Valoración del estado de la microcirculación cerebral en pacientes con infartos lacunares mediante el estudio de la reactividad cerebrovascular por Doppler transcraneal

Descripció del recurs: 5 març 2002Títol obtingut de la portada digitalitzadaIntroducción: La valoración funcional de la microcirculación (arteriolas) puede proporcionar una valiosa información referente a la extensión del proceso de arteriolosesclerosis difusa en pacientes con enfermedad de pequeño vaso (microangiopatía cerebral). Objetivo: Evaluar el estado funcional de la microcirculacion cerebral en pacientes con un primer infarto lacunar sintomatico mediante el estudio de la reactividad cerebrovascular por Doppler transcraneal. Material y Métodos: Se realizaron estudios de reactividad cerebrovascular en 46 pacientes con un primer infarto lacunar sintomático y en 46 individuos sanos de similar edad y sexo con los pacientes. El estudio de reactividad cerebrovascular se llevo a cabo mediante la cuantificación del porcentage de incremento en la velocidad media de fluhjo determinada por Doppler transcraneal, tras la administración endovenosa de 15mg/kg de acetazolamida. Resultados: La reactividad cerebrovascular fue significativamente (p<0,001) menor en los pacientes con infartos lacunares (50± 12,7%) en comparación con los controles sanos (65,2±12,4%). El analisis de regresión logistica puso de manifiesto que el sexo masculino (OR 2,3 ; p<0,02) la edad (OR 3,6; p<0,005) y la presencia de infartos lacunares en la resonancia magnética (OR 5,3 ; p<0,001) fueron factores que se asociaban de forma independiente con la reducción de la reactividad cerebrovascular. Se identificó mediante una curva ROC un valor de reactividad cerebrovascular de 55,6% como el punto de corte que mejor discriminaba entre tener o no infartos lacunares en la resonancia magnética (sensibilidad 67%, especificidad 82%) . Además, se pudo observar que la reactividad cerebrovascular fue significativamente (p=0,02) menor en los pacientes con multiples infartos lacunares (46,38±12,6%) en comparación con aquellos que mostraban un infarto lacunar único en la resonancia magnética (54,83±11,58%). Asimismo, se observó una tendencia hacia una correlación negativa entre la reactividad cerebrovascular y el número total de infartos lacunares en la resonancia magnética. Un analisis de regresión logistica identificó el antecedente de hipertensión arterial (OR 7,24; IC 95% 2,95-17,79) y la reactividad cerebrovascular (OR 0,8; IC 95% 0,81-0,93) como factores predictores independientes para presentar un primer infarto lacunar sintomático. Conclusion: La reactividad cerebrovascular determinada por Doppler transcraneal constituye un marcador de riesgo para un primer infarto lacunar sintomático. El estudio de la reactividad cerebrovascular permitiría evaluar la gravedad y extensión del proceso de arterioloesclerosis difusa en pacientes con microangiopatía cerebral.Summary Background and purpose: Functional assessment of small arteries and arterioles could provide valuable information regarding the extend of diffuse arteriolosclerosis in patients with small-vessel disease. Therefore, we attempted to clarify the role of cerebrovascular reactivity as a risk marker for first-ever symptomatic lacunar infarction. Methods: Forty-six patients with lacunar infarction and 46 sex and age matched controls were prospectively evaluated. Cerebral hemodynamics were studied with transcranial Doppler ultrasonography. Cerebrovascular reactivity was examined by calculating the percent increase in mean flow velocity occurring after 15 mg/Kg acetazolamide administration (Diamox Test). Results : CVR was significantly (p< 0,0001, student's t test) lower in cases (50,0 ± 12,7 %) as compared with controls (65,2 ± 12,4%). A multiple logistic regression analysis identified male sex (OR 2,3, p=0,02), age (OR 3,6, p<0,005) and the presence of LI on MRI (OR 5,3, p<0,001) as significant and independent factors associated with a reduction of CVR. Moreover, a cut-point of 55,6% (sensibility 67%, specificity 82%) was established as threshold value for distinguishing between pathological and normal CVR. CVR was significantly (p=0,02) lower in patients with multiple (46,38 ± 12,6%) than with single (54,83 ± 11,58%) lacunar infarction. In addition, a trend of negative correlation was found between CVR and the number of LI (r= - 0,26, p=0,08). In the multiple logistic model, history of hypertension ( OR 7,24; 95%IC 2,95- 17,79) and CVR (OR 0,8; 95%IC 0,81-0,93) emerge as significant and independent predictors of first-ever LI. Conclusion: These data suggest that impaired cerebrovascular reactivity is a predictor of first-ever lacunar infarction

Rationale and design of the AXIOMATIC-SSP phase II trial: Antithrombotic treatment with factor XIa inhibition to Optimize Management of Acute Thromboembolic events for Secondary Stroke Prevention

MRI; Milvexian; Stroke preventionResonancia magnética; Milvexian; Prevención de ictusRessonància magnètica; Milvexian; Prevenció d'ictusBackground Individuals with ischemic stroke or transient ischemic attack (TIA) have a high early risk of ischemic stroke despite dual antiplatelet therapy. The risk of ischemic stroke, and associated disability, represents a significant unmet clinical need. Genetic variants resulting in reduced factor XI levels are associated with reduced risk for ischemic stroke but are not associated with increased intracranial bleeding. Milvexian is an oral small-molecule inhibitor of FXIa that binds activated factor XI with high affinity and selectivity and may reduce the risk of stroke when added to antiplatelet drugs without significant bleeding. We aimed to evaluate the dose-response relationship of milvexian in participants treated with dual antiplatelets. Methods We began a phase II, double-blinded, randomized, placebo-controlled trial at 367 sites in 2019. Participants (N = 2366) with ischemic stroke (National Institutes of Health Stroke Scale score ≤7) or high-risk TIA (ABCD2 score ≥6) were randomized to 1 of 5 doses of milvexian or placebo for 90 days. Participants also received clopidogrel 75 mg daily for the first 21 days and aspirin 100 mg for 90 days. The efficacy endpoint was the composite of ischemic stroke or incident infarct on magnetic resonance imaging. Major bleeding, defined as type 3 or 5 bleeding according to the Bleeding Academic Research Consortium, was the safety endpoint. Participant follow-up will end in 2022. Conclusion The AXIOMATIC-SSP trial will evaluate the dose-response of milvexian for ischemic stroke occurrence in participants with ischemic stroke or TIA.This study is sponsored by Bristol Myers Squibb and Janssen Research & Development, LLC

Efficacy and Safety of Oral Factor XIa Inhibitors in Stroke Prevention: A Systematic Review and Meta-Analysis

Anticoagulation; Factor Xia inhibitors; Ischemic strokeAnticoagulació; Inhibidors del factor Xia; Ictus isquèmicAnticoagulación; Inhibidores del factor Xia; Ictus isquémicoIntroduction: Despite preventive measures, stroke rates remain high in the primary and secondary prevention settings. Factor XIa inhibition may offer a novel, safe and effective antithrombotic option for stroke prevention. Methods: We conducted a systematic review and meta-analysis including all available randomized controlled clinical trials (RCTs) that investigated the efficacy and safety of factor XIa inhibitors versus controls in primary or secondary stroke prevention. The primary efficacy and safety outcomes of interest were symptomatic ischemic stroke (IS) and the composite of major bleeding and clinically relevant non-major bleeding. Results: Four phase II dose-finding RCTs were included, comprising a total of 4732 patients treated with factor XIa inhibitors versus 1798 controls. Treatment with factor XIa inhibitors did not reduce the risk of IS compared to controls (RR: 0.89; 95% CI: 0.67–1.17). The composite of symptomatic IS and covert infarcts on brain MRI (RR: 1.01; 95% CI: 0.87–1.18), the composite of symptomatic IS and transient ischemic attack (TIA; RR: 0.78; 95% CI: 0.61–1.01), and the composite of major adverse cardiovascular events (RR: 1.07; 95% CI: 0.87–1.31) did not differ between the treatment groups. Treatment with factor XIa inhibitors did not increase the risk of the composite of major bleeding and clinically relevant non-major bleeding (RR: 1.19; 95% CI: 0.65–2.16), major bleeding alone (RR: 1.19; 95% CI: 0.64–2.22), intracranial bleeding (RR: 0.91; 95% CI: 0.26–3.19) or all-cause mortality (RR: 1.21; 95% CI: 0.77–1.90). Conclusion: This meta-analysis provides reassuring evidence regarding the safety of factor XIa inhibitors. These findings, coupled with potential signals of efficacy in reducing IS (and TIA), underscore the importance of ongoing phase III RCTs for providing definitive data regarding the effect of factor XIa inhibition on stroke prevention

Cost-effectiveness of ticagrelor plus aspirin versus aspirin in acute ischaemic stroke or transient ischaemic attack: an economic evaluation of the THALES trial

Health economics; StrokeEconomía de la salud; IctusEconomia de la salut; IctusObjective THALES demonstrated that ticagrelor plus aspirin reduced the risk of stroke or death but increased bleeding versus aspirin during the 30 days following a mild-to-moderate acute non-cardioembolic ischaemic stroke (AIS) or high-risk transient ischaemic attack (TIA). There are no cost-effectiveness analyses supporting this combination in Europe. To address this, a cost-effectiveness analysis was performed. Methods Cost-effectiveness was evaluated using a decision tree and Markov model with a short-term and long-term (30-year) horizon. Stroke, mortality, bleeding and EuroQol-5 Dimension (EQ-5D) data from THALES were used to estimate short-term outcomes. Model transitions were based on stroke severity (disabling stroke was defined as modified Rankin Scale >2). Healthcare resource utilisation and EQ-5D data beyond 30 days were based on SOCRATES, another trial in AIS/TIA that compared ticagrelor with aspirin. Long-term costs, survival and disutilities were based on published literature. Unit costs were derived from national databases and discounted at 3% annually from a Swedish healthcare perspective. Results One-month treatment with ticagrelor plus aspirin resulted in 12 fewer strokes, 4 additional major bleeds and cost savings of €95 000 per 1000 patients versus aspirin from a Swedish healthcare perspective. This translated into increased quality-adjusted life-years (0.04) and reduced societal costs (−€1358) per patient over a lifetime horizon. Key drivers of cost-effectiveness were number of patients experiencing subsequent disabling stroke and degree of disability. Findings were robust over a range of input assumptions. Conclusion One month of treatment with ticagrelor plus aspirin is likely to improve outcomes and reduce costs versus aspirin in mild-to-moderate AIS or high-risk TIA.AstraZeneca funded the THALES trial and the cost-effectiveness analysis of this study

Time Course for Benefit and Risk of Ticagrelor and Aspirin in Acute Ischemic Stroke or Transient Ischemic Attack

Aspirin; Acute Ischemic Stroke, BenefitAspirina; Accidente cerebrovascular isquémico agudo; BeneficioAspirina; Accident cerebrovascular isquèmic agut; BeneficiBackground and objectives: The goal of this work was to investigate the short-term time-course benefit and risk of ticagrelor with aspirin in acute mild-moderate ischemic stroke or high-risk TIA in The Acute Stroke or Transient Ischemic Attack Treated with Ticagrelor and ASA for Prevention of Stroke and Death (THALES) trial. Methods: In an exploratory analysis of the THALES trial, we evaluated the cumulative incidence of irreversible efficacy and safety outcomes at different time points during the 30-day treatment period. The efficacy outcome was major ischemic events defined as a composite of ischemic stroke or nonhemorrhagic death. The safety outcome was major hemorrhage defined as a composite of intracranial hemorrhage and fatal bleedings. Net clinical impact was defined as the combination of these 2 endpoints. Results: This analysis included a total of 11,016 patients (5,523 in the ticagrelor-aspirin group, 5,493 in the aspirin group) with a mean age of 65 years, and 39% were women. The reduction of major ischemic events by ticagrelor occurred in the first week (4.1% vs 5.3%; absolute risk reduction 1.15%, 95% CI 0.36%-1.94%) and remained throughout the 30-day treatment period. An increase in major hemorrhage was seen during the first week and remained relatively constant in the following weeks (absolute risk increase ≈0.3%). Cumulative analysis showed that the net clinical impact favored ticagrelor-aspirin in the first week (absolute risk reduction 0.97%, 95% CI, 0.17%-1.77%) and remained constant throughout the 30 days. Discussion: In patients with mild-moderate ischemic stroke or high-risk TIA, the treatment effect of ticagrelor-aspirin was present from the first week. The ischemic benefit of ticagrelor-aspirin outweighs the risk of major hemorrhage throughout the treatment period, which may support the use of 30-day treatment with ticagrelor and aspirin in these patients. Classification of evidence: This study provides Class II evidence that, for patients with mild-moderate ischemic stroke or high-risk TIA, the ischemic benefit of ticagrelor-aspirin outweighs the risk of major hemorrhage throughout the 30-day treatment period.This study is supported by AstraZeneca

Effectiveness of Thrombectomy in Stroke According to Baseline Prognostic Factors: Inverse Probability of Treatment Weighting Analysis of a Population-Based Registry

Stroke; Thrombectomy; PrognosisIctus; Trombectomia; PronòsticIctus; Trombectomía; PronósticoBackground and purpose: In real-world practice, the benefit of mechanical thrombectomy (MT) is uncertain in stroke patients with very favorable or poor prognostic profiles at baseline. We studied the effectiveness of MT versus medical treatment stratifying by different baseline prognostic factors. Methods: Retrospective analysis of 2,588 patients with an ischemic stroke due to large vessel occlusion nested in the population-based registry of stroke code activations in Catalonia from January 2017 to June 2019. The effect of MT on good functional outcome (modified Rankin Score ≤2) and survival at 3 months was studied using inverse probability of treatment weighting (IPTW) analysis in three pre-defined baseline prognostic groups: poor (if pre-stroke disability, age >85 years, National Institutes of Health Stroke Scale [NIHSS] >25, time from onset >6 hours, Alberta Stroke Program Early CT Score 3), good (if NIHSS <6 or distal occlusion, in the absence of poor prognostic factors), or reference (not meeting other groups' criteria). Results: Patients receiving MT (n=1,996, 77%) were younger, had less pre-stroke disability, and received systemic thrombolysis less frequently. These differences were balanced after the IPTW stratified by prognosis. MT was associated with good functional outcome in the reference (odds ratio [OR], 2.9; 95% confidence interval [CI], 2.0 to 4.4), and especially in the poor baseline prognostic stratum (OR, 3.9; 95% CI, 2.6 to 5.9), but not in the good prognostic stratum. MT was associated with survival only in the poor prognostic stratum (OR, 2.6; 95% CI, 2.0 to 3.3). Conclusions: Despite their worse overall outcomes, the impact of thrombectomy over medical management was more substantial in patients with poorer baseline prognostic factors than patients with good prognostic factors

Predictors of Recurrent Stroke After Embolic Stroke of Undetermined Source in the RE‐SPECT ESUS Trial

Risk factors; Secondary prevention; Stroke predictorsFactores de riesgo; Prevención secundaria; Predictores de accidentes cerebrovascularesFactors de risc; Prevenció secundària; Predictors d'accidents cerebrovascularsBackground We sought to determine recurrent stroke predictors among patients with embolic strokes of undetermined source (ESUS). Methods and Results We applied Cox proportional hazards models to identify clinical features associated with recurrent stroke among participants enrolled in RE‐SPECT ESUS (Randomized, Double‐Blind, Evaluation in Secondary Stroke Prevention Comparing the Efficacy and Safety of the Oral Thrombin Inhibitor Dabigatran Etexilate Versus Acetylsalicylic Acid in Patients With Embolic Stroke of Undetermined Source) trial, an international clinical trial evaluating dabigatran versus aspirin for patients with ESUS. During a median follow‐up of 19 months, 384 of 5390 participants had recurrent stroke (annual rate, 4.5%). Multivariable models revealed that stroke or transient ischemic attack before the index event (hazard ratio [HR], 2.27 [95% CI, 1.83–2.82]), creatinine clearance <50 mL/min (HR, 1.69 [95% CI, 1.23–2.32]), male sex (HR, 1.60 [95% CI, 1.27–2.02]), and CHA2DS2‐VASc ≥4 (HR, 1.55 [95% CI, 1.15–2.08] and HR, 1.66 [95% CI, 1.21–2.26] for scores of 4 and ≥5, respectively) versus CHA2DS2‐VASc of 2 to 3, were independent predictors for recurrent stroke. Conclusions In RE‐SPECT ESUS trial, expected risk factors previously linked to other common stroke causes were associated with stroke recurrence. These data help define high‐risk groups for subsequent stroke that may be useful for clinicians and for researchers designing trials among patients with ESUS.This study was supported by Boehringer Ingelheim

Role of telemedicine in the management of oral anticoagulation in atrial fibrillation: a practical clinical approach

COVID-19; Direct oral anticoagulant; TelemedicineCOVID-19; Anticoagulante oral directo; TelemedicinaCOVID-19; Anticoagulant oral directe; TelemedicinaCompared with face-to-face consultations, telemedicine has many advantages, including more efficient use of healthcare resources, partial relief of the burden of care, reduced exposure to COVID-19, treatment adjustment, organization of more efficient healthcare circuits and patient empowerment. Ensuring optimal anticoagulation in atrial fibrillation patients is mandatory if we want to reduce the thromboembolic risk. Of note, telemedicine is an excellent option for the long-term management of atrial fibrillation patients. Moreover, direct oral anticoagulants may provide an added value in telemedicine (versus vitamin K antagonists), as it is not necessary to monitor anticoagulant effect or make continuous dosage adjustments. In this multidisciplinary consensus document, the role of telemedicine in anticoagulation of this population is discussed and practical recommendations are provided.V Barrios has received consultancy/lecture fees from Bayer, BMS/Pfizer, Boehringer Ingelheim and Daiichi Sankyo. S Cinza-Sanjurjo has received honoraria for presentations from Bayer, Boehringer-Ingelheim, Daiichi Sankyo and Pfizer-BMS; advisory board fees from Bayer, Boehringer-Ingelheim, Daiichi Sankyo and Pfizer-BMS; and funding for studies from Bayer. J García-Alegría reports consulting fees and/or lectures honoraria from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb and Daiichi Sankyo. R Freixa-Pamias has received honoraria for presentations from Bayer, Boehringer-Ingelheim, Daiichi Sankyo and Pfizer-BMS. F Llordachs-Marques. No potential conflicts of interest were declared by the author. CA Molina reports consulting fees and/or honoraria from Novo Nordisk, Bayer, Pfizer, BMS, Daiichi Sankyo and Boehringer Ingelheim. A Santamaría has received honoraria per conferences from Octapharma, Novo Nordisk, Bayer, Pfizer, BMS, Sobi, Shire, Sanofi, LEO Pharma, Rovi, Daiichi Sankyo, Werfen and Ferrer. D Vivas reports no potential conflicts of interest were declared by the author. C Suárez has received speaker and/or advisory fees from Bayer, Pfizer/BMS, Daiichi Sankyo. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed

Endovascular equipoise shift in a phase III randomized clinical trial of sonothrombolysis for acute ischemic stroke

Sonotrombolisis; Endovascular; Cambio de equilibrio clínicoSonothrombolysis; Endovascular; Equipoise shiftSonotrombolisis; Endovascular; Canvi d'equilibri clínicBackground: Results of our recently published phase III randomized clinical trial of ultrasound-enhanced thrombolysis (sonothrombolysis) using an operator-independent, high frequency ultrasound device revealed heterogeneity of patient recruitment among centers. Methods: We performed a post hoc analysis after excluding subjects that were recruited at centers reporting a decline in the balance of randomization between sonothrombolysis and concurrent endovascular trials. Results: From a total of 676 participants randomized in the CLOTBUST-ER trial we identified 52 patients from 7 centers with perceived equipoise shift in favor of endovascular treatment. Post hoc sensitivity analysis in the intention-to-treat population adjusted for age, National Institutes of Health Scale score at baseline, time from stroke onset to tPA bolus and baseline serum glucose showed a significant (p < 0.01) interaction of perceived endovascular equipoise shift on the association between sonothrombolysis and 3 month functional outcome [adjusted common odds ratio (cOR) in centers with perceived endovascular equipoise shift: 0.22, 95% CI 0.06-0.75; p = 0.02; adjusted cOR for centers without endovascular equipoise shift: 1.20, 95% CI 0.89-1.62; p = 0.24)]. After excluding centers with perceived endovascular equipoise shift, patients randomized to sonothrombolysis had higher odds of 3 month functional independence (mRS scores 0-2) compared with patients treated with tPA only (adjusted OR: 1.53; 95% CI 1.01-2.31; p = 0.04). Conclusion: Our experience in CLOTBUST-ER indicates that increasing implementation of endovascular therapies across major academic stroke centers raises significant challenges for clinical trials aiming to test noninterventional or adjuvant reperfusion strategies

APRIL: A double-blind, placebo-controlled, randomized, Phase Ib/IIa clinical study of ApTOLL for the treatment of acute ischemic stroke

Inflammation; Neuroprotection; StrokeInflamació; Neuroprotecció; IctusInflamación; Neuroprotección; IctusIn the reperfusion era, a new paradigm of treating patients with endovascular treatment (EVT) and neuroprotective drugs is emerging as a promising therapeutic option for patients with acute ischemic stroke (AIS). In this context, ApTOLL, a Toll-like receptor 4 (TLR4) antagonist with proven neuroprotective effect in preclinical models of stroke and a very good pharmacokinetic and safety profile in healthy volunteers, is a promising first-in-class aptamer with the potential to address this huge unmet need. This protocol establishes the clinical trial procedures to conduct a Phase Ib/IIa clinical study (APRIL) to assess ApTOLL tolerability, safety, pharmacokinetics, and biological effect in patients with AIS who are eligible for EVT. This will be a multicenter, double-blind, randomized, placebo-controlled, Phase Ib/IIa clinical study to evaluate the administration of ApTOLL together with EVT in patients with AIS. The study population will be composed of men and non-pregnant women with confirmed AIS with a <6h window from symptoms onset to ApTOLL/placebo administration. The trial is currently being conducted and is divided into two parts: Phase Ib and Phase IIa. In Phase Ib, 32 patients will be allocated to four dose ascending levels to select, based on safety criteria, the best two doses to be administered in the following Phase IIa in which 119 patients will be randomized to three arms of treatment (dose A, dose B, and placebo).The study is supported by grants from the Spanish Ministry of Science, Innovation and Universities (RTC-2017-6651-1 and RTC2019-006795-1). The funder was not involved in the study design, collection, analysis, interpretation of data, the writing of this article or the decision to submit it for publication