This article describes the definition and epidemiological characteristics of TIA/mild stroke, risk stratification and early clinical assessment, early initiation of secondary prevention to effectively reduce stroke recurrence, and the use of dual antiplatelet therapy in non-cardiogenic ischemic mild stroke and early TIA.
1. Definition and epidemiological characteristics of TIA/light stroke
(1) Definition
Among acute cerebrovascular events, transient ischemic attack (TIA) and acute ischemic mild stroke (“mild stroke”), because of their common characteristics of “non-disabling” and “early instability”, are often referred to as “mild stroke”. Because of their common characteristics such as “non-disabling” and “early instability”, they are often treated or studied as a category of “acute non-disabling cerebrovascular events”.
Transient ischemic attack (TIA).
Time-based definition: TIA is a sudden focal neurological deficit (brain, spinal cord or retina) of <24h duration due to vascular causes.
Histology-based definition: TIA is a transient neurological deficit caused by cerebral, spinal cord or retinal ischemia without acute infarction .Specific clinical and research operating principles for the diagnosis of TIA are detailed in the Chinese Expert Consensus Update on Transient Ischemic Attack (2011).
Ischemic mild stroke.
In 2010, Stroke published six definitions of mild stroke and the relationship between clinical outcome to explore the best definition of mild stroke. The study included a consecutive cohort of 760 patients with acute ischemic stroke, divided into 6 groups according to the following definitions.
A, NIHSS must be 0 or 1 for each item and 0 for each item of consciousness.
B, lacunar-like syndrome (small vessel occlusion).
C, motor impairment only (including dysarthria or ataxia); with or without sensory impairment.
D, lowest baseline NIHSS score in each category (total score < 9) without aphasia, neglect or any impairment at the level of consciousness.
E, lowest baseline NIHSS score per item with a total score ≤ 9.
F, baseline NIHSS ≤ 3; good short-term regression defined as patient discharged home; good intermediate regression defined as modified Rankin scale score ≤ 2 at 3 months.
Patients with definition A and definition F had the best short- and intermediate-term regression (74% and 90% for definition A and 71% and 90% for definition F, respectively). Patients with anterior circulation stroke with definition C were more likely to be discharged compared with patients with posterior circulation stroke (P=0.021). Older patients with definition E had poorer midterm regression compared with younger patients (P=0.001), whereas patients with definitions A, D, and F did not have different regressions in any subgroup.
The currently used definition of ischemic light stroke: a sudden focal light neurological deficit (defined as an NIHSS score ≤3) of vascular origin lasting ≥24h, or neurological deficit due to an ischemic infarction associated with clinical symptoms on imaging rather than due to a cerebral hemorrhage detected on imaging.
(2) TIA and mild stroke are the most important medical emergencies
TIA and mild ischemic stroke are traditionally considered to be “benign, reversible ischemic syndromes” with a lower risk of recurrence than complete, disabling strokes. However, studies have shown that the risk of TIA and early stroke is high ^ The risk of stroke within 7 d for TIA patients is 4-10% and the risk of stroke at 90 d is 10-20% (mean 11%), with the risk of recurrence at 90 d for high-risk patients with an ABCD2 score of 3 or more being 14% or more; the risk of recurrence at 90 d for mild stroke is 18%.
In contrast, the risk of recurrence within 90 d for acute stroke was 2% to 7% (mean 4%), which was significantly lower than for TIA and mild stroke patients. Therefore, T1A and light stroke are serious “stroke warning” events requiring urgent intervention, the most important emergency and the best time for secondary prevention, and need to be updated.
(3) TIA and mild stroke are the most common cerebrovascular events
Because of their “non-disabling” characteristics, TIA and mild stroke are easily ignored by the public and doctors. At present, the diagnosis and treatment of TIA in China is seriously underestimated and misjudged, and TIA accounts for only 6% of cerebrovascular hospitalization, which is much lower than the proportion of about 30% in developed countries, and the problem of “untimely and irregular treatment” is prominent.
The epidemiological study of adult TIA in China showed that the awareness rate of TIA among Chinese adults was only 3.12% (sample size 98,000, 162 nationally representative community epidemiological surveys), which is much lower than the 8.7% awareness rate in the US adult survey 10 years ago. However, in practice, TIA and mild stroke remain the most common cerebrovascular events, accounting for 38% of hospitalizations for acute ischemic cerebrovascular events according to the Chinese National Stroke Registry based on inpatient populations.
According to a community-based epidemiological study of TIA in Chinese adults, the prevalence of standardized TIA in the Chinese population is as high as 2.4%, and the number of people with TIA in China is estimated to be 10-12 million, which is much higher than the 5 million people with stroke.
2. Risk stratification and early clinical assessment
Risk stratification optimizes the allocation of medical resources and initiates urgent clinical assessment and secondary prevention of TIA and mild stroke, which helps to reduce the high risk of recurrence of stroke in early stages. The most commonly used tool for early stroke risk stratification in TIA is the ABCD scoring system, of which the ABCD2 score is the most widely used as a good predictor of short-term stroke risk in TIA.
Recent studies have shown that adding TIA episode frequency with imaging (ABCD3 and ABCD3-I) to the ABCD2 score can more effectively assess the risk of early stroke in patients with TIA. It is recommended that patients with suspected TIA should have an early ABCD2 assessment and undergo a comprehensive examination and evaluation as early as possible. The main objective of the evaluation is to determine the etiology and possible pathogenesis leading to TIA.
Some studies have shown that CT angiography (CTA) and magnetic resonance angiography (MRA) can be useful in predicting recurrence, and there is a need to develop recurrence prediction scales specifically for mild stroke.
3. Early initiation of secondary prevention is effective in reducing stroke recurrence
The EXPRESS study showed that early and aggressive intervention significantly reduced the risk of stroke recurrence at 90 d by 80% compared with delayed intervention and did not increase the risk of intracranial hemorrhage or other bleeding in the early intervention group compared with delayed intervention.
All patients in the SOS-TIA study with a confirmed TIA or probable TIA received a stroke prevention program that initiated an emergency intervention using the TIA 24-hour clinic, resulting in a significant reduction in the risk of stroke recurrence.
The Chinese Guidelines for Secondary Prevention of Ischemic Stroke and Transient Ischemic Attack 2010 and the Chinese Guidelines for the Diagnosis and Treatment of Acute Ischemic Stroke 2010, both published in February 2010, also emphasize that secondary prevention should be implemented from the acute phase. The aim is to remind neurologists to accurately grasp the best time to start secondary prevention of stroke/TIA, to move forward the gate of secondary prevention, and to standardize secondary prevention treatment.
4. Application of dual antiplatelet therapy in non-cardiogenic ischemic mild stroke and early TIA
Patients with mild stroke and TIA are at high risk of stroke recurrence in the acute phase. However, 13% of stroke events recur within 90 d in the acute phase, even with aspirin, the only aspirin recommended by the guidelines.
The MATCH study, which included 7600 patients with ischemic stroke and TIA, compared the efficacy of aspirin combined with clopidogrel therapy with that of clopidogrel alone.
The SPS3 study, which enrolled 3020 cases of mild subcortical stroke, found an increased risk of bleeding with clopidogrel combined with aspirin therapy, and the study had to be terminated early. Thus, dual-antibody therapy is not suitable for all patients with stroke and TIA. This has long been considered a “no-go” area in the prevention and treatment of cerebrovascular disease by international evidence-based guidelines for cerebrovascular disease.
The key to breaking this “no-go” zone is to identify the optimal state (“sweetspot”) for dual antibiotic therapy in stroke and TIA patients, and to target patients in this state, which should be those with the highest risk of stroke and lowest risk of bleeding. This state should be the one with the highest risk of recurrence and the lowest risk of bleeding.
The CHANCE (Clopidogrel Efficacy in People at Risk for Acute Non-Disabling Cerebrovascular Events) study was designed for acute, short-course dosing in patients with mild stroke and TIA, breaking the “no-go” rule for dual antibiotic therapy in cerebrovascular disease.
The CHANCE study was conducted in 5170 patients with acute (within 24h of onset) ischemic mild stroke or TIA with high risk of recurrence (TIA is traditionally defined as “based on 24h time”) with clopidogrel in combination with aspirin as a dual antiplatelet therapy (clopidogrel at a compliance dose of 300mg on the first day, followed by The relative risk of stroke recurrence at 90 d was reduced by 32% (8.2% versus 11.7%, risk ratio 0.68%, 95% CI 0.57-0.81, absolute risk reduction 3.5%) after 90 d of 75 mg/d combined with aspirin for 21 d.)
There was no statistically significant difference in the occurrence of moderate or severe bleeding (0.3% per group = 0.73) or cerebral hemorrhage (0.3% per group, P = 0.98) between the clopidogrel combined with aspirin dual therapy group and the aspirin monotherapy (75 mg/d) group.
The CHANCE study found that the significant benefit of dual antiplatelet therapy was seen in the first few days after TIA and ischemic stroke, when the underlying atherosclerotic plaque is most unstable and the risk of stroke recurrence is highest. A meta-analysis of large clinical trials, such as CHANCE, also demonstrated that the results of the CHANCE study were consistent with those of other previous international population-based studies.
The CHANCE trial is not suitable for extrapolation to all patients with TIA and mild stroke: the study first excluded patients with cardiogenic etiology requiring anticoagulation, thrombolysis, patients with moderately severe (MIHSS >3) ischemic stroke at risk of hemorrhagic transformation, and patients with simple sensory, visual or vertigo symptoms or an ABCD2 score <4 for low risk of stroke recurrence. .
Whether the results apply to patients with a slow metabolic genotype of the hepatic cytochrome P-450 (CYP) isozyme (the enzyme that metabolizes clopidogrel to its active form in vivo) gene polymorphism requires further study. In particular, it is important to emphasize that the results of this trial are not widely applicable to the cumulative bleeding risk of clopidogrel combined with aspirin treatment compared with aspirin or clopidogrel alone 90 d after the onset of ischemic stroke to offset the benefit.
Standard Article Entry Criteria
A, Age ≥40 years.
B, Acute non-disabling ischemic stroke (NIHSS ≤3 at randomization) and study drug available within 24 h of symptom onset. The time of symptom onset is defined as “the last time it appeared normal”.
C. Patients with T1A (neurological deficits due to focal cerebral or retinal ischemia with complete resolution within 24 h) with intermediate to high risk of stroke (ABCD2 score ≥4 at randomization) and study drug can be administered within 24 h of symptom onset. The time of symptom onset was defined as “the time of last appearance of normalcy”.
D. Informed consent was signed.
Exclusion criteria
A, Diagnosis of hemorrhage or other pathological brain disorders such as vascular malformations, tumors, abscesses, or other common non-ischemic brain diseases (e.g., multiple sclerosis) based on baseline head CT or MRI.
B, Presence of only sensory symptoms alone (e.g., numbness), vision changes alone, dizziness or vertigo alone, but no evidence of acute infarction on baseline head CT or MRI.
C, mRS >2 points at randomization (pre-onset history assessment).
D, NIHSS score of 4 at randomization.
E, Clear indication for anticoagulation (suspicion of cardiogenic embolism, such as atrial fibrillation, known prosthetic heart valve, suspected endocarditis, etc.).
F, Presence of contraindications to the use of clopidogrel or aspirin.
G, Known history of allergy.
H, Severe hepatic insufficiency or renal insufficiency.
(Remarks: Severe hepatic insufficiency means ALT value > 2 times the upper limit of normal or AST value > 2 times the upper limit of normal; severe renal insufficiency means creatinine value > 1.5 times the upper limit of normal)
I. Severe heart failure, asthma.
J, presence of coagulation disorders, systemic bleeding.
K, previous coagulation disorder or history of systemic bleeding.
L, Prior history of thrombocytopenia or neutropenia.
M, Prior history of drug-induced hematologic disorders or abnormal liver function.
N, Leukopenia (<2X109/L) or thrombocytopenia (<100 X109/L).
O, Use of thrombolytic drugs within 24 h prior to randomization.
P, History of intracranial hemorrhage.
Q, Anticipated need for long-term non-investigational anti-platelet aggregation drugs, or non-steroidal anti-inflammatory drugs that affect platelet function.
R, Use of heparin or oral anticoagulants within 10 d prior to randomization.
S, Gastrointestinal bleeding or major surgery within 3 months prior to randomization.
T, TIA or mini-stroke due to angioplasty or vascular surgery.
U, Other planned surgical procedures or mediated sex therapy may require discontinuation of trial medication.
V, TIA or mini-stroke due to angioplasty or vascular surgery.
W, Patients with severe non-cardiovascular disease with an expected survival time of <3 months.
X, Women of childbearing age who are not using effective contraception and have a positive pregnancy test on record.
Y, Patients who are undergoing experimental drug or instrumentation trials.
5.Consensus recommendations
Recommended intensity of treatment recommended diagnosis recommended Class I based on Class A evidence or high expert consensus Class A evidence Multiple randomized controlled trials (RCTs) meta-analysis or systematic evaluation of multiple RCTs or 1 RCT with adequate sample size (high quality) Class A evidence Multiple or 1 prospective cohort study with adequate sample size, using reference (gold) standards, blinded assessment (high quality) Class II based on Class B evidence and expert consensus Level B evidence at least 1 higher quality RCT Level B evidence at least 1 prospective cohort study or well-designed retrospective case-control study using gold standard and blinded evaluation (higher quality) Category III based on Level C evidence and expert consensus Level C evidence not randomized but well-designed controlled studies, or well-designed cohort studies or case-control studies Level C evidence retrospective, non-blinded evaluation of controlled studies Class IV based on Level D evidence and expert consensus Level D evidence no contemporaneous controlled case series analysis or expert opinion Level D evidence no contemporaneous controlled case series analysis or expert opinion
(1) TIA and mild stroke are the most important cerebrovascular emergencies, and the risk of stroke recurrence is higher the earlier the stroke occurs and should be given high priority (Class I, Level C evidence).
(2) Risk stratification tools such as ABCD2 are recommended to identify patients at risk of TIA/mild stroke as soon as possible and to initiate comprehensive interventions such as vascular evaluation, antithrombotic, plaque stabilization and blood pressure management (Class I, Level C evidence).
(3) Patients at high risk of stroke recurrence (ABCD2 score ≥4) with acute non-cardiac TIA (defined by 24h time) or mild stroke (NIHSS score ≤3) in the acute phase (within 24h of onset) should be treated with clopidogrel combined with aspirin for 21d (clopidogrel first day load 300mg) followed by clopidogrel monotherapy (75mg/d Thereafter, both clopidogrel and aspirin can be used as first-line agents for long-term secondary prevention (Class I, Level A evidence).