Context Following percutaneous coronary intervention (PCI), short-term clopidogrel
therapy in addition to aspirin leads to greater protection from thrombotic
complications than aspirin alone. However, the optimal duration of combination
oral antiplatelet therapy is unknown. Also, although current clinical data
suggest a benefit for beginning therapy with a clopidogrel loading dose prior
to PCI, the practical application of this therapy has not been prospectively
studied.
Objectives To evaluate the benefit of long-term (12-month) treatment with clopidogrel
after PCI and to determine the benefit of initiating clopidogrel with a preprocedure
loading dose, both in addition to aspirin therapy.
Design, Setting, and Participants The Clopidogrel for the Reduction of Events During Observation (CREDO)
trial, a randomized, double-blind, placebo-controlled trial conducted among
2116 patients who were to undergo elective PCI or were deemed at high likelihood
of undergoing PCI, enrolled at 99 centers in North America from June 1999
through April 2001.
Interventions Patients were randomly assigned to receive a 300-mg clopidogrel loading
dose (n = 1053) or placebo (n = 1063) 3 to 24 hours before PCI. Thereafter,
all patients received clopidogrel, 75 mg/d, through day 28. From day 29 through
12 months, patients in the loading-dose group received clopidogrel, 75 mg/d,
and those in the control group received placebo. Both groups received aspirin
throughout the study.
Main Outcome Measures One-year incidence of the composite of death, myocardial infarction
(MI), or stroke in the intent-to-treat population; 28-day incidence of the
composite of death, MI, or urgent target vessel revascularization in the per-protocol
population.
Results At 1 year, long-term clopidogrel therapy was associated with a 26.9%
relative reduction in the combined risk of death, MI, or stroke (95% confidence
interval [CI], 3.9%-44.4%; P = .02; absolute reduction,
3%). Clopidogrel pretreatment did not significantly reduce the combined risk
of death, MI, or urgent target vessel revascularization at 28 days (reduction,
18.5%; 95% CI, −14.2% to 41.8%; P = .23). However,
in a prespecified subgroup analysis, patients who received clopidogrel at
least 6 hours before PCI experienced a relative risk reduction of 38.6% (95%
CI, −1.6% to 62.9%; P = .051) for this end
point compared with no reduction with treatment less than 6 hours before PCI.
Risk of major bleeding at 1 year increased, but not significantly (8.8% with
clopidogrel vs 6.7% with placebo; P = .07).
Conclusions Following PCI, long-term (1-year) clopidogrel therapy significantly
reduced the risk of adverse ischemic events. A loading dose of clopidogrel
given at least 3 hours before the procedure did not reduce events at 28 days,
but subgroup analyses suggest that longer intervals between the loading dose
and PCI may reduce events.
Aspirin is a cornerstone of therapy for patients undergoing coronary
intervention. Its use is considered a standard of care before the procedure
and lifelong following revascularization. Adding to aspirin a short course
(2-4 weeks) of an adenosine diphosphate (ADP) P2Y12 receptor antagonist
(ticlopidine or clopidogrel) leads to even greater protection from thrombotic
complications following a percutaneous coronary intervention (PCI) with a
stent.1-4 However,
the optimal timing for the initiation of clopidogrel and aspirin, as well
as their duration of treatment following a PCI procedure, remains unknown.
The results of multiple observational and nonrandomized studies suggest
that treating patients with an ADP receptor antagonist prior to a planned
PCI may provide additional, incremental benefit beyond that provided by aspirin,
and even beyond that of glycoprotein (Gp) IIb/IIIa antagonists.5-7 Despite
the consistency of this observation, patient or procedural characteristics
may have biased the results in favor of pretreatment. More definitive data
regarding the benefit of pretreatment with clopidogrel were recently reported
in the subset of 2658 patients undergoing PCI as part of a larger trial of
combined antiplatelet therapy for acute ischemic heart disease, the PCI-Clopidogrel
in Unstable angina to prevent Recurrent Events (PCI-CURE) study.8 However,
the duration of pretreatment (a median of 10 days) as well other factors make
these results hard to extrapolate and logistically difficult to apply to patients
undergoing elective PCI.
The most appropriate duration of dual antiplatelet therapy following
PCI has not been prospectively studied, to our knowledge. The current standard
of 4 weeks is relatively arbitrary, and while adequate for preventing most
cases of stent thrombosis, this duration is not necessarily consistent with
the duration of heightened risk for complications following a PCI or the long-term
risk for thrombotic events throughout the vasculature.9-11 The
PCI-CURE study8 has provided the best data
to date regarding the benefit of continuing clopidogrel and aspirin beyond
4 weeks after PCI, with patients taking clopidogrel for a mean of 9 months
(maximum, 1 year) experiencing an overall 31% relative reduction in the risk
of cardiovascular death, myocardial infarction (MI), and stroke.
The CREDO (Clopidogrel for the Reduction of Events During Observation)
trial was designed to evaluate the efficacy and safety of clopidogrel therapy
for 1 year and the efficacy and safety of a loading dose of clopidogrel prior
to elective PCI.
Patients potentially eligible for enrollment were identified at participating
US and Canadian sites among patients referred for a planned PCI or coronary
angiogram and were approached about participation by the site investigator
and nurse coordinator. Patients were considered eligible for enrollment in
the study if they had symptomatic coronary artery disease with objective evidence
of ischemia (eg, symptoms of angina pectoris, positive stress test results,
or dynamic electrocardiographic [ECG] changes); were referred for PCI, or
thought to be at high likelihood for requiring PCI with either stent placement
with or without conventional balloon angioplasty or another revascularization
device; were at least 21 years old; provided informed consent before randomization;
and agreed to comply with all protocol-specified procedures.
Major exclusion criteria included contraindications to antithrombotic/antiplatelet
therapy; greater than 50% stenosis of the left main coronary artery; failed
coronary intervention in the previous 2 weeks; coronary anatomy not amenable
to stent placement; persistent ST elevation within 24 hours prior to randomization;
planned staged interventional procedure; and administration of the following
medications prior to randomization: GpIIb-IIIa inhibitor within 7 days, clopidogrel
within 10 days, or thrombolytics within 24 hours.
All patients provided written informed consent, and the institutional
review board at each participating center approved the protocol.
Randomization and Blinding
Patients were randomly assigned to groups using a prospective randomization
schedule. The randomization was performed in blocks of 2 and stratified by
center. When a patient was ready to be randomized, the site dispensed a drug
package that contained a unique 4-digit random number; this number was entered
on the case report form and provided an identifier of the treatment assigned.
After investigators satisfactorily completed screening procedures, obtained
informed consent, and reviewed all inclusion and exclusion criteria, patients
were entered into the study and received study drug (clopidogrel or matching
placebo). A patient was considered to be randomized upon opening of the study
medication. The study was conducted on a double-blind basis: investigators
were blind to treatment allocation from randomization until the end of the
study period.
Following randomization, and 3 to 24 hours prior to PCI, patients received
either a 300-mg loading dose of clopidogrel or matching placebo. All patients
also received 325 mg of aspirin.
Immediately after the PCI procedure was completed, both groups received
75 mg/d of clopidogrel and 325 mg/d of aspirin through day 28. After 28 days
and until the end of the study period, the pretreatment group continued to
receive 75 mg/d of clopidogrel, whereas the no-pretreatment group received
matching placebo. Both groups continued to receive standard therapy including
aspirin (81-325 mg/d, at the discretion of the investigator) until the end
of the 12-month treatment period.
Twenty percent of all patients could be prespecified at the time of
randomization to receive a GpIIb-IIIa receptor antagonist (primarily abciximab)
at the time of PCI. Bail-out GpIIb-IIIa inhibitor use was allowed for all
patients at the discretion of the physician performing PCI.
Follow-up assessment was performed on days 2, 28, 60, 180, 270, and
365 following randomization.
The primary 1-year outcome was the composite of death, MI, and stroke
in the intent-to-treat population. The primary outcome of interest at 28 days
was the composite of death, MI, or urgent target vessel revascularization
in the per-protocol population, which included all randomized patients who
underwent PCI. Prespecified secondary analyses included the individual components
of the composite end points, administration of clopidogrel less than 6 hours
or at least 6 hours before PCI, and the need for target vessel revascularization
or any revascularization at 1 year.
Death was defined as mortality from any cause (cardiovascular or nonvascular).
Cardiovascular death was defined as any death with a clear cardiovascular
(including hemorrhagic) or unknown cause. Only deaths due to a clear and documented
nonvascular cause were documented as nonvascular. Acute Q-wave MI was defined
as the presence of a new significant Q wave with a duration of at least 0.04
seconds or a depth equal to one fourth of the corresponding R-wave amplitude
in 2 or more contiguous leads. A periprocedural non–Q-wave MI was defined
as the elevation of the serum levels of creatine kinase (CK) or CK-MB isoenzyme
to at least 3 times the upper limit of normal in 2 samples collected at different
sampling times, with an increase of at least 50% over the previous trough
level. In patients undergoing elective coronary artery bypass graft (CABG)
surgery, postsurgical MI was defined as the elevation of CK or CK-MB isoenzyme
to at least 5 times the upper limit of normal. The criteria for postdischarge
or repeat Q-wave MI were the same as for acute Q-wave MI. Postdischarge non–Q-wave
MI was defined as the elevation of CK or CK-MB isoenzyme at least twice the
upper limit of normal in 2 samples collected at different sampling times.
Stroke was defined as a new focal neurologic deficit of vascular origin lasting
at least 24 hours. Stroke was further classified as an intracranial hemorrhage,
ischemic infarction (if a computed tomographic or magnetic resonance imaging
scan was available), or of uncertain cause. Urgent target vessel revascularization
was defined as CABG initiated within 24 hours of the index procedure due to
an inadequate or unstable result of the index procedure, even if ongoing myocardial
ischemia was not present; repeat PCI or CABG of the target vessel initiated
within 1 week of (re)hospitalization for acute MI or unstable angina; or repeat
PCI or CABG of the culprit vessel initiated within 24 hours of the last episode(s)
of ischemia. Any revascularization was defined as any peripheral revascularization
or PCI or CABG performed on any coronary vessel.
All potential events were identified by site investigators or through
screening of protocol-specified ECGs and laboratory tests, blinded to treatment
assignment. An independent clinical events committee, also blinded to treatment
assignment, adjudicated all outcome events, and all analyses were based on
the committee's classification of the end points.
Secondary end points focused on safety and included the incidence of
major bleeding events and of early discontinuation of study drugs at 28 days
and 1 year. Bleeding was defined as major, minor, or insignificant using a
modification of the Thrombolysis in Myocardial Infarction (TIMI) bleeding
criteria. Major bleeding was defined as intracranial bleeding or bleeding
associated with a decrease in hemoglobin of more than 5 g/dL (or, when hemoglobin
values were not available, a hematocrit decrease of at least 15%). Hematocrit
and hemoglobin measurements were adjusted for any packed red blood cell (PRBC)
or whole blood transfusions between baseline and posttreatment hemoglobin
measurements, with the number of units of PRBC and whole blood combined being
added to the change in hemoglobin level. Three times the number of units of
PRBCs and whole blood combined was added to the change in hematocrit. Bleeding
that met the criteria for major bleeding events but was associated with a
surgical procedure (eg, CABG) was also considered separately from other bleeding.
Based on a projected 1-year event rate of 20% for the composite of death,
MI, or any revascularization, and using a 2-sided α level of .05, a
study with 1814 patients would have 80% power to detect a 25% relative risk
reduction (RRR). The planned sample size was increased by 10% to allow for
patients randomized but lost to follow-up, giving a total overall sample size
of 2000 patients. The expected rate of the primary end point in the placebo
group at 28 days was 13.4%, based on the event rate seen in the EPISTENT trial
in patients who underwent PCI but did not receive ticlopidine prior to the
intervention.6 Based on the 28-day event rate
of 8.9% in EPISTENT patients who began ticlopidine therapy prior to the procedure,
and the likely impact of suboptimal initiation of ticlopidine before intervention,
the estimated 28-day event rate in the clopidogrel pretreated arm was 7.5%.
All hypothesis tests were performed using 2-sided tests at the 5% significance
level. The 28-day efficacy outcome was analyzed in the per-protocol population,
which constituted all randomized patients who underwent PCI at the time of
initial angiography. The per-protocol population was studied to evaluate the
specific effect of clopidogrel therapy administered before PCI. All other
analyses were in the intent-to-treat population, which included all patients
as randomized.
For time-to-event variables, Kaplan-Meier estimates were used and the
groups were compared with a log-rank test. Relative risk reductions and associated
95% confidence intervals (CIs) were estimated from the Cox proportional hazards
model. The same method was used to investigate a number of population subgroups
that were prespecified at the time of protocol development: diabetes, sex,
timing of loading dose (3 to <6 hours, 6 to <12 hours, and 12 to 24
hours prior to PCI), GpIIb-IIIa antagonist use, clinical diagnosis (acute
coronary syndrome or not), and treatment (stent or not).
Incidence of bleeding was compared using the Fisher exact test. Analyses
were performed with SAS version 6.12 (SAS Institute Inc, Cary, NC).
Between June 1999 and April 2001 in 99 centers in the United States
and Canada, 2116 patients who were to undergo a planned PCI or were deemed
at high likelihood to undergo PCI were enrolled into the study (Figure 1). Baseline demographics in the 2 treatment groups were
well matched, although there was less use of statins and calcium channel blockers
in the clopidogrel arm (Table 1).
By design, the majority of patients enrolled underwent PCI following initial
angiogram—86% in both groups.
Procedural characteristics of patients undergoing PCI at the time of
initial angiogram (per-protocol population) were similar in the 2 groups,
although the use of GpIIb-IIIa antagonists was more common in the pretreatment
cohort (Table 2). The mean duration
between study drug loading dose and PCI was 9.8 hours. Fifty-one percent of
patients received their loading dose between 3 and less than 6 hours before
their PCI and 49% between 6 and 24 hours prior to PCI.
Among patients undergoing PCI, pretreatment with a clopidogrel loading
dose was associated with a nonsignificant 18.5% relative reduction in the
combined end point of death, MI, or urgent target vessel revascularization
at 28 days (6.8% pretreatment vs 8.3% no pretreatment; 95% CI, −14.2%
to 41.8%; P = .23) (Figure 2A). For each component of the combined end point there were
fewer events in patients receiving clopidogrel pretreatment (pretreatment
vs no pretreatment: death, 0 vs 4; MI, 52 vs 60; urgent target vessel revascularization,
9 vs 12; total, 61 vs 76). Results were similar when the 28-day end point
was analyzed in the intent-to-treat population (6.2% vs 7.8%; RRR, 20.9%; P = .15).
When the per-protocol population was analyzed based on the prespecified
time-to-treatment intervals of 3 to 6 hours, 6 to 12 hours, and 12 to 24 hours
prior to the PCI, an important interaction was noted in the duration of pretreatment
and the degree of protection from adverse cardiac events. Among the 893 patients
receiving their loading dose of study medication 3 to less than 6 hours prior
to PCI, no benefit of clopidogrel pretreatment was found (RRR, −13.4%;
95% CI, 29.8% to −83.3% P = .60). On the other
hand, in the 230 patients treated 6 to less than 12 hours prior to PCI and
in the 621 patients treated 12 to 24 hours before PCI, the relative reduction
in the combined end point was 35.5% (95% CI, 73.3% to −55.6%; P = .32) and 40.1% (95% CI, 67.6% to −10.7%; P = .09), respectively. Therefore, among patients in whom
study drug was initiated at least 6 hours prior to PCI, those randomized to
clopidogrel experienced a 38.6% relative reduction in the combined end point
that was of borderline statistical significance (95% CI, −1.6% to 62.9%; P = .051) (Figure 2B).
To ensure that this finding was not due to some systematic difference in the
populations, the background characteristics of these patients were examined
and found to be similar regardless of the timing of the pretreatment (all P>.30). This benefit of early pretreatment, and the lack
of benefit with less than 6 hours of pretreatment, appeared similar among
all important subgroups (Figure 3A
and B).
Patients treated with a GpIIb-IIIa antagonist, either specified at the
time of randomization to receive GpIIb-IIIa at the time of PCI or receiving
one during the procedure as "bail-out" therapy, were another important prespecified
subgroup. Of the per-protocol population, 45% received a GpIIb-IIIa antagonist;
approximately half were specified at the time of randomization and half as
"bail-out" therapy. Among the 991 patients who did not receive a GpIIb-IIIa
antagonist, clopidogrel pretreatment did not significantly influence the occurrence
of the combined end point (6.4% pretreated vs 6.7% no pretreatment; P = .81). However, a trend toward benefit was suggested
in patients who did receive a GpIIb-IIIa antagonist and were randomized to
clopidogrel pretreatment, with a 30% relative reduction in events (7.3% pretreated
vs 10.3% no pretreatment but receiving a GpIIb-IIIa antagonist; P = .12), with similar benefit irrespective of the timing of GpIIb-IIIa
antagonist use. Again, as in the overall per-protocol population, the degree
of benefit of clopidogrel pretreatment among patients receiving and not receiving
GpIIb-IIIa inhibitors appeared to be influenced by the timing of pretreatment
(Figure 3).
Overall, clopidogrel pretreatment at 28 days did not significantly increase
major or minor bleeding (Table 3).
Minor bleeding increased nonsignificantly in patients who also received a
GpIIb-IIIa antagonist (2.8% pretreatment vs 1.0% no pretreatment; P = .08). Importantly, there were no fatal bleeds or intracranial hemorrhages.
Nearly all major bleeding events were associated with invasive procedures
(either the index PCI or CABG) in both groups.
A total of 63% of patients in the clopidogrel group and 61% of patients
in the control group completed the full 1-year course of study drug. The primary
reasons for cessation of study drug are listed in Figure 1.
For the entire study population, randomization to long-term treatment
was associated with a 26.9% reduction in the relative risk of the combined
end point of death, MI, and stroke at 1 year (95% CI, 3.9%-44.4%; P = .02) (Figure 4). A similar
level of benefit was found in the individual components of this end point,
although individual outcomes were not significant (Table 4). The degree of benefit was similar among all subgroups,
although several were not significant (Figure
5). Treatment randomization did not appear to influence the rate
of target vessel revascularization or any other revascularization during the
follow-up period. Among patients not undergoing PCI there were a total of
18 primary outcome events: 7 in those randomized to clopidogrel and 11 in
those randomized to placebo.
In the intent-to-treat population, a relative reduction of 19.7% in
the combined end point of death, MI, and stroke was achieved by 28 days in
those randomized to a clopidogrel loading dose (95% CI, −13.3% to 43.1%; P = .21). Although the treatment effect from day 29 until
the end of follow-up at 1 year was not a prespecified analysis, continued
treatment with clopidogrel beyond 4 weeks was associated with a further RRR
of 37.4% in the combined end point (95% CI, 1.8%-60.1%; P = .04).
Patients treated with clopidogrel for 1 year experienced a trend toward
an increase in major bleeding (8.8% clopidogrel vs 6.7% placebo; P = .07). Approximately two thirds of all major bleeds occurred in
patients undergoing CABG, with all such patients experiencing a high incidence
of major bleeds (Table 3).
This study is the first randomized trial, to our knowledge, to assess
optimal initiation and duration of dual antiplatelet therapy with an ADP-receptor
antagonist and aspirin in a population undergoing elective revascularization.
Our major finding is that continuation of dual antiplatelet therapy with clopidogrel
and aspirin for at least 1 year, instead of the current standard of 2 to 4
weeks, leads to a statistically and clinically significant reduction in major
thrombotic events. Although the data from this trial do not directly support
the routine administration of a 300-mg loading dose of clopidogrel between
3 and 24 hours prior to PCI (the 18.5% reduction in adverse events did not
reach statistical significance), the data suggest that when a 300-mg loading
dose can be administered more than 6 hours before PCI it may well offer substantial
benefit. Furthermore, the long-term combination of aspirin and clopidogrel
was relatively safe and the efficacy extended to a large population of patients
who undergo elective percutaneous coronary revascularization.
The potential benefit of pretreatment prior to PCI has been recognized
for a number of years based on the results of a number of retrospective and
nonrandomized analyses.5-7 Despite
the lack of rigorous data supporting pretreatment with clopidogrel, this practice
has become commonplace, as highlighted in this study by clopidogrel pretreatment
being the single most common reason for a screened patient being ineligible
for study enrollment. Patients enrolled in CURE who underwent PCI and who
were randomized to receive clopidogrel experienced a significantly lower incidence
of adverse cardiovascular events at both 30 days and at a mean of 9 months,
but pretreatment was given for a median of 10 days.8 In
CREDO, although pretreatment with clopidogrel 3 to 24 hours before PCI did
not improve outcomes, those who received pretreatment more than 6 hours before
did have fewer events, supporting the hypothesis that pretreatment with clopidogrel
that is of adequate duration or dose to provide its full antiplatelet effects
does provide substantial protection from the acute thrombotic complications
associated with PCI. Although some early studies suggested that near maximal
effects of clopidogrel could be achieved within 3 hours of a 300-mg loading
dose,12 more recent studies have found that
6 hours or longer is needed with a 300-mg dose, or larger loading doses in
the range of 450 to 600 mg may be necessary to achieve maximal effects more
rapidly.13-15
The apparent benefit of pretreatment, specifically those pretreated
more than 6 hours prior to the procedure, showed a similar pattern among all
subgroups. Surprisingly, patients treated with a GpIIb-IIIa receptor antagonist
experienced a relative benefit even greater than in those not receiving one.
This finding, which needs to be confirmed, highlights the importance of inhibiting
platelet activation, as achieved with clopidogrel and aspirin, even in the
setting of near-complete inhibition of platelet aggregation via GpIIb-IIIa
antagonists. No conclusions can be drawn from CREDO regarding the potential
concomitant benefit of adding a GpIIb-IIIa antagonist to patients already
adequately pretreated with clopidogrel, but this important question is currently
being addressed in the Intracoronary Stenting and Antithrombotic Regimen—Rapid
Early Action for Coronary Treatment (ISAR-REACT) trial, in which patients
pretreated with a 600-mg loading dose of clopidogrel are randomly assigned
to abciximab or placebo.16 Nonetheless, the
results of our trial, smaller single-center trials, and those of a recent
large comparative trial of GpIIb-IIIa antagonists strongly suggest a complementary
role of parenteral GpIIb-IIIa inhibition with dual oral antiplatelet in the
setting of PCI, without a concomitant increase in the risk of major bleeding.7,17
The long-term risk for thrombotic events in patients following PCI has
not always been fully appreciated. Primary emphasis has been on the prevention
of procedural complications and thrombosis of the treated vessel and attempts
to minimize restenosis. However, once a patient has developed a coronary stenosis
sufficiently severe to require revascularization, the atherosclerotic burden
throughout the arterial system can already be considered extensive and the
subsequent risk for death, MI, or stroke heightened. Importantly, the risk
of patients with a high C-reactive protein level at baseline for subsequent
major events, including death, has been well documented in recent studies
of coronary intervention.18 Clopidogrel, coadministered
with aspirin, has been shown to markedly reduce the risk associated with an
elevated baseline C-reactive protein level prior to PCI.19 These
results are consistent with the important role platelets play in the inflammatory
system20,21 and the potential
for agents such as clopidogrel that diminish many of the consequences of platelet
activation, not just aggregation.22 Accordingly,
the benefit of combined therapy in reducing the events of death, stroke, or
MI may reflect a more potent anti-inflammatory effect as compared with aspirin
monotherapy.
The results of our study support the recent CURE trial findings and
expand the benefit of prolonged clopidogrel and aspirin to a more stable,
less acutely ill population.23 The timing of
this benefit emphasizes the risk of major thrombotic events in this population
and highlights the need for improved long-term protection. The CREDO trial
could not assess whether clopidogrel and aspirin treatment beyond 1 year would
continue to reduce risk, but the Clopidogrel for High Atherothrombotic Risk
and Ischemic Stabilization, Management and Avoidance (CHARISMA) trial, which
will include more than 15 000 high-risk but stable patients, with a mean
anticipated follow-up of 42 months, will definitively establish whether clopidogrel
(in addition to low-dose aspirin) should be continued beyond 1 year.24
Despite the clear benefit of clopidogrel and aspirin for preventing
thrombotic events, the risk of spontaneous bleeding was not significantly
affected. Although a trend toward an increase in major bleeding was identified
in patients receiving long-term clopidogrel, the majority of this was CABG-related,
in which the incidence of major bleeding was high in both groups. Further
evaluation of any correlation between the timing of study drug discontinuation
and bleeding incidence will help identify the optimal dosing regimen prior
to invasive procedures. Also, recent analysis from the CURE trial identified
an important correlation between increasing aspirin dose and the risk of major
bleeds, without an increase in efficacy, suggesting that better adherence
to lower aspirin doses can also help minimize bleeding risk.25
There are several aspects of the current trial that limit the ability
to draw specific conclusions regarding the potential benefit of clopidogrel
pretreatment and the true risk reduction associated with long-term therapy.
Despite the suggestion of a relationship between the duration of pretreatment
and treatment effect, the size of the subgroups prevents the establishment
of definitive conclusions and recommendations regarding pretreatment. Also,
due to the relatively high proportion of patients who discontinued both clopidogrel
and placebo prior to the completion of the full year of follow-up, it is possible
that the risk reduction associated with long-term clopidogrel in this population
may have been underestimated. Finally, because patients were not rerandomized
after 28 days of therapy, it is not completely possible to separate the treatment
benefit of long-term therapy from that of pretreatment, although it is difficult
to postulate an influence of pretreatment on late thrombotic events that are
not associated with the treated coronary lesion.
In conclusion, the results of the CREDO trial indicate that in patients
undergoing PCI, the continuation of clopidogrel and aspirin therapy for 1
year leads to a significant reduction in irreversible atherothrombotic events
compared with treatment for only 4 weeks. Although a 300-mg loading dose of
clopidogrel administered more than 3 hours prior to the procedure was not
significantly better than administration of clopidogrel without a loading
dose immediately after the procedure, the subgroup analysis of patients treated
at least 6 hours prior to PCI suggested a significant reduction in periprocedural
major adverse cardiac events, with or without the concomitant use of a GpIIb-IIIa
antagonist.
1.Bertrand ME, Legrand V, Boland J.
et al. Randomized multicenter comparison of conventional anticoagulation versus
antiplatelet therapy in unplanned and elective coronary stenting: The Full
Anticoagulation Versus Aspirin and Ticlopidine (FANTASTIC) Study.
Circulation.1998;98:1597-1603.Google Scholar 2.Leon MB, Baim DS, Popma JJ.
et al. A clinical trial comparing three antithrombotic-drug regimens following
coronary artery stenting.
N Engl J Med.1998;339:1665-1671.Google Scholar 3.Schomig A, Neumann F, Kastrati A.
et al. A randomized comparison of antiplatelet and anticoagulant therapy after
placement of coronary-artery stents.
N Engl J Med.1996;334:1084-1089.Google Scholar 4.Urban P, Macaya C, Rupprecht H-J.
et al. Randomized evaluation of anticoagulation versus antiplatelet therapy
after coronary stent implantation in high-risk patients: the Multicenter Aspirin
and Ticlopidine Trial after Intracoronary Stenting (MATTIS).
Circulation.1998;98:2126-2132.Google Scholar 5.Steinhubl SR, Lauer MS, Mukherjee DP.
et al. The duration of pretreatment with ticlopidine prior to stenting is
associated with the risk of procedure-related non-Q-wave myocardial infarctions.
J Am Coll Cardiol.1998;32:1366-1370.Google Scholar 6.Steinhubl SR, Ellis SG, Wolski K, Lincoff AM, Topol EJ. Ticlopidine pretreatment before coronary stenting is associated with
sustained decrease in adverse cardiac events: data from the Evaluation of
Platelet IIb/IIIa Inhibitor for Stenting (EPISTENT) Trial.
Circulation.2001;103:1403-1409.Google Scholar 7.Topol EJ, Moliterno DJ, Herrmann HC.
et al. Comparison of two platelet glycoprotein IIb/IIIa inhibitors, tirofiban
and abciximab, for the prevention of ischemic events with percutaneous coronary
revascularization.
N Engl J Med.2001;344:1888-1894.Google Scholar 8.Mehta S, Yusuf S, Peters R.
et al. Effects of pretreatment with clopidogrel and aspirin followed by long-term
therapy in patients undrgoing percutaneous coronary intervention: the PCI-CURE
study.
Lancet.2001;358:527-533.Google Scholar 9.van Domburg RT, Foley DP, de Jaegere PPT.
et al. Long term outcome after coronary stent implantation: a 10 year single
centre experience of 1000 patients.
Heart.1999;82(suppl II):II27-II34.Google Scholar 10.Thel MC, Califf RM, Tardiff BE.
et al. Timing of and risk factors for myocardial ischemic events after percutaneous
coronary intervention (IMPACT-II).
Am J Cardiol.2000;85:427-434.Google Scholar 11.Schulen H, Kastrati A, Dirschinger J.
et al. Intracoronary stenting and risk for major adverse cardiac events during
the first month.
Circulation.1998;98:104-111.Google Scholar 12.Savcic M, Hauert J, Bachmann F, Wyld PJ, Geudelin B, Cariou R. Clopidogrel loading dose regimens: kinetic profile of pharmacodynamic
responses in healthy subjects.
Semin Thromb Hemost.1999;25(suppl 2):15-19.Google Scholar 13.Seyfarth H-J, Koksch M, Roethig G.
et al. Effect of 300- and 450-mg clopidogrel loading doses on membrane and
soluble P-selectin in patients undergoing coronary stent implantation.
Am Heart J.2002;143:118-123.Google Scholar 14.Muller I, Seyfarth M, Rudiger S.
et al. Effect of a high loading dose of clopidogrel on platelet function in
patients undergoing coronary stent placement.
Heart.2001;85:92-93.Google Scholar 15.Helft G, Osende JI, Worthley SG.
et al. Acute antithrombotic effect of front-loaded regimen of clopidogrel
in patients with atherosclerosis on aspirin.
Arterioscler Thromb Vasc Biol.2000;20:2316-2321.Google Scholar 16.Berger PB, Steinhubl SR. Clinical implications of Percutaneous Coronary Intervention–Clopidogrel
in Unstable angina to prevent Recurrent Events (PCI-CURE) study: a US perspective.
Circulation.2002;106:2284-2287.Google Scholar 17.Bonz AW, Lengenfelder B, Strotmann J.
et al. Effect of additional temporary glycoprotein IIb/IIIa receptor inhibition
on troponin release in elective percutaneous coronary interventions after
pretreatment with aspirin and clopidogrel (TOPSTAR trial).
J Am Coll Cardiol.2002;40:662-668.Google Scholar 18.Chew D, Bhatt D, Robbins M.
et al. Incremental prognostic value of elevated baseline C-reactive protein
among established markers of risk in percutaneous coronary intervention.
Circulation.2001;104:992-997.Google Scholar 19.Chew DP, Bhatt DL, Robbins MA.
et al. Effect of clopidogrel added to aspirin before percutaneous coronary
intervention on the risk associated with C-reactive protein.
Am J Cardiol.2001;88:672-674.Google Scholar 20.Page CP. Platelets as inflammatory cells.
Immunopharmacology.1989;17:51-59.Google Scholar 21.Neumann F-J, Marx N, Gawaz M.
et al. Induction of cytokine expression in leukocytes by binding of thrombin-stimulated
platelets.
Circulation.1997;95:2387-2394.Google Scholar 22.Klinkhardt U, Graff J, Harder S. Clopidogrel, but not abciximab, reduces platelet leukocyte conjugates
and P-selectin expression in human ex vivo in vitro model.
Clin Pharmacol Ther.2002;71:176-185.Google Scholar 23.The Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial
Investigators. Effects of clopidogrel in addition to aspirin in patients with acute
coronary syndromes without ST-segment elevation.
N Engl J Med.2001;345:494-502.Google Scholar 24.Bhatt DL, Marso SP, Hirsch AT, Ringleb PA, Hacke W, Topol EJ. Amplified benefit of clopidogrel versus aspirin in patients with diabetes
mellitus.
Am J Cardiol.2002;90:625-627.Google Scholar 25.Peters RJG, Zao F, Lewis BS, Fox KAA, Yusuf S.for the CURE Investigators. Aspirin dose and bleeding events in the CURE study.
Eur Heart J.2002;4(suppl):510.Google Scholar