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Early versus Late Initiation of Direct Oral Anticoagulants in Post-ischaemic Stroke Patients with Atrial Fibrillation

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Year of Publication: 2023

Authors: Urs Fischer, Masatoshi Koga, Daniel Strbian, ..., Jesse Dawson

Journal: New England Journal of Medicine

Citation: N Engl J Med 2023;388:2411-21. DOI: 10.1056/NEJMoa2303048

Link: https://doi.org/10.1056/NEJMoa2303048

PDF: https://www.nejm.org/doi/pdf/10.1056/NEJMoa2303048

Clinical Question

What is the safety and efficacy of early versus later initiation of DOACs in patients with acute ischemic stroke and atrial fibrillation, using imaging-based stroke severity classification to guide timing?

Bottom Line

Early DOAC initiation showed a trend toward fewer composite events (2.9% vs 4.1%) at 30 days with no increase in symptomatic intracranial hemorrhage (0.2% in both groups). Recurrent ischemic stroke was numerically lower with early treatment. No formal hypothesis was tested; the trial was designed to estimate treatment effects and their precision. Results support that early DOAC initiation is reasonable when guided by imaging-based severity classification.

        Major Points
        Trial designed to estimate treatment effects and precision -- no superiority or noninferiority hypothesis was tested.
Primary composite outcome at 30 days: 2.9% early vs 4.1% later (OR 0.70, 95% CI 0.44-1.14; risk difference -1.18 percentage points, 95% CI -2.84 to 0.47).
Recurrent ischemic stroke at 30 days: 1.4% vs 2.5% (OR 0.57, 95% CI 0.29-1.07); at 90 days: 1.9% vs 3.1% (OR 0.60, 95% CI 0.33-1.06).
Symptomatic ICH was 0.2% in both groups at both 30 and 90 days -- no excess bleeding risk with early initiation.
Major extracranial bleeding at 30 days: 0.3% early vs 0.5% later (OR 0.63, 95% CI 0.15-2.38).
Systemic embolism at 30 days: 0.4% early vs 0.9% later (OR 0.48, 95% CI 0.14-1.42).
Exploratory 90-day composite: 3.7% early vs 5.6% later (OR 0.65, 95% CI 0.42-0.99).
Post hoc analysis: 98% probability that early treatment increases primary-outcome risk by no more than 0.5 percentage points.
Imaging-based stroke severity classification used: minor (≤1.5 cm), moderate (cortical superficial branch territory), major (larger territorial or brainstem/cerebellar >1.5 cm).
37% had minor stroke, 40% moderate, 23% major. Median NIHSS at randomization was 3.
Approximately 50% were receiving aspirin at screening. Thrombolysis given in ~39%, thrombectomy in ~22%.
Functional independence (mRS 0-2) similar between groups at 30 and 90 days (~63% and ~66%).
Any SAE by 90 days: 13.9% early vs 15.8% later.
No apparent heterogeneity across prespecified subgroups (age, infarct size, NIHSS), though trial not powered for subgroup analysis.

      

Design

Study Type: International, multicenter, randomized, open-label, assessor-blinded trial (estimation framework -- no hypothesis testing)

Randomization: 1

Blinding: Open-label with blinded outcome assessment. Telephone assessors unaware of group assignment. Independent clinical events committee blinded to assignment adjudicated all events. Stroke severity classification not centrally adjudicated.

Enrollment Period: November 6, 2017 to September 12, 2022

Follow-up Duration: 90 days

Centers: 103

Countries: Switzerland, Germany, Austria, United Kingdom, Ireland, Belgium, France, Norway, Sweden, Slovakia, Portugal, Italy, Greece, Israel, India, Japan

Sample Size: 2013

Analysis: Modified intention-to-treat (excluding site closure, incorrect enrollment, declined consent). Penalized logistic regression for low event rates, adjusted for stratification factors (age, NIHSS, infarct size). Risk difference derived from estimated OR. Missing outcomes imputed via multivariate multiple imputation by chained equations (50 datasets). Post hoc exchangeably weighted bootstrapping for probability estimates. Ordinal logistic regression for mRS shift. No multiplicity adjustment. Sample size based on expected 95% CI width of ≥2.0 percentage points, not powered for hypothesis testing.

Inclusion Criteria

Acute ischemic stroke confirmed on CT or MRI (or clinical diagnosis >24h with imaging excluding other causes)
Nonvalvular atrial fibrillation: permanent, persistent, paroxysmal, or newly diagnosed during hospitalization
Stroke severity classified by imaging: minor (≤1.5 cm), moderate (cortical superficial branch territory of MCA/ACA/PCA), major (larger territorial infarcts or brainstem/cerebellar >1.5 cm)
Timing window: within 48h of onset for minor/moderate (early group) or within protocol-specified windows for randomization
Prior thrombolysis or thrombectomy allowed

Exclusion Criteria

Therapeutic anticoagulation at stroke onset (prophylactic LMWH for VTE prevention allowed)
Confluent parenchymal hematoma within infarcted brain tissue (Heidelberg PH-1 or PH-2) at randomization
Intracranial hemorrhage remote from infarcted tissue
Petechial hemorrhagic transformation was NOT an exclusion criterion

Baseline Characteristics

Characteristic	Control	Active
N	1007	1006
Age - median [IQR]	78 [71-84] years	77 [70-84] years
Female	45.3%	45.6%
Region - Central Europe	61.4%	61.1%
Region - UK/Ireland	24.8%	24.8%
Region - Japan	9.2%	9.8%
Region - Israel	1.7%	1.7%
Region - India	2.9%	2.6%
History of ischemic stroke	13.9%	12.7%
History of TIA	5.1%	4.5%
History of systemic embolism	3.1%	1.9%
Hypertension	66.8%	68.6%
Myocardial infarction	8.6%	8.0%
Diabetes	16.0%	18.4%
CHA2DS2-VASc score - median [IQR]	5 [4-6]	5 [4-6]
Prestroke mRS 0-2	89.3%	88.5%
Prestroke mRS 3-5	10.7%	11.5%
Minor stroke	37.1%	37.6%
Moderate stroke	39.4%	39.7%
Major stroke	23.4%	22.8%
NIHSS at admission - median [IQR]	5 [2-11]	5 [2-12]
NIHSS at randomization - median [IQR]	3 [1-6]	3 [1-6]
Thrombolysis	38.2%	39.7%
Thrombectomy	23.5%	21.0%

Arms

Field	Early DOAC Initiation	Control
Intervention	DOAC initiation within 48 hours after stroke onset for minor or moderate stroke, or on day 6 or 7 for major stroke. Any approved DOAC at appropriate dose.	DOAC initiation on day 3 or 4 for minor stroke, day 6 or 7 for moderate stroke, or day 12-14 for major stroke (1-3-6-12 day rule). Any approved DOAC at appropriate dose.
Duration	90-day follow-up	90-day follow-up

Outcomes

Outcome	Type	Control	Intervention	HR / OR / RR
Composite of recurrent ischemic stroke, systemic embolism, major extracranial bleeding, symptomatic intracranial hemorrhage, or vascular death within 30 days after randomization	Primary	41/1007 (4.1%)	29/1006 (2.9%)	1.19%
Recurrent ischemic stroke at 30 days	Secondary	25/991 (2.5%)	14/984 (1.4%)	OR 0.57 (95% CI 0.29-1.07)
Recurrent ischemic stroke at 90 days	Secondary	30/965 (3.1%)	18/968 (1.9%)	OR 0.60 (95% CI 0.33-1.06)
Symptomatic intracranial hemorrhage at 30 days	Secondary	2/991 (0.2%)	2/984 (0.2%)	OR 1.02 (95% CI 0.16-6.59)
Symptomatic intracranial hemorrhage at 90 days	Secondary	2/965 (0.2%)	2/968 (0.2%)	OR 1.00 (95% CI 0.15-6.45)
Major extracranial bleeding at 30 days	Secondary	5/991 (0.5%)	3/984 (0.3%)	OR 0.63 (95% CI 0.15-2.38)
Major extracranial bleeding at 90 days	Secondary	8/965 (0.8%)	3/968 (0.3%)	OR 0.40 (95% CI 0.10-1.31)
Systemic embolism at 30 days	Secondary	9/991 (0.9%)	4/984 (0.4%)	OR 0.48 (95% CI 0.14-1.42)
Systemic embolism at 90 days	Secondary	10/965 (1.0%)	4/968 (0.4%)	OR 0.42 (95% CI 0.12-1.21)
Vascular death at 30 days	Secondary	10/991 (1.0%)	11/984 (1.1%)	OR 1.12 (95% CI 0.47-2.65)
Vascular death at 90 days	Secondary	16/965 (1.7%)	17/968 (1.8%)	OR 1.04 (95% CI 0.52-2.08)
Death from any cause at 90 days	Secondary	48/995 (4.8%)	45/994 (4.5%)	OR 0.93 (95% CI 0.61-1.43)
Nonmajor bleeding at 30 days	Secondary	27/991 (2.7%)	30/984 (3.0%)	OR 1.13 (95% CI 0.67-1.93)
Nonmajor bleeding at 90 days	Secondary	41/965 (4.2%)	39/968 (4.0%)	OR 0.94 (95% CI 0.59-1.47)
mRS 0-2 at 30 days	Secondary	626/1000 (62.6%)	624/997 (62.6%)	OR 0.93 (95% CI 0.79-1.09)
mRS 0-2 at 90 days	Secondary	654/994 (65.8%)	659/989 (66.6%)	OR 0.93 (95% CI 0.79-1.09)
Exploratory 90-day composite (same as primary)	Secondary	54/965 (5.6%)	36/968 (3.7%)	OR 0.65 (95% CI 0.42-0.99)
Any Serious Adverse Event by 90 days	Adverse	157/993 (15.8%)	132/947 (13.9%)
Nonvascular Death before 30 days	Adverse	11	13

Subgroup Analysis

Prespecified subgroup analyses by age (<70 vs >=70), infarct size (minor, moderate, major), and NIHSS (<10 vs >=10) showed no apparent heterogeneity of treatment effect. Trial was not powered for subgroup analysis, and confidence intervals were not adjusted for multiplicity.

Criticisms

No formal hypothesis testing (no superiority or noninferiority design) -- the trial provides estimates of treatment effect and precision but cannot confirm or refute a definitive benefit.
Low median NIHSS at randomization (3), suggesting a relatively mild stroke population, which limits applicability to more severe strokes.
Only 23% had major strokes; early treatment for major stroke was defined as day 6-7 (same as the later group for moderate stroke), so the 'early' window for major strokes was not truly ultra-early.
Patients with parenchymal hematoma (Heidelberg PH-1 or PH-2) at randomization were excluded, so safety of early anticoagulation in this higher-risk group remains unknown.
Stroke severity classified by site investigators without central adjudication, introducing potential misclassification.
Predominantly European population (>85%); limited generalizability to non-White populations. No data on race/ethnicity collected.
Patients already on therapeutic anticoagulation at stroke onset were excluded.
Treatment compliance was imperfect: 949/1006 (94.3%) in early group and 935/1007 (92.8%) in later group received treatment per protocol.
One site (13 patients) excluded for GCP nonadherence.
Approximately 50% were on aspirin at screening, which may have reduced early recurrence risk in the later-treatment group.
Open-label design with potential performance bias, though outcome assessment was blinded.
Confidence intervals for all outcomes overlap null -- individual component analyses are underpowered.

Funding

Swiss National Science Foundation (32003B_197009; 32003B_169975), Swiss Heart Foundation, Stroke Association UK (2017/02), Intramural Research Fund for Cardiovascular Diseases of the National Cerebral and Cardiovascular Center Japan. No industry involvement.

Based on: ELAN (New England Journal of Medicine, 2023)