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REVIEW
CLINICIAN’S CORNER
Scan for Author
Audio Interview
Association of Clopidogrel Pretreatment
With Mortality, Cardiovascular Events,
and Major Bleeding Among Patients Undergoing
Percutaneous Coronary Intervention
A Systematic Review and Meta-analysis
Anne Bellemain-Appaix, MD
Stephen A. O’Connor, MD
Johanne Silvain, MD, PhD
Michel Cucherat, MD, PhD
Farzin Beygui, MD, PhD
Olivier Barthélémy, MD
Jean-Philippe Collet, MD, PhD
Laurent Jacq, MD
François Bernasconi, MD
Gilles Montalescot, MD, PhD
for the ACTION group
I
N ADDITION TO ASPIRIN, CLOPIDOgrel has been shown to improve ischemic outcomes of patients with
stable coronary artery disease following percutaneous coronary intervention (PCI)1-3 and of patients with
acute coronary syndromes (ACS) who
were either medically treated4 or who
had undergone either revascularization by fibrinolysis or PCI.5-7 However, clopidogrel efficacy seems to be
genetically altered in about 30% of
white patients with suboptimal platelet inhibition, causing subsequent increased thrombotic event rates after
coronary stenting.8-11
CME available online at
www.jamanetworkcme.com
and questions on p 2523.
Author Audio Interview available at
www.jama.com.
Context Clopidogrel pretreatment is recommended for patients with acute coronary syndromes (ACS) and stable coronary artery disease who are scheduled for percutaneous coronary intervention (PCI), but whether using clopidogrel as a pretreatment for PCI is associated with positive clinical outcomes has not been established.
Objective To evaluate the association of clopidogrel pretreatment vs no treatment
with mortality and major bleeding after PCI.
Data Sources MEDLINE, EMBASE, Cochrane Controlled Trials Register databases,
and reference lists of qualifying articles.
Study Selection Studies reporting clinical data on mortality and major bleeding were
included. Of the 392 titles identified, 15 articles published between August 2001 and
September 2012 met the inclusion criteria: 6 randomized controlled trials (RCTs),
2 observational analyses of RCTs, and 7 observational studies.
Data Extraction Quality of studies was assessed with the Ottawa Scale and the Jadad Score as appropriate. Results were independently extracted by 2 reviewers. A randomeffect model was applied. Pretreatment was defined as the administration of clopidogrel before PCI or catheterization. The main analysis was performed on RCTs and
confirmed by observational analyses and observational studies. Prespecified subgroups—
clinical presentation and clopidogrel loading dose—were analyzed. The primary efficacy and safety end points were all-cause mortality and major bleeding. Secondary
end points included major cardiac events.
Results Of the 37 814 patients included in the meta-analysis, 8608 patients had participated in RCTs; 10 945, in observational analyses of RCTs; and 18 261, in observational studies. Analysis of RCTs showed that clopidogrel pretreatment was not associated with a reduction of death (absolute risk, 1.54% vs 1.97%; OR, 0.80; 95% CI,
0.57-1.11; P= .17) but was associated with a lower risk of major cardiac events (9.83%
vs 12.35%; OR, 0.77; 95% CI, 0.66-0.89; P⬍.001). There was no significant association between pretreatment and major bleeding overall (3.57% vs 3.08%; OR, 1.18;
95% CI, 0.93-1.50; P=.18). Analyses from observational analyses of RCTs and observational studies were consistent for all results.
Conclusions Among patients scheduled for PCI, clopidogrel pretreatment was not
associated with a lower risk of mortality but was associated with a lower risk of major
coronary events.
www.jama.com
JAMA. 2012;308(23):2507-2516
Although the administration of a
clopidogrel loading dose is necessary in
the immediate peri-PCI setting, it is uncertain whether clopidogrel pretreat-
©2012 American Medical Association. All rights reserved.
Author Affiliations are listed at the end of this article.
Corresponding Author: Gilles Montalescot, MD, PhD,
Institut de Cardiologie, Bureau 2-236, PitiéSalpêtrière Hospital, 47 Boulevard de l’Hôpital, 75013
Paris, France ([email protected]).
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CLOPIDOGREL, MORTALITY, CV EVENTS, AND BLEEDING
ment (ie, treatment given in enough time
before catheterization to be effective) is
efficient when the coronary status is not
known yet. Indeed, this pretreatment can
either delay coronary artery bypass graft
surgery or increase unnecessarily the risk
of bleeding in patients who in the end
do not need revascularization or who go
to the operating room immediately afterundergoingcoronaryangiogram.This
issue has been assessed in various studies, with different clopidogrel-loading
doses, timing, and clinical presentations,
but none of these studies was powered
for mortality. On this basis, the current
European Society of Cardiology (ESC)
and American College of Cardiology and
AmericanHeartAssociation(ACC/AHA)
guidelines give a grade Ib to pretreatment
in non–ST-elevation acute coronary syndrome (NSTE-ACS) scheduled for an invasive strategy.12,13
Previous meta-analyses have suggested a favorable risk-benefit ratio, but
they examined specific clinical situations like primary PCI of ST-elevation
myocardial infarction (STEMI)14 or focused on composite ischemic end
points.15 No global appraisal of clopidogrel pretreatment in PCI is available. Although data have accumulated
over the past 10 years, the question of
a benefit with pretreatment on major
clinical outcomes remains unanswered. We aimed to gather enough
power from all the available data from
randomized trials and registries involving patients with coronary artery disease (stable or with ACS) undergoing
catheterization for potential revascularization to evaluate the association between clopidogrel pretreatment and
clinical end points of mortality and major bleeding.
METHODS
Study Design
The main analysis included only randomized controlled trials (RCTs)3,7,16-18
and the PCI subgroups of RCTs for clopidogrel pretreatment vs no pretreatment5,6 that fulfilled the inclusion crite-
ria, regardless of clinical presentation.
Two confirmatory analyses were performed using the same method: (1)
analyses of observational reports of
RCTs19,20 and (2) analyses of observational studies21-26 (TABLE 1 and TABLE 2).
Study Selection and Data Extraction
We conducted Cochrane Controlled
Trials Registry and MEDLINE and
EMBASE database searches for published articles from January 1980
through September 2012 using the following predefined search terms clopidogrel and pretreatment, or loading dose
or preload or timing or upstream. Abstracts from selected major cardiology
scientific meetings (AHA, ACC, ESC,
and Transcatheter Cardiovascular
Therapeutics) were reviewed. References from reviews and selected articles were also reviewed for potential
relevant citations. We used no language restrictions. Studies were selected by 2 independent reviewers
(A.B.A. and S.A.O.).
Table 1. Study Review Registries
Design
No. of
Patients
Cohort
Feldman et
al,25 2010
Chan et al,22
2003
Source
Retrospective trials
Amin et al,21
2011
End Points
Bleeding Definitions a
Lower loading doses
or no clopidogrel
before PCI
Death, MI,
ST
600 mg LD ⬍2 h or
just before
undergoing the
procedure
300 mg LD
immediately
after PCI
Death, MI,
UTVR,
stroke
TIMI major or minor
bleeding or
vascular
complication or
transfusion
Major: ⱖ4 g/dL
hemoglobin;
Minor; ⱖ2 ⬍4
g/dL
TIMI major or minor
bleeding
Peri-intervention LD
Death, MI,
UTVR,
stroke
300 mg LD after PCI
Death,
recurrent
ACS,
ST
300 mg LD
immediately
after PCI
Death, MI,
UTVR
Pretreatment
No Pretreatment
1913
ⱖ600 mg LD ⬍2 h or
ⱖ 300 mg LD ⬍6 h
or 75 mg MD
⬎1 wk
Cohort
1041
75 mg MD ⱖ5 d or 300
mg LD ⱖ12 h or
600 mg LD ⱖ2 h
Cohort
4809
300 mg before PCI
56.6%, ⬍2 h;
27.2%, 2-6 h;
16.2%, ⬍6 h
(mean 2.1 h)
Cohort
5955
Fefer et al,24
2009
Cohort
383
Szük et al,26
2007
Cohort
4160
Dose not specified
before hospital or
before catheter
laboratory LD
300-600 mg LD before
PCI (in emergency
department or on
transfer to catheter
laboratory
300 mg ⬎6 h and
⬍24 h before PCI
Prospective trials
Dörler et al,23
2011
Death, MI,
UTVR
Intracranial, ⱖ5 g/dL
hemoglobin,
transfusion, or
surgery
Major
Clinically significant b
Follow-up
In hospital to
1y
In hospital to
1y
30 d, 6 mo,
and 1 y
(death
only)
In hospital
In hospital to
30 d
30 d
Abbreviations: LD, loading dose; MD, maintenance dose; MI, myocardial infarction; UTVR, urgent target vessel revascularization; TIMI, Thrombolysis in Myocardial Infarction.
a Bleeding definition includes the TIMI major and minor definition except for PCI-CURE, for which major bleeding is defined as substantially disabling bleeding, intraocular bleeding leading
to the loss of vision, or bleeding necessitating transfusion of 2 or more units of blood and REPLACE-2 and ACUITY PCI for which it is defined as clinically significant bleeding events.
b Intracranial, intraocular, retroperitoneal, or with hemoglobin level decrease of more than 4 g/dL; or overt bleeding with hemoglobin level decrease of more than 3 g/dL; or transfusion of
more than 2 units of blood.
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CLOPIDOGREL, MORTALITY, CV EVENTS, AND BLEEDING
Eligibility Criteria and Data Extraction
We restricted our analysis to trials that
met all of the following inclusion criteria: (1) patients with coronary artery disease scheduled for catheterization, PCI, or both; (2) controlled
comparison between clopidogrel pretreatment and no pretreatment (ie, placebo or no treatment) through random or nonrandom allocation; (3) data
supplied on clopidogrel loading dose;
(4) available data on at least mortality
and bleeding. Randomized controlled
trials, registries, and prespecified subgroups of studies reporting data on pretreatment with clopidogrel were considered for analysis. Full-text articles
and meeting abstracts were included.
Exclusion criteria were duplicate reports, the lack of control group, and ongoing studies. Data extraction and information on study design, clinical and
safety outcomes were performed independently by 2 reviewers (A.B.A. and
S.A.O.). Discrepancies were resolved by
consensus.
End Points Definitions
The primary efficacy end point was
mortality (by any cause). The primary
safety end point was major bleeding
(each study definition).
Secondary end points included the
composite end point of major cardiac
events but also the individual end points
of myocardial infarction (MI), stroke, or
urgent revascularization, as defined in
each study. Cardiovascular (CV) death,
minor bleeding, and stent thrombosis
were also analyzed when available. Stent
Table 2. Study Review of Randomized Controlled Trial Study Characteristics
No. of
Patients
Randomized to
Pretreatment
After Decision
for
Catheterization
or PCI
335
Yes
600 mg
ARMYDA5 PRELOAD,17
2010
409
Yes
600 mg LD
4-8 h Before
PCI
Davlouros et al,16 2009
199
Yes
900 mg LD
PRAGUE-8,18 2008
1028
Yes
600 mg LD
Plus 2-h wait
to PCI
⬎6 h Before
PCI
CREDO,3 2002
2116
No
300 mg LD
3-24 h Before
PCI
(mean,
9.8 h)
then long
term MD
5026
No
PCI CLARITY,6 2005
1863
Yes
300 mg LD
(subgroup)
300 mg LD
REPLACE-2,19 2004 c
5919
Yes
300 mg LD
PCI CURE,5 2001 b
2658
No
300 mg LD
Before PCI or
in catheter
laboratory
Before PCI or
in catheter
laboratory
(median 3
d) then 75
mg MD
PCI (ⱕ48 h)
then 75
mg MD
for at least
30 d
Median 10 d
before
PCI, then
75 mg
MD for
3-12 mo
Source
Randomized controlled trials a
PROBE-CIPAMI,7 2011 a
After randomization subgroup b
ACUITY PCI,20 2007 c
Pretreatment
Timing
No Pretreatment
600 mg LD in
catheter
laboratory
600 mg LD in
catheter
laboratory
before PCI
900 mg LD ⫹
direct PCI
600 mg LD in
catheter
laboratory
before PCI
Major Coronary
Event End
Points
Follow-up
Death, MI, or
UTVR
7 d or hospital
discharge
CV death, MI, or
UTVR
30 d
Death, MI, stroke,
or UTVR
30 d
Death,
periprocedural
MI, stroke, or
UTVR
7 d or hospital
discharge
No pretreatment
28-d
clopidogrel
Death, MI, or
UTVR per
protocol
analysis
28 d to 1 y
300 mg LD after
PCI ⬍2 h
(subgroup)
Placebo LD and
MD
open-label
300 mg LD
then 75 mg
MD if PCI
300 mg LD after
PCI then 75
mg MD for at
least 30 d
Death, MI, or
UTVR
30 d to 1 y
CV death, MI, or
stroke
30 d to 1 y
Death, MI, or
UTVR
30 d to 1 y
No LD then 75
mg for 4 wk
CV death, MI, or
UTVR
30 d to 1 y
Abbreviations: CV, cardiovascular; LD, loading dose; MD, maintenance dose; MI, myocardial infarction; PCI, percutaneous coronary intervention; TIMI, Thrombolysis in Myocardial Infarction; UTVR, urgent target vessel revascularization.
a Randomized for clopidogrel pretreatment vs no pretreatment.
b After randomization subgroup defined as randomized comparison.
c Observational studies from randomized controlled trial database (prespecified nonrandomized subgroup analysis of randomized controlled trial).
©2012 American Medical Association. All rights reserved.
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CLOPIDOGREL, MORTALITY, CV EVENTS, AND BLEEDING
thrombosis was defined using the definiteplus probable Academic Research
Consortium definition.27
Outcomes were based on the longest
follow-up available for each study. Pretreatment was defined as the administration of clopidogrel before PCI or catheterization that included any loading
dose of more than 300 mg or a maintenance dose of 75 mg or more when administrated for more than 5 days before
PCI. End points, definitions, and study
details are provided in Table 1.
Assessment and Reporting Risk
of Bias in Included Studies
The quality of RCTs included in the
meta-analysis was assessed for descriptive purpose by the Jadad score for
RCTs,28 and the quality of nonrandomized studies by the Newcastle-Ottawa
Scale for cohort studies (http://www.ohri
.ca/programs/clinical_epidemiology
/oxford.htm; see eTables 1 and 2 available at http://www.jama.com).
Statistical Analysis
To provide an estimation on the association between clopidogrel pretreatment and clinical outcomes, the results of studies were combined using
a random model because we anticipated potential heterogeneity across the
studies, especially between the observational studies. The results were confirmed by the Mantel-Haenszel fixedeffect model to avoid small studies being
overly weighted. The main analysis was
performed on RCTs and confirmation
was sought through the analyses of observational data from RCTs and through
observational studies.
Sensitivity analyses were performed after assessment of heterogeneity, on the
following subgroups: (1) clinical presentation: elective PCI16-19,21,26; NSTEACS (defined as studies having a majority of patients with ACS involved in the
study)3,5,20,22,25; and STEMI6,7,23,24; (2)
clopidogrel doses: pretreatment ⬍600
mg3,5,6,19-26,29,30 vs ⱖ600 mg.7,16-18 Furthermore, to analyze more contemporary practice of pretreatment (typically
a few hours before PCI), we conducted
a sensitivity analysis that removed the 2
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large studies—Clopidogrel in Unstable
Angina to Prevent Recurrent Events (PCI
CURE) and Clopidogrel as Adjunctive
Reperfusion Therapy (PCI Clopidogrel
as Adjunctive Reperfusion Therapy
[CLARITY])—that had several days of
pretreatment. To test the eventual effect of length of follow-up, we also performed a sensitivity analysis that replaced the 1-year by the 28-day follow-up
results of the Clopidogrel for the Reduction of Events During Observation
(CREDO) trial.
Because all studies included in the
main analysis had different clinical presentations, loading doses, and timing
of pretreatment, we examined the extent of heterogeneity between trials with
the Cochran Q test; a P cut-off value of
.10 was considered significant for
heterogeneity. An I2 test for heterogeneity between subgroups is reported in
each figure.31
All probability values were 2 tailed
and P = .05 was considered statistically
significant. Odds ratios (ORs) with 95%
CIs were calculated by use of RevMan
software version 5.0 (The Cochrane
Collaboration) and the language R using
the meta-package.32
Publication bias was evaluated by
using funnel-plot graphs to check symmetrical distribution and convergence
toward the pooled effect as the weight
of the trials increased and by the fill and
trim method.33
RESULTS
Studies and Patient Characteristics
Fifteen studies representing a total of
37 814 patients were included; of those,
5 RCTs focused solely on pretreatment,3,7,16-18 2 RCTs included PCI subgroups comparing pretreatment with no
pretreatment and were included in the
RCTs’ primary analysis5,6 (8608 patients both); 2 prespecified nonrandomized subgroup analyses of pretreatment in RCTs19,20 (10 945 patients) were
analyzed separately; and 6 registries21-26 (18 261 patients) were also analyzed separately (FIGURE 1). For the
main analysis of RCTs, 4283 patients
were pretreated (49.76%) and 4325
were not (50.24%). Seventy-five per-
cent had ACS (n=6510) including 25%
of STEMI patients (n = 2158); the remaining patients had elective PCI
(n=2098). An observational study23 that
did not provide the loading dose of
clopidogrel was excluded from the loading-dose subgroup analysis. Although
another observational study24 did not
provide the exact timing of pretreatment, it was included because the delay time in treatment to procedure was
considered sufficient.
For all studies, patients in the control groups were those who received a
loading dose of clopidogrel within 2
hours of undergoing PCI7,16,17,25,34 or immediately after PCI.6,19-24,26 The longest follow-up varied from the time patients were in the hospital to a
maximum of 1 year, with a mean follow-up time of 192 days (7-365 days;
Table 1). No heterogeneity existed between RCTs for major end points or for
ischemic end points. Significant heterogeneity was found between observational analyses of RCTs (although not
for death) and between observational
studies for all end points.
Mortality
In the RCT cohort of patients (n=8608),
clopidogrel pretreatment was not significantly associated with a reduction of
all-cause mortality (absolute risk, 1.54%
vs 1.97%; OR, 0.80; 95% CI, 0.57-1.11;
P=.17). These results were consistent
across the observational analyses of RCTs
and the observational studies analyses
(FIGURE 2). Cardiovascular death was
available in 4 to 7 RCTs5,6,16,17(n=5129
patients), and the association between
clopidogrel pretreatment and reduction of CV death was not present (absolute risk, 1.54% vs 1.97%; OR, 0.78;
95% CI, 0.44-1.39; P = .41). This end
point was available for only 1 observational study,21 with consistent results
(absolute risk, 1.44% vs 1.92%; OR,
0.80; 95% CI, 0.57-1.11; P =.17).
Safety
Clopidogrel pretreatment was not associated with a higher risk of major
bleeding in the main analysis of RCTs
(absolute risk, 3.57% vs 3.08%; OR,
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CLOPIDOGREL, MORTALITY, CV EVENTS, AND BLEEDING
1.18; 95% CI, 0.93-1.50; P=.18). Similar findings were obtained in observational analyses of RCTs and in the
pooled analysis of observational studies (FIGURE 3).
Minor bleeding events were exploratory safety end points, available in 5
RCTs only.3,5,6,17,34 There was a significant association between clopidogrel
pretreatment and minor bleeding (absolute risk, 3.66% vs 2.74%; OR, 1.47;
95% CI, 1.02-2.14; P = .04); however,
this was not confirmed in observational analyses of RCTs (OR, 1.01; 95%
CI, 0.84-1.21; P = .91) or in observational studies (OR, 1.09; 95% CI, 0.801.47; P=.58) but data were available in
only one19 and two22,25 studies of these
groups, respectively.
Figure 1. Study Selection
392 Abstracts identified through electronic database search
41 Duplicate reports excluded
351 Abstracts screened
300 Excluded
280 Not relevant
2 Meta-analyses
13 Reviews/opinion articles
4 Letters to the editor
1 Study with ticlopidine pretreatment
51 Full-text articles assessed for eligibility
36 Excluded
3 Studies of efficacy of anti-GpIIb/IIIa (2, no placebo group)
11 Dose comparison studies, 300 vs 600 mg
2 Patients taking clopidogrel before study enrollment
1 Study of preloading before CABG surgery
2 No sufficient bleeding or death data
17 Biological studies
Secondary End Points
Major Coronary Event and Myocardial Infarction. In the main analysis,
clopidogrel pretreatment was significantly associated with a reduction of
major coronary events (absolute risk,
9.83% vs 12.35%; OR, 0.77; 95% CI,
0.66-0.89, P⬍.001; Figure 3) and MI
(absolute risk, 4.53% vs 5.90%; OR,
0.75; 95% CI, 0.62-0.92, P = .004).
These results were confirmed in the
pooled analyses of observational studies but not in the analyses of observational studies of RCTs (Figure 3).
Other End Points. Stent thrombosis was exploratory because of its availability in only 1 RCT, in which the association was not significant with
clopidogrel pretreatment vs no pretreatment (absolute risk, 0.98% vs 0.00%;
OR, 5.07; 95% CI, 0.24-106.35;
P = .30)17 and 4 observational studies,21,24-26 including 7497 patients, in
which clopidogrel pretreatment was significantly associated with a reduction
in probable and definite stent thrombosis (absolute risk, 0.78% vs 1.66%;
OR, 0.49; 95% CI, 0.31-0.78, P=.003).
Stroke was reported in 5 of the 7
RCTs3,6,7,16,34 (n=5541 patients). No significant association existed between
clopidogrel pretreatment and the reduction in stroke (absolute risk, 0.54%
vs 0.94%; OR, 0.59; 95% CI, 0.311.12, P = .11); data were available for
15 Studies included in qualitative synthesis
15 Studies included in quantitative synthesis
(meta-analysis)
5 RCTs randomized for clopidogrel pretreatment
vs no pretreatment
2 PCI subgroup of RCTs for clopidogrel
pretreatment vs no pretreatment
2 Prespecified subgroup analyses of pretreatment
in RCTs
6 Registries
References of the excluded articles are available at http://www.jama.com. CABG indicates coronary artery
bypass; GPIIb/IIIa, glycoprotein IIb/IIIa; PCI, percutaneous coronary intervention; and RCT, randomized controlled trial.
only 1 observational study,25 for which
no association existed between pretreatment and reduction in stroke (absolute risk, 0.21% vs 0.00%; OR, 3.69;
95% CI, 0.15-90.90, P=.42).
Urgent revascularization was available in 5 RCTs 3,7,16-18 (n = 4087 patients) and 4 observational studies22,23,25,26 (n=15 965 patients). There
was no significant association between urgent revascularization and
clopidogrel pretreatment in the primary analysis of the RCTs (absolute
risk, 1.47% vs 1.61%; OR, 0.91; 95% CI,
0.56-1.49; P = .71). Results were consistent in the observational studies
analysis (absolute risk, 5.34% vs 2.15%;
OR, 0.98; 95% CI, 0.74-1.30; P =.89).
There were no available data on these
end points from observational analyses of RCTs.
©2012 American Medical Association. All rights reserved.
There was no heterogeneity between RCTs as assessed by the Cochran Q test, but significant heterogeneity was found in observational
analyses of RCTs and observational
studies for several end points.
Subset Analyses
Results for the prespecified RCT subsets of clinical presentation are summarized in eFigure 1 (available at http:
//www.jama.com). For all-cause
mortality, a significant association existed between clopidogrel pretreatment
and a reduction of death in the STEMI
subgroup only (absolute risk, 1.28% vs
2.54%; OR, 0.50; 95% CI, 0.26-0.96;
P=.04; number needed to treat, 79; eFigure 2). Clopidogrel pretreatment in
STEMI was also significantly associated
with a reduction in major coronary
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CLOPIDOGREL, MORTALITY, CV EVENTS, AND BLEEDING
events (absolute risk, 3.56% vs 6.36%;
OR, 0.54; 95% CI, 0.36-0.81; P=.003;
number needed to treat, 36) as well as
in patients with NSTE ACS (absolute
risk, 13.91% vs 17.19%; OR, 0.78; 95%
CI, 0.66-0.91; P=.002; number needed
to treat, 30) but not in the lower-risk
population of elective PCI (eFigure 1).
Safety outcomes did not differ across
the 3 subgroups of clinical presentation by treatment (eTable 3). Similarly, little difference existed between
the groups of doses (⬍600 vs ⱖ600 mg)
on the various efficacy and safety end
points (eTable 4). Because there was no
significant heterogeneity between subgroups by clinical presentation and
clopidogrel loading dose, these results
are only exploratory and should not
been considered as definitive.
The other sensitivity analyses on pretreatment delay (excluding PCI CURE
and PCI CLARITY) and duration of follow-up (using the 28-day results of
CREDO) showed results similar to
those of the main analysis.3
COMMENT
Although data have accumulated over the
past 10 years about the efficacy and safety
of clopidogrel pretreatment, the association of this strategy with a decrease in allcause death remains uncertain because
no large RCT has addressed this issue.
The current meta-analysis collected information in a population of more than
37 000 patients and found no significant association between clopidogrel pretreatment and survival nor between clopidogrel pretreatment and major bleeding.
This meta-analysis demonstrated, however, a significant association between
clopidogrel pretreatment and the reduction of major coronary events or MIs in
the primary RCTs analyses combining all
types of patients, with fully consistent
results obtained from observational
analyses of RCTs and observational stud-
ies. Although no significant heterogeneity existed for clinical presentation, the
higher-risk STEMI population appeared
to gain the most benefit from pretreatment. In contrast, patients undergoing
elective PCI had no apparent benefit from
clopidogrel pretreatment, questioning the
need of such a systematic strategy at least
in low-risk patients.
Clopidogrel pretreatment has been
largely accepted and applied in accordance with the ACC/AHA and ESC
guidelines,12,13,35 which are based on evidence from the results of 3 studies performed in the early 2000s. First, in the
PCI-CURE substudy,5 clopidogrel pretreatment (300 mg loading dose with a
median of 10 days before catheterization) was associated with a 30% reduction of the composite end point of CV
death, MI, and urgent target vessel revascularization at 30 days, without
significant difference in major bleeding. Although all-cause mortality was not
Figure 2. All-Cause Mortality Analysis
All-Cause Mortality
No. of Patients
No. of Events
Pretreatment
Source
RCTs
17
ARMYDA-5 PRELOAD, 2010
1
Davlouros et al,16 2009
0
18
PRAGUE 8, 2008
1
7
CIPAMI, 2007
1
6
CLARITY PCI, 2005
13
3
CREDO, 2002
18
PCI CURE,5 2001
32
Overall
66
Relative
Weight, %
No
Pretreatment
Pretreatment
No
Pretreatment
OR
(95% CI)
0
2
0
4
24
24
31
204
96
513
164
933
1053
1313
205
103
515
171
930
1063
1345
3.03 (0.12-74.80)
0.18 (0.01-3.85)
3.02 (0.12-74.25)
0.26 (0.03-2.32)
0.53 (0.27-1.05)
0.75 (0.41-1.40)
1.06 (0.64-1.75)
1.0
1.2
1.0
2.2
23.2
28.3
43.1
85
4283
4325
0.80 (0.57-1.11)
P = .17
100
Favors
Pretreatment
0.1
Favors No
Pretreatment
1.0
10
Odds Ratio (95% CI)
Observational analyses of RCTs a
REPLACE-2,19 2004
ACUITY PCI,20 2007
Overall
114
105
14
49
5087
3511
832
1515
1.34 (0.77-2.34)
0.92 (0.65-1.30)
31.8
68.2
219
63
8598
2347
1.04 (0.74-1.46)
P = .83
100
0.1
1.0
10
Odds Ratio (95% CI)
Observational studies
Amin et al,21 2011
Dörler et al,23 2011
Feldman et al,25 2010
Fefer et al,24 2009
Szük et al,26 2007
Chan et al,22 2003
Overall
13
209
18
12
6
76
19
110
18
6
18
12
923
4879
467
217
1481
4477
990
1076
574
166
2679
332
0.73 (0.36-1.49)
0.39 (0.31-0.50)
1.24 (0.64-2.41)
1.56 (0.57-4.25)
0.60 (0.24-1.52)
0.46 (0.25-0.86)
16.2
24.0
17.0
11.9
12.9
17.8
334
183
12 444
5817
0.68 (0.42-1.09)
P = .11
100
0.1
1.0
10
Odds Ratio (95% CI)
a The number of patients represent those who were followed up at 1 year.
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CLOPIDOGREL, MORTALITY, CV EVENTS, AND BLEEDING
Figure 3. Major Bleeding and Major Cardiovascular Event Analyses
Major Bleeding
No. of Patients
No. of Events
Pretreatment
Source
RCTs
ARMYDA-5 PRELOAD,17 2010
0
Davlouros et al,16 2009
3
PRAGUE 8,18 2008
2
CIPAMI,7 2007
14
CLARITY PCI,6 2005
5
CREDO,3 2002
93
PCI CURE,5 2001
36
Overall
Pretreatment
No
Pretreatment
OR
(95% CI)
0
3
1
15
10
71
33
204
103
513
164
933
1053
1313
205
96
515
171
930
1063
1345
Not Estimable
0.93 (0.18-4.72)
2.01 (0.18-22.26)
0.97 (0.45-2.08)
0.50 (0.17-1.46)
1.35 (0.98-1.87)
1.12 (0.69-1.81)
—
2.2
1.0
10.0
5.0
56.3
25.4
133
4283
4325
1.18 (0.93-1.50)
P = .18
100
153
Favors
Pretreatment
0.1
Observational analyses of RCTs a
REPLACE-2,19 2004
ACUITY PCI,20 2007
Overall
Overall
Favors No
Pretreatment
1.0
10
152
190
38
70
5051
3511
881
1528
0.69 (0.48-0.99)
1.19 (0.90-1.58)
47.7
52.3
342
108
8562
2409
0.92 (0.54-1.57)
P = .75
100
0.1
Observational studies
Amin et al,21 2011
Dörler et al,23 2011
Feldman et al,25 2010
Fefer et al,24 2009
Szük et al,26 2007
Chan et al,22 2003
Relative
Weight, %
No
Pretreatment
1.0
10
9
42
4
3
20
36
10
15
7
1
11
3
923
4879
467
217
1481
4477
990
1076
574
166
2679
332
0.96 (0.39-2.39)
0.61 (0.34-1.11)
0.70 (0.20-2.41)
2.31 (0.24-22.44)
3.32 (1.59-6.95)
0.89 (0.27-2.90)
18.9
23.6
14.5
6.6
21.4
15.1
114
47
12 444
5817
1.13 (0.58-2.19)
P = .72
100
0.1
1.0
10
Odds Ratio (95% CI)
Major Coronary Event
No. of Events
Pretreatment
Source
RCTs
17
ARMYDA-5 PRELOAD, 2010
21
Davlouros et al,16 2009
15
18
PRAGUE 8, 2008
17
7
CIPAMI, 2007
5
CLARITY PCI,6 2005
34
CREDO,3 2002
89
PCI CURE,5 2001
240
Overall
421
No. of Patients
Favors
Pretreatment
Pretreatment
No
Pretreatment
OR
(95% CI)
18
13
19
12
58
122
292
204
96
513
164
933
1053
1313
205
103
515
171
930
1063
1345
1.19 (0.62-2.31)
1.09 (0.49-2.42)
0.89 (0.46-1.74)
0.42 (0.14-1.21)
0.57 (0.37-0.88)
0.71 (0.53-0.95)
0.81 (0.67-0.98)
4.9
3.4
4.8
1.9
11.2
24.2
49.7
534
4283
4325
0.77 (0.66-0.89)
P <.001
100
0.1
Observational analyses of RCTs b
REPLACE-2,19 2004
ACUITY PCI,20 2007
Overall
Overall
1.0
10
462
657
102
262
5087
3511
832
1515
0.72 (0.58-0.91)
1.10 (0.94-1.29)
48.0
52.0
1119
364
8598
2347
0.90 (0.60-1.36)
P = .62
100
0.1
Observational studies
Amin et al,21 2011
Dörler et al,23 2011
Feldman et al,25 2010
Fefer et al,24 2009
Szük et al,26 2007
Chan et al,22 2003
Relative
Weight, %
Favors No
Pretreatment
No
Pretreatment
75
480
39
47
41
638
87
173
41
56
127
63
923
4879
467
217
1481
4477
990
1076
574
166
2679
332
0.92 (0.66-1.27)
0.57 (0.47-0.69)
1.18 (0.75-1.87)
0.54 (0.34-0.86)
0.57 (0.40-0.82)
0.71 (0.53-0.95)
1320
547
12 444
5817
0.70 (0.56-0.88)
P = .002
1.0
10
17.3
22.7
12.7
12.7
15.9
18.7
100
0.1
1.0
10
Odds Ratio (95% CI)
For a definition of major bleeding for each study, see Table 1.
a The number of patients represents those who were followed up at 30 days.
b The number of patients represents those who were followed up at 1 year.
©2012 American Medical Association. All rights reserved.
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CLOPIDOGREL, MORTALITY, CV EVENTS, AND BLEEDING
reported in the study, CV death was not
different between groups and reduction in major coronary events was driven
by the decrease in periprocedural MI.
Second, the CREDO trial3 demonstrated an interaction between the timing of pretreatment and the protection
from adverse CV events in stable patients undergoing scheduled angioplasty. Indeed, although not powered to
show a difference in ischemic end points,
the group of patients loaded with 300 mg
of clopidogrel at least 6 hours before PCI
experienced a 38.6% decrease in major
coronary events that reached significance among those pretreated at least 15
hours before the procedure.3,36
Third, the CLARITY-PCI substudy6
found a significant decrease in major
coronary events, with no increased risk
of bleeding in patients undergoing secondary PCI after fibrinolysis associated
with clopidogrel pretreatment. Additional evidence comes from smaller studies and a meta-analysis that used different doses of clopidogrel for elective
PCI,37,38 NSTEMI,39,40 and STEMI,39,41 and
from the CURRENT-OASIS 7 subgroup
analysis of patients with ACS undergoing PCI.42 In the latter, all patients were
pretreated with 600 mg followed by 150
mg of a maintenance dose for 7 days and
75 mg daily thereafter, which significantly reduced by 14% the combined primary end point of CV death, MI, and
stroke compared with the standard
300-mg loading dose and 75-mg maintenance dose; there was no excess of
thrombosis in MI major bleeding.43
With this accumulation of data,
administration of clopidogrel before PCI
became the rule with a class I recommendation. The ESC recommends pretreatment with a 300-mg loading dose for
more than 6 hours before elective PCI
(or 600 mg ⬎2 hours before; class Ic),42
and a 600-mg loading dose as soon as
possible for primary PCI for patients with
STEMI (class Ic).42 The low level of evidence reflects the absence of indisputable evidence. In the more recent ESC
guidelines, the higher loading dose of 600
mg for PCI for patients with NSTE-ACS
has a class Ib recommendation when
ticagrelor or prasugrel is not an option.12
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The ACC/AHA PCI guidelines for
patients undergoing elective PCI and
patients with NSTE-ACS or STEMI who
are scheduled for PCI also recommends
pretreatment with a 300- to 600-mg loading dose (preferably 600 mg) as early as
possible before PCI (class Ib
recommendation).13,44
Several issues remain unresolved
with regard to the evidence supporting the recommendations. First, many
of the patients included had their PCIs
postponed for up to several days after
pretreatment and therefore do not accurately reflect contemporary practice
of early revascularization, often performed within hours of first medical
contact. Our meta-analysis includes the
most recent studies including registries and may better reflect current realworld practice. The concordance between RCTs and observational studies
supports our findings.
Second, it is unclear whether all patients or just certain types of presentation should be pretreated, although the
recommendations are quite broad in favor of pretreatment. Our data suggest
a benefit limited to the patients at higher
risk, STEMI especially, with a significant association between clopidogrel
pretreatment and the reduction in hard
outcomes. However, because of the absence of significant heterogeneity by
condition, these results are only informative and would need additional exploration in specific trials.
Third, none of the studies or previous meta-analyses was adequately powered to show a benefit on all-cause mortality. The results of our meta-analysis,
which is powered for mortality, do not
support clopidogrel pretreatment on this
basis in the overall PCI population.
The reasons clopidogrel pretreatment does not decrease mortality in the
stable patients could not be ascertained but several hypotheses may be
generated. First, the benefit of this treatment may be related to baseline platelet reactivity, which is lower in more
stable patients.45,46 Second, clopidogrel, both for loading and maintenance
doses, is associated with moderate level
of inhibition and a wide variability in re-
sponse that may explain the absence of
effect on mortality.47
Third, the benefit expected from pretreatment during the waiting period for
catheterization of patients with NSTEACS may not be detectable with clopidogrel, which has a slow onset of action, a delay of action critical in the
current era when the speed at which patients transfer to the catheterization
laboratory is faster than it was 10 years
ago. Progress has been made in time to
catheterization, in PCI procedures, and
in new antiplatelet strategies, which
challenges the concept of pretreatment. Some studies have shown that delays to revascularization can be substantially shortened in NSTE-ACS48,49
while studies like ACCOAST (A Comparison of Prasugrel at PCI or Time of
Diagnosis of Non-ST Elevation Myocardial Infarction, NCT01015287) and
ATLANTIC (A 30 Day Study to Evaluate Efficacy and Safety of Pre-hospital
vs In-hospital Initiation of Ticagrelor
Therapy in STEMI Patients Planned for
Percutaneous Coronary Intervention
[PCI], NCT01347580) are evaluating,
in the modern era of PCI, the concept
of pretreatment with new P2Y12 inhibitors in NSTE-ACS and STEMI, respectively. These studies are needed to understand better the role of pretreatment
not evaluated in the large pivotal trials
that tested the new P2Y12 inhibitors prasugrel (no pretreatment) and ticagrelor (systematic pretreatment).
Fourth, most of the serious events, in
particular death, do not occur in the catheterization laboratory but are delayed by
days or weeks when clopidogrel is actually effective and death then relates to
other factors of poor prognosis.
Fifth, one-third of elective coronary angiograms are normal,50 which
does not justify clopidogrel pretreatment that exposes patients to bleeding risk with no benefit to be expected
on ischemic events or mortality.18
Finally, some patients with NSTEACS could be reoriented toward urgent coronary artery bypass revascularization, during which clopidogrel
exposure may double the rate of reoperation because of bleeding, thus in-
©2012 American Medical Association. All rights reserved.
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CLOPIDOGREL, MORTALITY, CV EVENTS, AND BLEEDING
creasing transfusions and deaths. 51
Bleeding in general is a driver of mortality, and the present meta-analysis
suggests a significant excess of major
bleeding in lower-risk patients.
We acknowledge several limitations of our study that, as in all systematic reviews, may have been influenced by several forms of bias; we tried
to minimize selection bias by using a
predefined search strategy, with independent selection and data extraction
by 2 independent reviewers, without
any language restriction and including registries and RCTs as well as their
sub-analyses. Furthermore, funnel plots
or the fill and trim method did not suggest any publication bias. This metaanalysis, however, was not performed
on individual data. For the initial selection of studies, data abstractors were
not blinded to authors, affiliations, and
journals. Observational data have limitations inherent to the nature of the data
collected with potential serious biases. The pooled analyses of these studies have been reported separately and
should be seen only as supportive of the
main analysis performed on RCTs.
Despite regrouping a large number
of patients, this meta-analysis of randomized trials only may have had an
insufficient statistical power to definitely exclude an effect on mortality. Because the CIs are wide, and even if an
OR of 0.80 was found, it is not reasonably possible to exclude that the pretreatment efficacy may be greater (at
best a reduction of mortality of 43%)
or smaller (at worse an increase in mortality of 11%). Bleeding could furthermore have mitigated the mortality benefit, but the information on fatal
bleeding is lacking in most publications.
Because of varied designs, end point
definitions, patient presentations, clopidogrel loading doses, timing of loading before PCI, other drug regimens and
durations of follow-up, we have conducted several confirmatory subset
analyses along with the main analysis
on RCTs that was not hampered by any
heterogeneity between trials. The fact
that observational studies analyses are
fully consistent with the RCTs analysis support our findings.
Furthermore, because we cannot
completely exclude a potential interaction between clopidogrel pretreatment and an unknown factor of heterogeneity, and although no multilevel
meta-analysis was done, we performed multiple sensitivity analyses that
do not suggest any difference from the
main analysis when considering many
of these covariate variables. It is thus
unlikely that such unidentified interactions could affect the primary end
point of the study. In all cases, most
subgroup comparisons must be viewed
as exploratory and not as definitive, and
specific research on these subgroups
should be performed to better understand the effect of pretreatment.
In conclusion, among patients scheduled for PCI, clopidogrel pretreatment was not associated with a lower
risk of overall mortality, but was associated with a significantly lower risk of
a major coronary event. Although a pretreatment strategy has been recommended for years in patients undergoing PCI, this study shows the limits of
the available evidence, with no significant benefit on hard outcomes. The
value of pretreatment, including with
new antiplatelet agents, needs to be assessed in large prospective studies.
Author Affiliations: Service de Cardiologie-La Fontonne Hospital, Antibes (Drs Bellemain-Appaix, Jacq,
and Bernasconi); Institut de Cardiologie, INSERM
UMRS937, Pitié-Salpêtrière Hospital (AP-HP), Université Paris 6 (Drs O’Connor, Silvain, Beygui, Barthélémy, Collet, and Montalescot); Unité Mixte de Recherche du Centre National de Recherche Scientifique
5558, Université Claude Bernard Lyon 1, Lyon (Dr
Cucherat), France.
Author Contributions: Drs Bellemain-Appaix,
O’Connor, and Montalescot had full access to all of
the data in the study and take responsibility for the
integrity of the data and the accuracy of the data analysis.
Study concept and design: Bellemain-Appaix,
O’Connor, Silvain, Montalescot.
Acquisition of data: Bellemain-Appaix, O’Connor,
Silvain.
Analysis and interpretation of data: BellemainAppaix, O’Connor, Silvain, Cucherat, Beygui,
Barthélémy, Collet, Jacq, Bernasconi, Montalescot.
Drafting of the manuscript: Bellemain-Appaix,
O’Connor, Silvain, Montalescot.
Critical revision of the manuscript for important intellectual content: Bellemain-Appaix, O’Connor, Silvain,
Cucherat, Beygui, Barthélémy, Collet, Jacq, Bernasconi,
Montalescot.
Statistical analysis: Bellemain-Appaix, O’Connor,
Silvain, Cucherat, Beygui.
©2012 American Medical Association. All rights reserved.
Administrative, technical, or material support:
Bellemain-Appaix, Montalescot.
Study supervision: Bellemain-Appaix, Collet, Jacq,
Bernasconi, Montalescot.
Conflict of Interest Disclosures: All authors have
completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Montalescot reported that he has received research grants
from Bristol-Myers Squibb, sanofi-aventis, Eli Lilly,
Guerbet Medical, Medtronic, Boston Scientific,
Cordis, Stago, Centocor, Fondation de France,
INSERM, Fédération Française de Cardiologie, and
Société Française de Cardiologie; consulting fees
from sanofi-aventis, Eli Lilly, Bristol-Myers Squibb,
The Medicines Company, and Schering Plough; lectures fees from Bristol-Myers Squibb, sanofiaventis, Eli Lilly, Merck Sharpe & Dohme, Cordis,
GlaxoSmithKline, and Schering Plough. Dr Collet
reported he has received research grants from
Bristol-Myers Squibb, sanofi-aventis, Eli Lilly, Guerbet Medical, Medtronic, Boston Scientific, Cordis,
Stago, Centocor, Fondation de France, INSERM,
Federation Francaise de Cardiologie, and Société
Française de Cardiologie; consulting fees from
sanofi-aventis, Eli Lilly, and Bristol-Myers Squibb;
and lecture fees from Bristol-Myers Squibb, sanofiaventis, and Eli Lilly. Dr Bellemain-Appaix reported
that she had received research grants from DaiichiSankyo, Eli Lilly, Fédération Française de Cardiologie, and Société Française de Cardiologie and lecture fees from AstraZeneca. Dr Silvain reported that
he has received research grants from sanofi-aventis,
Daiichi-Sankyo, Eli Lilly, Brahms, INSERM, Fédération Française de Cardiologie, and Société Française
de Cardiologie; consulting fees from DaiichiSankyo, Eli Lilly; and speaker honoraria from
AstraZeneca, Daiichi Sankyo, Eli Lilly, Iroko Cardio
and Servier. Dr O’Connor reported that he has
received grants from A Menarini and the European
Society of Cardiology. M Cucherat has received
research grants from Bristol-Myers Squibb,
AstraZeneca, Bayer, and Haute Autorité de Santé;
consulting fees from Bayer, Bristol-Myers Squibb;
and speaker honoraria from Bristol-Myers Squibb.
The other authors report no conflicts.
Funding/Support: No external source of funding.
The study was led by the ACTION study group
(http://www.action-coeur.org).
Online-Only Material: eTables 1-4, eFigures 1 and
2, eReferences, and the Author Audio Interview are
available at http://www.jama.com.
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