(Stroke. 2000;31:1779.)
© 2000 American Heart Association, Inc.
Comments, Opinions, and Reviews |
Thienopyridines or Aspirin to Prevent Stroke and Other Serious Vascular Events in Patients at High Risk of Vascular Disease?
A Systematic Review of the Evidence From Randomized Trials
From the Department of Medicine (G.J.H.), University of Western Australia, Perth, Australia; Clinical Trial Service Unit (C.L.M.S.), University of Oxford, Oxford, UK; and the University of Tasmania (D.W.D.), Tasmania, Australia.
Correspondence to Dr Cathie Sudlow, Specialist Registrar in Neurology, Department of Neurology, Derriford Hospital, Plymouth PL6 8DH, UK. E-mail cathie.sudlow{at}platelet.freeserve.co.uk
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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Background and Purpose—Aspirin is the most widely studied and prescribed antiplatelet drug for patients at high risk of vascular disease. We aimed to establish how the thienopyridines (ticlopidine and clopidogrel) compare with aspirin in terms of effectiveness and safety.
Methods—We did a systematic review of all unconfounded randomized trials comparing either ticlopidine or clopidogrel with aspirin for patients at high risk of vascular disease. The primary outcome was vascular events (stroke, myocardial infarction, or vascular death). Adverse outcomes were intracranial and extracranial hemorrhage, upper and lower gastrointestinal disturbances, neutropenia, thrombocytopenia, and skin rash.
Results—In 4 trials among 22 656 patients (including 9840
presenting with a transient ischemic
attack/ischemic stroke), the thienopyridines reduced the odds
of a vascular event by 9% (odds ratio 0.91, 95% CI 0.84 to 0.98;
2P=0.01), preventing 11 (95% CI 2 to 19) events per
1000 patients treated for 
2 years. The thienopyridines produced
significantly less gastrointestinal hemorrhage and upper
gastrointestinal upset (indigestion/nausea/vomiting) than did aspirin.
Both thienopyridines increased the odds of skin rash and of diarrhea
(ticlopidine by 2-fold and clopidogrel by approximately one third).
Only ticlopidine increased the odds of neutropenia.
Conclusions—The thienopyridines appear modestly more effective than aspirin in preventing serious vascular events in high-risk patients. Clopidogrel appears to be safer than ticlopidine and as safe as aspirin, making it an appropriate, but more expensive, alternative antiplatelet drug for patients unable to tolerate aspirin. However, there is insufficient information to determine which particular types of patients would benefit most, and which least, from clopidogrel instead of aspirin.
Key Words: cardiovascular diseases • cerebrovascular disorders • meta-analysis • platelet aggregation • randomized controlled trials
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Aspirin is the most widely studied and prescribed antiplatelet agent. It inhibits platelet activation by irreversibly inhibiting platelet cyclooxygenase and thromboxane production and prevents about a quarter of serious vascular events (ie, stroke, myocardial infarction [MI], or vascular death) among patients at high risk of vascular disease. In the Antiplatelet Trialists’ (APT) overview1 of randomized trials of antiplatelet therapy, no antiplatelet regimen was shown to be definitely more effective than aspirin in the prevention of vascular events, but small differences could not be excluded. The thienopyridine derivatives, ticlopidine and clopidogrel, are antiplatelet drugs that act through a mechanism different from that of aspirin, by inhibiting the binding of ADP to its platelet receptor. In the APT overview, ticlopidine, when compared directly with aspirin among almost 3500 patients, produced a promising but nonsignificant reduction in the odds of a vascular event of 10% (95% CI -1 to 24).1 The results of a large randomized trial comparing the new thienopyridine agent, clopidogrel, with aspirin among almost 20 000 patients at high risk of vascular disease have since added substantially to the available evidence from randomized trials for the effects of the thienopyridines versus aspirin.2
Therefore, we carried out a systematic review of the randomized evidence for the effectiveness and safety of the thienopyridines (ticlopidine and clopidogrel) compared with aspirin for the prevention of vascular events among patients at high risk of vascular disease. We considered both thienopyridines together, because they are chemically very similar and act on platelets through the same mechanism. Because of our particular interest in the management of patients with cerebrovascular disease, we also considered specifically those patients with a previous transient ischemic attack (TIA) or ischemic stroke.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Identification of Trials
We sought all unconfounded randomized trials comparing either ticlopidine or clopidogrel with aspirin among patients at high risk of vascular disease (those with symptoms of ischemia of the cerebral, coronary, or peripheral circulations) who were followed up for at least 1 month for the occurrence of vascular events. We searched the specialized trial registers of the Cochrane Stroke Group and the Antithrombotic Trialists’ Collaboration, Medline, and Embase and contacted Sanofi, the pharmaceutical company that developed and manufactures ticlopidine and clopidogrel.
Outcome Measures
The primary outcome of effectiveness was vascular events,
defined as stroke, MI, or death, from a vascular cause. This composite
outcome encapsulates all serious events that are likely to be affected
by antiplatelet drugs and thus increases the statistical power to
detect any true difference in effectiveness between the thienopyridines
and aspirin. Secondary effectiveness outcomes were any stroke
(ischemic or hemorrhagic), ischemic stroke, MI,
vascular death, or all-cause mortality. We classified deaths as
vascular if they were due to ischemic stroke, intracranial
hemorrhage, MI, or other vascular causes (including
extracranial hemorrhage) or as being of unknown cause.
The main adverse outcomes were intracranial hemorrhage, extracranial hemorrhage, gastrointestinal hemorrhage, neutropenia, and thrombocytopenia. Other adverse outcomes were skin rash, diarrhea, and the composite outcome of indigestion, nausea, or vomiting (to capture upper gastrointestinal upset).
We used each trial’s own definitions of the various outcome events.
Data Collection and Analysis
Two reviewers (G.J.H., C.L.M.S.) independently extracted
methodological details and relevant data from trial reports. We
resolved any disagreements by discussion and consensus. We obtained
additional unpublished data from the principal investigators of the
largest trial.2
We analyzed data by intention to treat and used the Peto
observed-minus-expected method in Cochrane review
software3 to obtain a weighted estimate of the odds ratio
(OR) for each outcome event. We assessed statistical
heterogeneity with a standard
2 test. We calculated absolute risk reductions
by the difference in risk between the 2 treatment groups and expressed
these as events prevented per 1000 patients treated.
Full details of the methods can be found in the full Cochrane Library electronic publication, on which the present article is based.3
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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We identified 4 completed trials, involving a total of 22 656 patients. The qualifying event was a recent TIA or ischemic stroke in 9840 patients, a recent MI in 6302 patients, and symptomatic peripheral arterial disease in 6514 patients. Aspirin was compared with ticlopidine in 3 trials (3471 patients)4 5 6 and with clopidogrel in 1 trial (19 185 patients).2 The duration of follow-up varied between
1 and 3 years, with an average of 2 years. The average
age of the patients included was 63 years, approximately two thirds
were male, and most were white. The main characteristics of the trials
included are summarized in the
Table
.
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The available data mainly reflected the results of the 2 largest trials, which together accounted for >98% of the patients and 99% of the vascular events.2 6 With the exception of thrombocytopenia, data for all outcome events of effectiveness and of safety were available from both of these trials but were not always available from the 2 smaller trials.
All Patients at High Risk of Vascular Disease
Effects on Serious Vascular Events (Stroke, MI, or Vascular
Death)
Compared with allocation to aspirin, allocation to a
thienopyridine was associated with a modest, yet statistically
significant, reduction in the odds of a serious vascular event (12.0%
for thienopyridine versus 13.0% for aspirin; OR 0.91, 95% CI 0.84 to
0.98; 2P=0.01), corresponding to the prevention or delay of
11 (95% CI 2 to 19) vascular events per 1000 patients treated for 2
years (Figure 1).
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The patients in the thienopyridine group also experienced a significant
reduction in the odds of any stroke (5.7% for thienopyridine versus
6.4% for aspirin; OR 0.88, 95% CI 0.79 to 0.98), corresponding to the
prevention or delay of 7 (95% CI 1 to 13) strokes per 1000 patients
treated for 2 years (Figure 2). There was
also a nonsignificant trend toward a reduction in ischemic
stroke (OR 0.90, 95% CI 0.81 to 1.01), MI infarction (OR 0.88, 95% CI
0.76 to 1.01), vascular or unknown cause of death (OR 0.93, 95% CI
0.82 to 1.06), and death from any cause (OR 0.95, 95% CI 0.85 to
1.05) (Figure 2).
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Adverse Effects
There was no clear difference between the thienopyridines and
aspirin in the odds of experiencing an intracranial hemorrhage
(0.3% for thienopyridine versus 0.4% for aspirin; OR 0.82, 95% CI
0.53 to 1.27) or an extracranial hemorrhage (8.8% for
thienopyridine versus 8.9% for aspirin; OR 1.00, 95% CI 0.91 to
1.09). The thienopyridines were associated with a significant reduction
in the odds of gastrointestinal hemorrhage (1.8% for
thienopyridine versus 2.5% for aspirin; OR 0.71, 95% CI 0.59 to 0.86)
and of indigestion/nausea/vomiting (14.8% for thienopyridine versus
17.1% for aspirin; OR 0.84, 95% CI 0.78 to 0.90) but with an
increased odds of diarrhea and of skin rash (Figure 3). There was substantial
heterogeneity between the results for ticlopidine and
clopidogrel for diarrhea
(21df=17.9,
2P=0.00002) and for skin rash
(21df=13.4,
2P=0.0003) (Figure 3). Hence, compared with aspirin,
ticlopidine produced an 2-fold increase in the odds of skin rash
(11.8% for ticlopidine versus 5.5% for aspirin; OR 2.2, 95% CI 1.7
to 2.9) and of diarrhea (20.4% for ticlopidine versus 9.9% for
aspirin; OR 2.3, 95% CI 1.9 to 2.8), whereas clopidogrel produced a
smaller increase of approximately one third in the odds of skin rash
(6.0% for clopidogrel versus 4.6% for aspirin; OR 1.3, 95% CI 1.2 to
1.5) and of diarrhea (4.5% for clopidogrel versus 3.4% for aspirin;
OR 1.3, 95% CI 1.2 to 1.6) (Figure 3).
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Ticlopidine was associated with an excess of neutropenia,
<1.2x109 neutrophils per liter (2.3% for
ticlopidine versus 0.8% for aspirin; OR 2.7, 95% CI 1.5 to 4.8), but
clopidogrel was not (0.1% for clopidogrel versus 0.2% for aspirin; OR
0.63, 95% CI 0.29 to 1.36; test for heterogeneity
between results for ticlopidine and clopidogrel,
21df=8.9;
2P=0.003) (Figure 3
). Nor did clopidogrel produce an
excess of thrombocytopenia, <100x109
platelets per liter (0.26% versus 0.26%; OR 1.00, 95% CI 0.57 to
1.74) (Figure 3). There were no published trial data available
for the frequency of thrombocytopenia associated with ticlopidine
compared with aspirin.
Analyses Restricted to Patients Presenting With Stroke
or TIA
Among the 9840 patients with TIA/ischemic stroke, the
thienopyridines produced proportional benefits similar to those found
overall, in terms of vascular events (16.8% for thienopyridine versus
18.3% for aspirin; OR 0.90, 95% CI 0.81 to 1.00) and in terms of any
stroke (10.4% for thienopyridine versus 12.0% for aspirin; OR 0.86,
95% CI 0.75 to 0.97). The absolute reduction of 14 (95% CI -1 to
29) vascular events per 1000 patients treated for 2 years was
similar to that observed among all high-risk patients. However, the
risk of stroke among patients with a previous TIA or ischemic
stroke in the aspirin group (12.0%) was almost twice as high as that
for all high-risk patients (6.4%). Therefore, the absolute reduction
of 16 strokes (95% CI 3 to 28) per 1000 patients was approximately
twice as large as that for all high-risk patients combined.
The results for adverse effects among patients with TIA/ischemic stroke were similar to those for all patients combined (data not shown).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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This systematic review considered all of the available evidence from randomized trials of a thienopyridine (either ticlopidine or clopidogrel) versus aspirin, constituting >20 000 patients and >2500 vascular events. Most of the data were from the 2 largest trials.2 6 Data were incomplete for several outcome events in only a very small minority of patients, and we would not expect this to alter any of the conclusions of the review.
Prevention of Vascular Events
A combined analysis of all of the evidence showed the
thienopyridines to be modestly, yet significantly, more effective than
aspirin in preventing serious vascular events among patients at high
risk of vascular disease, with no heterogeneity between
the results for ticlopidine and clopidogrel. However, there is
considerable uncertainty about the size of the additional benefit: the
wide 95% CI suggests that among high risk patients in general, the
proportional reduction in the odds of a vascular event might be as
small as 2% or as large as 16%, so that treatment with a
thienopyridine rather than aspirin for 2 years might prevent or
delay anywhere between 2 and 19 vascular events per 1000 patients.
This overall uncertainty means that the magnitude of the additional benefit for particular types of patients is even more uncertain, and the results of subgroup analyses must be interpreted with caution. However, patients presenting with TIA/ischemic stroke experienced proportional benefits that were similar to those for all high-risk patients combined. This suggests that the absolute benefit of treatment in a patient with a history of ischemic cerebrovascular disease is likely to depend on the absolute risk of the vascular outcome being considered. We did not seek separate data for the subsets of patients with MI or peripheral arterial disease, but there is no particularly convincing a priori reason to expect the proportional effects of the thienopyridines versus aspirin among these patients to differ substantially from the overall result. A subgroup analysis of the Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events (CAPRIE) trial data2 suggested that patients with peripheral arterial disease might derive particular benefit from clopidogrel, whereas those with an MI might not benefit at all. But the statistical heterogeneity among the 3 subgroups of patients included was only marginally significant (P=0.04), and this finding may simply have been due to chance.
Adverse Effects
There were no clear differences between the thienopyridines and
aspirin in the risks of either intracranial or extracranial bleeding.
Aspirin produced more gastrointestinal hemorrhage and upper
gastrointestinal upset than did the thienopyridines. However, although
evidence from randomized trials shows that aspirin doses ranging from
75 to 1500 mg daily are similarly effective in the long-term prevention
of vascular events, the adverse effects of aspirin on the
gastrointestinal tract are more frequent at higher doses.7
Because the doses of aspirin used in the trials ranged from 325 to 1500
mg daily (Table), it is conceivable that a lower daily aspirin
dose might compare more favorably with the thienopyridines in terms of
these adverse gastrointestinal effects. The thienopyridines produced
more skin rash and diarrhea than did aspirin, and indirect comparisons
between the results for the 2 thienopyridines suggested that the excess
risks of both of these were greater with ticlopidine than with
clopidogrel.
Data from the CAPRIE study2 showed clopidogrel to be at
least as safe as aspirin (325 mg daily). Because severe episodes of
skin rash and diarrhea occurred very infrequently, the excess of each
among patients given clopidogrel rather than aspirin was only 1 or 2
per 1000 patients over 2 years. The excess risks of severe
gastrointestinal bleeding and of severe upper gastrointestinal upset
with aspirin were of similar magnitude: 2 or 3 per 1000
patients.2 Ticlopidine was also associated with an excess
of neutropenia. In addition, observational studies have shown
ticlopidine to be associated with both thrombocytopenia and thrombotic
thrombocytopenic purpura.8 9 10 By contrast, clopidogrel
has not (so far) been associated with adverse hematological problems,
either during the CAPRIE trial or subsequently on the open market. The
preliminary results of a direct randomized comparison between the
safety profiles of ticlopidine and clopidogrel used in combination with
aspirin among 1000 patients undergoing coronary artery
stenting also suggested the safety and tolerability of clopidogrel to
be superior to that of ticlopidine.11
Conclusions and Implications for Clinical Practice and for
Future Research
The main conclusions of the present review are as follows: (1)
On average, the thienopyridines provide slightly more protection than
does aspirin against vascular events among high-risk patients, but the
extent of added benefit is uncertain, both overall and especially for
individual patients. (2) Clopidogrel appears to be safer than
ticlopidine. (3) Clopidogrel is at least as safe as aspirin.
If an alternative antiplatelet drug to aspirin is to be used,
clopidogrel is therefore the most appropriate choice. However,
clopidogrel is much more expensive than aspirin: the cost of treating
1000 patients for 2 years with clopidogrel instead of aspirin is
currently $1.6 million (US dollars).12 Substituting
aspirin with clopidogrel among all high-risk patients might prevent as
many as 19 vascular events at a cost of $85 000 per event prevented
or as few as 2 vascular events at $800 000 per event prevented.
Thus, the prescribing costs may well exceed the cost of a vascular
event (eg, in Australia the estimated annual cost of a stroke is
$35 000).12 At present, it seems prudent to infer
that clopidogrel should not replace aspirin as the first-choice
antiplatelet agent for all patients at high risk of vascular
disease. Cost-effectiveness might be improved by using clopidogrel
among those patients considered to be at highest risk of vascular
events, perhaps including those who suffer recurrent ischemic
events on aspirin, because they are likely to derive the greatest
absolute benefit. But, this is speculative, and an analysis
based on individual patient data would be required to address the issue
of which types of patients benefit most (and which least) from
thienopyridines compared with aspirin. However, clopidogrel would seem
to be an appropriate alternative antiplatelet drug for patients who
are intolerant of, or allergic to, aspirin, provided that we accept the
lack of direct evidence among such patients, because they were excluded
from the trials.
A further important question not addressed by the present review is whether the combination of clopidogrel and aspirin is both safe and more effective than either drug alone. Because aspirin and clopidogrel have different mechanisms of action on platelets, the addition of clopidogrel to aspirin might well lead to greater additional benefit than replacing aspirin with clopidogrel.13 Several ongoing randomized trials are now comparing the combination with aspirin alone in a range of high vascular risk conditions.
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Acknowledgments |
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We are very grateful to Hazel Fraser, Cochrane Stroke Group Coordinator, for her help in preparing this review; the Cochrane referees, Professors Charles Warlow and Peter Sandercock (Cochrane Stroke Group Editors) and Dr Daniel Bereczki, for their helpful comments on previous versions of the full electronic version of this review; Professors Michael Gent and Robin Roberts for providing additional unpublished data from the CAPRIE trial and for their helpful comments on previous versions of the review; Sanofi for providing details of the Schoop study; and the Royal Perth Hospital Clinical Staff Education Fund and the Wellcome Trust, UK, for supporting Drs Hankey and Sudlow, respectively, while undertaking this work. This article is based on a Cochrane systematic review, the full electronic version of which is published in the Cochrane Library.
Received March 10, 2000; revision received April 21, 2000; accepted April 21, 2000.
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References |
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1. Antiplatelet Trialists’ Collaboration. Collaborative overview of randomised trials of antiplatelet therapy, I: prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. BMJ. 1994;308:81–106.
2. CAPRIE Steering Committee. A randomised blinded trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet. 1996;348:1333–1338.
3. Hankey GJ, Sudlow CLM, Dunbabin DW. Thienopyridine Derivatives (Ticlopidine, Clopidogrel) Versus Aspirin in Preventing Stroke and Other Serious Vascular Events in High Vascular Risk Patients. Oxford, UK: The Cochrane Library; Issue 1, 2000. Update software.
4. Toghi H, Murakami M. The effect of ticlopidine on TIA compared with aspirin: a double-blind twelve-month and open 24-month follow-up study. Jpn J Med. 1987;26:117–119.
5. Schoop W. Open randomised study comparing ticlopidine with acetylsalicylic acid in the prevention of contralateral thrombosis in patients initially presenting with unilateral thrombosis. Guildford, UK: Sanofi Winthrop; 1983. Sanofi internal report 001.6.174.
6. Hass WK, Easton JD, Adams HP, Pryse-Phillips W, Molony BA, Anderson S, Kamm B, for the Ticlopidine Aspirin Stroke Study Group. A randomised trial comparing ticlopidine hydrochloride with aspirin for the prevention of stroke in high-risk patients. N Engl J Med. 1989;321:501–507.[Abstract]
7. Sudlow C, Baigent C. Antiplatelet Treatment (Secondary Prevention of Stroke and Secondary Prevention of Ischaemic Cardiac Events). In: Godlee F, Goldman D, eds. Clinical Evidence (Issue 3). London, UK: BMJ Publishing Group and the American College of Physicians, American Society of Internal Medicine; 2000.
8. Moloney BA. An analysis of the side effects of ticlopidine. In: Hass WK, Easton JD, eds. Ticlopidine, Platelets and Vascular Disease. New York, NY: Springer; 1993:117–139.
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