Walter Valesky, MD

Labovitz AJ, Rose DZ, Fradley MG, Meriwether J, Renati S, Martin R, Kasprowicz T, Murtagh R, Kip K, Beck T, et al. Early Apixaban Use Following Stroke in Patients With Atrial Fibrillation: Results of the AREST Trial. Stroke. 2021;52:1164-1171.

In the era of direct oral anticoagulant (DOAC) therapy, a paucity of clinical trials exist guiding anticoagulation for atrial fibrillation (AF) after acute ischemic stroke (AIS). European Heart Rhythm Association guidelines promoted (by expert panel) a 1-3-6-12 day approach with anticoagulation started after 1 day in patients with a transient ischemic attack (TIA), after 3 days in those with small strokes, after 6 days in those patients with moderate strokes and approximately 2 weeks in those with large arterial distribution strokes.­1 Guidelines from the American Heart Association are extremely broad and recommend starting anticoagulation after 4-14 days in patients with ischemic stroke.2 Additionally, these recommendations are based on data that do not adequately reflect the current management of AF using DOACs.3 Labovitz et al. attempt to give clarity to this topic with an open-label, randomized trial to evaluate the safety of early use of apixaban in patients with recent stroke compared to warfarin. 

In the AREST trial, the authors enrolled patients with onset of symptoms of AIS or TIA within 3-5 days or within 3 days, respectively. These patients also had a history of AF or newly diagnosed AF confirmed using usual methods by an electrophysiologist. Once randomized, patients in the apixaban group were started on day 0-3 for TIA, day 3-5 for small-sized AIS (<1.5cm in largest dimension), and day 7-9 for medium-sized AIS (>1.5cm but less than a full vascular territory). Patients randomized to receive warfarin were started at 1-week post-TIA or 2 weeks post-stroke. Patients with large-sized AIS (entire vascular territory) and brainstem strokes were excluded. In addition, patients with obvious contraindications to anticoagulation use such as intracranial hemorrhage (ICH), hemorrhagic transformation, as well as those with AIS believed to be from non-embolic etiologies were excluded.

Patients were followed for 180 days with interim follow up. The primary outcome was a composite end point of fatal stroke and recurrent ischemic stroke or TIA. The investigators targeted enrollment of 120 patients to detect an absolute risk reduction of 16.5% in the apixaban group but stopped enrollment after 91 patients because of the change in guideline recommendations favoring DOACs over warfarin. 

Of the 91 subjects enrolled, 88 were randomized to receive either warfarin (47) or apixaban (41). The groups were evenly distributed with a mean National Institutes of Health Stroke Scale  of 6.8, with TIA, small strokes, and medium strokes accounting for 27%, 29.5% and 43%, respectively. Among the randomized subjects, 68% had pre-existing AF with a mean CHA2DS2-VASc score of 4.1. There was a significantly lower number of patients with a pre-existing diabetes in the apixaban group compared to the warfarin group.

The difference in primary outcome between the two groups was not statistically significant. In the apixaban group, 17% of the subjects met the primary composite outcome compared to 25.5% in the warfarin group. Hemorrhagic transformation occurred in more patients in the apixaban group than in the warfarin group, 12.2% vs 10.6%, respectively (not statistically significant). No symptomatic ICH occurred in the apixaban group. One patient in the warfarin group developed symptomatic ICH. 

Previous randomized trials of early initiated DOACs after AIS were limited by low median NIHSS and follow up of no longer than one month.4-5 The AREST trial improves on these limitations by recruiting patients with more severe strokes (mean NIHSS of 6.8) and obtaining longer follow up (180 days). However, the study is underpowered to determine efficacy in its primary outcome and with stroke subgroups. Additionally, the changes in practice guidelines recommending DOACs over warfarin for eligible patients with AF diminishes the significance of this study being practice changing as the comparator group (warfarin) is no longer the standard of care for these patients.6 

A delicate balance of stroke recurrence versus hemorrhage must be weighed when starting anticoagulation after ischemic stroke. Although this trial did not reach a statistically significant endpoint to shift that balance, it gives a sound methodology to approach this question when reviewing the results of pending trials comparing early initiation of DOACs with current guideline-recommended initation.7-10

References:

  1. Heidbuchel H, Verhamme P, Alings M, et al. EHRA Practical Guide on the use of new oral anticoagulants in patients with non-valvular atrial fibrillation: executive summary†. European Heart Journal. 2013;34(27):2094-2106. doi:10.1093/eurheartj/eht134
  2. Powers WJ, Rabinstein AA, Ackerson T, et al. Guidelines for the Early Management of Patients With Acute Ischemic Stroke: 2019 Update to the 2018 Guidelines for the Early Management of Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke. 2019;50(12).
  3. Paciaroni M, Agnelli G, Falocci N, et al. Early Recurrence and Cerebral Bleeding in Patients With Acute Ischemic Stroke and Atrial Fibrillation: Effect of Anticoagulation and Its Timing: The RAF Study. Stroke. 2015;46(8):2175-2182. doi:10.1161/STROKEAHA.115.008891
  4. Hong K-S, Kwon SU, Lee SH, et al. Rivaroxaban vs Warfarin Sodium in the Ultra-Early Period After Atrial Fibrillation–Related Mild Ischemic Stroke: A Randomized Clinical Trial. JAMA Neurol. 2017;74(10):1206.
  5. Butcher KS, Ng K, Sheridan P, et al. Dabigatran Treatment of Acute Noncardioembolic Ischemic Stroke. Stroke. 2020;51(4):1190-1198. doi:10.1161/STROKEAHA.119.027569
  6. January CT, Wann LS, Calkins H, et al. 2019 AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation. Journal of the American College of Cardiology. 2019;74(1):104-132.
  7. Fischer U. (2017, Nov 6 – 2021, Oct 31). Early Versus Late Initiation of Direct Oral Anticoagulants in Post-ischaemic Stroke Patients With Atrial fibrillatioN (ELAN): an International, Multicentre, Randomised-controlled, Two-arm, Assessor-blinded Trial (ELAN).  Identifier NCT03148457.   https://clinicaltrials.gov/ct2/show/NCT03148457
  8. Oldgren J, Asberg S. (2017, Feb 15 – 2021 May). TIMING of Oral Anticoagulant Therapy in Acute Ischemic Stroke With Atrial Fibrillation.  Identifier NCT02961348.   https://clinicaltrials.gov/ct2/show/NCT02961348
  9. Warach S, Truman JM, Lawrence P (2017, Jun 14 – 2021 August). Optimal Delay Time to Initiate Anticoagulation After Ischemic Stroke in Atrial Fibrillation (START).  Identifier NCT03021928.   https://clinicaltrials.gov/ct2/show/NCT03021928
  10. Werring D. (2019, Jun 18 – 2022 Sep 30). OPTIMAS: OPtimal TIMing of Anticoagulation After Acute Ischaemic Stroke: a Randomised Controlled Trial (OPTIMAS). Identifier NCT03759938. https://clinicaltrials.gov/ct2/show/NCT03759938