The EGYPT cooperation aimed at performing a meta-analysis to evaluate the benefits from the early administration of Gp IIb–IIIa inhibitors in patients undergoing primary angioplasty, based on individual data of 1662 patients enrolled in 11 randomised trials.13–23
The main finding of this meta-analysis is that facilitation with Gp IIb–IIIa inhibitors improved preprocedural recanalisation. In the analysis limited to the abciximab trials, there was a significant mortality reduction with early versus late abciximab administration. It is of note that other subanalyses also demonstrated improvement in postprocedural TIMI 3 flow, MBG, distal embolisation and ST-segment resolution achieved with early abciximab, although the interaction was statistically significant only for MBG and improved ST-segment resolution. Comparisons between agents must be made with extreme caution given the uncontrolled features of the trials, the possible subtherapeutic dosages utilised in some of the studies and the differences in timing of early administration. Also, it must be noted that none of the studies compared agents, so inferences are based on differences between early versus late administration for each agent. Nevertheless, this is the first demonstration of mortality benefits from pharmacological facilitation in STEMI patients undergoing primary angioplasty and indicates a need for further studies to identify the best strategy.
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 hypothesised that the 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 ASSENT-4 trial30
showed harmful effects from facilitation with full-dose tenecteplase in patients undergoing primary angioplasty, despite improved preprocedural recanalisation. These data have been explained by a potential intracoronary prothrombotic rebound at the time of angioplasty induced by lysis,31
which could be limited by the administration of Gp IIb–IIIa inhibitors. These benefits may, however, be counterbalanced by a larger incidence of bleeding complications, particularly in elderly patients.32
Several randomised trials have been conducted to investigate the benefits from the early administration of Gp IIb–IIIa inhibitors in patients undergoing primary angioplasty.13–23,27–29
As the adjunctive use of Gp IIb–IIIa inhibitors, mostly 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.
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 compared with late administration.33
In a recent meta-analysis performed on pharmacological facilitation in primary angioplasty, no overall benefits in short-term (30 days) mortality were observed with inhibitors of Gp IIb–IIIa inhibitors,34
and their use was discouraged by the authors in daily clinical practice, unless in randomised trials.
That meta-analysis did not include all currently available trials, however, and analysed only a restricted number of endpoints with a limited duration of follow-up. Furthermore, no prespecified subanalysis was performed according to the type of molecule. In a recent smaller meta-analysis, restricted to abciximab and including randomised trials and non-randomised subgroup analyses, early abciximab did result in significant benefits in terms of myocardial perfusion and an increased number of aborted infarctions but without significant impact on mortality compared with late administration.35
Although significantly improved preprocedural recanalisation was the major benefit of early Gp IIb–IIIa inhibitors, there were also suggestions of improved myocardial reperfusion. Most notably, complete ST-segment resolution was significantly better overall. Several studies have reported an association between this marker and mortality. Early abciximab, but not the small molecules, was also associated with increased MBG 3 compared with late use. The underlying mechanisms for these beneficial effects may be the diminished distal embolisation of platelet aggregates (as observed in the current meta-analysis) or inhibition of the direct interaction of platelets with the reperfused endothelium by abciximab.36 37
The survival benefits of early Gp IIb–IIIa inhibitors did not significantly change across most of the subgroups analysed.
Disappointing results have been observed in the Facilitated Intervention with Enhanced Reperfusion Speed to Stop Events (FINESSE) trial, recently presented at the 2007 annual meeting of the European Society of Cardiology.29
The trial was prematurely stopped due to slow recruitment, with the inclusion of up to 2500 STEMI patients. No advantages in terms of clinical outcome were observed at 3-month follow-up with facilitation by either combotherapy (abciximab and half-dose reteplase) or abciximab, compared with late periprocedural abciximab administration, despite higher patency rates, mainly with combotherapy. It must be remarked that the FINESSE trial did include several centres with large variability in experience and skills, whereas our meta-analysis included trials mainly conducted at high-volume and highly experienced primary PCI centres. In addition, the slow recruitment rate observed in the FINESSE trial (approximately a mean of 10 patients a year enrolled per centre over 4 years) may have led to a selection bias. Finally, even though the aim of the trial was to investigate facilitation, more than 50% of patients were enrolled and randomly assigned in primary PCI centres. Longer follow-up data and a more extensive analysis will certainly provide important additional information before final conclusions can be drawn from that trial.
The Ongoing Tirofiban in Myocardial Infarction Evaluation 2 (On-TIME-2) trial,38
investigating the early administration of high-dose tirofiban, will certainly provide additional important data on this relevant issue.
We were unable to obtain individual patient data from three randomised trials,27–29
whereas the ADMIRAL trial was not included, because it did not compare early versus late administration of Gp IIb–IIIa inhibitors.
Even though the meta-analysis was based on individual patient data, this can not overcome the potential heterogeneity among trials caused by different inclusion and exclusion criteria and the fact that angiographic and ECG data were not analysed by a central core laboratory.
Enzymatic infarct size was estimated by peak creatine kinase levels, whereas the use of scintigraphic techniques would have potentially improved the results of the meta-analysis. The beneficial effects observed in terms of preprocedural recanalisation might have translated into benefits in terms of left ventricular remodelling and larger survival benefits at long-term follow-up, such as up to 3–5 years, which unfortunately were unavailable from current randomised trials.
On the basis of their prognostic implications and availability, we analysed major but not minor bleeding complications.
High-dose tirofiban has been demonstrated to provide higher inhibition of platelet aggregation, compared with a standard bolus dose, as used in trials included in the current meta-analysis and abciximab.39 40
Whether the early administration of this therapy may provide benefits is currently tested in the ongoing On-TIME 2 trial.38
Several factors may have hampered the potential benefits of early eptifibatide administration, such as the restricted number of patients and trials included in the current meta-analysis, the relatively short-term follow-up (available in the vast majority of patients only at 30 days) and the shorter duration of drug administration before angioplasty, compared with other Gp IIb–IIIa inhibitors.
Moreover, it has to be pointed out that this meta-analysis was primarily performed to evaluate early versus late use of Gp IIb–IIIa inhibitors with respect to surrogate markers and clinical endpoints. Given the nature of the randomised studies included in this meta analysis, head-to-head comparisons suggesting significant benefit for early abciximab may reflect larger differences between early versus late abciximab and cannot be interpreted as reflecting the superiority of abciximab over other agents.
Finally, as the patients enrolled in the current randomised trials have for the most part been highly selected, caution should be exercised in extending the conclusion of this meta-analysis to the vast majority of STEMI patients undergoing primary angioplasty. As a result of the higher risk profile, however, at least similar benefits might potentially be expected in trial-ineligible compared with trial-eligible patients.41