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BACKGROUND: Dual antiplatelet treatment has been shown to lower the risk of recurrent stroke as compared with aspirin alone when treatment is initiated early (≤24 hours) after an acute mild stroke. The effect of clopidogrel plus aspirin as compared with aspirin alone administered within 72 hours after the onset of acute cerebral ischemia from atherosclerosis has not been well studied. METHODS: In 222 hospitals in China, we conducted a double-blind, randomized, placebo-controlled, two-by-two factorial trial involving patients with mild ischemic stroke or high-risk transient ischemic attack (TIA) of presumed atherosclerotic cause who had not undergone thrombolysis or thrombectomy. Patients were randomly assigned, in a 1:1 ratio, within 72 hours after symptom onset to receive clopidogrel (300 mg on day 1 and 75 mg daily on days 2 to 90) plus aspirin (100 to 300 mg on day 1 and 100 mg daily on days 2 to 21) or matching clopidogrel placebo plus aspirin (100 to 300 mg on day 1 and 100 mg daily on days 2 to 90). There was no interaction between this component of the factorial trial design and a second part that compared immediate with delayed statin treatment (not reported here). The primary efficacy outcome was new stroke, and the primary safety outcome was moderate-to-severe bleeding - both assessed within 90 days. RESULTS: A total of 6100 patients were enrolled, with 3050 assigned to each trial group. TIA was the qualifying event for enrollment in 13.1% of the patients. A total of 12.8% of the patients were assigned to a treatment group no more than 24 hours after stroke onset, and 87.2% were assigned after 24 hours and no more than 72 hours after stroke onset. A new stroke occurred in 222 patients (7.3%) in the clopidogrel-aspirin group and in 279 (9.2%) in the aspirin group (hazard ratio, 0.79; 95% confidence interval [CI], 0.66 to 0.94; P = 0.008). Moderate-to-severe bleeding occurred in 27 patients (0.9%) in the clopidogrel-aspirin group and in 13 (0.4%) in the aspirin group (hazard ratio, 2.08; 95% CI, 1.07 to 4.04; P = 0.03). CONCLUSIONS: Among patients with mild ischemic stroke or high-risk TIA of presumed atherosclerotic cause, combined clopidogrel-aspirin therapy initiated within 72 hours after stroke onset led to a lower risk of new stroke at 90 days than aspirin therapy alone but was associated with a low but higher risk of moderate-to-severe bleeding. (Funded by the National Natural Science Foundation of China and others; INSPIRES ClinicalTrials.gov number, NCT03635749.).
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Aspirina , Clopidogrel , Accidente Cerebrovascular Isquémico , Inhibidores de Agregación Plaquetaria , Humanos , Aspirina/administración & dosificación , Aspirina/efectos adversos , Aspirina/uso terapéutico , Aterosclerosis/complicaciones , Aterosclerosis/tratamiento farmacológico , Clopidogrel/administración & dosificación , Clopidogrel/efectos adversos , Clopidogrel/uso terapéutico , Método Doble Ciego , Quimioterapia Combinada , Hemorragia/inducido químicamente , Ataque Isquémico Transitorio/tratamiento farmacológico , Ataque Isquémico Transitorio/etiología , Accidente Cerebrovascular Isquémico/tratamiento farmacológico , Accidente Cerebrovascular Isquémico/etiología , Inhibidores de Agregación Plaquetaria/administración & dosificación , Inhibidores de Agregación Plaquetaria/efectos adversos , Inhibidores de Agregación Plaquetaria/uso terapéutico , Prevención Secundaria , Accidente Cerebrovascular/tratamiento farmacológico , Accidente Cerebrovascular/etiología , Resultado del TratamientoRESUMEN
BACKGROUND: The atherosclerotic sources of embolism are a significant contributor to embolic stroke of undetermined source (ESUS). However, there is limited evidence for the efficacy of intensive dual antiplatelet therapy for ESUS. We conducted an investigation to determine whether gene-directed dual antiplatelet therapy could reduce the risk of recurrent stroke in patients with ESUS. METHODS: CHANCE-2 (Clopidogrel in High-Risk Patients with Acute Nondisabling Cerebrovascular Events-II) was an investigator-initiated, multicenter, randomized, double-blind, placebo-controlled trial that objectively compared ticagrelor plus aspirin and clopidogrel plus aspirin in patients with minor stroke or transient ischemic attack who carried CYP2C19 loss-of-function alleles in China. All study participants were classified into ESUS and non-ESUS groups for the prespecified exploratory analysis. Cox proportional hazards models were used to assess the interaction of the state of ESUS with the effects of dual antiplatelet therapy with ticagrelor-aspirin versus clopidogrel-aspirin, adjusting for sociodemographic and clinical factors. RESULTS: The subgroup analysis comprised 5796 participants (90.4% of the total 6412 participants) in the CHANCE-2 trial, with a median age of 64.9 years (range, 57.0-71.4 years), of whom 1964 (33.9%) were female. These participants underwent diffusion-weighted imaging as part of the study protocol. After systematic evaluation, 15.2% of patients (881/5796) were deemed to have ESUS. The incidence of stroke recurrence in patients with ESUS was found to be 5.6% in the ticagrelor-aspirin group and 9.2% in the clopidogrel-aspirin group (hazard ratio, 0.57 [95% CI, 0.33-0.99]; P=0.04). In patients without ESUS, the respective incidence rates were 5.6% and 7.5% (hazard ratio, 0.72 [95% CI, 0.58-0.90]; P<0.01). The P value was 0.56 for the treatment × ESUS status interaction effect. CONCLUSIONS: In this prespecified exploratory analysis, ticagrelor with aspirin was superior to clopidogrel with aspirin for preventing stroke at 90 days in patients with acute ischemic stroke or transient ischemic attack who carried CYP2C19 loss-of-function alleles and were classified as ESUS. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04078737.
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Aspirina , Clopidogrel , Terapia Antiplaquetaria Doble , Accidente Cerebrovascular Embólico , Inhibidores de Agregación Plaquetaria , Ticagrelor , Humanos , Persona de Mediana Edad , Femenino , Masculino , Inhibidores de Agregación Plaquetaria/uso terapéutico , Anciano , Clopidogrel/uso terapéutico , Aspirina/uso terapéutico , Ticagrelor/uso terapéutico , Método Doble Ciego , Terapia Antiplaquetaria Doble/métodos , Accidente Cerebrovascular Embólico/tratamiento farmacológico , Accidente Cerebrovascular Embólico/etiología , Citocromo P-450 CYP2C19/genética , Accidente Cerebrovascular/tratamiento farmacológicoRESUMEN
BACKGROUND: A randomized trial suggested that treatment with metoclopramide reduces the risk of pneumonia in patients with acute stroke and a nasogastric tube. We assessed whether this finding could be replicated in a post hoc analysis of the randomized PRECIOUS trial (Prevention of Complications to Improve Outcome in Elderly Patients With Acute Stroke). METHODS: PRECIOUS was an international, 3×2 partial-factorial, randomized controlled, open-label clinical trial with blinded outcome assessment assessing preventive treatment with metoclopramide, paracetamol, and ceftriaxone in patients aged ≥66 years with acute ischemic stroke or intracerebral hemorrhage and a National Institutes of Health Stroke Scale score ≥6. In the present study, we analyzed patients who had a nasogastric tube within 24 hours after randomization. Patients who were allocated to metoclopramide (10 mg TID) were compared with patients who were not. Treatment was started within 24 hours after symptom onset and continued for 4 days or until discharge if earlier. The primary outcome was pneumonia in the first week after stroke. The score on the modified Rankin Scale after 90 days was a secondary outcome and analyzed with ordinal logistic regression. RESULTS: From April 2016 through June 2022, a total of 1493 patients were enrolled with 1376 included in this analysis, of whom 1185 (86%) had ischemic stroke and 191 (14%) had intracerebral hemorrhage. The first day after randomization, 329 (23.9%) patients had a nasogastric tube, of whom 156 were allocated to metoclopramide and 173 to standard care. Metoclopramide was not associated with a reduction of pneumonia (41.0% versus 35.8%; adjusted odds ratio, 1.35 [95% CI, 0.79-2.30]) or with poor functional outcome (adjusted odds ratio, 1.07 [95% CI, 0.71-1.61]). CONCLUSIONS: In patients with stroke who had a nasogastric tube shortly after stroke onset, metoclopramide for 4 days did not reduce pneumonia or have an effect on the functional outcome.
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OBJECTIVE: To investigate whether an earlier time to achieving and maintaining systolic blood pressure (SBP) at 120 to 140 mmâ Hg is associated with favorable outcomes in a cohort of patients with acute intracerebral hemorrhage. METHODS: We pooled individual patient data from randomized controlled trials registered in the Blood Pressure in Acute Stroke Collaboration. Time was defined as time form symptom onset plus the time (hour) to first achieve and subsequently maintain SBP at 120 to 140 mmâ Hg over 24 hours. The primary outcome was functional status measured by the modified Rankin Scale at 90 to 180 days. A generalized linear mixed models was used, with adjustment for covariables and trial as a random effect. RESULTS: A total of 5761 patients (mean age, 64.0 [SD, 13.0], 2120 [36.8%] females) were included in analyses. Earlier SBP control was associated with better functional outcomes (modified Rankin Scale score, 3-6; odds ratio, 0.98 [95% CI, 0.97-0.99]) and a significant lower risk of hematoma expansion (0.98, 0.96-1.00). This association was stronger in patients with bigger baseline hematoma volume (>10 mL) compared with those with baseline hematoma volume ≤10 mL (0.006 for interaction). Earlier SBP control was not associated with cardiac or renal adverse events. CONCLUSIONS: Our study confirms a clear time relation between early versus later SBP control (120-140 mmâ Hg) and outcomes in the one-third of patients with intracerebral hemorrhage who attained sustained SBP levels within this range. These data provide further support for the value of early recognition, rapid transport, and prompt initiation of treatment of patients with intracerebral hemorrhage.
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Antihipertensivos , Accidente Cerebrovascular , Femenino , Humanos , Persona de Mediana Edad , Masculino , Presión Sanguínea/fisiología , Antihipertensivos/uso terapéutico , Antihipertensivos/farmacología , Resultado del Tratamiento , Hemorragia Cerebral/tratamiento farmacológico , Accidente Cerebrovascular/tratamiento farmacológico , Hematoma/tratamiento farmacológicoRESUMEN
INTRODUCTION: Recruitment is complete in the fourth INTEnsive ambulance-delivered blood pressure Reduction in hyper-ACute stroke Trial (INTERACT4), a multicenter, prospective, randomized, open-label, blinded endpoint assessed trial of prehospital blood pressure (BP) lowering initiated in the ambulance for patients with a suspected acute stroke and elevated BP in China. According to the registered and published trial protocol and developed by the blinded trial Steering Committee and Operations team, this manuscript outlines a detailed statistical analysis plan for the trial prior to database lock. METHODS: Patients were randomized (1:1) to intensive (target systolic BP 130-140 mm Hg within 30 min) or guideline-recommended BP management (BP lowering only considered if systolic BP >220 mm Hg) group. Primary outcome is an ordinal analysis of the full range of scores on the modified Rankin scale at 90 days. A modified sample size of 2,320 was estimated to provide 90% power to detect a 22% reduction in the odds (common odds ratio of 0.78) of a worse functional outcome using ordinal logistic regression, on the assumption of 5% patients with missing outcome and 6% patients with a stroke mimic. CONCLUSION: The statistical analysis plan for the trial has been developed to ensure transparent, verifiable, and prespecified analysis and to avoid potential bias in the evaluation of the trial intervention.
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BACKGROUND: Elevated homocysteine levels are associated with increased blood coagulation and platelet activity and may modulate the response to antiplatelet therapies. We aimed to investigate the effects of homocysteine levels on the efficacy and safety of ticagrelor-acetylsalicylic acid (ASA) versus clopidogrel-ASA among patients with minor stroke or transient ischemic attack who carried CYP2C19 loss-of-function alleles. METHODS: We conducted a post hoc analysis of the CHANCE-2 (The Clopidogrel in High-risk Patients with Acute Nondisabling Cerebrovascular Events-II) trial. Participants were randomly assigned to treatment with ticagrelor-ASA or clopidogrel-ASA. We categorized participants into groups with elevated and non-elevated homocysteine levels, based on the median level. The primary efficacy outcome was recurrent stroke within 90-day follow-up. The primary safety outcome was severe or moderate bleeding within 90 days. RESULTS: A total of 2740 participants were randomly assigned to receive ticagrelor-ASA and 2700 to receive clopidogrel-ASA. Use of ticagrelor-ASA was associated with a reduced risk of recurrent stroke among participants with elevated homocysteine levels (74 [5.3%] v. 119 [8.5%]; hazard ratio [HR] 0.60, 95% confidence interval [CI] 0.45-0.81), but not among those with non-elevated levels (86 [6.4%] v. 87 [6.7%]; HR 0.97, 95% CI 0.71-1.32; p = 0.04 for interaction). When analyzed as a continuous variable, the benefits of ticagrelor-ASA with regard to recurrent stroke increased as homocysteine levels increased (p = 0.04 for interaction). No significant interaction between homocysteine levels and treatment with regard to severe or moderate bleeding was observed (p = 0.7 for interaction). We found a significant interaction between homocysteine levels and therapy with regard to recurrent stroke in females (p = 0.04 for interaction) but not males. INTERPRETATION: In comparison with clopidogrel-ASA, ticagrelor-ASA conferred more benefit to patients with elevated homocysteine levels, particularly to female patients, in this secondary analysis of a randomized controlled trial involving patients with minor ischemic stroke or TIA. TRIAL REGISTRATION: ClinicalTrials.gov, no. NCT04078737.
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Ataque Isquémico Transitorio , Accidente Cerebrovascular , Humanos , Femenino , Clopidogrel/uso terapéutico , Ticagrelor/uso terapéutico , Inhibidores de Agregación Plaquetaria/uso terapéutico , Ataque Isquémico Transitorio/tratamiento farmacológico , Resultado del Tratamiento , Accidente Cerebrovascular/prevención & control , Aspirina/uso terapéutico , Infarto Cerebral , Hemorragia/inducido químicamente , Homocisteína/uso terapéutico , Quimioterapia CombinadaRESUMEN
After a stroke, most patients have dysphagia, which can lead to aspiration pneumonia, malnutrition, and adverse functional outcomes. Protective interventions aimed at reducing these complications remain the cornerstone of treatment. Dietary adjustments and oral hygiene help mitigate the risk of aspiration pneumonia, and nutritional supplementation, including tube feeding, might be needed to prevent malnutrition. Rehabilitative interventions aim to enhance swallowing function, with different behavioural strategies showing promise in small studies. Investigations have explored the use of pharmaceutical agents such as capsaicin and other Transient-Receptor-Potential-Vanilloid-1 (TRPV-1) sensory receptor agonists, which alter sensory perception in the pharynx. Neurostimulation techniques, such as transcranial direct current stimulation, repetitive transcranial magnetic stimulation, and pharyngeal electrical stimulation, might promote neuroplasticity within the sensorimotor swallowing network. Further advancements in the understanding of central and peripheral sensorimotor mechanisms in patients with dysphagia after a stroke, and during their recovery, will contribute to optimising treatment protocols.
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Trastornos de Deglución , Desnutrición , Neumonía por Aspiración , Rehabilitación de Accidente Cerebrovascular , Accidente Cerebrovascular , Estimulación Transcraneal de Corriente Directa , Humanos , Trastornos de Deglución/etiología , Trastornos de Deglución/terapia , Estimulación Transcraneal de Corriente Directa/efectos adversos , Accidente Cerebrovascular/complicaciones , Accidente Cerebrovascular/terapia , Neumonía por Aspiración/complicaciones , Neumonía por Aspiración/prevención & control , Desnutrición/complicacionesRESUMEN
Cerebral small vessel disease (cSVD) causes lacunar stroke (25% of ischaemic strokes), haemorrhage, dementia, physical frailty, or is 'covert', but has no specific treatment. Uncertainties about the design of clinical trials in cSVD, which patients to include or outcomes to assess, may have delayed progress. Based on experience in recent cSVD trials, we reviewed ways to facilitate future trials in patients with cSVD.We assessed the literature and the LACunar Intervention Trial 2 (LACI-2) for data to inform choice of Participant, Intervention, Comparator, Outcome, including clinical versus intermediary endpoints, potential interventions, effect of outcome on missing data, methods to aid retention and reduce data loss. We modelled risk of missing outcomes by baseline prognostic variables in LACI-2 using binary logistic regression.Imaging versus clinical outcomes led to larger proportions of missing data. We present reasons for and against broad versus narrow entry criteria. We identified numerous repurposable drugs with relevant modes of action to test in various cSVD subtypes. Cognitive impairment is the most common clinical outcome after lacunar ischaemic stroke but was missing more frequently than dependency, quality of life or vascular events in LACI-2. Assessing cognitive status using Diagnostic and Statistical Manual for Mental Disorders Fifth Edition can use cognitive data from multiple sources and may help reduce data losses.Trials in patients with all cSVD subtypes are urgently needed and should use broad entry criteria and clinical outcomes and focus on ways to maximise collection of cognitive outcomes to avoid missing data.
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RATIONALE: A large proportion of stroke survivors will have long-lasting, debilitating neurological impairments, yet few efficacious medical treatment options are available. Etanercept inhibits binding of tumor necrosis factor to its receptor and is used in the treatment of inflammatory conditions. Perispinal subcutaneous injection followed by a supine, head down position may bypass the blood brain barrier. In observational studies and one small randomized controlled trial the majority of patients showed improvement in multiple post stroke impairments. AIM: Perispinal Etanercept to improve STroke Outcomes (PESTO) investigates whether perispinal subcutaneous injection of etanercept improves quality of life and is safe in patients with chronic, disabling, effects of stroke. METHODS AND DESIGN: PESTO is a multicenter, international, randomized placebo-controlled trial. Adult participants with a history of stroke between 1 and 15 years before enrollment and a current modified Rankin scale between 2 and 5 who are otherwise eligible for etanercept are randomized 1:1 to single dose injection of etanercept or placebo. STUDY OUTCOMES: The primary efficacy outcome is quality of life as measured using the Short Form 36 Health Inventory at day 28 after first injection. Safety outcomes include serious adverse events. SAMPLE SIZE TARGET: A total of 168 participants assuming an improvement of the SF-36 in 11% of participants in the control arm and in 30% of participants in the intervention arm, 80% power and 5% alpha. DISCUSSION: PESTO aims to provide level 1 evidence on the safety and efficacy of perispinal etanercept in patients with long-term disabling effects of stroke.
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BACKGROUND: Risk of recurrence after minor ischemic stroke is usually reported with transient ischemic attack. No previous meta-analysis has focused on minor ischemic stroke alone. The objective was to evaluate the pooled proportion of 90-day stroke recurrence for minor ischemic stroke, defined as a National Institutes of Health Stroke Scale severity score of ≤5. METHODS AND RESULTS: Published papers found on PubMed from 2000 to January 12, 2021, reference lists of relevant articles, and experts in the field were involved in identifying relevant studies. Randomized controlled trials and observational studies describing minor stroke cohort with reported 90-day stroke recurrence were selected by 2 independent reviewers. Altogether 14 of 432 (3.2%) studies met inclusion criteria. Multilevel random-effects meta-analysis was performed. A total of 6 randomized controlled trials and 8 observational studies totaling 45 462 patients were included. The pooled 90-day stroke recurrence was 8.6% (95% CI, 6.5-10.7), reducing by 0.60% (95% CI, 0.09-1.1; P=0.02) with each subsequent year of publication. Recurrence was lowest in dual antiplatelet trial arms (6.3%, 95% CI, 4.5-8.0) when compared with non-dual antiplatelet trial arms (7.2%, 95% CI, 4.7-9.6) and observational studies 10.6% (95% CI, 7.0-14.2). Age, hypertension, diabetes, ischemic heart disease, or known atrial fibrillation had no significant association with outcome. Defining minor stroke with a lower National Institutes of Health Stroke Scale threshold made no difference - score ≤3: 8.6% (95% CI, 6.0-11.1), score ≤4: 8.4% (95% CI, 6.1-10.6), as did excluding studies with n<500%-7.3% (95% CI, 5.5-9.0). CONCLUSIONS: The risk of recurrence after minor ischemic stroke is declining over time but remains important.
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Estudios Observacionales como Asunto , Recurrencia , Humanos , Factores de Tiempo , Accidente Cerebrovascular Isquémico/epidemiología , Accidente Cerebrovascular Isquémico/diagnóstico , Factores de Riesgo , Ensayos Clínicos Controlados Aleatorios como Asunto , Medición de Riesgo , Accidente Cerebrovascular/epidemiología , Inhibidores de Agregación Plaquetaria/uso terapéutico , Índice de Severidad de la EnfermedadRESUMEN
BACKGROUND AND OBJECTIVES: The Ticagrelor or Clopidogrel with Aspirin in High-Risk Patients with Acute Nondisabling Cerebrovascular Events II (CHANCE-2) trial showed that among Chinese patients with minor ischemic stroke or transient ischemic attack (TIA) who were carriers of CYP2C19 loss-of-function alleles, dual-antiplatelet therapy with ticagrelor-aspirin reduced the 90-day risk of stroke without increased severe or moderate bleeding compared with clopidogrel-aspirin. However, whether dual-antiplatelet therapy with ticagrelor was superior to clopidogrel beyond the 90 days of follow-up remained unclear. In this study, we reported 1-year follow-up outcomes of the CHANCE-2 trial. METHODS: The CHANCE-2 trial is a randomized, double-blind, placebo-controlled trial at 202 centers in China. Patients with a minor stroke or TIA who carried CYP2C19 loss-of-function alleles were randomized within 24 hours after symptom onset, in a 1:1 ratio, to receive ticagrelor and placebo clopidogrel or to receive clopidogrel and placebo ticagrelor for 90 days; both groups received aspirin for the first 21 days. After day 90, treatment was as per the choice of the clinician and the patient. RESULTS: Among 6,412 patients, the proportion of patients on ticagrelor plus aspirin, clopidogrel plus aspirin, ticagrelor alone, clopidogrel alone, aspirin alone, other antiplatelet, and no antiplatelet beyond month 3 to 1 year was 0.09%, 1.56%, 0.13%, 2.66%, 73.65%, 0.78%, and 21.13% in the ticagrelor-aspirin group and 0.03%, 1.63%, 0.19%, 2.60%, 72.83%, 0.66%, and 22.06% in the clopidogrel-aspirin group, respectively. The primary outcome of new stroke occurred in 252 patients (7.91%) in the ticagrelor-aspirin group and 310 patients (9.73%) in the clopidogrel-aspirin group by 1 year of follow-up (hazard ratio 0.80; 95% CI 0.68-0.95; p = 0.007); new stroke beyond 3 months to 1 year occurred in 61 patients (2.07%) and 67 patients (2.32%) (p = 0.48), respectively. Primary safety outcome of severe or moderate bleeding occurred in 17 patients (0.53%) in the ticagrelor-aspirin group and 20 patients (0.63%) in the clopidogrel-aspirin group (p = 0.61). DISCUSSION: For CYP2C19 loss-of-function allele carriers, early dual-antiplatelet therapy with ticagrelor is superior to clopidogrel at 1 year in reducing recurrent stroke. TRIAL REGISTRATION INFORMATION: URL: clinicaltrials.gov. Unique identifier: NCT04078737. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for patients with minor stroke or TIA with TIACYP2C19 loss-of-function, ticagrelor plus aspirin for 21 days is superior to clopidogrel plus aspirin in reducing the 1-year risk of recurrent stroke.
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Ataque Isquémico Transitorio , Accidente Cerebrovascular , Humanos , Ticagrelor/uso terapéutico , Clopidogrel/uso terapéutico , Prevención Secundaria , Citocromo P-450 CYP2C19/genética , Ataque Isquémico Transitorio/tratamiento farmacológico , Ataque Isquémico Transitorio/genética , Inhibidores de Agregación Plaquetaria/uso terapéutico , Accidente Cerebrovascular/tratamiento farmacológico , Accidente Cerebrovascular/genética , Infarto Cerebral , Aspirina/uso terapéuticoRESUMEN
INTRODUCTION: The Tranexamic acid for IntraCerebral Haemorrhage-2 (TICH-2) trial reported no significant improvement in death and dependency at day 90 despite reductions in haematoma expansion, early neurological deterioration and early death. However, significant recovery after stroke, particularly intracerebral haemorrhage (ICH), may take more than 3 months. Here we report the participant outcomes at 1 year after stroke. PATIENTS AND METHODS: TICH-2 was a prospective randomised controlled trial that tested the efficacy and safety of tranexamic acid in spontaneous ICH when given within 8 h of onset. Patients with ICH on anticoagulation were excluded. Centralised blinded telephone follow up was performed for patients from the United Kingdom at 1 year. The primary outcome was modified Rankin Scale at 1 year. Secondary outcomes included Barthel index, Telephone Interview Cognitive Status-modified, EuroQoL-5D and Zung Depression Scale. This was a prespecified secondary analysis of the TICH-2 trial. RESULTS: About 2325 patients were recruited into the trial (age 68.9 ± 13.8 years; 1301 male, 56%). About 1910 participants (82.2%) were eligible for day 365 follow up. 57 patients (3.0%) were lost to follow up. Tranexamic acid did not reduce the risk of poor functional outcome at 1 year (adjusted OR 0.91 95% CI 0.77-1.09; p = 0.302). However, Cox proportional hazard analysis revealed significant survival benefit in the tranexamic acid group (adjusted HR 0.83, 95% CI 0.70-0.99; p = 0.038). CONCLUSION: There was no difference in functional outcome at 1 year after ICH. Tranexamic acid may reduce mortality at 1 year without an increase in severely dependent survivors. But this should be interpreted with caution as this is a result of secondary analysis in a neutral trial.
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Importance: Cervical artery dissection is the most common cause of stroke in younger adults. To date, there is no conclusive evidence on which antithrombotic therapy should be used to treat patients. Objective: To perform an individual patient data meta-analysis of randomized clinical trials comparing anticoagulants and antiplatelets in prevention of stroke after cervical artery dissection. Data Sources: PubMed.gov, Cochrane database, Embase, and ClinicalTrials.gov were searched from inception to August 1, 2023. Study Selection: Randomized clinical trials that investigated the effectiveness and safety of antithrombotic treatment (antiplatelets vs anticoagulation) in patients with cervical artery dissection were included in the meta-analysis. The primary end point was required to include a composite of (1) any stroke, (2) death, or (3) major bleeding (extracranial or intracranial) at 90 days of follow-up. Data Extraction/Synthesis: Two independent investigators performed a systematic review according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, and inconsistencies were resolved by a principal investigator. Main Outcomes and Measures: The primary outcome was a composite of (1) ischemic stroke, (2) death, or (3) major bleeding (extracranial or intracranial) at 90 days of follow-up. The components of the composite outcome were also secondary outcomes. Subgroup analyses based on baseline characteristics with a putative association with the outcome were performed. Logistic regression was performed using the maximum penalized likelihood method including interaction in the subgroup analyses. Results: Two randomized clinical trials, Cervical Artery Dissection in Stroke Study and Cervical Artery Dissection in Stroke Study and the Biomarkers and Antithrombotic Treatment in Cervical Artery Dissection, were identified, of which all participants were eligible. A total of 444 patients were included in the intention-to-treat population and 370 patients were included in the per-protocol population. Baseline characteristics were balanced. There were fewer primary end points in those randomized to anticoagulation vs antiplatelet therapy (3 of 218 [1.4%] vs 10 of 226 [4.4%]; odds ratio [OR], 0.33 [95% CI, 0.08-1.05]; P = .06), but the finding was not statistically significant. In comparison with aspirin, anticoagulation was associated with fewer strokes (1 of 218 [0.5%] vs 10 of 226 [4.0%]; OR, 0.14 [95% CI, 0.02-0.61]; P = .01) and more bleeding events (2 vs 0). Conclusions and Relevance: This individual patient data meta-analysis of 2 currently available randomized clinical trial data found no significant difference between anticoagulants and antiplatelets in preventing early recurrent events.
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Fibrinolíticos , Inhibidores de Agregación Plaquetaria , Disección de la Arteria Vertebral , Humanos , Disección de la Arteria Vertebral/tratamiento farmacológico , Disección de la Arteria Vertebral/complicaciones , Fibrinolíticos/uso terapéutico , Inhibidores de Agregación Plaquetaria/uso terapéutico , Anticoagulantes/uso terapéutico , Anticoagulantes/efectos adversos , Ensayos Clínicos Controlados Aleatorios como Asunto , Accidente Cerebrovascular/prevención & control , Accidente Cerebrovascular/tratamiento farmacológico , Accidente Cerebrovascular/etiología , Disección de la Arteria Carótida Interna/tratamiento farmacológicoRESUMEN
BACKGROUND AND OBJECTIVES: An important proportion of patients with spontaneous intracerebral hemorrhage (ICH) undergo neurosurgical intervention to reduce mass effect from large hematomas and control the complications of bleeding, including hematoma expansion and hydrocephalus. The Tranexamic acid (TXA) for hyperacute primary IntraCerebral Hemorrhage (TICH-2) trial demonstrated that tranexamic acid (TXA) reduces the risk of hematoma expansion. We hypothesized that TXA would reduce the frequency of surgery (primary outcome) and improve functional outcome at 90 days in surgically treated patients in the TICH-2 data set. METHODS: Participants enrolled in TICH-2 were randomized to placebo or TXA. Participants randomized to either TXA or placebo were analyzed for whether they received neurosurgery within 7 days and their characteristics, outcomes, hematoma volumes (HVs) were compared. Characteristics and outcomes of participants who received surgery were also compared with those who did not. RESULTS: Neurosurgery was performed in 5.2% of participants (121/2325), including craniotomy (57%), hematoma drainage (33%), and external ventricular drainage (21%). The number of patients receiving surgery who received TXA vs placebo were similar at 4.9% (57/1153) and 5.5% (64/1163), respectively (odds ratio [OR] 0.893; 95% CI 0.619-1.289; P -value = .545). TXA did not improve outcome compared with placebo in either surgically treated participants (OR 0.79; 95% CI 0.30-2.09; P = .64) or those undergoing hematoma evacuation by drainage or craniotomy (OR 1.19 95% 0.51-2.78; P -value = .69). Postoperative HV was not reduced by TXA (mean difference -8.97 95% CI -23.77, 5.82; P -value = .45). CONCLUSION: TXA was not associated with less neurosurgical intervention, reduced HV, or improved outcomes after surgery.
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Antifibrinolíticos , Hemorragia Cerebral , Hematoma , Procedimientos Neuroquirúrgicos , Ácido Tranexámico , Humanos , Ácido Tranexámico/uso terapéutico , Ácido Tranexámico/administración & dosificación , Masculino , Femenino , Hemorragia Cerebral/cirugía , Hemorragia Cerebral/tratamiento farmacológico , Antifibrinolíticos/uso terapéutico , Antifibrinolíticos/administración & dosificación , Persona de Mediana Edad , Anciano , Procedimientos Neuroquirúrgicos/métodos , Resultado del Tratamiento , Hematoma/cirugía , Hematoma/tratamiento farmacológico , Método Doble CiegoRESUMEN
OBJECTIVES: Evidence of the optimal antiplatelet therapy for elderly patients who had a stroke is limited, especially those elder than 80 years. This study aimed to explore the efficacy and safety of dual antiplatelet therapy (DAPT) in old-old patients compared with younger patients in the ticagrelor or Clopidogrel with aspirin in High-risk patients with Acute Non-disabling Cerebrovascular Events-II (CHANCE-2) trial. METHODS: CHANCE-2 was a randomised, double-blind, placebo-controlled trial in China involving patients with high-risk transient ischaemic attack or minor stroke with CYP2C19 loss-of-function alleles. In our substudy, all enrolled patients were stratified by age: old-old (≥80 years), young-old (65-80 years) and younger (<65 years). The primary outcomes were stroke recurrence and moderate to severe bleeding within 90 days, respectively. RESULTS: Of all the 6412 patients, 406 (6.3%) were old-old, 2755 (43.0%) were young-old and 3251 (50.7%) were younger. Old-old patients were associated with higher composite vascular events (HR 1.41, 95% CI 1.00 to 1.98, p=0.048), disabling stroke (OR 2.43, 95% CI 1.52 to 3.88, p=0.0002), severe or moderate bleeding (HR 8.40, 95% CI 1.95 to 36.21, p=0.004) and mortality (HR 7.56, 95% CI 2.23 to 25.70, p=0.001) within 90 days. Ticagrelor-aspirin group was associated with lower risks of stroke recurrence within 90 days in younger patients (HR 0.68, 95% CI 0.51 to 0.91, p=0.008), which was no differences in old-old patients. CONCLUSION: Elderly patients aged over 80 in CHANCE-2 trial had higher risks of composite vascular events, disabling stroke, severe or moderate bleeding and mortality within 90 days. Genotype-guided DAPT might not be as effective in old-old patients as in younger ones. TRIAL REGISTRATION NUMBER: NCT04078737.
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Importance: Comparisons are limited for immediate-intensive and delayed-intensive statin for secondary stroke prevention and neuroprotection in patients with acute mild ischemic stroke or transient ischemic attack (TIA) from atherosclerosis. Objective: To estimate whether immediate-intensive statin therapy is safe and can lower the risk of recurrent stroke compared with delayed-intensive statin in patients with acute mild ischemic stroke or high-risk TIA from atherosclerosis. Design, Setting, and Participants: The Intensive Statin and Antiplatelet Therapy for High-Risk Intracranial or Extracranial Atherosclerosis (INSPIRES) trial, a double-blind, placebo-controlled, 2 × 2 factorial, randomized clinical trial enrolled patients from September 2018 to October 2022. The trial was conducted at 222 hospitals in China. Patients aged 35 to 80 years with mild ischemic stroke or high-risk TIA of presumed atherosclerosis within 72 hours of symptom onset were assessed. Interventions: Patients were randomly assigned to receive immediate-intensive atorvastatin (80 mg daily on days 1-21; 40 mg daily on days 22-90) or 3-day delayed treatment (placebo for days 1-3, followed by placebo and atorvastatin, 40 mg daily on days 4-21, and then atorvastatin, 40 mg daily on days 22-90). Main Outcomes and Measures: The primary efficacy outcome was new stroke within 90 days, and a secondary efficacy outcome was poor functional outcome. Moderate to severe bleeding was the primary safety outcome. Results: A total of 11â¯431 patients were assessed for eligibility, and 6100 patients (median [IQR] age, 65 [57-71] years; 3915 men [64.2%]) were enrolled, with 3050 assigned to each treatment group. Within 90 days, new stroke occurred in 245 patients (8.1%) in the immediate-intensive statin group and 256 patients (8.4%) in the delayed group (hazard ratio, 0.95; 95% CI, 0.80-1.13). Poor functional outcome occurred in 299 patients (9.8%) and 348 patients (11.4%) in the immediate-intensive and delayed-intensive statin groups, respectively (odds ratio, 0.83; 95% CI, 0.71-0.98). Moderate to severe bleeding occurred in 23 of 3050 patients (0.8%) and 17 of 3050 patients (0.6%), in the immediate-intensive and delayed-intensive statin groups, respectively. Conclusions and Relevance: Immediate-intensive statin initiated within 72 hours did not reduce the risk of stroke within 90 days and may be associated with improved functional outcomes without significant difference in moderate to severe bleeding, compared with 3-day delayed-intensive statin in Chinese patients with acute mild ischemic stroke or TIA from atherosclerosis. Trial Registration: ClinicalTrials.gov Identifier: NCT03635749.
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Atorvastatina , Inhibidores de Hidroximetilglutaril-CoA Reductasas , Ataque Isquémico Transitorio , Accidente Cerebrovascular Isquémico , Humanos , Masculino , Persona de Mediana Edad , Femenino , Anciano , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Inhibidores de Hidroximetilglutaril-CoA Reductasas/administración & dosificación , Método Doble Ciego , Accidente Cerebrovascular Isquémico/tratamiento farmacológico , Accidente Cerebrovascular Isquémico/prevención & control , Atorvastatina/uso terapéutico , Atorvastatina/administración & dosificación , Ataque Isquémico Transitorio/tratamiento farmacológico , Adulto , Isquemia Encefálica/tratamiento farmacológico , Anciano de 80 o más Años , Prevención Secundaria/métodos , Inhibidores de Agregación Plaquetaria/uso terapéutico , Inhibidores de Agregación Plaquetaria/administración & dosificaciónRESUMEN
Blood Pressure Variability (BPV) is associated with cardiovascular risk and serum uric acid level. We investigated whether BPV was lowered by allopurinol and whether it was related to neuroimaging markers of cerebral small vessel disease (CSVD) and cognition. We used data from a randomised, double-blind, placebo-controlled trial of two years allopurinol treatment after recent ischemic stroke or transient ischemic attack. Visit-to-visit BPV was assessed using brachial blood pressure (BP) recordings. Short-term BPV was assessed using ambulatory BP monitoring (ABPM) performed at 4 weeks and 2 years. Brain MRI was performed at baseline and 2 years. BPV measures were compared between the allopurinol and placebo groups, and with CSVD and cognition. 409 participants (205 allopurinol; 204 placebo) were included in the visit-to-visit BPV analyses. There were no significant differences found between placebo and allopurinol groups for any measure of visit-to-visit BPV. 196 participants were included in analyses of short-term BPV at week 4. Two measures were reduced by allopurinol: the standard deviation (SD) of systolic BP (by 1.30 mmHg (95% confidence interval (CI) 0.18-2.42, p = 0.023)); and the average real variability (ARV) of systolic BP (by 1.31 mmHg (95% CI 0.31-2.32, p = 0.011)). There were no differences in other measures at week 4 or in any measure at 2 years, and BPV was not associated with CSVD or cognition. Allopurinol treatment did not affect visit-to-visit BPV in people with recent ischemic stroke or TIA. Two BPV measures were reduced at week 4 by allopurinol but not at 2 years.
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Hipertensión , Ataque Isquémico Transitorio , Accidente Cerebrovascular Isquémico , Humanos , Presión Sanguínea , Ataque Isquémico Transitorio/diagnóstico por imagen , Ataque Isquémico Transitorio/tratamiento farmacológico , Ataque Isquémico Transitorio/etiología , Alopurinol/uso terapéutico , Accidente Cerebrovascular Isquémico/complicaciones , Accidente Cerebrovascular Isquémico/tratamiento farmacológico , Ácido Úrico , Factores de Riesgo , Monitoreo Ambulatorio de la Presión ArterialRESUMEN
Background: Infections and fever after stroke are associated with poor functional outcome or death. We assessed whether prophylactic treatment with anti-emetic, antibiotic, or antipyretic medication would improve functional outcome in older patients with acute stroke. Methods: We conducted an international, 2∗2∗2-factorial, randomised, controlled, open-label trial with blinded outcome assessment in patients aged 66 years or older with acute ischaemic stroke or intracerebral haemorrhage and a score on the National Institutes of Health Stroke Scale ≥ 6. Patients were randomly allocated (1:1) to metoclopramide (oral, rectal, or intravenous; 10 mg thrice daily) vs. no metoclopramide, ceftriaxone (intravenous; 2000 mg once daily) vs. no ceftriaxone, and paracetamol (oral, rectal, or intravenous; 1000 mg four times daily) vs. no paracetamol, started within 24 h after symptom onset and continued for four days. All participants received standard of care. The target sample size was 3800 patients. The primary outcome was the score on the modified Rankin Scale (mRS) at 90 days analysed with ordinal logistic regression and reported as an adjusted common odds ratio (an acOR < 1 suggests benefit and an acOR > 1 harm). This trial is registered (ISRCTN82217627). Findings: From April 2016 through June 2022, 1493 patients from 67 European sites were randomised to metoclopramide (n = 704) or no metoclopramide (n = 709), ceftriaxone (n = 594) or no ceftriaxone (n = 482), and paracetamol (n = 706) or no paracetamol (n = 739), of whom 1471 were included in the intention-to-treat analysis. Prophylactic use of study medication did not significantly alter the primary outcome at 90 days: metoclopramide vs. no metoclopramide (adjusted common odds ratio [acOR], 1.01; 95% CI 0.81-1.25), ceftriaxone vs. no ceftriaxone (acOR 0.99; 95% CI 0.77-1.27), paracetamol vs. no paracetamol (acOR 1.19; 95% CI 0.96-1.47). The study drugs were safe and not associated with an increased incidence of serious adverse events. Interpretation: We observed no sign of benefit of prophylactic use of metoclopramide, ceftriaxone, or paracetamol during four days in older patients with a moderately severe to severe acute stroke. Funding: This project has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No: 634809.
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BACKGROUND AND AIMS: Uncertainty persists over the effects of blood pressure (BP) lowering in acute stroke. The INTEnsive ambulance-delivered blood pressure Reduction in hyper-Acute stroke Trial (INTERACT4) aims to determine efficacy and safety of hyperacute intensive BP lowering in patients with suspected acute stroke. Given concerns over the safety of this treatment in the pre-hospital setting, particularly in relation to patients with intracerebral hemorrhage, we provide an update on progress of the study and profile of participants to date. METHODS: INTERACT4 is an ongoing multicentre, ambulance-delivered, randomized, open-label, blinded endpoint trial of pre-hospital BP lowering in patients with suspected acute stroke and elevated BP in China. Patients are randomized via a mobile phone digital system to intensive (target systolic BP [SBP] <140mmHg within 30 min) or guideline-recommended BP management. Primary outcome is an ordinal analysis of the full range of scores on the modified Rankin scale scores at 90 days. RESULTS: Between March 2020 and April 2023, 2053 patients (mean age 70 years, female 39%) were recruited with a mean BP 178/98 mmHg in whom 45% have a diagnosis of primary intracerebral hemorrhage upon arrival at hospital. At the time of presentation to hospital, the mean SBP was 160 and 170mmHg in the intensive and control groups (Δ10 mmHg), respectively. The independent data and safety monitoring board has not identified any safety concerns and recommended continuation of the trial. The sample size was reduced from 3116 to 2320 after meetings in August 2022 as the stroke mimic rate was persistently lower than initially estimated (6% vs 30%). The study is expected to be completed in late 2023 and the results announced in May 2024. CONCLUSIONS: INTERACT4 is on track to provide reliable evidence of the effectiveness of ambulance-delivered intensive BP lowering in patients with suspected acute stroke. TRIAL REGISTRATION: ClinicalTrials.gov NCT03790800 ; registered on 2 January 2019. Chinese Trial Registry ChCTR1900020534 , registered on 7 January 2019.