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Glycoprotein IIb-IIIa inhibitors during PCI: current indications

An article from the e-journal of the ESC Council for Cardiology Practice

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.

Acute Coronary Syndromes (ACS)


 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.

References


1) ACC/AHA Guidelines for Percutaneous Coronary Intervention (Revision of the 1993 PTCA Guidelines)—Executive Summary, A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1993 Guidelines for Percutaneous Transluminal Coronary Angioplasty) Endorsed by the Society for Cardiac Angiography and Interventions Circulation 2001;103:3019-3041
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11413094

2) Topol EJ, Mark DB, Lincoff AM, et al. Outcomes at 1 year and economic implications of platelet glycoprotein IIb/IIIa blockade in patients undergoing coronary stenting: results from a multicentre randomised trial. EPISTENT Investigators. Evaluation of Platelet IIb/IIIa Inhibitor for Stenting. Lancet 1999;354:2019-24.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10636365

3) Marso SP, Lincoff AM, Ellis SG, et al. Optimizing the percutaneous interventional outcomes for patients with diabetes mellitus: results of the EPISTENT (Evaluation of platelet IIb/IIIa inhibitor for stenting trial) diabetic substudy. Circulation 1999;100:2477-84.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10604884

4) Roffi M, Mukherjee D, Chew DP, et al. Lack of benefit from intravenous platelet glycoprotein IIb/IIIa receptor inhibition as adjunctive treatment for percutaneous interventions of aortocoronary bypass grafts: a pooled analysis of five randomized clinical trials. Circulation 2002;106:3063-7.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12473552

5) Kastrati A, Mehilli J, Schuhlen H, et al.; Intracoronary Stenting and Antithrombotic Regimen-Rapid Early Action for Coronary Treatment Study Investigators A clinical trial of abciximab in elective percutaneous coronary intervention after pretreatment with clopidogrel. N Engl J Med 2004;350:232-8.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14755810

6) Lincoff AM, Bittl JA, Harrington RA, et al.; REPLACE-2 Investigators. Bivalirudin and provisional glycoprotein IIb/IIIa blockade compared with heparin and planned glycoprotein IIb/IIIa blockade during percutaneous coronary intervention: REPLACE-2 randomized trial. JAMA 2003;289:853-63.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14556866

7) Montalescot G, Barragan P, Wittenberg O, et al.; Platelet glycoprotein IIb/IIIa inhibition with coronary stenting for acute myocardial infarction. Abciximab before Direct Angioplasty and Stenting in Myocardial Infarction Regarding Acute and Long-Term Follow-up.ADMIRAL Investigators. N Engl J Med 2001;344:1895-903.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11419426

8) Antoniucci D, Migliorini A, Parodi G, et al. Abciximab-supported infarct artery stent implantation for acute myocardial infarction and long-term survival: a prospective, multicenter, randomized trial comparing infarct artery stenting plus abciximab with stenting alone. Circulation 2004;109:1704-6
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15066943

9) Kastrati A, Mehilli J, Schlotterbeck K, et al. on behalf of the Leipzig Prehospital Fibrinolysis study Early administration of reteplase plus abciximab vs. abciximab alone in patients with acute myocardial infarction referred for percutaneous coronary intervention: a randomized controlled trial. JAMA 2004;291:947-54
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14982910
10) Dudek D, Zmudka K, Kaluzag L, et al. Facilitated percutaneous coronary intervention in patients with acute myocardial infarction transferred from remote hospitals. Am J Cardiol 2003; 91: 227-9
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12521638

VolumeNumber:

Vol3 N°28

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.