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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
1679
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1680 Stroke August 2010
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)
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
References
1. Hankey GJ, Jamrozik K, Broadhurst RJ, Forbes S, Anderson CS.
6, severe disability 2 (2) 3 (2) Long-term disability after first-ever stroke and related prognostic factors in
7, death 20 (19) 17 (13) the Perth Community Stroke Study. Stroke. 2002;33:1034 1040.
2. Hankey GJ, Spiesser J, Hakimi Z, Bego G, Carita P, Gabriel S. Rate,
Follow-up mRS score, 3.4 (2.1) 3.3 (1.9) 0.48 degree and predictors of recovery from disability following ischemic
mean (SD) stroke. Neurology. 2007;68:15831587.
3. Hankey GJ, Spiesser J, Hakimi Z, Carita P, Gabriel S. Time frame and
predictors of recovery from disability following recurrent ischemic stroke.
were not eligible for study entry if they were severely Neurology. 2007;68:202205.
disabled, thus minimizing the potential for important imbal- 4. Bhatt DL, Topol E; on behalf of the CHARISMA Executive Committee.
ance in stroke severity at baseline. Clopidogrel added to aspirin versus aspirin alone in secondary prevention
and high-risk primary prevention: rationale and design of the CHARISMA
Third, the mRS was assessed later after the stroke end point trial. Am Heart J. 2004;148:263268.
among patients assigned clopidogrel than those assigned 5. Bhatt DL, Fox KA, Hacke W, Berger PB, Black HR, Boden WE, Cacoub
placebo (163 days median for patients assigned clopidogrel P, Cohen EA, Creager MA, Easton JD, Flather MD, Haffner SM, Hamm
versus 130 days for patients assigned placebo, P0.03), CW, Hankey GJ, Johnston SC, Mak K-H, Mas J-L, Montalescot G,
Pearson TA, Steg G, Steinhubl SR, Weber M, Brennan DM, Fabry-
introducing the possibility of bias favoring the outcome of Ribaudo L, Booth J, Topol EJ; for the CHARISMA Investigators. Clopi-
patients assigned clopidogrel (ie, longer time to recover dogrel and aspirin versus aspirin alone for the prevention of athero-
between stroke end point and functional assessment). thrombotic events. N Engl J Med. 2006;354:1706 1717.
Fourth, the mRS is quite insensitive to small, but some- 6. Rankin J. Cerebral vascular accidents in patients over 60. 2. Prognosis.
Scott Med J. 1957;2:200 215.
times clinically meaningful, changes in functional status.6 7. de Haan J, Horn J, Limburg M, van der Meulen J, Bossuyt P. A comparison
Fifth, the mRS was assessed by a wide range of health of stroke scales with measures of disability, handicap and quality of life.
professionals, some of whom may not have been well trained Stroke. 1993;24:1178 1181.