By Michael H. Crawford, MD
Professor of Medicine, Lucy Stern Chair in Cardiology, University of California, San Francisco
SYNOPSIS: A prospective, blinded, randomized study of early vs. later administration of oral anticoagulation after ischemic stroke in patients with atrial fibrillation calibrated by cerebral imaging showed no significant difference in 30-day outcomes.
SOURCE: Fischer U, Koga D, Strbian M, et al. Early versus later anticoagulation for stroke with atrial fibrillation. N Engl J Med 2023;388:2411-2421.
The risk of both recurrent stroke and intracranial hemorrhage (ICH) is highest in the first few days after an ischemic stroke. Also, the risk of ICH increases with the size of the stroke. Accordingly, some delay the initiation of direct-acting oral anticoagulants (DOACs) for one to 12 days after an ischemic stroke, with longer delays for larger strokes. Is earlier DOAC administration safe?
Fisher et al conducted a randomized study of early vs. late administration of DOACs in post-ischemic stroke with atrial fibrillation (AF) patients using imaging-based selection criteria. There were 103 stroke centers involved in 15 countries. CT or MRI was used to confirm the diagnosis and estimate the size of the defect. An infarct of ≤ 1.5 cm in diameter was considered small. An infarct involving the distribution of a cortical superficial branch of the middle, anterior, or posterior cerebral artery was moderate. Larger infarcts in the distribution of these arteries or a brainstem or cerebellar infarct greater than 1.5 cm was considered major. Researchers permitted intravenous thrombolysis or thrombectomy, but not therapeutic anticoagulation at stroke onset. The authors excluded patients with intra-infarct hematomas or ICH.
Patients were randomized 1:1 to early (< 48 hours) DOACs after a minor or moderate stroke, at day 6 or 7 after a major stroke, or to later DOACs at day 3 or 4 after a minor stroke, day 6 or 7 after a moderate stroke, or day 12-14 after a major stroke. The primary outcome was a combination of recurrent ischemic stroke, systemic embolism, major extracranial bleeding, symptomatic ICH, or vascular death within 30 days. Secondary outcomes were components of the primary outcome at 30 and 90 days.
Investigators enrolled 2,013 patients between 2017 and 2022. Their median age was 77 years, 45% were women, 37% experienced minor stroke, 40% a moderate stroke, and 23% a major stroke. The primary outcome occurred in 2.9% of the early treatment group and 4.1% of the later treatment group (OR, 0.70; 95% CI, 0.44-1.14). Recurrent ischemic stroke occurred in 1.4% of the early group and 2.5% of the later group by 30 days (OR, 0.57; 95% CI, 0.29-1.07) and 1.9% and 3.1%, respectively, at 90 days (OR, 0.60; 95% CI, 0.33-1.06).
Symptomatic ICH occurred in 0.2% of both groups at 30 days. All-cause mortality was 4.5% in the early group and 4.8% in the later group (OR, 0.93; 95% CI, 0.61-1.43). Any adverse event by 90 days was 13.9% in the early group and 15.8% in the later group. There was no prespecified subgroup in whom the results were different. The authors concluded that for patients who experienced ischemic stroke, there was no significant difference in post-ischemic stroke complications at 30 days between early vs. later DOAC administration.
COMMENTARY
The timing of DOAC administration after stroke associated with AF has been controversial for years and a frequent subject of lawsuits for both too early and too late administration. Various professional societies have proposed guidelines, such as the European Stroke Organization, which recommends delaying DOAC administration for three days for minor strokes, six days for major ones, and 12 for severe based on clinical criteria.1 The American Heart Association/American Stroke Association recommends delaying two to 14 days if there is a higher risk of ICH based on what appears through imaging.2 Some experts have recommended the one-, three-, six-, 12-day delay for transient ischemic attacks and minor, moderate, and major strokes, respectively.3 The results of the Fisher et al study would support any of these recommendations.
This was a unique study in that the authors did not test any statistical hypotheses for inferiority or superiority. The authors said the results provide qualitative data of use clinically. I suppose they mean for clinical decision-making. In this regard, their results for ICH and recurrent stroke are of the most interest. ICH rates were very low and the same in both strategies. Ischemic rates also were low, and there was no difference between the two strategies. Thus, the authors concluded earlier DOAC administration was reasonable. The strengths of the study include the use of imaging to determine stroke size.
However, there was no central imaging analysis. Other weaknesses include the exclusion of patients already on anticoagulants for AF for other reasons and patients with hemorrhagic transformation. Also, there was a lack of race and ethnicity data. Since the clinical trajectory already was leaning toward earlier DOAC administration for AF-associated stroke patients, I am not sure how much this study will change practice.
REFERENCES
1. Klijn CJ, Paciaroni M, Berge E, et al. Antithrombotic treatment for secondary prevention of stroke and other thromboembolic events in patients with stroke or transient ischemic attack and non-valvular atrial fibrillation: A European Stroke Organisation guideline. Eur Stroke J 2019;4:198-223.
2. 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. Stroke 2021;52:e364-e467.
3. 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. Eur Heart J 2013;34:2094-2106.
A prospective, blinded, randomized study of early vs. later administration of oral anticoagulation after ischemic stroke in patients with atrial fibrillation calibrated by cerebral imaging showed no significant difference in 30-day outcomes.
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