Stroke-2010-Bath-732-8

8/10/2019 Stroke-2010-Bath-732-8

1/8

Hans-Christoph Diener, Conrado Estol and Robin RobertsPhilip M.W. Bath, Daniel Cotton, Rene H. Martin, Yuko Palesch, Salim Yusuf, Ralph Sacco,

Subgroup AnalysisFunctional Outcome and Recurrence in Acute, Mild Ischemic Stroke : PRoFESS

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

Print ISSN: 0039-2499. Online ISSN: 1524-4628Copyright 2010 American Heart Association, Inc. All rights reserved.

is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231Strokedoi: 10.1161/STROKEAHA.109.564906

2010;41:732-738; originally published online February 24, 2010;Stroke.

http://stroke.ahajournals.org/content/41/4/732

World Wide Web at:The online version of this article, along with updated information and services, is located on the

http://stroke.ahajournals.org//subscriptions/is online at:StrokeInformation about subscribing toSubscriptions:

http://www.lww.com/reprints

Information about reprints can be found online at:Reprints:

document.Permissions and Rights Question and Answerprocess is available in theRequest Permissions in the middle column of the Web page under Services. Further information about thisOnce the online version of the published article for which permission is being requested is located, click

can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office.StrokeinRequests for permissions to reproduce figures, tables, or portions of articles originally publishedPermissions:

by guest on May 26, 2013http://stroke.ahajournals.org/Downloaded from
http://stroke.ahajournals.org/content/41/4/732http://stroke.ahajournals.org//subscriptions/http://stroke.ahajournals.org//subscriptions/http://stroke.ahajournals.org//subscriptions/http://www.lww.com/reprintshttp://www.lww.com/reprintshttp://www.lww.com/reprintshttp://www.ahajournals.org/site/rights/http://www.ahajournals.org/site/rights/http://stroke.ahajournals.org/http://stroke.ahajournals.org/http://stroke.ahajournals.org/http://stroke.ahajournals.org/http://stroke.ahajournals.org//subscriptions/http://www.lww.com/reprintshttp://www.ahajournals.org/site/rights/http://stroke.ahajournals.org/content/41/4/732

8/10/2019 Stroke-2010-Bath-732-8

2/8

Effect of Combined Aspirin and Extended-ReleaseDipyridamole 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, n

672) or clopidogrel (75 mg/d, n

688). Theprimary 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

Patients with ischemic stroke are at increased risk ofhaving another event, and long-term antiplatelet therapyis 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 indi-vidually 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 hasbeen 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 IngelheimPharmaceuticals, 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

[email protected] 2010 American Heart Association, Inc.

Stroke is available at http://stroke.ahajournals.org DOI: 10.1161/STROKEAHA.109.564906

732 by guest on May 26, 2013http://stroke.ahajournals.org/Downloaded from
http://stroke.ahajournals.org/http://stroke.ahajournals.org/http://stroke.ahajournals.org/http://stroke.ahajournals.org/http://stroke.ahajournals.org/

8/10/2019 Stroke-2010-Bath-732-8

3/8

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 dete-

rioration (secondary to thrombus extension) and early recur-rence. 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 ische-

mic stroke in a randomized design.

Patients and MethodsThe PRoFESS trial protocol11 and primary results12,13 have beenpublished. In brief, PRoFESS compared the effect of combined Asp

(25 mg BID) and ER-DP (200 mg BID) versus clopidogrel (75 mgdaily), and telmisartan (80 mg daily, an angiotensin receptor antag-onist) 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 amean duration of 30 months. All patients received best medical careindependent of treatment assignment.

Inclusion/Exclusion CriteriaThe aim of this post hoc PRoFESS subgroup analysis was to assessthe relative safety, efficacy, and tolerability of Asp/ER-DP versusclopidogrel in patients with acute ischemic stroke. Patients wereincluded if they were enrolled in the main trial and had been

randomized within 72 hours of stroke onset.11 The time of 72 hourswas chosen a priori to mirror a parallel study describing a compar-ison of telmisartan with placebo15 and has the advantage of including

a moderately large sample size of 1360 patients. Some of thePRoFESS inclusion criteria are relevant specifically to assessment ofantiplatelet agents in acute stroke: ischemic stroke; symptoms

persisting for 24 hours, or if 24 hours, then computed tomo-graphic or magnetic resonance evidence of a new stroke; hospital-

Figure 1. Patient flow through the trial.

Table 1. Patient Characteristics at Enrollment

Characteristic

Asp/ER-DP

(n672)

Clopidogrel

(n688)

Whole

Trial

Demographics

Age, y, mean (SD) 67.2 (9.2) 66.7 (8.8) 66.1 (8.6)

Sex, male, n (%) 425 (63.2) 459 (66.7) 13 022 (64.0)

Ethnicity, n (%)

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)

Clinical history, n (%)

Previous stroke/transient

ischemic attack

159 (23.7) 185 (26.9) 4997 (24.6)

Atrial fibrillation 15 (2.2) 9 (1.3) 540 (2.7)

Hypertension 472 (70.2) 484 (70.4) 15 048 (74.0)

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)

Ischemic heart disease 94 (14.0) 105 (15.3) 3304 (16.3)

Smoker

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)

Antiplatelet therapy

Asp 355 (52.8) 369 (53.6) 10 168 (50.0)

Clopidogrel 90 (13.4) 73 (10.6) 3143 (15.5)

DP 29 (4.3) 23 (3.3) 1110 (5.5)

Time from stroke, days 2.4 (0.7) 2.4 (0.7) 26.9 (27.3)

0 6 (0.9) 5 (0.7)

1 82 (12.2) 79 (11.5)

2 238 (35.4) 258 (37.5)

3 346 (51.5) 346 (50.3)

Clinical details

Blood pressure, mm Hg,

mean (SD)

Systolic 146 (16.2) 147 (16.3) 144 (16.6)

Diastolic 84 (10.3) 84 (10.0) 84 (10.5)

Body mass index, kg/m2,

mean (SD)

26.9 (4.7) 26.9 (4.8) 26.8 (5.0)

TOAST classification, n (%)Large-artery

atherosclerosis

136 (20.2) 149 (21.7) 5805 (28.6)

Cardioembolism 7 (1.0) 11 (1.6) 369 (1.8)

Small-artery occlusion 407 (60.6) 401 (58.3) 10 578 (52.0)

Other determined

etiology

10 (1.5) 13 (1.9) 416 (2.1)

Undetermined etiology 112 (16.7) 114 (16.6) 3148 (15.5)

Missing 16 (0.1)

(Continued)

Bath et al Aspirin/Dipyridamole for Acute Ischemic Stroke 733

http://stroke.ahajournals.org/http://stroke.ahajournals.org/http://stroke.ahajournals.org/http://stroke.ahajournals.org/

8/10/2019 Stroke-2010-Bath-732-8

4/8

ized; age 55 years, or 50 to 54 years if 2 additional vascular riskfactors were present; seated systolic blood pressure 121 to180 mm Hg; seated diastolic blood pressure 110 mm Hg; andneurologically stable.11

Key exclusion criteria were dysphagia preventing oral medication;severe dependency at time of randomization (modified Rankin Scalescore [mRS] 3); hypersensitivity to or intolerance of any of theinterventions; currently taking or needing anticoagulation; knowncurrent active peptic ulcer disease; known hemostatic disorder orsystemic bleeding; thrombocytopenia (platelets 100109/L orneutropenia [1.2109/L]); known severe renal insufficie ncyor renal artery stenosis; known severe coronary artery disease orrecent myocardial infarction (MI); and patient scheduled for carotidendarterectomy.

OutcomesThe primary outcome in this post hoc subgroup analysis wasfunctional outcome measured by the mRS at 30 days after random-ization. Functional outcome was chosen because it is the usualmeasure in acute stroke trials; a more conventional trial time of 90days (the usual time point in many acute stroke trials) was notpossible because mRS was not measured at this point. Secondaryoutcomes were studied at 7, 30, and 90 days and included symptom-atic hemorrhagic transformation of the infarct, cerebral edema,recurrent stroke, MI, composite vascular events (combination ofnonfatal stroke, nonfatal MI, and vascular death), death, cognition(Mini Mental State Examination [MMSE]), bleeding, and seriousadverse events. Where possible, ordered categorical outcomes wereanalyzed with ordinal statistical approaches to improve statisticalpower.16,17 Major bleeding was defined as a hemorrhagic event thatresulted in clinically significant disability, symptomatic intracranialhemorrhage, intraocular bleeding causing loss of vision, the need for

transfusion of 2 or more units of red cells or the equivalent amountof whole blood, or the need for hospitalization. Tolerability wasmeasured by adherence to therapy in the first 90 days.

AnalysesData are shown as the number of subjects (%) or mean (SD).Comparisons were performed with binary logistic regression (dichot-omous data), ordinal logistic regression (ordered categorical data), ormultiple regression (continuous data). Ordinal regression assumesthat treatment effects are proportional, ie, constant across theoutcome categories. Statistical models were adjusted for the baselineprognostic covariates of age, sex, severity (National Institutes ofHealth Stroke Scale [NIHSS] score), systolic blood pressure; andassignment to telmisartan or placebo. Analyses were not adjusted forthe change in protocol (amendment 2) from combined Asp and

clopidogrel to clopidogrel alone (enacted after the MATCH trial waspublished7) because this affected only 153 (11%) patients recruited

Table 1. Continued

Characteristic

Asp/ER-DP

(n672)

Clopidogrel

(n688)

Whole

Trial

mRS score, n (%)

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 disabi lity) 184 (27.4) 189 (27.5) 5081 (25.0)

3 (moderate disability) 97 (14.4) 103 (15.0) 2891 (14.2)

4 (moderately severe

disability)

70 (10.4) 62 (9.0) 1926 (9.5)

5 (severe disability) 1 (1.0)

NIHSS score, mean (SD) 2.9 (2.8) 3.1 (2.9) 2.8 (2.9)

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.

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

30, and 90 After Enrollment

Asp/ER-DP

(n672)

Clopidogrel

(n688) OR (95% CI)

7 days

Lost to follow-up, n (%) 1 (0.15) 0 (0.0)

Ceased treatment, n (%) 57 (8.5) 23 (3.3) 2.62 (1.59, 4.32)

Hemorrhagic

transformation, n (%)

1 (0.15) 2 (0.29)

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)

Stroke recurrence, n (%) 6 (0.89) 3 (0.44) 2.13 (0.53, 8.58)

MI, n (%) 1 (0.15) 0 (0.0)

Combined vascular, n (%) 8 (1.19) 3 (0.44) 2.91 (0.76, 11.10)

Death, n (%) 1 (0.15) 0 (0.0)

SAEs, n (%) 13 (1.94) 9 (1.31) 1.51 (0.64, 3.56)

30 days

Lost to follow-up, n (%) 5 (0.74) 1 (0.15) 7.87 (0.65, 94.9)


Hemorrhagic


1 (0.15) 2 (0.29)


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)


MI, n (%) 2 (0.30) 0 (0.0)


Death, n (%) 5 (0.74) 1 (0.15)

SAEs, n (%) 30 (4.46) 24 (3.49) 1.30 (0.75, 2.26)

MMSE 30, n (%) 407 (66.7) 442 (69.5) 0.86 (0.67, 1.10)

90 days

Lost to follow-up, n (%) 5 (0.74) 7 (1.02) 0.77 (0.22, 2.79)


Hemorrhagic


1 (0.15) 2 (0.29)


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)


MI, n (%) 2 (0.30) 2 (0.29)


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 26 indicates a

poor outcome. Significant findings are in boldface type.

*For nonacute patients, OR1.01; 95% CI, 0.961.07; P0.61).

Treatment-time (acute vs nonacute) interaction, P0.74.

734 Stroke April 2010


8/10/2019 Stroke-2010-Bath-732-8

5/8

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 supportingclopidogrel. Statistical significance was set at P0.05. Analyseswere performed with SAS version 9.1.

ResultsThis 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 ofpatients 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 AdherenceFollow-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 mRSscore in 50 patients (Asp/ER-DP n28, clopidogrel n22)

and for MMSE in 114 patients (Asp/ER-DP n62, clopi-

dogrel 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, clopi-

dogrel n10).

OutcomeThere 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 assign-

ment) 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 proportion-

ality)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 theeffect of treatment and components of 9 predefined sub-

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

use of aspirin, dipyridamole, both, or clopidogrel; telmisar-

tan; 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], transientischemic 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 in-

cluded major bleeding, 6 versus 4; minor bleeding, 1 versus2; gastrointestinal bleeding, 0 versus 0; and transfusions, 1

versus 0, respectively. No serious adverse events were re-

ported as edema extension or cerebral hemorrhage during the

90 days.

DiscussionThe 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 differ-

ences between the treatment groups for MI, death, or cogni-

tion (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, al-

though 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 withincreased intracranial bleeding and trends in major and

Figure 2. mRS scores at day30. Comparison was made byordinal logistic regression.OR0.97; 95% CI, 0.79 to1.19; P0.75.



8/10/2019 Stroke-2010-Bath-732-8

6/8

8/10/2019 Stroke-2010-Bath-732-8

7/8

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 bothAsp/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 stabil-

ity and absence of severe dependency (mRS 3), thus

explaining why patients had very mild stroke (mean NIHSS

score

3). Second, no patients were recruited during thehyperacute phase (6 hours of onset) of stroke; indeed, most

patients entered the trial on day 3 (mean time to recruit-

ment58 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 antiplate-let 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 PRo-

FESS 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 topatients 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 (Asp-

clopidogrel-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.

AcknowledgmentsWe 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 tech-nical assistance. Drs Yusuf, Sacco, and Diener were co-chief

investigators of PRoFESS; Drs Bath, Estol, and Roberts weremembers of the trial steering committee; and Drs Martin and Palesch

and Daniel Cotton were biostatisticians supporting the trial.

Source of FundingBoehringer Ingelheim sponsored and funded PRoFESS and reviewed

the manuscript.

DisclosuresDrs Bath, Yusuf, Sacco, Diener, Estol, and Roberts have received

consulting and/or lecture fees from Boehringer Ingelheim; DrsMartin and Palesch have received consulting fees from Boehringer

Ingelheim; and Daniel Cotton is an employee of BoehringerIngelheim.

References1. Antithrombotic Trialists Collaboration. Collaborative meta-analysis of

randomised trials of antiplatelet therapy for prevention of death, myo-

cardial infarction, and stroke in high risk patients. BMJ. 2002;324:7186.

2. Algra A, van Gijn J. Aspirin at any dose above 30 mg offers only modest

protection after cerebral ischaemia.J Neurol Neurosurg Psychiatry. 1996;

60:197199.

3. Diener HC, Cunha L, Forbes C, Sivenius J, Smets P, Lowenthal A.

European Stroke Prevention Study 2. Dipyridamole and acetylsalicylicacid in the secondary prevention of stroke. J Neurol Sci. 1996;143:113.

4. CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel

versus aspirin in patients at risk of ischaemic events (CAPRIE).Lancet.

1996;348:13291339.

5. The ESPRIT Study Group. Aspirin plus dipyridamole versus aspirin alone

after cerebral ischaemia of arterial origin (ESPRIT): randomised con-

trolled trial. Lancet. 2006;367:16651673.

6. Bhatt DL, Fox KAA, Werner Hacke CB, Berger PB, Black HR, Boden

WE, Cacoub P, Cohen EA, Creager MA, Easton JD, Flather MD, Haffner

SM, Hamm CW, Hankey GJ, Claiborne Johnston S, Mak K-H, Mas J-L,

Montalescot G, Pearson TA, Steg PGD, Steinhubl SR, Weber MA,

Brennan DM, Fabry-Ribaudo L, Booth J, Topol EJ, for the CHARISMA

Investigators. Clopidogrel and aspirin versus aspirin alone for the pre-

vention of atherothrombotic events.N Engl J Med. 2006;354:17061717.

7. Diener HC, Bogousslavsky J, Brass LM, Cimminiello C, Csiba L, Kaste

M, Leys D, Matias-Guiu J, Rupprecht HJ. Aspirin and clopidogrelcompared with clopidogrel alone after recent ischaemic stroke or transient

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) arenot shown to improve visualization of the relevant part of the figure.



8/10/2019 Stroke-2010-Bath-732-8

8/8

ischaemic attack in high-risk patients (MATCH): randomised, double-

blind, placebo-controlled trial. Lancet. 2004;364:331337.

8. International Stroke Trial Collaborative Group. The International Stroke

Trial (IST); a randomised trial of aspirin, subcutaneous heparin, both, or

neither among 19435 patients with acute ischaemic stroke.Lancet. 1997;

349:15691581.

9. CAST (Chinese Acute Stroke Trial) Collaborative Group. CAST: ran-

domised placebo-controlled trial of early aspirin use in 20,000 patients

with acute ischaemic stroke. Lancet. 1997;349:16411649.

10. Kennedy J, Hill MD, Ryckborst K, Elliaziw M, Demchuk MAM, Buchan

AM, for the FASTER Investigators. Fast assessment of stroke and

transient ischaemic attack to prevent early recurrence (FASTER): a ran-

domised controlled pilot trial. Lancet Neurol. 2007;6:961969.

11. Diener H-C, Sacco RL, Yusuf S, for the Steering Committee and

PRoFESS Study Group. Rationale, design and baseline data of a ran-

domized, double-blind, controlled trial comparing two antithrombotic

regimens (a fixed-dose combination of extended-release dipyridamole

plus ASA with clopidogrel) and telmisartan versus placebo in patients

with strokes: the prevention regimen for effectively avoiding second

strokes trial (PRoFESS). Cerebrovasc Dis. 2007;23:368380.

12. Sacco RL, Diener H-C, Yusuf S, Cotton D, Ounpuu S, Lawton W,

Palesch Y, Martin R, Albers GW, Bath PM, Bornstein N, Chan BPL,

Chen S-T, Cunha L, Dahlof B, De Keyser J, Donnan GA, Estol C,

Gorelick PB, Gu V, Hermansson K, Hillbrich L, Kaste M, Lu C, Machnig

T, Pais P, Roberts R, Skvortsova V, Teal P, Toni D, VanderMaelen C,

Voight T, Weber M, Yoon B-W, the PROFESS Study Group. Aspirin andextended-release dipyridamole versus clopidogrel for recurrent stroke.

N Engl J Med. 2008;359:12381251.

13. Yusuf S, Diener H-C, Sacco RL, Cotton D, Ounpuu S, Lawson WA,

Palesch Y, Martin RH, Albers GW, Bath PM, Bornstein N, Chan BPL,


Gorelick PB, Gu V, Hermansson K, Hilbrich L, Kaste M, Lu C, Machnig

G, PP, Roberts R, Skvortsova V, Teal P, Toni D, VanderMaelen C,

Voight T, Weber M, Yoon B-W, for the PROFESS Study Group. Telm-

isartan to prevent recurrent stroke and cardiovascular events. N Engl

J Med. 2008;359:12251237.

14. Diener H-C, Sacco RL, Yusuf S, Cotton D, Ounpuu S, Lawton W,

Palesch Y, Martin R, Albers GW, Bath PM, Bornstein N, Chan BPL,


Gorelick PB, Gu V, Hermansson K, Hillbrich L, Kaste M, Lu C, Machnig

T, Pais P, Roberts R, Skvortsova V, Teal P, Toni D, VanderMaelen C,

Voight T, Weber M, Yoon B-W, for the Prevention Regimen for Effec-

tively Avoiding Second Strokes (PRoFESS) study group. Effects of

aspirin plus extended-release dipyridamole versus clopidogrel and telm-

isartan on disability and cognitive function after recurrent stroke inpatients with ischaemic stroke in the Prevention Regimen for Effectively

Avoiding Second Strokes (PRoFESS) trial: a double-blind, active and

placebo-controlled study. Lancet Neurol. 2008;7:875884.

15. Bath PM, Martin RH, Palesch Y, Cotton D, Yusuf S, Sacco R, Diener HC,

Toni D, Estol C, Roberts R; PRoFESS Study Group. Effect of telmisartan

on functional outcome, recurrence, and blood pressure in patients with

acute mild ischemic stroke: a PRoFESS subgroup analysis. Stroke. 2009;

40:35413546.

16. The Optimising Analysis of Stroke Trials (OAST) Collaboration. Can we

improve the statistical analysis of stroke trials? statistical re-analysis of

functional outcomes in stroke trials. Stroke. 2007;38:19111915.

17. Bath PMW, Geeganage CM, Gray LJ, Collier T, Pocock S. Use of ordinal

outcomes in vascular prevention trials: comparison with binary outcomes

in published stroke trials. Stroke. 2008;39:28172823.

18. European Stroke Prevention Study Group (ESPS). European stroke pre-

vention study: principle end points. Lancet. 1987;2:13511354.19. Sprigg N, Gray LJ, England T, Willmot MR, Zhao L, Sare GM, Bath

PMW. A randomised controlled trial of triplet antiplatelet therapy

(aspirin, clopidogrel and dipyridamole) in the secondary prevention of

stroke: safety, tolerability and feasibility. PloS One. 2008;3:e2852.

20. Markus HS, Droste DW, Kaps M, Larrue V, Lees KR, Siebler M,

Ringelstein EB. Dual antiplatelet therapy with clopidogrel and aspirin in

symptomatic carotid stenosis evaluated using Doppler embolic signal

detection; the clopidogrel and aspirin for reduction of emboli in symp-

tomatic carotid stenosis (CARESS) trial. Circulation. 2005;111:

22332240.

738 Stroke April 2010


Stroke-2010-Bath-732-8

Documents

Transcript of Stroke-2010-Bath-732-8