Acute coronary artery occlusion is a dynamic process that involves three essential processes: compromise of vascular integrity, platelet activation and aggregation, and acceleration of the coagulation cascade with fibrin formation. Although the role of thrombin (factor IIa) is well documented in blood coagulation, fibrin formation, and thrombus stabilization, it is also central to interplay among these processes. Angiographic, intravascular ultrasound (IVUS), and pathologic studies during acute coronary syndromes (ACS) have helped delineate the pathophysiology of coronary artery occlusion: atherosclerotic plaque rupture leads to release of tissue factor (TF), which has broad impact to stimulate platelets and generate thrombin. TF activates factor VII, which activates the common pathway via the extrinsic pathway, and also activates factor IX, activating the intrinsic pathway (Fig. 15-1).¹ Subsequent generation of factor Xa leads to thrombin activation.

Inhibition of thrombin, along with the other serine proteases, is crucial in breaking this cycle and allowing either endogenous or exogenous fibrinolysis to occur. Thrombin is a well-suited target for therapeutics given its central role in arterial thrombosis. Current clinically available anticoagulants work via direct inhibition of either thrombin or an immediate upstream target, largely factor Xa.

Mechanisms of Action

Heparin was first studied in ACS in 1988 and has been a mainstay for acute ischemic heart disease therapy since then. Heparins represent a heterogeneous group of negatively charged, heavily sulfated glycosaminoglycans. Heparins have a heterogeneous effect on the coagulation cascade, although most of the effect is mediated through binding with antithrombin, causing a conformational change leading to inactivation of multiple enzymes in the coagulation cascade. While factors IXa, XIa, and XIIa are targets as well, thrombin (factor IIa) and factor Xa are the most clinically relevant. As mentioned, thrombin inhibition leads to inhibition of fibrin formation and factors needed for its cross-linking and stabilization. Heparins also have an impact on arterial and venous thrombosis by increasing vessel wall permeability and binding to von Willebrand factor, leading to some inhibition in platelet activation. Unfractionated heparin (UFH) represents a heterogeneous compound with some important limitations:

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  Propensity to bind to plasma proteins

  
  
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  Inability to inhibit clot-bound thrombin

  
  
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  Does not inhibit thrombin’s activation of platelets via protease-activated receptor-1 (PAR-1)

  
  
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  Can induce an immune-mediated response, leading to heparin-induced thrombocytopenia

Low-molecular-weight heparins (LMWHs) are modified derivatives of UFH created by depolymerizing the larger heparin molecules. LMWH exert most of their anticoagulant effect via antithrombin-mediated inhibition of coagulation factors. Factor Xa is more affected than factor IIa in a ratio of 2:1 to 3:1. LMWHs have a benefit biochemically over heparin in that they have less of a propensity to bind to plasma proteins and cells, leading to a more predictable anticoagulant response and requiring less monitoring. However, LMWHs can cause heparin-induced thrombocytopenia, cannot inhibit clot bound thrombin, and do not inhibit thrombin’s activation of platelets.

Pharmacology and Dosing

Unfractionated Heparin

One of the major challenges in predicting the pharmacologic response to UFH is the significant heterogeneity in the product delivered. Appropriate levels of anticoagulation can be monitored by either activated partial thromboplastin time (aPTT) levels or activated clotting time (ACT) levels, with the latter being used in many catheterization labs. Although the following discussion is based on current guidelines and represents current practice, it is important to note recent data that show less correlation between ACT levels and hard clinical outcomes. With concurrent glycoprotein (GP) IIb/IIIa inhibition, the intravenous (IV) loading dose of UFH is 50 to 70 U/kg to achieve a therapeutic ACT of 200 to 250 seconds. Without concurrent GP IIb/IIIa inhibition, the IV loading dose of UFH is 70 to 100 IU/kg to achieve a therapeutic ACT of 250 to 300 seconds (HemoTec device; HemoTec Medical, Munich, Germany) or 300 to 350 seconds (Hemochron device; Accriva, Piscataway Township, NJ). These are listed as a Class I, Level of Evidence (LOE) C in the most recent American College of Cardiology (ACC)/American Heart Association (AHA)/Society for Cardiovascular Angiography and Interventions (SCAI) ST-segment elevation myocardial infarction (STEMI) guidelines.² ACTs may be checked as soon as 5 minutes after bolus is given. If therapeutic ACT has not been achieved, additional bolus doses of 2000 to 5000 IU can be given to achieve target ACT. Continuation of heparin after percutaneous coronary intervention (PCI) has not been shown to be beneficial, but rather increases bleeding complications.

Low-Molecular-Weight Heparin

An intrinsic benefit to LMWH use is the predictability of its anticoagulant effect. Enoxaparin is the most widely studied and clinically used LMWH. The plasma half-life of enoxaparin is approximately 4 to 6 hours with peak effect seen within 3 to 5 hours after subcutaneous injection and a duration of action of up to 12 hours in normal renal function. Enoxaparin is hepatically metabolized and renally cleared (40% of actual dose and 10% of its active metabolites). There is little binding to plasma proteins and a more uniform molecular structure, leading to its more predictable effect. Routine monitoring is not necessary. Anti–factor Xa activity is the monitoring test of choice, with a suggested therapeutic range of 0.8 to 1.8 IU/mL.

Maintenance enoxaparin dosing is dependent on age, renal function, and clinical scenario. Standard dosing is 1 mg/kg administered subcutaneously every 12 hours provided age <75 years and creatinine clearance (CrCl) >30 mL/min. In patients with age >75 years, a lower dose of 0.75 mg/kg per dose has been associated with lower bleeding complications. In patients with CrCl >15 mL/min but less than 30 mL/min, 1 mg/kg subcutaneously every 24 hours is recommended. In patients with CrCl <15 mL/min, enoxaparin is contraindicated. While no specific recommendations are noted in the guideline for concurrent GP IIb/IIIa use, some experts feel 0.75 mg/kg per dose may be more appropriate than a full dose. For ACS patients undergoing PCI, therapeutic anti–factor Xa levels were observed in 98% of those who received subcutaneous enoxaparin between 2 and 8 hours prior.^3,4 For patients who received subcutaneous enoxaparin more than 8 hours prior to PCI, an IV enoxaparin dose of 0.3 mg/kg resulted in therapeutic anti–factor Xa levels in nearly all patients.⁴ Table 15-1 summarizes key concepts in pharmacology and dosing of UFH, LMWH, and fondaparinux.

Clinical Trials

Unfractionated Heparin

Over the past 2 decades, UFH has been a cornerstone therapy for ACS. A meta-analysis of 6 small trials showed that combination of heparin and aspirin conferred a 33% relative risk reduction in myocardial infarctions compared to aspirin alone.⁵ Subsequent ACS studies included UFH in the control arm. In a meta-analysis of trials testing LMWH, the UFH arm had an average rate of death and reinfarction of 11.0% in non–ST-segment elevation (NSTE) ACS and 11.8% in STEMI.⁶ The cumulative rates of major bleeding for UFH in these studies were 1.8% among STEMI patients and 5.4% among NSTE-ACS patients.

Some initial studies showed the rates of ischemic events to be related to degree of antithrombotic activity. A meta-analysis of six randomized controlled trials compared UFH to different regimens of antithrombotic and antiplatelet therapies to assess whether level of antithrombotic activity as measured by ACT had an effect on 7-day ischemic event rates.⁷ A total of 5216 patients were included in the ischemic event rate analysis with only 15% of patients receiving stents and initially no patients receiving dual antiplatelet therapy. Of note, the vast majority of these patients had their ACT measured via the Hemochron device, and the ACT levels were divided into 25-second intervals for analysis, starting at 275 seconds. Ischemic end points followed a U-shaped distribution with relation to minimum ACT levels, with the lowest event rate at 7 days being 6.6% among patients with minimum ACT between 350 and 375 seconds. This optimal range was consistent among different subgroups, including diabetics, those presenting with ACS, and those receiving stents. Of note, minimum ACT levels above 375 seconds showed an increase in ischemic event rate, supporting the hypothesis of heparin-induced platelet activation at higher levels.

In the same analysis, rates of major and minor bleeding indexed for maximum ACT levels showed a similar U-shaped distribution. The lowest rate of major and minor bleeding was 8.6% and was seen among patients with maximum ACT levels between 325 and 350 seconds. There was a steady increase in bleeding rates with higher ACT levels, with a substantial increase between 350 and 375 seconds (12.4%) and ACT levels beyond that.

Based on these data, the STEMI guidelines have included target ACT levels to help guide dosing for antithrombotics. However, more recent data suggest less correlation between ACT levels and ischemic and bleeding event rates after ACS and PCI. This is likely due to multiple advances in medical therapy (eg, newer thienopyridines, earlier initiation of antiplatelet therapies, lower antithrombotic dosages) as well as changes in procedural technique (eg, radial access, smaller sheaths, changes in stent design).

Subsequent analysis of those receiving abciximab showed that concurrent GP IIb/IIIa inhibition has lower optimal ACT ranges with a plateau of ischemic events from 275 to 375 seconds, but a steady increase in bleeding risk with ACT levels from 275 to 375 seconds. The analysis of the different devices used was consistent with the 28% lower readings with the HemoTec device compared to the Hemochron device.

Low-Molecular-Weight Heparin

Multiple early clinical trials were conducted showing the efficacy of enoxaparin in different clinical scenarios. A meta-analysis done in 2007 looked at 6 randomized controlled trials comparing enoxaparin with UFH in NSTE-ACS patients and 6 randomized controlled trials comparing enoxaparin with UFH in STEMI patients.⁶ In the NSTE-ACS cohort, there were 21,945 patients, with a consistent enoxaparin dose of 1 mg/kg twice a day versus varying dosages of UFH. There was a modest reduction in the combined ischemic end point of death and nonfatal myocardial infarction (MI) in the group receiving enoxaparin compared to UFH (10.0% vs 11.0%; odds ratio, 0.90 [95% confidence interval [CI], 0.81-0.996]; P = .043). This was driven by a reduction in nonfatal MI (8.0% vs 9.1%; OR, 0.87 [95% CI, 0.79-0.96]; P = .005), and there was no reduction in death (3.0% each; OR, 0.99 [95% CI, 0.83-1.18]; P = .890) (Fig. 15-2). However, there was also a non–statistically significant increase in major bleeding in the enoxaparin group (6.3% vs 5.4%; OR, 1.13 [95% CI, 0.84-154]; P = .419) (Fig. 15-3). The net effect of death, nonfatal MI, and nonfatal bleeding was not different between enoxaparin and UFH (14.1% vs 14.3%; OR, 0.97 [95% CI, 0.86-1.09]; P = .607).

In the pooled STEMI cohort, there were 27,131 patients, with the EXTRACT-TIMI 25 trial providing the majority of patients (n = 20,479). The enoxaparin dose was 1 mg/kg twice daily in most of the trials. In EXTRACT-TIMI 25, the dose of enoxaparin was reduced to 0.75 mg/kg twice daily for patients over the age of 75. The dose of UFH was most often 60 units/kg as a bolus with a continuous infusion of 12 units/kg/h. The combined ischemic end point was lower in the enoxaparin group than UFH group (9.6% vs 11.7%; OR, 0.78 [95% CI, 0.67-0.91]; P = .002). Similar to the NSTE-ACS cohort, this combined end point was driven mainly by nonfatal MI (3.4% vs 5.1%; OR, 0.64 [95% CI, 0.52-0.78]; P <.001) with no difference in mortality (6.6% vs 7.1%; OR, 0.92 [95% CI, 0.84-1.01]; P = .097) (see Fig. 15-2). The rates of major bleeding were also higher with LMWH in the STEMI cohort (2.6% vs 1.8%; OR, 1.45 [95% CI, 1.23-1.72]; P < .001) (see Fig. 15-3). The net effect of death, nonfatal MI, and nonfatal bleeding was lower in the enoxaparin group (11.1% vs 12.9%; OR, 0.84 [95% CI, 0.73-0.97]; P = .018).

One of the challenges in the clinical application of earlier trials is the lack of contemporary use of PCI. Three major clinical scenarios specifically warrant comment: elective PCI, PCI in NSTE-ACS, and PCI in STEMI, with a brief discussion on rescue PCI after fibrinolysis.

The Safety and Efficacy of Enoxaparin in Percutaneous Coronary Intervention Patients and International Randomized Evaluation (STEEPLE) study compared 2 doses of IV enoxaparin versus UFH in elective PCI.⁸ This was an open-label randomized trial where 3528 patients were randomized to 1 of 3 arms (0.5 mg/kg IV enoxaparin vs 0.75 mg/kg IV enoxaparin vs UFH) with a primary outcome of major or minor bleeding not related to coronary artery bypass grafting (CABG). Approximately 94% of patients received a stent (>50% drug-eluting stent [DES]). The trial was deemed to be underpowered to assess for differences in ischemic end points. The occurrence of major or minor bleeding within the first 48 hours was lower in the 0.5 mg/kg enoxaparin arm compared to UFH (5.9% vs 8.5%; P = .01). The occurrence of major or minor bleeding within the first 48 hours was also lower in the 0.75 mg/kg enoxaparin arm (6.5% vs 8.5%; P = .05). Importantly, major bleeding was significantly lower in both LMWH groups (1.2% vs 2.8% in the UFH arm; P = .004 for the 0.5 mg/kg enoxaparin arm and P = .007 for the 0.75 mg/kg enoxaparin arm). Conclusions from this trial were that lower dose enoxaparin (0.05 mg/kg) was deemed superior to UFH in elective PCI in decreasing rates of major or minor non–CABG-related bleeding, driven predominantly by decreased rates of major bleeding. It is important to note that the trial was underpowered to detect differences in ischemic end points that might have offset the reduction in bleeding.

In the Enoxaparin Versus Unfractionated Heparin in High-Risk Patients With Non-ST Segment Elevation Acute Coronary Syndromes Managed With an Intended Early Invasive Strategy (SYNERGY) trial, 9978 patients were analyzed after randomization to either enoxaparin or UFH.⁹ Of these patients, over 47% received PCI and 19% underwent CABG. This trial was included in the meta-analysis discussed earlier. In the overall analysis, there was no difference in the combined ischemic end point of death and nonfatal MI (14.0% vs 14.5%; hazard ratio [HR], 0.96 [95% CI, 0.86-1.06]). Specifically, in patients undergoing PCI, there was no difference in ischemic complications, with similar rates of abrupt closure (1.3% vs 1.7%), threatened abrupt closure (1.1% vs 1.0%), unsuccessful PCI (3.6% vs 3.4%), or emergency CABG (0.3% each). However, there was an increase in Thrombolysis in Myocardial Infarction (TIMI) major bleeding (9.1% vs 7.6%; P = .008), but not in Global Use of Strategies to Open Occluded Arteries (GUSTO) severe bleeding (2.7% vs 2.2%; P = .08) or transfusions (17.0% vs 16.0%; P = .16). Compared to previous NSTE-ACS trials, the patients in SYNERGY were older, and a more aggressive antiplatelet strategy was used. Conclusions from this trial were that enoxaparin was noninferior to UFH in terms of preventing ischemic end points both in the overall cohort and the PCI subgroup, despite the short duration of antithrombotic use prior to PCI (<48 hours) compared to those undergoing medical therapy. However, there was an increase in overall bleeding, but not in life-threatening bleeding or bleeding requiring transfusions.

As compared to EXTRACT-TIMI 25, which was a fibrinolysis study, the ATOLL trial enrolled patients undergoing primary PCI. The ATOLL trial randomized 910 patients to either enoxaparin 0.5 mg/kg IV or UFH in an open-label fashion.¹⁰ Stents were implanted in 95% of patients (18% DES). Roughly three-fourths of patients in both arms received GP IIb/IIIa inhibitors. This trial did not meet its primary composite end point of net clinical benefit of death, complication of MI, procedure failure, or major bleeding (28% in the enoxaparin arm vs 24% in UFH arm; risk ratio [RR], 0.83 [95% CI, 0.68-1.01]; P = .063). However, there was a net reduction in its main secondary end point, which was a combined ischemic end point of death, nonfatal MI or ACS, or urgent revascularization (7% vs 11%; RR, 0.59 [95% CI, 0.38-0.91]; P = .015), and no difference in procedural failure, defined as definite stent thrombosis, bailout use of GP IIb/IIIa inhibitor, non-TIMI 3 flow after procedure, or <50% reduction in ST elevation after procedure (26% vs 28%; RR, 0.94 [95% CI, 0.75-1.19]; P = .61). In addition, there was also no difference in rates of major or minor bleeding (11% vs 12%; RR, 0.92 [95% CI, 0.64-1.32]; P = .65) or rates of blood transfusions (2% each; RR, 0.81 [95% CI, 0.32-2.04]; P = .65). Conclusions from this trial were that although enoxaparin led to fewer combined ischemic events compared to UFH with no increase in procedural failure or clinically significant bleeding in patients with STEMI undergoing a primary PCI strategy, enoxaparin was not superior to UFH in net clinical benefit.

Rescue PCI has become more of a historical clinical scenario, but with STEMI networks often encompassing large geographical areas, it is still occasionally encountered. EXTRACT-TIMI 25 was discussed previously as a part of the large meta-analysis comparing LMWH to UFH. One notable subgroup analysis from this landmark trial was evaluation of rescue PCI within 30 days of initial event.^11,12 While noting limitations in any post hoc analysis, this was a relatively robust analysis, with 2272 patients in the enoxaparin group undergoing PCI within 30 days and 2404 patients in the UFH group undergoing PCI within 30 days. The only pre-PCI variable that differed between the 2 groups was concomitant use of a GP IIb/IIIa inhibitor, which was higher in the UFH group (15.4% vs 19.2%; P = .001). Among patients undergoing PCI, enoxaparin use was associated with a decreased incidence of the combined ischemic end point of death or nonfatal MI at 30 days (10.7% vs 13.8%; RR, 0.77 [95% CI, 0.66-0.90]; P = .001), which was driven by a decrease in nonfatal MI (8.2% vs 11.3%; RR, 0.73 [95% CI 0.61-0.87]; P < .001). There was also no difference in TIMI major or minor bleeding (4.6% vs 4.0%; RR, 1.15 [95% CI, 0.88-1.51]; P = .310). Conclusions from this trial were that enoxaparin is superior to UFH in rescue PCI after fibrinolysis in preventing the combined end point of death and nonfatal MI without an increased risk in major or minor bleeding.

Summary and Guidelines

Medical Management and Fibrinolysis

UFH provides the background upon which subsequent anticoagulants have been tested. Meta-analysis of UFH shows continued efficacy and a broader application given contraindications for other agents. In the most recent 2012 focused update from the ACC/AHA on unstable angina (UA)/non–ST-segment elevation MI (NSTEMI) patients undergoing an initial medical management strategy, enoxaparin and UFH carried a Class I recommendation with LOE A given the numerous randomized clinical trials comparing these two therapies.¹³ The decreased ischemic event rates at the expense of slightly increased incidence of major bleeding shapes the Class IIa indication that for patients undergoing initial medical management, enoxaparin may be preferable to UFH. Duration of anticoagulation therapy in medically managed patients should be 48 hours for UFH and for the duration of hospitalization, up to 8 days, for enoxaparin.

Based on the 2013 focused update from the ACC/AHA on STEMI, both UFH (LOE C) and enoxaparin (LOE A) are Class I indications for adjunctive anticoagulation with fibrinolysis.² The current guidelines do not recommend a particular agent, despite the findings of EXTRACT-TIMI 25.

Percutaneous Coronary Intervention

In UA/NSTEMI patients undergoing an early invasive strategy, both enoxaparin and UFH have a Class I, LOE A recommendation for initiation as soon as possible.¹³ In those undergoing PCI, anticoagulation should be discontinued as soon as PCI is completed, provided PCI was uncomplicated. Of note, in the STEMI guidelines, enoxaparin is not recommended due to the lack of supporting evidence, as the ATOLL trial failed to meet its primary composite end point of net clinical benefit of death, complication of MI, procedure failure, or major bleeding.

In patients undergoing PCI after fibrinolysis, UFH (LOE C) or enoxaparin (LOE B) may be continued through PCI.² Additional boluses of UFH may be needed to achieve target ACT, depending on whether concurrent GP IIb/IIIa inhibitors are used. If subcutaneous enoxaparin was last given >8 hours prior to PCI, a single dose of 0.3 mg/kg of IV enoxaparin should be given.

Mechanism of Action

Pentasaccharides derive their name from the pentasaccharide sequence of heparin (Fig. 15-4). The only available pentasaccharide is fondaparinux. Fondaparinux works through a high affinity toward antithrombin (AT), leading to a conformational change in AT. This conformational change leads to markedly increased affinity for factor Xa with little effect on its AT activity. The effect of fondaparinux is dependent on AT levels, and once plasma AT is depleted, the antithrombotic effect plateaus. The binding of fondaparinux to AT is reversible; however, the binding of AT to factor Xa is irreversible and requires subsequent clearance from plasma. The effect on thrombin is indirect via decreased thrombin generation from decreased factor Xa levels.

Thrombocytopenia is often seen with fondaparinux with reported rates of moderate and severe thrombocytopenia of 2.9% and 0.2%, respectively, in clinical trials. In addition, although fondaparinux does not cross-react with the serum of patients with heparin-induced thrombocytopenia, it can induce the production of anti-PF4 antibodies, leading to a low risk of heparin-induced thrombocytopenia. This association is controversial. Similar to heparin and LMWH, fondaparinux cannot inhibit factor Xa bound to prothrombinase complex.

Pharmacology and Dosing

Fondaparinux has 100% bioavailability after subcutaneous administration, reaching maximum serum concentrations in less than 2 hours. The antithrombotic effect is thought to be linear in most healthy patients with doses between 2 and 8 mg. The plasma half-life is slightly longer in elderly patients (21 hours) as compared to younger patients (17 hours). Based on this plasma half-life, the drug reaches steady-state levels after 3 to 4 days. Most of the drug is excreted unmodified in the urine, and moderate to severe renal insufficiency decreases clearance by 40% to 55% (see Table 15-1). There is some evidence to suggest that fondaparinux may be dialyzable.

Clinical trials assessing fondaparinux in deep vein thrombosis (DVT) prophylaxis and ACS have used doses of 2.5 mg subcutaneously once daily. Some DVT and pulmonary embolism trials have used larger dosages (up to 7.5 mg daily), but these doses are not recommended for ACS patients. Currently, there is no antidote, and protamine is not effective in reversing the effects of fondaparinux. Nonspecific agents, such as recombinant factor VIIa (rFVIIa), rapidly restored thrombin generation time and normalized mildly elevated aPTT in patients who received a single large dose of 10 mg of subcutaneous fondaparinux. Despite this biochemical relationship, the clinical efficacy of reducing bleeding with rFVIIa has not been tested.

aPTT and international normalized ratio (INR) are not effective monitoring tools for fondaparinux activity. Although aPTT and prothrombin time experience an average mild increase with fondaparinux, the increase is mild at best, and it is unclear whether it is dose dependent. There is minimal interference with INR, making fondaparinux an ideal tool for monitoring oral anticoagulation with warfarin. The most effective monitoring tool is anti–factor Xa activity, which closely reflects anticoagulation with fondaparinux.

Clinical Trials

There have been two major clinical trials looking at the role of fondaparinux across the ACS spectrum. The Fifth Organization to Assess Strategies in Acute Ischemic Syndromes (OASIS-5) trial was a randomized, double-blind, double-dummy trial to assess whether patients who presented with NSTE-ACS had lower rates of ischemia and bleeding with fondaparinux (2.5 mg daily) or enoxaparin (1 mg/kg twice daily for a mean of 6 days).¹⁴ A total of 20,078 patients were randomized, and there was no difference in the primary outcome of death, MI, or refractory ischemia at 9 days (5.8% vs 5.7%; HR, 1.01 [95% CI, 0.90-1.13]; P = .007 for noninferiority). This effect persisted at 30 days (8.0% vs 8.6%; HR, 0.93 [95% CI, 0.84-1.02]; P = .13) and 180 days (12.3% vs 13.2%; HR, 0.93 [95% CI, 0.86-1.00]; P = .06). A decrease in mortality was noted in the fondaparinux group at both 30 days (2.9% vs 3.5%; HR, 0.83 [95% CI, 0.71-0.97]; P = .02) and at 180 days (5.8% vs 6.5%; HR, 0.89 [95% CI, 0.80-1.00]; P = .05). The primary safety outcome was incidence of major bleeding, which was lower in the fondaparinux group compared to the enoxaparin group at 9 days (2.2% vs 4.1%; HR, 0.52 [95% CI, 0.44-0.61]; P < .001), 30 days (3.1% vs 5.0%; HR, 0.62 [95% CI, 0.54-0.72]; P < .001), and 180 days (4.3% vs 5.8%; HR, 0.72 [95% CI, 0.64-0.82]; P < .001). The net clinical benefit of death, MI, refractory ischemia, and major bleeding consistently favored fondaparinux over enoxaparin at 9 days (7.3% vs 9.0%; HR, 0.81 [95% CI, 0.73-0.89]; P < .001), and this persisted over 30 days (10.2% vs 12.4%; HR, 0.82 [95% CI, 0.75-0.89]; P < .001) and 180 days (15.0% vs 17.1%; HR, 0.86 [95% CI, 0.81-0.93]; P < .001). An interesting finding was noted in the 39.5% of patients who underwent PCI. Although rates of overall procedural complications were not different between the 2 groups, there was a higher rate of catheter-related thrombi in patients who received fondaparinux (0.9% vs 0.4%; HR, 3.59 [95% CI, 1.64-7.84]; P = .001). Conclusions from this trial were that fondaparinux had similar rates of combined ischemic end point and lower incidence of major bleeding compared to enoxaparin up to 180 days from initial randomization in patients who presented with NSTE-ACS, but higher rates of catheter-associated thrombi in those undergoing PCI.