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© The European Society of Cardiology 2005. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

The use of GP IIb/IIIa inhibitors into new perspectives: pre-catheterization laboratory administration

Farzin Beygui and Gilles Montalescot^*

Department of Cardiology, Pitié-Salpêtrière University Hospital, 47–83 Bd de l'Hôpital, 75013 Paris, France

^* Corresponding author. E-mail address: gilles.montalescot{at}psl.ap-hop-paris.fr

	Abstract

Top Abstract Introduction Primary PCI and GP... Rationale for facilitated... Primary PCI facilitated by... Primary PCI facilitated by... Pre-catheterization laboratory... Conclusions References

 
There is a general consensus that primary percutaneous coronary intervention (PCI) is the most adequate approach to reperfusion therapy in ST-elevation acute myocardial infarction (STEMI), associated with more efficient reperfusion and less mortality, recurrent ischaemia, stroke, and major bleeding complications compared with fibrinolysis. The systematic use of intravenous GP IIb/IIIa inhibitors, especially abciximab as an adjunctive therapy to primary PCI, is associated with a further reduction of mortality and ischaemic events in this setting. Nevertheless, the need for transfer from centres without round-the-clock PCI facility, may delay myocardial reperfusion and reduce the benefit of primary PCI. In order to accelerate the flow restoration in the infarct-related artery, during the gap between presentation and primary PCI, several pharmacological approaches have been proposed. The facilitation of primary PCI by full or half-dose fibrinolytics alone or in association with GP IIb/IIIa inhibitors has raised some unresolved safety and efficacy issues. Recent trials of the early administration of GP IIb/IIIa inhibitors prior to primary PCI have shown improved flow restoration and myocardial perfusion compared with in-catheterization laboratory administration of such treatments. Although such trials have been underpowered to detect differences regarding clinical outcomes among patient groups, the administration of intravenous abciximab is recommended as soon as possible in STEMI patients who are candidates to direct primary PCI. Further, large trials are needed to assess the efficacy, safety, and cost-effectiveness of facilitation strategies and to eventually identify subgroups of patients in whom such strategies would be most beneficial.

Key Words: GP IIb/IIIa inhibitors • Primary PCI • Faciliatated PCI

	Introduction

Top Abstract Introduction Primary PCI and GP... Rationale for facilitated... Primary PCI facilitated by... Primary PCI facilitated by... Pre-catheterization laboratory... Conclusions References

 
Early reperfusion therapy is universally considered as the primary treatment for ST-elevation acute myocardial infarction (STEMI). Both mechanical reperfusion by primary percutaneous coronary interventions (PCIs) and pharmacological reperfusion by fibrinolysis are efficient methods, restoring coronary flow in the infarct-related artery, reducing infarct size, and saving lives.¹ Although fibrinolysis is still used as the first line reperfusion strategy in most countries, there is general consensus that primary PCI, is the most adequate approach to reperfusion therapy, associated with more efficient reperfusion, less short- and long-term death, myocardial infarction (MI), recurrent ischaemia, stroke, and less frequent major bleeding complications.^2,3

On the other hand, there is also general consensus that in patients presenting very early (<2 h) after the onset of the STEMI, fibrinolysis is associated with excellent outcome, especially in centres without round-the-clock PCI facility or more generally in any situation where PCI could be delayed, leaving enough time (1 h) for fibrinolysis to be efficient at least in half of the cases.^4,5 Such strategy is nevertheless associated with potential fibrinolysis-related bleeding complications and the need for urgent unplanned PCI in about one-third of patients, justifying transfer to a tertiary centre with round-the-clock PCI facility.⁶

There are two major drawbacks to the benefit of primary PCI for acute STEMI: first, the successful recanalization of the infarct-related artery does not always result in adequate myocardial perfusion because of potential distal embolization of thrombi during PCI and second, the transfer delay may reduce the benefit of primary PCI.^7–9 Early administration of GP IIb/IIIa inhibitors may be a solution to both previous problems.

	Primary PCI and GP IIb/IIIa inhibitors

Top Abstract Introduction Primary PCI and GP... Rationale for facilitated... Primary PCI facilitated by... Primary PCI facilitated by... Pre-catheterization laboratory... Conclusions References

 
GP IIb/IIIa inhibitors prevent distal embolization and have been shown to reduce ischaemic events, death, and MI in acute coronary syndromes without increasing the risk of intracranial or severe haemorrhage.¹⁰ The benefit of GP IIb/IIIa therapy in the specific setting of primary PCI for STEMI has been widely demonstrated in terms of pre-PCI coronary flow, angiographic parameters, or combined ischaemic endpoints of death/MI/urgent target-vessel revascularization.^11–14 A recent meta-analysis¹⁵ of eight major randomized trials comparing abciximab vs. placebo as adjunctive therapy to primary PCI in STEMI demonstrated a significant reduction of mortality both at 30 days (2.4 vs. 3.4%, P=0.047) and 6–12 months (4.4 vs. 6.2%, P=0.01) by the active therapy. The authors estimated that the number of patients to be treated by abciximab was 100 and 55.6 to prevent one death at 30 days and 6–12 months, respectively, making this strategy cost-effective.

Other GP IIb/IIIa inhibitors, eptifibatide and tirofiban, have been less extensively studied in this setting. Nevertheless, they have been reported to improve outcome in the general setting of PCI for acute coronary syndromes.¹⁶

Although the systematic use of abciximab as adjunctive therapy to primary PCI for STEMI is already recommended,¹⁷ the timing of the administration of GP IIb/IIIa inhibitors still remains a matter of debate.

	Rationale for facilitated primary PCI

Top Abstract Introduction Primary PCI and GP... Rationale for facilitated... Primary PCI facilitated by... Primary PCI facilitated by... Pre-catheterization laboratory... Conclusions References

 
The rationale for the facilitation of primary PCI by a pharmacological approach is based on three major considerations:

1. The progressive and irreversible nature of the ischaemia-related myocardial necrosis.^18,19
   
2. The inverse relationship between time to reperfusion and both the extent of the salvaged myocardium and survival.^20–23
   
3. The relationship between the anterograde coronary flow, prior to primary PCI and both contractility recovery and survival after STEMI.^24–26
   

Hence, the facilitated PCI strategy providing an early restoration of a certain degree of flow prior to primary PCI appears to be a logical and attractive option in STEMI patients.

Several pharmacological approaches to facilitation of primary PCI have been more or less successfully studied.

	Primary PCI facilitated by fibrinolytics

Top Abstract Introduction Primary PCI and GP... Rationale for facilitated... Primary PCI facilitated by... Primary PCI facilitated by... Pre-catheterization laboratory... Conclusions References

 
Early trials with fibrinolytics in STEMI followed by immediate angiography/PCI vs. ischaemia-oriented angiography did not show any significant benefit of the combination of full-dose fibrinolytics and immediate or early PCI.^27–29 More recently, the ASSENT-4 trial studying facilitated primary PCI by full-dose tenecteplase without GP IIb/IIa inhibitors vs. primary PCI alone with provisional use of GP IIb/IIa inhibitors was aborted because of higher rates of ischaemic events and mortality in the tenecteplase arm. Other recent trials studying the effect of low-dose fibrinolysis as a pharmacological facilitation approach prior to PCI, compared with primary PCI alone have provided controversial results regarding clinical outcomes. In these pilot trials, fibrinolysis prior to PCI was associated with higher rates of TIMI grade 2 or 3 coronary flow but the clinical outcomes were either comparable or worse with such strategy compared with primary PCI alone especially in those treated by streptokinase.^30–32

The fibrinolysis-related secondary platelet activation and haemorrhagical risk have been incriminated in explaining such poor results.³³

	Primary PCI facilitated by low-dose fibrinolytics+full-dose GP IIb/IIIa inhibitors combination therapy

Top Abstract Introduction Primary PCI and GP... Rationale for facilitated... Primary PCI facilitated by... Primary PCI facilitated by... Pre-catheterization laboratory... Conclusions References

 
The previous findings have led rationally to other pilot trials studying the combination therapy with low-dose fibrinolysis, to reduce haemorrhagical risk, and full dose of GP IIb/IIIa inhibitors, to control the secondary prothrombotic risk, prior to PCI.

The BRAVE trial³⁴ randomized 253 STEMI patients to receive either half-dose reteplase or placebo combined with full-dose abciximab prior to transfer for primary PCI. The patient group with combination therapy showed higher rates of TIMI grade 3 flow (40 vs. 18%, P<0.001) compared with those pre-treated with abciximab alone. Nevertheless, the study failed to show any difference between the two groups regarding infarct size and mortality. Moreover, combination therapy was associated with a trend towards higher rates of major bleeding complications (5.6 vs. 1.6%) and combined endpoint of death, re-infarction, and stroke (6.4 vs. 4.7%) compared with primary PCI with GP IIb/IIIa inhibitors alone.

The ongoing, large, multi-centre, double-blinded, randomized trial, FINESSE trial,³⁵ comparing early low-dose fibrinolytic+GP IIb/IIIa inhibitor combination therapy vs. early GP IIb/IIIa inhibitor alone, vs. post-angiography use of GP IIb/IIIa inhibitor prior to primary PCI may provide the answer to the safety and efficacy issues of diverse facilitation strategies.

	Pre-catheterization laboratory administration of GP IIb/IIIa inhibitors alone

Top Abstract Introduction Primary PCI and GP... Rationale for facilitated... Primary PCI facilitated by... Primary PCI facilitated by... Pre-catheterization laboratory... Conclusions References

 
Considering the unsuccessful or unresolved issues of fibrinolytic facilitation with or without GP IIb/IIIa inhibitors, the early administration of GP IIb/IIIa alone, in STEMI patients, prior to PCI, remains for the moment the most realistic facilitation strategy.

Early administration of abciximab in the emergency room or the mobile intensive care unit, was tested for the first time in the ADMIRAL trial,¹³ assessing primary PCI with or without abciximab; higher patency rates and better outcomes were found in patients who received abciximab early. In such patients, compared with those receiving abciximab later, abciximab reduced the most the risk of the primary endpoint (death/re-infarction/urgent target-vessel revascularization) both at 30 days [odds ratio (OR)=0.12 vs. 0.67] and 6 months (OR=0.11 vs. 0.69).

Several recent randomized trials have studied the effect of early administration of GP IIb/IIIa inhibitors compared to their administration in the cardiac catheterization laboratory, prior or during primary PCI (Table 1). All these trials are underpowered to detect significant differences in hard clinical outcomes among the studied groups. Surrogate endpoints, such as pre-PCI TIMI flow grade and/or ST-segment elevation regression were used to assess the efficacy of the early administration of GP IIb/IIIa inhibitors. While the results are quite heterogenous between the trials, there is a general trend towards better myocardial perfusion, assessed by ST-segment resolution, and higher rates of infarct-related artery patency prior to PCI in patients with early GP IIb/IIIa therapy.^36–43 A recent meta-analysis from our centre studied the effect of early administration of GP IIb/IIIa inhibitors (tirofiban or abciximab), compared to its administration during primary PCI, in a pooled population of 931 STEMI patients.⁴⁴ The study showed a significant increase in rates of TIMI grade 2/3 flow (OR=1.69, 95% CI=1.28–2.22, P<0.001) and TIMI grade 3 flow (OR=1.85, 95% CI=1.26–2.71, P<0.001), by the early use of GP IIb/IIIa inhibitors. Odds ratios were similar between the two tested drugs. The analysis also showed a non-significant trend in favour of early GP IIb/IIIa therapy regarding mortality (OR=0.72, 95% CI 0.37–1.4), re-infarction (OR=0.73, 95% CI=0.31–1.77), and the composite ischaemic endpoint (OR=0.78, 95% CI=0.51–1.20). Since the publication of the prior meta-analysis, two other randomized trials have been published. The INTAMI pilot trial randomized 102 patients to receive either eptifibatide early or late, prior to primary PCI.⁴³ Although the study showed significantly higher rates of TIMI grade 3 flow in the early eptifibatide group, it failed to show any difference in ST-segment elevation resolution and clinical outcomes between the two groups. The REOPRO-BRIDGING trial randomized 52 patients to receive abciximab either at presentation or after qualifying angiogram.⁴² Despite its small population size, the study showed a significant improvement of myocardial reperfusion (pre-PCI ST-segment elevation resolution 55 vs. 42%, P=0.005), TIMI flow grade (TIMI grade 3 flow 29 vs. 7%, P<0.05), and myocardial blush grade (grade 2/3 46 vs. 11%, P=0.004) by the early use of abciximab. The study also showed non-significant trends towards less in-hospital complications, including major bleeding, cardiogenic shock, ventricular fibrillation and stroke (3.6 vs. 18.5%), and 30 days composite event rate, death, re-infarction, and target-vessel revascularization (0 vs. 3.7%), in patients with early abciximab therapy.

View this table: [in this window] [in a new window]   Table 1 Randomized trials comparing early vs. late administration of GP IIb/IIIa inhibitors as adjunctive therapy to primary PCI for STEMI

 
The heterogeneity of the previous results may have several explanations. First, despite an undoubtful class effect, there might be differences between GP IIb/IIIa inhibitors in STEMI patients as it has been reported in non-STEMI and unstable angina or in PCI settings.^45,46 Moreover, abciximab is still the only GP IIb/IIIa inhibitor that has demonstrated its efficacy regarding hard clinical outcomes after primary PCI for STEMI. Indeed, a recent but yet unpublished pooled analysis of six abciximab studies comparing early with late administration showed impressive results not only on admission patency rates but also on micro-perfusion as evaluated by ST-segment resolution; furthermore, an absolute but non-significant 2% reduction in mortality was found with early abciximab (J. Godicke et al., personal communication).

Secondly, there are differences between studies regarding the inclusion criteria (STEMI <6 or 12 h) and the time from symptom to GP IIb/IIIa inhibitors administration both in patients with early (average time from 38 to 259 min) and late (average time from 82 to 374 min) administration of the drug. The studies with very early administration of GP IIb/IIIa inhibitors (<2 h after the symptom onset) appear to be those were the effect of the drug on the infarct-related pre-PCI flow and/or mortality is the most important.^38–40,42 The longer time to presentation and administration of the drug reduces on one hand the amount of myocardium to be salvaged and consequently may reduce the potential effect of the early administration of GP IIb/IIIa inhibitors. On the other hand, it may also change the architecture of the thrombus which becomes more resistant to the ‘dethrombotic’ effect of the drugs.

	Conclusions

Top Abstract Introduction Primary PCI and GP... Rationale for facilitated... Primary PCI facilitated by... Primary PCI facilitated by... Pre-catheterization laboratory... Conclusions References

 
The vital importance of an early restoration of the flow in the infarct-related artery in patients presenting with STEMI, and the potential gap between presentation and primary PCI widely justify the attempts to pharmacological facilitation of primary PCI.

The use of fibrinolytics with or without GP IIb/IIIa inhibitors have raised serious or unresolved safety and efficacy issues.

There is strong evidence that the GP IIb/IIIa inhibitor abciximab reduces mortality (roughly by 25%) in the setting of primary PCI and its use should be recommended in the absence of precise contraindication. Hence, the timing of its administration may no more be a true matter of debate. The early administration of GP IIb/IIIa inhibitors is associated with a significant degree of flow restoration, a potentially better myocardial reperfusion, and no significant increase in major bleeding complications. Although underpowered, the current available evaluations point to an additive (but still non-significant) 25% reduction of mortality with a pre-catheterization laboratory administration in comparison to an in-catheterization laboratory administration of the same drug. Considering the few downsides of such an early GP IIb/IIIa facilitation strategy, its generalization may already be recommended in patients presenting with a STEMI and who are candidates to direct primary PCI. The benefit of low-dose fibrinolytic+GP IIb/IIIa inhibitor combination therapy, the potential differences between different GP IIb/IIIa inhibitors, the identification of patient subgroups profiting most from different strategies, and the role of other anticoagulants (low-molecular weight heparins, direct thrombin inhibitors) or anti-platelet regimens (high loading doses of clopidogrel), still remain unresolved issues. Specific and adequately sized trials are needed to answer these important questions.

Conflict of interest: none declared.

	References

Top Abstract Introduction Primary PCI and GP... Rationale for facilitated... Primary PCI facilitated by... Primary PCI facilitated by... Pre-catheterization laboratory... Conclusions References

 

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