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Clopidogrel pre-treatment is associated with reduced in-hospital mortality in primary percutaneous coronary intervention for acute ST-elevation myocardial infarction

Jakob Dörler, Michael Edlinger, Hannes F. Alber, Johann Altenberger, Werner Benzer, Georg Grimm, Kurt Huber, Otmar Pachinger, Herwig Schuchlenz, Peter Siostrzonek, Gerald Zenker, Franz Weidinger
DOI: http://dx.doi.org/10.1093/eurheartj/ehr360 2954-2961 First published online: 15 September 2011


Aims Pre-treatment with clopidogrel results in a reduction of ischaemic events in non-ST-elevation acute coronary syndromes. Data on upstream clopidogrel in the setting of primary percutaneous coronary intervention (PCI) are limited. The aim of this study was to investigate whether clopidogrel loading before arrival at the PCI centre may result in an improved outcome of primary PCI for ST-elevation myocardial infarction (STEMI).

Methods and results In a multicentre registry of acute PCI, 5955 patients undergoing primary PCI in Austria between January 2005 and December 2009 were prospectively enrolled. The patients consisted of two groups, a clopidogrel pre-treatment group (n = 1635 patients) receiving clopidogrel before arrival at the PCI centre and a peri-interventional clopidogrel group (n = 4320 patients) receiving clopidogrel at a later stage. Multiple logistic regression analysis including major confounding factors stratified by the participating centres was applied to investigate the effect of pre-treatment with clopidogrel on the in-hospital mortality. Additionally, two subgroups, with or without the use of GP IIb/IIIa antagonist therapy in the catheterization laboratory, were analysed. On univariate analysis, clopidogrel pre-treatment was associated with a reduced in-hospital mortality (3.4 vs. 6.1%, P< 0.01) after primary PCI. On multivariate analysis, clopidogrel pre-treatment remained an independent predictor of in-hospital mortality [odds ratio (OR) = 0.60, 95% confidence interval (CI) 0.35–0.99; P =0.048], especially in patients receiving additional GP IIb/IIIa antagonist therapy in the catheterization laboratory (OR = 0.40, 95% CI 0.19–0.83; P =0.01).

Conclusion Clopidogrel pre-treatment before arrival at the PCI centre is associated with reduced mortality in a real world setting of primary PCI. These results strongly support the recommendation of clopidogrel treatment ‘as soon as possible’ in patients with STEMI undergoing pimary PCI.

  • Primary PCI
  • ST-elevation myocardial infarction
  • Clopidogrel
  • Pre-treatment


Early reperfusion results in a reduced mortality and is the major goal of ST-elevation myocardial infarction (STEMI) treatment.13 Compared with fibrinolysis, primary percutaneous coronary intervention (PCI) is more effective in achieving patency of the infarct-related artery and reduces mortality, re-infarction, and stroke. Thus, primary PCI has become the preferred reperfusion strategy.4 Early administration of adjunctive antithrombotic therapy with acetylsalicylic acid (ASA) and heparin leads to improved initial patency of the infarct-related artery.5 Additional platelet inhibition with clopidogrel, an adenosine-diphosphate-receptor (ADP-receptor) inhibitor, improves outcome of patients with stable coronary artery disease undergoing PCI and of patients with acute coronary syndromes undergoing PCI or receiving fibrinolytic or no reperfusion therapy.69 Therefore, current guidelines recommend early initiation of antithrombotic therapy with ASA and heparin as well as an early loading dose of an ADP-receptor antagonist in acute coronary syndromes.1,3 Despite this clear recommendation, data from randomized controlled trials (RCT) regarding the optimal timing for clopidogrel pre-treatment in primary PCI (before or during PCI) is lacking. We sought to determine the impact of clopidogrel pre-treatment on the outcome of STEMI patients referred for primary PCI in contemporary clinical practice.


The Austrian Acute PCI Registry has been implemented in 2005 as a nationwide, prospective, multicentre registry of interventional reperfusion therapy in acute myocardial infarction. At the time of analysis, 19 of the 25 PCI centres with experience in acute PCI (with at least 50 cases per year) participated in the registry. For reasons of voluntariness and lack of funding, some centres were not able to participate over the complete inclusion period from January 2005 to December 2009. Consecutive patients were enrolled by each participating centre. Data management, storage, and analyses were performed by the Department of Medical Statistics, Informatics and Health Economics of Innsbruck Medical University.

The registry is conducted in accordance with the Declaration of Helsinki and the study protocol was approved by the ethical committee of Innsbruck Medical University (UN2467).

Study population

A total of 5955 consecutive patients who were admitted to the participating centres within 24 h of symptom onset and considered to undergo primary PCI for reperfusion of STEMI were included. The patient's status was followed until discharge with all events occurring during hospitalization after the index myocardial infarction being accounted for.


According to CARDS data standards,10 STEMI was diagnosed in the presence of persistent angina pectoris for at least 20 min and ST-segment elevation of ≥1 mm in at least two standard leads or ≥2 mm in at least two continuous pre-cordial leads, or the presence of a presumable new left bundle branch block.11

Two kinds of treatment groups were considered for the analysis: a pre-treatment and a peri-interventional group. The clopidogrel pre-treatment group consisted of patients who received clopidogrel either pre-hospital by the emergency physician or at the referring hospital or during transfer to the PCI centre. In the peri-interventional group, patients received treatment in the PCI centre either in the emergency room of the PCI centre (intermediate), in the catheterization laboratory, or in the intensive care unit shortly after the intervention (late). Patients with on-going clopidogrel treatment before the index event were allocated to the clopidogrel pre-treatment group. Similarly, patients with on-going ASA therapy receiving heparin pre-treatment as well were allocated to the ASA/heparin pre-treatment group. Stroke was defined as peri-interventional ischaemic stroke with a prolonged neurologic deficit of more than 24 h. Bleeding included any intracranial haemorrhage, a drop of haemoglobin of ≥5 g/dL (decrease in haematocrit of ≥15% if haemoglobin was unavailable), need for blood transfusion or surgical intervention.

Concerning adjunctive antithrombotic treatment other than clopidogrel, pre-treatment was defined as application before arrival at the PCI centre, either pre-hospital or at a referring hospital prior to transfer to primary PCI. In contrast, late treatment was defined as application after arrival at the PCI centre. Angiographic success was defined as post-procedural TIMI flow II or III.

Data collection

A detailed overview of data collected in the Austrian Acute PCI-Registry was published previously.12 Data are recorded using an internet-based questionnaire and included demographic data, risk factors, prior coronary interventions or bypass surgery, prior myocardial infarction as well as the occurrence of cardiogenic shock or resuscitation before or during the interventional procedure of the index event. Furthermore, mode of admission and time delays were assessed. In those patients of the pre-treatment group (10.3%) and of the peri-interventional group (13.5%) who did not receive balloon angioplasty but were treated either conservatively or by coronary bypass surgery, the delay from symptom onset to PCI was defined as the time from onset of pain to arrival at the catheterization laboratory and the time from arrival at the PCI centre to arrival at the catheterization laboratory was used as a surrogate for the door to balloon time.

Antithrombotic treatment before arrival in the catheterization laboratory included standard therapy with heparin and aspirin as well as the use of GP IIb/IIIa antagonists. The time of application of antithrombotic therapy in relation to the admission at the PCI centre was also documented (pre-treatment, late treatment). Peri-interventional treatment data included PCI with drug-eluting or bare-metal stent or with balloon angioplasty alone as well as TIMI flow before and after intervention. Furthermore, adjunctive therapies with GP IIb/IIIa antagonists in the catheterization laboratory, bivalirudin, or the use of thrombus aspiration were recorded.

In-hospital outcome variables were assessed at discharge from the PCI hospital and included mortality, major bleeding, ischaemic stroke, re-infarction, and staged PCI.

Statistical analysis

Categorical variables are shown in percentages and corresponding numbers. Continuous variables are summarized by the mean with the standard deviation (SD) or by the median with 25th and 75th percentiles, respectively. Differences in the characteristics between the two treatment groups were assessed using χ2 tests (categorical variables), Mann–Whitney U or t-test (continuous variables) as appropriate. With ordinal variables, we used a χ2 test to check for a trend. For all reported tests, a two-sided P-value of <0.05 was considered statistically significant. We predefined the following covariates which potentially influence both the decision to administer clopidogrel early and the in-hospital mortality: cardiogenic shock, resuscitation, previous myocardial infarction, year of intervention (2008–2009 vs. 2005–2007), gender (male vs. female), age (in completed years), diabetes mellitus, ASA/heparin pre-treatment, GP IIb/IIIa antagonist pre-treatment, secondary transfer, and delay from onset of pain to PCI. Multiple logistic regression analysis, stratified by PCI centre, was used to assess the relation between clopidogrel pre-treatment and in-hospital mortality adjusted for the above-mentioned covariates, thereby estimating odds ratios (OR) and the accompanying 95% confidence intervals (CI). This basic model was then extended to a model including GP IIb/IIIa antagonist therapy in the catheterization laboratory and an additional analysis of the two separate subgroups was added according to whether GP IIb/IIIa antagonist therapy in the catheterization laboratory had been applied or not. Furthermore, a possible effect modification by GP IIb/IIIa antagonist treatment in the catheterization laboratory on the relation between clopidogrel pre-treatment and mortality was tested through an interaction term in the regression analysis. To verify the robustness of our analysis, we performed an additional analysis with stratification on estimated propensity scores, by stratifying on quintiles.13 All covariates were included, to incorporate the information of the potential confounders as completely as possible, and the balance was well achieved. The statistical analyses were performed in Stata/Mp 10.1.


For the current analysis, data were available of 5955 consecutive patients undergoing primary PCI for STEMI who were included in the Austrian Acute PCI Registry between January 2005 and December 2009. Of each patient, only the first episode was considered during the observation period (with multiple possible outcomes). According to the pre-specified definitions, 1635 patients (27.5%) received clopidogrel before arrival at the PCI centre (pre-treatment group), and 4320 patients (72.5%) at a later time point (peri-interventional group). Of the latter group, 3245 patients (75.1%) received clopidogrel in-hospital before arrival at the catheterization laboratory and 1075 patients (24.9%) received it in the catheterization laboratory or shortly after PCI.

Baseline characteristics and demographics

A detailed overview of baseline characteristics is shown in Table 1. Patients of the pre-treatment group were more likely to be men, diabetic, more often had prior myocardial infarction, or received previous PCI. Despite the higher rate of previous events, these patients were less often in cardiogenic shock or underwent resuscitation at the index event. The rate of antithrombotic pre-treatment with ASA and heparin was higher in the clopidogrel pre-treatment group, whereas the peri-interventional clopidogrel group more often received GP IIb/IIIa antagonists in-hospital before primary PCI.

View this table:
Table 1

Baseline characteristics of patients according to treatment group

Peri-interventional characteristics and treatment

The pre-procedural TIMI flow and peri-interventional adjunctive therapy with GP IIb/IIIa antagonists or bivalirudin were similar in both groups. The rates of post-procedural TIMI 3 flow, of thrombus aspiration and interventional treatment with either PCI alone, PCI with bare metal stent or drug eluting stent showed a moderate, though statistically significant difference (Table 2).

View this table:
Table 2

Peri-interventional characteristics and treatment

Time delays and mode of admission

Comparing clopidogrel pre-treatment with peri-interventional treatment, the delay from symptom onset to first medical contact [74 (31–175) min vs. 90 (32–235) min; P< 0.01], the transfer time from onset of pain to PCI [3.0 (2.0–5.5) h vs. 3.5 (2.1–6.5) h; P< 0.01] as well as the time from arrival at the PCI centre to the catheterization laboratory [15 (3–39) min vs. 35 (15–62) min; P< 0.01] and the total ischaemic time [3.4 (2.4–5.6) h vs. 3.8 (2.5–6.7) h; P< 0.01] were shorter in the pre-treatment group. Concerning the mode of admission, the rate of secondary transfer was higher in the pre-treatment group (42 vs. 27%; P< 0.01). Consequently, the rate of primary transfer was higher in the peri-interventional treatment group (55 vs. 58%; P =0.04). The rate of self-admission and in-hospital referral was higher in the peri-interventional treatment group (3 vs. 15%; P< 0.01).

In-hospital outcome

Patients who received clopidogrel pre-treatment had an overall mortality of 3.4% compared with 6.1% in patients who received peri-interventional clopidogrel (P< 0.01). In addition, re-infarction rates (0.6 vs. 1.4%; P =0.02) as well as ischaemic stroke (0.7 vs. 1.4%, P =0.05) were also lower in the pre-treatment group, whereas bleeding rates (1.0 vs. 1.0%, P =0.90) and the rate of a second elective revascularization (4.4 vs. 4.6%; P =0.85) procedure were similar in both groups. Trend analysis according to the timing of clopidogrel treatment (pre-treatment, intermediate, or late) showed stepwise increased rates of mortality, re-infarction, and stroke (Table 3).

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Table 3

In-hospital outcome in primary percutaneous coronary intervention according to clopidogrel treatment timing

Multiple logistic regression analysis, stratified by PCI centre, was performed to compare clopidogrel pre-treatment and peri-interventional treatment and included the major confounders shock, resuscitation, previous myocardial infarction, year of intervention (2008–2009 and 2005–2007) gender, age, diabetes mellitus, ASA/heparin treatment, GP IIb/IIIa antagonist pre-treatment, secondary transfer, the time from onset of pain to PCI, and GP IIb/IIIa antagonist therapy in the catheterization laboratory. Clopidogrel pre-treatment remained independently associated with a reduced in-hospital mortality in the basic model as well as in the extended regression model (OR = 0.60, 95% CI 0.35–0.99; P =0.048; Table 4). This observation also appeared in the complementary propensity score analysis (OR = 0.58, 95% CI 0.36–0.91; P =0.02). Furthermore, the extended model showed that GP IIb/IIIa antagonist therapy in the catheterization laboratory did not influence the mortality (Table 4). The subgroup analysis demonstrated a pronounced benefit of clopidogrel pre-treatment in patients with GP IIb/IIIa antagonist therapy in the catheterization laboratory (OR = 0.40, 95% CI 0.19–0.83; P =0.01), which did not apply to the patients without such treatment (OR = 0.88, 95% CI 0.39–1.95; P =0.75). The interaction term of clopidogrel pre-treatment and GP IIb/IIIa antagonist co-treatment in the multivariate model was P =0.13.

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Table 4

Association of clopidogrel pre-treatment and covariates with in-hospital mortality after primary PCI in multiple logistic regression analyses


The present study suggests that clopidogrel pre-treatment (before arrival at the PCI centre) is independently associated with reduced in-hospital mortality and, to our knowledge, represents the first analysis of pre-hospital clopidogrel administration in a real-world setting of primary PCI. Clopidogrel pre-treatment is independently associated with a risk reduction of in-hospital mortality with an OR of 0.60 (P< 0.05) in the multiple regression analysis. Furthermore, it is associated with a reduction of early re-infarction without resulting in higher bleeding rates.

Dual antiplatelet inhibition with ASA and clopidogrel yields significant benefits in patients with coronary artery disease undergoing elective PCI and in acute coronary syndromes.6,8,1417 As delayed absorption and metabolism may influence pharmacokinetics and -dynamics, especially in patients with acute myocardial infarction, different strategies to improve baseline platelet inhibition have been investigated in these patients. However, although current guidelines recommend an early application, ‘as soon as possible’, additionally to an appropriate loading dose, optimal timing of clopidogrel treatment in the settings of primary PCI is not clear.1,3

In a previous prospective study with 292 consecutive STEMI patients, clopidogrel application before primary PCI (in the emergency department or the intensive care unit) was independently associated with a higher TIMI myocardial perfusion rate and a lower re-infarction rate after 30 days.18 Another non-randomized observational study in 383 patients comparing clopidogrel treatment before PCI with a treatment start after primary PCI confirmed these results by showing a significant reduction in a composite endpoint, including recurrent acute coronary syndrome, stent thrombosis, congestive heart failure, and/or death at 30 days.19

As the above-mentioned observational studies were underpowered to demonstrate beneficial effects of clopidogrel pre-treatment in terms of early mortality, Vlaar et al.20 performed a meta-analysis of 26 RCT of patients undergoing PCI for STEMI. Clopidogrel pre-treatment was associated with a higher initial patency and a lower mortality of 2.4 vs. 4.6% compared with patients receiving clopidogrel after PCI.20 In contrast to our study, this meta-analysis, however, does not adequately reflect contemporary practice of clopidogrel pre-treatment: patients with a late treatment start of clopidogrel did not receive a loading dose. Moreover, the patients in the late treatment group received clopidogrel after PCI, whereas 75% of patients in the peri-interventional group of our cohort received clopidogrel before arrival at the catheterization laboratory. Starting clopidogrel after the intervention without any loading dose could result in a relevant delay of platelet inhibition. Sufficient platelet inhibition is achieved 1–2 h after a loading dose of 600 mg clopidogrel.21,22 Thus, clopidogrel pre-treatment before arrival at the PCI centre may lead to better primary PCI results. Consequently, recent guidelines recommend an early treatment start such that the majority of patients receive clopidogrel before intervention.3,12

A delayed effect of peri-interventional clopidogrel treatment may explain the beneficial effect of additional platelet inhibition with GP IIb/IIIa antagonists as previously reported in non-selected STEMI patients and a post hoc analysis of the APEX AMI trial.23,24 In contrast, addition of abciximab in patients pre-treated with a 600 mg loading dose of clopidogrel did not further reduce events in the recent BRAVE III trial.25 Although upstream platelet inhibition with GP IIb/IIIa antagonists might reduce the influence of pre-PCI clopidogrel treatment, GP IIb/IIIa antagonist pre-treatment was not associated with in-hospital mortality and did not confound the effect of clopidogrel pre-treatment. Furthermore, the beneficial effect was not associated with higher bleeding rates in the patients receiving clopidogrel pre-treatment, whereas unselected upstream GP IIb/IIIa inhibition resulted in higher bleeding as well as mortality rates in the FINESSE trial and may explain the absence of a beneficial effect of clopidogrel pre-treatment in the CRUSADE cohort.26,27 Furthermore, as upstream GP IIb/IIIa antagonist therapy did not influence the effect of clopidogrel pre-treatment, we additionally analysed the influence of GP IIb/IIIa antagonist therapy applied in the catheterization laboratory. Interestingly, although the interaction term for clopidogrel pre-treatment and GP IIb/IIIa antagonists therapy was not significant, patients receiving this therapy showed a pronounced benefit after clopidogrel pre-treatment. GP IIb/IIIa antagonist treatment in the catheterization laboratory is usually administered in case of high thrombus burden upon decision of the interventionalist. Thus, the current results suggest that a selected group of STEMI patients characterized by a more severe pro-thrombotic state benefit most from a combined platelet inhibition. Further studies may be warranted to identify the patients who benefit from a more intensive platelet inhibition beyond early ADP-receptor antagonism.

At present, no randomized controlled data are available with regard to the impact of clopidogrel pre-treatment. The present study, to our knowledge, is the first analysis in a large cohort showing that pre-hospital clopidogrel administration is associated with reduced in-hospital mortality in a real world setting of primary PCI and that patients receiving combined platelet inhibition with clopidogrel pre-treatment and GP IIb/IIIa antagonists in the catheterization laboratory benefit most. Whether an earlier treatment with clopidogrel might mitigate the advantage of more potent ADP-receptor antagonists or whether an early start of these newer agents might further improve outcomes compared with clopidogrel in the real world setting is not known. Moreover, the effect of peri-interventional GP IIb/IIIa antagonists in combination with improved and early ADP receptor inhibition needs to be addressed in future studies.


The present study has all the limitations inherent to registries while reflecting the real world setting of primary PCI.28 Imbalances regarding baseline characteristics and upstream medication with respect to the two groups are unavoidable. We were not able to distinguish between specific loading doses, and the exact times of clopidogrel application and parameters of kidney function were not available for analysis. The main reason for the latter is that the data form is filled out in the catheterization laboratory at the time of primary PCI, when these parameters are not yet available. Exact timing of clopidogrel loading is difficult to achieve in a registry because it depends on the documentation of either the referring hospital or the emergency physician.

Moreover, as the present registry is focused on hard clinical endpoints and documentation of minor bleedings is not reliable, we did not attempt to record minor bleedings. Although information on some baseline characteristics were incomplete, there were no missing values in the most relevant characteristics (clopidogrel treatment, cardiogenic shock, resuscitation, age) in the data provided by the participating centres.

As the current data set is derived from a hospital-based registry, patients who died before admission to the PCI centre as well as patients who were not considered for primary PCI could not be taken into account. Furthermore, patients with chronic clopidogrel treatment before the index episode were not documented separately but referred to the pre-treatment group. These patients may represent a high-risk group and we cannot exclude a bias due to potentially higher pre-hospital death rates in that specific subgroup. Consequently, the data are representative for primary PCI but not for the entire STEMI population.


In a large multicentre registry of all-comer patients undergoing primary PCI, clopidogrel treatment before arrival at the PCI centre is independently associated with reduced in-hospital mortality. These data strongly support recommendations in current guidelines of clopidogrel loading ‘as soon as possible’.


Data management and analysis were supported by the Austrian Society of Cardiology.

Conflict of interest: none declared.


Participants of the Austrian Acute PCI Registry. J. Altenberger, M. Pichler, Department of Internal Medicine 2; Cardiology, Paracelsus Medical University, Salzburg. W. Benzer, Department of Interventional Cardiology, Academic Teaching Hospital, Feldkirch. G. Bonner, F. Weidinger, 2nd Medical Department, Hospital Rudolfstiftung, Vienna. T. Brunner, 2nd Department of Medicine, Central Hospital Wiener Neustadt. G. Gaul, 2nd Department of Medicine, Hanusch Hospital, Vienna. F. Gratze, G. Zenker, Department of Internal Medicine, General Hospital Bruck. M. Juhasz, H. Silberbauer, Department of Medicine, Krankenhaus der Barmherzigen Brüder Eisenstadt. K. Kerschner, F. Leisch, 1st Medical Department, City Hospital Linz. H. Krappinger, H. Wimmer, Department of Medicine, General Hospital Villach. K. Laubreiter, G. Grimm, 2nd Medical Department, General Hospital Klagenfurt. P. Siostrzonek, Department of Internal Medicine/Cardiology, Krankenhaus Barmherzige Schwestern Linz. H. Mayr, 3rd Department of Medicine, General Hospital St. Poelten. T. Neunteufl, G. Maurer, 2nd Department of Medicine, Medical University Vienna. G. Norman, H. Weber, 1st Department of Medicine, Danube Hospital Vienna. O. Pachinger, J. Dörler, H.F. Alber, Department of Internal Medicine 3, Cardiology, Innsbruck Medical University. F.X. Roithinger, Department of Medicine, General Hospital Mödling. G. Unger, K. Huber, 3rd Department of Medicine (Cardiology and Emergency Medicine), Wilhelminenspital, Vienna. H. Wallner, Department of Medicine, Kardinal Schwarzenberg‘sches Krankenhaus, Schwarzach. W. Weihs, H. Schuchlenz, Department of Cardiology and Intensive Care Medicine, General Hospital Graz.


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