Glycoprotein IIb-IIIa inhibitors during PCI: current indications

 Based on the results of large randomised trials with PTCA and stent implantation of the late ‘90s, the use of IIb/IIIa inhibitors have become an accepted standard enforced by the AHA/ACC guidelines for percutaneous intervention 2001 (1). The late follow-up of a meta-analysis of trials using abciximab has suggested that not only a reduction in periprocedural myocardial infarctions but also a reduction in 1-year mortality can be achieved (2). Furthermore, subgroup analysis indicated that there was consistent benefit irrespective of age, gender, clinical and lesion characteristics, especially in diabetic patients(3) but excluding interventions on vein grafts(4).

Only recently, the advantage of IIb/IIIa inhibitors has been challenged by 2 large randomised trials which have mainly included stable patients.
The first study, ISAR-REACT(5) has randomised over 2000 patients with stable angina who received a 600mg dose of clopidogrel at least 2 hours before PCI. There was no difference in the combined end-point of death, myocardial infarction and urgent TVR (Target Vessel Revascularisation) at 30 days, which occurred in 4% of the abciximab and placebo groups, with a statistically significant disadvantage of the abciximab group in terms of thrombocytopenia and need of blood transfusions (1.9% vs. 0.7%).
The second trial, REPLACE-2(6), showed that bivalirudin with provisional IIb/IIIa inhibitors and heparin plus elective IIb/IIIa inhibitors were equivalent with regard to suppression of acute ischaemic end points. Bivalirudine, however, was preferrable because it was associated with less bleeding. The lack of advantage of IIb/IIIa inhibitors was also present in diabetic patients, both in these trials and in the recently reported (Kastrati et al.) ISAR-SWEET trial. These trials, however, excluded enrolment of patients with highly unstable syndromes.
The ongoing ISAR-REACT II trial will specifically address the need of IIb/IIIa inhibitors in patients with unstable angina and non-ST elevation MI (STEMI) pretreated with high dose clopidogrel.
The ACUITY trial (trial design reported by Stone et al. Am Heart J,2004;148(5):764-75) will randomise 13,800 patients with ACS undergoing an invasive strategy.

Other patients potentially benefiting from the use of IIb/IIIa inhibitors are those with STEMI. IIb/IIIa inhibitors plus stenting of the infarct related artery have already shown evidence of reduced events, especially in trials enrolling patients at high risk (7,8).
The attention is now shifting from periprocedural administration in the Cath-Lab to earlier treatment with abciximab at the time of initial diagnosis, making a better use of the time delay due to transportation and Cath-Lab activation. (9, and Flather et al, presented at the ESC congress 2004).
In patients with an expected long delay before the procedure, multi-centre trials are exploring the use of a combined treatment with abciximab and reduced dose lytics (trial designs reported by Ellis SG et al. Am Heart J, 2004;147(4):E16 and Di Mario C et al. Am Heart J, 2004;148:378-85). This approach has the potential of achieving TIMI2 and 3 flow in >80% of patients before angioplasty(10).
A study of infarct size measured with cardiac magnetic resonance in patients with very recent onsets of symptoms (64% within 2 hours) has shown that the combination of IIb/IIIa inhibitors and reteplase before angioplasty achieves the lowest infarct size (5.3%) ever reported in controlled STEMI trials (Thiele et al. presented at the AHA congress 2004).

Nevertheless, in the first completed randomised trial (10), the administration of half-dose lytics in combination with abciximab before direct PCI did not reduce infarct size as compared with abciximab alone. Given the high risk of intracranial bleeding, particularly in elderly patients, and the current lack of evidence for its efficacy, facilitation of direct PCI by half-dose lytics plus GP IIb/IIIa receptor blockade cannot be recommended yet.

IIb/IIIa inhibitors, especially abciximab, may become a standard in angioplasty for STEMI if the ongoing randomised trials confirm the efficacy and safety of its early use.

New evidence is modifying the role of Glycoprotein IIb/IIIa inhibitors during PCI as defined by the current guidelines.
In high-risk patients with unstable syndromes because of recurrent angina, changes in ECG, or rises in troponin levels, IIb/IIIa inhibitors remain indicated. When delays are expected for angiography and angioplasty, prefer small molecules such as integrilin and tirofiban. Immediately before angioplasty and when treatment involves complex lesions or diffuse disease, prefer the recombinant antibody abciximab.
Pre-treatment with high-doses of the ADP inhibitor clopidogrel and replacement of heparin with the direct thrombin inhibitor bivalirudin enable a more selective use of IIb/IIIa inhibitors in stable syndromes, including in patients with diabetes mellitus.

Based on the results of large randomised trials with PTCA and stent implantation of the late ‘90s, the use of IIb/IIIa inhibitors have become an accepted standard enforced by the AHA/ACC guidelines for percutaneous intervention 2001 (1). The late follow-up of a meta-analysis of trials using abciximab has suggested that not only a reduction in periprocedural myocardial infarctions but also a reduction in 1-year mortality can be achieved (2). Furthermore, subgroup analysis indicated that there was consistent benefit irrespective of age, gender, clinical and lesion characteristics, especially in diabetic patients(3) but excluding interventions on vein grafts(4).

Only recently, the advantage of IIb/IIIa inhibitors has been challenged by 2 large randomised trials which have mainly included stable patients.
The first study, ISAR-REACT(5) has randomised over 2000 patients with stable angina who received a 600mg dose of clopidogrel at least 2 hours before PCI. There was no difference in the combined end-point of death, myocardial infarction and urgent TVR (Target Vessel Revascularisation) at 30 days, which occurred in 4% of the abciximab and placebo groups, with a statistically significant disadvantage of the abciximab group in terms of thrombocytopenia and need of blood transfusions (1.9% vs. 0.7%).
The second trial, REPLACE-2(6), showed that bivalirudin with provisional IIb/IIIa inhibitors and heparin plus elective IIb/IIIa inhibitors were equivalent with regard to suppression of acute ischaemic end points. Bivalirudine, however, was preferrable because it was associated with less bleeding. The lack of advantage of IIb/IIIa inhibitors was also present in diabetic patients, both in these trials and in the recently reported (Kastrati et al.) ISAR-SWEET trial. These trials, however, excluded enrolment of patients with highly unstable syndromes.
The ongoing ISAR-REACT II trial will specifically address the need of IIb/IIIa inhibitors in patients with unstable angina and non-ST elevation MI (STEMI) pretreated with high dose clopidogrel.
The ACUITY trial (trial design reported by Stone et al. Am Heart J,2004;148(5):764-75) will randomise 13,800 patients with ACS undergoing an invasive strategy.

Other patients potentially benefiting from the use of IIb/IIIa inhibitors are those with STEMI. IIb/IIIa inhibitors plus stenting of the infarct related artery have already shown evidence of reduced events, especially in trials enrolling patients at high risk (7,8).
The attention is now shifting from periprocedural administration in the Cath-Lab to earlier treatment with abciximab at the time of initial diagnosis, making a better use of the time delay due to transportation and Cath-Lab activation. (9, and Flather et al, presented at the ESC congress 2004).
In patients with an expected long delay before the procedure, multi-centre trials are exploring the use of a combined treatment with abciximab and reduced dose lytics (trial designs reported by Ellis SG et al. Am Heart J, 2004;147(4):E16 and Di Mario C et al. Am Heart J, 2004;148:378-85). This approach has the potential of achieving TIMI2 and 3 flow in >80% of patients before angioplasty(10).
A study of infarct size measured with cardiac magnetic resonance in patients with very recent onsets of symptoms (64% within 2 hours) has shown that the combination of IIb/IIIa inhibitors and reteplase before angioplasty achieves the lowest infarct size (5.3%) ever reported in controlled STEMI trials (Thiele et al. presented at the AHA congress 2004).

Nevertheless, in the first completed randomised trial (10), the administration of half-dose lytics in combination with abciximab before direct PCI did not reduce infarct size as compared with abciximab alone. Given the high risk of intracranial bleeding, particularly in elderly patients, and the current lack of evidence for its efficacy, facilitation of direct PCI by half-dose lytics plus GP IIb/IIIa receptor blockade cannot be recommended yet.

The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.