Opinion
EDITORIAL
Anticoagulation Timing for Atrial Fibrillation
in Acute Ischemic Stroke
Time to Reopen Pandora’s Box?
Kelvin K. H. Ng, MBBS; William Whiteley, BMBCh
Most stroke physicians will have been asked the best time to
start anticoagulation for a patient with atrial fibrillation (AF)
and acute ischemic stroke. There is no question that long-
term anticoagulation with a
direct oral anticoagulant or
Related article
warfarin sodium reduces the
risk of strokes in patients with AF, but the right time to start
anticoagulation is uncertain.
The best available evidence comes from participants with
AF randomly allocated to receive heparins, aspirin, or pla-
cebo in acute ischemic stroke.1,2 In a meta-analysis of these
trials, use of heparins led to more cases of intracranial hem-
orrhage (ICH) (summary odds ratio, 2.89 [95% CI, 1.19-7.01];
no significant heterogeneity) but no clear reduction of recur-
rent ischemic stroke (summary odds ratio, 0.68 [95% CI, 0.44-
1.06]; no significant heterogeneity) or reduced death or
disability.3 At 14 days after stroke, the reduction in ischemic
stroke (2.6%) was similar to the increase in ICH (2.4%) for par-
ticipants with AF in the International Stroke Trial who were
treated with unfractionated heparin, 12 500 U compared with
those who did not receive heparin.4 Therefore, there is no clear
indication from randomized trials that early anticoagula-
tion—at least with a heparin—is advantageous in patients with
AF who have experienced a stroke. Most clinical guidelines
either avoid specific recommendations or recommend wait-
ing up to 2 weeks following a stroke before starting an oral
anticoagulant.5,6
The balance between harm and benefit might favor anti-
coagulation soon after an ischemic stroke if agents have a lower
risk than heparin of ICH. Observational studies of direct oral
anticoagulants for AF soon after ischemic stroke report a low
risk of early symptomatic ICH, so they are promising agents
for this clinical indication.7-9 However, unconfounded com-
parator groups are needed to determine whether a strategy of
early anticoagulation with direct oral anticoagulants is better
than delayed treatment.
For this reason, the Triple AXEL (Exploratory Clinical Study
to Assess the Effects of Xarelto [Rivaroxaban] Versus Warfa-
rin on Ischemia, Bleeding, and Hospital Stay in Acute Cere-
bral Infarction Patients With Non-valvular Atrial Fibrillation)
open-label randomized trial10 reported in this issue of JAMA
Neurology is interesting. The authors report 4-week magnetic
resonance imaging and clinical outcomes in 183 of 195 partici-
pants with AF who were randomly allocated to receive open-
label rivaroxaban or dose-adjusted warfarin (target interna-
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tional normalized ratio, 2-3) within 5 days (median, 2 days) of
a diffusion-weighted imaging–defined small ischemic stroke.
Most participants allocated to receive warfarin had not
reached the target international normalized ratio within 5 days
(54.5% of participants had an INR<2 at 5 days), in contrast to
the comparatively rapid onset of action of rivaroxaban. There-
fore, anticoagulation in the warfarin group was delayed—
albeit to a small degree—in comparison with rivaroxaban. How-
ever, the dose of rivaroxaban was low early in the study (10 mg
daily for 5 days followed by 20 mg daily thereafter), so the trial
may have underestimated the risks and benefits of full-dose
anticoagulation on the early risk of stroke recurrence.10
By 4 weeks after randomization, there were similar fre-
quencies in both groups of new brain lesions as seen on fluid-
attenuated inversion-recovery magnetic resonance imaging,
indicating ischemia (rivaroxaban, 28 of 95 [29.5%] vs warfa-
rin, 31 of 87 [35.6%]; relative risk, 0.83 [95% CI, 0.54-1.26]);
clinical ischemic stroke recurrence (1 patient receiving rivar-
oxaban and 1 patient receiving warfarin); any new lesions as
seen on gradient-recalled echo or susceptibility-weighted
imaging magnetic resonance imaging, indicating hemor-
rhage (rivaroxaban, 30 of 95 [31.6%] vs warfarin, 25 of 87
[28.7%]; relative risk, 1.10 [95% CI, 0.70-1.71]); and clinically
symptomatic ICH (0 patients receiving rivaroxaban and 0 pa-
tients receiving warfarin).10
The rates of new hemorrhagic and ischemic lesions seen
on MRI results are high. For example, in participants with AF
allocated to receive apixaban in the MRI substudy of the
AVERROES (Apixaban Versus ASA to Prevent Stroke in AF Pa-
tients Who Have Failed or Are Unsuitable for Vitamin K An-
tagonist Treatment) trial,11 new infarction was detected by MRI
in 12 of 479 participants (2.5%) and new microbleeds were de-
tected in 26 of 377 participants (6.9%) after a median of 1 year,
although baseline prevalence of MR-defined infarction (26%)
and microbleeds (10%) was higher. Whether the findings in
Triple AXEL10 were owing to different MRI methods, differ-
ent definitions of MRI findings, or a higher risk population is
not clear.
The median volume of infarct in the patients randomized
into the Triple AXEL study10 was small (3.5 cm3). There are few
data exploring the association between diffusion-weighted
imaging lesion volume and the risk and timing of anticoagu-
lation. Because the absolute risk of ICH varies with stroke se-
verity, some expert committees have recommended that an-
ticoagulation for AF should be started 3 days after a mild
(Reprinted) JAMA Neurology Published online September 11, 2017 E1
 Opinion Editorial

ischemic stroke and 12 days after a severe stroke (and after brain
imaging was repeated).12 This approach has yet to be tested for
benefit. This is important, because adding to the complexity
of decision making about anticoagulation may lead to re-
duced uptake in clinical practice.13
Strategies of early vs late direct oral anticoagulants will be
compared in at least 3 upcoming randomized trials: Early Ver-
sus Late Initiation of Direct Oral Anticoagulants in Post-
ischemic Stroke Patients With Atrial fibrillation (ELAN; Clini-
calTrials.gov identifier: NCT03148457), Optimal Delay Time to
Initiate Anticoagulation After Ischemic Stroke in Atrial Fibril-
lation (START; ClinicalTrials.gov identifier: NCT03021928),
and Timing of Oral Anticoagulant Therapy in Acute Ischemic
Stroke With Atrial Fibrillation (ClinicalTrials.gov identifier:
NCT02961348). If these trials achieve their predicted rates of
hemorrhagic and ischemic events, the optimal delay for the
initiation of anticoagulation in patients with different types of
acute ischemic stroke should become clearer.
In summary, the Triple AXEL trial shows that starting an-
ticoagulation for AF with warfarin or rivaroxaban at a median
of 2 days after mild acute stroke did not lead to a high risk of
symptomatic ICH or a detectable reduction in early ischemic
stroke. Early anticoagulation with a direct oral anticoagulant
and warfarin in patients with mild stroke is feasible, but
whether this is of benefit to all patients with acute stroke and
AF has yet to be demonstrated.

ARTICLE INFORMATION
Author Affiliations: Department of Medicine
(Neurology), McMaster University, Hamilton,
Ontario, Canada (Ng); Centre for Clinical Brain
Sciences, University of Edinburgh, Edinburgh,
Scotland (Whiteley).
Corresponding Author: William Whiteley, BMBCh,
Centre for Clinical Brain Sciences, University of
Edinburgh, Edinburgh EH16 4SB, Scotland (william
.whiteley@ed.ac.uk).
Published Online: September 11, 2017.
doi:10.1001/jamaneurol.2017.1919
Conflict of Interest Disclosures: None reported.
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