 days are still uncertain. | IIb | C |
| Reworded | For patients with AIS with lumbar punctures within 7 days, the safety of intravenous thrombolysis is uncertain. | IIb | C |
| Unchanged | In patients with AIS with abnormal baseline glucose (<50 mg/dL (2.78 mmol/L) or >400 mg/dL (22.2 mmol/L)), the benefit of intravenous thrombolysis is uncertain once the abnormal glucose level is corrected. | IIb | C |
| Reworded | In patients with AIS presenting with seizures, if evidence suggests that limb dysfunction is due to stroke rather than post-seizure paralysis, intravenous thrombolysis may be beneficial. | IIa | C |
| Reworded | In patients with AIS with a known or suspected extracranial carotid artery dissection and stroke symptom onset <4.5 hours, intravenous thrombolysis should be cautiously considered. | IIa | C |
| Reworded | The efficacy and safety of intravenous thrombolysis have not been established in patients with AIS with a known or suspected intracranial carotid artery dissection. | IIb | C |
| Reworded | In patients with AIS with a small or moderate-sized (<10 mm) unruptured intracranial aneurysm, intravenous thrombolysis may be cautiously considered. | IIa | C |
| Reworded | In patients with AIS with a large unruptured or unstable intracranial aneurysm, the efficacy and safety of intravenous thrombolysis are uncertain. | IIb | C |
| Reworded | In patients with AIS with unruptured or untreated intracranial vascular malformations, the efficacy and safety of intravenous thrombolysis are not known. | IIb | C |
| Reworded | Patients with AIS with neuroectodermal tumours may benefit from intravenous thrombolysis. | IIa | C |
| Reworded | In patients with AIS with an acute myocardial infarction (MI), consideration can be given to administering intravenous thrombolysis with an appropriate dose for AIS, followed by percutaneous coronary intervention or stent placement for acute coronary syndrome. | IIa | C |
| Reworded | In patients with AIS with a recent MI (>3 months), intravenous thrombolysis may be beneficial if it is a non-ST-elevation MI, or an ST-elevation MI involving the right ventricle/inferior wall. | IIa | C |
| Reworded | In patients with AIS with a recent MI (>3 months), the safety and risk of intravenous thrombolysis are uncertain if ST is elevated and involves the left ventricle/anterior wall. | IIb | C |
| Unchanged | In severe AIS with acute pericarditis, which may lead to severe disability (mRS 3–5), the benefit of intravenous thrombolysis is not clear. An urgent cardiologist consultation is required. | IIb | C |
| Unchanged | In patients with mild or moderate AIS with acute pericarditis or left atrial/ventricular thrombus, the risk and benefit of intravenous thrombolysis are unknown. | III | C |
| Unchanged | Severe AIS related to a left atrial/ventricular thrombus, atrial myxoma or papillary fibroids may have severe disability (mRS 3–5). The safety and efficacy of intravenous thrombolysis are unknown. | IIb | C |
| Reworded | After patients with AIS undergo cardiovascular or cerebrovascular DSA, intravenous thrombolysis may be beneficial. Patients should be carefully assessed for indications, contraindications and relative contraindications. | IIa | A |
| Reworded | The efficacy and safety of intravenous thrombolysis in patients with AIS with malignancy are unknown. If the expected survival period is >6 months, with no other contraindications or coagulopathy or bleeding, careful consideration of intravenous thrombolysis can be considered. | IIb | C |
| Unchanged | Pregnant women with moderate or severe stroke may benefit from intravenous thrombolysis if the benefits outweigh the risk of intrauterine bleeding. | IIb | C |
| Unchanged | The benefits and risks of intravenous thrombolysis for patients with AIS within 14 days of post partum are non-conclusive. | IIb | C |
| Reworded | Urokinase is safe for those unsuitable for intravenous rt-PA treatment within 6 hours of onset. However, the validity needs further confirmation by high-quality RCTs with large sample size. | IIb | B |
| In a multicentre retrospective study, urokinase had similar functional independence in Chinese patients with AIS, but with a higher risk of extracranial bleeding compared with patients treated with rt-PA.75
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| New recommendation | TNK 0.4 mg/kg is harmful to treat patients with AIS with an NIHSS score >6. | III | B |
| The NOR-TEST2 Part A trial involved patients with NIHSS scores ≥ 6 within 4.5 hours. Patients who accepted TNK (0.4 mg/kg) had a lower likelihood of favourable functional outcome (32% vs 51%, OR 0.45, 95% CI 0.25 to 0.80, p=0.0064), more frequent ICH (21% vs 7%, OR 3.68, 95% CI 1.49 to 9.11, p=0.0031) and a higher rate of mortality at 3 months (16% vs 5%, OR 3.56, 95% CI 1.24 to 10.21, p=0.013).76
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| New recommendation | TNK 0.25 mg/kg intravenous push has been proven non-inferior to intravenous standard dosage of rt-PA to treat patients with AIS with <4.5 hours of onset. | IIa | B |
| In the TASTE-A study, TNK 0.25 mg/kg (maximum 25 mg) was associated with a smaller perfusion lesion volume (median 12 mL vs 35 mL, adjusted OR 0.55, 95% CI 0.37 to 0.81, p=0.0030) compared with rt-PA 0.9 mg/kg (maximum 90 mg) in patients with AIS treated within 4.5 hours, with the non-significant difference in safety outcomes.77 The AcT trial indicated a non-inferiority of TNK (0.25 mg/kg) in the functional outcome compared with rt-PA (36.9% vs 34.8%, unadjusted risk difference 2.1%, 95% CI 2.6% to 6.9%) in patients with AIS treated within 4.5 hours.78 The TRACE-2 trial found that, compared with rt-PA 0.9 mg/kg (maximum 90 mg), recombinant human TNK 0.25 mg/kg (maximum 25 mg) showed an efficacy (62% vs 58%, RR 1.07, 95% CI 0.98 to 1.16), which was non-inferior to rt-PA in patients eligible for intravenous thrombolysis with AIS.79
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| New recommendation | For patients with anterior circulation LVO type of AIS who present within 4.5 hours of symptom onset, the efficacy of intravenous TNK (0.25 mg/kg) is non-inferior to intravenous rt-PA (0.9 mg/kg) before IA MT. The TNK might offer better reperfusion outcomes, while the incidence of sICH remains similar. | IIa | B |
| The EXTEND-IA TNK trial focusing on the efficacy and safety of TNK (0.25 mg/kg) and rt-PA (0.9 mg/kg) before thrombectomy revealed that 22% of patients in the TNK group were reperfused >50% of the affected vascular area compared with 10% in the rt-PA group.80 The rate of any ICH was 3% in the TNK group and 2% in the rt-PA group. Patients in the TNK group also showed a better functional outcome (mRS 2 vs 3) at 90 days than those treated with rt-PA. In the TEMPO-1 trial, 66% had excellent functional outcomes at 90 days and a high recanalisation rate: 0.1 mg/kg (39% complete and 17% partial), 0.25 mg/kg (52% complete and 9% partial).81 Administration of TNK in patients with minor stroke and anterior circulation LVO is feasible and safe. |
| Reworded | Besides performing in clinical trials, ultrasound-assisted thrombolysis is not recommended as an adjunct treatment to intravenous thrombolysis. Similarly, image-guided desmoteplase thrombolysis is not recommended. | III | B |
| New recommendation | Other fibrinolytic agents and thrombolytics, except for rt-PA, TNK and urokinase, are not recommended. | III | B |