Apixaban Vs ASA en Ictus Embólico de Fuente Indeterminada

Published December 22, 2023
NEJM Evid 2023; 3 (1)

DOI: 10.1056/EVIDoa2300235
ORIGINAL ARTICLE
Apixaban versus Aspirin for Embolic Stroke of

Undetermined Source
Tobias Geisler, M.D.,1 Timea Keller, M.Sc.,1 Peter Martus, Ph.D.,2 Khouloud Poli, M.D.,3,4 Lina Maria Serna-Higuita, M.D.,2
Juergen Schreieck, M.D.,1 Meinrad Gawaz, M.D.,1 Johannes T€ unnerhoff, M.D.,3,4 Paula Bombach, M.D.,4,5
Thomas N€agele, M.D., Uwe Klose, Ph.D., Parwez Aidery, M.D.,1 Patrick Groga-Bada, M.D.,1 Andrea Kraft, M.D.,7
6 6
Frank Hoffmann, M.D.,7 Carsten Hobohm, M.D.,8 Katrin Naupold, M.D.,8 Ludwig Niehaus, M.D.,9 Marc Wolf, M.D.,10
Hansj€org B€azner, M.D.,10 Jan Liman, M.D.,11,12 Rolf Wachter, M.D.,13,14,15 Hubert Kimmig, M.D.,16 Werner Jung, M.D.,17
Roman Huber, M.D.,18 Regina Feurer, M.D.,18 Alfred Lindner, M.D.,19 Katharina Althaus, M.D.,20 Felix J. Bode, M.D.,21
Gabor C. Petzold, M.D.,21 Thanh N. Nguyen, M.D., Ph.D.,22,23 Brian Mac Grory, M.D., Ph.D.,24,25
Matthew Schrag, M.D., Ph.D.,26 Jan C. Purrucker, M.D.,27 Christine S. Zuern, M.D.,11,28 Ulf Ziemann, M.D.,3,4
Sven Poli, M.D.,3,4 for the ATTICUS Investigators*
Abstract
BACKGROUND Rivaroxaban and dabigatran were not superior to aspirin in trials of
patients with embolic stroke of undetermined source (ESUS). It is unknown whether
apixaban is superior to aspirin in patients with ESUS and known risk factors for
cardioembolism.
METHODS We conducted a multicenter, randomized, open-label, blinded-outcome trial

of apixaban (5 mg twice daily) compared with aspirin (100 mg once daily) initiated within Drs. Geisler and Poli contributed
equally to this article.
28 days after ESUS in patients with at least one predictive factor for atrial fibrillation or a
patent foramen ovale. Cardiac monitoring was mandatory, and aspirin treatment was *A complete list of the ATTICUS
Investigators is provided in the
switched to apixaban in case of atrial fibrillation detection. The primary outcome was any Supplementary Appendix,
new ischemic lesion on brain magnetic resonance imaging (MRI) during 12-month follow- available at evidence.nejm.org.
up. Secondary outcomes included major and clinically relevant nonmajor bleeding. The author affiliations are listed
at the end of the article.
RESULTS A total of 352 patients were randomly assigned to receive apixaban (178
Dr. Geisler can be contacted at
patients) or aspirin (174 patients) at a median of 8 days after ESUS. At 12-month follow-
tobias.geisler@med.uni-tuebingen.
up, MRI follow-up was available in 325 participants (92.3%). New ischemic lesions de or at the Department of
Cardiology and Angiology,
occurred in 23 of 169 (13.6%) participants in the apixaban group and in 25 of 156 (16.0%)
University Hospital T€ ubingen,
participants in the aspirin group (adjusted odds ratio, 0.79; 95% confidence interval, 0.42 Otfried-M€ uller-Str. 10, 72076
T€ubingen, Germany; and Dr. Poli
to 1.48; P=0.57). Major and clinically relevant nonmajor bleeding occurred in five and
can be contacted at sven.poli@uni-
seven participants, respectively (1-year cumulative incidences, 2.9 and 4.2; hazard ratio, tuebingen.de or at the Department
of Neurology & Stroke, University
0.68; 95% confidence interval, 0.22 to 2.16). Serious adverse event rates were 43.9 per
Hospital T€ ubingen, Hoppe-Seyler-
100 person-years in those given apixaban and 45.7 per 100 person-years in those given Str. 3, 72076 T€ ubingen, Germany.
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aspirin. The Apixaban for the Treatment of Embolic has been published.9 Its latest version (2.1), original version,
Stroke of Undetermined Source trial was terminated after and amendments are available in the protocol provided with
a prespecified interim analysis as a result of futility. the full text of this article.
CONCLUSIONS Apixaban treatment was not superior The protocol was approved by the German Federal Institute
to cardiac monitoring-guided aspirin in preventing new for Drugs and Medical Devices, a central ethics committee,
ischemic lesions in an enriched ESUS population. (Funded and the institutional review boards of all participating cen-
by Bristol-Myers Squibb and Medtronic Europe; Clinical- ters. All participants provided written informed consent.
Trials.gov number, NCT02427126.) The trial was conducted in accordance with the Declaration
of Helsinki and the International Council for Harmonization
Good Clinical Practice Guidelines.
A steering committee, supported by the Center for Clinical

Introduction Trials at T€ubingen University, Germany, oversaw the trial
E
mbolic stroke of undetermined source (ESUS) design, analysis, data collection, and decision to publish
accounts for a quarter of ischemic stroke and is (Supplementary Appendix). Site investigators gathered the
associated with a stroke recurrence of approxi- data. Safety outcomes and study conduct were monitored
mately 4.5% per year.1,2 The optimal secondary preven- by an independent Data Safety Monitoring Board. The
tion strategy in patients with ESUS is unclear. two principal investigators (T.G. and S.P.) wrote the first
draft of the manuscript. A statistician (P.M.) performed
Oral anticoagulation is superior to antiplatelet therapy in data analysis and attests to data integrity. All authors and
preventing atrial fibrillation–related stroke.3 Despite the investigators vouch for the accuracy and completeness of
high rate of atrial fibrillation detection in up to 16% of the data, reporting of adverse events, and fidelity of the
patients with cryptogenic stroke during 3 to 12 months of trial to the protocol. The funding industry had no role in
continuous cardiac monitoring,4,5 recent randomized trials the trial design, data collection, analysis, interpretation,
did not demonstrate superiority of anticoagulation with writing of the manuscript, or decision to publish.
rivaroxaban or dabigatran over aspirin in patients with
unselected ESUS.6,7 The web-based secuTrial application (interActive Systems)
served for randomization and as the electronic data cap-
To overcome the limitations of these trials, we conducted ture system.
the Apixaban for the Treatment of Embolic Stroke of
Undetermined Source (ATTICUS) randomized trial, which PARTICIPANTS
aimed to include patients with ESUS with “enrichment The trial was conducted at 16 stroke centers in Germany.
factors” associated with an increased risk of atrial fibrilla- Patients were eligible within 3 to 28 days after ESUS as
tion and cardioembolism. We hypothesized that “enriched defined by Hart et al.1 Patients had to have at least one
ESUS” may have a higher probability than “unselected clinical, electrocardiographic, or echocardiographic enrich-
ESUS” to benefit from oral anticoagulation compared with ment factor predictive for atrial fibrillation (CHA2DS2-
aspirin. We selected apixaban because its bleeding risk VASc score greater than or equal to four; atrial high-rate
was found to be similar to that of aspirin in patients with episode(s) [i.e., any episode of greater than or equal to 20
atrial fibrillation.8 supraventricular extrasystoles with an accelerated cycle
length lasting less than 30 seconds]; left atrial size greater
than 45 mm, spontaneous echo contrast, or flow velocity
less than or equal to 0.2 m/s in the left atrial appendage)10
Methods or a patent foramen ovale. (The CHA2DS2-VASc score
assesses the risk of ischemic stroke among participants
TRIAL DESIGN AND OVERSIGHT with atrial fibrillation [according to congestive heart fail-
This investigator-initiated multicenter, randomized, open- ure, hypertension, age older than 75 years, diabetes, stroke
label, blinded-outcome trial was funded by Bristol-Myers or transient ischemic attack, vascular disease, age 65 to
Squibb/Pfizer and Medtronic. The trial protocol (version 1.2) 74 years, and sex] and ranges from zero to nine, with
NEJM EVIDENCE 2
higher scores indicating a greater ischemic stroke risk.) embolic new ischemic lesions on MRI; a composite of
Insertable or external cardiac monitoring was initiated major and clinically relevant nonmajor bleeding classified
within 28 days of index ESUS and mandatory throughout according to the International Society on Thrombosis
study conduct. The complete list of inclusion and exclusion and Hemostasis12; Montreal Cognitive Assessment (scores
criteria is shown in the trial protocol. range from 0 to 30, with scores below 26 indicating a cog-
nitive decline and scores of 26 and higher being consid-
RANDOMIZATION AND TRIAL TREATMENT ered normal)13; EuroQol-5 Dimensions-5 Levels (which
Participants were randomly assigned (1:1 ratio) to either consist of a questionnaire whose results are scaled to an
5 mg of open-label apixaban twice daily or 100 mg of index, with an index of 1 representing the best possible
nonenteric-coated aspirin once daily. Web-based random- quality of life and values below 0 indicating quality of life
ization with an implemented random number generation worse than death, and a visual analogue scale ranging
process ensured allocation concealment. Block randomi- from 0 [worst health you can imagine] to 100 [best health
zation with block lengths of four and six in a random order you can imagine])14; and Stroke Impact Scale 16 (which
was used. Randomization was stratified by centers. Apixa- assesses physical function covering activities of daily liv-
ban was reduced to 2.5 mg twice daily in participants with ing, mobility, and hand function; scores range from 0 to
creatinine clearance 15 to 29 ml/min or with two of the 100, with higher scores indicating a better functional
three criteria: age 80 years or older, body weight 60 kg or status).15 The exploratory outcome of atrial fibrillation
less, or serum creatinine 1.5 mg/dl or higher (133 lmol/l). incidence was analyzed because of its relevance for inter-
Participants were switched from aspirin to apixaban within pretation of results. All bleeding, ischemic, and serious
14 days of core laboratory–adjudicated atrial fibrillation adverse events and atrial fibrillation were centrally adjudi-
detection defined as episodes 2 minutes or longer with an cated by two independent blinded raters, and a third was
insertable cardiac monitor or 30 seconds or more with an consulted in case of discrepancy.
external cardiac monitor (three 40-second two-lead elec-
trocardiographic measurements per day). The trial treat- STATISTICAL ANALYSIS
ment duration for an individual patient was 12 months. A The trial was planned with an adaptive design16 to enroll a
phone interview was conducted 30 days after cessation of maximum of 600 participants with 12-month follow-up,
study treatment to assess for adverse events. expecting 10% of participants with any new ischemic
lesion in the aspirin group,17,18 to detect an improvement
OUTCOMES of 7.5 percentage points in the apixaban group with 90%
The primary outcome was any new ischemic lesion on power. It was expected that 30% or fewer of participants
diffusion-weighted or fluid-attenuated inversion recovery in the aspirin group would be switched to apixaban as a
brain magnetic resonance imaging (MRI) compared with result of atrial fibrillation detection.10 An interim analysis
baseline during 12-month follow-up. MRIs were conducted was planned for the first 200 randomly assigned partici-
using the same scanner at baseline, within 14 days of atrial pants who completed the 12-month follow-up and allowed
fibrillation detection, and at 12 months. All MRIs were for stopping because of efficacy (Pa1 = 0.013084) or
evaluated independently by two blinded neuroradiologists futility (Pa0 = 0.3).9 Details are provided in the Supple-
at the imaging core laboratory (the neuroradiology depart- mentary Appendix and the statistical analysis plan.
ment at T€ ubingen University, Germany) by slice-to-slice
comparison of previous images.11 New ischemic lesions were Unless otherwise specified, all analyses were performed
counted and classified as embolic or nonembolic (subcortical in the intention-to-treat population, which included all
infarcts <2 cm1). Interrater agreement, as determined by the participants who underwent randomization excluding one
kappa statistic, was 0.52. A third independent rater resolved patient who withdrew consent and did not allow use of
disagreements. collected data. The primary analysis determined whether
the proportion of participants with any new ischemic
Secondary outcomes assessed during the 12-month follow- lesion differed between treatment groups using a one-
up period were a composite of any recurrent stroke and sided Cochran–Mantel–Haenszel test stratified by centers
systemic embolism; a composite of major adverse cardio- at a level of 0.05. Participants with missing MRI were
vascular events (any recurrent stroke, myocardial infarc- excluded from the primary analysis. Sensitivity analyses
tion, or death from cardiovascular or unknown cause); were planned with worst-case (“new ischemic lesion”)
NEJM EVIDENCE 3
and best-case (“no new ischemic lesion”) imputation. No treatment groups (Table 1 and Table S1 in the Supplemen-
other imputation of missing data was performed. Second- tary Appendix). The representativeness of the trial popula-
ary outcomes were assessed for descriptive purposes. tion is summarized in Table S2.
One-year cumulative incidences were computed for sec-
ondary outcomes. Hazard ratios were estimated using PRIMARY OUTCOME
the Fine–Gray subdistribution hazard model including The primary outcome of any new ischemic lesion was
death as competing risk. Montreal Cognitive Assessment assessable in 325 of 352 participants (92.3%); MRI was
and patient-related outcomes were tested using baseline- missing in 9 participants (5.1%) in the apixaban group and
adjusted analysis of covariance and treatment group as 18 participants (10.3%) in the aspirin group (Fig. 1).
factor. To determine the heterogeneity of the treatment
effect, an interaction test was performed between prespe-
The primary outcome occurred in 23 of 169 participants
cified subgroups and treatment assignment. The treatment
(13.6%) in the apixaban group and in 25 of 156 participants
effect on the primary outcome and the composite outcome
(16.0%) in the aspirin group. The adjusted odds ratio for
of major and nonmajor clinically relevant bleeding was
the primary outcome in the apixaban group compared
examined across the prespecified subgroups (in the Sup-
with the aspirin group was 0.79 (95% confidence interval
plementary Appendix).
[CI], 0.42 to 1.48; P=0.57). Worst-case and best-case
imputation including all 352 participants did not alter
interpretation of results (Table 2).
Results
SECONDARY OUTCOMES
PARTICIPANTS AND TREATMENT The composite outcome of any recurrent stroke and sys-
A total of 353 participants were recruited at 16 stroke temic embolism occurred in 11 participants (6.2%) in the
centers in Germany between January 2016 and August apixaban group and in 13 participants (7.6%) in the aspirin
2020 and assigned randomly to either the direct apixaban group (1-year cumulative incidences, 5.7 and 6.4; hazard
group (178 participants) or the aspirin group with cardiac ratio, 0.81; 95% CI, 0.36 to 1.80) (Fig. 2A and Table 2).
monitoring–guided switch to apixaban upon diagnosis of No hemorrhagic stroke occurred.
atrial fibrillation (175 participants) (Fig. 1). A total of 352
participants were analyzed (Fig. 1). After interim analysis, The composite outcome of major adverse cardiovascular
trial enrollment was terminated as a result of futility at the events (any recurrent stroke, myocardial infarction, or
recommendation of the data safety monitoring board on death from cardiovascular or unknown cause) occurred in
August 5, 2020. Follow-up of enrolled patients was contin- 13 participants (7.3%) in the apixaban group and in 15 par-
ued because there were no safety concerns; study visits ticipants (8.8%) in the aspirin group (1-year cumulative
including MRI and therapy over 12 months continued incidences, 5.9 and 7.6; hazard ratio, 0.83; 95% CI, 0.40
according to the protocol in all enrolled participants. to 1.75) (Table 2 and Fig. S1).
The mean age (–SD) was 68.4 – 10.5 years, and 48.6% Thirty-seven of the 48 participants (77.1%) with any new
were female. All participants had at least one cardioem- ischemic lesion had embolic lesions, which occurred in 18
bolic enrichment factor, and 36.6% had multiple cardi- participants (10.7%) in the apixaban group and in 19 parti-
oembolic enrichment factors. At screening, the median cipants (12.2%) in the aspirin group (odds ratio, 0.81; 95%
score on the National Institutes of Health Stroke Scale CI, 0.40 to 1.62) (Table 2).
(scores range from 0 to 41, with higher scores indicating
more neurologic deficits) because of index ESUS was 1 Results were similar when considering the actual antith-
(interquartile range, 0 to 3). Of the participants, 1.7% had rombotic treatment at onset of events or observation of
major stroke according to imaging criteria. The median new ischemic lesions (Table S3).
time from index ESUS to randomization was 8 days (inter-
quartile range, 6 to 12). History of cancer and patent fora- Cognitive function and patient-reported outcomes were
men ovale were more frequent in the apixaban group. All similar in both treatment groups except the scores on the
other baseline characteristics, including patent foramen EuroQol visual analogue scale, which were higher (that is,
ovale as a sole enrichment factor, were balanced between better function) in the apixaban group (Table S4).
NEJM EVIDENCE 4
1634 Assessed for eligibility
1282 Were excluded

1203 Did not meet inclusion criteria
56 Declined to participate
22 Had other reasons
353 Underwent randomization
1 Withdrew consent immediately after

randomization (aspirin group) and did
not allow usage of any collected data
352 Were included in the

intention-to-treat population
178 Were assigned to receive apixaban 174 Were assigned to receive aspirin
173 Received at least one dose of aspirin

178 Received at least one dose of apixaban
1 Did not receive a dose of aspirin
2 Had no assessable baseline

MRI available
2 Died before MRI follow-up
3 Received a cardiac
2 Had no assessable baseline pacemaker and had no MRI
MRI available follow-up
2 Died before MRI follow-up 2 Had no assessable MRI
4 Withdrew consent follow-up
1 Was lost to follow-up 7 Withdrew consent
1 Was withdrawn from the
trial by investigator’s
decision*
1 Was lost to follow-up
169 Had MRI follow-up eligible for 156 Had MRI follow-up eligible for
primary end point analysis primary end point analysis
Figure 1. Trial Flowchart.

The intention-to-treat population comprised 352 participants and was used for clinical outcome analyses. Magnetic resonance imaging
(MRI) follow-up eligible for primary outcome analysis was available in 325 participants (92.3%). *The local investigator deemed further
trial procedures unfeasible in the participant because of the participant’s clinical status after ST-elevation myocardial infarction.
SAFETY treatment at onset of bleeding events (Tables S3 and S5).

The composite of major and clinically relevant nonmajor Any serious adverse event occurred in 50 participants
bleeding occurred in five participants (2.8%) in the apixaban (28.1%) in the apixaban group and in 55 participants (31.6%)
group and in seven participants (4.0%) in the aspirin group in the aspirin group. Serious adverse event rates were 43.9
(1-year cumulative incidences, 2.9 and 4.2; hazard ratio, per 100 person-years in the group treated with apixaban
0.68; 95% CI, 0.22 to 2.16) (Table 2 and Fig. 2B). Results and 45.7 in the group treated with aspirin. Details on serious
were similar when considering the actual antithrombotic adverse events are provided in Tables S6 and S7.
NEJM EVIDENCE 5
Table 1. Characteristics of the Participants at Baseline*
Characteristic Apixaban Group (n5178) Aspirin Group (n5174)

Age — yr 68.6 – 11.1 68.3 – 9.8
Female sex — no. (%) 86 (48.3) 85 (48.9)
Body-mass index† 27.7 – 5.2 27.7 – 4.9
Blood pressure — mm Hg
Systolic 131.2 – 13.8 131.9 – 12.7
Diastolic 77.4 – 9.7 77.4 – 9.7
Current smoker — no. (%) 27 (15.2) 26 (14.9)
Creatinine clearance — ml/min 87.2 – 34.1 88.1 – 38.6
Median time from index stroke to randomization (IQR) — days 8 (6–12) 8 (6–12)
Major index stroke — no. (%) 2 (1.1) 4 (2.3)
Median NIHSS score (IQR)‡ 1 (0–3) 1 (0–3)
Medical history — no. (%)
Hypertension 153 (86.0) 150 (86.2)
Diabetes mellitus 52 (29.2) 48 (27.6)
Previous TIA or stroke 24 (13.5) 30 (17.2)
Previous myocardial infarction 4 (2.2) 7 (4.0)
Coronary artery disease 12 (6.7) 17 (9.8)
Congestive heart failure 3 (1.7) 4 (2.3)
Aortic or peripheral arterial occlusive disease 7 (3.9) 9 (5.2)
Previous venous thromboembolism 5 (2.8) 4 (2.3)
History of cancer 21 (11.8) 9 (5.2)
History of gastrointestinal bleeding, ulcer, or gastritis 5 (2.8) 2 (1.1)
Liver disease 3 (1.7) 7 (4.0)
Kidney disease 10 (5.6) 11 (6.3)
Median CHA2DS2-VASc score (IQR)§ 5 (4–6) 5 (4–5)
Cardiac monitoring — no. (%)
Implanted cardiac monitor 168 (94.4) 168 (96.6)
External cardiac monitor 10 (5.6) 6 (3.4)
* Plus–minus values are presented as the means (–SD). There were no significant differences between the treatment groups except with respect to
history of cancer (P=0.026) and patent foramen ovale (P=0.008) (Table S1). P values were calculated using Student’s t-test or the Mann–Whitney test
for continuous variables, depending on the data distribution, and the chi-square test or Fisher’s exact test for categorical variables as appropriate.
Percentages may not total 100 because of rounding. IQR denotes interquartile range.
† The body-mass index is the weight in kilograms divided by the square of the height in meters.
‡ Scores on the National Institutes of Health Stroke Scale (NIHSS) range from 0 to 41, with higher scores indicating worse neurologic deficits.
§ The CHA2DS2-VASc score assesses the risk of ischemic stroke among participants with atrial fibrillation (according to congestive heart failure,
hypertension, age older than 75 years, diabetes, stroke or transient ischemic attack [TIA], vascular disease, age 65 to 74 years, and sex) and ranges
from zero to nine, with higher scores indicating a greater ischemic stroke risk.
ATRIAL FIBRILLATION DETECTION aspirin group (1-year cumulative incidences, 22.9 and
A total of 336 participants (95.4%) underwent implanted 27.6; hazard ratio, 0.78; 95% CI, 0.51 to 1.19) (Table 2 and
cardiac monitoring, and 16 (4.5%) underwent external Fig. S2). Forty-five of the 49 participants (91.8%) with
cardiac monitoring (Table 1). Impaired wound healing atrial fibrillation detection were switched to apixaban in
required a switch to external cardiac monitoring in one the aspirin group. The latter was analyzed as randomly
participant in each treatment group. assigned except for the on-treatment analyses.
Atrial fibrillation was detected in 40 participants (22.5%) The adjusted odds ratio for any new ischemic lesion in
in the apixaban group and 49 participants (28.2%) in the participants with atrial fibrillation in the apixaban group
NEJM EVIDENCE 6
Table 2. Efficacy and Safety Outcomes*
Apixaban Group Aspirin Group Odds Ratio or Hazard

Outcome (N5178) (N5174) Ratio (95% CI)
Primary outcome: any new ischemic lesion on MRI during 23/169 (13.6) 25/156 (16.0) 0.79 (0.42–1.48)‡§
12 months of follow-up — no. of participants (%)†
Worst-case imputation 32 (18.0) 43 (24.7) 0.65 (0.38–1.09)‡¶
Best-case imputation 23 (12.9) 25 (14.4) 0.86 (0.47–1.60)‡jj
Secondary efficacy outcomes
Embolic new ischemic lesion on MRI during 12 months 18/169 (10.7) 19/156 (12.2) 0.81 (0.40–1.62)‡
of follow-up — no. of participants (%)†
Composite of any recurrent stroke and systemic 11 (5.7) 13 (6.4) 0.81 (0.36–1.80)‡‡
embolism** — no. of participants (1-year cumulative
incidence)††
Composite of major adverse cardiovascular events (any 13 (6.9) 15 (7.6) 0.83 (0.40–1.75)‡‡
recurrent stroke, myocardial infarction, or death from
cardiovascular or unknown cause)** — no. of
participants (1-year cumulative incidence)††
Ischemic stroke — no. of participants (1-year cumulative 11 (5.7) 12 (5.9) 0.88 (0.39–1.99)‡‡
incidence)††
Systemic embolism — no. of participants (1-year 0 (0) 1 (0.6) NC
cumulative incidence)††
Myocardial infarction — no. of participants (1-year 1 (0.6) 3 (1.8) 0.32 (0.03–3.12)‡‡
Death from cardiovascular or unknown cause§§ — no. 1 (0.6) 1 (0.6) 0.95 (0.06–14.8)‡‡
of participants (1-year cumulative incidence)††
Death from any cause — no. of participants (1-year 3 (1.7) 4 (2.4) 0.72 (0.16–3.22)‡‡
Safety outcome— no. of participants (1-year cumulative
incidence)††
Composite of major and clinically relevant nonmajor 5 (2.9) 7 (4.2) 0.68 (0.22–2.16)‡‡
bleeding
Major bleeding¶¶ 1 (0.6) 1 (0.6) 0.95 (0.06–14.8)‡‡
Intracranial hemorrhage 0 (0) 0 (0) NC
Gastrointestinal bleeding 1 (0.6) 0 (0) NC
Fatal bleeding 0 (0) 0 (0) NC
Clinically relevant nonmajor bleeding 4 (2.3) 6 (3.6) 0.64 (0.18–2.29)‡‡
Exploratory outcomes — no. of participants (1-year
Atrial fibrillation 40 (22.9) 49 (27.6) 0.78 (0.51–1.19)‡‡
* All outcomes were confirmed by independent adjudication committees. NC denotes nonconvergence of the model.
† Denominator is indicated whenever different from the total number of participants.
‡ Odds ratios and 95% confidence intervals (CIs) were estimated using the Cochran–Mantel–Haenszel test stratified by centers.
§ P=0.57 for the primary outcome of at least one new ischemic lesion on magnetic resonance imaging (MRI) during 12 months of follow-up.
¶ P=0.135 for the primary outcome of at least one new ischemic lesion on MRI during 12 months of follow-up for worst-case imputation.
jj P=0.76 for the primary outcome of at least one new ischemic lesion on MRI during 12 months of follow-up for best-case imputation.
** All strokes received neuroimaging and were confirmed by the adjudication committee as ischemic.
†† This indicates the one-year cumulative incidence of the secondary outcomes.
‡‡ Hazard ratios and 95% CIs were estimated using the Fine–Gray subdistribution hazard model including death as competing risk. Because
secondary outcomes were assessed for descriptive purposes and not in a confirmatory sense, P values were not computed, and only CIs
unadjusted for multiple comparisons are shown.
§§ The cause of death could not be determined in two cases (one in each treatment group). Both were counted as deaths from cardiovascular causes.
¶¶ Two major bleeding events were confirmed by the adjudication committee as one gastrointestinal bleeding (in the apixaban group) and one
traumatic bleeding (in the aspirin group).
NEJM EVIDENCE 7
A Composite of any Recurrent Stroke and Systemic Embolism
100% 10%
8% |||||||||||||||||||||||| ||| |
80%
Aspirin |||| ||||
| | ||| ||||||||||||||||||||||||||| || |
6% | | | | |
Cumulative Incidence (%)

| | | || || ||||||
| | |
60% | | | | Apixaban
4% | | |
| |
40% 2%
0% |
20% 0 6 12 18 24 30 36 42 48 54 60
||||| |||||||||||||||| || | || | |
| | | | | | || || | | | | | |||||| ||||||
||||||||||||||||||||||| | || ||| | | | |
| | | | | | |
| | | |
| |
0% ||
0 6 12 18 24 30 36 42 48 54 60
Time Since Randomization (Weeks)
No. at Risk
Aspirin 174 165 161 160 158 157 155 149 149 141 8
Apixaban 178 173 170 165 163 162 162 161 161 151 7
B Major and Clinically Relevant Nonmajor Bleedings

100% 10%
8%
80%
6%
Cumulative Incidence (%)
60%
||| |||| |||||||||||||||||||||||||||| ||| |
4% Aspirin
|
| | | | | | | || || ||||||||||||||||||||||||||||||||| || |
| | | | Apixaban
40% 2% | |
| || | | | | | |
0% || |
20% 0 6 12 18 24 30 36 42 48 54 60
|| || | | | | | |||||| |||||||||||||||||||||||||
||||||||| |||||||||||||||| || | || | |
|| | | | | | | | | | | | || ||| | | | |
| || | | | |
0% || |
0 6 12 18 24 30 36 42 48 54 60
Time Since Randomization (Weeks)
No. at Risk
Aspirin 174 171 167 163 161 160 159 154 154 145 7
Apixaban 178 175 173 170 169 168 166 166 165 156 8
Figure 2. Time-to-Event Curves for First Recurrent Stroke or Systemic Thromboembolism and
First Major or Clinically Relevant Nonmajor Bleeding.
Insets show the same data on an enlarged y axis. The composite of any recurrent stroke and systemic embolism is shown in Panel A.
Major and clinically relevant nonmajor bleedings are shown in Panel B.
NEJM EVIDENCE 8
Subgroup Apixaban Aspirin Odds Ratio (95% CI)
Age
<65 years 6 (58) 7 (55) 0.79 (0.24–2.54)
65 to <75 years 10 (50) 7 (58) 1.82 (0.64–5.42)
≥75 years 7 (61) 11 (43) 0.38 (0.13–1.05)
Sex
Female 11 (81) 10 (78) 1.07 (0.42–2.72)
Male 12 (88) 15 (78) 0.66 (0.28–1.52)
Creatinine clearance at baseline
<60 ml per minute 6 (35) 5 (25) 0.83 (0.22–3.22)
≥60 ml per minute 17 (134) 20 (131) 0.81 (0.39–1.62)
Time from index stroke to randomization
<8 days 13 (81) 9 (66) 1.21 (0.49–3.13)
≥8 days 10 (88) 16 (90) 0.59 (0.25–1.37)
Hypertension
No 3 (25) 3 (20) 0.77 (0.13–4.64)
Yes 20 (144) 22 (136) 0.84 (0.43–1.61)
Diabetes
No 12 (121) 19 (112) 0.54 (0.24–1.15)
Yes 11 (48) 6 (44) 1.88 (0.65–5.96)
Previous TIA or stroke
No 19 (146) 21 (130) 0.78 (0.39–1.52)
Yes 4 (23) 4 (26) 1.58 (0.24–5.51)
CAD/MI/CHF
No 22 (157) 21 (139) 0.92 (0.48–1.76)
Yes 1 (12) 4 (17) 0.29 (0.01–2.38)
History of cancer
No 21 (148) 24 (149) 0.86 (0.45–1.63)
Yes 2 (21) 1 (7) 0.63 (0.05–14.90)
CHA2DS2-VASc score
2 to 4 6 (66) 11 (70) 0.54 (0.17–1.50)
5 7 (55) 8 (50) 0.77 (0.25–2.31)
≥6 10 (48) 6 (36) 1.32 (0.44–4.25)
Patent foramen ovale
No 17 (118) 23 (128) 0.77 (0.38–1.52)
Yes 5 (42) 2 (23) 1.42 (0.28–10.50)
0.05 0.1 0.2 0.5 1.0 2.0 5.0 10.0 20.0
Apixaban Better Aspirin Better
Figure 3. Exploratory Analyses of Treatment Effects on the Primary Outcome (Any New Ischemic Lesion
on Magnetic Resonance Imaging during 12 Months of Follow-up) in Prespecified Subgroups.
The CHA2DS2-VASc score assesses the risk of ischemic stroke among participants with atrial fibrillation (according to congestive heart
failure, hypertension, age older than 75 years, diabetes, stroke or transient ischemic attack [TIA], vascular disease, age 65 to 74 years, and
sex) and ranges from zero to nine, with higher scores indicating a greater ischemic stroke risk. CAD/MI/CHF denotes coronary artery
disease/myocardial infarction/congestive heart failure; and CI, confidence interval.
compared with the aspirin group was 0.45 (95% CI, 0.13 nonmajor bleeding was consistent across subgroups (Fig. 3
to 1.60), and it was 1.04 (95% CI, 0.49 to 2.18) in partici- and Fig. S3).
pants without atrial fibrillation detected (Table S8).
PER-PROTOCOL AND SUBGROUP ANALYSES

A total of 261 participants (74.1%) completed the study Discussion
per protocol (Table S9). Results for the primary and sec- In an enriched ESUS population, the proportion of partici-
ondary outcomes in the per-protocol population were simi- pants with new ischemic lesions at 1 year was similar in the
lar to those in the primary analysis (Tables S10–S12). The direct apixaban group (13.6%) and the cardiac monitoring–
treatment effect on the primary outcome and the compos- guided aspirin group (16.0%). This was reflected by similar
ite safety outcome of major and clinically relevant recurrent stroke incidence rates of 5.7 and 5.9, respectively.
NEJM EVIDENCE 9
The incidence rates of major and clinically relevant nonma- monitoring was longer than the 30 seconds used in previ-
jor bleeding were also similar (2.9 and 4.2, respectively). ous randomized trials on prolonged cardiac monitoring
after cryptogenic stroke.4,5,23-25 This may still be too short
Our hypothesis was that apixaban treatment in all patients to imply subsequent ischemic events. In randomized trials
would be more effective than cardiac monitoring–guided including patients at high risk, oral anticoagulation was
aspirin in preventing new central nervous system ischemic not beneficial if indicated after device-detected atrial
lesions in patients with ESUS if these were further selected fibrillation episodes of 6 minutes or longer,26 and an
by factors associated with an increased risk of atrial fibril- increased thromboembolic risk was only seen if they
lation and cardioembolism. lasted 24 hours or longer.27
The high proportion of participants with new ischemic The lack of temporal relationship between stroke and pre-
lesions and embolic lesion pattern and the high incidence ceding device-detected atrial fibrillation28,29 and the low
of recurrent stroke indicate successful enrichment. stroke risk of younger patients with atrial fibrillation and
without other cardiovascular risk factors30 may imply
Our neutral results, however, are consistent with the New additional causes underlying cardioembolism other than
Approach Rivaroxaban Inhibition of Factor Xa in a Global atrial fibrillation. The Atrial Cardiopathy and Antithrom-
Trial versus Acetylsalicylic Acid to Prevent Embolism botic Drugs in Prevention after Cryptogenic Stroke ran-
in Embolic Stroke of Undetermined Source (NAVIGATE domized trial, a second randomized trial that investigated
ESUS) randomized trial and the Randomized, Double- apixaban versus aspirin in enriched ESUS, used the con-
Blind, Evaluation in Secondary Stroke Prevention Compar- cept of atrial cardiopathy as a risk factor for stroke and
ing the Efficacy and Safety of the Oral Thrombin Inhibitor was also neutral (hazard ratio for recurrent stroke, 1.00;
Dabigatran Etexilate versus Acetylsalicylic Acid in Patients 95% CI, 0.64 to 1.55).31,32
with Embolic Stroke of Undetermined Source (RE-SPECT
ESUS) trial that compared direct oral anticoagulation with Patients with patent foramen ovale have not been previ-
aspirin for unselected ESUS with lower event rates.6,7,19 ously shown to benefit from anticoagulation over aspirin.33
Accordingly, we did not observe a modulation of treat-
Ischemic lesions might not be as effectively prevented by ment effect by patent foramen ovale (Fig. 3).
anticoagulation as recurrent stroke. Despite anticoagulation,
5.5% of patients with atrial fibrillation have been reported to In ATTICUS, the incidence of major and clinically rele-
develop new ischemic lesions within 2 years (53% of which vant nonmajor bleeding was similar in both treatment
were embolic lesions).20 Although 77% of ATTICUS partici- groups and comparable with that in studies investigating
pants with new ischemic lesions had embolic lesions, we apixaban in patients with atrial fibrillation.8,34 Despite
observed no additional treatment effect with apixaban com- early initiation of study treatment (median 8 days com-
pared with aspirin. Recurrent stroke rates were also similar, pared with 37 days in NAVIGATE ESUS6 and 44 days in
but ATTICUS was not powered for this clinical outcome. RE-SPECT ESUS7), no intracranial hemorrhage occurred.
Early initiation of direct oral anticoagulants within the
Atrial fibrillation was detected in 25.3% of participants, first week after atrial fibrillation–related stroke has only
less than the anticipated 30%10 but higher than 3% in recently been shown to be safe.35,36
NAVIGATE ESUS and 1% in RE-SPECT ESUS without
mandatory systematic arrhythmia screening.6,7 The switch Our trial has limitations. ATTICUS was open label. There
of 45 participants in the aspirin group to apixaban may was no central reading for imaging before enrollment.
have reduced a possible effect size in ATTICUS. ATTICUS used new ischemic lesions on MRI as a surro-
gate for ischemic stroke because they are predictive of
Compared with atrial fibrillation that is detected during clinical stroke and occur more frequently, which permitted
initial stroke workup, later device-detected atrial fibrilla- a more efficient trial design.11 ATTICUS had a short
tion may not be as relevant to recurrent ischemic events follow-up. Post hoc analysis of RE-SPECT ESUS suggested
and the necessity of anticoagulation.21,22 that in unselected ESUS, dabigatran may have had an
effect on stroke recurrence beyond 1 year.7 The small sam-
The 2-minute atrial fibrillation threshold used in the ple size of ATTICUS resulted in an insufficient power,
95.4% of ATTICUS participants with implanted cardiac which could also be a reason analyses had not reached
NEJM EVIDENCE 10
19
statistical significance in favor of apixaban. Although Department of Neurology, Marienhospital Stuttgart, Stuttgart, Germany
20
enrollment of major stroke was allowed in ATTICUS, Department of Neurology, University Hospital Ulm, Ulm, Germany
21
most participants had mild ischemic stroke. Extrapolation Division of Vascular Neurology, Department of Neurology, University
Hospital Bonn, Bonn, Germany
of the treatment effect to major stroke is not possible. 22
Department of Radiology, Boston Medical Center, Boston
Finally, the trial population was from German centers, 23
Department of Neurology, Boston Medical Center, Boston
which have a high proportion of white participants. Gener- 24
Duke Clinical Research Institute, Durham, NC
alizability of the results to other ethnic populations may 25
Department of Neurology, Duke University School of Medicine, Dur-
not be possible (Table S2). ham, NC
26
Department of Neurology, Vanderbilt University School of Medicine,
In conclusion, direct apixaban was not superior to aspirin Nashville, TN
27
Department of Neurology, University Hospital Heidelberg, Heidelberg,
with cardiac monitoring–guided switch to apixaban after
Germany
atrial fibrillation detection in preventing new ischemic lesions 28
Department of Cardiology, Universit€
atsspital Basel, Basel, Switzerland
in an enriched ESUS population with mild ischemic stroke.
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NEJM EVIDENCE 12

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NEJM Evid 2023; 3 (1)

Apixaban versus Aspirin for Embolic Stroke of

METHODS We conducted a multicenter, randomized, open-label, blinded-outcome trial

A steering committee, supported by the Center for Clinical

1282 Were excluded

353 Underwent randomization

1 Withdrew consent immediately after

352 Were included in the

173 Received at least one dose of aspirin

2 Had no assessable baseline

Figure 1. Trial Flowchart.

SAFETY treatment at onset of bleeding events (Tables S3 and S5).

Characteristic Apixaban Group (n5178) Aspirin Group (n5174)

Apixaban Group Aspirin Group Odds Ratio or Hazard

Cumulative Incidence (%)

B Major and Clinically Relevant Nonmajor Bleedings

0.05 0.1 0.2 0.5 1.0 2.0 5.0 10.0 20.0

Apixaban Better Aspirin Better

PER-PROTOCOL AND SUBGROUP ANALYSES

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