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

Continued from previous page Several other recent studies have also examined the efficacy and safety of the combination of LMWHs and GP IIb/IIIa antagonists in the catheterization laboratory (Table 1). Kereiakes et al. reported the results of a pilot study comparing two doses of dalteparin (40 or 60 IU/kg) in combination with abciximab for anticoagulation during elective PCI in 107 patients.⁴⁶ Randomized enrollment was halted because three acute thrombotic events occurred in the 40 IU/kg group. Death, myocardial infarction or the requirement for urgent coronary revascularization occurred in 3 of the 27 patients (11.1%) who received 40 IU/kg dalteparin, and in 13 of the 76 patients (17.1%) who received 60 IU/kg dalteparin. Major bleeding occurred in 3.7% of patients who received 40 IU/kg dalteparin and in 2.6% of patients who received 60 IU/kg dalteparin. The NICE 4 study was an open-label observational trial that evaluated the combination of reduced-dose enoxaparin (0.75 mg/kg) plus the standard intravenous dose of abciximab in 818 patients undergoing PCI.^43,44 The incidence of death, myocardial infarction or urgent revascularization at 30 days was 6.5%, similar to the incidence in historical control groups receiving UFH and abciximab. The rate of major bleeding (0.4% overall, and 0.2% non-CABG major bleeding) was lower than in any of the prior studies of UFH and abciximab for coronary intervention. The recently published Coronary Revascularization Utilizing Integrilin and Single-bolus Enoxaparin (CRUISE) trial compared the LMWH enoxaparin with UFH, in combination with GP IIb/IIIa antagonists in patients with ACS undergoing non-emergency PCI with planned stent implantation.47 A total of 261 patients were treated with aspirin and eptifibatide, and randomly assigned to treatment with either enoxaparin (0.75 mg/kg intravenous bolus) or UFH (60 IU/kg intravenous bolus). There were no significant differences between the treatment groups in the rates of bleeding events or clinical outcomes (Table 1), suggesting that eptifibatide can be safely and effectively combined with enoxaparin or UFH for PCI. UA/NSTEMI: Future studies. The studies described above, along with observational data from NICE 3³⁴ and randomized data from INTERACT,³⁸ provide valuable evidence of the combination of LMWHs and GP IIb/IIIa antagonists. Randomized studies such as INTERACT also strongly suggest that the combination of LMWHs with GP IIb/IIIa antagonists may be clinically more effective than standard therapy with UFH. However, concern remains regarding the transition to the catheterization laboratory of high-risk patients, who are transferred more rapidly than patients in the INTERACT trial. The Superior Yield of the New Strategy of Enoxaparin, Revascularization and Glycoprotein IIb/IIIa Inhibitors (SYNERGY) study is a prospective, randomized, open-label, multicenter study in high-risk patients with UA/NSTEMI who are to undergo early catheterization or PCI.⁴⁸ SYNERGY directly compares first-line therapy with enoxaparin and UFH with adjunctive use of thienopyridines and procedural GP IIb/IIIa antagonists (Figure 4).⁴⁸ The target enrollment for SYNERGY is 10,000 patients in 500 centers worldwide. The primary endpoint is the composite of death or nonfatal myocardial infarction during the first 30 days after enrollment. The A-Z trial is an ongoing randomized trial divided into two parts; the “A” (Aggrastat) phase and the “Z” (Zocor) phase. The “A” phase compared the efficacy of enoxaparin with that of UFH, in combination with oral aspirin and the GP IIb/IIIa antagonist tirofiban, in patients with NSTEMI.⁴⁹ Patients were randomized to receive 1 mg/kg enoxaparin every 12 hours (n = 2,026) or weight-adjusted UFH (n = 1961).⁵⁰ There was a trend toward a reduced incidence of the primary endpoint of the composite of death, myocardial infarction or refractory ischemia at 7 days for the enoxaparin group compared with UFH for the intention-to-treat population (8.4% versus 9.4%; p = 0.23) and for the on-treatment population (8.5% versus 9.5%; p = 0.308).50 No differences in the safety endpoints of TIMI major bleed, TIMI major or minor bleed or transfusion were observed.⁵⁰ The “Z” phase will determine whether the early use of an aggressively dosed statin is superior in efficacy to a current trial-based “accepted care” of a lower dose statin started 3–6 months after an acute event.⁴⁹ Our evolving perspectives on the use of LMWHs and GP IIb/IIIa antagonists in ACS are reflected in the ACC/AHA 2002 practice guidelines on the management of patients with UA/NSTEMI.⁵ Several significant changes regarding the use of LMWHs and GP IIb/IIIa antagonists have been incorporated in the most recent version.⁵ Table 2 summarizes the changes to the guidelines that impact on the use of LMWHs and GP IIb/IIIa antagonists in the management of patients with UA/NSTEMI. LMWHs and GP IIb/IIIa antagonists: STEMI. Despite the substantial reduction in adverse events with the use of thrombolytic therapy in patients with acute myocardial infarction, there are additional improvements that are possible by further increasing reperfusion rates and preventing recurrent ischemic events. TIMI grade 3 reperfusion rates are restored in only 50–60% of patients after fibrinolytic therapy.^51–53 Furthermore, clot lysis has a demonstrable prothrombotic effect, since when the clot breaks down it exposes clot-bound thrombin. Fibrinolytic drugs themselves can also directly activate platelets.⁵⁴ The early medical management of acute myocardial infarction therefore necessitates a combined approach, involving a fibrinolytic drug, antiplatelet drug(s) and an antithrombin drug, recognizing that adjunctive antithrombotic therapy may also increase the risk of bleeding events.⁵⁵ Although our traditional antithrombin agent has been UFH (except perhaps in combination with streptokinase), there is now good clinical evidence supporting the use of enoxaparin as an acceptable alternative antithrombotic drug for the medical management of acute myocardial infarction.^56,57STEMI: Combination therapy. In the large-scale GUSTO V trial (n = 16,588), half-dose reteplase plus abciximab demonstrated a reduction in recurrent ischemic events or the need for urgent revascularization.⁵⁸ However, there was no significant difference in mortality or the composite of death or myocardial infarction, and combination therapy was associated with an increase in bleeding complications, with a trend toward increased intra-cranial hemorrhage in the elderly. The Treatment with Enoxaparin and Tirofiban in Acute Myocardial Infarction (TETAMI) trial of 1,224 patients with STEMI who were not eligible for reperfusion therapy compared enoxaparin treatment with UFH, with and without tirofiban, in a 2 x 2 factorial design.⁵⁹ The primary study objective, which was to demonstrate that enoxaparin given for 2–8 days in STEMI patients not reperfused would significantly reduce the combined incidence of death, reinfarction, or recurrent angina at 30-days, was not met. There were no significant differences between the treatment groups in the incidence of the primary efficacy endpoint, and no significant differences in safety were observed (Table 3). Interestingly, additional therapy with tirofiban did not appear to be beneficial in this population. This study, however, had a number of limitations, including pretreatment with intravenous UFH prior to randomization, in 28% of all randomized patients. Furthermore, the trial included a heterogeneous patient population. Patients with clinical signs of left ventricular dysfunction were included in the trial and this may have diluted the impact of antithrombotic therapy, which would probably be more effective in preventing reinfarction or recurrent angina, rather than progression to death from irreversible pump failure. The study may also have been underpowered to detect differences in the event rates observed. There is mounting evidence, however, to suggest that both GP IIb/IIIa antagonists and LMWHs do appear to provide incremental clinical benefit in patients with STEMI. The ENTIRE-TIMI 23 trial⁶⁰ compared enoxaparin to UFH as adjuncts to either half-dose tenecteplase plus abciximab or full-dose tenecteplase (n = 483). Soon after the administration of tenecteplase, TIMI grade 3 reperfusion rates in the enoxaparin group were similar to those in the UFH group (51% versus 50%). The enoxaparin group had a lower incidence of ischemic events at 30 days, as well as fewer bleeding complications when used with tenecteplase alone (Table 3). The Assessment of the Safety and Efficacy of a New Thrombolytic regimen (ASSENT)-3 trial⁶¹ of approximately 6,000 patients with STEMI tested three different reperfusion regimens: 1) full-dose tenecteplase plus enoxaparin; 2) half-dose tenecteplase plus reduced-dose, weight-adjusted UFH and abciximab; and 3) full-dose tenecteplase plus weight-adjusted UFH. The overall incidence of ischemic events (30-day mortality, in-hospital reinfarction of refractory ischemia) in patients receiving enoxaparin and in those receiving UFH and abciximab were significantly lower than in those receiving UFH only (11.4%, 11.1% and 15.4%, respectively; p p = 0.41).⁶² No excess of in-hospital major bleeding complications were observed after combination therapy with enoxaparin (2.0%) or abciximab (2.9%) compared with UFH (3.0%).⁶² The subsequent ASSENT-3 plus study⁶³ compared pre-hospital treatment with tenecteplase in combination with enoxaparin or weight-adjusted UFH in 1,639 patients with acute myocardial infarction. Pre-hospital thrombolysis reduced treatment delay by 40–45 minutes, and pre-hospital use of UFH in combination with tenecteplase appeared as safe and efficacious as when given in-hospital. Pre-hospital and in-hospital use of enoxaparin in combination with tenecteplase reduced in-hospital ischemic events compared with UFH, but appeared to be associated with an elevated risk of major bleeding and intracranial hemorrhage in the elderly. Further trials with tenecteplase and reduced doses of enoxaparin are required in the elderly, but given the promising efficacy data, the ease of administration and lack of monitoring, enoxaparin in combination with tenecteplase is still a promising strategy in both pre-hospital and in-hospital treatment, although dosing in the elderly, particularly for pre-hospital thrombolysis, will need to be refined. STEMI: Future studies. The Enoxaparin and Thrombolysis Reperfusion for Acute Myocardial Infarction Treatment (EXTRACT)-TIMI 25 trial is a large-scale efficacy powered definitive phase III registration pathway trial comparing enoxaparin to UFH in patients with STEMI receiving thrombolysis with alteplase, reteplase, tenecteplase or streptokinase. The primary endpoint is the composite of death or myocardial infarction at 30 days; approximately 21,000 patients will be enrolled in 1,250 centers worldwide. Discussion. The message that consistently emerges from almost every modern-day ACS study is that we can significantly improve on the standard antithrombotic therapy with unfractionated heparin and aspirin. Accumulating evidence suggests that combination therapy with LMWHs and GP IIb/IIIa antagonists is well tolerated and may improve outcomes in patients with ACS. Initial concerns about the potential risk of increased bleeding complications with LMWHs, even with patients going into the catheterization laboratory, have not been borne out, though they do need further study. Since the individual LMWHs are not necessarily interchangeable, the available evidence for (and experience with) each individual drug should be considered when choosing a combination regimen. Procedural anticoagulation with LMWHs, with or without GP IIb/IIIa antagonists, has also been shown to be effective and safe during PCI in smaller observational trials and preliminary safety studies such as CRUISE and in invasively managed patients in INTERACT. Although there is a relative lack of data from large-scale clinical trials, studies such as SYNERGY will provide further clarification and support for combination therapy in patients with ACS undergoing PCI. Revisions to the ACC/AHA guidelines for the management of patients with UA/NSTEMI reflect recent and emerging evidence on the use of LMWHs and GP IIb/IIIa antagonists. The recommendation for the use of LMWHs has been upgraded to class I, level A of evidence, and specifically enoxaparin is now identified as being preferable to UFH in the absence of renal failure and in patients not undergoing bypass surgery within 24 hours (class II, level of evidence A). The revised guidelines also include the combined use of a LMWH and a GP IIb/IIIa antagonist. Summary. Over the coming years, as the standard of care for patients with ACS continues to advance, LMWHs (with or without the addition of a GP IIb/IIIa antagonist) are likely to replace UFH in both conservatively and invasively managed patients. As additional data become available, the role of LMWHs and GP IIb/IIIa antagonists in these patients will be clarified, particularly in invasively managed high-risk patients (SYNERGY) and medically managed STEMI patients (EXTRACT-TIMI 25). The “optimal” treatment regimen for the medical and invasive management of patients with ACS continues to evolve over time.