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Gorelick PB, Richardson D, Kelly M, et al. Aspirin and Ticlopidine for Prevention of Recurrent Stroke in Black Patients: A Randomized Trial. JAMA. 2003;289(22):2947–2957. doi:10.1001/jama.289.22.2947
Author Affiliations: Departments of Neurologic Sciences (Drs Gorelick, Ruland, and Leurgans, and Ms Harris) and Preventive Medicine (Dr Richardson and Ms Hung), Rush Medical College, Chicago, Ill; Department of Mathematics and Computer Science, Lake Forest College, Lake Forest, Ill (Dr Richardson); Department of Medicine, Division of Neurology, Cook County Hospital, Chicago, Ill (Dr Kelly); and the Department of Neurology, University of Maryland, Baltimore (Dr Kittner).
Context Blacks are disproportionately affected by stroke, and they are about
2 times more likely than most other individuals in the United States to die
of or experience stroke.
Objective To determine the efficacy and safety of aspirin and ticlopidine to prevent
recurrent stroke in black patients.
Design, Setting, and Patients Randomized, double-blind, investigator-initiated, multicenter trial
of 1809 black men and women who recently had a noncardioembolic ischemic stroke
and who were recruited between December 1992 and October 2001 from 62 academic
and community hospitals in the United States and followed up for up to 2 years.
Intervention A total of 902 patients received 500 mg/d of ticlopidine and 907 received
650 mg/d of aspirin.
Main Outcome Measures Recurrent stroke, myocardial infarction, or vascular death was the composite
primary end point (according to intention-to-treat analysis). The secondary
outcome was fatal or nonfatal stroke.
Results The blinded phase of the study was halted after about 6.5 years when
futility analyses revealed a less than 1% probability of ticlopidine being
shown superior to aspirin in the prevention of the primary outcome end point.
The primary outcome of recurrent stroke, myocardial infarction, or vascular
death was reached by 133 (14.7%) of 902 patients assigned to ticlopidine and
112 (12.3%) of 907 patients assigned to aspirin (hazard ratio, 1.22; 95% confidence
interval, 0.94-1.57). Kaplan-Meier curves for time to event for the primary
outcome did not differ significantly (P = .12 by
log-rank test). Kaplan-Meier curves for time to the secondary outcome of fatal
or nonfatal stroke approached a statistically significant reduction favoring
aspirin over ticlopidine (P = .08 by log-rank test).
The frequency of laboratory-determined serious neutropenia was 3.4% for patients
receiving ticlopdine vs 2.2% for patients receiving aspirin (P = .12) and 0.3% vs 0.2% for thrombocytopenia, respectively (P = .69). One ticlopidine-treated patient developed thrombocytopenia,
which was thought to be a case of possible thrombotic thrombocytopenia purpura,
and recovered after therapy with plasmapheresis.
Conclusions During a 2-year follow-up, we found no statistically significant difference
between ticlopidine and aspirin in the prevention of recurrent stroke, myocardial
infarction, or vascular death. However, there was a nonsignificant trend for
reduction of fatal or nonfatal stroke among those in the aspirin group. Based
on these data and the risk of serious adverse events with ticlopidine, we
regard aspirin as a better treatment for aspirin-tolerant black patients with
noncardioembolic ischemic stroke.
Blacks are disproportionately affected by stroke, yet they have been
underrepresented in clinical trials.1-8 Recommendations
for stroke prevention in this population have been based largely on trials
that have included few black participants. This may not be an optimal practice
because blacks are among those with a higher prevalence of major cardiovascular
risk factors, a different distribution of atherosclerotic occlusive cerebral
vascular lesions, vascular biological differences such as low renin hypertension,
and a different pattern of use of medical procedures and access to care8-13 that
could influence outcome.
A subgroup analysis of the Ticlopidine Aspirin Stroke Study (TASS)14,15 suggested a more favorable risk-benefit
profile for nonwhites than whites. Specifically, among the 495 black and 108
nonwhite and nonblack study participants, there was a 24.1% relative risk
reduction (RRR) for stroke and death at 2 years favoring ticlopidine (500
mg/d) over aspirin (1300 mg/d), and 10% fewer serious adverse events (SAEs).15 Overall in TASS, there was a 12% RRR for nonfatal
stroke or death from any cause (P = .05) favoring
ticlopidine at 3 years.
The current study was designed in 1993, with the belief that a targeted
recurrent stroke prevention study for blacks was justified given their disproportionate
stroke burden, promising data for ticlopidine as a recurrent stroke preventive
treatment in nonwhites, and the lack of previous substantial representation
of blacks in stroke clinical trials. The primary outcome of the African American
Antiplatelet Stroke Prevention Study (AAASPS) was the composite end point
of recurrent stroke, myocardial infarction, or vascular death.
A description of the design and methods of AAASPS has been reported
previously16 in accordance with criteria proposed
by the Consolidated Standards of Reporting Trials.17,18 That
article16 included a discussion of barriers
to black participation in clinical trials and how they were overcome,12,19,20 the rationale for
study drug selection, relationships established with primary care physicians,
management of cardiovascular risk factors, and other major aspects of the
study. The diagnosis of stroke and stroke subtype was determined after review
of source documents and case report forms and by application of criteria from
the Trial of ORG 10172 in Acute Stroke Treatment (TOAST)21 by
local principal investigators for the entry stroke and by the AAASPS adjudication
committee for all outcome events. Entry and outcome stroke cases received
computed tomography or magnetic resonance imaging of the head.
At the time our study design was developed in the early to mid-1990s,
we believed that there was uncertainty about the preferred aspirin dose for
recurrent stroke prevention.22 Given this uncertainty,
we opted for an aspirin dose of 650 mg/d in accordance with the recommendations
by Barnett et al.22
Eligibility criteria included black (African American) race; 29-85 years
of age inclusive; noncardioembolic ischemic stroke with onset at least 7 days
but not more than 90 days; cranial computed tomographic scan or magnetic resonance
image of the brain consistent with occurrence of the entry cerebral infarct;
measurable neurological deficit that correlates at onset with entry cerebral
infarct; informed consent; and availablity of patient to be followed up in
an outpatient treatment program.16
Exclusion criteria included transient ischemic attack, subarachnoid
hemorrhage, cardiac source embolism, iatrogenic stroke, nonatherosclerotic
stroke, postoperative stroke occurring within 30 days of operation, or carotid
endarterectomy as primary treatment measure for entry cerebral infarct; mean
arterial blood pressure higher than 130 mm Hg on 3 consecutive days; modified
Barthel index of less than 10; history of dementia or neurodegenerative disease;
severe comorbid condition (eg, cancer) judged to limit survival during 2-year
follow-up; enrollment in another clinical trial; allergy or sensitivity to
study drugs; woman of childbearing potential; gastrointestinal tract bleeding,
bleeding diathesis, or platelet or other hematologic abnormality (judged to
be a contraindication for administration of study drugs) currently active
or clinically active in the past year; hematuria or positive stool guaiac
test related to major bleeding source; and prolonged prothrombin time or partial
thromboplastin time, blood urea nitrogen level higher than 40 mg/dL, serum
creatinine level higher than 2.0 mg/dL (176.8 µmol/L), thrombocytopenia
or neutropenia defined by the lower limit of normal for the platelet count
or white blood cell count (unless absolute neutrophil count of at least 1800/mm3), or liver function tests 2 or more times the upper limit of normal.
All sites had to receive formal approval from their institutional review board
before the study could commence at a local site.
The primary hypothesis of this randomized, double-blind, investigator-initiated
clinical trial was that ticlopidine (500 mg/d) was more effective than aspirin
(650 mg/d) in preventing the composite outcome of recurrent stroke, myocardial
infarction, or vascular death (death due to ischemic or hemorrhagic stroke,
myocardial infarction, sudden death, pulmonary embolism, heart failure, visceral
or limb infarction, or a vascular procedure or operation) among blacks with
noncardioembolic ischemic stroke who were followed up for up to 2 years. The
prespecified secondary hypotheses were that the incidence of the outcome end
points of recurrent stroke or death; nonfatal or fatal stroke; recurrent stroke,
myocardial infarction, or death from all causes; vascular death; death from
all causes; or myocardial infarction would be lower in ticlopidine-treated
patients compared with aspirin-treated patients followed up for up to 2 years.
The ratio of those receiving ticlopidine and aspirin was 1:1, and the
sequence was stratified by site to balance the treatment groups. All study
personnel were masked (blinded) from treatment assignment with the exception
of 1 study statistician who developed the randomization algorithm. After written
informed consent was obtained, local study site personnel called a dedicated
automated telephone registration system for AAASPS, which was operated by
the Moffitt Cancer Research Institute at the University of South Florida in
Tampa, to register a study participant.23
Ticlopidine was packaged as 250-mg tablets and aspirin as 325-mg coated
tablets. The placebo tablets had identical physical properties. Study medications
were dispensed from plastic bottles. Medication compliance was determined
by pill count at each follow-up visit. A dose of 250 mg of ticlopidine was
administered with a placebo aspirin tablet twice a day with meals. A dose
of 325 mg of aspirin was administered with a placebo ticlopidine tablet twice
a day with meals.
Before entry into the study, at 12 months, 24 months, and at any time
a study participant experienced an outcome event or terminated from the trial,
the following laboratory studies were obtained: complete blood count and platelet
count; blood urea nitrogen; serum creatinine; total cholesterol, low-, high-
and very low-density lipoprotein cholesterol, and triglycerides; total bilirubin,
alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase,
and alkaline phosphatase; serum glucose and electrolytes; and urinalysis.
Complete blood count and platelet count were performed every 2 weeks during
the first 3 months of the study or at any unscheduled time the local investigative
team deemed that it was indicated.
Study participants were examined in person at baseline; every 2 weeks
during the first 3 months; and at 6, 10, 12, 16, 20, and 24 months; and at
any unscheduled time the investigative team deemed that it was indicated for
reason of patient safety, medication compliance, or the occurrence of outcome
events or SAEs. Telephone contact was made during study months for which patients
did not have an in-person examination to screen for medication compliance,
outcome events, and SAEs. Because blacks are more likely to experience cyclical
neutropenia,15 and the incidence of severe
neutropenia with ticlopidine use is uncommon (<1%),15 we
believe that study personnel remained blinded in relation to laboratory data.
Before entry into the trial, acute hospital care and stroke diagnostic
evaluations were at the discretion of the local principal investigator or
primary care physician. Study patients received verbal instruction and written
materials about stroke prevention, and a booklet about the AAASPS program
that was developed in collaboration with the AAASPS community advisory board.
This booklet also listed medications that were to be avoided or were contraindicated.
Study patients were educated about possible SAEs of the study medications
and given contact information to use in the event questions or problems arose.
For study patients who reached an outcome end point, local principal investigators
were given the option to treat these patients with open-label aspirin or to
transition patients to community care for stroke prevention according to their
primary care physicians.
The AAASPS included several mechanisms to ensure patient safety: a predetermined
laboratory "panic" value system whereby the main laboratory notified the local
investigative team and the clinical safety monitor of a critical value; an
internal AAASPS inhouse safety committee; and an external data safety and
monitoring board that was appointed by the National Institutes of Health.
Data from blacks and nonwhites in TASS14,15 were
used to develop sample size estimates for AAASPS. We anticipated that AAASPS
patients would generally be in poorer health than those in TASS. A 2-year
event rate of 25% was projected for the AAASPS aspirin treatment group. A
total of 1410 patients would be required to achieve 80% power to detect a
25% RRR with respect to the 2-year primary event rate based on use of a 2-tailed
log-rank test with an overall α level of .05. Allowing for an increase
of 15% for attrition due to voluntary withdrawal and loss to follow-up, and
an additional 7% to allow for interim analyses using the Lan-DeMets strategy
with O'Brien-Fleming boundaries, a total sample size of 1800 was estimated
to yield 306 primary outcome events.24,25 Interim
analyses were performed at information times of 15%, 23%, 35%, 67%, and 76%,
after which the blinded treatment phase of the study was terminated.
All analyses were conducted using SAS (SAS Institute Inc, Cary, NC)
and S-Plus (Mathsoft, Cambridge, MA) statistical software according to the
intention-to-treat principle and were based on available patient data through
March 31, 2002. Categorical values were compared using χ2 tests
and the Fisher exact test. Continuous data were compared using Wilcoxon and t tests. Time-to-event curves were calculated using the
Kaplan-Meier method and were compared between treatment groups using the log-rank
test. Cox proportional hazards modeling was also used to compare treatment
groups while adjusting for various covariates such as age, sex, and entry
stroke subtype and severity.26 Secondary end
points, as well as prespecified subgroups (sex, entry stroke subtype, and
stroke severity, and various categories of elapsed time between onset of the
index stroke and start of treatment), were analyzed using similar methods.
Study patients who dropped out of the study were censored at the time of their
Fultility analyses were performed and presented to the data safety and
monitoring board (DSMB) appointed by the National Institutes of Health (NIH)
as part of study interim analysis reports. These analyses were conducted to
assess the likelihood of observing a statistically significant result if the
trial was to continue to full information (the observance of 306 primary outcome
events). The method of futility analysis was that of conditional power, as
defined by the conditional probability of rejecting the hypothesis of no treatment
difference at the end of the trial given current interim data. This method
was chosen before the trial began. The conditional probability was computed
by simulating the number and timing of future events based on the current
event rates. Simulations were performed using S-Plus. A conditional power
close to zero indicated little chance of crossing the statistical boundary
were the trial to go to completion.
The main AAASPS organizational components are listed at the end of the
article, with a listing of local sites, the investigative team at each local
site, and the number of study patients enrolled at each site. Also, we performed
routine audits at 27 centers that were our larger enrollment centers, and
at 4 centers for cause (3 sites for possible difficulty with data collection
and follow-up procedures, and at 1 site for possibly entering a participant
for whom several key data points did not match the source documentation).
In all audits, all issues were resolved, and no major action was required
to be taken by the AAASPS clinical or data management centers.
Recruitment commenced on December 12, 1995, and was completed on October
1, 2001. A total of 1809 patients were enrolled in the study; 902 in the ticlopidine
group and 907 in the aspirin group. The number of patients enrolled by study
year was 354 in 1996, which included December 12, 1995 through December 31,
1996; 326 in 1997; 315 in 1998; 303 in 1999; 314 in 2000; and 197 from January
1 through October 1, 2001.
Futility analyses were computed as part of the statistical analyses
presented to the NIH-appointed DSMB as part of study interim analysis reports.
The latest such report was based on available patient data through March 31,
2002, and suggested that there was less than a 1% chance that ticlopidine-treated
patients would have a superior outcome compared with aspirin-treated patients
if the trial were to continue to completion. After careful review of this
report and consultation with study staff, the study scientific advisory committee,
and other external experts, the DSMB recommended that the blinded phase of
the study end on July 15, 2002. At that juncture, study participants were
given the option of remaining in the study taking study-sponsored open-label
aspirin or transition into the community for stroke prevention therapy according
to their community physician.
Figure 1 summarizes the status
of patients in the trial by treatment group. Three hundred seventy participants
(41.0%) in the ticlopidine group and 403 participants (44.4%) in the aspirin
group completed the 24-month examination. In general, all types of withdrawal
were slightly more common in patients receiving ticlopidine, but a statistically
significant difference was observed for withdrawal due to SAEs (15.1% for
ticlopidine vs 11.5% for aspirin; P = .02). The time-to-occurrence
of lost to follow-up and voluntary withdrawal did not differ significantly
between treatment groups (P>.25 for each comparison).
At the time the blinded phase of the study was halted, excluding patients
with outcome events, 47.1% of the ticlopidine group and 46.5% of the aspirin
group had not completed the 2-year follow-up, and 149 participants remained
in the ticlopidine group and 176 in the aspirin group (P = .11). Overall, the study database contained an average of 1.54
years of follow-up data per study patient. Median follow-up was 710 days for
ticlopidine-treated patients and 716 days for aspirin-treated patients. On
average, study participants completed 88% of study visits.
Baseline characteristics of patients in the 2 treatment groups are balanced
and are summarized in Table 1.
Blacks have a higher risk of lacunar infarction than whites.8 Furthermore,
our eligibility criteria excluded those with atrial fibrillation, cardiac
sources of embolism that would require warfarin therapy, or large artery carotid
occlusive disease treated by carotid endarterectomy, which would serve to
increase the likelihood of enrolling lacunar infarction patients into the
study. Drug compliance was assessed by pill count. Overall, median compliance
was 91%; 90% in the ticlopidine group and 92% in the aspirin group.
A total of 245 primary outcomes (the composite of recurrent stroke,
myocardial infarction, or vascular death) occurred during the trial (Table 2). There were 133 primary outcomes
among the ticlopidine-treated patients and 112 among the aspirin-treated patients.
As shown by Kaplan-Meier curves in Figure
2, there was no statistically significant difference between treatment
groups in the occurrence of the primary outcome end point (P = .12 by log-rank test; the O'Brien-Fleming boundaries were not crossed).
Cox proportional hazards modeling that included key covariates, such as treatment
group assignment, age, and baseline risk factors, showed a similar treatment
difference (P = .11).
There were slightly more fatal (4 vs 2) or nonfatal (102 vs 84) recurrent
strokes among ticlopidine-treated patients, but this was not statistically
significant (Table 2). However,
the Kaplan-Meier curves indicate time to fatal or nonfatal stroke (Figure 2) approached a statistically significant
difference (P = .08 by log-rank test) in favor of
the aspirin-treated patients.
Secondary outcomes including any recurrent stroke, death (all cause),
vascular death, recurrent stroke or death (all cause), and the composite end
point of recurrent stroke, myocardial infarction, or death (all cause) were
not statistically significantly different between treatment groups (Table 2). Overall, we observed a 2-year
primary event rate of 19.7% among ticlopidine-treated patients and 16.3% among
those treated with aspirin.
We compared recurrent stroke subtype and severity between treatment
groups and did not find a statistically significant difference (Table 3). Also, we extended the follow-up data for the primary outcome
cluster by adding information from April to December 2002. There were 5 additional
events: 3 strokes and 1 myocardial infarction in the ticlopidine group and
1 stroke in the aspirin group. The primary outcome findings, however, were
not substantially changed (P = .08 by log-rank test).
In addition to the intention-to-treat analysis, we performed an on-treatment
analysis for the primary event outcome cluster. For each patient, we computed
the percentage of time on blinded study medication prior to the occurrence
of an outcome event or completion of the study (whichever came first). We
then performed log-rank tests on subgroups of patients based on this percentage
(ie, those having a percentage on blinded study medication (≥60% or ≥80%).
We observed P = .10 for the 60% cutoff and P = .11 for the 80% cutoff compared with P = .12 overall. Thus, we did not find a statistically significant
difference based on intention-to-treat or on-treatment analyses.
Data on patients reporting SAEs appear in Table 4. Overall, 532 patients reported SAEs: 270 (29.9%) among
ticlopidine-treated patients and 262 (28.9%) among aspirin-treated patients.
Diarrhea (0.3% vs 0.2%), neutropenia (3.4% vs 2.2%), and thrombocytopenia
(0.3% vs 0.2%) were slightly more frequent among ticlopidine-treated patients,
but this did not reach statistical significance. One case of thrombocytopenia,
which occurred early after the enrollment phase of the study was initiated,
was diagnosed as a possible case of thrombotic thrombocytopenic purpura. The
patient recovered after treatment with plasmapheresis. Gastrointestinal tract
hemorrhage was slightly more common in aspirin-treated patients (0.9% vs 0.4%),
but this did not reach statistical significance. The time-to-occurrence of
a SAE did not differ significantly between the treatment groups (P = .39), but the time-to-occurrence of a SAE did (P = .003) (not shown in Table 4).
For study patients who had to permanently discontinue blind phase medication
due to a SAE (not shown in Table 4),
thrombocytopenia (0.2% vs 0.0%), neutropenia (1.8% vs 1.2%), and rash (1.7%
vs 0.6%) were more common among ticlopidine-treated patients, but only the
occurrence of rash differed significantly between the treatment groups (P = .02). Gastrointestinal tract hemorrhage requiring premature
discontinuation of study medication (not shown in Table 4) was more common among aspirin-treated patients but did
not reach statistical significance (0.6% vs 0.2%; P =
Ticlopidine, a unique inhibitor of platelet aggregation,27,28 was
approved for clinical use in the early 1990s by the US Food and Drug Administration
to reduce the risk of fatal or nonfatal thrombotic stroke in patients with
stroke precursors and in patients who have had a completed thrombotic stroke.
Two large clinical trials, TASS14 and the Canadian
American Ticlopidine Study (CATS),29 showed
efficacy for ticlopidine in stroke prevention. The CATS intention-to-treat
analysis showed a RRR of 23.3% (P = .02) for the
composite outcome of stroke, myocardial infarction, or vascular death favoring
ticlopidine over placebo. Reversible severe neutropenia and reversible severe
skin rash occurred in ticlopidine-treated patients in about 1% of cases and
diarrhea in 2% of cases. In TASS, the RRR favoring ticlopidine over aspirin
at 3 years for the primary end point of nonfatal stroke or death from any
cause was 12% (95% confidence interval [CI], −2% to 26%) with a marginally
significant difference in primary events (P = .048).
In addition, there was an RRR of 21% (95% CI, 4%-38%; P = .02) for fatal or nonfatal stroke favoring ticlopidine at 3 years,
and ticlopidine was more effective than aspirin in both men and women. Diarrhea
(20%), skin rash (14%), and severe but reversible neutropenia (<1%) occurred
in patients receiving ticlopidine.
Efficacy data from our trial of black patients with noncardioembolic
ischemic stroke did not show a reduction of the composite outcome of recurrent
stroke, myocardial infarction, or vascular death among ticlopidine-treated
patients (P = .12 by log-rank test). The outcome
of fatal or nonfatal stroke approached a statistically significant difference
(P = .08 by log-rank test) favoring the aspirin treatment
The blinded phase of our study was halted by the data and safety monitoring
board appointed by the National Institutes of Health after the recruitment
and follow-up phases of the study had been ongoing for about 6.5 years because
futility analyses indicated a less than 1% chance of ticlopidine being significantly
better than aspirin therapy in the prevention of our primary outcome if the
trial were to continue to completion. These analyses also indicated a 40%
to 50% likelihood of aspirin being significantly better than ticlopidine in
reducing the risk of recurrent fatal or nonfatal stroke if the trial were
to continue to completion. The decision of the data and safety monitoring
board to stop the study was based on the potential futility of ticlopidine
use for the primary study outcome end point and the small likelihood, but
potential for SAEs among ticlopidine-treated patients.
Based on data from a subanalysis of nonwhite patients in TASS,15 we believed that there was a substantial likelihood
that ticlopidine would be more effective than aspirin in reducing vascular
events among a high-risk stroke population. We hypothesized that ticlopidine,
a more global platelet inhibitor, would be more effective in black ischemic
stroke patients with a substantial stroke and cardiovascular disease risk
profile and that aspirin might prove to be an inferior platelet inhibitor
in these high-risk patients. In retrospect, we are somewhat surprised by our
results because TASS showed a modest reduction in the primary outcome of stroke
or all-cause death favoring ticlopidine over aspirin.14 Furthermore,
clopidogrel, a compound in the same drug class as ticlopidine, has also been
studied. The Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events
(CAPRIE) study showed a modest benefit with 75 mg/d of clopidogrel compared
with 325 mg/d of aspirin for the reduction of recurrent stroke, myocardial
infarction, or vascular death among patients who entered with either recent
ischemic stroke, recent myocardial infarction, or symptomatic peripheral arterial
disease.30 In a CAPRIE subanalysis of 6431
patients with stroke, there was only a nonstatistically significant reduction
of ischemic stroke, myocardial infarction, or vascular death favoring clopidogrel
(RRR, 7.3%; 95% CI, −5.7% to 18.7%; P = .26).
However, the CAPRIE subanalysis of stroke patients30 and
the TASS subanalysis of nonwhites15 were not
adequately powered statistically to be conclusive.
We are uncertain why ticlopidine was not superior to aspirin in reducing
major vascular events in our study patients. We used a lower aspirin dose
than in TASS,14,15 but we can
only speculate whether this or some other biological difference in response
to therapy might explain our findings. Overall, there is a relative paucity
of scientific information about biological differences in drug response by
race or ethnic group.31 We are not aware of
such published information for aspirin and ticlopidine in blacks.
The drop-out rate in our study was generally higher than most recurrent
stroke prevention trials. In the CAPRIE study, for example, the number of
study participants withdrawn or lost to follow-up was 22 (0.2%) of 9553 among
those receiving clopidogrel and 20 (0.2%) of 9546 among those receiving aspirin.30 In our study, the corresponding figures for lost
to follow-up or voluntary withdrawal were 15.2% in the ticlopidine treatment
group and 13.3% for those receiving aspirin. Most of these were due to voluntary
withdrawal, which we defined as the patient deciding to discontinue participation
unrelated to an AE but rather to personal preference. We believe that our
higher drop-out rate can be attributed to study participants of generally
lower socioeconomic status, who have traditionally had less access to medical
care, and less involvement in clinical trials.8,9,12,20 In
an AAASPS exploratory study, we found that voluntary withdrawal occurred for
such reasons as distrust of the medical establishment, fear of continuation
in a blinded trial, and pressure from family members, primary caregivers,
or primary care physicians.20
We believe that our drop-out rate did not limit our ability to detect
a treatment effect because we anticipated this level of attrition and accounted
for it in our sample size calculation. In addition, we conducted both intention-to-treat
and on-treatment analyses and did not find a statistically significant difference
between treatment groups for the primary event outcome cluster. Therefore,
it is unlikely that our findings are due to a switch to open-label aspirin
therapy during the course of the trial thereby diluting the ticlopidine treatment
group. We note that the number of primary outcomes was less than the projected
number of 306, which was due to premature stoppage of the study. However,
had the study continued to completion, we estimated the occurrence of at least
310 outcome events. Thus, the nonborderline nature of the study results, a
futility analysis that showed a less than 1% chance of ticlopidine performing
better than aspirin, and loss of information that did not occur substantially
more in one treatment group than the other, makes it unlikely that loss of
information significantly affected our results.
Our recurrent primary event rates were lower than expected. For example,
the expected 2-year event rate was projected to be 25% in the aspirin group
but was observed to be 16.3%. Our rate, however, for stroke and death is similar
to that of the recently completed Warfarin Aspirin Recurrent Stroke Study
(WARSS).32 WARSS had a preponderance of lacunar
infarctions at entry (56%), similar to AAASPS (67.5%), and the rate of recurrent
stroke and death in WARSS was 16.0% at 2 years for the aspirin group. The
corresponding rate for our aspirin group, derived by taking the 1-year rate
from our aspirin study participants because most had completed 1 year of follow-up,
and multiplying this estimate by a factor of 2, was 16.1%; a figure quite
similar to that of WARSS. Our study was not designed to determine if the lower-than-expected
rates for stroke were due to baseline characteristics in the sample, better
control of risk factors, or more widespread use of concomitant therapies.
We speculate, however, that this lower-than-expected rate could be related
to better control of risk factors as we noted increasing use of cholesterol-lowering
agents during the study period.
The SAEs with ticlopidine have been well described.14,29,33-36 Our
SAE data show that slightly more occurred among ticlopidine-treated patients
(29.9%) overall than aspirin-treated patients (28.9%). In addition, there
were slightly more clinically reported SAEs of diarrhea in the ticlopidine-treated
patients (0.3% vs 0.2%), but more clinically reported SAEs of major gastrointestinal
tract bleeding among aspirin-treated patients (0.9% vs 0.4%).
We defined serious neutropenia as a laboratory-determined absolute neutrophil
count of less than 1000/mm3 and serious thrombocytopenia as a laboratory-determined
platelet count of less than 100 000/mm3. In either case, once
the absolute neutrophil count or platelet count reached the critical prespecified
level, the blinded phase study medication was discontinued. We observed a
higher percentage of laboratory-determined serious neutropenia (3.4% vs 2.2%)
among ticlopidine-treated patients and about the same percentage of laboratory-determined
serious thrombocytopenia (0.3% vs 0.2%) among the treatment groups. All cases
of neutropenia were reversible, but one case of thrombocytopenia resulted
in possible thrombotic thrombocytopenic purpura in a patient who recovered
after treatment with plasmapheresis.
Our data support the prior TASS subanalysis findings15 suggesting
that some key AEs might be less frequent in ticlopidine-treated nonwhites.
We observed lower percentages of diarrhea (8.4% in ticlopidine-treated patients
vs 9.0% in TASS subanalysis vs 20.4% in TASS overall14)
and rash (5.9% vs 9.0% in TASS subanalysis vs 11.9% in TASS overall).
Based on data from the IMS Health's National Prescription Audit Plus
and National Disease and Therapeutic Index of Dispensed Prescriptions for
nonaspirin antiplatelet agents used specifically or "customized" for stroke
or transient ischemic attack patients in 2002, generic and branded ticlopidine
was third in market share with an estimated 3.2% of dispensed oral antiplatelet
prescriptions; dipyridamole was second at 17.9%; and clopidogrel was first
at 78.9% (personal communication from David Milbauer, Marketing Research,
Boehringer Ingelheim Pharmaceuticals Inc. Data extracted April 2003). Aspirin
use is not captured in the IMS Health Index of Dispensed Prescriptions because
it is an over-the-counter medication. With an estimated 4 million stroke survivors
and between 600 000 and 750 000 strokes occurring in the United
States annually, of which about 85% are ischemic, up to 108 800 persons
in the United States could be taking ticlopidine and up to 20 400 persons
could receive ticlopidine as an initial stroke prevention therapy each year.
Our findings do not support the use of ticlopidine as a first-line agent for
blacks for recurrent stroke prevention, provide substantial data to challenge
the subanalysis of TASS that suggested benefits of ticlopidine in recurrent
stroke prevention in nonwhite patients,15 and
provide new data to challenge current guidelines on secondary stroke prevention.
The implications and relevance of our data as they affect other antiplatelet
agents for recurrent stroke prevention in blacks remain speculative as we
did not directly compare our study agents with clopidogrel or the combination
aspirin plus extended-release dipyridamole. Furthermore, the clinical trials
that tested these other agents had relatively few or no black enrollees.30,37 For clinicians who remain unconvinced
about the efficacy or safety of these other agents, aspirin could be the preferred
agent for recurrent stroke prevention in blacks. However, administration of
these other agents in black patients will vary based on patient and physician
Prior systematic reviews and guideline statements suggest that aspirin
is of benefit in a wide range of patients with suspected acute ischemic stroke
to reduce the risk of early stroke recurrence38 and
as an initial choice of therapy for recurrent stroke prevention.39-41 Before
our study was completed, thienopyridine derivatives (ticlopidine and clopidogrel)
appeared to be modestly more effective than aspirin in the prevention of serious
vascular events in high-risk patients.42 Aspirin
is much less expensive than other major antiplatelet agents, is readily available,
easy to use, and relatively safe. Head-to-head comparison with other agents
indicates that it may be difficult to outperform aspirin as a stroke prevention
therapy in some noncardioembolic ischemic stroke patients.31,32,43,44
Our data call into question the superiority of the thienopyridine ticlopidine
in black noncardioembolic ischemic stroke patients, and suggest that ticlopidine
is unlikely to be superior to aspirin for prevention of recurrent stroke and
major vascular events in these patients. Furthermore, ticlopidine may have
a less favorable and potentially SAE profile. Therefore, aspirin is a reasonable
first choice prevention agent in aspirin-tolerant black patients with noncardioembolic
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