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1678
© 2018 American Heart Association, Inc.
Recent clinical trial and registry data show that patients
with acute cerebral ischemic events are at high and
immediate risk of experiencing potentially more severe and
disabling recurrent ischemic events, especially strokes.1–3
Aspirin reduces the risk of subsequent stroke and death after
acute cerebral ischemia4,5 and is recommended for secondary
Continuing medical education (CME) credit is available for this article. Go to http://cme.ahajournals.org to take the quiz.
Received January 2, 2018; final revision received April 24, 2018; accepted May 14, 2018.
From the Department of Medicine and Therapeutics, Chinese University of Hong Kong, Shatin (K.S.L.W.); Department of Neurology and Stroke Centre,
Bichat Hospital, Paris Diderot University, France (P.A.); Stanford Stroke Center, Stanford University, CA (G.W.A.); Global Medicines Development,
AstraZeneca, Gothenburg, Sweden (H.D., P.H., A.H., M.K., P.L.); Department of Neurology, University of California, San Francisco (J.D.E.); Department
of Biostatistics, Harvard University, Boston, MA (S.R.E.); Department of Neurology, University of Pennsylvania, Philadelphia (S.E.K.); Department of
Cerebrovascular Medicine, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan (K.M.); Stroke Unit, Hospital Vall d’Hebron, Barcelona, Spain
(C.A.M.); Department of Neurology, Beijing Tiantan Hospital, China (Y.W.); and Dean’s Office, Dell Medical School, University of Texas at Austin (S.C.J.).
Current address for Dr Evans: Biostatistics Center, George Washington University, Washington DC, MD.
Guest Editor for this article was Markku Kaste, MD, PhD.
Presented in part at the International Stroke Conference, Houston, TX, February 22–24, 2017.
Correspondence to S. Claiborne Johnston, MD, PhD, The Dean’s Office, Dell Medical School, University of Texas at Austin, 1401 Red River, Austin,
TX 78712. E-mail clay.johnston@utexas.edu
Background and Purpose—SOCRATES (Acute Stroke or Transient Ischemic Attack Treated With Aspirin or Ticagrelor
and Patient Outcomes), comparing ticagrelor with aspirin in patients with acute cerebral ischemia, found a nonsignificant
11% relative risk reduction for stroke, myocardial infarction, or death (P=0.07). Aspirin intake before randomization
could enhance the effect of ticagrelor by conferring dual antiplatelet effect during a high-risk period for subsequent
stroke. Therefore, we explored the efficacy and safety of ticagrelor versus aspirin in the patients who received any aspirin
the week before randomization.
Methods—A prespecified subgroup analysis in SOCRATES (n=13 199), randomizing patients with acute ischemic stroke
(National Institutes of Health Stroke Scale score of ≤5) or transient ischemic attack (ABCD2 score of ≥4) to 90-day
treatment with ticagrelor or aspirin. Patients in the prior-aspirin group had received any aspirin within the week before
randomization. Primary end point was time to stroke, myocardial infarction, or death. Safety end point was PLATO
(Study of Platelet Inhibition and Patient Outcomes) major bleeding.
Results—The 4232 patients in the prior-aspirin group were older, had more vascular risk factors, and vascular disease than
the other patients. In the prior-aspirin group, the primary end point occurred in 138/2130 (6.5%) of patients on ticagrelor
and in 177/2102 (8.3%) on aspirin (hazard ratio, 0.76; 95% confidence interval, 0.61–0.95; P=0.02); in patients with no
prior-aspirin usage an event occurred in 304/4459 (6.9%) and 320/4508 (7.1%) on ticagrelor and aspirin, respectively
(hazard ratio, 0.96; 95% confidence interval, 0.82–1.12; P=0.59). The treatment-by-prior-aspirin interaction was not
statistically significant (P=0.10). In the prior-aspirin group, major bleeding occurred in 0.7% and 0.4% of patients on
ticagrelor and aspirin, respectively (hazard ratio, 1.58; 95% confidence interval, 0.68–3.65; P=0.28).
Conclusions—In this secondary analysis from SOCRATES, fewer primary end points occurred on ticagrelor treatment
than on aspirin in patients receiving aspirin before randomization, but there was no significant treatment-by-prior-aspirin
interaction. A new study will investigate the benefit-risk of combining ticagrelor and aspirin in patients with acute cerebral
ischemia (URL: https://www.clinicaltrials.gov. Unique identifier: NCT03354429).
Clinical Trial Registration—URL: https://www.clinicaltrials.gov. Unique identifier: NCT01994720.
(Stroke. 2018;49:1678-1685. DOI: 10.1161/STROKEAHA.118.020553.)
Key Words: aspirin ◼ platelet aggregation inhibitors ◼ stroke ◼ ticagrelor ◼ transient ischemic attack
Efficacy and Safety of Ticagrelor in Relation to
Aspirin Use Within the Week Before Randomization
in the SOCRATES Trial
K.S. Lawrence Wong, MD; Pierre Amarenco, MD; Gregory W. Albers, MD; Hans Denison, MD, PhD;
J. Donald Easton, MD; Scott R. Evans, PhD; Peter Held, MD, PhD;
Anders Himmelmann, MD, PhD; Scott E. Kasner, MD; Mikael Knutsson, PhD;
Per Ladenvall, MD, PhD; Kazuo Minematsu, MD, PhD; Carlos A. Molina, MD; Yongjun Wang, MD;
S. Claiborne Johnston, MD, PhD; for the SOCRATES Steering Committee and Investigators
Stroke is available at http://stroke.ahajournals.org DOI: 10.1161/STROKEAHA.118.020553
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Wong et al Acute Cerebral Ischemia: Ticagrelor/Prior Aspirin 1679
prevention.6 In the CHANCE trial (Clopidogrel in High-Risk
Patients With Acute Nondisabling Cerebrovascular Events),
dual antiplatelet therapy with clopidogrel (P2Y12 recep-
tor antagonist) and aspirin significantly reduced the risk for
stroke versus aspirin alone in a Chinese population with acute
minor stroke or transient ischemic attack (TIA).1 However, a
large unmet medical need persists for novel, effective treat-
ment options to improve outcomes among patients with acute
minor ischemic stroke and TIA, particularly given the vari-
ability in clopidogrel response.7
The SOCRATES trial (Acute Stroke or Transient Ischemic
Attack Treated With Aspirin or Ticagrelor and Patient
Outcomes) investigated whether ticagrelor, a reversibly bind-
ing, direct-acting, oral P2Y12 receptor antagonist and inhibitor
of ENT1 (type 1 equilibrative nucleoside transporter),8,9 was
superior to aspirin for prevention of the composite of stroke,
myocardial infarction, and death, when initiated within 24
hours after symptom onset in patients with acute cerebral
ischemia.10 A nonsignificant 11% relative risk reduction of the
primary end point was found in SOCRATES.3
Addition of ticagrelor for patients who received aspirin
before randomization in SOCRATES may confer the effect of
dual antiplatelet therapy since aspirin’s antiplatelet effect per-
sists during the first week when the risk of new stroke events
is highest. This prespecified analysis of SOCRATES explored
ticagrelor safety and efficacy in patients receiving aspirin
before randomization.
Methods
Data underlying the findings described in this article may be obtained
in accordance with AstraZeneca’s data sharing policy available at
https://astrazenecagrouptrials.pharmacm.com/ST/Submission/
Disclosure.
SOCRATES design and primary results have been presented
previously.3,10 The trial was approved by the relevant Institutional
Review Board/Ethics Committee at each site. Patients provided writ-
ten informed consent before any study-specific procedures were
performed.
Patients (n=13 199) with a noncardioembolic, nonsevere isch-
emic stroke (National Institutes of Health Stroke Scale score of ≤5)
or high-risk TIA (ABCD2 score of ≥4 or symptomatic ipsilateral ste-
nosis of an extra or intracranial artery) were randomized (interactive
web-based randomization system) within 24 hours of symptom onset
to double-blinded treatment with ticagrelor 180 mg loading dose
on day 1 followed by 90 mg twice daily for days 2 to 90 or aspirin
300 mg on day 1 followed by 100 mg daily for days 2 to 90.
Concomitant medication information, particularly aspirin use,
was collected; including start and stop date for medications initi-
ated or stopped during the month before randomization. The prior-
aspirin subgroup were patients receiving any aspirin within 7 days
before randomization. Atherosclerosis was assessed by atherosclero-
sis, small-vessel disease, cardiac pathology, other causes, dissection
phenotyping (ASCOD) to assign stroke cause and grade; A0=no ath-
erosclerotic disease; A1 (likely causal)=≥50% ipsilateral stenosis of
extracranial or intracranial arteries or a mobile thrombus in the aortic
arch; A2 (causal relationship possible but uncertain)=<50% stenosis
of extracranial or intracranial artery or an aortic arch plaque of >4 mm
in thickness without mobile thrombus; A3 (unlikely causal)=plaque
without stenosis or a stenosis in an artery contralateral to the cere-
bral infarct or a concomitant coronary or peripheral arterial disease;
A9=insufficient information to grade atherosclerosis (no assessment of
either intracranial arteries or extracranial arteries).11 The prior-aspirin
group was also analyzed by aspirin dose (>150 mg versus ≤150 mg),
to explore any dose-related impact on efficacy of prior-aspirin use,
and by start day of aspirin treatment as either (1) starting the day
before or the same day as randomization, representing patients
receiving an acute treatment with aspirin after onset of symptoms but
before randomization, for example, as part of prehospital emergency
care or at the emergency ward, or (2) starting earlier than the day
before randomization considered as a proxy for chronic treatment,
that is, aspirin treatment was ongoing at the time of the index event,
since the start date was out of the possible time window of 24 hours
between the start of the index event and randomization.
The primary end point for SOCRATES was the time from random-
ization to first occurrence of any event from the composite of stroke
(ischemic or hemorrhagic), myocardial infarction, or death at 90 days;
each of these components was based on standard definitions.10 An
exploratory analysis of the primary end point at 7 days was performed;
at this time point, because of platelet lifespan and renewal, any effect
of aspirin intake before randomization is expected to have disappeared
and a sufficient number of events was expected to have occurred to
make it possible to detect an early treatment effect. The secondary
efficacy end point was ischemic stroke. The primary safety end point
was PLATO (Study of Platelet Inhibition and Patient Outcomes) major
bleeding. An independent Clinical Event adjudication Committee,
blinded to study treatment, adjudicated all components of the efficacy
end point and classified all bleeding events, not considered as minimal
by the investigator, according to the PLATO bleeding definition.10,12
Statistical Methods
The prior-aspirin subgroup analysis was prespecified and explor-
atory. Efficacy analyses were based on the intention-to-treat prin-
ciple using adjudicated events and including all randomized patients.
Safety analyses of bleeding events were performed for patients
receiving at least one dose of randomized treatment. Time from
randomization to the first occurrence of any event for a given end
point was analyzed by the Cox proportional hazards model with
treatment as the only factor. Interaction between treatment assign-
ment and prior-aspirin indicator was evaluated by including terms
for treatment, prior-aspirin indicator, and treatment-by-prior-aspirin
indicator interaction in the Cox model. Interaction terms with a P
value of <0.05 were considered to be statistically significant. This
conservative approach of assessing interaction in subgroup analyses
(rather than using P<0.10) was considered appropriate, given that
the primary outcome of the SOCRATES trial was not statistically
significant (P=0.07).3
Baseline characteristics were compared for patients in the prior-
aspirin subgroup and those with no prior-aspirin usage. Categorical
variables were presented as percentages and continuous variables as
median with interquartile range or mean with SD. χ2 test and t test were
performed for comparison of categorical variables and continuous vari-
ables, respectively. P values of <0.05 were considered significant.
Results
Baseline characteristics were balanced among ticagrelor and
aspirin groups.3 Criteria for prior-aspirin usage was met in
4232 patients (ticagrelor, 2130; aspirin, 2102), whereas 8967
patients (ticagrelor, 4459; aspirin, 4508) did not use aspirin
in the 7 days before randomization (Table 1). There were
multiple differences in baseline factors among prior- and no
prior-aspirin subgroups, mainly driven by the chronic treat-
ment prior-aspirin group (Table 1). There were some patients
who had received clopidogrel before randomization (Table 1);
a sensitivity analysis excluding these patients did not impact
on the overall results of this study. The distribution of patients
with ipsilateral atherosclerotic stenosis (A1–A2) was similar
in the prior-aspirin and no prior-aspirin subgroups. However,
patients with chronic treatment in the prior-aspirin subgroup
had higher atherosclerotic burden overall (A1–A3) and higher
presence of ipsilateral stenosis versus patients with acute
treatment (Table 2).
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1680 Stroke July 2018
In the prior-aspirin group, a primary end point occurred
in 138/2130 (Kaplan-Meier%, 6.5%) patients randomized to
ticagrelor and in 177/2102 (Kaplan-Meier%, 8.3%) patients
randomized to aspirin (hazard ratio [HR], 0.76; 95% con-
fidence interval [CI], 0.61–0.95; P=0.02). For the no prior-
aspirin group, 304/4459 (Kaplan-Meier%, 6.9%) of patients
randomized to ticagrelor and 320/4508 (Kaplan-Meier%,
7.1%) of patients randomized to aspirin experienced a primary
end point (HR, 0.96; 95% CI, 0.82–1.12; P=0.59; Table 3;
Figure [A]). The treatment-by-prior-aspirin interaction did not
reach statistical significance (P=0.10). The stroke component
was the major contributor to primary end point events. There
was a consistent pattern for the effect in patients in the prior-
aspirin group randomized to ticagrelor on deaths and myocar-
dial infarctions (Table 3).
The effect on the secondary efficacy end point, ischemic
stroke, in patients with prior-aspirin usage randomized to
ticagrelor (HR, 0.78; 95% CI, 0.62–0.99; P=0.04) was consis-
tent with that on the primary end point (Table 3).
The primary end point censored at day 7 in the prior-
aspirin subgroup showed that 80/2130 (3.8%) of patients
treated with ticagrelor and 107/2102 (5.1%) treated with
Table 1. Baseline Characteristics of the Participants by Prior Aspirin
Characteristics Prior Aspirin (n=4232)
Prior Aspirin Chronic
Treatment (n=1731)
Prior Aspirin Acute
Treatment (n=2501)
No Prior Aspirin
(n=8967)
P Value (Prior Aspirin
vs No Prior Aspirin)
Age, y, mean (SD) 67.1 (11.5) 70.4 (10.4) 64.8 (11.6) 65.3 (11.2) <0.0001
Female sex, n (%) 1748 (41.3) 731 (42.2) 1017 (40.7) 3735 (41.7) 0.70
Race, n (%) <0.0001
White 3008 (71.1) 1468 (84.8) 1540 (61.6) 5776 (64.4)
Black 126 (3.0) 37 (2.1) 89 (3.6) 113 (1.3)
Asian 1039 (24.6) 197 (11.4) 842 (33.7) 2867 (32.0)
Other 59 (1.4) 29 (1.7) 30 (1.2) 211 (2.4)
Region, n (%) <0.0001
Asia and Australia 1059 (25.0) 199 (11.5) 860 (34.4) 2912 (32.5)
Europe 2415 (57.1) 1197 (69.2) 1218 (48.7) 5126 (57.2)
North America 613 (14.5) 241 (13.9) 372 (14.9) 441 (4.9)
Central and South America 145 (3.4) 94 (5.4) 51 (2.0) 488 (5.4)
Systolic BP, mm Hg, median (IQR) 150 (135–165) 150 (135–165) 150 (134–166) 150 (138–165) 0.09
Diastolic BP, mm Hg, median (IQR) 80 (74–90) 80 (73–90) 82 (74–91) 85 (80–93) <0.0001
BMI, kg/m2, median (IQR) 26.3 (23.9–29.7) 27.1 (24.2–30.5) 26.0 (23.6–29.1) 26.0 (23.4–29.1) <0.0001
History of, n (%)
Hypertension 3196 (75.5) 1523 (88.0) 1673 (66.9) 6534 (72.9) <0.01
Diabetes mellitus 1170 (27.6) 616 (35.6) 554 (22.2) 2042 (22.8) <0.0001
Dyslipidemia 2016 (47.6) 1061 (61.3) 955 (38.2) 3012 (33.6) <0.0001
Ischemic stroke 639 (15.1) 469 (27.1) 170 (6.8) 954 (10.6) <0.0001
TIA 394 (9.3) 244 (14.1) 150 (6.0) 462 (5.2) <0.0001
Myocardial infarction 312 (7.4) 235 (13.6) 77 (3.1) 236 (2.6) <0.0001
Coronary artery disease 510 (12.1) 375 (21.7) 135 (5.4) 634 (7.1) 0.0001
Congestive heart failure 136 (3.2) 105 (6.1) 31 (1.2) 346 (3.9) 0.06
Taking clopidogrel before randomization,
n (%)
209 (4.9) 80 (4.6) 129 (5.2) 247 (2.8) <0.0001
Time to randomization <12 h, n (%) 1108 (26.2) 647 (37.4) 461 (18.4) 3716 (41.4) <0.0001
Ischemic stroke as a qualifying event, n (%) 2893 (68.4) 1154 (66.7) 1739 (69.5) 6774 (75.5) <0.0001
Qualifying TIA baseline ABCD2 score of ≤5,
n (%)*
967 (72.2) 398 (69.0) 569 (74.7) 1603 (73.1) 0.55
Qualifying ischemic stroke baseline NIHSS
score of ≤3†
2092 (72.3) 800 (69.3) 1292 (74.3) 4425 (65.3) <0.0001
BMI indicates body mass index; BP, blood pressure; IQR, interquartile range; NIHSS, National Institutes of Health Stroke Scale; and TIA, transient ischemic attack.
*%Calculated based on total TIA patients.
†%Calculated on total stroke patients.
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Wong et al Acute Cerebral Ischemia: Ticagrelor/Prior Aspirin 1681
aspirin experienced a primary end point (HR, 0.73; 95% CI,
0.55–0.98; P=0.04). In the no prior-aspirin group, a primary
end point occurred within 7 days in 175/4459 (3.9%) in the
ticagrelor group and 209/4508 (4.6%) in the aspirin group
(HR, 0.84; 95% CI, 0.69–1.03; P=0.10; Figure [B]).
Table 3 shows the impact of timing and dose of prior aspi-
rin on outcome. The HR for the primary end point for patients
with prior-aspirin usage randomized to ticagrelor versus aspi-
rin was similar in patients receiving an acute treatment (HR,
0.72; 95% CI, 0.54–0.97; P=0.03) and patients on chronic
Table 2. ASCOD Atherosclerosis Grade by Prior Aspirin
ASCOD Atherosclerosis
Grade
No. of Patients, %
Prior Aspirin
(n=4232)
Prior Aspirin Chronic
Treatment (n=1731)
Prior Aspirin Acute
Treatment (n=2501)
No Prior Aspirin
(n=8967)
A0 1581 (37.4) 547 (31.6) 1034 (41.3) 3374 (37.6)
A1 384 (9.1) 152 (8.8) 232 (9.3) 736 (8.2)
A2 635 (15.0) 302 (17.4) 333 (13.3) 1326 (14.8)
A3 780 (18.4) 382 (22.1) 398 (15.9) 1116 (12.4)
A9 822 (19.4) 333 (19.2) 489 (19.6) 2372 (26.5)
Missing 30 (0.7) 15 (0.9) 15 (0.6) 43 (0.5)
A0, no atherosclerotic disease; A1 (likely causal), ≥50% ipsilateral stenosis of extracranial or intracranial arteries
or a mobile thrombus in the aortic arch; A2 (causal relationship possible but uncertain), <50% stenosis of extracranial
or intracranial artery or an aortic arch plaque of >4 mm in thickness without mobile thrombus; A3 (unlikely causal),
plaque without stenosis or a stenosis in an artery contralateral to the cerebral infarct or a concomitant coronary or
peripheral arterial disease; A9, insufficient information to grade atherosclerosis (no assessment of either intracranial
arteries or extracranial arteries).11 ASCOD indicates Atherosclerosis, Small-Vessel Disease, Cardiac Pathology, Other
Causes, Dissection.
Table 3. Efficacy Outcome by Prior-Aspirin Subgroup
Efficacy Outcome Prior Aspirin*
Ticagrelor 90 mg bd (n=6589) Aspirin 100 mg OD (n=6610)
HR (95% CI) P Value
P Value
Interaction‡n
Patients With
Events, % KM%† n
Patients With
Events, % KM%†
Composite of stroke/
MI/death
Yes 2130 138 (6.5) 6.5 2102 177 (8.4) 8.3 0.76 (0.61–0.95) 0.02 0.10
No 4459 304 (6.8) 6.9 4508 320 (7.1) 7.1 0.96 (0.82–1.12) 0.59
Prior-aspirin therapy, by
start day*
Chronic
treatment§
890 58 (6.5) 6.6 841 66 (7.8) 7.4 0.82 (0.58–1.17) 0.27 0.58
Acute
treatment‖
1240 80 (6.5) 6.5 1261 111 (8.8) 8.8 0.72 (0.54–0.97) 0.03
Prior-aspirin therapy,
by dose*
Dose >150
mg
792 51 (6.4) 6.5 796 64 (8.0) 8.0 0.80 (0.55–1.15) 0.23 0.74
Dose ≤150
mg
1338 87 (6.5) 6.6 1306 113 (8.7) 8.4 0.74 (0.56–0.98) 0.03
Stroke Yes 2130 126 (5.9) 6.0 2102 154 (7.3) 7.2 0.80 (0.63–1.01) 0.06 0.41
No 4459 264 (5.9) 6.0 4508 296 (6.6) 6.6 0.90 (0.76–1.06) 0.21
MI Yes 2130 8 (0.4) 0.4 2102 10 (0.5) 0.5 0.79 (0.31–1.99) 0.61 0.26
No 4459 17 (0.4) 0.4 4508 11 (0.2) 0.3 1.57 (0.73–3.35) 0.25
Death Yes 2130 16 (0.8) 0.8 2102 25 (1.2) 1.2 0.63 (0.34–1.18) 0.15 0.02
No 4459 52 (1.2) 1.2 4508 33 (0.7) 0.7 1.60 (1.03–2.47) 0.04
Ischemic stroke Yes 2130 123 (5.8) 5.8 2102 153 (7.3) 7.1 0.78 (0.62–0.99) 0.04 0.29
No 4459 262 (5.9) 5.9 4508 288 (6.4) 6.4 0.92 (0.78–1.08) 0.31
bd indicates twice daily; CI, confidence interval; HR, hazard ratio; KM, Kaplan-Meier; MI, myocardial infarction; and OD, once daily.
*Patients in the prior-aspirin subgroup had received aspirin within 7 d before randomization.
†Kaplan-Meier %; the event rate at 90 d.
‡Interaction between treatment assignment and prior aspirin indicator was evaluated by including terms for treatment, prior-aspirin indicator, and treatment-by-
prior-aspirin indicator interaction in the Cox model (P<0.05 was considered statistically significant).
§Start of treatment occurring earlier than the day before randomization.
‖Start of treatment occurring the day before or the same day as randomization.
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1682 Stroke July 2018
treatment (HR, 0.82; 95% CI, 0.58–1.17; P=0.27); P value for
interaction was 0.58.
In the prior-aspirin group, major bleeding occurred in
0.7% of patients randomized to ticagrelor and in 0.4% ran-
domized to aspirin (HR, 1.58; 95% CI, 0.68–3.65; P=0.28),
with no increase of life-threatening bleedings, including
intracranial bleedings (Table 4). The combination of major or
minor bleedings in the prior-aspirin group was more common
among patients randomized to ticagrelor versus aspirin (HR,
1.76; 95% CI, 1.09–2.85; P=0.02).
Discussion
In this prespecified exploratory analysis of SOCRATES, there
was a trend toward a better treatment effect of ticagrelor over
aspirin in patients who received aspirin in the 7 days before
randomization, although the interaction for treatment by prior
aspirin was not statistically significant when using the con-
servative threshold of P<0.05. Power to detect an interaction
effect is generally less than that for the main effect. Failure
to identify significant interaction does not imply homogene-
ity of effects and could be because of low power. In fact, the
Figure. Kaplan-Meier curves for the primary end point (time to stroke, myocardial infarction, or death) in patients randomized to the aspirin or ticagrelor
groups with or without taking aspirin before randomization: (A) full 90-d treatment period; (B) censored at 7 d. bd indicates twice daily; CI, confidence interval;
HR, hazard ratio; and od, once daily.
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Wong et al Acute Cerebral Ischemia: Ticagrelor/Prior Aspirin 1683
differences in the magnitude of subgroup-specific treatment
effects (HR=0.76 in the prior-aspirin group versus HR=0.96
in no prior-aspirin group) suggests a degree of treatment effect
heterogeneity. However, results from subgroup analyses must
be interpreted with caution because these can increase both
false-positive and false-negative errors. Therefore, the obser-
vation in this study should primarily be hypothesis-generating
with necessary confirmation coming from a future study.
Interestingly, a recent publication based on reanalyses of
clinical trial data with aspirin versus control in acute minor
stroke and TIA demonstrated that aspirin substantially reduces
the risk of early recurrent stroke and reduces disability after
recurrent stroke.13 Thus, aspirin’s preventive effect in the early
period after acute cerebral ischemic events may be substan-
tial, and a residual aspirin effect during the first week of treat-
ment in SOCRATES may have provided additional benefit to
ticagrelor, by conferring partial dual antiplatelet therapy.
An enhanced antiplatelet effect of clopidogrel with aspirin
was seen in several studies. Studies investigating microem-
bolization from atherosclerotic cerebral arteries in connec-
tion with acute cerebral ischemic events showed a reduction
in events with dual antiplatelet therapy.14,15 Furthermore,
the CHANCE trial of Chinese patients with minor ischemic
stroke or TIA found a 32% relative risk reduction of a stroke at
90 days with a regimen including clopidogrel with aspirin ver-
sus one that included only aspirin.1 The ongoing POINT trial
(Platelet-Oriented Inhibition in New TIA and Minor Ischemic
Stroke) is investigating whether the promising results of clopi-
dogrel and aspirin versus aspirin in acute cerebral ischemic
events demonstrated in CHANCE could be confirmed in a
Western population.16
The higher vascular disease burden in the prior-aspirin
group may reflect that aspirin was used more frequently for
prevention of atherothrombotic diseases in this subgroup.
Potentially, patients with a higher vascular event risk in the
prior-aspirin group, and with the index event occurring dur-
ing aspirin treatment (breakthrough stroke), may have ben-
efited more from intense antiplatelet therapy provided by
ticagrelor.17 However, a large proportion of patients in the
prior-aspirin group only received acute treatment before ran-
domization, thus most likely after the start of the index event,
and these patients benefited from ticagrelor at least as much
as those with aspirin chronic treatment before randomiza-
tion. Diminishing clinical effect of aspirin with long-term use
has been hypothesized and could explain higher event rates
in those previously taking aspirin who were randomized to
aspirin and a trend toward better treatment effect of ticagre-
lor13,17; however, this would not explain the similar effect seen
in those who received only acute aspirin treatment before
randomization. The observation that patients who received
only acute treatment with aspirin after the index event had a
favorable outcome may indicate the benefit of dual antiplate-
let with ticagrelor and aspirin in the acute setting of cerebral
ischemic events. Finally, atherosclerotic phenotyping could
not confirm an increased prevalence of ipsilateral atheroscle-
rotic stenosis in the prior-aspirin group; a higher prevalence
of ipsilateral atherosclerotic stenosis could have rendered this
subgroup more responsive to ticagrelor, as shown in a recent
SOCRATES publication.18 Although atherosclerotic pheno-
type was more common in the chronic treatment than in the
acute treatment prior-aspirin group, this difference did not
translate into a differentiated treatment effect.
Taking all these findings together, it is reasonable to
assume that the initial dual antiplatelet effect from aspirin
intake 7 days before randomization during the period with the
highest risk for new stroke events was the major contributor to
Table 4. Safety Outcomes by Prior-Aspirin Subgroup
Safety Outcomes*
Prior Aspirin
Ticagrelor 90 mg bid (n=6549) Aspirin 100 mg OD (n=6581)
HR (95% CI) P Value
P Value
Interaction‡
Bleeding According
to PLATO Bleeding
Definition n
Patients With
Events, % KM%† n
Patients With
Events (%) KM%†
Major Yes 2107 14 (0.7) 0.7 2083 9 (0.4) 0.4 1.58 (0.68–3.65) 0.28 0.07
No 4442 17 (0.4) 0.4 4498 29 (0.6) 0.7 0.60 (0.33–1.09) 0.09
Major, fatal/life-
threatening
Yes 2107 7 (0.3) 2083 7 (0.3)
No 4442 15 (0.3) 0.4 4498 20 (0.4) 0.5 0.77 (0.39–1.50) 0.44
Fatal bleeding Yes 2107 1 (0) 2083 1 (0)
No 4442 8 (0.2) 4498 3 (0.1)
Intracranial
hemorrhage
Yes 2107 4 (0.2) 2083 4 (0.2)
No 4442 8 (0.2) 0.2 4498 14 (0.3) 0.3 0.58 (0.25–1.39) 0.23
Major, other Yes 2107 7 (0.3) 2083 2 (0.1)
No 4442 2 (0) 4498 9 (0.2)
Major or minor Yes 2107 45 (2.1) 2.3 2083 26 (1.2) 1.2 1.76 (1.09–2.85) 0.02 0.14
No 4442 61 (1.4) 1.4 4498 56 (1.2) 1.3 1.12 (0.78–1.60) 0.55
bid indicates twice daily; CI, confidence interval; HR, hazard ratio; KM, Kaplan-Meier; and OD, once daily.
*Safety analysis set.
†Kaplan-Meier %, the event rate at 90 d.
‡Kaplan-Meier %, hazard ratio, and 95% confidence intervals were not calculated if the total number of events was <15.
by guest on July 1, 2018http://stroke.ahajournals.org/Downloaded from
1684 Stroke July 2018
the potential treatment effect of ticagrelor in the prior-aspirin
group, observed in the 7-day analysis, as well as at 90 days.
In a secondary publication from the PEGASUS-TIMI 54
trial (Prevention of Cardiovascular Events in Patients With
Prior Heart Attack Using Ticagrelor Compared to Placebo
on a Background of Aspirin-Thrombolysis In Myocardial
Infarction 54), addition of ticagrelor to aspirin for long-term
secondary prevention in patients with coronary disease pro-
vided a significant relative risk reduction of stroke by 25%,
but with more major bleeding (HR, 2.32; 95% CI, 1.68–3.21;
P<0.001).19 In CHANCE, major bleeding event rates were
similar for aspirin alone and the combination of clopidogrel
and aspirin.1 In SOCRATES, the number of major bleed-
ing events were few and similar for ticagrelor and aspirin.12
Overall, major or minor bleeding tended to be more common
on ticagrelor than aspirin in the prior-aspirin group, which
may reflect a more pronounced antiplatelet effect, whereas
severe, life-threatening bleeding rates were not.
Although this global data set is of reasonable size to jus-
tify subgroup analyses, the results from these analyses should
be interpreted with caution for several reasons. The primary
outcome in SOCRATES was not statistically significant. The
prior-aspirin usage was not randomly assigned and there were
differences in baseline factors among the subgroups; however,
the key comparator of interest was randomized: treatment with
ticagrelor or aspirin. In addition, the effect of aspirin intake
before randomization would gradually disappear during the
first treatment week, providing only a partial dual antiplate-
let therapy in the ticagrelor prior-aspirin subgroup. Therefore,
the findings about bleeding risk and efficacy of combining
ticagrelor and aspirin versus aspirin alone in patients with
acute stroke or TIA need to be confirmed in a randomized trial.
In conclusion, the results of the present analyses and the
literature on dual antiplatelet therapy in patients with acute
cerebral ischemic events support the hypothesis that the com-
bination of ticagrelor and aspirin may be a more effective treat-
ment than aspirin alone in preventing subsequent ischemic
events in patients with acute minor ischemic stroke or TIA.
This hypothesis will be addressed in the THALES trial (Acute
Stroke or Transient Ischemic Attack Treated With Ticagrelor
and ASA for Prevention of Stroke and Death; URL: http://
www.clinicaltrials.gov. Unique identifier: NCT03354429).
Acknowledgments
Editorial support (formatting tables and figures, coordinating
reviews, and preparing the article for submission) was provided by
Jackie Phillipson (Zoetic Science, an Ashfield company, part of UDG
Healthcare plc, Macclesfield, United Kingdom); this assistance was
funded by AstraZeneca.
Sources of Funding
The trial was funded by AstraZeneca.
Disclosures
Dr Wong reports honoraria as a member of a steering committee for
Johnson & Johnson, AstraZeneca (modest), and Bayer (modest); hono-
raria for participation in clinical trials, contributions to advisory boards,
or oral presentations from Bayer (modest), Sanofi-Aventis (modest),
Bristol-Myers Squibb, Boehringer Ingelheim (modest), and Pfizer
(modest). Dr Amarenco reports receipt of significant research grant
support from AstraZeneca, Sanofi, and Bristol-Myers Squibb (for http://
www.TIAregistry.org), the French Government and Pfizer (for the TST
trial [Treat Stroke to Target]), and Boston Scientific (for the WATCH-AF
registry [Warfarin Aspirin Ten(X)-a Inhibitors LAA Closure in Cerebral
Infarct and Hemorrhage and AF registry]). He has received modest con-
sultant/advisory board fees from Amgen and Bristol-Myers Squibb. He
has also received modest honoraria from Amgen (speaker activities),
Pfizer (Studies of PCSK9 Inhibition and the Reduction of Vascular
Events program Executive Committee), AstraZeneca (SOCRATES
trial [Acute Stroke or Transient Ischemic Attack Treated With Aspirin
or Ticagrelor and Patient Outcomes] Executive Committee), and Kowa
(PROMINENT [Pemafibrate to Reduce Cardiovascular Outcomes by
Reducing Triglycerides in Patients With Diabetes study] Executive
committee), and significant honoraria from Bayer (XANTUS
[Xarelto® for Prevention of Stroke in Patients With Atrial Fibrillation
study] Executive Committee), AstraZeneca (THALES [Acute Stroke
or Transient Ischemic Attack Treated With Ticagrelor and ASA for
Prevention of Stroke and Death trial] Executive Committee), and
Fibrogen (ALPINE program trials Data and Safety Monitoring Board
member). Dr Albers reports equity interest and consulting fees from
iSchemaView (significant), and consultant fees from Janssen (mod-
est). Drs Denison, Held, Himmelmann, Knutsson, and Ladenvall are
employees of AstraZeneca (all significant). Dr Easton received research
grant support from AstraZeneca (significant) for the SOCRATES trial
(URL: http://www.clinicaltrials.gov. Unique identifier: NCT01994720)
and receives research support (significant) from the National Institutes
of Health (NIH)/National Institute of Neurological Disorders and Stroke
as a coprincipal investigator for the POINT trial (Platelet-Oriented
Inhibition in New TIA and Minor Ischemic Stroke; U01 NS062835-
01A1); POINT received some free study drug and placebo from Sanofi
(URL: http://www.clinicaltrials.gov. Unique identifier: NCT00991029).
He also receives support (modest) from Boehringer Ingelheim as a
consultant for the planning and conduct of the RE-SPECT ESUS trial
(Dabigatran Etexilate for Secondary Stroke Prevention in Patients With
Embolic Stroke of Undetermined Source; URL: http://www.clinical-
trials.gov. Unique identifier: NCT02239120). Dr Evans is a statistical
consultant to AstraZeneca (significant). Dr Kasner reports a grant from
Astra Zeneca during the conduct of this study; as well as grants from
Bayer (significant), Bristol Myers Squibb, WL Gore (significant), and
Acorda (all others modest); consulting fees from Merck, Boehringer
Ingelheim, Abbvie, Medtronic, and Johnson & Johnson (modest), out-
side the submitted work. Dr Minematsu reports honoraria (all modest
for seminar presentations) from Bayer Yakuhin, Otsuka Pharmaceutical,
Boehringer Ingelheim, AstraZeneca, Pfizer, Mitsubishi Tanabe Pharma
Cooperation, Japan Stryker, Kowa, Nihon Medi-Physics Co, BMS,
Sumitomo Dainippon Pharma Co, Daiichi Sankyo, Asteras Pharma,
and immediate family members have received modest honoraria from
Nippon Chemiphar. He has also received modest honoraria (for a
supervising brochure) from Sawai Pharmaceuticals, and modest fees
(advisory board) from CSL Behring and Medico’s Hirata. Dr Molina
serves in the Steering Committee (significant) of CLOTBUST-ER
trial (Combined Lysis of Thrombus With Ultrasound and Systemic
Tissue Plasminogen Activator for Emergent Revascularization in Acute
Ischemic Stroke; Cerevast); SOCRATES (AstraZeneca), IMPACT-24b
(Implant Augmenting Cerebral Blood Flow Trial 24 Hours From Stroke
Onset; Brainsgate), REVASCAT (Endovascular Revascularization With
Solitaire Device Versus Best Medical Therapy in Anterior Circulation
Stroke Within 8 Hours trial; Fundació Ictus Malaltia Vascular). He
has received honoraria for participation in clinical trials, contribution
to advisory boards, or oral presentations from AstraZeneca (modest),
Boehringer Ingelheim, Daiichi Sankyo, BMS, Covidien, Cerevast,
Brainsgate. Dr Molina has no ownership interest and does not own
stocks of any pharmaceutical or medical device company. Dr Wang
reports research grant support from AstraZeneca (modest). Dr Johnston
reports receiving research grants from the National Institutes of
Neurological Disorders and Stroke and NIH. His institution has received
research support from AstraZeneca. He has received research support
from Biogen (consulting agreement and compensation agreement—
both significant), and was a consultant to AstraZeneca as the Committee
Chair (significant) for SOCRATES. He has also received travel and
hotel expenses from AstraZeneca to attend meetings.
by guest on July 1, 2018http://stroke.ahajournals.org/Downloaded from
Wong et al Acute Cerebral Ischemia: Ticagrelor/Prior Aspirin 1685
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for the SOCRATES Steering Committee and Investigators
Ladenvall, Kazuo Minematsu, Carlos A. Molina, Yongjun Wang and S. Claiborne Johnston
Scott R. Evans, Peter Held, Anders Himmelmann, Scott E. Kasner, Mikael Knutsson, Per
K.S. Lawrence Wong, Pierre Amarenco, Gregory W. Albers, Hans Denison, J. Donald Easton,
Randomization in the SOCRATES Trial
Efficacy and Safety of Ticagrelor in Relation to Aspirin Use Within the Week Before
Print ISSN: 0039-2499. Online ISSN: 1524-4628
Copyright © 2018 American Heart Association, Inc. All rights reserved.
is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231Stroke
doi: 10.1161/STROKEAHA.118.020553
2018;49:1678-1685; originally published online June 18, 2018;Stroke.
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