Profound advancements in the management of acute coronary syndromes (ACS) have been realized in recent years. Initial medical therapy for non-ST segment elevation ACS has evolved to include the use of the combined treatment modalities of antiplatelet agents, antithrombin agents, and anti-ischemic therapies. Key trials have shown the therapeutic benefits of antiplatelet therapy with glycoprotein (GP) IIb/IIIa inhibitors in non-ST segment elevation ACS and percutaneous coronary intervention (PCI). Pooled data from major trials of GP IIb/IIIa inhibitors in non-ST segment elevation ACS show a significant reduction in death or nonfatal myocardial infarction (MI) through 30 days, (10.8% [IIb/IIIa] versus 11.8% [placebo]; odds ratio 0.91, 95% CI 0.84–0.98; p = 0.015).#1 The Fragmin and Fast Revascularization during Instability in Coronary Artery Disease-II (FRISC-II)#2 and Treat Angina with Aggrastat and Determine Cost of Therapy with an Invasive or Conservative Strategy-Thrombolysis in Myocardial Infarction 18 (TACTICS TIMI-18)#3 trials demonstrated the benefits offered by an early invasive management strategy in patients with non-ST segment elevation ACS. At the same time, antithrombin therapy choices have recently become more numerous and complex. Unfractionated heparin (UFH) has for years been the standard antithrombin agent used in non-ST segment elevation ACS. The low-molecular-weight heparins (LMWH) possess a number of pharmacodynamic as well as practical advantages over unfractionated heparin. LMWHs have greater anti-Xa:IIa activity compared with UFH.4# This results in increased proximal inhibition of the coagulation cascade and theoretically enhances their antithrombotic effect. UFH, but not LMWH, may activate platelets during therapy in non-ST segment elevation ACS.5# LMWH has a lower incidence of heparin-induced thrombocytopenia compared with UFH.6# LMWHs have more predictable antithrombin activity, longer half-life, greater bioavailability, potential benefits on von Willebrand factor,7 and have less non-specific binding to plasma proteins.8 They are easier to administer than UFH because they are given subcutaneously and do not require monitoring. Clinical trials, particularly the Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q Wave Coronary Events (ESSENCE) and Thrombolysis in Myocardial Infarction 11B (TIMI-11B) studies, have demonstrated the short- and long-term superiority of enoxaparin compared with UFH in preventing death or cardiac ischemic events in non-ST segment elevation ACS.9–12 The combination of potent antiplatelet therapy with GP IIb/IIIa inhibition and the proven antithrombin effect of LMWHs together with an early invasive management strategy in non-ST segment elevation ACS may provide the best approach to reduce ischemic events. This combination has thus far not been definitively evaluated in large clinical outcome trials. However, a number of registry studies and small trials, as well as substudy analyses from large clinical investigations, provide promising data on the combined use of these agents in patients with ACS. Low-molecular-weight heparin versus placebo ACS studies. Two early trials compared dalteparin with placebo in non-ST segment elevation ACS. The FRISC trial compared dalteparin with placebo in patients with unstable angina or non-Q wave MI.13 The primary endpoint was rate of death or new MI during the first 6 days of treatment. During the first 6 days, the rate of death or MI was significantly less in the dalteparin group (1.8% versus 4.8%, risk ratio 0.37 [95% CI 0.20–0.68]; p = 0.001). The incidence of major bleeding was the same in both groups during the acute phase. The FRISC II investigators examined the efficacy of long-term dalteparin treatment in patients with non-ST segment elevation ACS.14# The study found no significant differences between dalteparin and placebo groups in the primary endpoint of composite death or MI at 3 months (6.7% versus 8.0%, respectively; risk ratio 0.81 [95% CI 0.60–1.10]; p = 0.17). Low-molecular-weight heparin versus unfractionated heparin ACS studies. Four large (> 1,000 patients) published trials have directly compared LMWH with UFH in patients with non-ST segment elevation ACS. The ESSENCE trial8 (n = 3,171) demonstrated a reduction with enoxaparin in the combined primary endpoint of death, MI, and recurrent angina at 14 days of 16.6% versus 19.8% (p = 0.019). This effect persisted at 30 days (19.8% versus 23.3%; p = 0.016). No difference in the rate of major bleeding between the enoxaparin and UFH groups was observed. At one year, the benefit remained for the combined endpoint (32.0% versus 35.7%; p = 0.022).9 The TIMI 11B trial10 (n = 3,910) demonstrated a decrease in the primary endpoint of combined death, MI, and urgent revascularization at 8 days in the enoxaparin group (12.4% versus 14.5%; p = 0.048), without a significant difference in major hemorrhage during this time. Although neither ESSENCE nor TIMI 11B showed a significant reduction with enoxaparin in the endpoint of MI or death, a prospectively planned systematic overview of the data from these two trials showed that enoxaparin reduced the rate of death or MI at day 8 (4.1% versus 5.3%; p = 0.02) and at day 43 (7.1% versus 8.6%; p = 0.02).11 Enoxaparin did not significantly increase the rate of major hemorrhage during acute-phase treatment (1.3% versus 1.1%; p = 0.35). Trials comparing LMWHs other than enoxaparin with UFH have shown inconsistent results. The large (n = 3,468), randomized Fraxiparine in Ischaemic Syndrome (FRAXIS) trial#15 compared nadroparin with UFH in non-ST segment elevation ACS. No significant differences were observed between groups in the primary endpoint of cardiac death, MI, refractory angina, or recurrence of unstable angina at 14 days in either the short-term (6 ± 2 days) nadroparin treatment group (17.8% versus 18.1%; p = 0.85) or the 14-day nadroparin treatment group (20.0% versus 18.1%; p = 0.24). In addition, there was an increased incidence of major bleeding in the 14-day nadroparin group compared to the UFH group (3.5% versus 1.6%; p = 0.0035). In the Fragmin in Unstable Coronary Artery Disease (FRIC) study, a total of 1,482 patients were randomized to receive either dalteparin or UFH for 6 days, and then randomized to receive either dalteparin or placebo until day 45.#16 The study demonstrated comparable rates of the combined outcome of death, MI, or recurrent angina during the first 6 days (9.3% in the dalteparin group and 7.6 % in the UFH group, relative risk 1.18, 95% CI 0.84–1.66; p = 0.33). FRIC showed no benefit to extended therapy with dalteparin: the combined endpoint of death, MI, or recurrent angina between days 6 and 45 was 12.3% in both the dalteparin and placebo groups. No major differences occurred in rates of major hemorrhage. Figure 1 shows the odds ratio plots for these four trials. The point estimate of treatment benefit in the FRAXIS and FRIC trials favors UFH over dalteparin and nadroparin but the 95% confidence intervals do not exclude a potential benefit. Low-molecular-weight heparin systematic overview. A systematic overview by Eikelboom and colleagues of 12 randomized trials, containing a total of 17,157 patients, compared UFH and LMWH in unstable angina.17# This systematic overview included trials of different types of LMWHs, including enoxaparin, dalteparin, and nadroparin. The combined data demonstrate that either UFH or LMWH used for up to 7 days compared with placebo or untreated control had an odds ratio for death or MI of 0.53 (95% CI 0.38–0.73; p = 0.0001). Trials of LMWH demonstrate no reduction in death or MI compared with UFH at 7 days (odds ratio 0.88, 95% CI 0.69–1.12; p = 0.34). No benefit occurred with long-term therapy of up to 3 months of LMWH compared with placebo or untreated control (odds ratio 0.98, 95% CI 0.81–1.17; p = 0.80). In addition, longer-term LMWH was associated with an increased risk of major bleeding over placebo (odds ratio 2.26, 95% CI 1.63–3.15; p Key clinical issues. Despite the results of ESSENCE and TIMI-11B, LMWH, and enoxaparin in particular, has yet to gain widespread acceptance by physicians for use in non-ST segment elevation ACS. A number of factors may contribute to the rather limited use of these agents. First, significant uncertainty remains about the efficacy of these agents compared with UFH, due to the absence of any definitive study showing clear benefit on the hard endpoints of MI and death. Lack of routine monitoring and reversibility are concerns to some physicians. The 2000 ACC/AHA practice guidelines did not differentiate between the use of LMWH and UFH in the management of non-ST segment elevation ACS, but the recently updated guidelines recommend (Class IIa) enoxaparin over UFH if no CABG is planned within the next in 24 hours.#20 Data on the combination of LMWHs with GP IIb/IIIa inhibitors are limited in the settings of non-ST segment elevation ACS. In addition, the initial trials demonstrating the efficacy and safety of GP IIb/IIIa inhibitors used UFH as the antithrombin regimen. In patients undergoing catheterization and PCI, uncertainty exists about safety and efficacy with LMWH due to the lack of definitive randomized data. The inability to monitor LMWH quickly during coronary intervention and sheath management is also a concern for some physicians. GP IIb/IIIa inhibitors and LMWHs: Substudy data. A number of registry studies, substudy analyses, and small trials have evaluated combinations of LMWHs and GP IIb/IIIa inhibitors in non-ST segment elevation ACS patients, both with and without PCI. Two recently published, large, randomized trials of GP IIb/IIIa inhibitors in acute coronary syndromes had LMWH substudy analyses. In these substudies, use of either LMWH or UFH was at the discretion of the treating physician and was not a randomized assignment. The Platelet IIb/IIIa Antagonist for the Reduction of Acute Coronary Syndrome Events in a Global Organization Network B (PARAGON-B) trial randomized 5,225 patients with non-ST segment elevation ACS to lamifiban or placebo.#21 A total of 805 patients initially received LMWH instead of UFH in an open-label manner based on physician preference. Enoxaparin was the LMWH used in 91% of patients receiving LMWH. A subgroup of 411 lamifiban- and LMWH-treated patients was compared with the 2,205 patients receiving lamifiban and UFH.22# No significant differences were observed between groups in rates of death, MI, or severe recurrent ischemia at 30 days (10.2% versus 12.2% for the LMWH and UFH groups, respectively), or in death or MI at 30 days (9.0% versus 10.9%) or 6 months (11.9% versus 13.8%). Rates of major bleeding (1.5% versus 1.6%) and stroke at 30 days (0.7% versus 1.1%) were also similar between groups. A statistically significant reduction, however, occurred in revascularization at 30 days in the LMWH group (33.9% versus 44.3% of lamifiban-treated patients, 33.2% versus 43.4% of placebo-treated patients; p GP IIb/IIIa inhibitors and LMWHs: Randomized data. The first randomized data comparing UFH and LMWH with concurrent use of GP IIb/IIIa antagonists comes from the Antithrombotic Combination Using Tirofiban and Enoxaparin (ACUTE) studies. ACUTE-1 was a small pilot trial of 53 patients.25# In this double-blinded study, patients presenting with non-ST segment elevation ACS were randomized to tirofiban and either standard-dose UFH or enoxaparin 1 mg/kg subcutaneously every 12 hours. Angiography and PCI were postponed until after at least 48 hours of study drug administration. Of all patients, a total of 26.9% in the tirofiban/enoxaparin group and 29.6% in the tirofiban/UFH group underwent angioplasty. No significant differences in plasma tirofiban steady state levels and clearance between the UFH and enoxaparin groups was seen. A trend toward greater platelet inhibition in the enoxaparin group was observed, although this difference was not statistically significant. Despite this, the enoxaparin group tended towards lower median bleeding times. No major bleeding events occurred in either group, although there were more cutaneous and catheterization site bleeding events in the enoxaparin group (mostly minor bleeding events). In the ACUTE-II study, 525 patients presenting with non-ST segment elevation ACS were treated with tirofiban and randomly assigned to either standard-dose UFH or enoxaparin 1 mg/kg subcutaneously every 12 hours.#26 UFH or enoxaparin was administered for a total of 24–96 hours. Angiography and PCI was permitted after at least 24 hours, and 8 hours after the last enoxaparin dose. The primary endpoint was the rate of bleeding in each arm graded by the TIMI bleeding criteria assessed up to 24 hours after study drug cessation. Bleeding events were similar between groups. Any bleeding occurred in 4.5% of the enoxaparin group and 5.3% of the UFH group and major bleeding occurred in 0.6% and 0.5%, respectively. The combined outcome of death or MI at 30 days occurred in 9.2% of the enoxaparin group and 10.0% of the UFH group, a non-significant difference. Readmission for unstable angina (1.6 % versus 7.1%; p PCI and LMWH: Registry data. A number of registry studies have examined the use of LMWHs specifically in the setting of PCI, both with and without concurrent use of GP IIb/IIIa inhibitors. The National Investigators Collaborating on Enoxaparin (NICE) 1 and 4 registry studies29# compared outcomes in patients treated with enoxaparin in the setting of non-emergency PCI with historical controls. Enoxaparin was administered as an intravenous bolus at the time of intervention. In NICE 1, a total of 828 patients received enoxaparin 1mg/kg intravenously at the time of PCI without concurrent GP IIb/IIIa inhibition. At 30 days, major bleeding events occurred in 1.1% of patients; death or MI in 6.2%; and death, MI, or urgent revascularization in 7.7%. In NICE 4, a total of 818 patients received enoxaparin 0.75 mg/kg intravenously 5 minutes and a 0.25 mg/kg intravenous abciximab dose and a 0.125 mcg/kg/minute abciximab infusion for 12 hours. At 30 days, major bleeding occurred in 0.4%; death or MI in 6.6%; and death, MI, or urgent revascularization in 6.8%. These outcomes in NICE 1 and NICE 4 were similar to comparable cohorts in the EPISTENT and EPILOG studies, earlier trials examining GP IIb/IIIa inhibitors with UFH in the setting of PCI.30,31 # Choussat and colleagues32 evaluated a lower dose of intravenous enoxaparin (single bolus of 0.5 mg/kg) in 242 patients undergoing elective PCI. Peak anti-Xa level > 0.5 IU/ml was observed in 97.5% of patients, and clinical and safety outcomes were comparable to those seen in other registries. NICE 3 was an observational study of the combination of enoxaparin and glycoprotein IIb/IIIa inhibitors in non-ST segment elevation ACS.33# A total of 616 patients presenting with non-ST segment elevation ACS received enoxaparin 1 mg/kg subcutaneously twice a day in combination with either eptifibatide, tirofiban, or abciximab. A total of 292 patients went on to receive PCI, with combination therapy continuing until the time of intervention. Patients who received the last subcutaneous enoxaparin dose more than 8 hours prior to PCI were given an additional 0.3 mg/kg IV bolus of enoxaparin at the time of the procedure. Overall non-CABG major bleeding rates were low in all patients (1.9%) and in patients receiving PCI (1.0%). At 30 days, the rate of death or MI was low among all patients (3.7%). Collet and colleagues evaluated the safety and efficacy of enoxaparin in patients with non-ST segment elevation ACS undergoing PCI.#34 A total of 451 consecutive patients presenting with non-ST segment elevation ACS were treated initially with enoxaparin 1 mg/kg subcutaneously for at least 48 hours. Of these, 293 (65%) patients then underwent coronary angiography within 8 hours of the last LMWH injection and 132 (28%) underwent PCI. Glycoprotein IIb/IIIa inhibition was used in only 9.3% of the patients. Measured anti-Xa activity at the time of catheterization was high (> 0.5 IU/ml in 97.6% of patients), and remained stable over the 8-hour period between enoxaparin injection and catheterization (Figure 2). No abrupt closures or urgent revascularizations occurred after PCI. The rate of death or MI at 30 days was 6.2%. Major hemorrhage rates were 0.7% and 0.8% in the overall group and PCI group, respectively. Although these data are limited by lack of an UFH control group, they suggest that patients with non-ST segment elevation ACS receiving enoxaparin pretreatment within the preceding 8 hours can undergo both safe and effective PCI, without the need for further anticoagulation at the time of catheterization. Kereiakes and colleagues have recently published pilot trial data concerning the safety and efficacy of dalteparin in combination with abciximab during PCI.35# This was a dose-finding trial, which initially randomized 107 patients with non-ST segment elevation ACS undergoing PCI, after receiving initial medical stabilization therapy, to either receive dalteparin 40 or 60 IU/kg intravenously at the time of PCI. The 40 IU/kg group was discontinued early, after the randomization of 27 patients to this group, due to an increased incidence of thrombus observed in this group during catheterization. Anti-Xa and anti-IIa activity peaked at 30 minutes after the dalteparin bolus. The 60 IU/kg group achieved anti-Xa levels above 0.6 IU/ml more consistently than did the 40 IU/kg group. Major bleeding occurred in 3.7% of patients in the 40 IU/kg group, and 2.6% of patients in the 60 IU/kg group. Clinical events in the 60 IU/kg group were rare, with death, MI, and urgent revascularization occurring in 1.3%, 3.9%, and 1.3% of patients, respectively. The data suggest that dalteparin 60 IU/kg bolused at the time of PCI, compared to a 40 IU/kg bolus, results in a lower incidence of procedural thrombosis, more consistent appropriate antithrombotic effect, and a similar incidence of major bleeding. The optimal anti-Xa levels are not clearly defined for patients with ACS or patients with ACS undergoing PCI. Several investigations have begun to correlate anti-Xa levels to patient characteristics,36 anti-Xa levels after specific dosing regimens37 and the validity of bedside monitoring devices.38 The PEPCI trial37 showed that predictable anti-Xa levels could be achieved with a 0.3 mg/kg intravenous bolus of enoxaparin given 8 hours after subcutaneous enoxaparin administration (1 mg/kg q 12 hours) prior to PCI. The ELECT trial38 assessed the predictive value of a point-of-care device that measured enoxaparin anticoagulant effects. Preliminary data indicate that such a device may have use in specific patient populations that require anticoagulant monitoring. Ongoing studies and future directions. While current data suggest that LMWH, particularly enoxaparin, may be superior to UFH in non-ST segment elevation ACS with PCI and concurrent glycoprotein IIb/IIIa inhibition, to date no definitive data support clear superiority. The ongoing Superior Yield of the New strategy of Enoxaparin, Revascularization and GlYcoprotein IIb/IIIa inhibitors (SYNERGY) trial is a 10,000 patient, prospective, randomized study comparing enoxaparin with UFH in patients with non-ST segment elevation ACS treated with an early invasive management strategy.39 The Aggrastat to Zocor (A to Z) trial is another ongoing randomized trial assigning more than 5,000 patients with non-ST-elevation ACS to tirofiban and either enoxaparin or UFH, with early invasive versus conservative management at the discretion of individual treating physicians.40# Conclusions. Significant uncertainty remains within the clinical community about the use of LMWH in non-ST segment elevation ACS, specifically when these agents are combined with glycoprotein IIb/IIIa antagonists with a strategy of early invasive treatment. Trials comparing LMWH to UFH in non-ST segment elevation ACS have demonstrated that at least enoxaparin has superior efficacy to UFH in preventing a composite of death or ischemic cardiac events in low to modest risk patients not managed with an aggressive intervention strategy or with concurrent glycoprotein IIb/IIIa inhibition. Additional studies evaluating LMWHs in combination with glycoprotein IIb/IIIa inhibition with or without PCI suggest good safety and efficacy. These studies, however, were limited by modest sample sizes and designs that have relied on non-randomized and registry based data collection. The optimal strategy to use LMWHs in non-ST segment elevation ACS with PCI remains to be clarified. Ongoing trials will more clearly define the role of LMWH use in the setting of GP IIb/IIIa inhibition combined with early invasive strategies.
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