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Effect of Clopidogrel on the Rate and Functional Severity of Stroke Among High

Vascular Risk Patients : A Prespecified Substudy of the Clopidogrel for High


Atherothrombotic Risk and Ischemic Stabilization, Management and Avoidance
(CHARISMA) Trial
Graeme J. Hankey, Werner Hacke, J. Donald Easton, S. Claiborne Johnston,
Jean-Louis Mas, Danielle M. Brennan, Deepak L. Bhatt, Keith A.A. Fox and Eric J.
Topol

Stroke 2010, 41:1679-1683: originally published online July 1, 2010


doi: 10.1161/STROKEAHA.110.586727
Stroke is published by the American Heart Association. 7272 Greenville Avenue, Dallas, TX 72514
Copyright 2010 American Heart Association. All rights reserved. Print ISSN: 0039-2499. Online
ISSN: 1524-4628

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Effect of Clopidogrel on the Rate and Functional Severity of
Stroke Among High Vascular Risk Patients
A Prespecified Substudy of the Clopidogrel for High Atherothrombotic
Risk and Ischemic Stabilization, Management and Avoidance
(CHARISMA) Trial
Graeme J. Hankey, MD, FRACP, FRCP; Werner Hacke, MD, PhD; J. Donald Easton, MD;
S. Claiborne Johnston, MD, PhD; Jean-Louis Mas, MD; Danielle M. Brennan;
Deepak L. Bhatt, MD, MPH; Keith A.A. Fox, MD, FRCP, PhD; Eric J. Topol, MD; on behalf of the
CHARISMA Trial Investigators

Background and PurposeDisabling stroke is costly and considered by some patients a fate worse than death. We aimed
to determine whether clopidogrel reduces the rate and functional severity of stroke among high vascular risk patients,
including patients with previous transient ischemic attack or ischemic stroke, who were enrolled in the Clopidogrel for
High Atherothrombotic Risk and Ischemic Stabilization, Management and Avoidance (CHARISMA) trial.
MethodsWe randomly assigned 15 603 high vascular risk patients to receive clopidogrel (75 mg daily) or placebo in
addition to background acetylsalicylic acid and followed them for a median of 28 months. The main outcome of this
prespecified substudy was the functional severity of stroke outcome events as measured by the modified Rankin Scale
(mRS) score at 3 months after the stroke outcome.
ResultsDuring follow-up, 436 (2.8%) patients had a definite adjudicated stroke and a follow-up assessment of the mRS
at 3 months poststroke, of whom 202 had been randomly assigned clopidogrel and 234 placebo (relative risk reduction
14%, 95% CI: 4% to 29%, P0.12). There was no significant difference between the mean mRS scores at 3 months
after stroke among patients assigned clopidogrel compared with placebo (mean mRS 3.6 [SD 2.4] clopidogrel versus 3.3
[SD 2.1] placebo; P0.15). There was also no significant difference between the various categories of the mRS score
at 3 months after stroke among patients assigned to clopidogrel compared with placebo. Among 4320 patients with a
qualifying diagnosis of transient ischemic attack or ischemic stroke, 233 (5.4%) experienced a stroke during follow-up,
of whom 103 were randomly assigned clopidogrel and 130 placebo (relative risk reduction 20%, 95% CI: 3% to 38%).
There was no significant difference between the mean mRS scores at 3 months after stroke among patients with a
qualifying transient ischemic attack or ischemic stroke who were assigned clopidogrel compared with placebo (3.4 [SD
2.1] clopidogrel versus 3.3 [SD 1.9] placebo; P0.48).
ConclusionThe addition of clopidogrel to acetylsalicylic acid did not significantly alter the rate and functional severity
of stroke outcome events among high vascular risk patients enrolled in the CHARISMA trial. (Stroke. 2010;41:1679-
1683.)
Key Words: antiplatelet therapy cerebrovascular disease/stroke infarction stroke prevention stroke severity

M uch of the burden of stroke can be attributed to its high


rates of case fatality (20%) and dependency (50% of
survivors).13 Strategies for stroke prevention such as anti-
The Clopidogrel for High Atherothrombotic Risk and Ische-
mic Stabilization, Management and Avoidance (CHARISMA)
trial was designed to explore the hypothesis that long-term
platelet therapy are likely to be optimally effective if they can treatment with a combination of clopidogrel and acetylsali-
reduce fatal and disabling strokes at least as effectively as cylic acid (ASA) may be more effective than ASA alone in
they prevent nondisabling strokes. preventing the occurrence of the composite of stroke, myo-

Received April 6, 2010; accepted May 14, 2010.


From the Neurology Department (G.J.H.), Royal Perth Hospital, Perth, Australia; the Neurology Department (W.H.), Im Neuenheimer Feld 400,
Heidelberg, Germany; Brown University (J.D.E.), Providence, RI; UCSF Neurology (S.C.J.), San Francisco, Calif; Service de Neurologie (J.-L.M.),
Hopital Sainte-Anne, Paris, France; Cleveland Clinic (D.M.B.), Cleveland, Ohio; VA Boston Healthcare System (D.L.B.), Brigham and Womens
Hospital, and Harvard Medical School, Boston, Mass; the University and Royal Infirmary of Edinburgh (K.A.A.F.), Edinburgh, UK; and Scripps Health
and Scripps Translational Science Institute (E.J.T.), La Jolla, Calif.
Correspondence to Graeme J. Hankey, MD, FRACP, FRCP, Consultant Neurologist and Head of Stroke Unit, Royal Perth Hospital, 197 Wellington
Street, Perth, Australia 6000. E-mail gjhankey@cyllene.uwa.edu.au
2010 American Heart Association, Inc.
Stroke is available at http://stroke.ahajournals.org DOI: 10.1161/STROKEAHA.110.586727

1679
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1680 Stroke August 2010

cardial infarction, or death due to vascular causes among a


broad population of patients at high risk for vascular events.4,5
The rate of stroke, myocardial infarction, or vascular death
was 6.8% among patients assigned clopidogrel and 7.3%
among patients assigned placebo (relative risk: 0.93, 95% CI:
0.83 to 1.05).5
A secondary a priori hypothesis was that the addition of
clopidogrel to ASA may reduce the severity of stroke
outcome events, perhaps by minimizing the size of thrombus
formed on ruptured/eroded atherosclerotic plaque and thus
the size of emboli to the brain and resultant brain infarction.
However, it was also possible that adding clopidogrel to
aspirin could increase the severity of any hemorrhagic
strokes.
In this prespecified substudy of the CHARISMA trial, we
aimed to determine the effect of clopidogrel on the functional
severity of stroke as measured by the modified Rankin Scale
(mRS)6,7 among all high vascular risk subjects randomized in
the CHARISMA trial and followed-up for the occurrence of
stroke events. In addition to the prespecified analysis, we also
assessed the rate and severity of stroke events in those Figure. KaplanMeier survival curve showing the rate of stroke
patients recruited after a transient ischemic attack (TIA) or over 30 months follow-up among all high vascular risk patients
randomly assigned clopidogrel (CLOP; C) or placebo (PLAC; P)
stroke. on top of background ASA therapy in the CHARISMA trial
(intention-to-treat analysis).
Methods
Design dent) and 3 (dependent) was the need for assistance in any activities
The methods of the CHARISMA trial have been described in detail of daily living (eg, walking, bathing, dressing, grooming).
elsewhere.4,5 Briefly, CHARISMA was a multicenter, multinational,
randomized, parallel-group, double-blind trial of clopidogrel versus Statistical Methods
placebo in high-risk patients at risk of atherothrombotic events and
Data were analyzed on an intention-to-treat basis. KaplanMeier
who were receiving low dose ASA at the time of randomization. A
curves were generated to show time to first adjudicated stroke in
total of 15 603 patients with either clinically established cardiovas-
cular disease or multiple risk factors were randomly assigned to each treatment group. The mRS score was summarized by treatment
receive clopidogrel (75 mg per day) plus low-dose ASA (75 to 162 group using counts and percentage as well as mean, SD, minimum,
mg per day) or placebo plus low-dose ASA. Patients with a previous and maximum.
disabling condition such that they were bedridden or demented were In the patients who had an assessment of the mRS at 3 months
excluded from the trial. Patients were followed-up prospectively at 1, after their stroke, analysis of variance was used to test the difference
3, and 6 months, and every 6 months thereafter until the trial end. in mean scores between treatment groups. An adjusted analysis was
The median follow-up period was 28 months. The primary efficacy also performed using analysis of variance because the population
end point for the CHARISMA trial was a composite of stroke, was chosen based on an end point and could not be assumed to be
myocardial infarction, or death from cardiovascular causes. random. Adjustment factors included whether the patient was on the
study drug at the time of stroke (yes/no), time from randomization to
Subjects stroke (continuous days), and the initial mRS score. The poststroke
The population for the substudy on stroke severity consisted of all mRS score was also assessed on patients who did not permanently
high vascular risk patients randomized in the CHARISMA trial who discontinue the study drug before the functional outcome
experienced at least 1 adjudicated stroke end point during follow-up assessment.
and underwent an assessment of the functional severity of the stroke Only observed values were used in the analysis and presentations,
outcome event at 3 months after the event. that is, no attempt was made to impute missing values.

Outcome Evaluation
The primary outcome measure was functional severity of the first Results
stroke outcome event as defined by the mRS score at 3 months after
the stroke.6,7
Study Patients
All randomized subjects who experienced at least 1 stroke end Among the 15 603 high vascular risk patients randomized to
point as determined by the investigator were evaluated using the placebo (n7801) or clopidogrel (n7802), in addition to
mRS approximately 3 months (or at study end date or death if these background ASA, and followed for a median of 28 months,
occurred earlier) after the stroke to determine the severity of the 503 were reported by the investigator to have had a stroke. Of
stroke and the patients functional outcome. Assessments were made
after each stroke end point, but only the assessment after the initial these, 441 strokes were adjudicated as a stroke. The Figure is
adjudicated stroke was used for the primary analysis. a KaplanMeier curve showing the rate of stroke over the first
The assessment and scoring of the mRS was done by the same 30 months of follow-up according to the random treatment
observer immediately after the stroke and at the 3 months poststroke
allocation at Time 0. Among the 441 patients with adjudi-
follow-up assessment. The mRS was assessed incorporating all
activities that the patients could actually do, not what they thought cated stroke, 436 had an assessment of the mRS 3 months
they could do. The difference between a mRS score of 2 (indepen- after their stroke.
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Hankey et al Effect of Clopidogrel on Stroke 1681

Stroke Outcomes According to Randomized Table 1. Baseline Demographic and Other Prognostic Data
Treatment Group Among the 436 High Vascular Risk Patients Enrolled in the
Among the 436 patients who had an adjudicated definite CHARISMA Trial Who Experienced a Stroke Outcome Event
stroke during trial follow-up and underwent an assessment of During Follow-Up
functional stroke severity at 3 months poststroke, 202 had Treatment
been randomly assigned clopidogrel and 234 assigned aspirin
Clopidogrel Placebo
(relative risk reduction 14%, 95% CI: 4% to 29%, P0.12,
Added to ASA Added to ASA
2-tailed). Characteristic (N202/7802) (N234/7801)
Demographics
Baseline Demographic and Other
Age, mean years (SD) 68.1 (9.3) 68.2 (10.0)
Prognostic Factors
Table 1 shows that there were no significant differences in the Age, years, no. (%)
prevalence or level of baseline demographic and other prog- 65 71 (35) 89 (38)
nostic factors between the two treatment groups of patients 6574 75 (37) 69 (29)
who experienced a stroke during follow-up. 75 56 (28) 76 (32)
Gender, no. (%)
Duration of Study Drug Treatment Male 138 (68) 166 (71)
The 234 patients assigned placebo (who subsequently expe- Race, no. (%)
rienced a stroke) were treated with study drug for 17.1
White 184 (91) 209 (89)
months (median) compared with 16.1 months (median) for
Asian/Oriental 12 (6) 13 (6)
the 202 patients assigned clopidogrel (P0.43).
Black 5 (2) 8 (3)

Time Between First Adjudicated Stroke and Other 1 (1) 4 (2)


Follow-Up Assessment of Functional History of
Stroke Severity Hypertension 162 (80) 189 (81)
The median time between stroke and follow-up assessment of Current smoker, no. (%) 44 (22) 46 (20)
functional stroke severity was 163 days for patients on clopi- Hypercholesterolemia 130 (64) 149 (64)
dogrel versus 130 days for patients on placebo (P0.03). Congestive heart failure 19 (9) 15 (6)
Myocardial infarction 53 (26) 67 (29)
Pathological Subtype of Stroke Outcomes Atrial fibrillation 14 (7) 14 (6)
Among the 436 patients who had a stroke outcome, 369
Stroke 97 (48) 122 (52)
(85%) were ischemic (171 [84.7%] among patients assigned
clopidogrel versus 198 [84.6%] among patients assigned TIA 42 (21) 38 (16)
placebo), 41 (9%) were hemorrhagic (20 [9.9%] clopidogrel Diabetes 95 (47) 106 (45)
versus 21 [9.0%] ASA), and 26 (6%) were of uncertain Diabetic nephropathy 27 (13) 25 (11)
pathological type (11 [5.4%] clopidogrel versus 15 [6.4%] Peripheral arterial disease 41 (20) 56 (24)
ASA). Percutaneous coronary 27 (13) 32 (14)
intervention
Functional Outcome 3 Months After the First Coronary artery bypass graft 28 (14) 38 (16)
Stroke Outcome Event Carotid endarterectomy 20 (10) 16 (7)
Table 2 shows that there was no significant difference Peripheral angioplasty or 24 (12) 29 (12)
between the mean mRS scores at 3 months after stroke among bypass surgery
patients assigned clopidogrel compared with placebo (3.6 Baseline measures
[SD 2.3] clopidogrel versus 3.3 [SD 2.1] placebo; P0.15). Body weight (kg), mean (SD) 80 (17) 79 (17)
After adjusting for treatment group, on study drug at the time
Primary study inclusion criteria
of stroke, time from randomization to stroke, and initial mRS
None 3 (1.5) 0 (0)
score, similar results remained with no difference between
treatment groups. Asymptomatic (multiple risk 35 (18) 36 (15)
factors only)
Table 3 shows that there was also no significant difference
Symptomatic cerebrovascular 103 (51) 130 (55)
between the various categories of the mRS score at 3 months
disease
after stroke among patients assigned to clopidogrel compared
Symptomatic coronary artery 44 (22) 56 (24)
with placebo. Although patients assigned clopidogrel showed
disease
a small trend toward more severe stroke than placebo in each
Symptomatic peripheral 33 (16) 39 (17)
comparison, it is highly probable that this finding reflects
arterial disease
random error (chance). These results were consistent in
patients who did not permanently discontinue the study drug
(n261; clopidogrel: n122, placebo: n139) before the
poststroke functional outcome assessment (P0.09).
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1682 Stroke August 2010

Table 2. Summary of Functional Outcome as Measured by the Table 3. Summary of mRS Score by Dichotomization 3
mRS Score at 7 Days or at Hospital Discharge After the Months After Adjudicated Stroke
Adjudicated Stroke (Initial mRS Score) and 3 Months After the
Treatment
Adjudicated Stroke (Follow-Up mRS Score)
Treatment Clopidogrel Placebo
Added to ASA Added to ASA
Clopidogrel Placebo mRS Score (N202/7802) (N234/7801) P*
Added to ASA Added to ASA mRS scores: 12 versus 0.59
mRS Score (N202/7802 ) (N234/7801 ) P* 37
Initial mRS score, no. (%) N201 N231 1 and 2, no 88 (44) 108 (46)
1, no symptoms at all 24 (12) 19 (8) symptoms or no
significant disability
2, no significant 47 (23) 70 (30)
disability despite 37, slight disability 114 (56) 126 (54)
symptoms to death
3, slight disability 31 (15) 50 (22) mRS scores: 13 versus 0.11
47
4, moderate disability 30 (15) 30 (13)
13, no symptoms to 117 (58) 153 (65)
5, moderately severe 30 (15) 25 (11)
slight disability
disability
47, moderate disability 85 (42) 81 (35)
6, severe disability 25 (12) 29 (13)
to death
7, death 14 (7) 8 (4)
mRS scores: 14 versus 0.11
Initial mRS score, mean (SD) 3.6 (1.8) 3.4 (1.7) 0.16 57
Follow-up mRS score, no. n (%) N202 N234 14, no symptoms to 137 (68) 175 (75)
1, no symptoms at all 47 (23) 50 (21) moderate disability
2, no significant 41 (20) 58 (25) 57, moderately severe 65 (32) 59 (25)
disability despite disability to death
symptoms *P from a 2 test.
3, slight disability 29 (14) 45 (19)
4, moderate disability 20 (10) 22 (9) (3.4 [SD 2.1] clopidogrel versus 3.3 [SD 1.9] placebo;
5, moderately severe 11 (5) 14 (6) P0.48).
disability
6, severe disability 6 (3) 7 (3) Discussion
7, death 48 (24) 38 (16) The principal finding of this substudy of the CHARISMA
Follow-up mRS score, mean (SD) 3.6 (2.3) 3.3 (2.1) 0.15 trial was that there was no significant difference in the rate of
Adjusted mRS score, least 3.5 (0.1) 3.4 (0.1) 0.40
stroke, or severity of stroke, as measured by mRS score
squares mean (SD) between high vascular risk patients randomly assigned clopi-
*P from a t test.
dogrel (plus ASA) or placebo (plus ASA) and followed-up
for a median of 28 months.
A strength of this study is that is was a large randomized
Patients With Qualifying TIA or Ischemic Stroke
controlled trial in which a large number of strokes occurred in
Among the 15 603 high vascular risk patients randomized in
a broad range of high vascular risk patients and were
the main CHARISMA trial, 4320 patients were enrolled with
evaluated by assessors who were blind to the treatment
a qualifying diagnosis of documented cerebrovascular disease
allocation.
(TIA [n1233] or ischemic stroke [n3245]; 158 patients A weakness of the study is that although the hypotheses
with ischemic stroke also had a history of TIA), of whom and analyses were prespecified, it was a substudy and not the
2163 were assigned placebo and 2157 clopidogrel. primary aim of the trial. Patients were included in this
An adjudicated first stroke during follow-up (ie, a recurrent analysis of stroke severity on the basis of an end point, and
stroke for patients who qualified with stroke) occurred in 233 consequently it is not possible to assume that there was an
patients, of whom 103 were randomly assigned clopidogrel equal balance in important prognostic factors between the
and 130 to placebo (relative risk reduction 20%, 95% CI: treatment groups (ie, the comparison is not random). How-
3% to 38%). Most strokes were ischemic (n202 of 233 ever, Table 1 indicates there was no significant difference in
[87%]; 91 patients assigned clopidogrel versus 113 on pla- the prevalence of measured baseline demographic and other
cebo). A few strokes were hemorrhagic (n19 of 236 [8%]; important prognostic factors for stroke severity between the
10 clopidogrel versus 9 placebo). Only 12 strokes were of treatment groups.
unknown type. A second potential weakness is that the mRS was not
Table 4 shows that there was no significant difference assessed at the time of randomization (ie, at baseline),
between the mean mRS scores 3 months after (recurrent) introducing the possibility that there was some imbalance in
stroke among patients with a qualifying TIA or ischemic functional status at baseline due to chance among patients
stroke who were assigned clopidogrel compared with placebo randomized to the 2 treatment groups. However, patients
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Hankey et al Effect of Clopidogrel on Stroke 1683

Table 4. Summary of Functional Outcome as Measured by the in, or familiar with, its use. Many were not stroke physicians.
mRS Score at at 7 Days or at Hospital Discharge After the First However, many studies have shown that the mRS has high
Adjudicated Stroke Outcome Event (Initial mRS Score) and 3 interobserver reliability.6
Months After the First Adjudicated Stroke (Follow-Up mRS Score) Finally, the study is likely to have been underpowered to
Among Patients With a Qualifying TIA or Ischemic Stroke
reliably identify or exclude a modest but clinically important
Treatment effect of combination antiplatelet therapy on stroke severity
compared with monotherapy.
Clopidogrel Placebo
Added to ASA Added to ASA This trial fails to provide evidence that adding clopidogrel
mRS Score (N103/2157) (N130/2163) P to ASA significantly reduces the severity of stroke outcome
Initial mRS score, no. (%) N103 N130 0.93
events, as measured by the mRS, 3 months after stroke.
1, no symptoms at all 13 (13) 12 (9)
2, no significant disability 24 (23) 35 (27)
Sources of Funding
despite symptoms The CHARISMA trial was sponsored and funded by Sanofi-Aventis
and Bristol-Myers Squibb.
3, slight disability 20 (19) 26 (20)
4, moderate disability 16 (15) 25 (19) Disclosures
5, moderately severe 16 (15) 16 (12) G.J.H. has received consulting fees from Sanofi-Aventis, Bristol-
disability Myers Squibb, Bayer, and Boehringer Ingelheim and lecture fees
6, severe disability 10 (10) 12 (9) from Sanofi-Aventis, Bristol-Myers Squibb, Bayer, and Boehringer
Ingelheim. W.H. is a member of the executive Committee of
7, death 4 (4) 4 (3)
CHARISMA and has received consulting fees from Sanofi-Aventis
Initial mRS score, mean 3.4 (1.7) 3.4 (1.6) 0.84 and Bristol-Myers Squibb. J.D.E. has received consulting fees from
(SD) Sanofi-Aventis and Bristol-Myers Squibb. J.-L.M. has received
Follow-up mRS score, N103 N130 0.90 consulting fees from Sanofi-Aventis and Bristol-Myers Squibb.
no. (%) D.L.B. has received research grants (directly to the institution) from
Astra Zeneca, Bristol Myers Squibb, Eisai, Ethicon, Heartscape,
1, no symptoms at all 20 (19) 23 (18) Sanofi Aventis, and The Medicines Company. K.A.A.F. has received
2, no significant disability 22 (21) 31 (24) consulting fees from Sanofi-Aventis; lecture fees from Sanofi-
despite symptoms Aventis and Bristol-Myers Squibb; and grant support from Sanofi-
3, slight disability 22 (21) 30 (23) Aventis. E.J.T. has received research support from Sanofi-Aventis
and Bristol-Myers Squibb.
4, moderate disability 12 (12) 18 (14)
5, moderately severe 5 (5) 8 (6)
disability
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