Protocol for LASER: A Randomized Evaluation and an Associated Registry of Early Anticoagulation With Edoxaban After Ischemic Stroke in Patients With Atrial Fibrillation

Abstract

Background: The optimal timing of anticoagulation after stroke in patients with atrial fibrillation (AF) is unknown.Aim and Hypothesis: Our primary aim is to demonstrate the safety of edoxaban initiation within 5 days of AF related stroke. Our secondary aim is to determine predictors of hemorrhagic transformation (HT) after AF related stroke. We hypothesize that the rate of radiological HT will not be increased in patients starting edoxaban within 5 days of AF related stroke, relative to those in whom initiation is delayed. We hypothesize that the risk of HT in patients treated with edoxaban can be predicted using RNA expressed in leukocytes at time of stroke.Methods and Design: LASER (Lixiana Acute Stroke Evaluation Registry) is a randomized controlled trial with an associated registry (clinicaltrials.gov NCT03494530). One hundred and fifty patients with ischemic stroke and AF will undergo baseline Computed Tomography (CT) scan and will be randomized 2:1 within 5 days of symptom onset to early (≤5 days, n = 100) or delayed (6–14 days, n = 50) edoxaban initiation. Participants will undergo clinical assessment and repeat CT at 7 days and clinical assessment at 90 days.Study Outcomes: The primary outcome is the rate of incident radiological HT. Secondary outcomes include symptomatic HT, recurrent ischemic stroke, recurrent sub-clinical infarcts on follow up CT, systemic hemorrhagic complication rate, National Institute of Health Stroke Scale and modified Rankin Scale at day 7 and 90, mortality within 90 days, quality of life assessments at day 90, and predictors of HT, including RNA expression by 6 pre-selected candidate genes.Discussion: Event rates for both HT and recurrent ischemic events, in patients treated with early vs. delayed edoxaban initiation are unknown. The primary study endpoint of LASER is an objective performance criterion relevant to clinical decision making in patients with AF related stroke. This study will provide data required for a definitive safety/efficacy study sample size power calculation.

Risk of hemorrhagic transformation with early use of direct oral anticoagulants after acute ischemic stroke: A pooled analysis of prospective studies and randomized trials

“…Randomized trials currently assessing safety/efficacy of earlier versus later DOAC include ELAN (NCT03148457), START (NCT03021928), and OPTIMAS (NCT03759938). 26,[34][35][36] Even after pooling, our studies contain far too few patients to determine the effect of early DOAC initiation on the clinically relevant endpoints of symptomatic ischemic stroke, intracranial hemorrhage, and death. Based on low event rates, a sample size of approximately 3000 patients is required to adequately address this question, and trials like OPTIMAS have been designed accordingly.…”

Incremental value of the combined brain-cardiac CT protocol on prediction of atrial fibrillation after stroke

“…These results are consistent with previous studies suggesting that LAA thrombus results from atrial cardiopathy: dilatation of the atrium, endothelial dysfunction, and blood stasis are all factors that contribute to clot formation, as shown by Tsao et al 8 Our previous work also suggested the benefit of early diagnosis of LAA thrombus in the initiation of anticoagulation therapy without additional risk of bleeding. 6 Randomized studies comparing early versus late anticoagulation in patients with AF related stroke are ongoing and will provide safety as well as efficacy robust data on these strategies (ELAN 22 and LASER 23 trials)…”

Timing of Anticoagulation after Acute Ischemic Stroke in Patients with Atrial Fibrillation

“…The question of optimal timing to start DOAC will remain unanswered until randomized trials of early versus delayed DOAC are completed (Table 2). 122–125 Ongoing trials include LASER (Lixiana Acute Stroke Evaluation Registry, NCT03494530), TIMING (Timing of Oral Anticoagulant Therapy in Acute Ischemic Stroke With Atrial Fibrillation: a Prospective Multicenter Registry-based Non-inferiority Randomized Controlled Clinical Trial, NCT02961348), ELAN (Early Versus Late Initiation of Direct Oral Anticoagulants in Post-ischaemic Stroke Patients With Atrial fibrillation, NCT03148457), START (Optimal Delay Time to Initiate Anticoagulation After Ischemic Stroke in Atrial Fibrillation, NCT03021928) trials, and OPTIMAS (OPtimal TIming of Anticoagulation After Acute Ischemic Stroke, NCT03759938).…”

“…The observed current practice of delaying DOAC initiation in patients with larger infarcts is relevant to the ongoing RCTs, where randomization is either stratified by infarct volume/size 123 ELAN, NCT03148457 and/or includes arms with relatively broad initiation time windows of several days, extending up to 14 days after symptom onset. 122,124 OPTIMAS, NCT03759938 This form of stratification by infarct volume or by having broad initiation time windows where the decision to time the treatment at the treating physician’s discretion, even in the context of randomization, may play a role in introducing a bias. It may also limit the understanding of whether the timing of DOAC initiation should be adjusted based on infarct size and/or clinical severity of the index event to reduce the risk of HT.…”

“…The question of optimal timing to start DOAC will remain unanswered until randomized trials of early versus delayed DOAC are completed (Table 2). [122][123][124][125] Patients in the above-named trials are randomized to a DOAC, initiated as early as 48 hours and up to 5 days after onset, or delayed to 6-14 days. The primary endpoint in these trials is the composite of recurrent ischemic stroke and symptomatic HT.…”