Glycoprotein IIb/IIIa inhibitors in patients with unstable angina/non-ST–segment elevation myocardial infarction: Appropriate interpretation of the guidelines

doi:10.1016/j.ahj.2003.09.001

American Heart Journal

Volume 146, Issue 4, Supplement, October 2003, Pages S18-S22

https://doi.org/10.1016/j.ahj.2003.09.001 Get rights and content

Abstract

In 2002, the American College of Cardiology and the American Heart Association published an update to their guidelines for the management of patients with unstable angina and non-ST–segment elevation myocardial infarction. These revised guidelines make specific recommendations regarding the use of glycoprotein IIb/IIIa inhibitors. This article briefly reviews the evidence supporting the use of glycoprotein IIb/IIIa inhibitors in unstable angina and non-ST–segment elevation myocardial infarction, before moving on to discuss interpretation of these new guidelines.

Section snippets

ACS clinical trials

Intravenous GP IIb/IIIa inhibitors block the final common pathway of platelet activation and aggregation, and have been the subject of extensive clinical trials. A meta-analysis of >30,000 patients² found that there was an overall risk reduction of 21% for death/MI at 30 days in patients who received GP IIb/IIIa inhibitors and aspirin as support for percutaneous coronary intervention (PCI) or medical management of ACS compared with those who received placebo and aspirin. This study strongly

GP IIb/iIIIa inhibitors and PCI

Two meta-analyses of 6 ACS trials—PARAGON A, PARAGON B, PURSUIT, PRISM-PLUS, Platelet Receptor Inhibition for Ischemic Syndrome Management (PRISM), and Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries Trial IV in Acute Coronary Syndromes (GUSTO IV-ACS)—have recently been published. Boersma et al reviewed data from all 31,402 patients enrolled in the 6 trials.³ However, the meta-analysis by Roffi et al excluded 345 patients from the arm not containing heparin in the

Site for GP IIb/IIIa inhibitor administration

An analysis of the CAPTURE, PURSUIT, and PRISM-PLUS trials showed a 1.4% absolute risk reduction in adverse events in patients receiving GP IIb/IIIa inhibitors upstream of the thrombus.⁶ Around 22% of those patients went on to receive PCI. While these results are encouraging, there are few other data to support the use of upstream GP IIb/IIIa inhibitors. In the Treat Angina with Aggrastat and Determine Cost of Therapy with an Invasive or Conservative Strategy-Thrombolysis in Myocardial

GP IIb/IIIa inhibitors: a double-edged sword

Despite the recent positive findings that GP IIb/IIIa inhibitor therapy in combination with PCI reduces the absolute risk of death or MI, an apparently harmful thrombotic effect has been seen with suboptimal doses of GP IIb/IIIa inhibitors in some trials (eg, GUSTO IV-ACS) (Figure 5).

It is known that atheroma-associated cells such as activated platelets express a variety of receptors, including CD40 ligand (CD40L), an important prothrombotic and proinflammatory protein with GP IIb/IIIa binding

ACC/AHA guidelines

The results from these recent ACS clinical trials have been used to formulate updated ACC/AHA guidelines for the management of patients with ACS.¹ These guidelines and recommendations relate to the usefulness and applicability of certain treatments in particular situations. All recommendations are given ‘Class' and ‘Level of Evidence' classifications, which are defined as follows:

•
Class I recommendations are given in situations where an intervention is useful and effective.
•
Class IIa

Interpreting the updated ACC/AHA 2002 guidelines

The main difference between the new ACC/AHA recommendations and the older ones is that the updated guidelines favor an early invasive strategy in the management of patients with suspected ACS and those without ST-segment elevation after the acute ischemic insult.¹ The early invasive strategy is preferred for patients with high-risk indicators, and has a Class I, Level A recommendation. The high-risk indicators in this case include the following:

•
recurrent ischemia on treatment
•
elevated troponin

Conclusions

Clinical trials are the best source of data on which to base therapeutic decisions. Although it is logical to use published trial results to continually update one's knowledge about the use of GP IIb/IIIa inhibitors in patients with unstable angina/NSTEMI, it is also important to read and understand the ACC/AHA guidelines because they have been created from careful analysis of trial data and expert opinion, and have a very useful weighting system to indicate the importance of each

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Cited by (11)

Randomized comparison of upstream tirofiban versus downstream high bolus dose tirofiban or abciximab on tissue-level perfusion and troponin release in high-risk acute coronary syndromes treated with percutaneous coronary interventions: The EVEREST trial
2006, Journal of the American College of Cardiology
Citation Excerpt :
The contribution of GP IIb/IIIa inhibition in NSTE-ACS is shown in placebo-controlled trials in which upstream GP IIb/IIIa inhibition was initiated upon admission (13). Although these results are encouraging, there are few other data to support the use of upstream GP IIb/IIIa inhibitors (14). In the Treat Angina with Aggrastat and Determine Cost of Therapy with an Invasive or Conservative Strategy-Thrombolysis In Myocardial Infarction 18 (TACTICS-TIMI 18) trial (15), all patients received upstream GP IIb/IIIa inhibitors and were randomized to either early invasive or conservative treatment, so the design did not permit a definitive statement to be made as to whether upstream GP IIb/IIIa inhibition is helpful in patients who progress to an early invasive strategy.
We aimed to compare the effects of upstream tirofiban versus downstream high-dose bolus (HDB) tirofiban and abciximab on tissue level perfusion and troponin I release in high-risk non–ST-segment elevation acute coronary syndrome (ACS) patients treated with percutaneous coronary intervention (PCI).
Optimal timing and dosage of glycoprotein IIb/IIIa inhibitors for ACS remain to be explored.
We randomized 93 high-risk ACS patients undergoing PCI to receive upstream (in the coronary care unit) tirofiban, downstream (just prior to PCI) HDB tirofiban, and downstream abciximab. We evaluated the effects of the three drug regimens on tissue-level perfusion using the corrected Thrombolysis In Myocardial Infarction (TIMI) frame count, the TIMI myocardial perfusion grade (TMPG), and intracoronary myocardial contrast echocardiography (MCE) before and immediately after PCI and after cardiac troponin I (cTnI).
The TMPG 0/1 perfusion was significantly less frequent with upstream tirofiban compared with HDB tirofiban and abciximab both before (28.1% vs. 66.7% vs. 71%, respectively; p = 0.0009) and after PCI (6.2% vs. 20% vs. 35.5%, respectively; p = 0.015). Upstream tirofiban was also associated with a significantly higher MCE score index (0.88 ± 0.18 vs. 0.77 ± 0.32 vs. 0.71 ± 0.30, respectively; p < 0.05). Post-procedural cTnI elevation was significantly less frequent among patients in the upstream tirofiban group compared with the HDB tirofiban and abciximab groups (9.4% vs. 30% vs. 38.7%, respectively; p = 0.018). The cTnI levels after PCI were significantly lower with upstream tirofiban compared with HDB tirofiban (3.8 ± 4.1 vs. 7.2 ± 12; p = 0.015) and abciximab (3.8 ± 4.1 vs. 9 ± 13.8; p = 0.0002)
Among high-risk non–ST-segment-elevation ACS patients treated with an early invasive strategy, upstream tirofiban is associated with improved tissue-level perfusion and attenuated myocardial damage.
Effects of tirofiban plus clopidogrel versus clopidogrel plus provisional abciximab on biomarkers of myocardial necrosis in patients with non-ST-elevation acute coronary syndromes treated with early aggressive approach. Results of the CLOpidogrel, upstream TIrofiban, in cath Lab Downstream Abciximab (CLOTILDA) study
2005, American Heart Journal
Citation Excerpt :
The small patient population prevents the analysis of possible differences in outcome. However, a strong correlation has been found by several studies between adverse clinical events and peak values of myocardial necrosis markers.28-33 Moreover, in the PRISM-PLUS trial substudy, the reduction in the peak value of cTn I brought about by the combination of tirofiban and heparin compared with heparin alone was associated with a reduction of cardiovascular events.7
In non–ST-elevation acute coronary syndromes (NSTE-ACS), a strong correlation between adverse clinical events and peak values of myocardial necrosis markers has been found. In this study, we evaluated whether the adjunctive treatment with upstream tirofiban reduces the peak levels of cardiac troponin I and creatine kinase–MB (CK-MB) fraction in patients with NSTE-ACS undergoing early invasive strategy and pretreated with aspirin, heparin, and clopidogrel.
A total of 300 patients were randomized to receive tirofiban (group 1) or not (group 2). Serial marker samples were collected before and after coronary angiography in all cases and after percutaneous coronary intervention (PCI) when performed.
Between the 2 groups, no differences were observed in clinical and angiographic findings. Percutaneous coronary intervention was globally performed in 198 patients (66%) . Of 99 group 2 patients, 26 (26%) received abciximab just before PCI. No significant differences between the 2 groups were observed with regard to cardiac troponin I and CK-MB values at admission and at 6, 12, and 24 hours thereafter; peak values before coronary angiography; and peak values of index event. In addition, the cumulative biomarkers release of the index event was similar between the 2 groups. Major bleeding rate was 2% in group 1 and 1% in group 2 (P = not significant). Composite incidence of death, myocardial infarction, or rehospitalization for ACS at 30 days was 9% in group 1 and 10% in group 2.
In patients with NSTE-ACS undergoing early invasive strategy, the adjunctive administration of upstream tirofiban did not reduce the peak values and the cumulative release of myocardial necrosis markers, compared with aspirin, heparin, and clopidogrel given on admission and associated with selective use of abciximab just before PCI.
Practical implementation of the guidelines for unstable angina/non-ST-segment elevation myocardial infarction in the emergency department
2005, Annals of Emergency Medicine
Citation Excerpt :
Eptifibatide and tirofiban (small molecule agents) and abciximab (a monoclonal antibody fragment) are approved for use in patients with ACS and are recommended for patients undergoing early invasive therapy based on the CAPTURE, PURSUIT, PRISM-PLUS, and TACTICS-TIMI 18 trials (c7E3 Antiplatelet Therapy in Unstable Refractory Angina, Platelet glycoprotein IIb/IIIa in Unstable angina; Receptor Suppression Using Integrilin™ Therapy, Platelet Receptor Inhibition for ischemic Syndrome Management in Patients Limited to very Unstable Signs and symptoms, and Treat angina with Aggrastat® and determine Costs of Therapy with Invasive or Conservative Strategies-Thrombolysis In Myocardial Infarction-18, respectively) trials (Class IA). The 2 small-molecule agents eptifibatide and tirofiban provide reversible inhibition of the GP IIb/IIIa receptor and are indicated for patients receiving conservative therapy or early invasive therapy for ACS (Class IIaA).1,33-37 Abciximab is not indicated for patients receiving only medical management without cardiac catheterization; this is a Class IIIA recommendation based on the GUSTO-IV (Global Utilization of Streptokinase and tPA for Occluded arteries) ACS trial.
In the United States each year, >5.3 million patients present to emergency departments with chest discomfort and related symptoms. Ultimately, >1.4 million individuals are hospitalized for unstable angina and non–ST-segment elevation myocardial infarction. For emergency physicians and cardiologists alike, these patients represent an enormous challenge to accurately diagnose and appropriately treat. This update of the 2002 American College of Cardiology/American Heart Association Guidelines for the Management of Patients with Unstable Angina and Non–ST-Segment Elevation Myocardial Infarction (UA/NSTEMI) provides an evidence-based approach to the diagnosis and treatment of these patients in the emergency department, in-hospital, and after hospital discharge. Despite publication of the guidelines several years ago, many patients with UA/NSTEMI still do not receive guidelines-indicated therapy.
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Antiplatelet Intervention in Acute Coronary Syndrome
2009, American Journal of Therapeutics
Antiplatelet therapy in patients with unstable angina and non-ST-segment-elevation myocardial infarction: Findings from the CRUSADE National Quality Improvement Initiative
2007, Pharmacotherapy

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