Low-Molecular-Weight Heparins and Glycoprotein IIb/IIIa Antagonists in Acute Coronary Syndromes (Part I)

ABSTRACT: Traditional antithrombotic regimens for the management of acute coronary syndromes are far from optimal. There is considerable opportunity for improvement of standard treatment with unfractionated heparin and aspirin. The introduction of new antithrombotic drugs, such as low-molecular-weight heparins (LMWH), and more potent antiplatelet drugs, such as glycoprotein (GP) IIb/IIIa antagonists, has the potential to significantly improve clinical outcomes. The complementary anticoagulant/antiplatelet modes of action of LMWHs and GP IIb/IIIa antagonists mean that combining these drugs in the medical management of patients with acute coronary syndromes, including those who undergo percutaneous coronary intervention, may offer enhanced clinical benefits. Until recently, there was a lack of clinical data to support this approach, but several recent trials have confirmed the safety and efficacy of combination therapy with the LMWH enoxaparin and a GP IIb/IIIa antagonist in the management of patients with unstable angina/non-ST segment elevation myocardial infarction. The 2002 American College of Cardiology/American Heart Association guidelines on unstable angina/non-ST-segment elevation myocardial infarction reflect this new evidence. The combined use of a LMWH and a GP IIb/IIIa antagonist should now be viewed as safe and effective in the management of acute coronary syndromes. Definitive efficacy-powered superiority data will be available shortly.

Key words: acute coronary syndromes, combination therapy, glycoprotein IIb/IIIa antagonist, low-molecular-weight heparin

Current antithrombotic therapy for the medical and invasive management of patients with acute coronary syndromes (ACS) is far from optimal; patients remain at significant risk of death or recurrent ischemic events despite receiving standard treatment with unfractionated heparin (UFH) plus aspirin. However, antithrombotic drugs such as low-molecular-weight heparins (LMWHs) and platelet glycoprotein (GP) IIb/IIIa antagonists offer the potential to significantly improve clinical outcomes. There is now robust clinical evidence supporting the use of enoxaparin in preference to UFH for the medical management of patients with unstable angina/non-ST segment elevation myocardial infarction (UA/NSTEMI).^1–4 Enoxaparin is the preferred agent over UFH in patients with UA/NSTEMI in the current American College of Cardiology (ACC)/American Heart Association (AHA) guidelines [unless coronary artery bypass grafting (CABG) is planned within 24 hours; Class IIa recommendation].⁵ There is also preliminary evidence favoring enoxaparin in patients undergoing or proceeding to percutaneous coronary intervention (PCI).⁶ Other studies have demonstrated the clinical benefits of GP IIb/IIIa antagonists during PCI in patients with ACS.^7–15 Most investigators would agree that the current “standard” regimen of UFH and aspirin can be significantly improved upon. As better forms of therapy are considered, particularly antithrombotic drugs, it seems logical to investigate whether complementary mechanisms of action can produce a synergistic effect, leading to incremental improvements in efficacy and safety. A lot of attention has focused on the combination of antithrombotic therapy with antiplatelet therapy in inhibiting ongoing thrombus formation. Until recently, there have been relatively few data regarding the use of GP IIb/IIIa antagonists in conjunction with LMWHs in patients with ACS. In the last few years, more recent data indicate that this combination is safe and provides favorable clinical outcomes in both medically and invasively managed patients with ACS, and this review presents the clinical evidence for combining LMWHs and GP IIb/IIIa antagonists in these patients. LMWHs and GP IIb/IIIa antagonists: New therapeutic tools in ACS. UA, NSTEMI and ST-segment elevation myocardial infarction (STEMI) — collectively referred to as ACS — have a similar underlying pathology. Rupture or erosion of an atherosclerotic plaque triggers platelet activation and aggregation, thrombus formation and, ultimately, vascular occlusion.¹⁶ Tissue injury, thrombin production and platelet activation are central mechanisms in ACS, making the combination of anticoagulant and antiplatelet therapies a rational approach to treatment. UFH has several clinical and practical limitations as an anticoagulant, including an unpredictable dose response, possible antagonism by platelet factor 4, the potential for rebound thrombotic events after cessation of therapy, the risk of bleeding complications and the uncommon, but serious, side effects of heparin-induced thrombocytopenia.^17,18 UFH also requires the presence of the co-factor antithrombin III to exert its effect, and is effective against clot-bound thrombin but not circulating thrombin. Compared with UFH, LMWHs work more specifically upstream in the coagulation cascade, with a higher ratio of anti-factor Xa:factor IIa (thrombin) activity (Figure 1).^19,20 In addition, LMWHs are much less protein-bound than UFH. Furthermore, they are less susceptible to inactivation by platelet factor 421 and carry a lower risk of heparin-induced thrombocytopenia.²² As a result, LMWHs offer a more predictable dose response than UFH. Aspirin is a relatively weak antiplatelet drug that inhibits cyclo-oxygenase and blocks the formation of thromboxane, one of a number of important mediators of platelet activation. Our emerging understanding of the central role of GP IIb/IIIa in the process of platelet aggregation and the pathogenesis of thrombosis has enabled the development of specific GP IIb/IIIa antagonists.^23–27 Angatonists of GP IIb/IIIa block the final common pathway of the platelet activation/aggregation process which involves the binding of soluble fibrinogen and von Willebrand factor to activated platelet GP IIb/IIIa receptors, thus preventing platelet aggregation and the assembly of the critical mass of activated platelet membrane that is necessary for the propagation of a thrombus (Figure 2). At present, three GP IIb/IIIa antagonists are commercially available in the USA (abciximab, tirofiban and eptifibatide). LMWHs and GP IIb/IIIa antagonists: UA/NSTEMI. Several clinical trials have evaluated LMWHs in the management of patients with UA/NSTEMI. When evaluating these trials, it is important to bear in mind that the various LMWHs are prepared differently and are structurally different compounds. Enoxaparin showed efficacy benefits over UFH in the treatment of UA/NSTEMI in the Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q wave Coronary Events (ESSENCE) and Thrombolysis In Myocardial Infarction (TIMI) IIB trials,^1–4 while dalteparin and nadroparin have shown equivalent efficacy to UFH (Figure 3).^28–30 Several studies have also demonstrated the benefits of GP IIb/IIIa antagonists in UA/NSTEMI.^7–15UA/NSTEMI: Combination therapy. Both LMWHs and GP IIb/IIIa antagonists have been shown to improve outcomes in patients with ACS. Several additional studies have shown the potential benefit of combining the two (Table 1). The Antithrombotic Combination Using Tirofiban and Enoxaparin (ACUTE) study, a small pilot study of 55 patients with NSTEMI, showed a shorter adjusted bleeding time during treatment with enoxaparin plus the GP IIb/IIIa antagonist tirofiban compared with UFH plus tirofiban, and a trend toward greater and more predictable inhibition of platelet aggregation.³¹ There were no major or minor bleeding events (TIMI criteria) in either treatment group. The subsequent ACUTE II study was the first randomized trial comparing the safety of enoxaparin with UFH, in 525 patients receiving a GP IIb/IIIa antagonist.³² The incidence of the primary endpoint (all bleeding events within 24 hours of study drug cessation) was similar between the treatment groups (3.5% in the enoxaparin group versus 4.8% in the UFH group). The incidence of major bleeding was 0.3% with enoxaparin versus 1.0% with UFH.³² Clinical outcomes at 30 days were similar between the treatment groups, with a trend toward a somewhat lower rate of recurrent angina in the enoxaparin group.³² The Global Utilization of Streptokinase and tPA for Occluded Coronary Arteries (GUSTO) IV-ACS study was a large-scale trial (n = 7,800) that investigated the effect of the GP IIb/IIIa antagonist abciximab in patients with ACS who were not undergoing early interventional revascularization.³³ The majority of patients in the study received UFH and oral aspirin, but a prespecified subset of patients (n = 974) received dalteparin instead of UFH. The addition of abciximab therapy showed no benefit in patients treated with UFH. However, in the subset of dalteparin-treated patients, the incidence of death or myocardial infarction after 30 days was 11.3% in patients who received dalteparin alone versus 9.5% in patients who received dalteparin plus abciximab (bolus followed by 24-hour infusion), and 9.7% in patients who received dalteparin plus abciximab (bolus followed by 48-hour infusion) (p = NS). In the group that received UFH alone, the 30-day incidence of death or myocardial infarction was 8.0%, compared with 8.2% in those who received the 24-hour abciximab infusion and 9.1% in those who received the 48-hour abciximab infusion. However, the UFH and dalteparin groups cannot be truly compared because of differing baseline characteristics between groups. Further data relating to the combination of GP IIb/IIIa antagonists with LMWH come from the National Investigators Collaborating on Enoxaparin (NICE) 3 study.34 This was a multicenter, open-label, observational study that examined the feasibility, safety and preliminary efficacy of combination therapy with enoxaparin and a GP IIb/IIIa antagonist (tirofiban, eptifibatide or abciximab) in patients with ACS. Patients underwent angiography and, if necessary, PCI without the use of UFH. The primary endpoint was the incidence of non-CABG major bleeding. In 616 patients who received both enoxaparin and GP IIb/IIIa antagonist, the incidence of non-CABG major bleeding was 1.9%, which is very similar to a prespecified historical control rate of 2.0% for UFH plus a GP IIb/IIIa antagonist. The observed incidence of death, myocardial infarction and urgent revascularization also compared favorably with prior historical studies.^{10,12,35–37} The Integrilin and Enoxaparin Randomized Assessment of Acute Coronary Syndrome Treatment (INTERACT) study is the largest randomized comparison to date of LMWH versus UFH in ACS patients receiving GP IIb/IIIa antagonist.38 A total of 746 patients with high-risk ACS were randomized to receive eptifibatide plus either enoxaparin (1 mg/kg twice daily subcutaneously for 48 hours), or weight-adjusted UFH for 48 hours. Cardiac catheterization and coronary revascularization were performed at the discretion of the investigator. The primary safety endpoint was the incidence of major non-CABG related bleeding at 96 hours. Compared with UFH, enoxaparin significantly reduced the rate of non-CABG related major bleeding: 3.8% versus 1.1% at 48 hours (p = 0.014) and 4.6% versus 1.8% at 96 hours (p = 0.03), respectively. Furthermore, the rate of the secondary efficacy endpoint (death or myocardial infarction) was significantly lower in the enoxaparin group than in the UFH group (5% versus 9%, respectively; p = 0.03). Recurrent ischemia, determined by continuous electrocardiographic monitoring, was also significantly lower in the enoxaparin group compared with the UFH group, both during the initial 48 hours (14.3% versus 25.4%; p = 0.0002) and from 48–96 hours following study entry (12.7% versus 25.9%; p UA/NSTEMI: Catheterization laboratory issues. The Fragmin and Fast Revascularization During Instability in Coronary Artery Disease (FRISC II) study,³⁹ the Treat Angina with Aggrastat and Determine Cost of Therapy with an Invasive or Conservative Strategy-Thrombolysis in Myocardial Infarction (TACTICs-TIMI 18) study⁴⁰ and the Randomized Intervention Trial of Unstable Angina (RITA-3) study⁴¹ have suggested that an early invasive strategy is associated with a major reduction in clinical outcomes. The large-scale Global Registry of Acute Coronary Events (GRACE) study has shown that interventional approaches to managing ACS differ by geographic region and availability of facilities for PCI, and that interventional procedures are most commonly used in the United States.⁴² A post hoc analysis of the combined subset of patients from the ESSENCE and TIMI 11B trials who underwent PCI confirmed that treatment with enoxaparin (1 mg/kg twice daily), both before and during PCI, was effective and well tolerated in patients with UA/NSTEMI.⁶ Compared with UFH, enoxaparin was associated with a significant reduction in the incidence of death or myocardial infarction at 1 year (p = 0.003 for in-hospital PCI; p = 0.005 for PCI during treatment with enoxaparin). The observational NICE 1 pilot study of 828 patients showed that a single intravenous bolus of enoxaparin (1 mg/kg) administered immediately prior to the procedure provides a safe and effective degree of anticoagulation for PCI.^43,44 In this observational study, the overall incidence of major bleeding at 30 days was 1.1% and the incidence of non-CABG major bleeding was 0.5%. More data relating to the safety and efficacy of PCI following treatment with enoxaparin come from Collet et al.⁴⁵ A total of 451 patients with UA/NSTEMI were treated with subcutaneous enoxaparin (1 mg/kg twice daily) for at least 48 hours. The last dose of enoxaparin was administered within 8 hours of coronary angiography (n = 293), which was immediately followed by PCI when indicated (n = 132). In patients who underwent PCI, there were no in-hospital abrupt closures or urgent revascularizations, and the incidence of the combined efficacy endpoint (death or myocardial infarction) was only 3.0%. The incidence of major bleeding at 30 days was low in patients undergoing PCI (0.8%), which was similar to the incidence in patients who did not undergo catheterization (1.3%). Continued on next page