REVIEWS OF THERAPEUTICS

Timing of Initiation of Oral Anticoagulation after Acute

Ischemic Stroke in Patients with Atrial Fibrillation
Maureen A. Smythe*1,2 Dennis Parker,1,3 Candice L. Garwood,1,4 Adam Cuker,5,6 and
Steve R. Messe7
1
Department of Pharmacy Practice, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State
University, Detroit, Michigan; 2Department of Pharmacy Services, Beaumont Hospital, Royal Oak, Michigan;
3
Department of Pharmacy, Detroit Medical Center, Detroit Receiving Hospital, Detroit, Michigan; 4Department
of Pharmacy, Detroit Medical Center, Harper University Hospital, Detroit, Michigan; 5Department of Medicine,
Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; 6Department of Pathology
and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania;
7
Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania

Patients with atrial fibrillation (AF) who suffer an acute ischemic stroke are at risk for both hemor-
rhagic transformation and recurrent ischemic stroke in the acute post-stroke period. Oral anticoagu-
lants are recommended for secondary stroke prevention in patients with AF. The optimal time to
initiate anticoagulant therapy after acute ischemic stroke in patients with AF is uncertain. There is
concern that early initiation increases the risk of hemorrhagic transformation, whereas delayed initia-
tion leaves the patient at risk for recurrent ischemic stroke. In this article, we provide a review of the
risk of hemorrhagic transformation of acute ischemic stroke as well as review the literature and major
guidelines addressing the timing of anticoagulation initiation after an acute ischemic stroke in patients
with AF. Relevant articles published from 1990 to the present were identified using the PubMed and
Embase databases. The majority of available literature is observational data. Large ischemic lesions,
cerebral microbleeds, thrombolytic therapy, and other clinical factors may increase the risk of hemor-
rhagic transformation of an acute ischemic stroke. Parenteral anticoagulation within 48 hours is associ-
ated with an increased risk of hemorrhagic transformation and is not recommended. Insufficient data
exist to support the safety of routine oral anticoagulant (direct oral anticoagulants or warfarin) initia-
tion within 48 hours of an acute ischemic stroke. Direct oral anticoagulant initiation within 2 days of
an acute ischemic stroke is associated with a 5% rate of hemorrhagic transformation. Infarct size and
presence of hemorrhage are important factors in identifying the optimal time to initiation and should
guide decisions when available. A recommended framework for patient decision making is provided.
Randomized controlled trials in this area are needed to identify the optimal timing of anticoagulation
initiation, and such trials are under way.
KEY WORDS anticoagulants, acute stroke, atrial fibrillation, time factors, administration, oral.
(Pharmacotherapy 2020;40(1):55–71) doi: 10.1002/phar.2345

Conflict of interest: Adam Cuker has served as a consultant for Synergy CRO, and his institution has received research
support on his behalf from Alexion, Bayer, Novo Nordisk, Pfizer, Sanofi, Spark, and Takeda. Steve R. Messe has received
grant support from WL Gore, Mallinckrodt, Bayer, Novartis, and Biogen. Maureen A. Smythe, Dennis Parker, and Candice L
Garwood have no conflicts of interest to disclose.
*Address for correspondence: Maureen A. Smythe, Department of Pharmaceutical Services, Beaumont Hospital, 3601 West
13 Mile Road, Royal Oak, MI 48073; e-mail: Maureen.smythe@beaumont.org.
Ó 2019 Pharmacotherapy Publications, Inc.
56 PHARMACOTHERAPY Volume 40, Number 1, 2020
Patients who experience a cardioembolic
stroke present a common and difficult clinical
challenge. Cardioembolic strokes, most fre-
quently caused by atrial fibrillation (AF),
account for up to 20%–30% of all ischemic
strokes and are associated with larger infarct
volumes, a higher risk of hemorrhagic transfor-
mation (HTr), and worse outcomes compared
with ischemic strokes from other causes.1–3 In
the days immediately following a cardioembolic
stroke, there is a high risk for both early
ischemic recurrence and HTr of the infarcted
area.4 Although anticoagulant therapy can signif-
icantly reduce the long-term risk of recurrent
ischemic stroke, there is evidence that their
early initiation after an ischemic stroke will
increase the risk of HTr. Thus, the timing of ini-
tiation of anticoagulation therapy after a cere-
brovascular event is a vexing and uncertain
issue.
Vitamin K antagonists (VKAs) were the main-
stay of oral anticoagulant therapy for stroke pre-
vention in patients with AF for > 60 years.
However, within the past decade, four direct
oral anticoagulants (DOACs)—dabigatran, apixa-
ban, rivaroxaban, and edoxaban—were approved
and have been increasingly used for primary and
secondary prevention of stroke in patients with
nonvalvular AF. DOACs offer the advantage of a
significant reduction in intracranial hemorrhage
over VKAs in patients with AF, including those
with a history of prior stroke.5–7 However, the
pivotal DOAC stroke prevention trials in AF—
ARISTOTLE (apixaban), RE-LY (dabigatran),
ROCKET-AF (rivaroxaban), and ENGAGE-AF
TIMI (edoxaban)—excluded patients with an
ischemic stroke within the past 7–180 days,
depending on the trial and severity of the prior
stroke.6 In the rivaroxaban and apixaban AF tri-
als, patients with a prior stroke were enrolled
more than a year following the index stroke.5, 7
With competing risks of recurrent ischemia ver-
sus concern of HTr, the optimal timing for anti-
coagulant initiation or re-initiation in patients
following an acute ischemic stroke (AIS) related
to AF, and whether the timing should differ
based on the class of oral anticoagulant pre-
scribed, are important considerations and wor-
thy research priorities. We performed a review
of the literature to identify predictors of HTr
and reviewed the current literature evaluating
the optimal timing of anticoagulant initiation
following AIS. From this evidence, we provide
guidance for clinical decision making for when
to initiate anticoagulation therapy after an AIS
in patients with AF.
Methods
Data for this review were identified by search-
ing the Embase and PubMed (January 1990 to
present) databases using the following search
terms: atrial fibrillation and anticoagulation and
acute stroke or secondary stroke prevention and
timing. The above search was repeated using the
following terms in place of anticoagulation:
direct oral anticoagulants, aspirin, heparin, low-
molecular-weight heparin, novel oral anticoagu-
lants, warfarin, and vitamin K antagonist. The
search was repeated using combinations of the
above terms with hemorrhagic transformation,
or intra-cerebral bleeding, or intracranial hemor-
rhage. Articles not published in English were
excluded. Major North American and European
guidelines were reviewed. Additional literature
was obtained through a review of relevant refer-
ences of the identified articles. Observational
studies with less than 100 patients were
excluded.
Risk of Stroke Recurrence in Patients with AF
In the absence of antithrombotic therapy, the
risk of recurrent stroke within 14 days of the
index AIS in patients with AF was found to be
4.9% in a large international trial.8 Based on
data from the aspirin arm of the Heparin in
Acute Embolic Stroke (HAEST) trial, the Ameri-
can Heart Association reports a risk of recurrent
stroke of 8% within 14 days.9, 10 The estimated
daily risk of early stroke recurrence is 0.5%–
1.3%/day within the first 2 weeks in the absence
of anticoagulation.11 Predictive factors for
ischemic recurrence following stroke attributed
to AF include older age, left atrial enlargement,
left ventricular dysfunction, increasing
CHA2DS2-VASc score (a clinical stroke risk cal-
culator for patients with AF that incorporates
age, heart failure, hypertension, diabetes melli-
tus, prior cerebrovascular event, female sex, and
other vascular disease), and larger ischemic
lesion size of the index stroke.4, 12–14 Detection
of an atrial thrombus, although uncommon, is
also associated with a high risk of ischemic
stroke recurrence.12 The utility of using these
factors to inform timing of anticoagulant deci-
sions is uncertain. Some factors, including the
CHA2DS2-VASc score and the presence of large
 ANTICOAGULATION INITIATION AFTER STROKE Smythe et al
ischemic lesion, are also associated with an
increased risk of HTr. Although smaller volume
ischemic lesions have a lower risk of recurrent
ischemic events, they also have a lower risk of
intracranial bleeding events.13 Thus, a small
ischemic lesion volume is often a consideration
for the earlier time period of anticoagulation ini-
tiation.
Risk of Hemorrhagic Transformation in Patients
with Acute Ischemic Stroke
In patients who experience a stroke, HTr can
occur as a natural event in the evolution of the
infarct, although the incidence increases with
concomitant use of antithrombotic medication, a
thrombectomy procedure, or thrombolytic ther-
apy.15 Hemorrhagic transformation is a complex
and multifactorial process that may often be
related to reperfusion of the infarcted tissue but
can occur in the absence of recanalization ther-
apy. Ischemic injury results in a strong inflam-
matory response that contributes to a disrupted
blood-brain barrier and altered cerebral autoreg-
ulation.16, 17 Clinical stroke researchers have
characterized two types of HTr: hemorrhagic
infarction (HI) and parenchymal hematoma
(PH).16, 18 Hemorrhagic infarction refers to pete-
chial bleeding into the infarcted tissue. When
viewed using computed tomography (CT), HI is
a heterogeneous hyperdensity that can be subdi-
vided into type 1 (HI1, small distinct areas of
hyperdensity) and type 2 (HI2, a confluent
heterogeneous hyperdensity throughout the
infarct area without mass effect).19 Parenchymal
hematoma refers to a homogeneous, dense
hematoma that may extend outside of the infarct
area, causing edema and mass effect, and is
associated with increased mortality and
disability.16, 18 Parenchymal hematoma is also
subdivided into two types, type 1 (PH1) and
type 2 (PH2), which differ based on the size of
the hematoma relative to the underlying infarct,
less than or greater than 30%, respectively. Of
all types of HTr, PH2 is most associated with
symptomatic HTr and a poor prognosis.18, 20, 21
In a recent combined analysis of data from
two major trials of anticoagulation therapy in
patients with AF patients and AIS, HTr occurred
in 11% (symptomatic HTr in 9%) on repeat CT
imaging or magnetic resonance imaging (MRI)
at 24–72 hours.21 Of these events, 3.1% were
PH. The reported rate of HTr varies with fre-
quency and type of imaging: CT versus suscepti-
bility-weighted MRI. Susceptibility-weighted
57
MRI is more sensitive to the presence of HTr
relative to CT.17
Because HTr is a common complication of
stroke with a potentially devastating outcome,
identification of risk factors and predictors of
HTr is important to inform clinical management,
particularly with regard to initiation of anticoag-
ulation. The larger the volume of the ischemic
lesion, the higher the risk of PH, even after
adjusting for other factors including clinical
stroke severity.21–24 Reperfusion therapy is also
associated with a higher risk of HTr.21 Symp-
tomatic intracerebral hemorrhage in patients
with AIS treated with alteplase occurs in 2–7% of
patients and is associated with a poor outcome.25
There is concern that routine early initiation of
anticoagulation within the first 48 hours of AIS
in patients with AF may worsen or even cause
HTr.26 Cerebral microbleeds seen on susceptibil-
ity-weighted MRI have been shown to indepen-
dently increase the risk of oral anticoagulant–
related symptomatic intracranial hemorrhage,
particularly if the pattern is suggestive of amyloid
angiopathy.27, 28 Amyloid angiopathy is a distal
small vessel vasculopathy that increases in preva-
lence with increasing age and is associated with a
high rate of lobar and subarachnoid hemor-
rhages.29 Cerebral microbleeds also increase the
risk of HTr following thrombolytic therapy for
AIS.30, 31 Other factors suggested to increase the
risk of HTr include older age, hyperglycemia,
prior antiplatelet therapy, dual antiplatelet ther-
apy, triple therapy (two antiplatelet agents plus
anticoagulation), prior stroke, prior intracranial
hemorrhage, congestive heart failure, and uncon-
trolled hypertension.4, 13, 14, 17, 18, 21, 32 Given
that it incorporates many of these factors, a
higher CHA2DS2-VASc score is also a good pre-
dictor.4 Presence of these factors may influence
the decision on when to initiate anticoagulant
therapy.
Early Heparin Administration
Available evidence indicates that early antico-
agulation within the first 48 hours with heparin
is not beneficial. In a subanalysis of the Interna-
tional Stroke Trial (IST), involving 3169 patients
with AF, subcutaneous heparin initiated within
48 hours of stroke onset failed to provide a net
benefit, as the reduction in ischemic stroke was
offset by an increase in hemorrhagic stroke.8 A
subsequent meta-analysis of seven trials evaluat-
ing 4264 patients with acute cardioembolic
stroke supported the findings of IST, as heparins
58 PHARMACOTHERAPY Volume 40, Number 1, 2020
given within 48 hours resulted in no reduction
in death or disability but came at the cost of a
higher rate of symptomatic intracranial bleeding
compared with aspirin or no treatment: 2.5% vs
0.7% (odds ratio [OR] 2.89, 95% confidence
interval [CI] 1.19–7.01).33 HAEST was the only
randomized controlled trial of early heparin
therapy in patients with AF and AIS. Patients
(n=449) were randomized to dalteparin 100 IU/
kg twice daily or aspirin 160 mg daily within
30 hours of stroke onset. At 14 days, there was
no significant difference in the risk of recurrent
ischemic stroke (8.5% with dalteparin vs 7.5%
for aspirin; OR 1.13, 95% CI 0.57–2.24) or
symptomatic cerebral hemorrhage (2.7% with
dalteparin vs 1.8% with aspirin; OR 1.52, 95%
CI 0.42–5.46). Dalteparin was associated with a
trend toward more severe cerebral hemorrhage
and was associated with an increased risk of
extracranial hemorrhage (5.8% with dalteparin
vs 1.8% with aspirin; OR 3.4, 95% CI 1.09–
10.61).10 Of note, HAEST was not sufficiently
powered to detect a difference in symptomatic
cerebral hemorrhage. Overall, the available evi-
dence suggests no benefit and potential harm
when heparin is administered within 48 hours
of AIS in patients with AF.
Large Studies with VKA
Randomized controlled trials assessing the
optimal timing of oral anticoagulant initiation in
patients with AF after an acute cerebral ischemic
event are lacking. The benefit of warfarin in
patients with AF and AIS was first suggested by
the European Atrial Fibrillation Trial (EAFT).34
This was a randomized, multicenter, placebo-
controlled trial of anticoagulation versus aspirin
or placebo in 1007 patients with a TIA or minor
stroke within the previous 3 months. Oral anti-
coagulation (most often a coumarin derivative
with a target international normalized ratio
[INR] of 3) reduced all strokes by nearly two
thirds compared with placebo (hazard ratio
[HR] 0.34, 95% CI 0.2–0.57) and by 40% com-
pared with aspirin (HR 0.60, 95% CI 0.41–0.87)
without a significant increase in intracranial
bleeding. Anticoagulant therapy was initiated
within 2 weeks in 43% of the patients receiving
anticoagulants (n=225).
The landmark trial on the timing of anticoag-
ulation initiation in patients with AF and AIS is
the RAF study.4 RAF was a large, prospective,
international, multicenter, observational study
and is summarized in Table 1. VKA alone was
prescribed in 37% of patients, with another 36%
receiving VKA after low-molecular-weight hep-
arin treatment. The primary outcome was the
composite of stroke, TIA, symptomatic systemic
embolism, symptomatic cerebral bleeding, and
major extracerebral bleeding. In an adjusted
analysis, anticoagulation initiation between 4–
14 days after AIS onset significantly reduced the
composite outcome and ischemic events, with a
nonsignificant reduction in cerebral bleeding
compared with patients who had anticoagulant
initiation before day 4 or after 14 days. Late ini-
tiation of anticoagulant therapy (> 14 days)
increased the risk of an outcome event (HR
3.16, 95% CI 1.92–5.18). In contrast to findings
from the RAF study, data from the VISTA (Vir-
tual International Stroke Trials Archive) registry
suggested that earlier anticoagulation initiation,
within 2–3 days, can lower ischemic stroke risk
without an increase in symptomatic intracranial
hemorrhage (Table 1).35 Although 90-day out-
come events in VISTA were similar to those in
the RAF study, a number of intracerebral bleed-
ing events in VISTA occurred prior to anticoagu-
lant initiation. Differences in study design,
outcome events, concomitant hemostatic medi-
cations, imaging protocol, and the exclusion of
symptomatic HTr within the first 24–72 hours
in the RAF study likely contributed to the differ-
ent findings.4, 35
Observational Studies of Patients Receiving
DOACs Early after AIS
With the widespread use of DOACs and their
benefit in reducing intracranial hemorrhage
compared with VKAs, there is significant interest
in identifying the optimal time of DOAC initia-
tion after an AIS in patients with AF. In the RAF
study, the 93 patients who received DOACs had
favorable outcomes, with a 4.3% ischemic event
rate and 2.1% frequency of symptomatic
intracranial bleeding at 90 days.4 A number of
observational studies of DOAC use in patients
with AF after AIS have been conducted, and
those including more than 100 patients receiving
DOACs are summarized in Table 2.20, 36–43 As a
follow-up to the RAF study, RAF-NOACs
(DOACs were referred to in this study as
NOACs [non–vitamin K oral anticoagulants])
was a prospective, international, multicenter
study in which DOACs were administered a
median of 8 days after stroke onset.20 The 90-
day ischemic and hemorrhagic event rates were
60% lower than in the original RAF study,
Table 1. Large Studies of Patients Receiving Primarily Warfarin or Heparins: Impact of Timing of Anticoagulation Initiation on Ischemic and Hemorrhagic Outcomes
after Acute Ischemic Stroke in Patients with Atrial Fibrillation
Timing of
anticoagulation
initiation after acute Duration of follow-up
Study overview Antithrombotic ischemic stroke onset Stroke severity and outcomes Summary points
4
RAF Design: • 74.4% treated with Mean time: Mean NIHSS score: At 90 days: • Anticoagulation ini-
international, anticoagulants Ischemic: tiation within 4–
prospective, • 58.6% antiplatelets • 8.5 days DOAC • 11.9 LMWH alone 14 days after stroke
multicenter, prior to anticoagulant • 6.5 days LMWH • 6.9 LMWH then • 7.6% with TIA, onset led to reduc-
observational • 12.1 days VKA oral anticoagulant ischemic stroke, tion in ischemic
• 37.1% VKA or systemic
study • 14.7% LMWH • 8.3 oral anticoagu- events and cerebral
No. of patients: lant alone embolism bleeding
• 36% LMWH before VKA Hemorrhagic:
1029 • 12.1% DOACs • LMWH initiation
• 22.4% thrombolytic • 3.6% symp- with first few days
• 24.6% no anticoagulant tomatic intracra- after stroke onset
• 22.4% antiplatelets nial bleeding increased symp-
tomatic intracranial
bleeding
VISTA35 Design: • 31% anticoagulant Median time: 2 days Median NIHSS score: At 90 days: • Anticoagulation
nonrandomized alone (VKA) 14 (patients receiving Ischemic: within 2–3 days
cohort analysis of • 48% VKA and antiplatelets anticoagulants) after stroke onset
Virtual • 10% antiplatelet alone • 10% ischemic lowered ischemic
International stroke stroke without
• 37.5% thrombolysis Hemorrhagic:
Stroke Trials of those receiving excess risk of
Archive antithrombotics • 3% symptomatic intracerebral bleed
No. of patients: intracerebral
1644 hemorrhage
ANTICOAGULATION INITIATION AFTER STROKE Smythe et al

DOACs = direct oral anticoagulants; LMWH = low-molecular-weight heparin; NIHSS = National Institute of Health Stroke Severity; TIA = transient ischemic attack; VISTA = Virtual Interna-
tional Stroke Trials Archive; VKA = vitamin K antagonist.
59
60 PHARMACOTHERAPY Volume 40, Number 1, 2020
possibly indicating a lower risk population with
selection bias for DOAC therapy or a class effect
of DOAC versus VKA. Initiation of DOAC
within 3–14 days had a composite rate of stroke
recurrence and major bleeding of 2.1% versus
12.4% for initiation within 2 days and 9.1% for
initiation > 14 days from the index event. A
multivariate analysis, however, failed to show
timing of DOAC initiation as a significant factor
in the event rate, and hence, the optimal time of
initiation could not be determined. A subsequent
large observational DOAC study, the RELAXED
study, assessed the impact of the timing of
rivaroxaban therapy on outcomes in 1309 Japa-
nese patients.36 In Japan, rivaroxaban dosing for
AF is lower (15 mg once daily for a creatinine
clearance ≥ 50 ml/minute and 10 mg once daily
for a creatinine clearance of 15–49 ml/minute)
than the approved dosing in the United States.
Rivaroxaban was safely initiated within 3 days in
patients with small and medium infarcts and
within 6 days in those with large infarcts. Over-
all, rivaroxaban initiation within 14 days of
stroke onset was associated with a significant
reduction in recurrent ischemic stroke as com-
pared to initiation at ≥15 days: 2% versus 6.8%,
respectively (p=0.0034). In contrast, there was
no significant difference in major bleeding with
initiation of rivaroxaban within 14 days of
stroke onset compared with ≥15 days after
stroke onset (0.9% vs 0%, p=0.37). HTr was less
common among those treated within 14 days
compared to those treated later (14.6% vs
40.9%, p<0.001), but this likely reflects that the
HTr informed timing of initiation, not the
reverse.
In the SAMURAI-NVAF study, the outcomes
of early (within 4 days) DOAC initiation in 475
patients were compared to those of early war-
farin initiation in 662 patients.39 No significant
difference in the occurrence of stroke or sys-
temic embolism between patients receiving war-
farin and DOACs was found (adjusted HR 0.96,
95% CI 0.44–2.04). Although not statistically
significant, intracranial hemorrhage was less fre-
quent in patients receiving DOACs. Researchers
evaluated outcomes related to timing of antico-
agulation initiation in a post hoc analysis of
patients enrolled in the CROMIS–2 study.40 Out-
comes with early anticoagulation (within 4 days)
were compared to late initiation (5 days or after)
or without anticoagulant initiation. Patients in
the early anticoagulation group were less likely
to have a severe stroke, a large infarct, or signifi-
cant HTr on index imaging. Despite a higher
event rate in the late-start group, a multivariate
analysis revealed no significant difference in
patient outcomes related to the timing of antico-
agulation initiation.
Numerous other prospective or retrospective
observational studies have reported favorable out-
comes including a low rate of intracranial hemor-
rhage with DOAC initiation within 14 days of
stroke onset in patients with AF and AIS (Table 2).
Unfortunately, there is no standard definition of
“early anticoagulation.” Overall, in all studies, the
median time to DOAC initiation has ranged from
1.7–11 days, with many studies demonstrating
positive outcomes with initiation within 4 days of
stroke onset (Table 2).36–39, 41–43 The majority of
data, however, are in patients with low National
Institutes of Health Stroke Severity (NIHSS)
scores and small- to medium-sized infarcts. Cur-
rent observational data suggest a signal of concern
for DOAC initiation within 2 days of stroke onset.
The RAF-NOACs study contained the largest pop-
ulation of patients receiving DOACs with a large
stroke and found that DOAC initiation within
2 days had a higher composite rate of stroke
recurrence and major bleeding as compared with
initiation later than 2 days.20 In a combined anal-
ysis of the RAF and RAF-NOACs study, 5% of
patients with DOAC initiation within 24 hours of
stroke onset developed HTr.21 In a study con-
ducted in 235 patients, the median time to antico-
agulant initiation was 2 days, and although not
statistically significant, the frequency of intracra-
nial hemorrhage or symptomatic hemorrhagic
infarction was greater in the DOAC group com-
pared to the warfarin group.43
Important limitations to observational data
exist, which the clinician must weigh when
applying results of these studies to inform indi-
vidual patient decision making. These include
lack of a randomized comparator group, selec-
tion bias, and the potential for residual con-
founding despite statistical methods to account
for differences between treatment groups. The
dosing of DOACs varied across studies (full dose
vs reduced dose, as well as international differ-
ences in approved dosing) as did the presence of
concurrent hemostatic medications and reperfu-
sion strategies.
DOAC Pooled Analysis and Randomized
Controlled Trial
To address the limitations of the observational
data, a recent analysis was undertaken evaluat-
ing individual patient data of more than 4912
 ANTICOAGULATION INITIATION AFTER STROKE Smythe et al
patients from 7 prospective studies comparing
DOACs with VKA in patients with AF and
recent cerebral ischemia.44 The primary outcome
was the composite of recurrent AIS, intracranial
hemorrhage, and mortality. The median time
from index stroke to anticoagulation initiation
was 5 days. Anticoagulation was initiated in
81.3% of all patients within 14 days after the
index stroke. DOAC therapy reduced the com-
posite endpoint compared with warfarin (HR
0.82, 95% CI 0.67–1.00, p=0.05) and reduced
intracranial hemorrhage (HR 0.42, 95% CI 0.24–
0.71, p<0.01), with no significant difference in
recurrent AIS or mortality. The reduction in
intracranial hemorrhage persisted within sub-
groups including those with minor strokes
(NIHSS score ≤ 3) or severe strokes (NIHSS
score> 15), those who had anticoagulation initi-
ation ≤7 days after the index stroke, and those
receiving thrombolytics. The timing of anticoag-
ulant initiation of ≤7 days versus > 7 days after
the index stroke did not impact the association
between anticoagulant class and study end-
points. Of note, 70% of the recurrent AIS in the
VKA group occurred with an INR<2. Research-
ers conducted the first randomized, phase II,
multicenter, parallel-group, open-label study
(Triple AXEL) of 195 patients with AF and mild
to moderate stroke that compared rivaroxaban
10 mg once daily for 5 days, followed by 15 mg
or 20 mg once daily, with warfarin plus concur-
rent aspirin 100 mg/day until an INR of 1.7 was
reached.45 The primary endpoint was a compos-
ite of intracranial bleeding and recurrent
ischemic lesions on diffusion-weighted MRI at
4 weeks. The median time to anticoagulation
initiation was 2 days after stroke onset. Less
than 50% of patients in the warfarin group had
an INR above 2 at day 5. The primary endpoint
occurred in 49.5% of rivaroxaban-treated
patients and 54.5% of warfarin-treated patients
in the intention-to-treat analysis (relative risk
[RR] 0.91, 95% CI 0.69–1.2, p=0.49). One clini-
cal ischemic stroke occurred in each group, with
no symptomatic intracranial hemorrhage in
either group. Rivaroxaban was associated with a
significant reduction in hospital length of stay
(median 4 days vs 6 days, p<0.001). Rivaroxa-
ban therapy, initiated at 2 days from stroke
onset, resulted in comparable outcomes with
warfarin therapy in patients with AF and pre-
dominantly mild strokes. Although the radio-
graphic endpoints used in this study might not
be clinically meaningful, study results provided
61
important proof of concept information for lar-
ger well-designed trials that are currently ongo-
ing.
Ongoing Trials
The lack of high-level evidence regarding the
optimal timing of anticoagulation initiation after
AIS in patients with AF has led to the initiation
of several randomized controlled trials. To date,
four such investigations are under way. The
ELAN (Early Versus Late Initiation of Direct
Oral Anticoagulants in Post-ischaemic Stroke
Patients With Atrial fibrillatioN; NCT03148457),
OPTIMAS (OPtimal TIMing of Anticoagulation
After Acute Ischaemic Stroke; NCT03759938),
START (Optimal Delay Time to Initiate Antico-
agulation After Ischemic Stroke in Atrial Fibrilla-
tion; NCT03021928), and TIMING (TIMING of
Oral Anticoagulant Therapy in Acute Ischemic
Stroke With Atrial Fibrillation; NCT02961348)
trials are all designed to determine whether
there is a net benefit for initiating early anticoag-
ulation with DOACs in patients with AIS sec-
ondary to AF. All studies will randomize
patients to either an early-start group (ranging
from < 48 hours up to 96 hours after AIS onset)
or a control group where oral anticoagulation
will be initiated in accordance with current
guidelines. In all trials, the choice of DOAC is
not specified and is at the prescriber’s discretion.
These studies will collectively enroll approxi-
mately 9000 patients, with results anticipated by
2022.
These ongoing trials have similarities in aim,
but important design differences exist including
the primary study endpoint. Three trials (OTPI-
MAS, ELAN, and TIMING) have a composite
primary outcome including efficacy and safety
parameters; however, the individual components
of the endpoint and time frame of assessment
differ. The primary endpoint in OPTIMAS is
recurrent symptomatic stroke, symptomatic
intracranial hemorrhage, and systemic embolism
at 90 days. Other components of the composite
endpoint in TIMING and ELAN include all-
cause mortality, major bleeding, and vascular
death. The START trial uses separate ischemic
and hemorrhagic endpoints. Once completed, a
pooled analysis of individual patient data from
all of these studies is planned. These data should
provide more definitive answers regarding the
optimal timing of anticoagulation in patients
with stroke secondary to AF.
Table 2. Direct Oral Anticoagulant Observational Studies with Greater than 100 Patients: Impact of Timing of Anticoagulation Initiation on Ischemic and Hemorrhagic
62
Outcomes after Acute Ischemic Stroke in Patients with Atrial Fibrillation
Timing of
anticoagulation
initiation after acute Duration of follow-up
Study overview Antithrombotic ischemic stroke onset Stroke severity and outcomes Summary points

RAF-NOACS20,a Design: international, • 34% dabigatran • Median of 8 days • 40.9% Small lesion At 90 days: • DOAC initiation
prospective, • 33.6% rivaroxaban for dabigatran • 33.3% Medium Ischemic: within 2 days
multicenter study • 32.4% apixaban and rivaroxaban, lesion after stroke onset
No. of patients: 1127 • 62.7% antiplatelet 7 days for apixa- • 21.8% Large lesion • 2% ischemic had a composite
prior to DOAC ban stroke rate of recur-
• Mean NIHSS score
• 9.6% LMWH pre- 7.7 • 2.8% ischemic rence and major
DOAC stroke, TIA or bleeding of
systemic embo- 12.4% vs 2.1%
• 27.3% thrombolytic lism
before DOAC for initiation
Hemorrhagic: within 3–14 days
• 2.2% DOAC with
antiplatelet • 1.6% symp- and 9.1% for ini-
tomatic HTr tiation> 14 days
• LMWH before
DOACs
increased bleed
risk
RELAXED36 Design: multicenter • 100% rivaroxaban • Median 2.9 days • 1.4% small infarct At 90 days: • Significant
observational study • 32.4% thrombolytic for small and • 30% medium infarct Ischemic: reduction in
No. of patients: 1309 or endovascular medium infarcts • 30.9% large infarct recurrent
treatment • Median 5.8 days • Median NIHSS • 2.3% ischemic ischemic stroke
48.8% heparin for large infarcts score 8 stroke with initia-
• Hemorrhagic:
before DOAC (me- tion ≤ 14 days
dian of 10,000 uni- • 0.4% IC bleed vs initia-
ts/day for 3.3 days) • 0.2% hemor- tion ≥ 15 days
rhagic infarction after stroke
onset: 2% vs
6.8%
PHARMACOTHERAPY Volume 40, Number 1, 2020

Macha 201637 Design: single-center, • DOAC breakdown Group 1: Group 1: At discharge: • 89.7% had
retrospective study not provided Ischemic: DOAC initiation
No. of patients: 243 • 25.9% thrombolysis • Median 40.5 hrs • Median NIHSS within 7 days
4 study groups: Group 2: score 0 •Not reported after stroke onset
• 7.8% antiplatelet Group 2: Hemorrhagic:
Group 1: TIA or • Median 76.7 hrs without safety
minor stroke Group 3: • Median NIHSS • 0.8% asymp- concerns
(16.9%) score 5 tomatic IC hem-
Group 2: <1/3 • Median Group 3: orrhage
territory large vessel 108.4 hrs
stroke (70%) Group 4:

(continued)
Table 2 (continued)

Timing of
anticoagulation
initiation after acute Duration of follow-up
Study overview Antithrombotic ischemic stroke onset Stroke severity and outcomes Summary points
Group 3: • median • median NIHSS score • 0.4% symp-
Infratentorial 161.8 hrs 3 tomatic IC hem-
stroke (11.5%) Group 4: orrhage
Group 4: Large • All hemorrhages
territory stroke • Median NIHSS occurred in
(1.6%) score 15 group 2
Cappellari Design: prospective • DOAC breakdown • Mean 3.3 days • Small infarct 54% At 7 days: • No association
(2016)38 observational study not provided • 100% within • Medium infarct Ischemic: of early DOAC
No. of patients: 147 • 48% thrombolysis 7 days 22% use (1-3 days
• Large infarct 24% • 0% ischemic after stroke
stroke onset) and IC
• Mean NIHSS score Hemorrhagic:
8.2 bleeding
• 5.4% IC bleeding
(symptomatic in
only 1 of 8
patients)
Studies involving DOACs and warfarin
SAMURAI- Design: international, • 21.5% rivaroxaban DOAC: DOAC: At 90 days: • All patients
NVAF39 prospective, • 18% dabigatran Ischemic: underwent early
multicenter, • 2.2% apixaban • Median • Small infarct 29.9% stroke or systemic anticoagulant
observational study 4 daysWarfarin: • Medium infarct embolism: initiation
• 58.2% warfarin 56.3%
No. of patients: 1137 • 17.3% concurrent • median 3 days
(475 receiving antiplatelet • Large infarct 13.8% • 3.06% warfarin
DOACs) • 22.7% thrombolysis • Median NIHSS • 2.85% DOAC
or endovascular score 4 Hemorrhagic:
treatment IC hemorrhage:
ANTICOAGULATION INITIATION AFTER STROKE Smythe et al

• 1% warfarin
• 0.23% DOAC
(continued)
63
 64

Table 2 (continued)

Timing of
anticoagulation
initiation after acute Duration of follow-up
Study overview Antithrombotic ischemic stroke onset Stroke severity and outcomes Summary points
CROMIS-2 Design: international, Entire Cohort All patients: All patients: At 90 days (all • Event rate (is-
analysis40 prospective, patients): chemic, hemor-
multicenter, • 35% DOAC • median 11 days • Small infarct 8% Ischemic: rhagic, or death)
observational study • 65% warfarin • Large infarct 18% of 5% in the
No. of patients: 1355 • 19% thrombolysis • Median NIHSS • 1.7% TIA or late-start group
(474 receiving • 24% heparin pre- score 4 (2 in early ischemic stroke vs 2% in the
DOACs) treatment start) Hemorrhagic: early-start group
2 study groups: Early Specific DOAC not Multivariate
described • 0.15% IC hemor- •
start (0–4 days after rhage analysis found
stroke onset; n=358) no significant
vs late start (≥ difference in out-
5 days after stroke comes related to
onset) or no timing of antico-
anticoagulation agulation initia-
(n=997) tion
NOACISP41 Design: single-center, • 76% DOAC • Median of 5 days • Median NIHSS At least 3 mo: • No significant
observational cohort • 34% dabigatran for DOAC score 4 Ischemic: difference in
study • 14% apixaban • DOAC early-start ischemic stroke
No. of patients: 204 • 28% rivaroxaban group 4 days • 5.1%/yr early- when comparing
(155 receiving start DOAC early DOAC ini-
• 24% VKA • DOAC late-start
DOACs) • 22.5% thrombolysis group 15 days • 9.3%/yr late-start tiation vs late
2 study groups: early DOAC initiation
• median of 4 days
start (≤ 7 days after for warfarin • 11.3%/yr war-
stroke onset) or late farin
PHARMACOTHERAPY Volume 40, Number 1, 2020

start (> 7 days after Hemorrhagic:

stroke onset) • 0% all DOAC
• 1.3%/yr symp-
tomatic HTr
warfarin

(continued)
Table 2 (continued)

Timing of
anticoagulation
initiation after acute Duration of follow-up
Study overview Antithrombotic ischemic stroke onset Stroke severity and outcomes Summary points
42
Deguchi 2017 Design: single-center, • 62% DOAC Median DOAC: Median DOAC NIHSS At discharge: • For moderate
retrospective study • 8% dabigatran 3 days score 4 Ischemic: and severe
No. of patients: 300 • 36% rivaroxaban Median warfarin: Median warfarin NIHSS strokes, DOACs
(186 receiving 7 days score 9.5 •Not reported initiated earlier
• 15% apixaban Hemorrhagic
DOACs) • 3% edoxaban than warfarin: 4
• 38% warfarin • Hemorrhagic vs 7 days and 9
• 13.7% i.v. heparin infarction vs 11 days,
before oral antico- • 0% DOAC respectively
agulant • 0.9% Warfarin
• 17.3% recanaliza-
tion
da Vinci43 Design: prospective, • 49.8% DOAC Median DOAC: Median DOAC NIHSS At 30 days: • Not applicable
multicenter, • 13.2% apixaban 2 days score 6 Ischemic:
observational study • 14.9% dabigatran Median warfarin: Median warfarin NIHSS
No. of patients: 235 • 21.7% rivaroxaban 3 days score 16 • Recurrent stroke
(117 receiving • 50.2% warfarin • 6% DOAC
DOACs) • 33.2% heparin • 5.9% warfarin
Hemorrhagic
• 20.9% antiplatelet
• 31.1% thrombolytic • IC hemorrhage
or symptomatic
hemorrhagic
infarction
• 2.6% DOAC
ANTICOAGULATION INITIATION AFTER STROKE Smythe et al

• 0.8% Warfarin
DOAC = direct oral anticoagulant; HTr = hemorrhagic transformation; IC = intracranial; LMWH = low-molecular-weight heparin; NIHSS = National Institutes of Health Stroke Severity; IC = in-
tracranial; VKA = vitamin K antagonist.
a
DOACs were referred to in this study as NOACs (non–vitamin K oral anticoagulants).
65
66 PHARMACOTHERAPY Volume 40, Number 1, 2020
The Role of Antiplatelet Therapy Prior to
Anticoagulant Initiation
The superiority of oral anticoagulation versus
antiplatelet therapy for long-term stroke preven-
tion in patients with AF is well established. The
2018 American Heart Association acute stroke
guidelines recommend aspirin initiation within
24–48 hours after stroke onset, with a delay of
24 hours in those who receive alteplase.46 This
recommendation is based on data from two large
randomized, placebo-controlled trials that
together enrolled ~40,000 patients to evaluate
the safety and efficacy of aspirin treatment (160–
300 mg daily) within 48 hours after AIS.47, 48 A
pooled analysis of the data demonstrated that
aspirin offered a small benefit in reduction of
recurrent ischemic events and mortality over
placebo.49 Both studies included a small percent-
age of patients with AF (7% and 16%, respec-
tively).47, 48 The 2018 guidelines do not provide
a recommended dose of aspirin. Taking into
consideration the aspirin doses studied (160 mg
and 300 mg) and the oral aspirin dosage form
available in the United States, a dose of 162 mg
or 325 mg is appropriate.50 The American Col-
lege of Chest Physicians, the European Society
of Cardiology (ESC), and the Canadian stroke
guidelines recommend aspirin therapy initially
while awaiting the transition to oral anticoagu-
lant therapy after AIS in patients with AF.51–53
Aspirin continuation after warfarin initiation has
been recommended by many experts while
awaiting a therapeutic INR.11, 45 Importantly,
anticoagulation plus aspirin is not indicated for
the majority of patients with AF for long-term
stroke prevention; thus, when the patient is
therapeutically anticoagulated (the day of initia-
tion for a DOAC and when the INR is ≥2 for
patients taking warfarin), aspirin may often be
discontinued.9
Commentary on Available Evidence for
Anticoagulant Initiation
Recommendations for when to initiate antico-
agulation after an AIS in patients with AF are
provided by a number of different organiza-
tions.9, 51–54 Although there is substantial con-
cord among the various guidelines and
guidance documents, there is also disagreement
(Table 3). There are several probable reasons
for this. First, newer documents included more
recent evidence that was not available at the
time older documents were produced. Second,
although there is an abundance of evidence on
the timing of initiation of anticoagulation after
AIS in patients with AF (Tables 1 and 2), the
quality of the evidence is limited by inconsis-
tency, indirectness, imprecision, and risk of bias
inherent in the design of individual studies.55
Finally, some of the guidance documents (ESC
guideline, European Heart Rhythm Association
[EHRA] guideline) are based on expert opinion,
which is prone to bias.56 All of these factors
may contribute to different interpretations of
the evidence and different recommendations.
Recommendations for Initiation of
Anticoagulant Therapy
Early parenteral therapy with heparins is not
recommended in any guideline and is a class III
recommendation (harm) in the ESC guide-
lines.53 European guidelines endorse the “1-3-6-
12 day rule” (explained in Table 3), which
aligns the timing of anticoagulant initiation with
stroke size. The ESC guidelines use clinical
stroke severity, measured with the NIHSS score,
as a surrogate for stroke size.53 In 2015, the
EHRA guidance similarly endorsed using the
NIHSS to categorize stroke size; however, this
categorization scheme was removed from their
2018 recommendations in preference for the
nonspecific terms persisting mild, moderate, or
severe neurological deficit.57, 58 The empiric
time frames provided in the “1-3-6-12” rule rep-
resent consensus opinion with slight differences
between the EHRA and the ESC guidance
(Table 3). The majority of guidelines recom-
mend oral anticoagulant initiation within
2 weeks of stroke onset.9, 51, 53, 54, 57 A delay in
initiation beyond 14 days is recommended in
some of the guidelines for patients at high risk
of HTr.9, 51 Recommendations do not differenti-
ate the timing of oral anticoagulant initiation
based on the class of oral anticoagulant (VKA vs
DOAC).9, 51, 52 Nevertheless, important pharma-
codynamic and pharmacokinetic differences
exist between antithrombotic classes. With the
DOACs, peak antithrombotic effect occurs
within a few hours after a single dose (corre-
sponding to peak concentration), which is in
contrast to the delayed onset of action of a few
days with VKA. Whether the reduction in
intracranial bleeding seen with the DOACs com-
pared to warfarin in long-term stroke prevention
trials will translate into a lower risk of HTr after
an AIS in patients with AF remains to be deter-
mined. Animal data suggest that the risk of HTr
 ANTICOAGULATION INITIATION AFTER STROKE Smythe et al
Table 3. Guidance Recommendations for Anticoagulation Initiation After Acute Stroke in Patients with Atrial Fibrillation
Guidance document
Antithrombotic and
Thrombolytic Therapy
for Ischemic Stroke;
American College of
Chest Physicians
Evidence-Based Clinical
Practice Guideline
(2012)51
Antithrombotic Therapy
for Atrial Fibrillation;
CHEST Guideline and
Expert Panel Report
(2018)54
Guidelines for the
Prevention of Stroke in
Patients with Stroke
and TIA; American
Heart Association/
American Stroke
Association (2014)9
Canadian Stroke Best
Practice
Recommendations:
Secondary Prevention
of Stroke Guidelines
Update (2014)52
European Society of
Cardiology Guidelines
for the Management of
Atrial Fibrillation
Developed in
Collaboration with
EACTS (2016)53
European Heart Rhythm
Association Practical
Guide on the Use of
Non–Vitamin K
Antagonist Oral
Anticoagulants in
Patients with Atrial
Fibrillation (2018)57
67
Grade and level of
Recommendations evidence
• Oral anticoagulation should generally be initiated within 1– Not graded (all)
2 wks after stroke onset
• Consider earlier initiation in those at low risk of bleeding
complications (e.g., small infarct burden and absence of
hemorrhage on brain imaging)
• Consider delaying initiation in those at high risk of hemor-
rhagic complications (e.g., those with extensive infarct bur-
den or significant hemorrhagic transformation on brain
imaging)
• Bridge with aspirin until anticoagulation is therapeutic
• Very early anticoagulation (<48 hrs after acute ischemic Ungraded, Consensus
stroke onset) using heparinoids or VKA should not be used (both)
• Oral anticoagulation should usually be started within 2 wks
of acute ischemic stroke, but the optimal timing within this
period is not known
• For most patients with stroke or TIA in the setting of AF, it Class IIa, Level BaClass
is reasonable to initiate oral anticoagulant therapy within IIa, Level Ba
14 days of the onset of neurological symptoms
• In the presence of high risk for hemorrhagic conversion
(large infarct, hemorrhagic transformation on initial imaging,
uncontrolled hypertension, or hemorrhagic tendency), it is
reasonable to delay the initiation of oral anticoagulation
therapy beyond 14 days
• The time to start oral anticoagulation following TIA or Level CbLevel BcLevel
ischemic stroke is unclear Cb
• Routine use of bridging with heparin is not recommended
• Use antiplatelets until patient is anticoagulated
• Anticoagulation with heparin or LMWH immediately after Class III, Level AdClass
an ischemic stroke is not recommended in AF patients IIa, Level CeClass IIa,
• In patients with moderate to severe stroke who are receiving Level BfExpert opinion
anticoagulants, anticoagulation should be interrupted for 3–
12 days based on a multidisciplinary assessment of acute
stroke and bleeding risk
• In patients with AF who suffer a stroke, aspirin should be
considered for prevention of secondary stroke until the initi-
ation or resumption or oral anticoagulation
• Initiate oral anticoagulation using 1-3-6-12 rule after exclu-
sion of intracerebral bleedingg:
o TIA: initiate 1 day after acute event
o Mild stroke (NIHSS score<8): initiate 3 days after acute
event
o Moderate stroke (NIHSS score 8–16): evaluate
hemorrhagic transformation at day 6, initiate 6 days after
acute event
o Severe stroke (NIHSS score> 16): evaluate hemorrhagic
transformation at day 12, initiate 12 days after acute event
• Initiate DOAC only in absence of contraindication and when Expert opinion
stroke size is not expected to substantially increase the risk
of secondary hemorrhagic transformationg
• “Initiate” refers to either initial start or re-initiation
• TIA: continue if already taking DOAC, or initiate
DOAC ≥ 1 day after TIA onset
• Mild stroke: initiate DOAC ≥ 3 days after stroke onset
(continued)
68 PHARMACOTHERAPY Volume 40, Number 1, 2020
Table 3 (continued)

Grade and level of

Guidance document Recommendations evidence
• Moderate stroke: initiate DOAC ≥ 6–8 days after stroke
onset; rule out hemorrhagic transformation within 24 hrs
prior to initiation
• Severe stroke: initiate DOAC ≥ 12–14 days after stroke
onset; rule out hemorrhagic transformation within 24 hrs
prior to initiation
• Bridging with heparin or LMWH is not recommended
DOAC = direct oral anticoagulant; AF = atrial fibrillation; EACTS = European Association for Cardio-Thoracic Surgery; LMWH = low-molec-
ular-weight heparin; TIA = transient ischemic attack; VKA = vitamin K antagonist; NIHSS = National Institutes of Health Stroke Severity.
a
Recommendation in favor of treatment or procedure being useful/effective; some conflicting evidence from single randomized trial or non-
randomized studies.
b
Writing group consensus and/or supported by limited research evidence. Desirable effects outweigh or are closely balanced with undesirable
effects or vice versa, as determined by writing group consensus.
c
Evidence from a single randomized controlled trial or consistent findings from two or more well-designed nonrandomized and/or noncon-
trolled trials, and large observational studies. Desirable effects outweigh or are closely balanced with undesirable effects or vice versa.
d
Evidence or general agreement that the given treatment or procedure is not useful/effective, and in some cases may be harmful; data derived
from multiple randomized clinical trials or meta-analyses.
e
Weight of evidence/opinion is in favor of usefulness/efficacy; consensus of opinion of the experts and/or small studies, retrospective studies,
and registries.
f
Weight of evidence/opinion is in favor of usefulness/efficacy; data derived from a single randomized clinical trial or large nonrandomized
studies.
g
Identifies additional clinical factors for favoring early or delayed anticoagulation.

with DOACs may be lower than that of war-
farin.14
All patients with AF and AIS should receive
aspirin therapy with a delay of 24 hours if alte-
plase is administered.48 Aspirin is recommended
until oral anticoagulant therapy is initiated.51–53
In those treated with warfarin, some experts rec-
ommend aspirin continuation until a therapeutic
or near-therapeutic INR is attained.11, 45 The
majority of patients with AF are treated with
DOACs, as they are preferred over VKA for
stroke prevention due to their significant reduc-
tion in the risk of intracranial hemorrhage. The
optimal time to start (or re-initiate) these agents
after an AIS in patients with AF remains uncer-
tain. Clinicians must balance the risk of hemor-
rhagic complications of early initiation against
the potential for further ischemia from delayed
initiation of therapy. Recommendations from
multiple organizations have general alignment,
noting that early initiation of heparins within
48 hours of AIS should be avoided, and oral
anticoagulation can be initiated within 2 weeks
for the majority of patients, with the possible
exception of those at high risk of HTr (Table 3).
Existing evidence does not support routine use
of anticoagulant initiation within 48 hours. Fur-
ther, although some observational studies
included patients who had DOAC initiation
within 2 days, the 12.4% composite rate of
recurrence and major bleeding in the RAF-
NOACs study and the 5% HTr rate seen in the
combined RAF and RAF-NOACs study with
DOAC initiation within 2 days indicate that fur-
ther data are needed to support the safety of this
early time frame of initiation.20, 21 With respect
to warfarin, the American College of Chest
Physicians guidelines on AF recommend against
warfarin initiation within 48 hours of an acute
ischemic event (Table 3).54 Data from the VISTA
registry, however, indicate that warfarin initia-
tion within 2 days was not associated with an
increased risk of intracerebral bleed, and thus
this practice may be a reasonable therapeutic
option in select patients.35 The size of the initial
infarct will greatly influence the risk of HTr, and
thus an extremely small acute injury may sup-
port this early initiation of anticoagulation, par-
ticularly with warfarin, as it does not begin to
exhibit an anticoagulant effect for 2 days. Simi-
larly, the presence of a major concurrent indica-
tion for anticoagulation therapy such as left
ventricular thrombus, mechanical heart valve, or
left ventricular assist device could also alter this
guidance.17
The most significant decision is when to initi-
ate anticoagulant therapy within the 3–14-day
period after AIS and how individual patient fac-
tors and class of anticoagulant should inform
this decision. At this time, clinical equipoise
exists regarding when to initiate anticoagulation
within the 3–14-day window and also when to
 ANTICOAGULATION INITIATION AFTER STROKE Smythe et al 69
Table 4. Proposed Timing of Initiation of Anticoagulation with Direct Oral Anticoagulants after an Acute Ischemic Stroke
in Patients with Atrial Fibrillationa
Known infarct volume Unknown Infarct volume (no MRI or CT Hemorrhagic transformation or remote
characterized on MRI or CTb with reliable visualization of infarct)b hemorrhage present
• TIA (no acute infarct on • TIA (no acute infarct on MRI): initiate • Hemorrhagic infarction 1 or 2 (small
MRI): initiate as soon as as soon as possible after acute event or confluent petechiae): consider
possible after acute event • Mild stroke (NIHSS score<8): initi- delaying until at least day 6; evaluate
• Small stroke volume (<2 ate ≥ 3 days after acute event for stability of hemorrhage prior to ini-
cm3): initiate ≥ 3 days • Moderate stroke (NIHSS score 8–16): tiating
after acute event evaluate hemorrhagic transformation • Parenchymal hemorrhage 1 (homoge-
• Moderate stroke volume at day 6, initiate ≥ 6 days after acute neous hemorrhage occupying<1/3 of
(≥2 cm3 and < 30 cm3): event the infarct): consider delaying until
evaluate for hemorrhagic • Severe stroke (NIHSS score> 16): eval- day 12; evaluate for stability of hemor-
transformation at day 6, uate hemorrhagic transformation at rhage prior to initiating
initiate ≥ 6 days after day 12, initiate ≥ 12 days after acute • Parenchymal hemorrhage 2 (homoge-
acute event event neous hemorrhage occupying> 1/3 of
• Large stroke volume (≥30 the infarct, with mass effect) or hem-
cm3): evaluate hemor- orrhage remote from infarct: consider
rhagic transformation at delaying until days 12–28; evaluate for
day 12, initiate ≥ 12 days stability of hemorrhage prior to initiat-
after acute event ing
CT = computed tomography; MRI = magnetic resonance imaging; NIHSS = National Institutes of Health Stroke Severity.
a
If warfarin is used in place of a direct oral anticoagulant, initiate 2–5 days earlier. Very early warfarin initiation may be considered in those
with very small stroke volume.
b
Additional clinical factors may dramatically alter these time frames. Older age, left atrial enlargement, reduced left ventricular function or
segmental wall motion abnormalities, and left atrial or ventricular thrombus are associated with higher early ischemic stroke risk, whereas
uncontrolled hypertension, hyperglycemia, and thrombocytopenia are associated with increased risk of hemorrhage.

delay initiation beyond 14 days. As noted, HTr
of ischemic stroke can be a devastating compli-
cation, and it is reasonable to assume that anti-
coagulation increases this risk. Table 4 provides
our recommended approach, which is generally
concordant with existing guidelines but prefer-
entially focuses on acute infarct volume, as this
factor is more directly associated with hemor-
rhage risk than clinical stroke severity (NIHSS
score).22–24 Studies that have adjusted for both
have consistently demonstrated that the infarct
volume is independently and robustly associated
with hemorrhage risk, whereas clinical stroke
severity is not. Measuring the volume of infarct
is fairly straightforward and reproducible using
the ABC/2 method, which has been validated to
approximate the volumes of ischemic and hem-
orrhagic strokes.59, 60 Briefly, an estimated vol-
ume is calculated using the formula (A x B x
C)/2, where A is the greatest diameter on an
axial image, B is the widest diameter 90 degrees
to A, and C is the approximate number of slices
in which the stroke is visualized multiplied by
the slice thickness.59, 60 The pharmacokinetic
and pharmacodynamic differences between
DOACs and warfarin are well established, and
there is no evidence that these distinctions can
be disregarded when considering timing of their
initiation after stroke. Thus, we believe the
known difference in time to therapeutic antico-
agulation should be considered when deciding
on when to initiate oral anticoagulant therapy.
Given the delay in therapeutic anticoagulation
with warfarin relative to DOACs, warfarin can
generally begin 2–5 days sooner than a DOAC
would be started. Importantly, the suggested
time frames that we propose (Table 4) for initi-
ating anticoagulation are rough guidelines at
best and do not replace clinical judgment, which
may lead to wide variations in clinical practice.
Hopefully, results from additional observational
and trial data will inform and further refine this
difficult clinical decision making.
Conclusion
Patients with atrial fibrillation who suffer an
AIS are at risk for both recurrent ischemic
stroke and hemorrhagic transformation in the
acute post-stroke period. The optimal timing to
oral anticoagulant initiation after an acute stroke
in patients with AF is uncertain. Patient-specific
factors including infarct size and presence of
hemorrhage can influence the risk of ischemic
and hemorrhagic outcomes and must be consid-
ered in the decision-making process. Numerous
organizations have provided guidance on when
to initiate or re-initiate anticoagulant therapy
70 PHARMACOTHERAPY Volume 40, Number 1, 2020
based on the available observational data. The
VKAs and DOACs have important differences in
pharmacokinetic and pharmacodynamic effects
that should be considered. We provided a frame-
work of when to initiate oral anticoagulant ther-
apy, which includes consideration of infarct
volume, class of oral anticoagulant being started,
presence of hemorrhage, and additional clinical
patient factors. Randomized controlled trials
assessing the optimal time to anticoagulant initi-
ation after AIS onset are under way, and results
from these trials will further inform this impor-
tant clinical decision.
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