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

Non-ST-elevation acute coronary syndromes management: a fresh look at glycoprotein IIb/IIIa inhibitors

Claudio Cavallini* and Fabio Chirillo

Division of Cardiology, Ca' Foncello Hospital, Treviso, Italy

* Corresponding author. Tel: +39 0422 322767; fax: +39 0422 322662. E-mail address: clcaval{at}tin.it


   Abstract
Top
 Abstract
Introduction
 GP IIb/IIIa inhibitors in...
 International guidelines
 Conclusions
 References
 
Several randomized clinical trials have shown glycoprotein (GP) IIb/IIIa inhibition to be beneficial in non-ST-segment elevation acute coronary syndromes (NSTE-ACSs), producing a significant reduction in the risk of death and myocardial infarction. The greatest benefit was found in high-risk patients, such as those with diabetes, those with a positive troponin value at baseline or those undergoing early percutaneous coronary intervention. Data from large national registries have shown that early use of GP IIb/IIIa inhibitors is associated with a benefit consistent with that reported in clinical trials, the lowest adjusted rate of in-hospital mortality was found for hospitals with the highest rate of early use of these drugs. Upstream treatment with small-molecule GP IIb/IIIa inhibitors, in combination with an early aggressive interventional approach, is clearly beneficial and is strongly recommended by international guidelines in high-risk patients with NSTE-ACS. However, GP IIb/IIIa inhibitors appear to be markedly underused in current practice. Potential reasons for this inconsistency are discussed.

Key Words: Unstable angina • Coronary thrombosis • Platelets • GP IIb/IIIa inhibitors • Coronary angioplasty • Guidelines


   Introduction
Top
 Abstract
 Introduction
GP IIb/IIIa inhibitors in...
 International guidelines
 Conclusions
 References
 
In 1983, following on from basic research on the congenital platelet defect involved in Glanzmann thromboasthenia, Coller developed a chimeric monoclonal antibody able to inhibit platelet aggregation by blocking fibrinogen binding to glycoprotein (GP) IIb/IIIa receptors. Shortly afterwards, peptide and non-peptide molecules mimicking the RGD or KGD amino acid sequence responsible for fibrinogen binding to the GP IIb/IIIa receptors were synthesized. Over the past decade, several large-scale trials have been performed by comparing GP IIb/IIIa antagonists with placebo for the prevention of the ischaemic complications of percutaneous coronary intervention (PCI) and for the treatment of patients with acute coronary syndromes (ACSs). In this article, we will focus on the main results of studies with GP IIb/IIIa inhibitors in non-ST-segment elevation ACS (NSTE-ACS) and on the controversial points concerning the use of these drugs.


   GP IIb/IIIa inhibitors in NSTE-ACS: the facts
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 Abstract
 Introduction
 GP IIb/IIIa inhibitors in...
International guidelines
 Conclusions
 References
 
Efficacy
GP IIb/IIIa inhibitors have been shown to be beneficial in NSTE-ACS in patients treated conservatively,1 in patients undergoing early interventional management,2 and in those who have undergone both strategies.3,4 An analysis of pooled data from the PRISM-PLUS, PURSUIT, and CAPTURE trials (for explanation of trial acronyms, see Table 1), involving 12 296 patients, showed a 34% relative reduction in the rate of death or myocardial infarction (MI) during 24–48 h of medical management only (3.8 vs. 2.5%) among patients who received a GP IIb/IIIa inhibitor. In addition, in patients subsequently undergoing PCI, a further 41% reduction in procedure-related events was observed (8.0 vs. 4.9%).5


View this table:
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  		Table 1 Acronyms of clinical trials
 
In 2002, Boersma et al.6 carried out a meta-analysis on GP IIb/IIIa antagonists, analysing six large randomized placebo-controlled trials (GUSTO IV-ACS, PARAGON A and B, PRISM, PRISM-PLUS, and PURSUIT), involving 31 402 patients with NSTE-ACS not routinely scheduled for coronary revascularization. A modest reduction in the odds ratios (ORs) for death or MI in the active treatment arm (11.8 vs. 10.8%; OR, 0.91; P=0.015) was observed. However, the benefit was greater in specific subsets of patients such as those undergoing revascularization or presenting with high-risk features. Among the 11 965 (38%) patients undergoing PCI or coronary artery bypass grafting within 30 days, the OR for death or MI in the cohort assigned to GP IIb/IIIa antagonists was 0.89 (95% CI, 0.80–0.98). In patients with a positive troponin value at baseline, there was a 15% reduction in 30-day death or MI with GP IIb/IIIa antagonists when compared with placebo (10.3 vs. 12.0%). In contrast, no reduction in risk was seen in patients with negative troponin values. When the results of CAPTURE, PRISM, and PARAGON B trials were analysed, the treatment benefit in troponin-positive patients was even more striking (OR, 0.34).7 However, the GUSTO IV-ACS trial found no benefit with abciximab treatment in patients managed conservatively.8 Although there is no clear explanation for this finding, one hypothesis is that the dose of the infusion of abciximab used in this trial was suboptimal.9 In contrast, the small-molecule GP IIb/IIIa inhibitors have documented high steady levels of platelet inhibition during 48–72 h infusions.10 Accordingly, the 2002 American College of Cardiology/American Heart Association (ACC/AHA) Guidelines recommend only tirofiban and eptifibatide for upstream use in NSTE-ACS.11

NSTE-ACS patients with diabetes seem to receive the greatest benefit from treatment with GP IIb/IIIa inhibitors: in a meta-analysis by Roffi et al.,12 involving 7658 diabetic patients enrolled in GUSTO IV-ACS, PARAGON A and B, PRISM, PRISM-PLUS, and PURSUIT trials, GP IIb/IIIa inhibitors were associated with a significant reduction in mortality at 30 days (4.6 vs. 6.2%, P=0.007).

Further validation of the benefit of GP IIb/IIIa inhibition in the overall management of NSTE-ACS comes from the TACTICS TIMI-18 trial, which showed the benefit of an early invasive approach combined with the upstream use of tirofiban. The occurrence of death, MI, and recurrent ACS requiring re-hospitalization at 6 months was significantly reduced from 19.4% in the conservatively treated group to 15.9% in the early invasive group (OR, 0.78; P<0.025).13 The rate of death or MI was also significantly reduced, both at 30 days and at 6 months (P<0.0498). Before the introduction of GP IIb/IIIa inhibitors, the occurrence of MI in the first 2 weeks in patients with NSTE-ACS treated invasively was generally greater than that in patients assigned to conservative treatment in trials comparing the two strategies. The TACTICS TIMI-18 trial demonstrated the protective role of GP IIb/IIIa inhibitors in patients assigned to aggressive management, which also provided a significant reduction in the rate of early adverse events.

Safety
Clinical trials have clearly shown that the occurrence of major bleeding and thrombocytopaenia is low among patients treated with GP IIb/IIIa inhibitors. The absolute per cent increase in major bleeding during the study drug infusion was 0.8% in the PURSUIT trial and 0.6% in the PRISM-PLUS trial, whereas the absolute per cent increase in severe (i.e. <90 000 platelets/mm3) thrombocytopaenia was 0 and 0.8%, respectively.4,5


   International guidelines
Top
 Abstract
 Introduction
 GP IIb/IIIa inhibitors in...
 International guidelines
Conclusions
 References
 
On the basis of the results of controlled trials, both the ACC/AHA and the European Society of Cardiology (ESC) Guidelines recommend the use of GP IIb/IIIa inhibitors in all patients with NSTE-ACS, in whom PCI is planned.11,14 The ESC Guidelines also confer a class-A recommendation to the use of GP IIb/IIIa inhibitors in those patients with elevated troponin; the ACC/AHA recommendation is not so robust (class-IIa).

Although consistent data have been provided by large-scale clinical trials, and firm recommendations have been proposed by American and European Cardiology Societies, GP IIb/IIIa inhibition appears to be underused in current practice, representing a missed opportunity for improving outcome in this high-risk population. Potential reasons for this underutilization could include a number of controversial issues (‘hot questions’) that still surround the use of this class of drugs in NSTE-ACS.

Hot questions
Can the results of clinical trials be transferred to the real world?
The National Registry of Myocardial Infarction-4 (NRMI-4), which collected data on the management of patients with MI in the USA between July 2000 and July 2001, offered a distinct opportunity to analyse the influence of GP IIb/IIIa inhibitors on the clinical outcome of patients with ACS. Among the more than 60 000 patients with NSTE MI enrolled in the registry, 25.3% received GP IIb/IIIa inhibitors within 24 h of hospital admission—the unadjusted in-hospital mortality rate was significantly lower in patients who received early treatment with GP IIb/IIIa inhibitors (3.3%) than in those who did not (9.6%) (P<0.0001).15 After adjustment for clinical and hospital variables, the in-hospital mortality rate in patients who received early use of GP IIb/IIIa inhibitors remained significantly lower than that in patients who did not (OR, 0.88; 95% CI, 0.79–0.97), demonstrating a benefit consistent with that reported in clinical trials. Furthermore, the lowest adjusted rate of in-hospital mortality was found for hospitals with the highest rate of early use of GP IIb/IIIa inhibitors.

Is post-PCI creatine kinase-myocardial bound rise a valid endpoint?
A relevant part of the clinical benefit of GP IIb/IIIa inhibitors is represented by the prevention of peri-PCI myonecrosis, usually evidenced by a moderate increase in the plasma levels of biochemical markers of myocardial damage [serum creatine kinase (CK) or its subfraction CK-myocardial bound (CK-MB)], in the absence of new Q-waves on the echocardiograph. Whether elevation of these markers should be considered a clinically relevant endpoint has been one of the most troublesome questions in clinical practice for a long time. The latest contribution to this endless story comes from the ‘CK-MB and PCI study’, the first prospective trial specifically designed to assess the prognostic value of biochemical marker elevation after PCI.16 Almost 4000 consecutive patients treated with PCI in 16 Italian hospitals between February and October 2000 were enrolled and followed-up for 2 years. At the end of follow-up, all-cause mortality was significantly higher in patients with CK-MB elevation than that in those without (7.2 vs. 3.8%; P<0.001). After adjustment for variables known to influence prognosis in this population, post-PCI CK-MB peak value proved to be an independent predictor of mortality (OR per unit, 1.04; P=0.009), with a linear relationship between the CK-MB levels and the probability of death. The conclusion of this study was that procedural elevations in CK-MB influenced long-term mortality in this patient group.

A recent overview from Akkerhuis et al.,17 comparing the prognostic impact of spontaneous and peri-procedural microinfarcts in a large cohort of patients enrolled in five clinical trials (CAPTURE, EPIC, EPILOG, IMPACT II, and PURSUIT), found that the OR for 6-month mortality was similar at any level of increase in CK-MB peak values, for both spontaneous and PCI-related enzyme elevations. This seems to suggest that, regardless of the underlying pathophysiological circumstances, post-procedural and spontaneous CK-MB elevations tend to have similar prognostic significance.

Are GP IIb/IIIa inhibitors really necessary when clopidogrel is available?
Clopidogrel has become an important part of the anti-thrombotic strategy in NSTE-ACS because of its rapid platelet inhibition and its efficacy in the early prevention of clinical events in unstable patients.18 Clopidogrel is currently recommended, in combination with aspirin and heparin, as first-line therapy in patients with NSTE-ACS by both the ACC/AHA and ESC Guidelines.11,14 The superiority of GP IIb/IIIa antagonists over clopidogrel has not been clearly demonstrated; therefore, it has been asked whether the anti-platelet protection offered by clopidogrel could make the use of GP IIb/IIIa inhibitors unnecessary.

This issue has been recently addressed by the PEACE study, in which the degree of platelet activation was assessed using multiple agonists in patients with NSTE-ACS treated with aspirin and enoxaparin at baseline, after a clopidogrel loading dose and during infusion of eptifibatide following clopidogrel loading.19 Results indicate that eptifibatide provides greater significant potent anti-platelet activity when compared with aspirin and clopidogrel, suggesting an additive and immediate protection in the treatment of these patients. Two PCI/GP IIb/IIIa inhibitor trials, ESPRIT20 and ADVANCE,21 in which eptifibatide and tirofiban were tested against placebo in patients pre-treated with aspirin and clopidogrel, have produced similar findings: GP IIb/IIIa inhibitor therapy significantly reduced the ischaemic complications of PCI (relative risk reductions of 35 and 49%, respectively), supporting the concept that GP IIb/IIIa inhibition can provide a significant additive anti- thrombotic protection in high-risk patients treated with clopidogrel.

When to start GP IIb/IIIa therapy (upstream or downstream)?
In the light of clinical trials indicating an early invasive strategy as the best treatment for patients with NSTE-ACS, controversy has arisen regarding whether GP IIb/IIIa inhibitors should be started upstream for all patients or reserved only for patients selected for PCI. In the absence of randomized studies comparing the two options, no data on the preferred strategy are available. Multiple trials have shown that the benefit of upstream GP IIb/IIIa inhibitor therapy in NSTE-ACS occurs early, during the period of medical management preceding revascularization procedures, and any delay in treatment with GP IIb/IIIa inhibitors may translate into a reduction in the clinical efficacy of these drugs. In patients who are candidates for PCI, early treatment may lead to a reduction in the thrombus load at the culprit plaque,22,23 with a subsequent lowered risk of procedural ischaemic complications and microembolization. Recent data from Bolognese et al.24 have shown that upstream treatment with tirofiban in high-risk patients with NSTE-ACS undergoing PCI is associated with a better tissue-level perfusion [assessed using TIMI (thrombolysis in MI) myocardial perfusion grade and myocardial contrast echocardiography] than downstream treatment using the same drug. Finally, in high-risk patients, upstream tirofiban has been shown to be as effective in patients undergoing cardiac surgery as in those treated conservatively.3

In conclusion, upstream treatment with small- molecule GP IIb/IIIa inhibitors, in combination with an early and aggressive interventional approach, is clearly beneficial and should be considered the standard of care in all high-risk patients with NSTE-ACS.


   Conclusions
Top
 Abstract
 Introduction
 GP IIb/IIIa inhibitors in...
 International guidelines
 Conclusions
References
 
The treatment of ACS has evolved dramatically over the past decade. The contribution of GP IIb/IIIa antagonists in improving the prognosis of patients with NSTE-ACS and high-risk features is demonstrated by the results of large randomized trials in which upstream GP IIb/IIIa inhibition, initiated upon admission, led to a significant reduction in the risk of death and MI. The results of these trials have been confirmed by the findings from large national registries. These conclusions should prompt a stricter adherence to international guidelines favouring a wider utilization of early GP IIb/IIIa inhibition in combination with an early invasive approach in high-risk patients.

Conflict of interest: none declared.


   References
Top
 Abstract
 Introduction
 GP IIb/IIIa inhibitors in...
 International guidelines
 Conclusions
 References
 

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