RESUMO
BACKGROUND: increasing age is associated with a higher prevalence of atrial fibrillation (AF), and higher risks of stroke and bleeding. We report the effects of apixaban versus acetylsalicylic acid (ASA) in older patients (≥75 years and ≥85 years) compared with younger patients with AF unsuitable for vitamin K antagonists. METHODS: AVERROES (Apixaban Versus ASA to Prevent Stroke In AF Patients Who Have Failed or Are Unsuitable for Vitamin K Antagonist Treatment) trial (n = 5,599) included 1,898 patients ≥75 years and 366 patients ≥85 years. We compared the baseline characteristics and effects of apixaban compared with aspirin on clinical outcomes by age. RESULTS: compared with aspirin, apixaban was more efficacious for preventing strokes and systemic embolism in patients ≥85 years (absolute rate [AR] 1%/year on apixaban versus 7.5%/year on aspirin; hazard ratio [HR] 0.14, 95% confidence interval [CI] 0.02-0.48) compared with younger patients (AR 1.7%/year on apixaban versus 3.4%/year on aspirin; HR 0.50, 95% CI 0.35-0.69) (P-value for interaction = 0.05). Major haemorrhage was higher in patients ≥85 years compared with younger patients but similar with apixaban versus aspirin in both young and older individuals (4.9%/year versus 1.0%/year on aspirin and 4.7%/year versus 1.2%/year on apixaban) with no significant treatment-by-age interaction (P-value = 0.65). CONCLUSIONS: older patients with AF are at particularly high risk of stroke if given aspirin and have substantially greater relative and absolute benefits from apixaban compared with younger patients with no greater risk of haemorrhage. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov number: NCT00496769. URL: https://clinicaltrials.gov/ct2/show/NCT00496769.
Assuntos
Anticoagulantes/uso terapêutico , Aspirina/uso terapêutico , Fibrilação Atrial/tratamento farmacológico , Inibidores do Fator Xa/uso terapêutico , Pirazóis/uso terapêutico , Piridonas/uso terapêutico , Acidente Vascular Cerebral/prevenção & controle , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Anticoagulantes/efeitos adversos , Aspirina/efeitos adversos , Fibrilação Atrial/sangue , Fibrilação Atrial/complicações , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/mortalidade , Inibidores do Fator Xa/efeitos adversos , Feminino , Hemorragia/induzido quimicamente , Humanos , Masculino , Estudos Prospectivos , Pirazóis/efeitos adversos , Piridonas/efeitos adversos , Fatores de Risco , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/etiologia , Fatores de Tempo , Resultado do TratamentoRESUMO
Direct oral anticoagulants (DOACs) are effective in preventing and treating venous thromboembolism, and preventing stroke in atrial fibrillation. Until recently, there has been no specific reversal agent for DOACs. Now, a specific antidote for the direct thrombin inhibitor, dabigatran has been approved for use, and antidotes for factor Xa inhibitors (rivaroxaban, apixaban and edoxaban) are being developed. We review the evidence for currently used and emerging reversal strategies, and discuss possible clinical implications, including increased prescription of DOACs, use of DOACs in clinical situations previously felt to pose too great a risk of bleeding, and use of reversal agents beyond currently approved indications.
Assuntos
Antitrombinas , Dabigatrana/antagonistas & inibidores , Inibidores do Fator Xa , Pirazóis/antagonistas & inibidores , Piridinas/antagonistas & inibidores , Piridonas/antagonistas & inibidores , Rivaroxabana/antagonistas & inibidores , Tiazóis/antagonistas & inibidores , Anticorpos Monoclonais Humanizados/farmacologia , Anticoagulantes , Arginina/análogos & derivados , Arginina/farmacologia , Fator Xa/farmacologia , Hemorragia/induzido quimicamente , Hemorragia/prevenção & controle , Humanos , Piperazinas/farmacologia , Proteínas Recombinantes/farmacologia , Tromboembolia Venosa/tratamento farmacológicoRESUMO
Rationale Patients with transient ischemic attack or minor stroke are at high risk of early recurrent cerebrovascular events. Anticoagulation with heparin or warfarin acutely after ischemic stroke is at least as efficacious as aspirin for preventing recurrent events but is associated with an increased risk of clinical worsening due to hemorrhagic transformation. Aim and hypothesis We aim to demonstrate the safety of early anticoagulation with dabigatran, an oral direct thrombin inhibitor, in acute cerebrovascular syndrome patients. The primary hypothesis is that symptomatic hemorrhagic transformation rates in dabigatran and aspirin-treated patients will be similar. Sample size estimates At least 136 participants in two groups required to demonstrate an absolute between-group difference in the rate of hemorrhagic transformation of 5.6% with 80% power, assuming alpha = 5%. Methods and design A randomized, multicenter open-label clinical trial (NCT02295826). Three-hundred participants with a transient ischemic attack/ischemic stroke (National Institutes of Health Stroke Scale ≤ 9) will undergo magnetic resonance imaging within 72 h of symptom onset and will be randomized to aspirin 81 mg daily or dabigatran 150 mg twice daily for 30 days. Participants undergo repeat magnetic resonance imaging at 30 days and clinical assessment to 90 days. Study outcomes The primary outcome is the symptomatic hemorrhagic transformation rate. Secondary outcomes include recurrent stroke and new ischemic lesions on repeat magnetic resonance imaging. Discussion This study will determine the safety of early anticoagulation with dabigatran in patients with acute transient ischemic attack/ischemic stroke and will inform the design of a phase III randomized trial aimed at demonstrating reduced recurrent early ischemic events after acute transient ischemic attack/stroke.
Assuntos
Antitrombinas/uso terapêutico , Dabigatrana/uso terapêutico , Ataque Isquêmico Transitório/tratamento farmacológico , Acidente Vascular Cerebral/tratamento farmacológico , Administração Oral , Hemorragia Cerebral/diagnóstico por imagem , Feminino , Humanos , Ataque Isquêmico Transitório/diagnóstico por imagem , Imageamento por Ressonância Magnética , Masculino , Recidiva , Tamanho da Amostra , Acidente Vascular Cerebral/diagnóstico por imagem , Resultado do TratamentoRESUMO
Asymptomatic carotid stenosis (ACS) exceeding 50% is present in about 2% of 60-year-old patients and an even higher fraction of older individuals. The major independent risk factors include advancing age, male sex, tobacco smoking, and a history of vascular disease. The best available evidence does not support either population screening for ACS or routine carotid revascularization when ACS is discovered. There is an urgent need to identify patients with ACS and a sufficiently high risk of ipsilateral stroke (despite contemporary medical management) to warrant invasive treatment. The mainstays of medical management are antiplatelet therapy (usually low-dose aspirin), high-dose statins, blood pressure control, and smoking cessation. Patients with ACS should be periodically educated about symptoms of transient ischemic attack and stroke that require emergent medical attention. Current guidelines vary widely in recommendations regarding revascularization (ie, endarterectomy or carotid stenting). The benefits of revascularization strategies remain uncertain for patients with ACS who receive contemporary medical management.
Assuntos
Doenças Assintomáticas , Artérias Carótidas/patologia , Estenose das Carótidas/complicações , Acidente Vascular Cerebral/etiologia , Estenose das Carótidas/patologia , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Medição de Risco , Acidente Vascular Cerebral/patologiaRESUMO
BACKGROUND: Randomized clinical trials provide the most reliable evidence to guide the management of stroke and threatened stroke and reflect the interests of the stroke research community. The spectrum of phase III randomized clinical trials in stroke has not been previously characterized. METHODS: Phase III stroke randomized clinical trials published between 2012 and 2014 were identified by search of the Cochrane Central Register of Controlled Trials supplemented by recent publications known to the co-authors. RESULTS: Thirty-four randomized clinical trials were included involving 85 770 participants: 20 acute stroke randomized clinical trials (32 590 patients), 11 stroke prevention randomized clinical trials (28 964 patients), and three randomized clinical trials in which stroke was a major component of a composite primary outcome involving nonstroke patients (24 216 patients). Twenty-two (65%) trials were international, and eight (24%) were industry sponsored. Drugs were tested in 21 (62%) randomized clinical trials, with devices (n = 9), surgery (n = 3), and diet (n = 1) in the remainder. Thirteen (38%) randomized clinical trials were stopped early: seven for futility, three for efficacy, two for harm, and one for budget/administrative reasons. Overall, the results of seven (21%) randomized clinical trials were positive, five (15%) equivocal, 18 (53%) negative, and four (12%) inconclusive. Considering positive and definitively negative randomized clinical trials testing currently used interventions, 11 (32%) randomized clinical trials have direct implications for clinical management. CONCLUSIONS: The diversity of interventions, high-quality, and worldwide origins of recently published phase III randomized clinical trials reflects a vibrant international stroke research community. The current generation of stroke randomized clinical trials provides important guidance for stroke prevention and acute stroke care.
Assuntos
Ensaios Clínicos Fase III como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto , Acidente Vascular Cerebral/terapia , Ensaios Clínicos Fase III como Assunto/estatística & dados numéricos , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto/estatística & dados numéricosRESUMO
Atrial fibrillation (AF) is an important cause of preventable, disabling stroke and is increasingly prevalent with advancing age. As life expectancies increase around the world, AF-related stroke is a growing global public health concern. Most AF patients are elderly (≥75 years old) and increasing age is a consistent independent risk factor for AF-associated stroke. Warfarin anticoagulation is highly effective for stroke prevention in AF patients, but is underutilized especially in the elderly. Although elderly patients are at increased risk of hemorrhage with oral anticoagulants, the benefit for ischemic stroke reduction exceeds the risk of hemorrhage for most elderly patients. Consequently, age alone should not be considered a contraindication for anticoagulation. Novel oral anticoagulants such as dabigatran, rivaroxaban and apixaban are at least as effective as warfarin in preventing strokes in patients with AF. Relative to warfarin, these novel agents reduce the risk of intracranial hemorrhage, the most devastating complication of anticoagulation therapy in elderly AF patients. The novel oral anticoagulants are especially appealing for stroke prevention in elderly patients with AF.