Slightly Better Outcomes Observed With Earlier Initiation of Direct Oral Anticoagulants in Atrial Fibrillation

Urs Fischer, MD, MSc

Findings from an investigator-initiated, open-label trial (NCT03148457) published in the New England Journal of Medicine indicated that earlier initiation of direct oral anticoagulants (DOACs) in people with atrial fibrillation (AF) because of an acute ischemic stroke may be more beneficial.

Of 2013 participants (37% with minor stroke, 40% with moderate stroke, and 23% with major stroke), 1006 were assigned to early anticoagulation and 1007 to later anticoagulation. All told, the incidence of recurrent ischemic stroke, systemic embolism, major extracranial bleeding, symptomatic intracranial hemorrhage, or vascular death at 30 days was estimated to range from 2.8 percentage points lower to 0.5 percentage points higher with early than later use of DOACs.

Led by Urs Fischer, MD, MSc, chairman, Department of Neurology, University Hospital Basel, the study was designed to understand the distinct, precise differences of early vs later initiation of DOACs. No statistical hypothesis was tested for superiority or noninferiority, and the results were intended to provide qualitative data that may be of use to clinicians. In the trial, early anticoagulation occurring within 48 hours after a minor or moderate stroke or on day 6 or 7 after a major stroke, while later anticoagulation occurred day 3 or 4 after a minor stroke, day 6 or 7 after a moderate stroke, or day 12, 13, or 14 after a major stroke.

To better understand the effects of each treatment, assessors were unaware of the trial-group assignments. A deterministic minimization method was used with several stratification factors, including age (<70 years or ≥70 years) infarct size (minor, moderate, or major), National Institutes of Health Stroke Scale (NIHSS) score (<10 or ≥10), and trial site. The cohort had a median age of 77 years (IQR, 70-84), a median NIHSS score of 5 (IQR, 2-11) at admission and 3 (IQR, 1-6) at randomization.

The primary outcome, a composite of recurrent ischemic stroke, systemic embolism, major extracranial bleeding, symptomatic intracranial hemorrhage, or vascular death, occurred in 2.9% (n = 29) of participants in the early-treatment group and 4.1% (n = 41) in the later-treatment group. This resulted in an OR of 0.70 (95% CI, 0.44-1.14), and a derived risk difference of –1.18 percentage points (95% CI, –2.84 to 0.47).

"Current clinical practice is to delay the initiation of anticoagulation after ischemic stroke, as recommended in several guidelines that are based on expert consensus," Fischer et al wrote.¹ "For example, European guidelines suggest assessment of stroke severity with the use of the NIHSS score and delay of anticoagulation for 3 days after minor stroke, 6 days after moderate stroke, and 12 days after severe stroke on the basis of this score. American Heart Association–American Stroke Association guidelines recommend delaying anticoagulation beyond 14 days if there is a high risk of hemorrhagic transformation of an ischemic brain infarct and beginning anticoagulation between day 2 and day 14 if the risk of this complication is low."

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Of note, 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. Thirty days after randomization, major extracranial bleeding occurred in 3 participants (0.3%) in the early-treatment group and 5 participants (0.5%) in the later-treatment group (OR, 0.63; 95% CI, 0.15-2.38). By this time, symptomatic intracranial hemorrhage occurred in 2 individuals in each group (OR, 1.02; 95% CI, 0.16-6.59). Recurrent ischemic stroke was less frequent in the early-treatment group, occurring in 14 participants (1.4%), vs the later-treatment group, which had 25 individuals (2.5%; OR, 0.57; 95% CI, 0.29-1.07).

At 90 days, the early and later-treatment groups showed incidence rates of 3.7% and 5.6%, respectively, in composite-outcome events (OR, 0.65; 95% CI, 0.42-0.99). The cumulative rates of recurrent ischemic stroke at 90 days were 1.9% in the early-treatment group and 3.1% in the later treatment group (OR, 0.60; 95% CI, 0.33-1.06). Of note, findings showed a 98% probability that early treatment with DOACs would increase the risk of a primary-outcome event by no more than 0.5 percentage points.

Between the 2 groups, serious adverse events (AEs) occurred in 13.9% and 15.8% of participants in the early- and later-treatment groups, respectively. In subgroup analyses, no apparent heterogeneity of effects across prespecified subgroups with the use of treatment-by-covariate terms was observed.

REFERENCE
1. Fischer U, Koga M, Strbian D, et al. Early versus later anticoagulation for stroke with atrial fibrillation. New Eng J Med. Published online May 24, 2023. doi:10.1056/NEJMoa2303048