Review
Medical Management of Acute Stroke based on Japan Stroke Society Guidelines and the Japan Stroke Data Bank
2024 Volume 31 Issue 12 Pages 1652-1659
Details
2024 Volume 31 Issue 12 Pages 1652-1659
Stroke is a leading cause of death and disability in Japan, necessitating standardized treatment guidelines. The Japan Stroke Society (JSS) periodically revises its guidelines to incorporate new research. This review provides a short overview of acute stroke management based on JSS Guideline 2021 (revised 2023) and the Japan Stroke Data Bank (JSDB), and discusses future directions in stroke management. Acute stroke management emphasizes systemic support and complication management. Risk factor control during acute hospitalization is also crucial for preventing recurrent strokes in the chronic phase.
In ischemic stroke, super-acute recanalization therapies, including intravenous thrombolysis and mechanical thrombectomy, are the most important and effective. Antiplatelet therapy, particularly aspirin and clopidogrel, is recommended for noncardiogenic stroke and high-risk transient ischemic attack. In cardioembolic stroke, early initiation of direct oral anticoagulants might be considered according to stroke severity.
For brain hemorrhage, early blood pressure management is recommended. Specific reversal agents are advised for patients on anticoagulant therapy. Minimally invasive hematoma removal may improve outcomes for intracerebral hemorrhage.
Subarachnoid hemorrhage treatments reported from Japan include intravenous drugs to prevent vasospasm.
The JSDB revealed improvements in functional outcomes in patients with ischemic stroke over the past 20 years, although patients with hemorrhagic stroke showed no clear improvement. The evolving guidelines and research underscore the importance of stratified and timely intervention in stroke care.
Stroke is the fourth leading cause of death and the primary cause of bedridden status in Japan1). The Japan Stroke Data Bank (JSDB) is a nationwide, hospital-based, multicenter, prospective registry that has accumulated more than 270,000 cases from 130 facilities over the past 24 years and has reported real-world evidence for stroke medicine2, 3). The Japan Stroke Society (JSS) compiled the Guidelines for the Treatment of Stroke to standardize stroke treatment in Japan, and these have been revised every two years to reflect new findings. The upcoming 2025 edition is currently undergoing revision. This review provides a brief overview of the medical management of acute stroke based on the descriptions in the JSS Guidelines 2021 for the Treatment of Stroke [revised version 2023]4). We also discuss the latest research reports and future developments in the field of stroke medicine.
Stroke is a treatable emergency disease. Patients suspected of suffering a stroke should be promptly evaluated for the level of consciousness and airways, breathing, and circulation (ABC), and given emergency treatment. Neurological evaluations using the National Institutes of Health Stroke Scale (NIHSS), blood tests, electrocardiograms, and imaging of the head should then be performed to determine the diagnosis and the need for recanalization therapy or surgery. Fig.1 shows an example algorithm for acute stroke management. Understanding the medical system available at one’s own hospital is important, including factors such as nighttime availability of blood tests, imaging modalities and neurosurgical medical systems. Neurological symptoms are identified within a few minutes using the NIHSS, which is specialized for stroke symptoms, rather than a detailed neurological examination. Time should not be wasted on unnecessary examinations, particularly imaging. If ischemic stroke is strongly suspected based on the medical interview and neurological symptoms, the possibility of recanalization therapy should be considered and a specialist consulted as soon as possible. Intravenous recombinant tissue-type plasminogen activator (IV rt-PA) is recommended to be started within 60 min of arrival. The Standards and Guidelines Committee of the Society of NeuroInterventional Surgery suggests the following as ideal treatment times: within 30 min from arrival to brain imaging; within 60 min from arrival to arterial puncture; and within 90 min from arrival to reperfusion5).
ABC, airway, breathing, and circulation; BLS, basic life support; ALS, advanced life support; ECG, electrocardiogram; BP, blood pressure; HR, heart rate; JCS, Japan Coma Scale; GCS, Glasgow Coma Scale; NIHSS, National Institutes of Health Stroke Scale; TIA, transient ischemic attack; SCU, stroke care unit; ICU, intensive care unit; NCU, neurosurgical care unit; US, ultrasound; TTE, transthoracic echocardiogram; TEE, transesophageal echocardiogram.
Although acute stroke therapies, including reperfusion therapy for ischemic stroke and antihypertensive therapy for cerebral hemorrhage, are the top priority, systemic management during acute hospitalization is also important to optimize patient outcomes regardless of stroke type. Periodic assessment of respiratory status, tongue root depression, lung sounds, body temperature, changes in level of consciousness, and delirium symptoms, as well as continuous monitoring of SpO2, blood pressure (BP), heart rate, and electrocardiogram have been shown to improve stroke outcome and prevent complications6). If hypoxemia is present, airway clearance, ventilator management, and oxygen should be administered promptly. Reducing high BP as soon as possible in cases of intracerebral hemorrhage is reasonable, although lowering hypertension in the acute phase of ischemic stroke is not recommended except before intravenous thrombolysis. The INTERACT4 trial in China examined the effect of very early BP control, targeting systolic BP (SBP) between 130–140 mmHg initiated in the ambulance to improve outcomes in stroke patients within 2 h of onset. Prehospital BP reduction was associated with improved outcomes in hemorrhagic stroke, but poorer functional outcomes in ischemic stroke7). Conversely, marked hypotension should be corrected promptly with infusions and vasopressors. Assessing the risk of nutritional status, swallowing function (by water swallowing test, videofluoroscopic swallowing test, and swallowing endoscopy), blood glucose level, and delirium at the time of admission is mandatory. If the risk of delirium in the stroke patient is high, prevention such as environmental modifications should be implemented. If delirium occurs, atypical antipsychotics, alpha 2-agonist sedatives, and typical antipsychotics are recommended for delirium, but duration of administration should be as short as possible. Patients with impairment of consciousness, dysphagia, or unstable conditions should be fasted and administered intravenous fluids to reduce the risk of aspiration. Oral care is recommended to prevent aspiration pneumonia. A high-protein diet with adequate calories is appropriate for patients who are undernourished and at high risk of pressure ulcers. Enteral nutrition or total parenteral nutrition is appropriate for patients who are incapable of oral intake for more than 7 days. Hypoglycemia below 60 mg/dL should be corrected immediately.
1.2 Complication ManagementThe risk of complications, including infection, hemorrhagic complications, seizures, headache, and thrombolytic complications, should be assessed from the time of admission, and efforts should be made to prevent and treat complications. Among elderly patients, those with severe condition, or those on antithrombotic agents, prophylactic administration of anti-gastric ulcer drugs is appropriate to prevent gastrointestinal bleeding. Sudden onset or exacerbation of headache should be evaluated by neurological examination or imaging to rule out recurrent stroke, intracranial hemorrhage, cerebral venous thrombosis, neck or brain artery dissection, posterior reversible leukoencephalopathy, reversible cerebral vasocontraction syndrome, or infection8). Early mobilization is recommended to prevent deep vein thrombosis. Physical therapy and intermittent pneumatic compression are recommended for acute stroke patients with immobility.
1.3 Risk Factor ManagementRisk factor management in stroke patients is crucial in the chronic phase to prevent recurrent strokes. Assessment of risk factors and development of chronic treatment strategies might be reasonable during acute hospitalization. Diet, exercise, and antihypertensive therapy are recommended for hypertension. For type 2 diabetes, diet, exercise, and pharmacotherapy, including metformin, Glucagon-like peptide-1 (GLP-1) receptor agonists, or sodium/glucose cotransporter 2 (SGLT-2) inhibitors, appear reasonable. Statins are strongly recommended for dyslipidemia. If statins offer inadequate efficacy, ezetimibe or PCSK9 inhibitors are reasonable.
For non-valvular atrial fibrillation (NVAF), a direct oral anticoagulant (DOAC) is the first-line recommendation for patients with a CHADS2 score ≥ 1, followed by warfarin. Even if the CHADS2 score is 0, if the patient has cardiomyopathy, is 65–74 years old, or has concomitant vascular disease, persistent or permanent atrial fibrillation, renal dysfunction, low body weight, or left ventricular dysfunction, anticoagulants may be considered. In valvular atrial fibrillation, warfarin (PT-INR 2–3) is recommended.
The Table 1 shows an overview of the medical management of acute stroke. In the hyperacute phase of ischemic stroke, recanalization therapy should be considered regardless of the ischemic stroke classification. In the acute phase, the objective of care is to prevent exacerbation of cerebral infarction, hemorrhagic transformation, and intracranial hypertension. In the chronic phase, a strategy for preventing stroke recurrence should be developed, taking into account the risk of hemorrhagic complications.
| Disease Classification | Prescription Examples | Points |
|---|---|---|
|
Ischemic Stroke/TIA In case with blood pressure ＞220/120 mmHg, aortic dissection, acute myocardial infarction, heart failure, or renal failure, consider lowering blood pressure with caution. |
||
| ▶ Hyperacute Phase |
①Alteplase 0.6 mg/kg ②Mechanical thrombectomy by approved devices |
①Cerebrovascular imaging is essential for decision- making. Control blood pressure ＜180/105 after 24hr of IV tPA. ②Prompt blood pressure reduction after thrombectomy is appropriate. |
|
▶ Acute Phase i) Non-cardioembolic |
①Aspirin 160-300 mg/day ②Aspirin + clopidogrel: 300 mg, then 50-75 mg/day ③Cilostazol 100 mg twice/day + low-dose aspirin 81-300 mg/day ④Ozagrel sodium 80 mg twice/day, IV drip (2 h) ⑤Argatroban First 2 days: 60 mg/day, continuous IV; Next 5 days: 10 mg twice/day, IV drip (3 h) |
①Recommended within 48 h of onset ②Representative dual antiplatelet therapy. Aim for within 1 month. Recommended in the acute phase for high-risk TIA cases with ABCD2 score ≥ 4. ③Consider within 48 h of ischemic stroke ④Start within 5 days of onset. Effectiveness and safety in combination with other antithrombotic drugs are unknown. ⑤Anticoagulants: Recommended for non-cardiogenic cerebral infarction, excluding lacunar infarction within 48 h. Often used in combination with antiplatelet drugs in cases of major arterial stenosis or progressive cerebral infarction. |
| ii) Cardioembolic |
①Heparin 10,000-15,000 units/day ②Dabigatran 150 mg twice/day (high dose) or 110 mg twice/day (low dose) ③Rivaroxaban 15 mg once/day (usual dose) or 10 mg once/day (low dose) ④Apixaban 5 mg twice/day (usual dose) or 2.5 mg twice/day (low dose) ⑤Edoxaban 60 mg once/day (usual dose), 30 mg once/ day (low dose) or 15 mg once/day (low dose) |
①Consider in acute phase of cardioembolic stroke. Adjust to aim for APTT 1.5-2 times before administration. ②For elderly patients with high bleeding risk (e.g., ≥ 80 years old), edoxaban 15 mg once/day is also approved. |
| iii) Regardless of disease type |
①Edaravone 30 mg twice/day, IV drip (30 min) ②Hypertonic glycerol, 200 mL twice-three times/day, IV drip (30 min-1 h) |
①Start within 24 h, for 14 days. Contraindicated in cases with severe renal impairment. ②Consider acute phase of large cerebral infarctions with increased intracranial pressure. Be cautious of fluid overload in heart failure or renal failure cases. |
|
Brain Hemorrhage In the acute phase, consider lowering systolic blood pressure to ＜140 mmHg as early as possible and maintaining for 7 days. Collaborate with neurosurgery on surgical decision-making. |
||
| ▶ Acute Phaseh |
①Nicardipine hydrochloride 0.5-6 μg/kg/min, continuous IV ②Diltiazem hydrochloride 5-15 μg/kg/min, continuous IV ③Nitroglycerin 5-100 μg/min, continuous IV ④Glycerol 200 mL twice-three times/day, IV drip (30 min-1 h) ⑤ 20% Mannitol 1-3 g/kg once, IV drip (100 mL/3-10 min, up to 200 g/day) |
④-⑤Consider in the acute phase of large cerebral hemorrhage with increased intracranial pressure |
| ▶ Cerebral Hemorrhage During Anticoagulant Therapy |
①Prothrombin complex concentrate (Kcentra) 25-50 IU/kg, IV drip ②Menatetorenon 10-20 mg, IV ③Idarucizumab 5 g, IV ④Andexanet alfa IV (refer to package insert for Method A or B) |
①-②For rapid normalization of PT-INR ＜1.35 in cases of warfarin use ①Consider the risk of thromboembolic events. Adjust dosage based on weight and PT-INR. ②Vitamin K preparation. Not immediately effective. ③Specific neutralizing agent for dabigatran. ④Decoy protein for factor Xa inhibitors. Two administration methods based on type, dose, and time since last administration of Xa inhibitor. |
|
Subarachnoid Hemorrhage In mild to moderate cases, consider controlling systolic blood pressure less than 160mmHg. |
||
| Prevent Vasospasm |
①Clazosentan 300 mg by continuous IV (10 mg/h) within 15 days of onset ②Fasudil 30 mg IV drip in 30 min, twice-three times/day for 14 days Ozagrel sodium 80 mg/day, IV drip 14 days |
|
Intravenous thrombolysis with rt-PA is strongly recommended for ischemic stroke that can be treated within 4.5 h of onset, and should be started as soon as possible (within 1 h of hospital arrival at the latest). If the time of onset is unknown, intravenous thrombolysis may be considered if a diffusion weighted imaging/Fluid Attenuated Inversion Recovery (DWI/FLAIR) mismatch is identified within 4.5 h of discovery9). If SBP is greater than 185 mmHg or diastolic BP is greater than 110 mmHg, BP control by intravenous antihypertensive drug is necessary before IV rt-PA.
A meta-analysis of five randomized controlled trials (RCTs) reported that tenecteplase, which has not been approved for use in Japan, is non-inferior to alteplase in acute ischemic stroke10). Some foreign guidelines recommend tenecteplase as an alternative to alteplase11, 12). The T-FLAVOR trial is currently underway to evaluate safety and efficacy in Japanese patients13).
2.1.2 Mechanical ThrombectomyFor patients with occlusion of the internal carotid artery or horizontal middle cerebral artery diagnosed on imaging, mechanical thrombectomy using a stent retriever or aspiration catheter is recommended as soon as possible within 6 h of onset, followed by intravenous rt-PA. Beyond 6 h after onset, depending on indications based on neurological signs and brain imaging, treatment initiation within 16 h is recommended and within 24 h is reasonable. Mechanical thrombectomy is also reasonable in ischemic stroke with extensive ischemia defined as Alberta Stroke Programme Early CT Score (ASPECTS) 3–5 on CT or DWI of the brain, within 24 h of onset. For patients with stroke due to acute basilar artery occlusion, it is reasonable to start mechanical thrombectomy within 24 hours of onset, if the NIH stroke scale score is 10 or more and the posterior circulation-ASPECTS (pc-ASPECTS) score is 6 or more.
2.2 Antithrombotic Therapy 2.2.1 Anticoagulation TherapyThe optimal timing for initiating DOACs after acute ischemic stroke remains uncertain, because RCTs of DOACs have excluded acute-phase stroke patients. The ELAN study, an international multicenter RCT that evaluated the safety and efficacy of early DOAC initiation for cardiogenic cerebral embolism due to nonvalvular atrial fibrillation (NVAF), showed that the combined incidences of recurrent stroke, systemic embolism, severe bleeding, and symptomatic intracranial bleeding within 30 days were 2.9% and 4.1% in the early-start and usual groups, respectively14). A combined cohort study of the SAMURAI-NVAF and RELAXED studies showed that stroke recurrence and systemic embolism were lower in the group with early DOAC initiation started within 1, 2, 3, or 4 days for NVAF patients with transient ischemic attack (TIA), mild, moderate, and severe stroke, respectively15). DOAC administration may be considered in the early stage of cerebral infarction with NVAF, taking into consideration disease severity.
In Japan, argatroban, a selective antithrombin drug, is approved for non-cardiogenic and non-lacunar infarction in the early stage of onset (within 48 h).
The efficacy and safety of milvexian, a factor XIa inhibitor, for preventing recurrent stroke in patients with ischemic stroke or TIA is currently being investigated in a phase III RCT, the Librexia STROKE study, which is being conducted in 47 countries worldwide, including Japan. (https://clinicaltrials.gov/study/NCT05702034)
2.2.2 Antiplatelet TherapyAspirin is recommended as acute stroke therapy. The combination of two antiplatelet agents (aspirin and clopidogrel) is recommended as treatment for mild non-cardiogenic stroke and high-risk TIA (ABCD2 score ≥ 4) from acute to subacute phase, within approximately 1 month. When the treatment duration was longer and initiated later after stroke or TIA onset, dual antiplatelet therapy was no more effective than single antiplatelet therapy for preventing ischemic stroke and increased the risk of bleeding16).
Cilostazol alone or in combination with low-dose aspirin may be considered an acute-stage therapy17). In Japan, intravenous infusion of ozagrel sodium, an inhibitor of thromboxane A2 synthesis, is approved for the treatment of non-cardioembolic stroke within 5 days of onset. A meta-analysis showed that ozagrel improves motor palsy and neurological symptoms, although improvement of long-term outcomes by ozagrel remains unclear.
Prasugrel, a prodrug of a P2Y12 inhibitor, is considered to have earlier inhibitory effects on the adenosine diphosphate (ADP) receptor and is less impacted by CYP2C19 polymorphism compared to clopidogrel. As a result, prasugrel is recommended for ischemic stroke due to large artery atherosclerosis or small vessel occlusion at high risk of recurrent stroke. However, data supporting the efficacy of this agent in acute ischemic stroke are lacking and the loading dose of 20 mg, as approved for ischemic coronary disease treated with percutaneous coronary intervention, has not been approved for stroke patients.
2.3 OthersHypertonic glycerol and mannitol may be considered for the management of cerebral edema in patients with large cerebral infarction. Edaravone, which is approved in Japan for neuroprotective therapy, is reasonable for acute ischemic stroke within 24 h of onset.
As for determining the treatment strategy for paradoxical cerebral embolism, a shared decision-making process involving stroke neurologists, cardiologists and the patient is recommended.
Percutaneous patent foramen ovale (PFO) closure is recommended for patients under 60 years old with cryptogenic stroke, especially if the PFO is high-risk.
Reducing SBP to ＜140 mmHg as early as possible and maintaining the target BP within the first 24 h or up to 7 days appears reasonable. Intensive antihypertensive therapy with SBP reductions greater than 90 mmHg is not recommended to avoid acute kidney injury.
In a cluster RCT examining the effect of a treatment bundle for acute intracerebral hemorrhage that included early active antihypertensive treatment (target SBP ＜140 mmHg) along with algorithmic correction of hyperglycemia, hyperthermia, and abnormal blood coagulability, this treatment bundle was reported to predominantly reduce poor functional outcomes at 6 months18).
3.2 Management of Cerebral Edema and Intracranial HypertensionHypertonic glycerol can be considered in the acute phase of major cerebral hemorrhage. Mannitol (20%) may also be considered, although no significant evidence of effectiveness for acute cerebral hemorrhage has been accumulated.
3.3 Cerebral Hemorrhage Associated with Antithrombotic TherapyIn principle, antithrombotic agents should be discontinued. In the case of patients taking warfarin, administration of prothrombin complex concentrate with vitamin K is appropriate. If the patient is taking dabigatran, administration of idarucizumab is reasonable. Administration of andexanet alfa is reasonable if the patient is taking rivaroxaban, apixaban, or edoxaban. Blood coagulation factors are not currently recommended for cerebral hemorrhage in patients without coagulation abnormalities. The only medical treatment consistently demonstrated to decrease intra cerebral hemorrhage (ICH) growth in spontaneous ICH is recombinant factor VIIa (rFVIIa)19-21). An international multicenter RCT of active rFVIIa for the acute treatment of cerebral hemorrhage, the FASTEST trial, is underway and has enrolled 219 patients (total enrolled number, 480; target number, 860) from Japan as of the end of June 2024 22).
3.4 Surgical TreatmentMinimally invasive hematoma removal within 24 h in patients with acute supratentorial cerebral hemorrhage was reported to improve functional outcomes for patients with ICH at 180 days23). Collaboration with neurosurgeons is important for stroke neurologists to provide best management, considering surgical indications.
Intravenous clazosentan, fasudil, and ozagrel sodium may be considered to prevent cerebral vasospasm after subarachnoid hemorrhage. In Japan, intravenous fasudil, a rho kinase inhibitor, has been approved as an effective therapy for preventing cerebral vasospasm. The efficacy of ozagrel sodium, a thromboxane A2 synthase inhibitor, has also been reported. An RCT in Japan reported that administration of clazosentan after clipping and coiling procedures reduced cerebral ischemic complications related to cerebral vasospasm and death from all causes24).
We have evaluated secular changes in neurological severity and functional outcomes of patients with acute stroke using JSDB data. About 183,000 acute stroke patients registered to the JSDB from 2000 to 2019 were studied. In all three stroke types, age at onset increased and NIHSS and World Federation of Neurological Surgeons scores decreased throughout the 20-year period on multivariable analysis. Functional outcomes have improved in patients with ischemic stroke over the past 20 years, presumably in part due to the development of acute reperfusion therapy. Outcomes for patients with hemorrhagic stroke did not clearly improve within the same period2).
In conclusion, the management of acute stroke requires a comprehensive and multidisciplinary approach to optimize patient outcomes. The JSS Guideline 2021 for the Treatment of Stroke [revised version 2023] provides a framework for standardized care, while ongoing research continues to refine and improve strategies for stroke treatment. By incorporating the latest evidence and advances in stroke management, healthcare providers can enhance the quality of care and improve the prognosis for stroke patients.
Yoshimura has no personal financial interests.
