Use of abciximab prior to primary angioplasty in STEMI results in early recanalization of the infarct-related artery and improved myocardial tissue reperfusion – results of the Austrian multi-centre randomized ReoPro-BRIDGING Study

Mariann Gyöngyösia, Hans Domanovitsb, Werner Benzerc, Moritz Haugkb, Birgit Heinischa, Gottfried Sodeckb, Ronald Hödld, Georg Gaule, Gerhard Bonnerf, Johann Wojtaa, Anton Laggnerb, Dietmar Glogara and Kurt Huberg,* for the ReoPro-BRIDGING Study Group

a Department of Cardiology, University of Vienna, Austria
b Department of Emergency Medicine, University of Vienna, Austria
c Department of Interventional Cardiology, Academic Hospital, Feldkirch, Austria
d Department of Cardiology, University of Graz
e Hanusch Hospital, Vienna
f Rudolfstiftung, Vienna
g 3rd Department of Medicine (Cardiology and Emergency Medicine), Wilhelminenspital, Montleasrstrasse 37, A-1160 Vienna, Austria

Received June 14, 2004; revised August 27, 2004; accepted September 3, 2004 * Corresponding author. Tel.: +43 1 49150 2301; fax: +43 1 49150 2309 (E-mail: kurt.huber{at}wienkav.at).


    Abstract
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
AIMS: The aim of the ReoPro-BRIDGING Austrian multi-centre study was to investigate the effects of abciximab (ReoPro®) on early reperfusion in ST-elevation myocardial infarction prior to or during primary percutaneous coronary angioplasty (pPCI).

METHODS AND RESULTS: Fifty-five patients with STEMI were randomized either to start abciximab (0.25 mg/kg bolus followed by 10 μg/min infusion) during the organization phase for pPCI (Group 1, n=28) or immediately before pPCI (Group 2, n=27). The time between first bolus of abciximab and first balloon inflation of pPCI was 83±18 vs 21±13 min in Group 1 vs 2. The pre-pPCI ST-segment resolution (55±21.4% vs 42.4±18.2%, p=0.005), TIMI flow grade 3 (29% vs 7%, p=0.042), corrected TIMI frame count (58.4±32.7 vs 78.9±28.4 frame, p=0.018) %diameter stenosis (76.3 /63.5–100/ vs 100 /73.5–100/; median /interquartile range/, p=0.023), were significantly higher in Group 1 vs Group 2. Quantitative myocardial dye intensity measurement revealed a significantly higher grade of myocardial tissue perfusion (1 /0–9.25/ vs 0 /0–3.0/ grey pixel unit, p=0.048) in Group 1 before pPCI. Rapid release of cardiac enzymes was observed in Group 1 as compared with Group 2: rate of rise of CK was 210±209 vs 97±95 U/l/h (p=0.015). QRS score indicated a smaller infarct size in Group 1 (4.8±3.8 vs 7.6±3.5, p=0.011) on day 7.

CONCLUSION: The use of abciximab in the organization phase for pPCI results in signs of early recanalization of the infarct-related artery and a subsequent improved myocardial tissue reperfusion.


    Introduction
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
The primary goal of the treatment of acute coronary occlusion is to achieve early, complete and sustained epicardial and myocardial reperfusion and to counteract the development of myocardial infarction. A meta-analysis of clinical trials comparing pre-hospital fibrinolysis with hospital administration demonstrated a 17% relative reduction in mortality when the time to treatment was reduced by 1 h.1

The ADMIRAL multicentre randomized trial demonstrated the advantage of abciximab administration before primary percutaneous coronary angioplasty (pPCI) at both 30 days and 6 months in patients receiving the drug very early (en route to the catheterization laboratory).2,3 However, the randomization of this study did not originally target the benefit of early administration of abciximab, as compared with late (immediately before qualifying angiography or pPCI) application.

As abciximab is primarily a platelet aggregation inhibitor without fibrinolytic effect, only a few trials have studied the effect of abciximab combined with unfractionated heparin on reperfusion as an upstream medical therapy followed by planned pPCI for acute myocardial infarction. The early non-randomized trials, the GRAPE and ReoMI,4,5 reported the benefit of early administration of abciximab in AMI, achieving a high rate of TIMI 2 or 3 grade flow before pPCI. Three randomized trials, ReoMOBILE,6 ERAMI,7 and the study by Zorman et al.8 comparing the early (in emergency room) vs late (in catheterization laboratory) administration of abciximab reported different results, with only a statistical trend toward achieving a better clinical endpoint in ReoMOBILE and ERAMI, but a clear benefit of early abciximab therapy in the study by Zorman et al.

In spite of heterogenous outcomes, many of the studies showed an improved recanalization of the infarct-related artery when abciximab was given early, during the waiting phase for pPCI.2,8 However, even when TIMI 3 flow is achieved, patients may have less optimal reperfusion at the myocardial tissue level, and several mechanisms have been suggested to be involved, such as no reflow and distal embolisation.9

The aim of the ReoPro-BRIDGING Austrian multi-centre randomized study, therefore was to compare the effects of early (in the organization phase of pPCI) versus late (immediately before pPCI) administration of abciximab (ReoPro® Eli Lilly, Indianapolis, IN) on patency of the infarct-related artery and signs of early reperfusion, such as ST-segment resolution, and myocardial blush grade prior to pPCI.


    Methods
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Study population
Fifty-seven patients with ST-segment elevation myocardial infarction (STEMI) were enrolled in the study in six Austrian centres. All these centres had the capability of on-site pPCI. Criteria for study entry were chest pain persisting for more than 30 min, associated with an ST elevation of at least 0.1 mV in two or more electrocardiographic leads, and hospital admission within six hours of symptom onset.

Exclusion criteria were cardiogenic shock, prolonged (>20 min) cardiopulmonary resuscitation within two weeks prior to randomization, previous administration of fibrinolytic agents or GPIIb/IIIa antagonists, history of bleeding, active peptic ulceration, major surgery within one month, history of stroke or transient ischaemic attack, known renal insufficiency (serum creatinine level over 2.5 mg/dl) or platelet count of less than 120,000/mm3.

The study complies with the Declaration of Helsinki, and the locally appointed ethics committee approved the research protocol and written informed consent was obtained from all patients.

Patients were randomized to start abciximab as a bolus (0.25 mg/kg) followed by a 12-h infusion (at a rate of 0.125 μg/kg/min, with a max. dose of 10 μg/min) either immediately after randomization, during the organization phase for pPCI (Group 1, n=28) or after diagnostic coronary angiography, immediately before pPCI (Group 2, n=29), according to a centralized randomization (generation of randomization list for each centre and provision of the code in randomization envelope). The patient received the study drug in the emergency room/department of the hospital participating in the study. The patients remained blinded to the randomization code during the one-month follow-up. According to the single-blind randomization mode, the physician enrolling the patient in the study and the coronary interventionist was aware of the treatment arm, in order to avoid potential serious bleeding complications during pPCI in patients in Group 1. The physician treating and controlling the patient after pPCI was blinded to the randomization. All data analysis was blinded. Patients who did not receive the full dose abciximab, or who needed treatment other than pPCI for any reason, were excluded from the data analysis. Aspirin (250 mg bolus), and unfractionated heparin (60 U/kg) were given to all patients after randomization, and an additional bolus of unfractionated heparin was administered to maintain the activated clotting time between 200 and 300 s in all patients during the coronary procedure. Other medication was given at the investigator's discretion. Before and after pPCI, 100 ug intracoronary nitroglycerine was administered for qualifying and quantifying angiography. Stenting of the infarct-related artery was strongly recommended for each patient, and all patients with stents received 75 mg clopidogrel (after 300 mg loading dose immediately post-PCI) and 100 mg aspirin daily after stent implantation.

Electrocardiographic monitoring
The 12-lead electrocardiogram was recorded at presentation, immediately before pPCI, and every 2 h after pPCI during the first day, and on day 7. Sum of ST-segment elevations was measured in the 3 contiguous leads with the highest ST elevation. ST-segment resolution before and within 30 min after coronary angiography was defined as the ratio between pre-intervention or post-intervention values and initial sum of ST elevation. ST segment elevation was measured 0.08 s after the J point by the investigator who was blinded to the randomization.

An ST-segment decrease of ≥50% of the initial ST-segment elevation was also calculated, both before angiography and within 30 min thereafter.

In order to estimate the size of myocardial infarction, the 32-point Selvester QRS score was calculated at presentation and on days 1 and 7.10

Intra- and interobserver variabilities were determined by repeated analysis of sum of initial ST segment elevation and baseline Selvester QRS score of 35 patients. For intraobserver variability, one experienced observer analysed the ECGs twice in separate session; for the interobserver variability, two observers analysed the ECGs in different sessions. Linear regression analysis revealed a regression co-efficient of r=0.955 (p<0.001) for intra-, and of r=0.931 (p<0.001) for interobserver variability for ST segment elevation score, and of r=0.989 (p<0.001) for intra- and r=0.965 (p<0.001) for interobserver variability for Selvester score.

Coronary angiography
Coronary angiograms before and after pPCI of the infarct-related artery were evaluated for TIMI flow grade and corrected TIMI frame count.11 Angiograms were analysed quantitatively (ACOMPC, Siemens, Germany). Pre- and post-pPCI minimal lumen diameter, reference segment diameter, percentage diameter stenosis and length of the lesion were determined. Procedural time was recorded and success was defined as post-intervention diameter stenosis ≤50% with TIMI grade flow 3.

Myocardial blush grade (angiographic measure of myocardial perfusion) was defined9 as follows: 0: no myocardial blush or contrast density, 1: minimal myocardial blush or contrast density, 2: moderate myocardial blush or contrast density but less than that obtained during angiography of a contralateral or ipsilateral non-infarct-related artery, and 3: normal myocardial blush or contrast density. For myocardial blush grading, long, at least 16 s angiographic runs were made to see the venous phase of the contrast passage.9,12 Additionally to the visual score, the myocardial contrast dye intensity was determined by using Osiris 4.0 Software (Osiris Medical Imaging Software, Version 4.0, University Hospital of Geneva, Switzerland) before and after pPCI.12,13 For quantitative analysis, a rectangular ROI of 512X512 pixel matrix with a linear grey scale of 256 shades of grey was defined, and the myocardial dye intensity of the distal coronary bed of the infarct-related artery on the actual image was automatically calculated. Analysis was carried out from the frames before vessel visualization (pre-contrast myocardial dye intensity) to the point where contrast intensity was maximal (peak contrast intensity). The corrected peak myocardial contrast intensity was calculated as the difference between the peak and pre-contrast dye intensities and given in grey pixel units.9

All coronary angiographic and clinical data analyses were performed in an independent core laboratory (CardioData System Datenmanagement GmbH, Vienna, Austria), blinded to randomization. Corrected TIMI frame count of 40 qualifying angiograms was repeatedly measured by 1 observer for determination of intraobserver, and by 2 observers for calculation of interobserver variability. Linear regression analysis resulted in a regression co-efficient of r=0.996 (p<0.001) for the intra- and r=0.967 (p<0.001) for the interobserver variability. For the calculation of interobserver agreement by TIMI grade flow, 40 angiograms were analysed, and both observers categorized the TIMI flow grade into TIMI flow 3, 2, 1 and 0. The interobserver agreement was calculated with weighted κ statistics, which resulted in a κ value of 0.889, with upper and lower 95% confidence interval levels of 0.807 and 0.972.

Laboratory measurements
Venous blood samples for analyses of serum creatine phosphokinase (CK) and its myocardial fraction (CK-MB), plasma cardiac troponin T and myoglobin were obtained immediately after randomization (baseline value), immediately before diagnostic angiography (after upstream abciximab treatment in Group 1, and before initiation of abciximab therapy in Group 2), and at 4, 6, 8, 10, 12, 24 and 48 h after randomization. Serum fibrinogen and C-reactive protein were measured at baseline and at 24 and 48h. Red and white blood cell counts, platelet count and haematocrit were monitored in 4h intervals. Blood specimens were analysed for cardiac myoglobin by use of the OPUS Immunoassay System (Behrings Diagnostic Inc., Vienna, Austria) (normal range: 7–76 ng/ml). Serum levels of CK (normal: ≤80 U/l), CK-MB (normal: ≤10.0 U/l), cardiac troponin T (normal: <0.1 ng/ml), C-reactive protein (normal: ≤0.5 mg/dl) and fibrinogen (normal: ≤380 mg/dl) were determined by use of standard routine laboratory tests.

Endpoints of the study
Primary endpoints were TIMI flow grade, corrected TIMI frame count at the qualifying angiography and composite clinical endpoint, defined as death, repeated revascularization of the infarct-related artery, non-fatal re-infarction, major bleeding and non-fatal disabling stroke within 30 days.

Secondary endpoints were ST-segment resolution immediately before pPCI, infarct size as measured by cumulative CK release and QRS Selvester score, and myocardial tissue reperfusion assessed by myocardial blush grade.

Definitions
Death was defined as 'all-cause' death. Non-fatal re-infarction was determined as recurrent signs and symptoms of ischaemia at rest accompanied by new or recurrent ST segment elevations of ≥0.1 mV in at least 2 contiguous leads lasting >30 min, or new elevation of CK-MB or total CK above the upper limit of the normal range in at least 1 sample with a value ≥2 times the upper limit of normal. Target vessel revascularization was stated as any repeat percutaneous intervention of the infarct-related artery after the pPCI. Major bleeding was concerned if the bleeding was associated with a decrease in haemoglobin >2 g/dl. Disabling stroke was defined as Grade 3 to 6 according to modified Rankin scale. Cardiogenic shock (non-study endpoint) was regarded as hypotension (a systolic blood pressure of <90 mm Hg) for at least 30 min or the need for supportive therapy to maintain a systolic blood pressure of ≥90 mm Hg with end-organ hypoperfusion (cool extremities or a urine output < 30 ml/h), and a heart rate of ≥60 bpm.

Statistical analysis
Sample size calculation
The primary hypothesis of the study was that upstream treatment with abciximab would significantly improve the coronary blood flow into the ischaemic area. Although TIMI flow grade classification is widely used to assess angiographic outcome, it is limited by high interobserver variability and its categorical nature, the different degrees of complete perfusion in the coronary artery not being defined.14 In order to overcome these problems, the coronary blood flow was expressed by corrected TIMI frame count. The sample size was calculated at an α level of 0.05 and probability level of 0.80 and by using the mean (23.1 frames) values of corrected TIMI frame counts for 80 normal coronary arteries of non-study patients undergoing diagnostic coronary angiography in the Department of Cardiology, University of Vienna. As no corrected TIMI frame count data are available before and after abciximab treatment in patients with ST-elevation myocardial infarction; and as the mean values for the normal coronary arteries are in accordance with the values measured by Gibson et al.,11 we used the corrected TIMI frame count data of patients with 90 min after thrombolysis in acute myocardial infarction (mean value of 39.2 frames, standard deviation of 20.0).11 The power calculation indicated that a sample size of 25 was necessary in each group to enable detection of a mean difference of 16.1 frames (normalization of corrected TIMI frame count after thrombolysis), assuming a common standard deviation of 20.0 in both groups, by using a two-group t test with a 5% two-sided significance level between the groups. With regards to drop-outs, at least 27 patients were planned to be included in both groups.

Final statistical analysis
Continuous variables with normal distribution (corrected TIMI frame count, and all ECG parameters, including ST-resolution and QRS Selvester score, and the laboratory parameters) were presented as means±SD. The different time-points of the blood samples have been considered by using the cumulative CK, CK-MB and myoglobin release calculated via the area under the curve, and given as one value for each patient. The pre-pPCI (as a single time-point) levels of cardiac markers (after upstream treatment with abciximab in Group 1, and before initiation of abciximab therapy in Group 2) and the widely used parameter of CK elevation (rate of rise of CK, expressed as the difference between the peak and baseline CK, divided by the hours between) were also presented, as these parameters might characterise the effect of abciximab treatment on cardiac enzyme release. The continuous parameters not normally distributed (myocardial dye intensity, minimal lumen diameter and %diameter stenosis) were expressed as median with interquartile range. Categorical variables were expressed as percentages. Two-sided Student's t-tests and chi-square tests were performed for group comparisons for continuous variables with normal distribution and categorical variables. The non-normally distributed continuous parameters were assessed with the Mann-Whitney U -test. With focus on the outcome variables, the following separate analytical groups were created: pre-PCI patency of the infarct-related artery, e.g. coronary reperfusion (corrected TIMI frame count, TIMI 3 flow), pre-PCI tissue reperfusion (myocardial blush grade and myocardial dye intensity), and the pre-PCI quantitative angiographic parameters of the infarct-related lesion (minimal lumen diameter and %diameter stenosis) and electrocardiographic parameters (ST resolution and infarct size). The p-values yielded by the multiple comparisons were corrected for multiplicity using the method of Bonferroni-Holm. This procedure controls the overall type I error at the level of 5%. Statistical significance was defined as p<0.05.


    Results
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Clinical data
Two patients in Group 2 were excluded from the study, due to bronchial bleeding with immediate termination of the initiating abciximab therapy and postponing the pPCI in one patient, and a cardiogenic shock developed after randomization in the other patient, requiring emergency treatment, not receiving the study drug. Thus, the present analysis involves the data obtained on 55 patients who received the full dose of abciximab. Clinical variables for both groups are presented in Table 1. There were no differences between the groups as regards the age, gender, atherosclerotic risk factors and the location of infarction. The time between onset of symptoms and clinical presentation (113±62 vs 104±55 min in Groups 1 vs 2), and the organization time for pPCI (time between randomization with or without immediate initiation of abciximab and qualifying coronary angiography, 75±36 min in Group 1 and 79±35 min in Group 2) were similar in the 2 groups. According to the randomization principles, the duration of the pre-PCI abciximab infusion was significantly longer in Group 1 (time between the first bolus of abciximab and first balloon inflation 83±18 vs 21±13 min in Group 1 vs 2).


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Table 1. Clinical and angiographic data on patients in Group 1 (abciximab after clinical presentation) and Group 2 (abciximab after qualifying angiography)
 
Patency of the infarct-related artery
Coronary angiography revealed a significantly better TIMI flow grade (TIMI 3 flow 29% vs 7% in Group 1 vs Group 2, p=0.042) (Fig. 1) and corrected TIMI frame count after visualization of the infarct-related artery in Group 1 (Table 2). After pPCI, no difference was observed between the groups, as regards the TIMI 3 flow grade (89% vs 74% in Groups 1 vs 2) and the corrected TIMI frame count (34.3±12.6 vs 39.9±22.0 in Groups 1 vs 2).



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Fig. 1 TIMI flow grade for ST-segment elevation myocardial infarction patients in Group 1 (abciximab after presentation) and Group 2 (ReoPro after diagnostic angiography) before and after primary percutaneous coronary intervention.

 

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Table 2. Quantitative coronary angiography data on patients in Group 1 (abciximab after clinical presentation) and Group 2 (abciximab after diagnostic angiography)
 
Myocardial tissue reperfusion
Myocardial perfusion expressed as the myocardial blush grade 2+3 was significantly higher in patients of Group 1 as compared with Group 2 at the qualifying angiography (Table 2). Accordingly, the significantly higher myocardial dye intensity indicated a significantly better myocardial tissue reperfusion in Group 1 patients (Table 2) before pPCI. After pPCI, neither the myocardial blush grade 2 and 3 (93% vs 74%) nor the myocardial dye intensity (10 grey pixel unit with interquartile range of 5.0–13.5 vs 10 grey pixel unit with interquartile range of 4.0–10) differed (Fig. 1 and Table 2) between the groups, respectively.

Quantitative angiographic results of the infarct-related lesion
Quantitative angiography demonstrated a significantly larger pre-intervention minimal lumen diameter and smaller diameter stenosis in patients in Group 1 as compared with Group 2 (Table 2). The reference diameter and length of the infarct-related lesion, the total length of implanted stents and the implanted stent size did not differ between the groups. Post-PCI, no difference between the groups was observed as regards the minimal lumen diameter: 2.4 mm (2.08–2.58) vs 2.35 mm (1.96–2.66) or %diameter stenosis: 11.0% (7.1–18.3) vs 10.0 (6.4–19.8) in Groups 1 and 2, respectively.

Electrocardiogram
Significantly better ST-segment resolution was observed pre-pPCI after early administration of abciximab (Table 3). Similarly, the pre-pPCI ST-elevation decrease of ≥50% was significantly more frequent in patients in Group 1 (Table 3). No differences between the groups were demonstrated after pPCI. After pPCI, neither the ST segment resolution (74.6±19.1% vs 68.7±16.5% in Group 1 vs 2), nor the ST-elevation decrease ≥50% (89% vs 85% in Group 1 vs 2) was different between the groups.


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Table 3. Electrocardiographic signs of early reperfusion (ST resolution) and infarct size (QRS Selvester score) for patients in Group 1 (abciximab after clinical presentation) and Group 2 (abciximab after qualifying angiography)
 
The QRS Selvester score was not different at the clinical presentation (7.8±3.8 vs 8.2±3.9 in Groups 1 vs 2), but it was significantly lower in Group 1 than that in Group 2 on day 1 and 7 (Table 3).

Laboratory data
The baseline levels of CK (78±83 vs 68±67 U/l), CK-MB (5.9±11.6 vs 5.9±12.5 U/l), myoglobin (101±78 vs 90±68 ng/l) cardiac troponin T (0.13±0.4 vs 0.18±0.49) were similar in Groups 1 and 2, respectively.

A significantly more rapid release of CK, CK-MB and myoglobin (Fig. 2; Table 4) was observed in the patients in Group 1 immediately before pPCI (after upstream abciximab treatment in Group 1 but before initiation of abciximab therapy in Group 2), but not after pPCI, even if a trend toward higher levels of CK, CK-MB, cardiac troponin T and myoglobin was observed in the first 12 hours in Group 1. According to the rapid cardiac enzyme release in Group 1, the rate of rise of CK was higher in Group 1 than 2 (210±209 vs 97±95 U/l/h, p=0.015). A trends toward lower levels of CK (and CK-MB) and myoglobin was measured at 24 and 48h after onset of myocardial infarction in patients in Group 1 (Fig. 2). A weak trend toward lower cumulative CK, CK-MB and myoglobin release could be demonstrated in Group 1 vs Group 2 (for CK: 14,990±15,309 vs 18,614±15,979 U/lh, p=0.412; for CK-MB: 2146±1665 vs 2580±1462 U/lh, p=0.331 and for myoglobin: 5397±4956 vs 6399±4790 pg/mlh, p=0.596).



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Fig. 2 Serum levels of myoglobin and creatinine phosphokinase (CK) for ST-segment elevation myocardial infarction patients in Group 1 (abciximab after presentation) and Group 2 (abciximab after diagnostic angiography) at baseline, pre-primary percutaneous coronary angioplasty (pre-pPCI) and 4, 6, 8, 10, 12, 24 and 48 h after clinical presentation. * - * p=0.041; # - # p<0.016.

 

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Table 4. Serum levels of creatinine phosphokinase (CK), its myocardial fraction (CK-MB), myoglobin and cardiac troponin T (cTnT) for patients in Group 1 (abciximab after clinical presentation) and Group 2 (abciximab after qualifying angiography) before primary percutaneous coronary angioplasty (pre-pPCI, e.g., after upstream abciximab therapy in Group 1, and before initiation of abciximab in Group 2)
 
The serum levels of fibrinogen were similar in the two groups. However, serum C-reactive protein level at 48h was higher in Group 2 (Group 1 vs Group 2 baseline levels: 0.64±1.33 vs 0.99±0.99, p=0.397; at 24h: 2.36±3.83 vs 3.46±3.6, p=0.329; and at 48h: 3.76±3.38 vs 10.3±11.53 mg/dl, p=0.023).

Results of pPCI
Primary PCI was performed in 25 of the 28 patients in Group 1; angiography showed no significant stenosis of the infarct-related artery in one patient, and pPCI was unsuccessful in two patients. Stents were implanted in 22 patients, while three patients had been treated with balloon angioplasty only. Primary percutaneous coronary intervention was performed in 25 of the 27 patients in Group 2: pPCI was unsuccessful in two patients. Twenty-four patients with pPCI received stents, one patient was treated with balloon angioplasty alone The procedural time was significantly shorter in Group 1 (87±15 vs 116±29 min, p=0.023).

Cardiac events during 1-month follow-up
Minor complications occurred in six patients (three in each group) who suffered from groin haematoma, which could be treated conservatively in five patients; surgery was necessary in one patient (Group 2).

The following major complications occurred during the one-month follow-up: one patient in Group 1 suffered from cardiogenic shock accompanied by bleeding of unknown origin shortly after pPCI, and was treated successfully conservatively. One patient in Group 2 developed ventricular fibrillation with need for cardiopulmonary resuscitation one hour after reopening of the infarct-related artery. After successful repeated dilatation of the stent implanted previously in the infarct-related artery (target vessel revascularization), no further event occurred. Control angiography six days later displayed TIMI 3 flow.

In Group 2, the two patients with major bleedings were treated successfully medically. The patient in Group 2 with severely depressed ventricular function and haemodynamic instability was further treated successfully. One patient (Group 2) developed disabling stroke one day after pPCI.

TIMI 1 flow of the infarct-related artery was controlled angiographically in one patient in Group 2 seven days after pPCI, re-angiography showed TIMI 2 flow; no coronary intervention was performed. Non-infarct-related artery coronary intervention was performed in one patient of Group 1.

Thus, the rate of in-hospital complications was 1/28 (3.6%) in Group 1, and 5/27 (18.5%) in Group 2 (p=0.076). No patient suffered death or re-infarction.

One patient (Group 1) was re-hospitalised 13 days after AMI due to congestive heart failure, but as no signs of acute myocardial ischaemia were observed, no angiography was performed.

Post-infarct angina pectoris was recorded in three patients in Group 2 with no electrocardiographic or cardiac enzyme changes in two patients, and with electrocardiographic changes in one patient, who was listed for bypass operation 48 days after AMI.

The frequency of composite clinical endpoints at one month did not differ from the in-hospital complication rate. The rate of death, re-infarction and target vessel revascularization during the one month follow-up was not significantly different in the two groups: 0/28 (0%) in Group 1 and 1/27 (3.7%) in Group 2.


    Discussion
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Our study has provided evidence that the early administration of abciximab, during the organization phase for pPCI, results in early recanalization of the infarct-related artery and in effective reperfusion at the tissue level, as shown by more frequent ST-segment resolution, a higher TIMI grade flow, less severe coronary narrowing and corrected TIMI frame count, and as a consequence, higher myocardial blush grade and smaller infarct size.

Even if the majority of large randomized trials giving abciximab as an adjunctive treatment to pPCI, have demonstrated the benefit of abciximab in the clinical endpoint,2,15–17 the CADILLAC and the ISAR-2 angiographic and one-year study failed to show a better outcome as compared with placebo.18,19 However, the ADMIRAL study has shown, that the very early pre-PCI administration of abciximab as a first-line pre-catheter treatment for NSTEMI can lead to opening of the infarct-related artery, improvement of the success of stenting of pPCI, and a reduction in the rate of re-occlusion up to six months.2 Similarly, the GRAPE non-randomized trial and the randomized study by Zorman et al. demonstrated a significant, and the ReoMOBILe and ERAMI small randomized studies a strong trend favouring early Abx administration.4,6–8 The postulated mechanism of action of abciximab involves a rapid, time-dependent deaggregation of platelet-rich fresh thrombi.20–22 As a consequence, abciximab results in an early recanalization of the infarct-related artery, better visualization of the culprit lesion, and an improvement in microcirculation.3,23 In accordance with these previous studies, the early administration of abciximab in our study resulted in better epicardial perfusion and a higher TIMI grade flow. In parallel with the better reperfusion at a tissue level, as indicated by the qualitative and quantitative myocardial blush grade, the Selvester QRS score indicated a smaller infarct size.

After pPCI, no significant differences were demonstrated between the Groups (early versus late), as regards the TIMI grade flow, corrected TIMI frame count, ST-resolution and myocardial blush grade, indicating the determining role of pPCI in complete revascularization of the infarct-related myocardial area. However, restoration of epicardial flow, regardless of the method used, might abruptly terminate the myocardial infarction. It has been shown, that the successful reperfusion during the first hours ('golden hours'24) results in a considerable myocardial salvage.25,26 Consequently, early administration of abciximab might prevent infarct expansion (as indicated by the QRS score), even if it does not influence the short-term clinical outcome.

Similar to our study, in the recently published On-going Tirofiban In Myocardial Infarction Evaluation (On-TIME) trial, the early initiation of GP IIb/IIIa antagonist tirofiban was associated with a higher incidence of pre-PCI myocardial blush grade 2 or 3 as compared with late administration.27 However, early administration of tirofiban did not result in a higher grade of TIMI 3 flow (19% in early group and 15% in late group), even if combined incidence of TIMI 2 or 3 flow was significantly higher in the early group. The possible explanation for lack of efficacy of tirofiban in improvement of vessel patency grade in the On-TIME trial might be the inadequate dose27 and the short (59 min) administration time before primary angioplasty. Furthermore, the explanation of different results of the angiographic outcome between our study and the On-TIME study might be the longer exposure to GP IIb/IIIa antagonist (mean 83 min in our early group), and the type of GP IIb/IIIa antagonist. Tirofiban was significantly inferior to abciximab in the 30-day outcome of patients undergoing percutaneous coronary angioplasty,28 as only abciximab has the potential to influence the adhesion of platelets and endothelial cells and of platelets and white blood cells.28 Additionally, abciximab may improve endogenous fibrinolysis.22 Accordingly, early administration of abciximab resulted in a significantly higher rate of pre-PCI TIMI 3 flow (29% of our patients) in our study, even if a direct comparison between our and the On-TIME study might not be appropriate due to the considerable difference in the number of included patients. Accordingly, a larger randomized trial with similar design to that of our study should be conducted to confirm the beneficial effect of early administration of abciximab in STEMI on the short- and long-term (at least six months) clinical outcome, as our study was clearly underpowered for the assessment of clinical endpoints.

In our study, after early abciximab administration and achievement of a significantly better coronary flow, a severe narrowing of the infarct-related lesion was still detected in the patients in Group 1. These data suggest that abciximab is effective in the resolution of thrombi attached to the ruptured plaque, resulting in at least partial reopening of the acute coronary occlusion. However, the underlying lesion still has the characteristics of severe atherosclerosis, which should be treated with pPCI and stenting.3,15,17,18,29

Early reperfusion of the infarct-related artery in Group 1 resulted in an early and significantly enhanced initial release of cardiac enzymes. The combination of higher initial levels with an earlier peak and the strong trend toward a lower cumulative release of CK, CK-MB and myoglobin suggests a washout phenomenon early after restoration of the blood flow. Ong et al. demonstrated an improvement in global ejection fraction in patients with rapid release of CK after early reperfusion, and a negative correlation between time to peak enzyme level and degree of improvement in ejection fraction,30 suggesting a similar washout phenomenon. In contrast, the study by Cobbaert et al. suggested a reperfusion injury behind the acute and massive interstitial release of cardiac enzymes after thrombolysis-induced coronary reperfusion.31 Nevertheless, the QRS score indicated a smaller infarct-size in our Group 1 patients, and no differences in clinical outcome in the first 30 days was observed between the early and late Groups.

Limitations
All patients with stenting of the infarct-related artery received loading dose of clopidogrel immediately after pPCI. Administration of clopidogrel in the organization phase of pPCI might improve the patency of the infarct-related vessel; there is evidence of an effect of early clopidogrel treatment in unstable angina/non-ST segment elevation infarction,32,33 whereas insufficient data exist on early adjuvant therapy with clopidogrel in STEMI.

Two patients experienced serious acute complications, they did not receive the full dose of the study drug, and required emergency treatment; these two patients were excluded from the data analysis. Not performing the intention-to-treat analysis is a clear disadvantage of our study, even if the data on the two excluded patients do not influence the main results and conclusion of our study.

In conclusion, administration of abciximab to STEMI patients destined for pPCI as early as possible results in early epicardial and myocardial reperfusion, better TIMI flow grade, and myocardial blush grade and limitation of infarct size before pPCI. Accordingly, "bridging" the organization phase for pPCI in STEMI with pre-procedural abciximab treatment might become an important therapeutic tool in myocardial salvage.


    References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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