Effect of Combined Aspirin and Extended-Release Dipyridamole Versus Clopidogrel on

Functional Outcome and Recurrence in Acute, Mild Ischemic Stroke : PRoFESS

Subgroup Analysis
Philip M.W. Bath, Daniel Cotton, Rene H. Martin, Yuko Palesch, Salim Yusuf, Ralph Sacco,
Hans-Christoph Diener, Conrado Estol and Robin Roberts
Stroke. 2010;41:732-738; originally published online February 24, 2010;
doi: 10.1161/STROKEAHA.109.564906
Stroke is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright 2010 American Heart Association, Inc. All rights reserved.
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Effect of Combined Aspirin and Extended-Release

Dipyridamole Versus Clopidogrel on Functional Outcome
and Recurrence in Acute, Mild Ischemic Stroke
PRoFESS Subgroup Analysis
Philip M.W. Bath, MD, FRCP; Daniel Cotton, MS; Renee H. Martin, PhD; Yuko Palesch, PhD;
Salim Yusuf, MB, BS, DPhil; Ralph Sacco, MD; Hans-Christoph Diener, MD, PhD;
Conrado Estol, MD, PhD; Robin Roberts, MSc; for the PRoFESS Study Group
Background and PurposeLong-term antiplatelet therapy is effective at reducing recurrence after ischemic stroke.
However, the relative safety and efficacy of combined aspirin-dipyridamole or clopidogrel are not known in patients
with acute ischemic stroke.
MethodsThe factorial PRoFESS secondary prevention trial assessed antiplatelet and blood pressurelowering strategies
in 20 332 patients, 1360 of whom were randomized within 72 hours of ischemic stroke to combined aspirin (Asp; 25
mg BID) and extended-release dipyridamole (ER-DP; 200 mg BID, n672) or clopidogrel (75 mg/d, n688). The
primary outcome for this post hoc subgroup analysis was functional outcome at 30 days; secondary outcomes included
recurrence and death by 90 days. Analyses were adjusted for baseline prognostic variables and blood pressure treatment
assignment.
ResultsPatients were representative of the whole trial (age 67 years, National Institutes of Health Stroke Scale score 3,
small-artery occlusion 59%), and baseline variables were similar between treatment groups. The mean time from stroke
to recruitment was 58 hours. By 90 days, treatment was no longer being taken in 121 (18%) patients randomized to
Asp/ER-DP and in 86 (12.5%) assigned to clopidogrel (P0.006). Combined death or dependency (shift analysis of
modified Rankin Scale score at day 30) did not differ between treatment groups (odds ratio [OR]0.97; 95% CI, 0.79
to 1.19). Nonsignificant trends to reduced recurrence (OR0.56; 95% CI, 0.26 to 1.18) and vascular events (OR0.71;
95% CI, 0.36 to 1.37) were present with Asp/ER-DP. Rates of death, major bleeding, and serious adverse events did not
differ between treatment groups.
ConclusionsTreatment with combined Asp/ER-DP vs clopidogrel in 1360 patients with acute, mild ischemic stroke did
not differ in terms of effects on functional outcome, recurrence, death, bleeding, or serious adverse events. Both
treatments were practical to administer. (Stroke. 2010;41:732-738.)
Key Words: acute stroke aspirin clopidogrel dipyridamole ischemic stroke outcome
randomized controlled trial

atients with ischemic stroke are at increased risk of

having another event, and long-term antiplatelet therapy
is effective at reducing recurrence.1 Numerous trials of
secondary prevention have shown that aspirin (Asp) reduces
recurrence by a modest (relative risk reduction 13%2) but
worthwhile degree. Other antiplatelet agents are also individually effective, including extended-release dipyridamole
(ER-DP) and clopidogrel.3,4 Although combining Asp and DP
was more effective than either agent alone,3,5 combined Asp

and clopidogrel did not offer additional benefit over either

Asp or clopidogrel alone in patients with previous stroke,
largely owing to excess bleeding.6,7
Because the risk of stroke recurrence is highest in the first
few hours and days after an acute event, early commencement
of antiplatelet therapy should be most effective, and this has
been confirmed in 2 megatrials for Asp.8,9 However, the
safety and efficacy of DP and clopidogrel in acute ischemic
stroke have not been explored in large trials, although a small

Received August 6, 2009; accepted August 25, 2009.

From the Stroke Trials Unit (P.M.W.B.), University of Nottingham, Nottingham, UK; Biostatistics Group (D.C.), Boehringer Ingelheim
Pharmaceuticals, Ridgefield, Conn; Department of Biostatistics, Bioinformatics and Epidemiology (R.H.M., Y.P.), Medical University of South Carolina,
Columbia, SC; Population Health Research Institute (S.Y.), McMaster University, Hamilton, Canada; Division of Neurology (R.S.), University of Miami,
Miami, Fla; Department of Neurology (H.-C.D.), University Duisburg-Essen, Duisburg-Essen, Germany; Neurologic Center for Treatment and Research
(C.E.), Buenos Aires, Argentina; and Department of Clinical Epidemiology (R.R.), McMaster University, Hamilton, Canada.
Correspondence to Prof Philip Bath, Division of Stroke Medicine, University of Nottingham, City Hospital Campus, Nottingham NG5 1PB, UK. E-mail
philip.bath@nottingham.ac.uk
2010 American Heart Association, Inc.
Stroke is available at http://stroke.ahajournals.org

DOI: 10.1161/STROKEAHA.109.564906

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Bath et al

Aspirin/Dipyridamole for Acute Ischemic Stroke

Table 1.

733

Patient Characteristics at Enrollment

Asp/ER-DP
(n672)

Clopidogrel
(n688)

Age, y, mean (SD)

67.2 (9.2)

66.7 (8.8)

Sex, male, n (%)

425 (63.2)

459 (66.7)

13 022 (64.0)

White

398 (59.2)

378 (54.9)

11 697 (57.5)

Asian

224 (33.3)

237 (34.5)

6660 (32.8)

Black

28 (4.2)

51 (7.4)

816 (4.0)

Other

22 (3.3)

22 (3.2)

1159 (5.7)

159 (23.7)

185 (26.9)

4997 (24.6)

Characteristic

Whole
Trial

Demographics
66.1 (8.6)

Ethnicity, n (%)

Figure 1. Patient flow through the trial.

study suggested that combined Asp and clopidogrel might be

more effective at reducing recurrence than Asp alone.10
Beneficial effects of early antiplatelet therapy may reflect
several mechanisms, including treatment of the index event
(eg, salvage of at-risk penumbra) and minimization of deterioration (secondary to thrombus extension) and early recurrence. Differential effects between antiplatelet agents might
follow from differences in their antithrombotic activity and
propensity to induce hemorrhagic transformation.
The Prevention Regimen for Effectively Avoiding Second
Strokes (PRoFESS) trial is the largest study investigating the
prevention of recurrent stroke and compared, in a factorial
design, combined Asp and ER-DP with clopidogrel, and
telmisartan (angiotensin receptor antagonist) with placebo.11
A key intention of the protocol was to recruit patients within
10 days of ischemic stroke at a time when the risk of
recurrence was particularly high11; as a result, 39.9% of
patients were recruited within 10 days of the index event.1214
Furthermore, 1366 (6.7%) patients were recruited within 72
hours of the ictus, thereby providing the opportunity to
assess, post hoc, the safety, efficacy, and tolerability of
Asp/ER-DP versus clopidogrel in patients with acute ischemic stroke in a randomized design.

Patients and Methods

The PRoFESS trial protocol11 and primary results12,13 have been
published. In brief, PRoFESS compared the effect of combined Asp
(25 mg BID) and ER-DP (200 mg BID) versus clopidogrel (75 mg
daily), and telmisartan (80 mg daily, an angiotensin receptor antagonist) versus placebo in a 22 factorial design in patients with recent
ischemic stroke. Patients (N20 332) were randomized for 34
months from 695 centers in 35 countries and were followed up for a
mean duration of 30 months. All patients received best medical care
independent of treatment assignment.

Clinical history, n (%)

Previous stroke/transient
ischemic attack
Atrial fibrillation
Hypertension

15 (2.2)

9 (1.3)

472 (70.2)

484 (70.4)

15 048 (74.0)

540 (2.7)

Hypertension, treated

359 (53.4)

369 (53.6)

12 231 (60.1)

Diabetes mellitus

188 (28.0)

186 (27.0)

5743 (28.3)

Hyperlipidemia

271 (40.3)

276 (40.1)

9493 (46.7)

94 (14.0)

105 (15.3)

3304 (16.3)

Current

163 (24.3)

173 (25.2)

4308 (21.2)

Former

240 (35.7)

221 (32.1)

7352 (36.2)

Never

269 (40.0)

294 (42.7)

8663 (42.6)

355 (52.8)

369 (53.6)

10 168 (50.0)

Ischemic heart disease

Smoker

Antiplatelet therapy
Asp
Clopidogrel

90 (13.4)

73 (10.6)

3143 (15.5)

DP

29 (4.3)

23 (3.3)

1110 (5.5)

2.4 (0.7)

2.4 (0.7)

26.9 (27.3)

6 (0.9)

5 (0.7)

Time from stroke, days

0

82 (12.2)

79 (11.5)

238 (35.4)

258 (37.5)

346 (51.5)

346 (50.3)

146 (16.2)

147 (16.3)

Clinical details
Blood pressure, mm Hg,
mean (SD)
Systolic
Diastolic
Body mass index, kg/m2,
mean (SD)

84 (10.3)

84 (10.0)

144 (16.6)
84 (10.5)

26.9 (4.7)

26.9 (4.8)

26.8 (5.0)

136 (20.2)

149 (21.7)

5805 (28.6)

TOAST classification, n (%)

Large-artery
atherosclerosis

Inclusion/Exclusion Criteria

Cardioembolism

The aim of this post hoc PRoFESS subgroup analysis was to assess
the relative safety, efficacy, and tolerability of Asp/ER-DP versus
clopidogrel in patients with acute ischemic stroke. Patients were
included if they were enrolled in the main trial and had been
randomized within 72 hours of stroke onset.11 The time of 72 hours
was chosen a priori to mirror a parallel study describing a comparison of telmisartan with placebo15 and has the advantage of including
a moderately large sample size of 1360 patients. Some of the
PRoFESS inclusion criteria are relevant specifically to assessment of
antiplatelet agents in acute stroke: ischemic stroke; symptoms
persisting for 24 hours, or if 24 hours, then computed tomographic or magnetic resonance evidence of a new stroke; hospital-

Small-artery occlusion
Other determined
etiology
Undetermined etiology
Missing

7 (1.0)

11 (1.6)

407 (60.6)

401 (58.3)

10 (1.5)

13 (1.9)

416 (2.1)

112 (16.7)

114 (16.6)

3148 (15.5)

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369 (1.8)
10 578 (52.0)

16 (0.1)
(Continued)

734

Stroke

Table 1.

April 2010

Continued

Characteristic

Asp/ER-DP
(n672)

Clopidogrel
(n688)

Whole
Trial

Table 2. Cumulative Outcome and Safety Measures at Days 7,

30, and 90 After Enrollment
Asp/ER-DP
(n672)

mRS score, n (%)

Clopidogrel
(n688)

OR (95% CI)

0 (0.0)

23 (3.3)

2.62 (1.59, 4.32)

7 days

0 (no symptoms)

86 (12.8)

71 (10.3)

2853 (14.0)

1 (no significant
disability)

235 (35.0)

263 (38.2)

7580 (37.3)

2 (slight disability)

184 (27.4)

189 (27.5)

5081 (25.0)

3 (moderate disability)

97 (14.4)

103 (15.0)

2891 (14.2)

Hemorrhagic
transformation, n (%)

4 (moderately severe
disability)

70 (10.4)

62 (9.0)

1926 (9.5)

Intracranial bleeding, n (%)

0 (0.0)

0 (0.0)

Major bleeding, n (%)

1 (0.15)

1 (0.15)

Any bleeding, n (%)

1 (0.15)

1 (0.15)

Cerebral edema, n (%)

0 (0.0)

0 (0.0)

2.13 (0.53, 8.58)

Lost to follow-up, n (%)

Ceased treatment, n (%)

5 (severe disability)

NIHSS score, mean (SD)

2.9 (2.8)

3.1 (2.9)

1 (1.0)
2.8 (2.9)

1 (0.15)
57 (8.5)
1 (0.15)

2 (0.29)

TOAST indicates Trial of ORG 10172 in Acute Stroke Treatment. Data for the
whole trial are given for comparison. Values are No. (%) or mean (SD) as
shown.

Stroke recurrence, n (%)

6 (0.89)

3 (0.44)

MI, n (%)

1 (0.15)

0 (0.0)

Combined vascular, n (%)

8 (1.19)

3 (0.44)

2.91 (0.76, 11.10)

ized; age 55 years, or 50 to 54 years if 2 additional vascular risk

factors were present; seated systolic blood pressure 121 to
180 mm Hg; seated diastolic blood pressure 110 mm Hg; and
neurologically stable.11
Key exclusion criteria were dysphagia preventing oral medication;
severe dependency at time of randomization (modified Rankin Scale
score [mRS] 3); hypersensitivity to or intolerance of any of the
interventions; currently taking or needing anticoagulation; known
current active peptic ulcer disease; known hemostatic disorder or
systemic bleeding; thrombocytopenia (platelets 100109/L or
neutropenia [1.2109/L]); known severe renal insufficiency
or renal artery stenosis; known severe coronary artery disease or
recent myocardial infarction (MI); and patient scheduled for carotid
endarterectomy.

Death, n (%)

1 (0.15)

0 (0.0)

SAEs, n (%)

13 (1.94)

9 (1.31)

1.51 (0.64, 3.56)

1 (0.15)

7.87 (0.65, 94.9)

Outcomes
The primary outcome in this post hoc subgroup analysis was
functional outcome measured by the mRS at 30 days after randomization. Functional outcome was chosen because it is the usual
measure in acute stroke trials; a more conventional trial time of 90
days (the usual time point in many acute stroke trials) was not
possible because mRS was not measured at this point. Secondary
outcomes were studied at 7, 30, and 90 days and included symptomatic hemorrhagic transformation of the infarct, cerebral edema,
recurrent stroke, MI, composite vascular events (combination of
nonfatal stroke, nonfatal MI, and vascular death), death, cognition
(Mini Mental State Examination [MMSE]), bleeding, and serious
adverse events. Where possible, ordered categorical outcomes were
analyzed with ordinal statistical approaches to improve statistical
power.16,17 Major bleeding was defined as a hemorrhagic event that
resulted in clinically significant disability, symptomatic intracranial
hemorrhage, intraocular bleeding causing loss of vision, the need for
transfusion of 2 or more units of red cells or the equivalent amount
of whole blood, or the need for hospitalization. Tolerability was
measured by adherence to therapy in the first 90 days.

30 days
Lost to follow-up, n (%)

5 (0.74)

Ceased treatment, n (%)

88 (13.1)

Data are shown as the number of subjects (%) or mean (SD).

Comparisons were performed with binary logistic regression (dichotomous data), ordinal logistic regression (ordered categorical data), or
multiple regression (continuous data). Ordinal regression assumes
that treatment effects are proportional, ie, constant across the
outcome categories. Statistical models were adjusted for the baseline
prognostic covariates of age, sex, severity (National Institutes of
Health Stroke Scale [NIHSS] score), systolic blood pressure; and
assignment to telmisartan or placebo. Analyses were not adjusted for
the change in protocol (amendment 2) from combined Asp and
clopidogrel to clopidogrel alone (enacted after the MATCH trial was
published7) because this affected only 153 (11%) patients recruited

1.66 (1.17, 2.37)

Hemorrhagic
transformation, n (%)

1 (0.15)

2 (0.29)

Intracranial bleeding, n (%)

0 (0.0)

0 (0.0)

Major bleeding, n (%)

4 (0.60)

2 (0.29)

2.20 (0.39, 12.34)

Any bleeding, n (%)

4 (0.60)

3 (0.44)

1.41 (0.31, 6.45)

mRS score 26, n (%)*

229 (35.6)

228 (34.2)

1.11 (0.86, 1.44)

Stroke recurrence, n (%)

10 (1.49)

11 (1.60)

0.95 (0.40, 2.27)

MI, n (%)
Combined vascular, n (%)

2 (0.30)

0 (0.0)

15 (2.23)

11 (1.60)

1.46 (0.66, 3.25)

Death, n (%)

5 (0.74)

1 (0.15)

SAEs, n (%)

30 (4.46)

24 (3.49)

1.30 (0.75, 2.26)

407 (66.7)

442 (69.5)

0.86 (0.67, 1.10)

MMSE 30, n (%)

90 days
Lost to follow-up, n (%)

5 (0.74)

7 (1.02)

0.77 (0.22, 2.79)

Ceased treatment, n (%)

121 (18.0)

86 (12.5)

1.51 (1.12, 2.04)

Hemorrhagic
transformation, n (%)

1 (0.15)

2 (0.29)

Intracranial bleeding, n (%)

0 (0.0)

0 (0.0)

Major bleeding, n (%)

6 (0.89)

4 (0.58)

1.61 (0.45, 5.77)

Any bleeding, n (%)

7 (1.04)

6 (0.87)

1.22 (0.41, 3.67)

11 (1.64)

20 (2.91)

0.56 (0.26, 1.18)

2 (0.30)

2 (0.29)

Stroke recurrence, n (%)

MI, n (%)
Combined vascular, n (%)

Analyses

57 (8.3)

16 (2.38)

23 (3.34)

0.71 (0.36, 1.37)

Death, n (%)

5 (0.74)

6 (0.87)

0.91 (0.24, 3.56)

SAEs, n (%)

47 (6.99)

42 (6.10)

1.14 (0.74, 1.76)

SAE indicates serious adverse event. Values are No. (%) with ORs and (95%
CI). Comparison was made by binary logistic regression or multiple regression,
with adjustment for age, sex, severity (NIHSS score), systolic blood pressure,
and assignment to telmisartan or placebo. An mRS score of 2 6 indicates a
poor outcome. Significant findings are in boldface type.
*For nonacute patients, OR1.01; 95% CI, 0.96 1.07; P0.61).
Treatment-time (acute vs nonacute) interaction, P0.74.

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Bath et al

Aspirin/Dipyridamole for Acute Ischemic Stroke

735

Figure 2. mRS scores at day

30. Comparison was made by
ordinal logistic regression.
OR0.97; 95% CI, 0.79 to
1.19; P0.75.

very early in the trial. Odds ratios (ORs) and (95% CIs) are shown,
with an OR 1 favoring Asp/ER-DP and an OR 1 supporting
clopidogrel. Statistical significance was set at P0.05. Analyses
were performed with SAS version 9.1.

Results
This subgroup analysis of the PRoFESS trial12,13 examined
the effect of Asp/ER-DP versus clopidogrel in 1360 patients
(Asp/ED-DP n672, clopidogrel n688) randomized within
72 hours of stroke onset (Figure 1). The mean time from
stroke to recruitment was 58 hours, with the majority of
patients recruited during the third day after stroke onset
(Table 1). Treatment was started within 3 days of stroke in
853 patients (63%) and within 4 days in 1250 (92%). The
characteristics of patients in this analysis were broadly
similar to those of the whole trial (Table 1). The mean age
was 67 years, 65% were male, and stroke severity was mild,
with an NIHSS score of 3. The treatment groups were similar
for demographic and clinical measures (Table 1).

Follow-Up and Adherence

Follow-up at 90 days was completed for 667 (99.3%) patients
receiving Asp/DP and for 681 (99.0%) taking clopidogrel
(Table 2, Figure 1). At day 30, data were missing for mRS
score in 50 patients (Asp/ER-DP n28, clopidogrel n22)
and for MMSE in 114 patients (Asp/ER-DP n62, clopidogrel n52). By 90 days, treatment was no longer being
taken in 121 of 672 (18.0%) patients randomized to Asp/
ER-DP nor in 86 of 688 (12.5%) of those assigned to
clopidogrel (P0.006); the explanations were treatment
never started in 19 (Asp/ER-DP n9, clopidogrel n10),
adverse reaction in 39 (Asp/ER-DP n36 [mostly headache],
clopidogrel n3), and other in 22 (Asp/ER-DP n12, clopidogrel n10).

Outcome
There was no interaction between treatment and time of
recruitment, ie, acute versus nonacute (P0.74), so
subsequent analyses focused on the acute patients only.
Combined death or dependency (mRS score at 30 days after
randomization, with adjustment for the covariates of age, sex,
systolic blood pressure, severity, and antihypertensive assignment) did not differ between Asp/ER-DP and clopidogrel,
analyzed either as an ordered categorical outcome (ordered
mRS categories 0, 1, 2, 3, and 4 to 6 to maintain proportionality)16; OR0.97; 95% CI, 0.79 to 1.19; P0.75) (Figure 2)
or with dichotomization of the data at the median (mRS 2 to
6; OR1.14; 95% CI, 0.89 to 1.47; P0.29; Table 2). For
completeness, analysis of potential interactions between the
effect of treatment and components of 9 predefined sub-

groups (by age; sex; baseline systolic blood pressure; prior

use of aspirin, dipyridamole, both, or clopidogrel; telmisartan; and TOAST) were performed on functional outcome
(Figure 3), but no interactions were present.
A trend to a reduction in stroke recurrence with Asp/
ER-DP compared with clopidogrel was present at 90 days,
whether assessed as time to event (OR0.56; 95%, CI 0.26 to
1.18; P0.12; Figure 4) or as a shift in the distribution of
ordered categorical events (fatal stroke, dependent stroke
[mRS 2 to 5], independent stroke [mRS 0, 1], transient
ischemic attack, or no cerebrovascular event)17 (OR0.75;
95% CI, 0.41 to 1.35; P0.33; Figure 5). Similarly, the rate
of vascular events was nonsignificantly lower with Asp/
ER-DP than with clopidogrel at 90 days (OR0.71; 95% CI,
0.36 to 1.37; P0.30; Table 2). Other events, ie, MI and
death, though few, did not differ between treatment groups at
90 days. There was no difference in the MMSE score at 30
days.
The rates of serious adverse events were low and similar
between Asp/ER-DP and clopidogrel groups during the first
90 days: fatal, 5 versus 6 and nonfatal, 42 versus 36. Selected
serious adverse events relevant to antiplatelet treatment included major bleeding, 6 versus 4; minor bleeding, 1 versus
2; gastrointestinal bleeding, 0 versus 0; and transfusions, 1
versus 0, respectively. No serious adverse events were reported as edema extension or cerebral hemorrhage during the
90 days.

Discussion
The aim of the present post hoc subgroup analysis was to
investigate the relative safety, efficacy, and tolerability of 2
antiplatelet regimens when started in the acute phase of
ischemic stroke. Patients (n1360) were randomized within
72 hours of the onset of ischemia, and data for these subjects
form the basis of this report. In comparison with clopidogrel,
Asp/ER-DP did not alter functional outcome (assessed with
the mRS) at 30 days. Although there were nonsignificant
trends to lower rates of recurrence and composite vascular
outcomes with Asp/ER-DP at 90 days, there were no differences between the treatment groups for MI, death, or cognition (MMSE). When adverse events were considered, no
significant differences were observed, in particular for the
rates of all serious adverse events and for major bleeding.
The overall PRoFESS trial reported that recurrence rates
were comparable between Asp/ER-DP and clopidogrel, although it is important to note that Asp-ER-DP failed to show
noninferiority to clopidogrel, the primary outcome for the
whole trial.12 In addition, Asp/ER-DP was associated with
increased intracranial bleeding and trends in major and

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736

Stroke

April 2010

Figure 3. Forrest plot showing

a good functional outcome
(mRS score0, 1) at day 30 in
prespecified subgroups of
patients categorized at baseline
according to the following variables: age (70, 70 years);
sex; systolic blood pressure
(150, 150 mm Hg); premorbid history of Asp, DP, combined Asp/DP, and clopidogrel
use; and treatment assignment
(telmisartan, placebo). *All other
etiologic subtypes included
large-artery atherosclerosis, cardioembolism, other, and undetermined etiologies.

life-threatening bleeding compared with clopidogrel.12 These

differences between the results of the main trial and the
present subgroup analysis may be due to the fact that either
the subgroup analysis was of modest size and was relatively
underpowered to compare Asp/ER-DP and clopidogrel and/or
patients with acute stroke with short-term follow-up may
differ in their responses to antiplatelet agents.

Very limited data have been published on the short-term

use of DP or clopidogrel in stroke. The FASTER pilot trial
compared combined Asp and clopidogrel with Asp alone in
392 patients with transient ischemic attack or minor ischemic
stroke.10 Compared with Asp alone, combined Asp and
clopidogrel were associated with a nonsignificant reduction
in recurrent stroke at 90 days (risk ratio0.7; 95%, CI, 0.3 to

Figure 4. KaplanMeier plot for stroke

recurrence during the first 90 days.

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Bath et al

Aspirin/Dipyridamole for Acute Ischemic Stroke

737

Figure 5. Ordinal stroke (recurrence and severity) at day 90. Comparison was made by ordinal logistic regression. OR0.75; 95% CI,
0.41 to 1.35; P0.33. Note that the majority of patients who did not have stroke or transient ischemic attack (95% of all patients) are
not shown to improve visualization of the relevant part of the figure.

1.2; P0.19)10; the rate of intracranial hemorrhage did not

differ between the groups (clopidogrel 1% vs placebo 0%,
P0.5). Earlier trials involving DP (ESPS, ESPS II, ESPRIT,
and Sprigg et al3,5,18,19) or clopidogrel (CAPRIE, MATCH,
CARESS, and CHARISMA4,6,7,20) focused on patients with
subacute or chronic stroke, and very few patients were
enrolled during the acute phase (Figure 2 in Kennedy et al10).
Hence, the present subgroup analysis represents the largest
analysis of the safety, efficacy, and tolerability of both
Asp/ER-DP and clopidogrel in acute ischemic stroke.
Several comments need to be made about this PRoFESS
analysis. First, the results come from a subgroup of patients
entered into a very large secondary prevention trial, such that
patient characteristics reflected the inclusion criteria for a
study of vascular prophylaxis rather than acute intervention.
As a result, the trial was not designed to explicitly test the
comparison of antiplatelet agents in acute ischemic stroke.
Importantly, the inclusion criteria included neurologic stability and absence of severe dependency (mRS 3), thus
explaining why patients had very mild stroke (mean NIHSS
score3). Second, no patients were recruited during the
hyperacute phase (6 hours of onset) of stroke; indeed, most
patients entered the trial on day 3 (mean time to recruitment58 hours). Third, a lower dose of Asp was used than
was tested in the IST and CAST megatrials (50 mg vs 160 to
300 mg/d).8,9 Whether this difference is important in acute
stroke is unclear, although it is not in secondary prevention.2
Fourth, no patient had dysphagia, a stroke complication that
can limit administration of oral medications. Although
ER-DP cannot be administered via nasogastric tube, liquid
DP can be used in its place during tube feeding, so the
exclusion of dysphagic patients, as in PRoFESS, need not
occur in routine clinical practice. Last, the sample size was
too small to reliably detect any differences between antiplatelet strategies on functional outcome; in this respect, it is worth
noting that it took 2 megatrials of 20 000 patients each to
demonstrate that Asp improved functional outcome after
stroke, largely through reducing early recurrence.8,9
In summary, this post hoc subgroup analysis of the PRoFESS trial involving 1360 patients was neutral and did not
identify any significant differences between Asp/ER-DP and
clopidogrel on functional outcome in patients with acute
ischemic stroke. As a result, both of the antiplatelet strategies
appear to be safe when given in the short term after mild
stroke (and possibly transient ischemic attack) and their
administration is feasible; however, the results do not apply to
patients with moderate to severe stroke because no such

patients were included. The findings should not influence

clinical practice or guidelines because they were based on a
modestly sized and selected sample of patients. The ongoing
FASTER 2 (Asp-clopidogrel vs Asp) and TARDIS (Aspclopidogrel-DP vs Asp-DP; available at www.tardistrial.org/)
trials are examining the question of antiplatelet intensity in
patients with acute transient ischemic attack or ischemic
stroke.

Acknowledgments
We thank the patients included in this substudy; the investigators
(listed in the primary trial publications12,13) who enrolled patients
shortly after stroke into PRoFESS; and Vicky Hinstridge for technical assistance. Drs Yusuf, Sacco, and Diener were co-chief
investigators of PRoFESS; Drs Bath, Estol, and Roberts were
members of the trial steering committee; and Drs Martin and Palesch
and Daniel Cotton were biostatisticians supporting the trial.

Source of Funding
Boehringer Ingelheim sponsored and funded PRoFESS and reviewed
the manuscript.

Disclosures
Drs Bath, Yusuf, Sacco, Diener, Estol, and Roberts have received
consulting and/or lecture fees from Boehringer Ingelheim; Drs
Martin and Palesch have received consulting fees from Boehringer
Ingelheim; and Daniel Cotton is an employee of Boehringer
Ingelheim.

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