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Review | Clinician's Corner

Association of Clopidogrel Pretreatment With Mortality, Cardiovascular Events, and Major Bleeding Among Patients Undergoing Percutaneous Coronary Intervention:  A Systematic Review and Meta-analysis FREE

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
[+] Author Affiliations

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.


JAMA. 2012;308(23):2507-2516. doi:10.1001/jama.2012.50788.
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Published online

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 random-effect 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.

Figures in this Article

In addition to aspirin, clopidogrel has been shown to improve ischemic outcomes of patients with stable coronary artery disease following percutaneous coronary intervention (PCI)13 and of patients with acute coronary syndromes (ACS) who were either medically treated4 or who had undergone either revascularization by fibrinolysis or PCI.57 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.811

Quiz Ref IDAlthough the administration of a clopidogrel loading dose is necessary in the immediate peri-PCI setting, it is uncertain whether clopidogrel pretreatment (ie, treatment given in enoughtime 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 after undergoing coronary angiogram. 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 American Heart Association (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.

Study Design

The main analysis included only randomized controlled trials (RCTs)3,7,1618 and the PCI subgroups of RCTs for clopidogrel pretreatment vs no pretreatment5,6 that fulfilled the inclusion criteria, 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 studies2126 (Table 1 and Table 2).

Table Graphic Jump LocationTable 2. Study Review of Randomized Controlled Trial Study Characteristics
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.).

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

Quiz Ref IDThe 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 thrombosis was defined using the definite plus 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-OttawaScale for cohort studies (http://www.ohri.ca/programs/clinical_epidemiology/oxford.htm; see eTables 1 and 2).

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 fixed-effect 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 PCI1619,21,26; NSTE-ACS (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 mg3,5,6,1926,29,30 vs ≥ 600 mg.7,1618 Furthermore, to analyze more contemporary practice of pretreatment (typically a few hours before PCI), we conducted a sensitivity analysis that removed the 2 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

Studies and Patient Characteristics

Fifteen studies representing a total of 37 814 patients were included; of those, 5 RCTs focused solely on pretreatment,3,7,1618 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 registries2126 (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 percent 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.

Place holder to copy figure label and caption
Figure 1. Study Selection
Graphic Jump Location

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.

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.6,1924,26 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).

Place holder to copy figure label and caption
Figure 2. All-Cause Mortality Analysis
Graphic Jump Location

aThe number of patients represent those who were followed up at 1 year.

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, 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).

Place holder to copy figure label and caption
Figure 3. Major Bleeding and Major Cardiovascular Event Analyses
Graphic Jump Location

For a definition of major bleeding for each study, see Table 1.aThe number of patients represents those who were followed up at 30 days.bThe number of patients represents those who were followed up at 1 year.

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, 0.80-1.47; P = .58) but data were available in only one19 and two22,25 studies of these groups, respectively.

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,21,2426 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, 0.31-1.12, P = .11); data were available for 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 RCTs3,7,1618(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.

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. 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 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 ≥600 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

Quiz Ref IDAlthough 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 all-cause 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 studies. 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 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 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 real-world 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.

Quiz Ref IDThe 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 response 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 NSTE-ACS 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 NSTE-ACS could be reoriented toward urgent coronary artery bypass revascularization, during which clopidogrel exposure may double the rate of reoperation because of bleeding, thus increasing 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 meta-analysis, 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.

Quiz Ref IDIn 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.

Corresponding Author: Gilles Montalescot, MD, PhD, Institut de Cardiologie, Bureau 2-236, Pitié-Salpêtrière Hospital, 47 Boulevard de l’Hôpital, 75013 Paris, France (gilles.montalescot@psl.aphp.fr).

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: Bellemain-Appaix, 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.

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, sanofi-aventis, 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, sanofi-aventis, and Eli Lilly. Dr Bellemain-Appaix reported that she had received research grants from Daiichi-Sankyo, 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 Daiichi-Sankyo, 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: Author Audio Interview is available here.

This article was corrected for errors on March 7, 2013.

Leon MB, Baim DS, Popma JJ,  et al; Stent Anticoagulation Restenosis Study Investigators.  A clinical trial comparing three antithrombotic-drug regimens after coronary-artery stenting.  N Engl J Med. 1998;339(23):1665-1671
PubMed   |  Link to Article
Schömig A, Neumann FJ, Kastrati A,  et al.  A randomized comparison of antiplatelet and anticoagulant therapy after the placement of coronary-artery stents.  N Engl J Med. 1996;334(17):1084-1089
PubMed   |  Link to Article
Steinhubl SR, Berger PB, Mann JT III,  et al; CREDO Investigators.  Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial.  JAMA. 2002;288(19):2411-2420
PubMed   |  Link to Article
Chen ZM, Jiang LX, Chen YP,  et al; COMMIT (ClOpidogrel and Metoprolol in Myocardial Infarction Trial) collaborative group.  Addition of clopidogrel to aspirin in 45 852 patients with acute myocardial infarction.  Lancet. 2005;366(9497):1607-1621
PubMed   |  Link to Article
Mehta SR, Yusuf S, Peters RJ,  et al; Clopidogrel in Unstable angina to prevent Recurrent Events trial (CURE) Investigators.  Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention.  Lancet. 2001;358(9281):527-533
PubMed   |  Link to Article
Sabatine MS, Cannon CP, Gibson CM,  et al; Clopidogrel as Adjunctive Reperfusion Therapy (CLARITY)-Thrombolysis in Myocardial Infarction (TIMI) 28 Investigators.  Effect of clopidogrel pretreatment before percutaneous coronary intervention in patients with ST-elevation myocardial infarction treated with fibrinolytics.  JAMA. 2005;294(10):1224-1232
PubMed   |  Link to Article
Zeymer U, Arntz HR, Darius H, Huber K, Senges J. Efficacy and safety of clopidogrel 600 mg administered pre-hospitally to improve primary percutaneous Coronary Intervention in Patients With Acute Myocardial Infarction (CIPAMI).  Cardiology. 2007;108(4):265-272
PubMed   |  Link to Article
Collet JP, Hulot JS, Pena A,  et al.  Cytochrome P450 2C19 polymorphism in young patients treated with clopidogrel after myocardial infarction.  Lancet. 2009;373(9660):309-317
PubMed   |  Link to Article
Mega JL, Close SL, Wiviott SD,  et al.  Cytochrome p-450 polymorphisms and response to clopidogrel.  N Engl J Med. 2009;360(4):354-362
PubMed   |  Link to Article
Shuldiner AR, O’Connell JR, Bliden KP,  et al.  Association of cytochrome P450 2C19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy.  JAMA. 2009;302(8):849-857
PubMed   |  Link to Article
Simon T, Verstuyft C, Mary-Krause M,  et al; French Registry of Acute ST-Elevation and Non-ST-Elevation Myocardial Infarction (FAST-MI) Investigators.  Genetic determinants of response to clopidogrel and cardiovascular events.  N Engl J Med. 2009;360(4):363-375
PubMed   |  Link to Article
Hamm CW, Bassand JP, Agewall S,  et al; ESC Committee for Practice Guidelines; Document Reviewers.  ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation.  Eur Heart J. 2011;32(23):2999-3054
PubMed   |  Link to Article
Wright RS, Anderson JL, Adams CD,  et al.  2011 ACCF/AHA Focused Update of the Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction (Updating the 2007 Guideline).  Circulation. 2011;123(18):2022-2060
PubMed   |  Link to Article
Vlaar PJ, Svilaas T, Damman K,  et al.  Impact of pretreatment with clopidogrel on initial patency and outcome in patients treated with primary percutaneous coronary intervention for ST-segment elevation myocardial infarction.  Circulation. 2008;118(18):1828-1836
PubMed   |  Link to Article
Sabatine MS, Hamdalla HN, Mehta SR,  et al.  Efficacy and safety of clopidogrel pretreatment before percutaneous coronary intervention with and without glycoprotein IIb/IIIa inhibitor use.  Am Heart J. 2008;155(5):910-917
PubMed   |  Link to Article
Davlouros PA, Arseniou A, Hahalis G,  et al.  Timing of clopidogrel loading before percutaneous coronary intervention in clopidogrel-naive patients with stable or unstable angina: a comparison of 2 strategies.  Am Heart J. 2009;158(4):585-591
PubMed   |  Link to Article
Di Sciascio G, Patti G, Pasceri V, Gatto L, Colonna G, Montinaro A.ARMYDA-5 PRELOAD Investigators.  Effectiveness of in-laboratory high-dose clopidogrel loading versus routine pre-load in patients undergoing percutaneous coronary intervention.  J Am Coll Cardiol. 2010;56(7):550-557
PubMed   |  Link to Article
Widimsky P, Motovská Z, Simek S,  et al; PRAGUE-8 Trial Investigators.  Clopidogrel pretreatment in stable angina: for all patients >6 h before elective coronary angiography or only for angiographically selected patients a few minutes before PCI?.  Eur Heart J. 2008;29(12):1495-1503
PubMed   |  Link to Article
Saw J, Lincoff AM, DeSmet W,  et al; REPLACE-2 Investigators.  Lack of clopidogrel pretreatment effect on the relative efficacy of bivalirudin with provisional glycoprotein IIb/IIIa blockade compared to heparin with routine glycoprotein IIb/IIIa blockade.  J Am Coll Cardiol. 2004;44(6):1194-1199
PubMed
Stone GW, White HD, Ohman EM,  et al; Acute Catheterization and Urgent Intervention Triage strategy (ACUITY) trial investigators.  Bivalirudin in patients with acute coronary syndromes undergoing percutaneous coronary intervention.  Lancet. 2007;369(9565):907-919
PubMed   |  Link to Article
Amin AP, Kennedy KF, Pencina M,  et al; EVENT Investigators.  Effect of clopidogrel pretreatment on ischemic complications of percutaneous coronary intervention among bivalirudin-treated patients (from the EVENT registry).  Am J Cardiol. 2011;107(12):1751-1756
PubMed   |  Link to Article
Chan AW, Moliterno DJ, Berger PB,  et al;  TARGET Investigators.  Triple antiplatelet therapy during percutaneous coronary intervention is associated with improved outcomes including one-year survival.  J Am Coll Cardiol. 2003;42(7):1188-1195
PubMed   |  Link to Article
Dörler J, Edlinger M, Alber HF,  et al; Austrian Acute PCI Investigators.  Clopidogrel pre-treatment is associated with reduced in-hospital mortality in primary percutaneous coronary intervention for acute ST-elevation myocardial infarction.  Eur Heart J. 2011;32(23):2954-2961
PubMed   |  Link to Article
Fefer P, Hod H, Hammerman H,  et al.  Usefulness of pretreatment with high-dose clopidogrel in patients undergoing primary angioplasty for ST-elevation myocardial infarction.  Am J Cardiol. 2009;104(4):514-518
PubMed   |  Link to Article
Feldman DN, Fakorede F, Minutello RM, Bergman G, Moussa I, Wong SC. Efficacy of high-dose clopidogrel treatment (600 mg) less than 2 hours before percutaneous coronary intervention in patients with non-ST-segment elevation acute coronary syndromes.  Am J Cardiol. 2010;105(3):323-332
PubMed   |  Link to Article
Szük T, Gyöngyösi M, Homorodi N,  et al.  Effect of timing of clopidogrel administration on 30-day clinical outcomes: 300-mg loading dose immediately after coronary stenting versus pretreatment 6 to 24 hours before stenting in a large unselected patient cohort.  Am Heart J. 2007;153(2):289-295
PubMed   |  Link to Article
Cutlip DE, Windecker S, Mehran R,  et al; Academic Research Consortium.  Clinical end points in coronary stent trials.  Circulation. 2007;115(17):2344-2351
PubMed   |  Link to Article
Jadad AR, Moore RA, Carroll D,  et al.  Assessing the quality of reports of randomized clinical trials.  Control Clin Trials. 1996;17(1):1-12
PubMed   |  Link to Article
Steinhubl SR, Ellis SG, Wolski K, Lincoff AM, Topol EJ. Ticlopidine pretreatment before coronary stenting is associated with sustained decrease in adverse cardiac events.  Circulation. 2001;103(10):1403-1409
PubMed   |  Link to Article
Stone GW, Ellis SG, Colombo A,  et al.  Offsetting impact of thrombosis and restenosis on the occurrence of death and myocardial infarction after paclitaxel-eluting and bare metal stent implantation.  Circulation. 2007;115(22):2842-2847
PubMed   |  Link to Article
Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses.  BMJ. 2003;327(7414):557-560
PubMed   |  Link to Article
 R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. 2012. http://www.R-project.org/
Duval S, Tweedie R. Trim and fill.  Biometrics. 2000;56(2):455-463
PubMed   |  Link to Article
Widimsky P, Wijns W, Fajadet J,  et al; European Association for Percutaneous Cardiovascular Interventions.  Reperfusion therapy for ST elevation acute myocardial infarction in Europe.  Eur Heart J. 2010;31(8):943-957
PubMed   |  Link to Article
Taggart DP, Boyle R, de Belder MA, Fox KA. The 2010 ESC/EACTS guidelines on myocardial revascularisation.  Heart. 2011;97(6):445-446
PubMed   |  Link to Article
Steinhubl SR, Berger PB, Brennan DM, Topol EJ.CREDO Investigators.  Optimal timing for the initiation of pre-treatment with 300 mg clopidogrel before percutaneous coronary intervention.  J Am Coll Cardiol. 2006;47(5):939-943
PubMed   |  Link to Article
Lotrionte M, Biondi-Zoccai GG, Agostoni P,  et al.  Meta-analysis appraising high clopidogrel loading in patients undergoing percutaneous coronary intervention.  Am J Cardiol. 2007;100(8):1199-1206
PubMed   |  Link to Article
Patti G, Colonna G, Pasceri V, Pepe LL, Montinaro A, Di Sciascio G. Randomized trial of high loading dose of clopidogrel for reduction of periprocedural myocardial infarction in patients undergoing coronary intervention.  Circulation. 2005;111(16):2099-2106
PubMed   |  Link to Article
Cuisset T, Frere C, Quilici J,  et al.  Benefit of a 600-mg loading dose of clopidogrel on platelet reactivity and clinical outcomes in patients with non-ST-segment elevation acute coronary syndrome undergoing coronary stenting.  J Am Coll Cardiol. 2006;48(7):1339-1345
PubMed   |  Link to Article
Montalescot G, Sideris G, Meuleman C,  et al;  ALBION Trial Investigators.  A randomized comparison of high clopidogrel loading doses in patients with non-ST-segment elevation acute coronary syndromes.  J Am Coll Cardiol. 2006;48(5):931-938
PubMed   |  Link to Article
Dangas G, Mehran R, Guagliumi G,  et al;  HORIZONS-AMI Trial Investigators.  Role of clopidogrel loading dose in patients with ST-segment elevation myocardial infarction undergoing primary angioplasty.  J Am Coll Cardiol. 2009;54(15):1438-1446
PubMed   |  Link to Article
Wijns W, Kolh P, Danchin N,  et al; Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS); European Association for Percutaneous Cardiovascular Interventions (EAPCI).  Guidelines on myocardial revascularization.  Eur Heart J. 2010;31(20):2501-2555
PubMed   |  Link to Article
Mehta SR, Tanguay JF, Eikelboom JW,  et al;  CURRENT-OASIS 7 trial investigators.  Double-dose versus standard-dose clopidogrel and high-dose versus low-dose aspirin in individuals undergoing percutaneous coronary intervention for acute coronary syndromes.  Lancet. 2010;376(9748):1233-1243
PubMed   |  Link to Article
Kushner FG, Hand M, Smith SC Jr,  et al.  2009 focused updates: ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction (updating the 2004 guideline and 2007 focused update) and ACC/AHA/SCAI guidelines on percutaneous coronary intervention (updating the 2005 guideline and 2007 focused update) a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines [published correction appears in J Am Coll Cardiol. 2010;55(6):612].  J Am Coll Cardiol. 2009;54(23):2205-2241
PubMed   |  Link to Article
Ault KA, Cannon CP, Mitchell J,  et al.  Platelet activation in patients after an acute coronary syndrome: results from the TIMI-12 trial. Thrombolysis in Myocardial Infarction.  J Am Coll Cardiol. 1999;33(3):634-639
PubMed   |  Link to Article
Davì G, Patrono C. Platelet activation and atherothrombosis.  N Engl J Med. 2007;357(24):2482-2494
PubMed   |  Link to Article
Collet JP, Cayla G, Cuisset T,  et al.  Randomized comparison of platelet function monitoring to adjust antiplatelet therapy versus standard of care.  Am Heart J. 2011;161(1):5-12.e15
PubMed   |  Link to Article
Mehta SR, Granger CB, Boden WE,  et al;  TIMACS Investigators.  Early versus delayed invasive intervention in acute coronary syndromes.  N Engl J Med. 2009;360(21):2165-2175
PubMed   |  Link to Article
Montalescot G, Cayla G, Collet JP,  et al; ABOARD Investigators.  Immediate vs delayed intervention for acute coronary syndromes: a randomized clinical trial.  JAMA. 2009;302(9):947-954
PubMed   |  Link to Article
Patel MR, Peterson ED, Dai D,  et al.  Low diagnostic yield of elective coronary angiography.  N Engl J Med. 2010;362(10):886-895
PubMed   |  Link to Article
Biancari F, Airaksinen KE, Lip GY. Benefits and risks of using clopidogrel before coronary artery bypass surgery.  J Thorac Cardiovasc Surg. 2012;143(3):665-675.e4
PubMed   |  Link to Article

Figures

Place holder to copy figure label and caption
Figure 1. Study Selection
Graphic Jump Location

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.

Place holder to copy figure label and caption
Figure 2. All-Cause Mortality Analysis
Graphic Jump Location

aThe number of patients represent those who were followed up at 1 year.

Place holder to copy figure label and caption
Figure 3. Major Bleeding and Major Cardiovascular Event Analyses
Graphic Jump Location

For a definition of major bleeding for each study, see Table 1.aThe number of patients represents those who were followed up at 30 days.bThe number of patients represents those who were followed up at 1 year.

Tables

Table Graphic Jump LocationTable 2. Study Review of Randomized Controlled Trial Study Characteristics

References

Leon MB, Baim DS, Popma JJ,  et al; Stent Anticoagulation Restenosis Study Investigators.  A clinical trial comparing three antithrombotic-drug regimens after coronary-artery stenting.  N Engl J Med. 1998;339(23):1665-1671
PubMed   |  Link to Article
Schömig A, Neumann FJ, Kastrati A,  et al.  A randomized comparison of antiplatelet and anticoagulant therapy after the placement of coronary-artery stents.  N Engl J Med. 1996;334(17):1084-1089
PubMed   |  Link to Article
Steinhubl SR, Berger PB, Mann JT III,  et al; CREDO Investigators.  Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial.  JAMA. 2002;288(19):2411-2420
PubMed   |  Link to Article
Chen ZM, Jiang LX, Chen YP,  et al; COMMIT (ClOpidogrel and Metoprolol in Myocardial Infarction Trial) collaborative group.  Addition of clopidogrel to aspirin in 45 852 patients with acute myocardial infarction.  Lancet. 2005;366(9497):1607-1621
PubMed   |  Link to Article
Mehta SR, Yusuf S, Peters RJ,  et al; Clopidogrel in Unstable angina to prevent Recurrent Events trial (CURE) Investigators.  Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention.  Lancet. 2001;358(9281):527-533
PubMed   |  Link to Article
Sabatine MS, Cannon CP, Gibson CM,  et al; Clopidogrel as Adjunctive Reperfusion Therapy (CLARITY)-Thrombolysis in Myocardial Infarction (TIMI) 28 Investigators.  Effect of clopidogrel pretreatment before percutaneous coronary intervention in patients with ST-elevation myocardial infarction treated with fibrinolytics.  JAMA. 2005;294(10):1224-1232
PubMed   |  Link to Article
Zeymer U, Arntz HR, Darius H, Huber K, Senges J. Efficacy and safety of clopidogrel 600 mg administered pre-hospitally to improve primary percutaneous Coronary Intervention in Patients With Acute Myocardial Infarction (CIPAMI).  Cardiology. 2007;108(4):265-272
PubMed   |  Link to Article
Collet JP, Hulot JS, Pena A,  et al.  Cytochrome P450 2C19 polymorphism in young patients treated with clopidogrel after myocardial infarction.  Lancet. 2009;373(9660):309-317
PubMed   |  Link to Article
Mega JL, Close SL, Wiviott SD,  et al.  Cytochrome p-450 polymorphisms and response to clopidogrel.  N Engl J Med. 2009;360(4):354-362
PubMed   |  Link to Article
Shuldiner AR, O’Connell JR, Bliden KP,  et al.  Association of cytochrome P450 2C19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy.  JAMA. 2009;302(8):849-857
PubMed   |  Link to Article
Simon T, Verstuyft C, Mary-Krause M,  et al; French Registry of Acute ST-Elevation and Non-ST-Elevation Myocardial Infarction (FAST-MI) Investigators.  Genetic determinants of response to clopidogrel and cardiovascular events.  N Engl J Med. 2009;360(4):363-375
PubMed   |  Link to Article
Hamm CW, Bassand JP, Agewall S,  et al; ESC Committee for Practice Guidelines; Document Reviewers.  ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation.  Eur Heart J. 2011;32(23):2999-3054
PubMed   |  Link to Article
Wright RS, Anderson JL, Adams CD,  et al.  2011 ACCF/AHA Focused Update of the Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction (Updating the 2007 Guideline).  Circulation. 2011;123(18):2022-2060
PubMed   |  Link to Article
Vlaar PJ, Svilaas T, Damman K,  et al.  Impact of pretreatment with clopidogrel on initial patency and outcome in patients treated with primary percutaneous coronary intervention for ST-segment elevation myocardial infarction.  Circulation. 2008;118(18):1828-1836
PubMed   |  Link to Article
Sabatine MS, Hamdalla HN, Mehta SR,  et al.  Efficacy and safety of clopidogrel pretreatment before percutaneous coronary intervention with and without glycoprotein IIb/IIIa inhibitor use.  Am Heart J. 2008;155(5):910-917
PubMed   |  Link to Article
Davlouros PA, Arseniou A, Hahalis G,  et al.  Timing of clopidogrel loading before percutaneous coronary intervention in clopidogrel-naive patients with stable or unstable angina: a comparison of 2 strategies.  Am Heart J. 2009;158(4):585-591
PubMed   |  Link to Article
Di Sciascio G, Patti G, Pasceri V, Gatto L, Colonna G, Montinaro A.ARMYDA-5 PRELOAD Investigators.  Effectiveness of in-laboratory high-dose clopidogrel loading versus routine pre-load in patients undergoing percutaneous coronary intervention.  J Am Coll Cardiol. 2010;56(7):550-557
PubMed   |  Link to Article
Widimsky P, Motovská Z, Simek S,  et al; PRAGUE-8 Trial Investigators.  Clopidogrel pretreatment in stable angina: for all patients >6 h before elective coronary angiography or only for angiographically selected patients a few minutes before PCI?.  Eur Heart J. 2008;29(12):1495-1503
PubMed   |  Link to Article
Saw J, Lincoff AM, DeSmet W,  et al; REPLACE-2 Investigators.  Lack of clopidogrel pretreatment effect on the relative efficacy of bivalirudin with provisional glycoprotein IIb/IIIa blockade compared to heparin with routine glycoprotein IIb/IIIa blockade.  J Am Coll Cardiol. 2004;44(6):1194-1199
PubMed
Stone GW, White HD, Ohman EM,  et al; Acute Catheterization and Urgent Intervention Triage strategy (ACUITY) trial investigators.  Bivalirudin in patients with acute coronary syndromes undergoing percutaneous coronary intervention.  Lancet. 2007;369(9565):907-919
PubMed   |  Link to Article
Amin AP, Kennedy KF, Pencina M,  et al; EVENT Investigators.  Effect of clopidogrel pretreatment on ischemic complications of percutaneous coronary intervention among bivalirudin-treated patients (from the EVENT registry).  Am J Cardiol. 2011;107(12):1751-1756
PubMed   |  Link to Article
Chan AW, Moliterno DJ, Berger PB,  et al;  TARGET Investigators.  Triple antiplatelet therapy during percutaneous coronary intervention is associated with improved outcomes including one-year survival.  J Am Coll Cardiol. 2003;42(7):1188-1195
PubMed   |  Link to Article
Dörler J, Edlinger M, Alber HF,  et al; Austrian Acute PCI Investigators.  Clopidogrel pre-treatment is associated with reduced in-hospital mortality in primary percutaneous coronary intervention for acute ST-elevation myocardial infarction.  Eur Heart J. 2011;32(23):2954-2961
PubMed   |  Link to Article
Fefer P, Hod H, Hammerman H,  et al.  Usefulness of pretreatment with high-dose clopidogrel in patients undergoing primary angioplasty for ST-elevation myocardial infarction.  Am J Cardiol. 2009;104(4):514-518
PubMed   |  Link to Article
Feldman DN, Fakorede F, Minutello RM, Bergman G, Moussa I, Wong SC. Efficacy of high-dose clopidogrel treatment (600 mg) less than 2 hours before percutaneous coronary intervention in patients with non-ST-segment elevation acute coronary syndromes.  Am J Cardiol. 2010;105(3):323-332
PubMed   |  Link to Article
Szük T, Gyöngyösi M, Homorodi N,  et al.  Effect of timing of clopidogrel administration on 30-day clinical outcomes: 300-mg loading dose immediately after coronary stenting versus pretreatment 6 to 24 hours before stenting in a large unselected patient cohort.  Am Heart J. 2007;153(2):289-295
PubMed   |  Link to Article
Cutlip DE, Windecker S, Mehran R,  et al; Academic Research Consortium.  Clinical end points in coronary stent trials.  Circulation. 2007;115(17):2344-2351
PubMed   |  Link to Article
Jadad AR, Moore RA, Carroll D,  et al.  Assessing the quality of reports of randomized clinical trials.  Control Clin Trials. 1996;17(1):1-12
PubMed   |  Link to Article
Steinhubl SR, Ellis SG, Wolski K, Lincoff AM, Topol EJ. Ticlopidine pretreatment before coronary stenting is associated with sustained decrease in adverse cardiac events.  Circulation. 2001;103(10):1403-1409
PubMed   |  Link to Article
Stone GW, Ellis SG, Colombo A,  et al.  Offsetting impact of thrombosis and restenosis on the occurrence of death and myocardial infarction after paclitaxel-eluting and bare metal stent implantation.  Circulation. 2007;115(22):2842-2847
PubMed   |  Link to Article
Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses.  BMJ. 2003;327(7414):557-560
PubMed   |  Link to Article
 R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. 2012. http://www.R-project.org/
Duval S, Tweedie R. Trim and fill.  Biometrics. 2000;56(2):455-463
PubMed   |  Link to Article
Widimsky P, Wijns W, Fajadet J,  et al; European Association for Percutaneous Cardiovascular Interventions.  Reperfusion therapy for ST elevation acute myocardial infarction in Europe.  Eur Heart J. 2010;31(8):943-957
PubMed   |  Link to Article
Taggart DP, Boyle R, de Belder MA, Fox KA. The 2010 ESC/EACTS guidelines on myocardial revascularisation.  Heart. 2011;97(6):445-446
PubMed   |  Link to Article
Steinhubl SR, Berger PB, Brennan DM, Topol EJ.CREDO Investigators.  Optimal timing for the initiation of pre-treatment with 300 mg clopidogrel before percutaneous coronary intervention.  J Am Coll Cardiol. 2006;47(5):939-943
PubMed   |  Link to Article
Lotrionte M, Biondi-Zoccai GG, Agostoni P,  et al.  Meta-analysis appraising high clopidogrel loading in patients undergoing percutaneous coronary intervention.  Am J Cardiol. 2007;100(8):1199-1206
PubMed   |  Link to Article
Patti G, Colonna G, Pasceri V, Pepe LL, Montinaro A, Di Sciascio G. Randomized trial of high loading dose of clopidogrel for reduction of periprocedural myocardial infarction in patients undergoing coronary intervention.  Circulation. 2005;111(16):2099-2106
PubMed   |  Link to Article
Cuisset T, Frere C, Quilici J,  et al.  Benefit of a 600-mg loading dose of clopidogrel on platelet reactivity and clinical outcomes in patients with non-ST-segment elevation acute coronary syndrome undergoing coronary stenting.  J Am Coll Cardiol. 2006;48(7):1339-1345
PubMed   |  Link to Article
Montalescot G, Sideris G, Meuleman C,  et al;  ALBION Trial Investigators.  A randomized comparison of high clopidogrel loading doses in patients with non-ST-segment elevation acute coronary syndromes.  J Am Coll Cardiol. 2006;48(5):931-938
PubMed   |  Link to Article
Dangas G, Mehran R, Guagliumi G,  et al;  HORIZONS-AMI Trial Investigators.  Role of clopidogrel loading dose in patients with ST-segment elevation myocardial infarction undergoing primary angioplasty.  J Am Coll Cardiol. 2009;54(15):1438-1446
PubMed   |  Link to Article
Wijns W, Kolh P, Danchin N,  et al; Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS); European Association for Percutaneous Cardiovascular Interventions (EAPCI).  Guidelines on myocardial revascularization.  Eur Heart J. 2010;31(20):2501-2555
PubMed   |  Link to Article
Mehta SR, Tanguay JF, Eikelboom JW,  et al;  CURRENT-OASIS 7 trial investigators.  Double-dose versus standard-dose clopidogrel and high-dose versus low-dose aspirin in individuals undergoing percutaneous coronary intervention for acute coronary syndromes.  Lancet. 2010;376(9748):1233-1243
PubMed   |  Link to Article
Kushner FG, Hand M, Smith SC Jr,  et al.  2009 focused updates: ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction (updating the 2004 guideline and 2007 focused update) and ACC/AHA/SCAI guidelines on percutaneous coronary intervention (updating the 2005 guideline and 2007 focused update) a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines [published correction appears in J Am Coll Cardiol. 2010;55(6):612].  J Am Coll Cardiol. 2009;54(23):2205-2241
PubMed   |  Link to Article
Ault KA, Cannon CP, Mitchell J,  et al.  Platelet activation in patients after an acute coronary syndrome: results from the TIMI-12 trial. Thrombolysis in Myocardial Infarction.  J Am Coll Cardiol. 1999;33(3):634-639
PubMed   |  Link to Article
Davì G, Patrono C. Platelet activation and atherothrombosis.  N Engl J Med. 2007;357(24):2482-2494
PubMed   |  Link to Article
Collet JP, Cayla G, Cuisset T,  et al.  Randomized comparison of platelet function monitoring to adjust antiplatelet therapy versus standard of care.  Am Heart J. 2011;161(1):5-12.e15
PubMed   |  Link to Article
Mehta SR, Granger CB, Boden WE,  et al;  TIMACS Investigators.  Early versus delayed invasive intervention in acute coronary syndromes.  N Engl J Med. 2009;360(21):2165-2175
PubMed   |  Link to Article
Montalescot G, Cayla G, Collet JP,  et al; ABOARD Investigators.  Immediate vs delayed intervention for acute coronary syndromes: a randomized clinical trial.  JAMA. 2009;302(9):947-954
PubMed   |  Link to Article
Patel MR, Peterson ED, Dai D,  et al.  Low diagnostic yield of elective coronary angiography.  N Engl J Med. 2010;362(10):886-895
PubMed   |  Link to Article
Biancari F, Airaksinen KE, Lip GY. Benefits and risks of using clopidogrel before coronary artery bypass surgery.  J Thorac Cardiovasc Surg. 2012;143(3):665-675.e4
PubMed   |  Link to Article
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Bellemain-Appaix A, O'Connor SA, Silvain J. Association of Clopidogrel Pretreatment With Mortality, Cardiovascular Events, and Major Bleeding Among Patients Undergoing Percutaneous Coronary Intervention: A Systematic Review and Meta-analysis. JAMA. doi:10.1001/jama.2012.50788

eTable 1. Newcastle-Ottawa Scale for the Assessment of the Quality of the Nonrandomized Studies Included in the Meta-analysis

eTable 2. Jadad Score Calculation for the Assessment of the Quality of the Randomized Studies Included in the Meta-analysis

eTable 3. Main Results of End Points for Pretreatment vs No Pretreatment According to Clinical Presentation

eTable 4. Results From Pretreatment Loading Dose Subgroup Analysis

eFigure 1. Clinical Presentation and Clopidogrel Loading-Dose Subgroup Analyses

eFigure 2. ST-Elevated Myocardial Infarction Subgroup Analysis

eReferences for Excluded Trials

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