Several randomized trials  have shown that primary angioplasty is superior to thrombolysis in terms of survival in the treatment of ST-segment elevation myocardial infarction (STEMI). However, attempts to extend primary angioplasty to the vast majority of STEMI patients may be associated with longer delay to treatment, with a negative impact on survival [2–5]. Adjunctive abciximab has been shown to reduce mortality in patients undergoing primary angioplasty [6,7]. However, early administration of glycoprotein (Gp) IIb-IIIa inhibitors seems even more attractive for the potential benefits expected from early recanalization, that might overcome any potential delay to mechanical reperfusion [8,9]. The Early GlYcoprotein IIb-IIIa inhibitors in Primary angioplasTy (EGYPT) cooperation showed that early Gp IIb-IIIa inhibitors significantly improved pre-procedural TIMI flow, but only early abciximab was able to improve post-procedural epicardial and myocardial perfusion and mortality . The aim of the present study was to evaluate the long-term benefits in survival from early abciximab administration among STEMI patients undergoing primary angioplasty.
Summary. Background: Even although time to treatment has been shown to be a determinant of mortality in primary angioplasty, the potential benefits are still unclear from early pharmacological reperfusion by glycoprotein (Gp) IIb-IIIa inhibitors. Therefore, the aim of this meta-analysis was to combine individual data from all randomized trials conducted on upstream as compared with late peri-procedural abciximab administration in primary angioplasty. Methods: The literature was scanned using formal searches of electronic databases (MEDLINE and EMBASE) from January 1990 to December 2010. All randomized trials on upstream abciximab administration in primary angioplasty were examined. No language restrictions were enforced. Results: We included a total of seven randomized trials enrolling 722 patients, who were randomized to early (n = 357, 49.4%) or late (n = 365, 50.6%) peri-procedural abciximab administration. No difference in baseline characteristics was observed between the two groups. Follow-up data were collected at a median (25th–75th percentiles) of 1095 days (720–1967). Early abciximab was associated with a significant reduction in mortality (primary endpoint) [20% vs. 24.6%; hazard ratio (HR) 95% confidence interval (CI) = 0.65 (0.42–0.98) P = 0.02, Phet = 0.6]. Furthermore, early abciximab administration was associated with a significant improvement in pre-procedural thrombolysis in myocardial infarction (TIMI) 3 flow (21.6% vs. 10.1%, P < 0.0001), post-procedural TIMI 3 flow (90% vs. 84.8%, P = 0.04), an improvement in myocardial perfusion as evaluated by post-procedural myocardial blush grade (MBG) 3 (52.0% vs. 43.2%, P = 0.03) and ST-segment resolution (58.4% vs. 43.5%, P < 0.0001) and significantly less distal embolization (10.1% vs. 16.2%, P = 0.02). No difference was observed in terms of major bleeding complications between early and late abciximab administration (3.3% vs. 2.3%, P = 0.4). Conclusions: This meta-analysis shows that early upstream administration of abciximab in patients undergoing primary angioplasty for ST-segment elevation myocardial infarction (STEMI) is associated with significant benefits in terms of pre-procedural epicardial re-canalization and ST-segment resolution, which translates in to significant mortality benefits at long-term follow-up.
ligibility and search strategy
We identified all randomized trials comparing early upstream abciximab vs. its peri-procedural administration in STEMI patients undergoing primary angioplasty. The literature was scanned by formal searches of electronic databases (MEDLINE and EMBASE) from January 1990 to December 2010, the scientific session abstracts in Circulation, Journal of College of Cardiology, European Heart Journal and American Journal of Cardiology from January 1990 to December 2010. The following key words were used: randomized trial, myocardial infarction, reperfusion, primary angioplasty, facilitated angioplasty, Gp IIb-IIIa inhibitors and abciximab. No language restrictions were enforced. All principal investigators were contacted in order to provide individual patient’s data, which were transferred without patients’ identifiers (initials and birthday) to the Eastern Piedmont University, Novara, Italy. The dataset was checked for completeness and consistency and compared with the results of any publications. Queries were resolved by direct correspondence with the responsible study investigator. Data were managed according to the intention-to-treat principle.
Angiograms and electrocardiograms (ECGs) were not analyzed by a central core lab, but data were provided by each principal investigator. Analysis of angiograms was based on standard definitions [11–13]. In particular, distal embolization was defined as an abrupt ‘cutoff’ in the main vessel or one of the coronary branches of the infarct-related artery, distal to the angioplasty site . Even though ST-segment analysis was performed according to the pre-specified criteria of each trial, data were provided according to uniform thresholds (< 30%: no resolution; 30–70%: partial resolution; and > 70%: complete resolution).
The primary endpoint was mortality at long-term follow-up. Secondary endpoints were the rate of pre- and post-procedural thrombolysis in myocardial infarction (TIMI) 3 flow, complete ST-segment resolution and myocardial blush grade (MBG) 3 and distal embolization. The safety endpoint was the rate of major bleeding complications.
Statistical analysis was performed using the Review Manager 5.1 freeware package (Cochrane Collaboration, Software update, Oxford, UK) and spss 17.0 statistical package (SPSS Inc., Chicago, IL, USA). The pooled odds ratio (OR) was calculated using a fixed effect model (the Mantel–Haenszel method). Study weight calculation was based on the inverse variance of the effects estimates. Survival analyzes were performed with the use of Cox regression analysis stratified according to the trial . Survival was defined as the interval from randomization until death. Kaplan–Meier curves are presented with event rates reported as estimated probabilities. Heterogeneity across trials was assessed using the I2 statistic. The potential publication bias was examined by constructing a ‘funnel plot’, in which the standard error (SE) of the ln hazard ratio (HR) was plotted against the HR (mortality). In addition, a linear regression approach to measure funnel plot asymmetry was used . A landmark analysis was performed for patients who were event-free at 6 months follow-up in order to define benefits in terms of short-term (≤ 6 months) and long-term events (> 6 months).
Individual patient’s data were obtained from seven trials [16–22] out of nine [23,24]. A total of 722 patients were included, 357 patients (49.4%) randomized to early (administration started in the ambulance, in the community hospital before/during transportation to percutaneous coronary intervention (PCI) centers, or in the emergency room/intensive care unit of PCI hospitals) and 365 patients (50.6%) randomized to late (periprocedural) abciximab administration.
|Study||Period||Study design (number of patients)||Symptom duration (h)||Stent||Primary endpoints||Definition major bleeding complications|
|ReoPro-BRIDGING ||2003–2004||Early (n = 28) vs. late (n = 27) abciximab||< 6||Yes||Preprocedural TIMI 3 flow, cTFC and MACE||TIMI major|
|Relax-MI ||2003–2004||Early (n = 105) vs. late (n = 105) abciximab||< 6||Yes||Preprocedural TIMI 3 flow, ST resolution, myocardial salvage||TIMI major|
|Rakowski et al. ||2004||Early (n = 25) vs. late (n = 30) abciximab||< 12||Yes||Preprocedural TIMI 3 flow, ST resolution, LVF||Intracranial bleeding or haemoglobin loss > 5 g|
|ERAMI ||2001–2002||Early (n = 36) vs. late (n = 38) abciximab||< 12||NA||Preprocedural TIMI flow||TIMI major|
|Zorman et al. ||1998–2001||Early (n = 56) vs. late (n = 56) abciximab||< 12||Yes||Early (60 min) ST-segment resolution, preprocedural 3 TIMI flow||TIMI major|
|REOMOBILE ||2001–2002||Early (n = 52) vs. late (n = 48) abciximab||< 6||Yes||Preprocedural TIMI flow||TIMI major|
|Petronio et al. ||2006–2008||Early (n = 55) vs. late (n = 55) abciximab||< 6||Yes||Infarct size at 6 months||TIMI major|
|Variables||Early GP IIb-IIIa inh (n = 357)||Late GP IIb-IIIa inh (n = 365)|
|Previous MI (%)||3.9||7.1|
|Previous revascularization (%)||2.9||4.2|
|Killip class III/IV (%)||4.5||4.6|
|Anterior MI (%)||50.1||51|
|Symptom-onset to Gp IIb-IIIa inh time (min)|
|Ischemia time (min)|
|IRA, n (%)|
|Multivessel disease (%)||46.7||53.3|
|Coronary stenting (%)||90.8||90.8|
Follow-up data were collected at a median (25th–75th percentiles) of 1095 days (720–1967 days). As shown in Figs 1 and 2, early abciximab was associated with a significant reduction in mortality [20% vs. 24.6%; HR (95% CI) = 0.65 (0.42–0.98) P = 0.02, Phet = 0.6]. As shown by landmark analysis (Fig. 3), the benefits observed at short-term follow-up were not lost at long-term follow-up.
As shown in Fig. 4, no publication bias was observed. In addition, the intercept of the regression line did not significantly deviate from 0 [α (95% CI) = 0.68 (−0.33 to 1.69), P = 0.53].
Early abciximab administration was associated with a significant improvement in pre-procedural TIMI 3 flow [21.6% vs. 10.1%, OR (95% CI) = 2.46 (1.61, 3.77), P < 0.0001, Phet = 0.47] (Fig. 5), post-procedural TIMI 3 flow [90% vs. 84.8%, OR (95% CI) = 1.61 (1.02, 2.53) P = 0.04, Phet = 0.72] (Fig. 6), an improvement of myocardial perfusion as evaluated by post-procedural MBG 3 [52.0% vs. 43.2%, OR (95% CI) = 1.44 (1.03, 2.00), P = 0.03, Phet = 0.46] (Fig. 7) and complete ST-segment resolution [58.4% vs. 43.5%, OR (95% CI) = 1.92 (1.41, 2.62), P < 0.0001, Phet = 0.21] (Fig. 8) and a significant reduction in distal embolization [10.1% vs. 16.2%, OR (95% CI) = 0.57 (0.35, 0.93), P = 0.02, Phet = 0.94] (Fig. 9).
No difference was observed in terms of major bleeding complications between early and late abciximab administration [3.3% vs. 2.3%, OR (95% CI) = 1.49 (0.58–3.8), P = 0.4, Phet = 0.75].
The EGYPT-ALT cooperation aimed at evaluating long-term survival benefits from early abciximab administration in patients undergoing primary angioplasty by performing an individual patient’s data meta-analysis based on 722 patients enrolled in seven randomized trials. This is the first study to show such long-term follow-up data (median [25th–75th percentiles] = 1095 days [720–1967 days]) on this issue. The main finding of this meta-analysis is early upstream abciximab administration, improved pre- and post-procedural recanalization and a reduced risk of distal embolization with subsequent significant benefits in myocardial perfusion as evaluated by MBG ad ST-segment resolution. These results translated into significant benefits in long-term survival.
Recent investigations have demonstrated that time to treatment is a relevant issue in primary angioplasty, with a significant impact on mortality [3–5]. It has been hypothesized that early administration of pharmacological therapy may induce earlier reperfusion, resulting in reduced infarct size and improved survival, particularly when long-distance transportation is required [8,9].
The Assessment of the Safety and Efficacy of a New Treatment Strategy with Percutaneous Coronary Intervention (ASSENT-4) trial  showed harmful effects from facilitation with full-dose TNK in patients undergoing primary angioplasty, in spite of improved pre-procedural recanalization. These data have been explained by a potential intracoronary prothromotic rebound at the time of angioplasty induced by lysis , which could be limited by the administration of Gp IIb-IIIa inhibitors. However, these benefits may be counterbalanced by a larger incidence of bleeding complications, particularly in elderly patients . Several randomized trials have been conducted to investigate the benefits from early administration of abciximab in patients undergoing primary angioplasty [16–24]. In fact, as the adjunctive use of abciximab has been shown to reduce mortality among patients undergoing primary angioplasty [6,7], further benefits would be expected by an early reperfusion achieved by early drug administration.
In fact, a subanalysis of the Abciximab before Direct Angioplasty and Stenting in Myocardial Infarction Regarding Acute and Long-Term Follow-up (ADMIRAL) trial showed that early abciximab administration (in the emergency department or in the ambulance) did improve clinical outcome as compared with late administration .
In our previous EGYPT cooperation , we found that early Gp IIb-IIIa inhibitors significantly improved pre-procedural TIMI flow. However, only abciximab significantly improved epicardial and myocardial perfusion, reduced distal emblization and therefore improved short-term survival.
In the current meta-analysis restricted to abciximab, we included an additional randomized trial with a total of seven trials and 722 patients. It is the only available analysis with very long-term follow-up data [median (25th–75th percentiles) = 1095 (720–1967)]. We confirmed the benefits in terms of improvement in angiographic outcome and myocardial perfusion. Furthermore, we found a significant improvement in long-term survival with early upstream abciximab.
The benefits in long-term survival are clearly explained by the observed benefits in pre-procedural recanalization and post-procedural epicardial and myocardial perfusion. In fact, several studies have reported an association between this marker and long-term mortality [29,30].
However, disappointing results have been observed in the Facilitated Intervention with Enhanced Reperfusion Speed to Stop Events (FINESSE) trial . This trial was prematurely stopped as a consequence of slow recruitment, with the inclusion of up to 2500 STEMI patients. No advantages in terms of clinical outcome were observed at 1-year follow-up with facilitation by either combotherapy (abciximab and half-dose reteplase) or abciximab, as compared with late peri-procedural abciximab administration, in spite of higher patency rates, mainly with combotherapy.
Several factors may contribute to explain the different results between the EGYPT ALT and FINESSE trial .
It must be remarked that the FINESSE trial did include several centers with large variability in experience and skills, whereas our meta-analysis included trials mainly conducted at high-volume and highly experienced primary PCI centers. In addition, the slow recruitment rate observed in the FINESSE trial (approximately a mean of 10 patients per year enrolled per each center over 4 years) may have lead to a selection bias. Even though the aim of the trial was to investigate facilitation, more than 50% of patients have been enrolled and randomized in primary PCI centers.
Furthermore, our meta-analysis included randomized trials conducted in well-run networks. In fact, patients included in the present study showed a remarkably shorter time from symptoms onset to drug administration (120 vs. 165 min) and PCI (200 vs. 255 min) as compared with patients included in the FINESSE. It is well known that the benefits from facilitation may strictly depend on window of treatment, with most of the benefits from any adjunctive therapy restricted when applied in the golden hours, when the larger amount of myocardial salvage may facilitate the evaluation of benefits in terms of survival . In fact, subsequent subgroup analyzes from the FINESSE trial showed larger benefits in high-risk patients pre-treated within the first 4 h from symptoms onset [32,33].
In addition, a recent study  has shown that in STEMI patients thrombus composition is strictly dependent on the time from symptoms onset. In fact, a larger amount of platelets was observed within the first hours, whereas a decreasing percentage of platelets and a larger presence of fibrin were observed in the later phase. These findings may contribute to explain the higher percentage of pre-procedural TIMI flow observed with upstream abciximab in the present study (21.6%) as compared with the FINESSE trial (14.1%).
It is well known that optimal myocardial perfusion may have a dramatic impact on long-term remodeling of the left ventricle  and, therefore, on the occurrence of heart failure and long-term mortality, whereas only 1-year follow-up data were provided in the FINESSE trial. Even though we did not report data on the occurrence of heart failure, as shown by landmark analysis, some incremental benefits were observed up to 5–6 years follow-up.
The benefits from early Gp IIb-IIIa inhibitors have recently been supported from several registry data. In the prospective EUROTRANSFER registry , early abciximab administration significantly reduced 30-day and 1-year mortality. Similar findings have been observed in the EMILIA-ROMAGNA registry  were Gp IIb-IIIa inhibitors were associated with significant reduction in 2-year mortality, especially among high-risk patients. Similar findings have been observed in the retrospective analysis including patients enrolled in the The Assessment of Pexelizumab in Acute Myocardial Infarction (APEX-AMI) . In the MISSION registry, in-ambulance abciximab administration was associated with improved pre-procedural recanalization, left ventricular functional recovery and the reduced occurrence of heart failure at follow-up .
Therefore, in spite of the negative results of one large randomized trial , there is still a great deal of evidence to support the benefits from upstream abciximab in patients undergoing primary angioplasty.
We were unable to obtain individual patients’ data from the FINESSE trial. Even though the meta-analysis was based on individual patient’s data, this cannot overcome the potential heterogeneity among trials as a result of different inclusion and exclusion criteria, and to the fact that angiographic and ECG data were not analyzed by a central core-lab. Furthermore, some secondary endpoints (MBG and distal embolization) were not available from all the studies (Zorman et al., and REOMOBILE, respectively).
Based on their prognostic implications and availability, we analyzed major but not minor bleeding complications.
As the patients enrolled in the current randomized trials have for the most part been highly selected, some caution should be exercised in extending the conclusion of this meta-analysis to the vast majority of STEMI patients undergoing primary angioplasty. However, as a consequence of the higher risk profile, at least similar benefits might potentially be expected in trial-ineligible as compared with trial-eligible patients .
Data on the timing of clopidogrel administration were not collected. The availability of new oral antiplatelet therapies, with stronger and faster inhibition of platelet aggregation, may potentially reduce the benefits from adjunctive Gp IIb-IIIa inhibitors [41,42]. However, it must be recognized that the peak effects of these new compounds is still reached after 2 h from administration as compared with 10–15 min with intravenous Gp IIb-IIIa inhibitors. Furthermore, it has been shown that in the acute setting, especially in hemodynamically compromised patients, gastro-intestinal vascular vasoconstriction may reduce the absorption of any oral therapy and therefore delay the onset of action and overall efficacy of oral antiplatelet therapies .
This meta-analysis shows that early upstream abciximab administration is associated with significant benefits in terms of pre- and post-procedural epicardial recanalization, improved myocardial perfusion and less distal embolization, which translated into long-term survival benefits. Thus, until the results of additional large randomized trials with long-term follow-up data become available, early abciximab administration should be considered in patients undergoing primary angioplasty for STEMI.
G. De Luca: Conception and design; analysis and interpretation of data; drafting of the manuscript; statistical analysis. G. De Luca had full access to all the data in the study and took responsibility for the integrity of the data and the accuracy of the data analysis. F. Bellandi., M. Maioli, M. Noc, A.S. Petronio, M. De Carlo, H.-R. Arntz, S. Zorman, T. Rakowski, M. Gyongyosi, K. Huber and D. Dudek: administrative, technical or material support; critical revision of the manuscript; supervision. All authors declare that they participated in the study and that they have seen and approved the final version.
We are indebted to all institutions and investigators involved in the randomized trials included in this meta-analysis. This study has no financial support.
Disclosure of Conflict of Interests
The authors state that they have no conflict of interest.