Center for Stroke Research,
Chicago, Illinois
Department of Neurology,
Johns Hopkins Hospital,
Baltimore, Maryland
To the Editor:
Substantial clinical data support the use of antiplatelet therapy
in reducing the incidence of secondary atherothrombotic events in
individuals who have experienced a transient ischemic attack
(TIA) or stroke.1 The consensus based on recent trials is
that antiplatelet therapy can reduce the incidence of subsequent
ischemic events in those patients for whom carotid
endarterectomy is not indicated and for whom atrial
fibrillation is not a contributing factor.2 Aspirin has
been the antiplatelet drug most frequently evaluated, and numerous
trials support its efficacy. Ticlopidine, a thienopyridine
antiplatelet agent, is also effective in preventing recurrent
ischemic events in the stroke patient,3 but the
risk of bone marrow depression and questions about its superiority to
aspirin in reducing ischemic vascular events other than
subsequent stroke have been raised.4 5 6 Recently
clopidogrel, an analog of ticlopidine that has not demonstrated bone
marrow toxicity, was approved by the Food and Drug Administration for
use in patients at risk of recurrent ischemic events, including
stroke, myocardial infarction, and limb claudication. The clinical data
supporting the use of clopidogrel, however, may provide no compelling
justification for using clopidogrel in preference to aspirin in stroke
patients.
Although the CAPRIE (Clopidogrel versus Aspirin in Patients at Risk of
Ischemic Events) trial7 found a statistically
significant reduction in the combined incidence of stroke, myocardial
infarction, and vascular death for clopidogrel compared to aspirin, the
magnitude of the therapeutic advantage was small (an 8.7% relative
risk reduction, or a decrease in the absolute event rate from 5.83%/y
to 5.32%/y with clopidogrel). A difference of this magnitude would
require switching 200 patients from aspirin to clopidogrel to see even
1 less atherothrombotic event per year. Furthermore, the therapeutic
advantage attributable to clopidogrel was observed only when data from
stroke patients were pooled with those enrolled in the study on the
basis of a recent myocardial infarction or clinically active
peripheral arterial disease. When stroke
patients, a group totaling over 6400 individuals with over 12 000
patient-years of treatment, were evaluated in a post hoc
analysis, no significant difference in efficacy was seen
between clopidogrel and aspirin. The majority of the benefit of
clopidogrel over aspirin in CAPRIE occurred in the group enrolled
because of clinically active peripheral
arterial disease. Also, it has been suggested that
high-dose aspirin may be more effective than low-to-moderate-dose
aspirin in the secondary prevention of stroke.8 Thus, the
possibility exists that at higher doses aspirin may be more effective
than clopidogrel in the prevention of recurrent stroke.
Given these uncertainties surrounding the relative efficacy of
clopidogrel compared with aspirin in stroke patients, it is difficult
to justify switching patients to clopidogrel. No safety advantage for
clopidogrel was evident in CAPRIE. Both agents produced similar side
effect profiles (eg, upper gastrointestinal discomfort and general
bleeding disorders were the most common adverse events for both drugs).
Although upper gastrointestinal effects were somewhat more common in
the aspirin-treated patients, it is possible that the incidence of
these events would have been more comparable if a lower dose of aspirin
or an enteric-coated formulation had been used in CAPRIE.9
If one considers the higher cost of clopidogrel over aspirin and the
absence of a substantive safety advantage of clopidogrel over aspirin,
there is little basis for switching stroke patients to clopidogrel.
There is however, a place for clopidogrel in the treatment of stroke
patients. The questionable status of clopidogrel utilization relative
to aspirin should not detract from the conclusion that clopidogrel is
an effective antiplatelet agent that would most likely demonstrate
superiority to placebo if such a trial were ethically possible. There
are, for example, a number of patients who are unable to tolerate or
who have failed aspirin therapy, for whom clopidogrel may be indicated.
Also, the CAPRIE trial suggests there may be a role for clopidogrel in
the treatment of patients with peripheral vascular disease.
However, at present, aspirin must still be considered the
antiplatelet agent of choice for use in the prevention of recurrent
ischemic events in stroke patients.
Note: Dr Gorelick is on the Speakers Bureau for
Janssen/Excerpta Medica, Dupont, Roche Laboratories, and he has
consultant agreements with NPS, Esaii, Searle/Lorex.
References
1.
Antiplatelet Trialists' Collaboration.
Collaborative overview of randomized trials of antiplatelet
therapy, I: prevention of death, myocardial infarction, and stroke by
prolonged antiplatelet therapy in various categories of
patients. Br Med J.. 1994;308:81–106.
2.
Gorelick PB. Stroke prevention.
Arch Neurol.. 1995;52:347–355.
3.
Gent M, Blakely JA, Easton JD, Ellis DJ, Hachinski VC,
Harbison JW, Panak E, Roberts RS, Sicurella J, Turpie AG. The
Canadian American Ticlopidine Study (CATS) in thromboembolic
stroke. Lancet.. 1989;1:1215–1220.[Medline]
[Order article via Infotrieve]
4.
Hass WK, Easton JD, Adams HP, Pryse-Phillips W, Molony
BA, Anderson S, Kamm B. A randomized trial comparing ticlopidine
hydrochloride with aspirin for the prevention of stroke in high-risk
patients. N Engl J Med.. 1989;321:501–507.[Abstract]
5.
Noble S, Goa KL. Ticlopidine: a review of its
pharmacology, clinical efficacy and tolerability in the prevention of
cerebral ischaemia and stroke. Drugs Aging.. 1996;8:214–232.[Medline]
[Order article via Infotrieve]
6.
Bousser MG, Roberts RS, Gent M. Ticlopidine and
clopidogrel in secondary stroke prevention. Cerebrovasc
Dis.. 1997;7:17–23.
7.
CAPRIE Steering Committee. A randomized,
blinded trial of clopidogrel versus aspirin in patients at risk of
ischemic events (CAPRIE). Lancet.. 1996;348:1329–1339.[Medline]
[Order article via Infotrieve]
8.
Dyken ML, Barnett HJM, Easton JD, Fields WS, Fuster V,
Hachinski V, Norris JW, Sherman DG. Low-dose aspirin and stroke:
"It ain't necessarily so." Stroke.. 1992;23:1395–1399.
9.
Hirsh J, Dalen JE, Fuster V, Harker LB, Patrono C,
Roth G. Aspirin and other platelet-active drugs.
Chest.. 1995;108:247S–257S.
© 1998 American Heart Association, Inc.
Letters to the Editor
Clopidogrel and Its Use in Stroke Patients
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