CardioNerds Journal Club is a monthly forum for CardioNerds to discuss and breakdown recent publications on twitter and are produced with a corresponding infographic and detailed blog post. For more information, check out the CardioNerds Journal Club Page. This Journal Club focuses on the ELAN Trial

Table of contents for the The ELAN Trial summary:

• Visual abstract
• Summary
• References
• Credits
• Twitter Archive

Relevant literature

CVA: Cerebrovascular accident, TIA: transient ischemic attack, DOAC: direct oral anticoagulant, mRS : modified Rankin scale, AIS: acute ischemic stroke, ICH: Intracerebral hemorrhage

Relevant guidelines

2021 AHA/ASA guideline for the prevention of stroke in patients with stroke and TIA.⁵

2021 ESC Heart Rhythm association on the use of NOAC in patients with atrial fibrillation.⁶

2020 ESC guidelines for the diagnosis and management of atrial fibrillation.⁷

Study Rationale

The effect of early versus late initiation of anticoagulation after acute ischemic stroke in patients with known atrial fibrillation (AF) is unclear. It is crucial to address AF  for secondary stroke prevention. However, there continues to be a high concern for increased risk of intracranial hemorrhage with anticoagulation in the early post-stroke period. Currently, there is insufficient  data regarding the benefit and safety of early versus late initiation of direct oral anticoagulants (DOAC) in such settings.

Study Objectives

The study aims to assess the safety and efficacy of early vs late anticoagulation with DOACs in patients with recent stroke and known atrial fibrillation

• Trial
  • Conducted at 103 stroke centers in Europe, the Middle East, and Asia
  • 36,643 participants screened and 2032 participants enrolled between 11/6/2017 to 9/12/2022
• Intervention
  • Randomly assigned 1:1 to early initiation of DOAC or later initiation of DOACEarly treatment:
    • Initiation of DOAC within 48 hours after stroke onset in participants with minor or moderate strokeInitiation of DOAC on day 6 or 7 in those with major stroke
  • Later treatment:
    • Initiation of DOAC on day 3 or 4 in participants with a minor stroke
    • Initiation of DOAC on day 6 or 7 in participants with moderate stroke
    • Initiation of DOAC on day 12, 13, or 14 in participants with a major stroke
• Enrollment Criteria

Definition:

• Minor stroke: Infarct ≤1.5cm
• Moderate stroke: Infarct in the distribution of a cortical superficial branch of the middle, anterior, or posterior cerebral artery
• Major stroke: Larger infarcts in the distribution of the above arteries OR a brainstem or cerebellar infarct ≥ 1.5cm

• Outcomes
  • Primary Outcome: Composite recurrent ischemic stroke, systemic embolism, major extracranial bleeding, symptomatic intracranial hemorrhage, or vascular death within 30 days after randomization
  • Secondary Outcomes: Components of primary outcome assessed at 30 and 90 days (recurrent ischemic stroke, systemic embolism, major extracranial bleeding, symptomatic intracranial hemorrhage, vascular death, nonmajor bleeding, death from any cause, a binary outcome of a score of 0-2 vs 3-6 on the modified Rankin scale)
    • Rankin scale: disability score with 0-2 indicating slight or no disability to 6 indicating death

• Statistical Analysis
  • Primary composite outcome analyzed using the penalized logistic regression model (imposes a penalty to the logistic model for having too many variables which shrinks the coefficients of the less contributive variables to zero meaning regularization)
  • Secondary outcomes analyzed with the penalized logistic regression model; also analyzed as time-to-event outcomes with the use of penalized survival models

Notable Baseline Characteristics

• Of nearly 2032 participants who underwent randomization, the data from 2013 participants were analyzed. Most of the participants who were excluded were ineligible due to non-adherence of one of the sites to good clinical practice guidelines.
• Baseline demographic and clinical characteristics were similar in both treatment groups. About 45% of participants were female.
• The median NIHSS score was 5 at admission and 3 at randomization.Approximately 50% of the participants were receiving Aspirin at the time of screening.
• Intravenous thrombolysis or thrombectomy before randomization was allowed, but therapeutic anticoagulation at stroke onset was not allowed except for prophylactic anticoagulation.

Outcomes

Primary Outcome

• A primary outcome event occurred in 2.9% of participants in  early treatment group and 4.1% in the later treatment group.
• Death from nonvascular causes before 30 days occurred in 13 participants in the early treatment group and in 11 participants in the later treatment group.

Secondary Endpoints:

• Major intracranial bleeding by 30 days after randomization occurred in 3 participants (0.3%) in the early treatment group and 5 participants (0.5%) in the later treatment group (OR:0.63, CI 95%, 0.15-2.38).
• Symptomatic intracranial hemorrhage by 30 days occurred in 2 participants (0.2%) in both groups (OR: 1.02, CI 95%, 0.16-6.59)
• Recurrent ischemic stroke by 30 days occurred in 14 participants (1.4%) in early treatment group and 25 participants (2.5%) in the later treatment group (OR:0.57, CI 95%, 0.29-1.07).

Adverse Events

Any serious adverse events by 90 days occurred in 132 participants (13.9%) in the early treatment group and 157 participants (15.8%) in the later treatment group.

Conclusions

• The trial was designed to estimate the treatment effects of early initiation and later initiation of DOACS and provide qualitative data to guide clinicians.
  • The study ultimately found that the incidence of compositive of stroke, systemic embolism, hemorrhage, or death at 30 days was estimated to be in the range from 2.8% points lower to 0.5% points higher (95% CI) with the early use of DOACS than with later use
  • Based on this, early treatment can be supported
  • Comparing 90 day to the 30 day outcomes, there was no excessive risk associated with early anticoagulation use within this period

Limitations and Considerations:

• Exclusion of individuals on therapeutic anticoagulation at baseline
  • Limited statistical power to explore subgroups, hence limiting out ability to extrapolate any data from those results 
  • Lack of availability of information regarding ethnic background of participants in both cohorts, with assumption that the population studied is predominantly White as most participants are from European center, putting into question the generalizability of these results
  • Exclusion of patients with parenchymal hemorrhage
  • Study design is neither a superiority nor a noninferiority trial, hence it is not able to definitively prove that early vs late treatment would improve outcomes in this patient population

1. Labovitz AJ, Rose DZ, Fradley MG, et al. Early Apixaban Use Following Stroke in Patients With Atrial Fibrillation: Results of the AREST Trial. Stroke. 2021;52(4):1164-1171. doi:10.1161/STROKEAHA.120.030042
2. Oldgren J, Åsberg S, Hijazi Z, et al. Early Versus Delayed Non-Vitamin K Antagonist Oral Anticoagulant Therapy After Acute Ischemic Stroke in Atrial Fibrillation (TIMING): A Registry-Based Randomized Controlled Noninferiority Study [published correction appears in Circulation. 2022 Nov 8;146(19):e279]. Circulation. 2022;146(14):1056-1066. doi:10.1161/CIRCULATIONAHA.122.060666.
3. Kim JS, Lee KB, Chang DI, Cha JK, Lee JS. Early Administration of Edoxaban After Acute Ischemic Stroke in Patients With Non-valvular Atrial Fibrillation: A Pilot Randomized Trial. J Stroke. 2023;25(2):311-314. doi:10.5853/jos.2023.00325
4. Xu Y, Liu C, Li W, et al. Efficacy and safety of early anticoagulation after endovascular treatment in patients with atrial fibrillation [published online ahead of print, 2023 Mar 27]. Stroke Vasc Neurol. 2023;svn-2022-002082. doi:10.1136/svn-2022-002082
5. Kleindorfer DO, Towfighi A, Chaturvedi S, et al. 2021 Guideline for the Prevention of Stroke in Patients With Stroke and Transient Ischemic Attack: A Guideline From the American Heart Association/American Stroke Association [published correction appears in Stroke. 2021 Jul;52(7):e483-e484]. Stroke. 2021;52(7):e364-e467. doi:10.1161/STR.0000000000000375
6. Steffel J, Collins R, Antz M, et al. 2021 European Heart Rhythm Association Practical Guide on the Use of Non-Vitamin K Antagonist Oral Anticoagulants in Patients with Atrial Fibrillation [published correction appears in Europace. 2021 Jun 28;:]. Europace. 2021;23(10):1612-1676. doi:10.1093/europace/euab065
7. Hindricks G, Potpara T, Dagres N, et al. 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS): The Task Force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) Developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC [published correction appears in Eur Heart J. 2021 Feb 1;42(5):507] [published correction appears in Eur Heart J. 2021 Feb 1;42(5):546-547] [published correction appears in Eur Heart J. 2021 Oct 21;42(40):4194]. Eur Heart J. 2021;42(5):373-498. doi:10.1093/eurheartj/ehaa612

Summary

 Dr. Maryam Barkhordarian, Internal Medicine Resident, Hackensack Meridian Health

Dr. Emily  Lee, Internal Medicine Resident, University of Southern California

Visual abstract

Dr. Dhruv Krishnan, Internal Medicine Resident, Queen’s University

Trial Tweets

Dr. Ramy Doss, Cardiology Health, Trinity Health

Promo

 Adriana Mares , Medical Student, Texas Tech University at El Paso

 Dr. Chelsea Amo-Tweneboah, Internal Medicine resident, Stony Brook University

Under the guidance of House Chief

 Dr. Rawan Amir,  Cardiology fellow, Johns Hopkins University

Supported by House Faculty

 Dr. Jessie Holtzman, Cardiology Fellow, University of California San Francisco

 Dr. Patrick Zakka, Cardiology Fellow, University of California Los Angeles

 Dr. Karla Asturias, Cardiology Fellow, Oregon Health and Science University

All content reviewed by FIT experts

 Usman Hasnie, Cardiology Fellow, University of Alabama at Birmingham