Systematic Review

International Journal of Stroke

0(0) 1–9
Novel oral anticoagulant management ! 2016 World Stroke Organization
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DOI: 10.1177/1747493016660100
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Andrew Wassef1,2 and Ken Butcher1

Abstract
Background: Four nonvitamin K antagonist oral anticoagulants (NOACs) are approved for stroke prevention in
patients with nonvalvular atrial fibrillation (NVAF).
Aims: In this review, we assemble available evidence for the best management of ischemic and hemorrhagic stroke
patients in the context of NOAC use.
Summary of review: NOACs provide predictable anticoagulation with fixed dosages. The direct thrombin inhibitor
dabigatran and direct factor Xa inhibitors apixaban, edoxaban, and rivaroxaban are all noninferior to warfarin for the
prevention of ischemic stroke and systemic embolism and are associated with reduced incidence of intracranial hemor-
rhage. While these agents offer treatment options for NVAF patients, they also present challenges specific to the clinician
managing cerebrovascular disease patients.
Conclusions: We summarize available evidence and current approaches to the initiation, dosing, monitoring and
potential reversal of NOACs in stroke patients.

Keywords
Stroke, NOAC, nonvitamin K antagonist oral anticoagulant, secondary prevention

Received: 30 March 2016; accepted: 15 June 2016

clinicians are unfamiliar with management options for

Search strategy
PubMed searches were performed using the terms ‘‘sec-
ondary prevention of ischemic stroke’’ or ‘‘prevention
of ischemic stroke’’ and ‘‘randomized controlled trial’’
with individual terms ‘‘dabigatran,’’ ‘‘apixaban,’’
‘‘edoxaban,’’ or ‘‘rivaroxaban.’’ Separate searches iden-
tified registries, treatment guidelines, and meta-analyses
pertaining to secondary prevention of ischemic stroke
with NOACs. Large randomized clinical trials, meta-
analyses, and treatment guideline recommendations
were given preference in data selection.
Introduction
The nonvitamin K antagonist oral anticoagulants
(NOACs) include the direct thrombin inhibitor dabiga-
tran and the factor Xa inhibitors (FXaI) apixaban, rivar-
oxaban, and edoxaban. NOAC efficacy and safety for
reducing stroke and systemic embolic events (SEE) in
nonvalvular atrial fibrillation (NVAF) was demonstrated
in 4 phase 3 trials.1–4 NOACs have predictable pharma-
cokinetic profiles and are administered at fixed dosages
without routine laboratory monitoring.5,6 Relative to
warfarin, NOAC activity is more difficult to assess in
acute and interventional settings. Additionally, many
NOAC-associated bleeding including hemorrhagic
stroke. This article reviews NOAC efficacy and safety
for clinicians managing patients who have suffered
stroke or transient ischemic attack (TIA).
Efficacy and safety of NOACs for
secondary prevention of ischemic stroke
In phase 3 NVAF clinical testing, NOACs were non-
inferior to warfarin for prevention of stroke or SEE
and associated with a  50% risk of intracranial hem-
orrhage (ICH).1–4 These trials included patients with
prior stroke or TIA.1–4 The rivaroxaban trial enrolled
the greatest percentage of patients with prior stroke or
SEE (54%).2 In the edoxaban, dabigatran, and
1
Division of Neurology, Department of Medicine, University of Alberta,
Edmonton, Canada
2
Division of General Internal Medicine, Department of Medicine,
University of Alberta, Edmonton, Canada
Corresponding author:
Ken Butcher, Division of Neurology, 2E3 WMC Health Sciences Centre,
University of Alberta, 8440 112th St, Edmonton, Alberta T6G 2B7,
Canada.
Email: ken.butcher@ualberta.ca

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Table 1. Comparative efficacy and safety endpoints, relative to warfarin, for patients with or without prior history of stroke or TIA
in phase 3 NVAF trials.4,7–9

Prior stroke or TIA No history stroke or TIA

Ratea HR (95% CI)b Ratea HR (95% CI)b

Stroke or systemic embolism

Dabigatran 150 mg 2.07 0.75 (0.52–1.08) 0.87 0.75 (0.52–1.08)

Dabigatran 110 mg 2.32 0.84 (0.58–1.20) 1.34 0.93 (0.73–1.18)

Warfarin 2.78 1.45

Rivaroxaban 2.79 0.94 (0.77–1.16) 1.44 0.77 (0.58–1.01)

Warfarin 2.96 1.88

Apixaban 2.46 0.76 (0.56–1.03) 1.01 0.82 (0.65–1.03)

Warfarin 3.24 1.23

Edoxaban 60 mg 2.44 NR 1.24 NR

Edoxaban 30 mg 3.19 1.60

Warfarin 2.85 1.41

Major bleeding
Dabigatran 150 mg 4.15 1.01 (0.77–1.34) 3.10 0.91 (0.77–1.06)

Dabigatran 110 mg 2.74 0.66 (0.48–0.90) 2.91 0.85 (0.72–0.99)

Warfarin 4.15 3.43

Rivaroxaban 3.13 0.97 (0.79–1.19) 4.10 1.11 (0.92–1.34)

Warfarin 3.22 3.69

Apixaban 2.84 0.73 (0.55–0.98) 1.98 0.68 (0.58–0.80)

Warfarin 3.91 2.91

Edoxaban 60 mg 3.11 NR 2.61 NR

Edoxaban 30 mg 1.79 1.55

Warfarin 3.65 3.35

CI: confidence interval; HR: hazard ratio; NR: not reported; NVAF: nonvalvular atrial fibrillation; TIA: transient ischemic attack.
a
For dabigatran, edoxaban, and apixaban, value measured as % per year; for rivaroxaban, value measured as events/100 person-years.
b
For dabigatran, relative risk.

apixaban trials, 28%, 20%, and 19% of patients,
respectively, had prior stroke or TIA.1,3,4
In all four trials, stroke rates were consistently
higher in patients with a previous cerebrovascular
event, irrespective of warfarin or NOAC treatment,
reflecting elevated risk within this population.1–4
Secondary analyses of rivaroxaban, dabigatran, and
apixaban indicated consistent efficacy and safety
between patients with and without previous stroke or
TIA.7–9 Prespecified subgroup analysis for edoxaban
demonstrated no differences in safety or efficacy in
patients with or without prior stroke or TIA, consistent
with other NOACs (Table 1).4
Oral anticoagulation is recommended for NVAF
patients to prevent stroke recurrence. European, US,
and Canadian guidelines recommend NOACs over
Vitamin K antagonists (VKA), unless contraindicated,
based on net clinical benefit.6,10–13 NOAC doses are

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 Wassef and Butcher

Table 2. Dosing recommendations in NVAF patients.14–17,59–65

US EU Canada

Body Body Elderly Body

Elderly patients Renal function weight Elderly patients Renal function weight patients Renal function weight

Dabigatran, No adjustment CrCl > 30 mL/min: No 80 years: 110 mg bid CrCl 30–50 mL/min: No 80 years: CrCl 30–50 mL/min: No
150 mg, bid 150 mg bida adjustment 75–80 years: 150 mg bida, 150 mg or 110 mg bidc adjustment 110 mg bid 110 mg bid adjustmentd
CrCl 15–30 mL/min: 110 mg bid may be CrCl < 30 ml/min: 75 yearsg: CrCl < 30 ml/min:
75 mg bidb consideredc contraindicated 110 mg bid contraindicated

Apixaban, At least 2 of the following: age  80 years, SCr  1.5 mg/dL, weight  60 kg: 2.5 mg bide
5 mg, bid

Edoxaban, No adjustment CrCl > 95 mL/min: No No adjustment CrCl 15–50 mL/min: 60 kg: Not yet
60 mg, qd do not use adjustment 30 mg qd 30 mg qd approved
CrCl > 50–95 mL/min:
60 mg qd
CrCl 15–50 mL/min:
30 mg qd

Rivaroxaban, No adjustment CrCl 15–50 mL/min: No No adjustment CrCl 15–29 mL/min: No No CrCl 30–49 mL/min: No
20 mg, qdf 15 mg qd adjustment caution adjustment adjustment 15 mg qd adjustment
CrCl < 15 ml/min: CrCl < 30 ml/min:
not recommended not recommended

bid: twice daily; CrCl: creatinine clearance; NVAF: nonvalvular atrial fibrillation; qd: once daily; SCr: serum creatinine.
a
Reduce dose to 75 mg bid in patients with CrCl 30–50 mL/min receiving dronedarone or systemic ketoconazole.
b
Avoid P-gp coadministration in patients with CrCl < 30 mL/min.
c
Based on individual assessment.
d
Surveillance for body weight < 50 kg.
e
In Canada, 2.5 mg in patients with SCr  1.5 mg/dL who are also  80 years or whose body weight  60 kg.
f
Administered with food.
g
At high risk of bleeding, including elderly  75 years with  1 risk factor for bleeding.

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based on age, renal function, and body weight (Table 2).
All NOACs are contraindicated in the presence of mech-
anical heart valves.10,13–17 NOACs interact with the P-gly-
coprotein (P-gp) transporter and may be contraindicated
in patients taking P-gp inhibitors, due to increased bleed-
ing risk, and inducers, due to decreased efficacy.14–17 In
NOAC-treated patients with post-stroke seizures, pheny-
toin and carbamazepine—which induce P-gp, should be
used with caution. Non-P-gp-interacting alternatives, such
as levetiracetam may be preferred in this setting.
Timing of NOAC initiation after stroke
Patients with NVAF who have suffered TIA/ischemic
stroke are at high risk for recurrence and require long-
term anticoagulation.5,18 Stroke risk is high within 90
days of TIA.19 Anticoagulation timing after ischemic
stroke is controversial; acute heparin or warfarin treat-
ment reduces early recurrent stroke, but is offset by
comparable increases in symptomatic hemorrhagic
transformation (HT) rates.20,21
US guidelines recommend anticoagulant initiation
or re-initiation within 2 weeks of cardioembolic
stroke, except in patients with large infarcts or risk fac-
tors for hemorrhage.22 Following neuroimaging to rule
out HT, European guidelines recommend initiating or
resuming oral anticoagulants in patients with TIA 3
days after small nondisabling infarcts (National
Institutes of Health Stroke Scale (NIHSS) < 8), 5–7
days after moderate infarct (NIHSS 8–16), and 12–14
days after severe infarct (NIHSS > 16).6 These recom-
mendations are not based on data from clinical trials.
To minimize the potential for HT, phase 3 trials
excluded patients with: (a) severe or disabling stroke
within 6 months or any stroke within 14 days for dabi-
gatran; (b) severe stroke within 3 months, any stroke
within 14 days, or TIA within 3 days for rivaroxaban;
(c) stroke within 7 days for apixaban; and (d) any stroke
within 30 days for edoxaban. Safety data on early antic-
oagulation with NOACs following cardioembolic stroke
or TIA are limited. Uncontrolled studies of NOAC ini-
tiation within 7 days of stroke onset demonstrate the
feasibility of this approach, with no symptomatic
ICH.23,24 In a single-arm, open-label trial of dabigatran
initiation within 24 h of minor stroke, there was also no
symptomatic HT.25 Another single-arm, open-label trial
of rivaroxaban initiation within 14 days of mild and
moderate ischemic stroke also demonstrated no symp-
tomatic HT.26 In a Japanese registry, which enrolled
1192 patients with NVAF within 7 days of ischemic
stroke/TIA, NOAC initiation occurred a median of 4
days from index stroke.27 No HT was diagnosed prior
to discharge in NOAC users. Together, these studies
suggest NOAC initiation may be safe within 7 days of
ischemic stroke in a subset of patients; however,
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prospective trials are needed. Open-label studies of dabi-
gatran (clinicaltrials.gov NCT02415855), rivaroxaban
(clinicaltrials.gov NCT02129920), and apixaban (clini-
caltrials.gov NCT02283294) are ongoing.
Following anticoagulant-associated hemorrhagic
stroke, oral anticoagulant therapy can be restarted
4–8 weeks post-event for high cardioembolic risk
patients with low risk of new ICH (patients with deep
as opposed to lobar location and well-controlled
hypertension).6,28–30 There are no published studies of
re-anticoagulation after warfarin- or NOAC-related
intracranial bleed. Re-anticoagulation with NOACs is
theoretically preferable, given the marked reduction in
ICH rates relative to warfarin. A study of apixaban vs
acetylsalicylic acid and VKA in this patient population
is ongoing (clinicaltrials.gov NCT02415400).
Management of stroke in patients
taking a NOAC
One advantage of NOACs over VKAs is the lack of
requirement for routine laboratory testing. In acute
stroke, however, NOAC monitoring is helpful in facil-
itating thrombolysis or monitoring reversal attempts in
cases of intracranial bleeding.
Laboratory monitoring
There is no standard laboratory monitoring test for all
NOACs (Table 3). Dabigatran can increases activated
partial thromboplastin time (aPTT); the effect is vari-
able and assay reagent dependent.31,32 Although the
effect on aPTT is sensitive and prolonged with thera-
peutic values of dabigatran,33 the dose–response rela-
tionship is nonlinear. A normal aPTT may not
completely exclude some residual anticoagulant activity
depending on the assay used.33,34 The most accurate
coagulation tests for dabigatran are thrombin time
(TT), dilute thrombin time (dTT), and ecarin clotting
time (ECT); these correlate linearly with dabigatran
concentration.33,34 Although TT is most sensitive and
can rule out clinically significant residual anticoagulant
activity at normal TT values, the assay is overly
sensitive and may display abnormal values at clinically
insignificant dabigatran concentrations.33
FXaIs prolong prothrombin time (PT) and, to a
lesser extent aPTT, with variable anticoagulant- and
reagent-dependent effects.35,36 With a sensitive
thromboplastin reagent, PT measures rivaroxaban con-
centration with moderate accuracy and is prolonged at
peak drug levels.37 PT prolongation is a much less reli-
able measure of apixaban36 and edoxaban38 levels.
Nevertheless, a normal PT cannot exclude clinically
relevant anticoagulant activity and PT accuracy is not
improved by conversion to international normalized
Wassef and Butcher
Table 3. Monitoring and reversal of new oral anticoagulants.30–37,47–58
Anticoagulant monitoring
Oral anticoagulant Preferreda Possibleb
Dabigatran TT, dTT, ECT aPTT
Rivaroxaban
Apixaban Anti-Xa PT
Edoxaban
aPCC: activated prothrombin complex concentrate; aPTT: activated partial thromboplastin time; dTT: dilute thrombin time; ECT: ecarin clotting time;
PCC: prothrombin complex concentrate; PT: prothrombin time; TT: thrombin time.
a
Can exclude clinically significant anticoagulant activity.
b
Qualitative only.
c
Data on clinical endpoints lacking. Evidence based predominantly on coagulation testing, a surrogate marker of clinical efficacy.
d
Phase 3 data pending.
ratio (INR).36–38 INR measurements provided by
point-of-care testing (POCT; CoaguChekÕ Roche
Diagnostics) strongly correlated with rivaroxaban
plasma levels; however, significant anticoagulant activ-
ity was not detected in 10% of anticoagulated
patients.39 Apixaban levels and POCT results were
poorly correlated.39 There are no POCT data for edox-
aban. Anti-Xa activity best correlates with and is linear
across a large range of FXaI values.35–38 Normal anti-
Xa measures using NOAC-specific calibrators and con-
trols can exclude clinically important rivaroxaban,37
apixaban,36 and edoxaban38 concentrations although
quantitative anti-Xa measurements are dependent on
both the FXaI inhibitor and anti-Xa assay employed.35
Anti-Xa assays—calibrated for low molecular-weight
heparin treatment, rather than NOACs—are available
in most centers, although obtaining results in a timely
fashion may be challenging.
Thrombolysis
In a meta-analysis of stroke thrombolysis, any warfarin
use was associated with increased odds of HT.40
Thrombolysis is not recommended in warfarin-treated
patients with INR > 1.7 in the US41 and > 1.3 in the
UK.42 Presumably, patients on NOACs who receive
tissue plasminogen activator (tPA) have an increased
rate of HT; data in this population are sparse. In a
pooled analysis of 31 NOAC-treated ischemic stroke
patients who received tPA, the fatality rate was 6.5%
(two patients).43 This retrospective series included 15,
10, and 1 patient(s) who received dabigatran, rivarox-
aban, and apixaban, respectively.43 The mean elapsed
time between last NOAC dose and tPA administration
was 12 h (range 4–28 h).43
Specialized coagulation tests may help select patients
with undetectable or negligible anticoagulant activity
5
Anticoagulant reversalc
No role Direct (preferred) Non-specific In development
PT/INR Idarucizumab aPCC (FEIBA)
aPTT Andexanet alfad PCC, aPCC PER977
who can safely be thrombolyzed. An approach to
thrombolysis selection in dabigatran treated patients
using a calibrated TT and/or normal aPTT has been
reported.44 No prospective trials have assessed anti-
Xa levels after acute ischemic stroke in FXaI-prescribed
patients. US guidelines recommend against intravenous
tPA in patients taking NOACs unless an adequately
sensitive laboratory assay (TT, ECT, or anti-Xa assay
where appropriate) is within normal range or the
patient has not received a dose of these agents for-
> 48 h.41,45 In large vessel occlusion cases, intra-arterial
clot retrieval procedures are standard of care and the
authors suggest withholding bridging thrombolytic
therapy in these cases.46
Management of bleeding and ICH
American College of Chest Physicians guidelines recom-
mend prothrombin complex concentrates (PCC) over
fresh frozen plasma for life-threatening bleeds associated
with VKA anticoagulation.47 A recent randomized trial
demonstrated that PCCs normalize INR faster than
fresh frozen plasma in VKA-associated ICH.48 Use of
PCC is also associated with less hematoma expansion
and a trend toward reduced mortality without increased
risk of thrombotic events. One meta-analysis of reversal
studies reported a 10.6% overall mean mortality rate
following PCC administration.49 However, despite rever-
sal, poor outcomes are still common. In an open-label
warfarin-associated ICH study, PCC was associated
with a 43% mortality rate, despite INR normalization
in 71.8% of patients within 1 h of treatment.50
Unlike warfarin, NOACs are fast-acting with rela-
tively short half-lives. For major bleeds, including ICH,
rapid restoration of normal hemostasis is prudent
(Table 3). Tactics for achieving hemostasis have
focused on supplementing coagulation factors, or
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6 International Journal of Stroke 0(0)
more recently, on NOAC neutralization with direct
reversal agents. NOAC reversal with PCC has been
studied in vitro, animal models, and in healthy volun-
teers via coagulation parameter measurements.51 While
overwhelming the NOAC with precursor factors con-
tained in PCC is biologically plausible, effects on
patient bleeding and clinical outcomes are unproven.
Dabigatran reversal with activated factor VII
(FVIIa), 4-factor PCC, aPCC or FEIBATM (Factor
Eight Inhibitor Bypassing Activity), and the specific
antidote idarucizumab has been evaluated. Ex vivo
administration of FVIIa in healthy volunteers receiving
dabigatran improved endogenous thrombin potential, a
surrogate coagulation marker; further, activated PCCs
were superior to unactivated 4-factor PCCs for dabiga-
tran reversal.52 Another trial revealed no effect of 4-
factor PCCs on aPTT, TT, or ECT.53 Idarucizumab, a
human antibody fragment that binds and removes dabi-
gatran from the circulation, is the first specific reversal
agent approved in the US, Canada, Australia, and
Europe.54–57 In an interim analysis of 90 patients requir-
ing reversal due to bleeding or a need for urgent surgery,
administration of two 2.5 -g doses of idarucizumab
within 15 min rapidly corrected aPTT, dTT, and ECT.58
In healthy volunteers administered rivaroxaban, 4-
factor PCCs corrected PT, which is qualitatively but
not quantitatively prolonged by FXaIs.53 Other studies
demonstrated partial correction of some coagulation
parameters by PCCs in healthy volunteers taking rivar-
oxaban, but not anti-Xa activity.59,60 In edoxaban-trea-
ted volunteers, 4-factor PCCs corrected coagulation
parameters and reduced bleeding after punch biopsy;
coagulation parameter improvement by 4-factor PCC
was dose-dependent, with greatest correction from PCC
50 IU/kg.61 In ex vivo studies of rivaroxaban-treated
volunteers, activated PCCs corrected some coagulation
parameters, not including anti-Xa activity.52,59
Andexanet alfa (Portola Pharmaceuticals, San
Francisco, USA), a FXa analogue without anticoagulant
activity that binds and sequesters FXaI, is currently
being evaluated in patients with acute major bleeding
(NCT02329327). Andexanet alfa rapidly reversed rivar-
oxaban, apixaban, edoxaban, and enoxaparin effects in
phase 2 studies.62 The ANNEXA-A and ANNEXA-R
trials showed prompt reversal of anticoagulant activity
as measured by anti-Xa activity and thrombin gener-
ation of apixaban and rivaroxaban, respectively, in
healthy volunteers.63 As andexanet alfa has a short
half-life, coagulation parameters and unbound serum
NOAC concentrations rebounded after initial reversal63;
necessitating a bolus followed by infusion protocol.63
A nonspecific reversal agent, PER977 that electro-
statically binds heparin, low molecular weight heparin
and all commercially available NOACs is being inves-
tigated. A single intravenous dose restores baseline
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hemostasis within 10–30 min in volunteers administered
60 mg edoxaban.64 Studies of PER977 in healthy vol-
unteers exposed to edoxaban are ongoing (clinical-
trials.gov NCT02207257).
Conclusion
NOACs are effective for stroke prevention in NVAF
patients and are associated with marked reductions in
ICH. They demonstrate consistent benefits in patients
with and without prior ischemic stroke/TIA. Thus,
NOACs are recognized as first-line options for stroke
prevention in NVAF patients.
Management of patients taking NOACs and initi-
ation of NOACs in acute and subacute phases of ische-
mic and hemorrhagic stroke present particular
challenges. There is little evidence guiding management
in these situations; empiric decisions are ideally made
by stroke specialists. Sensitive and specific tests to
detect and quantify NOAC serum levels and specific
reversal agents will allow development of effective
protocols to manage ischemic and hemorrhagic stroke.
Acknowledgments
Medical writing assistance was provided by Blair Jarvis and
Terri Schochet, PhD, AlphaBioCom, LLC, King of Prussia,
PA, and funded by Daiichi Sankyo, Inc.
Contributions
AW and KB were equally involved in all aspects of manu-
script preparation and had full control over the content of
this manuscript.
Declaration of Conflicting Interests
The author(s) declared the following potential conflicts of
interest with respect to the research, authorship, and/or pub-
lication of this article: KSB has served on advisory boards
and received honoraria for speaking engagements for
Boehringer Ingelheim, Bayer, and Pfizer/BMS.
Funding
The author(s) received no financial support for the research,
authorship, and/or publication of this article.
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