CLINICAL PERSPECTIVE

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(Circulation. 2008;118:1828-1836.)
© 2008 American Heart Association, Inc.

Interventional Cardiology

Impact of Pretreatment With Clopidogrel on Initial Patency and Outcome in Patients Treated With Primary Percutaneous Coronary Intervention for ST-Segment Elevation Myocardial Infarction

A Systematic Review

Pieter J. Vlaar, MSc; Tone Svilaas, MD; Kevin Damman, MD; Bart J.G.L. de Smet, MD, PhD; Jan G.P. Tijssen, MD, PhD; Hans L. Hillege, MD, PhD; Felix Zijlstra, MD, PhD

From the University Medical Center Groningen, University of Groningen, Thorax Center, Departments of Cardiology (P.J.V., T.S., K.D., B.J.G.L.d.S., H.L.H., F.Z.) and Epidemiology (H.L.H.), Groningen, and Academic Medical Center, University of Amsterdam, Department of Cardiology, Amsterdam (J.G.P.T.), the Netherlands.

Correspondence to P.J. Vlaar, Thorax Center, Department of Cardiology, University Medical Center Groningen, Groningen, the Netherlands. E-mail p.j.j.vlaar{at}thorax.umcg.nl

Received October 31, 2007; accepted August 20, 2008.

	Abstract

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Background— The main goal of the initial treatment of ST-segment elevation myocardial infarction is prompt reperfusion of the infarct-related artery. The value of pretreatment with clopidogrel before primary percutaneous coronary intervention is currently unclear.

Methods and Results— Studies were retrieved through MEDLINE and Cochrane Controlled Trials Register searches over the past 20 years. Two authors independently performed the study selection and data extraction. Randomized controlled studies were included when the research subjects were unselected patients with ST-elevation myocardial infarction undergoing primary percutaneous coronary intervention. Pilot trials, studies that enrolled patients undergoing rescue percutaneous coronary intervention, and studies with angiographic assessment not performed by a core laboratory or 2 blinded investigators were excluded. Thirty-eight treatment groups, including 8429 patients, were included. Initial patency was higher in treatment groups in which patients received pretreatment with clopidogrel (34.3%; 95% confidence interval, 32.9 to 35.8) compared with those in which patients did not receive clopidogrel before initial coronary angiography (25.8%; 95% confidence interval, 24.5 to 27.1). In multivariate-weighted logistic regression analysis, pretreatment with clopidogrel was an independent predictor of early reperfusion (odds ratio, 1.51; 95% confidence interval, 1.31 to 1.74; P<0.0001) and improved clinical outcome.

Conclusions— Initial patency and clinical outcome were improved in treatment groups that received pretreatment with clopidogrel. These results in patients undergoing primary percutaneous coronary intervention are in line with the experience of pretreatment with clopidogrel in elective patients, non–ST-elevation coronary syndromes, and thrombolytic studies.

Key Words: angioplasty • clopidogrel • myocardial infarction • thrombosis

	Introduction

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The main goal of the initial treatment of ST-segment elevation myocardial infarction (STEMI) is prompt reperfusion of the infarct-related artery. Compared with thrombolysis, primary percutaneous coronary intervention (PCI) in STEMI increases the rate of patency of the infarct-related artery and reduces the rates of death, reinfarction, and stroke during follow-up.¹ However, PCI remains associated with a significantly longer delay between first medical contact and start of treatment.^2,3 In pursuit of minimizing myocardial damage, antiplatelet and antithrombin agents are often started on site by ambulance or emergency department staff. Early administration of these agents, so-called pretreatment, may result in early reperfusion and more complete platelet inhibition during primary PCI.^4–7 Post hoc analyses of large trials indicate that clinical outcome is improved in patients with patency on the coronary angiogram before primary PCI, suggesting that early reperfusion improves survival.⁸

Clinical Perspective p 1836

At the present time, no data have been published on the impact of pretreatment with clopidogrel in the setting of PCI for STEMI. Guidelines and recommendations for pretreatment with clopidogrel are based on experience in acute coronary syndromes and thrombolytic studies.⁹ Although data are lacking, pretreatment with clopidogrel is widely used in routine clinical practice. Evidence with regard to impact on early reperfusion and short-term outcome is necessary and should be examined in the context of available data from clinical trials.

We performed a systematic review to compare the incidence of initial coronary artery patency and short-term outcome in treatment groups of studies in which patients received pretreatment with clopidogrel with those in which patients did not receive clopidogrel before initial coronary angiography.

	Methods

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Study Selection and Data Extraction
We performed MEDLINE and Cochrane Controlled Trials Register searches for published articles over the past 20 years using the following keywords and Medical Subject Headings (MeSH) terms: "randomized," "percutaneous coronary intervention," "angioplasty," "stent," "balloon," "dilatat*," "myocard* infarct*," "myocardial infarction" [MeSH], "angioplasty, transluminal, percutaneous coronary" [MeSH], "stents" [MeSH], and "balloon dilatation" [MeSH]. Reference lists of selected articles were reviewed for other potentially relevant citations.

Two independent reviewers (P.J.V. and T.S.) performed the study selection. Studies were selected if they were randomized and controlled; published in English, French, or German; and enrolled unselected patients with STEMI undergoing primary PCI. By unselected, we meant no inclusion or exclusion criteria relative to type of infarction (eg, size and location) or angiographic characteristics (eg, visible thrombus and Thrombolysis in Myocardial Infarction [TIMI] flow). Included studies had to report pre-PCI angiographic and clinical characteristics, symptom duration <24 hours, and information with regard to pretreatment. We excluded pilot trials, studies that enrolled patients undergoing rescue PCI, and studies in which angiographic data were not assessed by a core laboratory or 2 blinded investigators. Subgroups of included studies reporting optional pretreatment with clopidogrel, pretreatment with glycoprotein IIb/IIIa inhibitor, or fibrinolysis were excluded from the analysis.

Data extraction was performed independently by 2 reviewers (P.J.V. and T.S.) who collected information on study design; baseline clinical characteristics; procedural details; and angiographic, short-term clinical, and safety outcomes. Authors were contacted in case of incomplete or unclear data.

End Points and Definitions
The primary end point was initial coronary artery patency before primary PCI. Secondary end points were short-term mortality, death/reinfarction, and in-hospital major bleeding.

Pretreatment with clopidogrel was defined as any thienopyridine given before the initial coronary angiogram. Coronary artery patency was defined as TIMI grade 2/3 flow on the initial coronary angiogram. Major bleeding was defined as the need for blood transfusion during hospitalization. Unless otherwise specified, mortality included both cardiac and noncardiac deaths. Reinfarction rates were defined as reported in the trials.

Statistical Analysis
Percentages and absolute numbers of primary and secondary end points were calculated for each treatment group separately and all groups combined. Corresponding exact 95% confidence intervals (CIs) for single proportions were determined according to the Wilson method.¹⁰ In univariate analysis, the treatment effect of clopidogrel was calculated by using weighted logistic regression analysis. For this analysis, treatment groups were split into 2: the group that did and the group that did not experience the end point as defined by the number of patients presented in the individual studies. Logistic regression was then performed, with the outcome variable being end point reached (yes versus no) weighted on number of patients in the subgroups. To account for baseline differences between the (nonrandomized) treatment groups of selected studies and to investigate the robustness of our findings, we carried out a number of secondary analyses. First, we constructed a multivariate-weighted logistic regression analysis, including baseline demographic variables available. Second, jackknife estimation was used to establish the robustness of the treatment effect in the multivariate model. Finally, we calculated a propensity score based on matching of all baseline demographic variables. Missing demographic values were imputed with expectation maximization as the estimation method. All probability values were 2 tailed, with statistical significance set at 0.05. Analyses were performed with SPSS version 12.0.2 (SPSS Inc, Chicago, Ill) and STATA version 10 (STATA Corp, College Station, Tex).

P.J. Vlaar and K. Damman had full access to and take full responsibility for the integrity of the data. All authors have read and agree to the manuscript as written.

	Results

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Twenty-six randomized controlled studies met our inclusion criteria (Figure 1).^11–36 Thirty-eight treatment groups comprising 8429 patients were extracted. All 8429 patients were pretreated with heparin and aspirin. Before pre-PCI coronary angiography, 4114 of the 8429 patients received a loading dose of clopidogrel. In 1 study, patients were pretreated with 600 mg clopidogrel³⁶ (see Table 1). In all other included studies, a 300-mg loading dose of clopidogrel was given as pretreatment (In 1 study,²⁶ ticlopidine 500 mg also was allowed). In the 4315 patients not pretreated, clopidogrel was administrated after PCI to all patients who underwent stent placement. All included studies were randomized controlled trials; however, differences were found with regard to trial design.

View larger version (23K): [in this window] [in a new window]   Figure 1. Flow diagram of study inclusion.

View this table: [in this window] [in a new window]   Table 1. Main Characteristics of the Included Subgroups

View this table: [in this window] [in a new window]   Table 1. Continued

Angiographic End Point
The incidence of patients with TIMI grade 2/3 flow on initial angiography was higher in patients receiving pretreatment with clopidogrel (34.3%; 95% CI, 32.9 to 35.8) compared with control patients (25.8%; 95% CI, 24.5 to 27.1; Table 2 and Figure 2). The unadjusted treatment effect of clopidogrel on early patency was an odds ratio (OR) of 1.53 (95% CI, 1.39 to 1.68; P<0.0001; Table 3). In multivariate analysis, clopidogrel pretreatment remained significantly associated with a higher percentage of patients with TIMI grade 2/3 flow (OR, 1.51; 95% CI, 1.31 to 1.74; P<0.0001). Jackknife estimation of the multivariate model and the propensity score–adjusted logistic regression analysis showed similar results (Table 4).

View this table: [in this window] [in a new window]   Table 2. Patency on the Initial Coronary Angiogram Before PCI and Clinical Outcome at 30 Days

View larger version (40K): [in this window] [in a new window]   Figure 2. Forrest-tree plot of primary end point. Percentages of TIMI grade 2/3 flow with corresponding 95% CIs for single proportions are shown for each treatment group separately and for all groups combined. pPCI indicates primary PCI; DES, drug-eluting stent; BMS, bare metal stent; and GPI, glycoprotein IIb/IIIa inhibitor.

View this table: [in this window] [in a new window]   Table 3. Effect of Pretreatment With Clopidogrel on Early Reperfusion and Adverse Event Rates in Univariate-Weighted Logistic Regression Analysis

View this table: [in this window] [in a new window]   Table 4. Effect of Pretreatment With Clopidogrel on Early Reperfusion and Adverse Event Rates in Multivariate-Weighted and Propensity Score–Adjusted Logistic Regression Analysis

Clinical and Safety Outcomes
Short-term follow-up ranged from in-hospital to 42 days after PCI (Table 1). Mortality was lower in patients receiving pretreatment with clopidogrel (2.4%; 95% CI, 2.0 to 3.0) compared with control patients (4.6%; 95% CI, 3.9 to 5.3). The combined end point of death/reinfarction also was lower in patients pretreated with clopidogrel (3.3%; 95% CI, 2.8 to 3.9) compared with control patients (6.3%; 95% CI, 5.6 to 7.2). The unadjusted treatment effect of clopidogrel was an OR of 0.52 (95% CI, 0.41 to 0.67; P<0.0001) for mortality and an OR of 0.50 (95% CI, 0.40 to 0.62; P<0.0001) for death/reinfarction (Table 3). In all multivariate logistic models, pretreatment with clopidogrel remained significantly associated with lower rates of mortality and death/reinfarction incidence (Table 4).

A proper analysis of the end point of major bleeding was not possible because only a minority of the studies supplied data on this end point.

	Discussion

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This systematic review found a higher initial patency rate and improved clinical outcome in terms of mortality and death/reinfarction in treatment groups that received pretreatment with clopidogrel.

Currently, the optimal timing to start therapy with clopidogrel for primary PCI in patients with STEMI is unclear. Substantial platelet inhibition can be achieved within 2 hours after a 300-mg loading dose of clopidogrel.^37–39 Because primary PCI remains limited by a time delay of 1 to 2 hours between the first medical contact and PCI, the time is theoretically sufficient to achieve effective platelet inhibition during PCI with a 300-mg loading dose of clopidogrel. Therefore, this may have an impact on initial patency rate.^4,39,40 Furthermore, platelet inhibition in patients undergoing primary PCI is important because it will translate to better procedural outcome, eg, by prevention of periprocedural infarct extension.^6,7,38,39 However, because patients with STEMI may have enhanced platelet reactivity, they may require more aggressive platelet inhibition. In addition, several studies have demonstrated a faster onset of platelet inhibition and increased clinical effect of a 600-mg compared with a 300-mg loading dose.^5,39,41

The clinical effect of pretreatment with clopidogrel has been investigated only in the context of elective patients, acute coronary syndromes, and thrombolytic studies. In elective patients, pretreatment with clopidogrel before stenting reduced the incidence of acute thrombotic complications and improved clinical outcome.^42–44 In the context of acute coronary syndromes, the Percutaneous Intervention in the Clopidogrel in Unstable angina to prevent Recurrent Events (PCI-CURE) study demonstrated that pretreatment with a 300-mg loading dose of clopidogrel (given for a median of 6 days before PCI) significantly reduced the incidence of major adverse cardiovascular events.⁴⁵ In addition, a substudy of this trial indicated that the benefit of pretreatment with clopidogrel was independent of the timing of PCI. The lowest absolute event rate was seen in patients treated within 48 hours before PCI.⁴⁶ In patients treated with thrombolysis for STEMI, additional administration of a 300-mg loading dose of clopidogrel resulted in a higher patency rate of the infarct-related artery and reduced the incidence of ischemic complications.⁴⁰

At the present time, no randomized controlled data are available with regard to the impact of pretreatment with clopidogrel before PCI in patients with STEMI. Our systematic review found a higher initial patency rate and improved clinical outcome in treatment groups that received pretreatment with clopidogrel. With an overall sample size of 8429 patients, our review has adequate power for initial patency, mortality, and death/reinfarction. In addition, the clinical benefits of pretreatment with clopidogrel outweigh the increased risk of perioperative blood loss in the subset of patients who are referred to cardiac surgery.⁴⁷

Study Limitations
This systematic review compared treatment groups of studies in which patients received pretreatment with clopidogrel with those in which patients did not and therefore is not a substitute for pooled analyses of individual patient data or a meta-analysis of randomized controlled trials. In addition, the inclusion of studies with different trial designs, PCI strategies (balloon angioplasty, stenting, excimer laser, thrombus aspiration), and pharmacological therapies during and after PCI (glycoprotein IIb/IIIa inhibitors, β-blockers, angiotensin-converting enzyme inhibitors) could have induced heterogeneity in our results. The results and conclusions of this analysis should be interpreted with these limitations in mind. However, we have carried out extensive analyses to assess the robustness of our findings. In these analyses, clopidogrel pretreatment was consistently associated with higher rates of TIMI grade 2/3 flow, lower mortality, and lower death/reinfarction rates. Another limitation was that multivariate analysis was possible for only a limited number of variables. Thus, the influence of some relevant variables such as symptom-to-balloon and symptom-to-drug times could not be analyzed. In addition, data on major bleeding were available in only a limited number of subgroups.

Conclusions
Initial patency and clinical outcome were improved in treatment groups that received pretreatment with clopidogrel. These results in patients undergoing primary PCI are in line with the experience of pretreatment with clopidogrel in elective patients, non–ST-elevation coronary syndromes, and thrombolytic studies.

	Acknowledgments

 
Disclosures

None.

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CLINICAL PERSPECTIVE

Although randomized data are lacking, patients undergoing primary percutaneous coronary intervention for ST-elevation myocardial infarction are often pretreated with a loading dose of clopidogrel. In this systematic review, we compared the incidence of initial coronary artery patency and short-term outcome in treatment groups of studies in which patients received pretreatment with clopidogrel with those in which patients did not receive clopidogrel before initial coronary angiography. A total of 38 treatment groups comprising 8429 patients were included. We found that initial patency and clinical outcome were improved in treatment groups that received pretreatment with clopidogrel. This is in line with the experience of pretreatment with clopidogrel in elective patients, non–ST-elevation coronary syndromes, and thrombolytic studies. The results of this systematic review strongly suggest that it is appropriate to give a loading dose of clopidogrel in patients as early as possible after ECG confirmation of ST-elevation myocardial infarction. The safety and efficacy of a higher loading dose of 600 mg clopidogrel before primary percutaneous coronary intervention and the relative merits of prasugrel versus clopidogrel are currently being investigated in randomized trials.

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Clinical Summaries
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