Beruflich Dokumente
Kultur Dokumente
DOI 10.1007/s00415-009-5035-4
ORIGINAL COMMUNICATION
Received: 12 May 2008 / Revised: 17 November 2008 / Accepted: 13 January 2009 / Published online: 14 March 2009
Springer-Verlag 2009
S. Uchiyama (&)
Department of Neurology, Tokyo Womens Medical University
School of Medicine, 8-1 Kawada-cho, Shinjuku-ku,
Tokyo 162-8666, Japan
e-mail: suchiyam@nij.twmu.ac.jp
Y. Fukuuchi
Ashikaga Red Cross Hospital, Tochigi, Japan
T. Yamaguchi
National Cardiovascular Center, Osaka, Japan
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Introduction
Stroke is a leading cause of death and disability worldwide.
In Japan, 234,000 patients are newly diagnosed with stroke
every year and 1,370,000 individuals have a history of
previous stroke [1]. Hemorrhagic and ischemic cerebrovascular diseases (CVD) together make up the third most
common cause of death in Japan [2] with 129,055 deaths
due to CVD recorded in 2005 [1].
The high prevalence of stroke in Japan emphasizes the
need for effective prevention strategies. Patients who have
had a previous stroke are at risk of recurrent events [3].
Currently, the use of antiplatelet agents is recommended
for the prevention of recurrent noncardioembolic stroke
[4, 5]. Before 2006, the antiplatelet agents approved in
Japan were aspirin, ticlopidine (an adenosine diphosphate
antagonist; grade A recommendation), and cilostazol (a
phosphodiesterase inhibitor; grade B recommendation) [5].
Use of antiplatelet agents is relatively infrequent in patients
with atherothrombotic conditions or risk factors in Japan
(21.3%) compared with the rest of the world (53.9%) [6].
889
Phase IIIb
Study period
Number of patients
749
1,172
Treatment duration
26 weeks
52 weeks
Randomization
Clopidogrel (75 mg) or ticlopidine (200 mg) once daily after a meal
Double blind
AL-P alkaline phosphatase, ALT serum alanine aminotransferase, AST aspartate aminotransferase, c-GTP c-glutamyl transpeptidase, LDH lactate
dehydrogenase, TIA transient ischemic attack, WBC white blood cells
123
890
123
serum alanine aminotransferase (ALT), serum bilirubin, cglutamyl transpeptidase (c-GTP), alkaline phosphatase
(AL-P), or lactate dehydrogenase (LDH), jaundice, hepatic
dysfunction, or nonicteric hepatic dysfunction. Serious
adverse drug reactions (ADRs) were events for which a
causal relation with the investigational drug could not be
ruled out by the investigator and that were life-threatening,
led to or prolonged hospitalization, or resulted in irreversible impairment or death [11].
The major secondary endpoint in this combined analysis
was the combined incidence of vascular events (cerebral
infarction, MI, or vascular death) with up to 52 weeks
follow-up.
Rationale for combining the two studies
To determine whether it was appropriate to combine the
data from the two studies, we confirmed that there was no
heterogeneity between Phase IIIa and Phase IIIb on the
hazard ratio of vascular events (p = 0.767). We have also
shown that the hazard ratio between the ticlopidine and
clopidogrel groups was similar despite the differences in
the lengths of the follow-up periods. The methods and
standards used for collecting and recording adverse events
were slightly different between the two studies; however,
this was based on recommendations and approval from the
Pharmaceutical and Medical Devices Agency (PMDA),
following the results of the Phase IIIa study.
Analyses
Safety variables
The primary safety analysis was on the combined endpoint
of accessory symptoms (symptoms reported by the patient
and considered by the investigator to be related to the study
drug) and abnormal laboratory changes. The observation
period for ADRs was from inclusion to the end of week 26
(Phase IIIa) or 52 (Phase IIIb). ADRs were categorized
as (a) accessory symptoms or (b) abnormal laboratory
hematologic or hepatic changes.
Efficacy variable
The primary efficacy variable was the observation of a
vascular event within the 52-week maximum period of
follow-up. Events were categorized as cerebral infarction,
MI, vascular death, transient ischemic attack (TIA),
amaurosis fugax, angina pectoris, peripheral artery occlusion, retinal artery occlusion, or other vascular event. The
combined efficacy endpoint was limited to vascular events
that could be definitively diagnosed (cerebral infarction,
MI, and vascular death).
891
Statistical analysis
Results
Patients
In the Phase IIIa study, 749 patients were enrolled and
randomly assigned to receive treatment. Nine patients did
not receive the study treatment and a further 26 were found
to be ineligible for inclusion in the safety population,
leaving 714 patients (clopidogrel, 366; ticlopidine, 348). A
further three patients failed to meet the inclusion criteria,
thus 711 patients were in the efficacy-evaluable population
(clopidogrel, 366; ticlopidine, 345). In the Phase IIIb study,
1,172 patients were enrolled. In all, 17 patients withdrew
prior to initiating treatment, leaving 1,155 patients in the
safety population (clopidogrel, 575; ticlopidine, 580).
Three patients did not meet the inclusion criteria, and
one patient was incorrectly randomized, therefore
1,151 patients were in the efficacy-evaluable population
(clopidogrel, 573; ticlopidine, 578).
In the combined analysis, the safety population comprised 941 patients in the clopidogrel group and 928
patients in the ticlopidine group. In total, 939 patients were
included in the efficacy-evaluable population for clopidogrel and 923 patients were included in the efficacyevaluable population for ticlopidine (Fig. 1).
Baseline characteristics for the Phase IIIa, IIIb and
combined populations are shown in Table 2. In both
Excluded: n = 52
Failure to meet GCP requirements, no
treatment
Clopidogrel 75 mg/day
Safety population:
Received treatment: n = 941
Safety population
Received treatment: n = 928
Total excluded: n = 2
Failure to meet inclusion criteria: n=1
Not enrolled: n = 1
Efficacy-evaluable population:
n = 939
Total excluded: n = 5
Failure to meet inclusion
criteria: n = 5
Efficacy-evaluable population:
n = 923
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892
p valuea
Ticlopidine
IIIb
Total
IIIa
IIIb
Total
366
575
941
348
580
928
Male, n (%)
251 (68.6)
415 (72.2)
666 (70.8)
238 (68.4)
429 (74.0)
667 (71.9)
211 (57.7)
321 (55.8)
532 (56.5)
203 (58.3)
329 (56.7)
532 (57.3)
64.7 8.9
64.3 9.4
64.4 9.2
65.1 8.8
64.7 9.2
64.8 9.0
0.374c
0.586d
0.599b
146 (39.9)
112 (19.5)
258 (27.4)
139 (39.9)
106 (18.3)
245 (26.4)
412 weeks
[12 weeks
101 (27.6)
114 (31.1)
100 (17.4)
363 (63.1)
201 (21.4)
477 (50.7)
86 (24.7)
121 (34.8)
113 (19.5)
361 (62.2)
199 (21.4)
482 (51.9)
Atherothrombotic infarction
72 (19.7)
172 (29.9)
244 (25.9)
72 (20.7)
171 (29.5)
243 (26.2)
Lacunar infarction
287 (78.4)
390 (67.8)
677 (71.9)
267 (76.7)
397 (68.4)
664 (71.6)
Hypertension
253 (69.1)
411 (71.5)
664 (70.6)
247 (71.0)
393 (67.8)
640 (69.0)
0.452b
Diabetes
94 (25.7)
114 (19.8)
208 (22.1)
81 (23.3)
121 (20.9)
202 (21.8)
0.860b
Hyperlipidemia
107 (29.2)
222 (38.6)
329 (35.0)
106 (30.5)
226 (39.0)
332 (35.8)
0.713b
134 (36.6)
344 (59.8)
478 (50.8)
130 (37.4)
386 (66.6)
516 (55.6)
0.113b
Co-morbidities, n (%)
v2 test
t test
c
d
Wilcoxon test
studies, there were more male than female patients and the
mean age was between 64 and 65 years. In total, 240
patients in the clopidogrel group and 322 in the ticlopidine
group discontinued treatment prematurely over the 52week follow-up period. The primary reason for discontinuation was adverse events, experienced by 185 patients in
the ticlopidine group compared with 134 in the clopidogrel
group. Other reasons for discontinuation included refusal
of medication or poor compliance (clopidogrel, 29; ticlopidine, 54), vascular events (clopidogrel, 28; ticlopidine,
28), loss to follow-up (clopidogrel, 13; ticlopidine, 14),
worsening of comorbid condition (clopidogrel, 5; ticlopidine, 5), and change in treatment (clopidogrel, 2;
ticlopidine, 2).
Safety and tolerability
Fewer patients in the clopidogrel group (35.0% [329/941])
experienced the combined safety endpoint of accessory
symptoms and abnormal laboratory changes compared with
those in the ticlopidine group (48.7% [452/928]). Using a
KaplanMeier analysis, it was estimated that, at 1 month,
83.4% of patients in the clopidogrel group were safety
event free compared with 69.9% in the ticlopidine group.
At both 2 and 12 months, the estimated incidence of safety
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893
0.9
Clopidogrel (n=941)
Ticlopidine (n=928)
0.8
0.7
0.6
0.5
0.4
0 (0)
2 (8)
4 (16)
6 (24)
8 (32)
10 (40)
12 (48)
Months (weeks)
Patients, n
Clopidogrel
Ticlopidine
941
928
705
535
623
466
569
427
350
264
333
244
321
231
177
272
205
290
221
301
228
311
234
322
Discussion
In this combined analysis of two Phase III trials of the
safety and efficacy of clopidogrel compared with ticlopidine in Japanese patients, clopidogrel was associated with
significantly fewer adverse events but without significant
difference in the incidence of secondary vascular events in
patients with a history of stroke. This observation is corroborated by findings from international studies which
suggest that both clopidogrel and ticlopidine are superior in
efficacy to aspirin [7, 9, 14]. However, while clopidogrel
123
894
Leukopenia
Neutropenia
Clopidogrel
Ticlopidine
Thrombocytopenia
Hepatic dysfunction
Increased AST
Increased ALT
Increased -GTP
Increased AL-P
Gastrointestinal disorders
10
15
20
25
30
35
40
45
50
Patients (%)
has a safety profile similar to that of aspirin [9, 14], ticlopidine is associated with significantly more adverse
events [7, 14].
The two populations studied in this trial were very
similar. The treatment period was different for the Phase
IIIa trial (26 weeks) compared with the Phase IIIb trial
(52 weeks), but there were no procedural differences
between the clopidogrel and ticlopidine groups in either
trial. As the populations were well matched between trials
and between treatment groups within each trial, it was
considered that the increased population size available in a
combined analysis would have greater statistical power.
Liver dysfunction (all laboratory measures) was
observed significantly more frequently in the ticlopidine
group than in the clopidogrel group. The incidences of
raised AST and AL-P levels were approximately doubled
and the incidence of raised c-GTP levels almost trebled in
the ticlopidine group compared with the clopidogrel group.
Previously, a much higher risk of liver damage during
ticlopidine treatment has been observed in Japan than in
populations from the rest of the world and liver function
tests are recommended when commencing ticlopidine
treatment [8]. Recent evidence has linked this increased
liver dysfunction susceptibility to certain human leukocyte
antigen types in the Japanese population [15]. In the
present study, the differences in measures of liver
123
895
Proportion of patients free of
leukopenia events
Clopidogrel: 98.4%
Ticlopidine: 97.1%
HR: 0.451 (96.6% CI: 0.238, 0.853)
1.00
0.98
Clopidogrel: 97.7%
Ticlopidine: 94.7%
HR: 0.402 (95% CI: 0.231, 0.700)
0.96
0.94
0.92
0.90
0 (0)
2 (8)
4 (16)
6 (24)
8 (32)
10 (40)
12 (48)
Months (weeks)
936
842
799
739
454
436
424
Ticlopidine
921
745
687
642
377
361
343
Clopidogrel
Clopidogrel: 99.6%
Ticlopidine: 98.0%
HR: 0.176 (95% CI: 0.051, 0.603)
1.00
0.98
Clopidogrel: 99.3%
Ticlopidine: 97.4%
HR: 0.082 (95% CI: 0.082, 0.575)
0.96
0.94
0.92
0.90
0 (0)
2 (8)
4 (16)
6 (24)
8 (32)
10 (40)
12 (48)
Months (weeks)
898
820
779
725
456
439
428
883
721
666
625
379
364
346
Clopidogrel
Ticlopidine
Clopidogrel: 90.7%
Ticlopidine: 77.1%
HR: 0.378 (95% CI: 0.293, 0.488)
1.00
0.90
Clopidogrel: 85.5%
Ticlopidine: 71.3%
HR: 0.455 (95% CI: 0.367, 0.565)
0.80
0.70
0.60
0.50
0 (0)
2 (8)
4 (16)
6 (24)
8 (32)
10 (40)
12 (48)
Months (weeks)
Clopidogrel
941
789
735
678
418
403
392
Ticlopidine
928
629
571
536
324
306
293
Clopidogrel (n=941)
Ticlopidine (n=928)
123
896
Clopidogrel
(n = 939)
Ticlopidine
(n = 923)
Hazard ratio
(95% CI)a
p valueb
24 (2.6)
23 (2.5)
0.769
0.591
Cerebral infarction
24
23
Myocardial infarction
Vascular death
Other vascular events, n (%)
10 (1.1)
11 (1.2)
6c
Angina pectoris
Peripheral arterial occlusion
3
2
4
1
34 (3.6)
34 (3.7)
Others
All vascular events, n (%)
CI confidence interval
a
Estimated using the Cox proportional hazards ratio (95% CI: Wald CI)
Log-rank test
Clopidogrel (n=939)
Ticlopidine (n=923)
0.99
0.98
0.97
0.96
0.95
0 (0)
2 (8)
4 (16)
6 (24)
8 (32)
10 (40)
12 (48)
Months (weeks)
Clopidogrel
939
853
809
748
458
440
427
Ticlopidine
923
758
700
653
382
367
349
123
897
8.
9.
10.
11.
12.
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