Bivalirudin alone versus UFH/enoxaparin plus GP IIb/IIIa inhibitors demonstrated statistical significance for both superiority and noninferiority on the primary composite end point (10.1% vs 11.7%; 95% CI, 0.77–0.97; superiority, P=.015; noninferiority, P<.001) and in the incidence of major bleeding (3.0% vs 5.7%; 95% CI, 0.43–0.65; superiority, P<.001; noninferiority, P<.001).⁸ Bivalirudin alone was not superior to UFH/enoxaparin plus GP IIb/IIIa inhibitors for the ischemic composite (7.8% vs 7.3%; 95% CI, 0.93–1.24; P=.32) but did meet the criteria for noninferiority on this end point.

Compared with UFH/enoxaparin plus GP IIb/IIIa inhibitors, a bivalirudin-alone strategy resulted in statistically significant superiority in non-CABG bleeding (5.7% vs 3.0%; P<.001), non-CABG minor bleeding (21.6% vs 12.8%; P<.001), any Thrombolysis in Myocardial Infarction (TIMI) scale bleeding (6.6% vs 4.0%; P<.001), TIMI scale major bleeding (1.9% vs 0.9%; P<.001), TIMI scale minor bleeding (6.4% vs 3.7%; P<.001), and the incidence of transfusion (2.7% vs 1.6%; P<.001). A significant reduction in access site major bleeding events occurred with bivalirudin alone compared with UFH/enoxaparin plus GP IIb/IIIa inhibitors (0.8% vs 2.6%; P<.05). Hematomas≥5 cm were also statistically significantly less likely to occur in the bivalirudin-alone group than in the UFH/enoxaparin plus GP IIb/IIIa inhibitors group (0.7% vs 2.2%; P<.05).

Timing of GP IIb/IIIa inhibition in ACS (upstream use [early] vs selective use in patients undergoing PCI [late]) was assessed to determine whether upstream GP IIb/IIIa inhibitor use reduces ischemic complications enough to justify the increase in bleeding. Routine upstream GP IIb/IIIa inhibition demonstrated a significantly higher incidence of major bleeding (6.1% vs 4.9%; 95% CI, 0.67–0.95; P<.009) in comparison with deferred use, but there was no statistically significant difference between the 2 strategies in net clinical outcomes (11.7% vs 11.7%; 95% CI, 0.89–1.11; P=.93).

Although the ACUITY trial demonstrated a significant reduction in bleeding with the use of bivalirudin, a recent trial demonstrated that age, creatinine clearance, and baseline hemoglobin levels also affect the incidence of major bleeding associated with GP IIb/IIIa inhibitors.^13,14 GP IIb/IIIa inhibitor dosing adjustments are more likely to reduce these major bleeding events than anticoagulant dose adjustments.^13,14 GP IIb/IIIa inhibitor doses should therefore be appropriately adjusted based on patient characteristics, or these agents should be reserved for "bail-out" purposes in this population.

Fondaparinux. Fondaparinux is a synthetic pentasaccharide that selectively inhibits factor Xa.^6,7,15 Fondaparinux does not interact with platelet factor 4; therefore, no definitive risk of HIT exists. Trials have been conducted to study the safety and efficacy of fondaparinux in ACS. The following 2 randomized, double-blind trials examined the effect of fondaparinux on the combined end point of death, MI, refractory ischemia, and reinfarction.

The Fifth Organization to Assess Strategies in Acute Ischemic Syndromes (OASIS-5) trial was conducted to compare the safety and efficacy of fondaparinux versus enoxaparin with or without GP IIb/IIIa inhibitors in 20,078 patients with ACS⁶ (Table 1). High-risk patients (those with elevated cardiac biomarkers or ST-segment deviation) who had UA or NSTEMI were randomized to subcutaneous (SC) fondaparinux 2.5 mg daily or SC enoxaparin 1 mg/kg twice daily (once daily in patients with creatinine clearance <30 mL/min within 24 hours of symptom onset).

No difference was detected in the primary efficacy outcome (incidence of death, MI, or refractory ischemia at 9 days); death, MI, or refractory ischemia occurred in 579 of the fondaparinux-treated patients and in 573 of the enoxaparin-treated patients (5.8% vs 5.7%, respectively; 95% CI, 0.90–1.13). The main secondary outcome (incidence of death or MI at 30 days) demonstrated similar results (4.1% in both groups). The authors observed that there was a trend towards a lower rate of death, MI, and refractory ischemia with fondaparinux compared with enoxaparin at 30 days (8.0% vs 8.6%; 95% CI, 0.84–1.02; P=.13), although the rates of these events were clinically similar.

The primary safety outcome (incidence of major bleeding at 9 days) was considerably improved in the fondaparinux group compared with the enoxaparin group (2.2% vs 4.1%; 95% CI, 0.44–0.61; P<.0001). There was a significant reduction in the number of fatal bleeding events (P=.005) and in the number of patients who experienced severe bleeding according to TIMI criteria (70 vs 126; 95% CI, 0.41–0.74; P<.001).¹⁶ Bleeding was also assessed using major and minor bleeding criteria.

Figure 3: Study drug administration during PCI: OASIS-5 trial

In patients who were sent to the catheterization laboratory, additional therapy may have been added. If enoxaparin was administered >6 hours before PCI, the patient received either intravenous (IV) UFH 0.013 mL/kg with a GP IIb/IIIa inhibitor or IV heparin 0.02 mL/kg without a GP IIb/IIIa inhibitor. If fondaparinux was administered <6 hours before PCI, patients not receiving a GP IIb/IIIa inhibitor received an additional 2.5 mg IV fondaparinux, and patients receiving a GP IIb/IIIa inhibitor received an additional 5 mg IV fondaparinux (Figure 3).⁶

The incidence of major bleeding at 48 hours after the procedure was significantly lower with fondaparinux than with enoxaparin (P<.001). Catheter guide wire thrombus formation occurred more frequently in patients treated with fondaparinux than in patients treated with enoxaparin (0.3% vs 0.1%, respectively; P=.08). The incidence of clinical events (any procedural complication, major bleeding, death, MI, or stroke) at Day 9 day was lower in the fondaparinux group than in the enoxaparin group (16.6% vs 20.6%, respectively; 95% CI, 0.73–0.90; P<.001), and this difference was sustained (death, MI, stroke, or major bleeding) at Day 30 (9.5% vs 11.7%; 95% CI, 0.70–0.93; P=.004). The incidence of major bleeding events at Days 9 (2.3% vs 5.1%) and 30 (2.8% vs 5.4%) was lower in the fondaparinux group, although this difference was not statistically significant. The number of patients undergoing PCI (fondaparinux group, 39.5%; enoxaparin group, 39.5%) or CABG (fondaparinux, 15.3%; enoxaparin, 14.5%) was similar in both groups.

In this trial, fondaparinux demonstrated noninferior efficacy versus enoxaparin in the outcomes of death, MI, or refractory ischemia at 9 days, with only a trend towards lower rates of this triple composite at 30 days; however, fondaparinux treatment resulted in significant reductions in major bleeding events in all safety outcomes measured. The investigators concluded that fondaparinux is an effective treatment for ACS and is associated with less bleeding than enoxaparin, which may account for the differences in mortality between the agents. However, when undergoing PCI, patients in the enoxaparin arm received UFH despite the results from the Superior Yield of the New Strategy of Enoxaparin, Revascularization and Glycoprotein IIb/IIIa Inhibitors (SYNERGY) trial, which demonstrated an increase in bleeding with an enoxaparin/heparin crossover.⁸ Therefore, if this OASIS-5 trial had been conducted using enoxaparin without UFH, the bleeding outcomes may have been less significantly different between the 2 groups.

The Organization for the Assessment of Strategies for Ischemic Syndromes 6 (OASIS-6) trial compared fondaparinux with the standard of care in 12,092 patients presenting with STEMI (median time between onset of chest pain and presentation, 4.8 hours)⁷ (Table 1). This trial evaluated the primary and composite outcome of death or reinfarction at 30 days. Secondary outcome measures included assessment at 9 days and final follow-up at 3 or 6 months. Bleeding classification included 2 assessments for comparison with the OASIS-5 and TIMI trials.^6,16 Events were classified as "severe," "minor," or "other" bleeds for comparison with TIMI trials and as "major" or "other minor" bleeds for comparison with the OASIS-5 trial.

Figure 4: OASIS-6 trial design

Patients who presented to the hospital with symptoms of STEMI and who were able to be randomized within 24 hours of symptom onset were enrolled. The time window was shortened to 12 hours after 4,300 patients were enrolled, based on the Cardiovascular Risk Reduction by Early Anemia Treatment with Epoetin beta (CREATE) trial.¹⁷ Patients were randomized to receive fondaparinux 2.5 mg daily or standard of care for 8 days. Standard of care in this trial was defined as placebo when UFH was not indicated (stratum 1) or UFH for ≤48 hours followed by placebo (stratum 2). UFH was indicated for patients who intended to use fibrin-specific thrombolytics, patients who were ineligible for fibrinolytics but eligible for antithrombotics, and patients who were scheduled for primary PCI (Figure 4).⁷

The primary end point (incidence of death or reinfarction at 30 days) was significantly lower with fondaparinux than with standard of care (9.7% vs 11.2%; 95% CI, 0.77–0.96; P=.008). Secondary end points of death or reinfarction at Day 9 and at study end were also significantly lower with fondaparinux than with standard therapy (Day 9, 7.4% vs 8.9%; 95% CI, 0.73–0.94; P=.003; study end, 13.4% vs 14.8%; P=.008). A significant reduction in the measurement of death or reinfarction was observed at Day 30 with fondaparinux versus placebo (11.2% vs 14.0%; 95% CI, 0.68–0.92; P<.05), but there was no statistical significance when fondaparinux was compared with UFH (8.3% vs 8.7%; 95% CI, 0.81–1.13; P=not significant). No statistically significant difference between fondaparinux and standard of care was observed in the incidence of refractory ischemia, cardiac arrest, or stroke. There was a trend towards fewer deaths and reinfarctions with fondaparinux versus stratum 2 at Day 30 in patients not undergoing PCI (11.5% vs 13.8%; 95% CI, 0.66–1.02; P=.08) and a significant decrease in deaths and reinfarctions with fondaparinux versus stratum 2 at study end (14.9% vs 19%; P=.04).

There was no significant difference between fondaparinux and standard of care in the incidence of severe hemorrhages at Day 9 based on modified TIMI criteria (1.0% vs 1.3%; 95% CI, 0.55–1.08; P=.13). A significant difference was observed in the number of patients who experienced cardiac tamponade with fondaparinux versus standard of care (28 vs 48; P=.02), and a trend towards a significant reduction in the incidence of severe hemorrhage with fondaparinux versus placebo was also observed (1.0% vs 1.6%; P=.06).

This trial examined the role of fondaparinux in patients presenting with STEMI, focusing on an option for patients without accessibility to PCI or cardiac surgery. Standard of care was reflected in the use of placebo and UFH, although the favorable results in stratum 1 (placebo) were predictable. There was no statistically significant difference in efficacy between fondaparinux and UFH in patients undergoing PCI.

Enoxaparin. Enoxaparin is an LMWH formed by fragmenting the large polysaccharide chains that comprise UFH.¹⁸ This fragmentation creates several potential clinical advantages for enoxaparin versus UFH: pharmacokinetic predictability, longer half-life, preferential binding of coagulation factors (factor Xa, tissue factor pathway inhibitor, von Willebrand factor), and a lower incidence of HIT, an immune-mediated reaction induced by large heparin molecules.^18,19

Enoxaparin has been thoroughly assessed for both safety and efficacy in reducing mortality, MI, and recurrent angina. Several large-scale, randomized, controlled trials have examined the effect of enoxaparin versus UFH in the combined end point of death, MI, or recurrent angina.

The multicenter, international, open-label SYNERGY trial compared enoxaparin with UFH in 10,027 patients with NSTEMI managed with an intended early invasive or aggressive approach (Table 1).⁸ The study was designed to examine the role of enoxaparin treatment in high-risk ACS patients, rather than in low- or moderate-risk patients, in a routine clinical practice setting.

Patients were included in the study if they presented with ischemic symptoms lasting ≥10 minutes that occurred within 24 hours of enrollment and if they met ≥2 of the following criteria: aged ≥60 years, troponin or creatinine kinase elevation above the upper limit of normal, or ST-segment or electrocardiogram changes. Patients were excluded from the study if they were at increased bleeding risk because of recent stroke or surgery or because of past or present bleeding disorder, if they had an INR >1.5, or if they had creatinine clearance <30 mL/min. No renal dosing adjustments were performed during the study.

Patients were randomized to receive either SC enoxaparin 1 mg/kg every 12 hours or weight-based IV UFH. UFH was administered as 60 units/kg (maximum, 5,000 units) IV bolus, followed by an infusion of 12 units/kg/h (maximum 1,000 units/h initially). The dose of UFH was then titrated to obtain an activated partial thromboplastin time of 1.5 to 2 times the institutional upper limit of normal (50–70 seconds). All patients received ASA therapy at enrollment; if ASA therapy was contraindicated or if patients were allergic to ASA, clopidogrel was administered instead. Among patients who transitioned to the catheterization laboratory, those who had received enoxaparin >8 hours before balloon inflation were given an additional 0.3 mg/kg IV enoxaparin before PCI. If the last enoxaparin dose was administered <8 hours before ballon inflation, no additional drug was administered. Catheterization could occur while the patient was receiving UFH, but the infusion was stopped while the patient was undergoing PCI. Additional IV UFH was administered, if needed, to achieve an activated clotting time of 250 seconds. Use of GP IIb/IIIa inhibitors was encouraged but not mandated.

The primary end point (incidence of all-cause death or nonfatal MI within 30 days of randomization) was similar in the enoxaparin and UFH groups (14% vs 14.5%; P=.4). The secondary end points (incidence of death or MI at 14 days; the combined incidence of all-cause mortality, nonfatal MI, stroke, or recurrent ischemia requiring revascularization at 14 days; and individual components of the composite at 14 and 30 days) failed to demonstrate statistically significant differences between groups (12.8% vs 13.4%; P=.38).

The number of procedures (diagnostic coronary angiography, PCI, CABG) performed was similar in both groups (92% vs 92.1%; 46.5% vs 47.4%; 19.3% vs 18%, respectively). The incidence of GP IIb/IIIa inhibitor use before and after catheterization was also similar in both groups (30.7% vs 31.5%).

TIMI major and Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO) bleeding scores (Table 2) were used to measure the primary safety end point (incidence of major bleeding or stroke) for comparison to other trials.^{10–12,16,20,21} Bleeding occurred more often in the enoxaparin group than in the UFH group. There was a statistically significant increase in TIMI major bleeding among patients treated with enoxaparin versus those treated with UFH (9.1% vs 7.6%; P=.008) but only a trend towards increased bleeding with the GUSTO scoring system in patients treated with enoxaparin versus those treated with UFH (2.7% vs 2.2; P=.08).

Figure 5: SYNERGY crossover data

Administration of a different anticoagulant from the study assignment before randomization and treatment crossover after randomization complicated the interpretation of the study results; confounding variables of prerandomization and postrandomization use of enoxaparin and UFH were removed in an effort to account for these influences. The number of patients who were prerandomized to UFH or enoxaparin (75%) was accounted for by an increase in sample size and a series of prespecified analyses to detect treatment differences due to crossover treatment regimens. Although the randomized treatments were assigned independently of prior enoxaparin or UFH treatment (Figure 5), 21% of patients randomized to enoxaparin had received UFH before randomization and 14% of patients randomized to UFH had received enoxaparin before randomization.⁸

Postrandomization crossover occurred in this study because of open-label drug assignment; 12% of patients assigned to receive enoxaparin received UFH, and 4% of patients assigned to receive UFH received enoxaparin. In a comparison of patients who received consistent therapy throughout randomization, enoxaparin statistically significantly reduced the number of deaths or MIs at 30 days (13.3% vs 15.9%; HR=0.82; 95% CI, 0.73–0.95). If patients crossed over to the alternative therapy, regardless of initial drug, there was an increased risk of bleeding (transfusions, no crossover vs crossover to enoxaparin: 15.3% vs 30.2%; transfusions, no crossover vs crossover to UFH: 15.1% vs 35.1%). Prerandomization anticoagulant treatment and postrandomization crossover have made it difficult to accurately analyze the results to determine which medication contributed the most benefit to the patient.

The Enoxaparin and Thrombolysis Reperfusion for Acute Myocardial Infarction Treatment (ExTRACT)-TIMI 25 study was a double-blind, multicenter trial that randomized 20,506 patients to compare UFH with enoxaparin as adjunctive therapy with fibrinolysis in patients with STEMI.²² The study was conducted to demonstrate whether enoxaparin would provide a consistent level of anticoagulation without the need for frequent monitoring, which is required with heparin treatment. The study used dose adjustments in the elderly to reduce episodes of major bleeding as seen in the Assessment of the Safety and Efficacy of New Thrombolytic Regimens III (ASSENT–3) Plus trial.²³

Patients included in the ExTRACT-TIMI 25 trial were aged ≥18 years, had experienced ≥20 minutes of ischemic symptoms while at rest within 6 hours of randomization, had ST-segment elevation, and were scheduled to undergo fibrinolysis. All patients received a fibrinolytic that was chosen at the physician's discretion (streptokinase, tenecteplase, alteplase, or reteplase) in addition to standard doses of ASA. Clopidogrel was used as an alternative in ASA-sensitive patients or was added to therapy at the investigator's discretion. Most patients in the trial (74.5%) received a fibrin-specific fibrinolytic agent.

An IV UFH bolus of 60 units/kg was followed within 15 minutes by an infusion of 12 units/kg/h, which was administered for ≥48 hours. The IV bolus was omitted if the patient had received at least 4,000 units of open-label UFH within 3 hours of randomization. Patients in the enoxaparin group received IV enoxaparin 30 mg and SC enoxaparin 1 mg/kg every 12 hours if aged ≤75 years. Patients aged >75 years received only 0.75 mg/kg SC enoxaparin every 12 hours with no IV bolus. Maximum doses of 100 mg in patients aged ≤75 years and 75 mg in patients aged >75 years were allowed for the first 2 SC injections. Patients with a creatinine clearance <30 mL/min were administered doses renally adjusted to 1 mg/kg every 24 hours. Therapy with enoxaparin continued until hospital discharge or for a maximum of 8 days.

PCI was allowed for rescue therapy in failed fibrinolysis or in recurrent myocardial ischemia or MI, but a deferment of ≥48 hours after randomization was recommended for elective procedures. These patients received masked study drug for antithrombotic therapy.

The primary end point (incidence of death or nonfatal MI at 30 days) was significantly lower for enoxaparin than for UFH (9.9% vs 12%; P<.001). There was no statistical difference between groups in death at 30 days. The incidence of urgent revascularization was significantly lower with enoxaparin than with UFH at Days 8 (1.4% vs 2.4%; 95% CI, 0.48–0.72; P<.001) and 30 (2.1% vs 2.8%; 95% CI, 0.62–0.88; P<.001), and patients treated with enoxaparin demonstrated a trend towards reduced need for revascularization at 48 hours versus those treated with UFH (0.7% vs 0.9%; 95% CI, 0.57–1.04; P=.09). The main secondary end point (incidence of death, nonfatal MI, or urgent revascularization) was significantly lower with enoxaparin than with UFH (11.7% vs 14.5%; P<.001). In subgroup analyses, there was no statistically significant difference between enoxaparin and UFH in the primary end point for patients aged >75 years (26.3% vs 24.8%) and for those in the streptokinase group (11.8% vs 10.2%).

Bleeding was assessed using the TIMI criteria. TIMI major bleeding at 30 days was significantly higher in the enoxaparin group versus the UFH group (2.1% vs 1.4%; P<.001). In all safety outcomes measured, enoxaparin was associated with significantly higher rates of major bleeding at 48 hours, 8 days, and 30 days. Intracranial hemorrhage was the only event that demonstrated no significant increase. Treatment with UFH 3 hours before randomization occurred in 15.9% of the patients randomized to enoxaparin, which may have contributed to the increased bleeding rates in this group. Subgroup analysis revealed that elderly patients (aged >75 years) who received a reduced dose of enoxaparin experienced fewer bleeding events than patients who received a full dose, although at the cost of more clinical events.

Three prespecified net clinical benefit end points comprised the efficacy and safety outcomes as additional secondary end points in the trial: death, nonfatal MI, or nonfatal disabling stroke; death, nonfatal recurrent MI, or nonfatal episode of major bleeding; and death, nonfatal MI, or nonfatal intracranial hemorrhage. The rates of the prespecified net clinical benefit end points were lower in the enoxaparin group than in the UFH group when assessed at 30 days (P<.001 for all).

DISCUSSION

UFH has been the primary antithrombotic agent used to treat ACS. Several alternatives to UFH, including bivalirudin, fondaparinux, and enoxaparin, have been demonstrated to be at least as effective as UFH. However, given the increased awareness of the association between bleeding events and adverse outcomes, clinicians must consider the potential effect of medications on bleeding when they are selecting a pharmacologic strategy. Enoxaparin, although effective, poses increased bleeding risks. The SYNERGY trial demonstrated similar efficacy with enoxaparin and UFH but failed to secure a place for enoxaparin in the treatment of high-risk patients who are undergoing early invasive procedures because of the increase in bleeding events and poor study design (crossover treatment).

Fondaparinux has recently demonstrated success in decreasing bleeding, although the lack of reversibility, potential for catheter thrombosis, and long half-life of the agent may be a deterrent for use in patients requiring invasive management. More studies are needed to compare fondaparinux with enoxaparin without adding UFH in this patient population. There may be a role for fondaparinux as an initial adjunctive antithrombotic agent in acute MI patients who are not undergoing PCI.

Bivalirudin offers a safer alternative to other antithrombotic agents, with a short half-life for easy titration and comparable efficacy to standard of care in patients who may undergo PCI. As demonstrated in the REPLACE-2 trial, bivalirudin monotherapy could provide a cost savings to hospitals. The ACUITY trial demonstrated that bivalirudin alone is a safer, more cost-effective option than heparin plus GP IIb/IIIa inhibitors for patients with ACS who are undergoing an early invasive strategy. However, ACUITY used its own definition of bleeding, which complicates direct comparison with other trials. Adding a GP IIb/IIIa inhibitor upstream to bivalirudin therapy does not reduce ischemic complications sufficiently to justify the increase in major bleeding events and costs.

Meticulous dosing of any agent based on the manufacturer's guidance relative to age and renal function may offer another opportunity to reduce bleeding complications. However, prudence should be used to evaluate the risks and benefits of adjusting doses from the proven efficacious regimens.

CONCLUSION

Antithrombotic agents will continue to be the mainstay therapy for the acute treatment of ACS. Newer antithrombotic agents provide reasonable alternatives to UFH in certain patient populations. More data and clinical experience are needed to determine the optimal agent to replace UFH as antithrombotic therapy.

Dr Speredelozzi is a pharmacy practice resident, Brigham and Women's Hospital, Boston, Mass. Dr Baroletti is a clinical practice manager, Brigham and Women's Hospital, and clinical assistant professor, Northeastern University, Boston, Mass. Mr Fanikos is assistant director of pharmacy, Brigham and Women’s Hospital, and clinical assistant professor, Northeastern University and Massachusetts College of Pharmacy and Health Sciences, Boston, Mass.

Disclosure Information: As related to products discussed in this article: Dr Speredelozzi and Dr Baroletti report no financial disclosures; Mr Fanikos discloses that he has served on speakers’ bureaus for and/or received honoraria from Sanofi-Aventis, GlaxoSmithKline, and The Medicine Company.

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