Current Cardiology Reports

, Volume 14, Issue 1, pp 40–48

Promise of Factor Xa Inhibition in Acute Coronary Syndromes

Authors

    • Department of CardiologyFlinders Medical Centre
  • Derek Chew
    • Department of CardiologyFlinders Medical Centre
New Therapies for Cardiovascular Disease (KW Mahaffey, Section Editor)

DOI: 10.1007/s11886-011-0228-8

Cite this article as:
Lee, L. & Chew, D. Curr Cardiol Rep (2012) 14: 40. doi:10.1007/s11886-011-0228-8

Abstract

Drugs that inhibit factor Xa have been shown to reduce mortality and morbidity in acute coronary syndromes (ACS). Presently, factor Xa inhibition is most often achieved indirectly with the heparins and, increasingly, fondaparinux. Despite effective anticoagulation with indirect factor Xa inhibition there remains considerable mortality and morbidity in ACS. The recently developed direct factor Xa inhibitors (the xabans) appear to offer promise as alternatives to the heparins. We review the evidence behind indirect and direct factor Xa inhibition in non-ST-segment elevation ACS, ST-segment elevation myocardial infarction, and with percutaneous coronary intervention.

Keywords

Acute coronary syndromeNSTEMIUnstable anginaSTEMINSTEACSHeparinUnfractionated heparinLow molecular weight heparinEnoxaparinFactor XaFactor Xa inhibitionApixabanRivaroxabanOtamixabanFondaparinux

Clinical Trial Acronyms

APPRAISE

Apixaban for Prevention of Acute Ischemic and Safety Events

ARISTOTLE

Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation

ATLAS-ACS TIMI-46

Rivaroxaban in Combination with Aspirin Alone or with Aspirin and a Thienopyridine in Patients with Acute Coronary Syndromes

ATLAS-2 ACS TIMI-51

The Second Trial of Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndromes

ATOLL

Intravenous Enoxaparin or Unfractionated Heparin in Primary Percutaneous Coronary Intervention for ST-Elevation Myocardial Infarction

EXTRACT-TIMI 25

Enoxaparin and Thrombolysis Reperfusion for Acute Myocardial Infarction Treatment Thrombolysis in Myocardial Infarction - Study 25

FUTURA

Fondaparinux Trial with Unfractionated Heparin During Revascularization in Acute Coronary Syndromes

GUSTO

Global Use of Strategies to Open Occluded Coronary Arteries

OASIS-5

Efficacy and Safety of Fondaparinux Versus Enoxaparin in ACS Patients

OASIS-6

Fondaparinux in ST Elevation Myocardial Infarction

PENTUA

Pentasaccharide in Unstable Angina

ROCKET-AF

Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation

RUBY-1

Study Evaluating Safety, Tolerability and Efficacy of YM150 in Subjects with Acute Coronary Syndromes

SEPIA-ACS 1 TIMI-42

Otamixaban for the Treatment of Patients with non-ST-Elevation Acute Coronary Syndromes

SEPIA-PCI

Otamixaban in Comparison to Heparin in Subjects Undergoing Non-Urgent Percutaneous Coronary Intervention

SYNERGY

Superior Yield of the New Strategy of Enoxaparin, Revascularization, and Glycoprotein (GP) IIb/IIIa Inhibitors.

Introduction

Anticoagulation therapy has been a mainstay of medical treatment for acute coronary syndromes (ACS) for the last 60 years. Despite advances in platelet inhibition, drugs that target the coagulation cascade, most notably factor Xa, still form the cornerstone of treatment across the entire spectrum of ACS. The recent development of drugs that inhibit factor Xa directly could represent a promising new therapeutic avenue for ACS.

The index event behind ACS is commonly coronary artery plaque rupture leading to exposure of thrombogenic plaque contents to the circulation, which precipitate platelet and coagulation cascade activation. A delicate balance exists at the ruptured plaque/circulation interface between thrombosis and lysis that determines the extent of thrombus burden following acute plaque rupture [1]. Thrombus formation following acute plaque rupture potentially leads to distal embolization, progression of vessel stenosis, and vessel occlusion. Reduction of the thrombus burden following plaque rupture will potentially reduce the extent of injury to myocardium subtended by the affected vessel. Figure 1 illustrates the mechanisms by which some of the currently available agents target the coagulation cascade.
https://static-content.springer.com/image/art%3A10.1007%2Fs11886-011-0228-8/MediaObjects/11886_2011_228_Fig1_HTML.gif
Fig. 1

The coagulation cascade and mode of actions of currently available antithrombotic agents. DTI includes bivalirudin and dabigatran; VKA includes warfarin; and XaI includes direct (rivaroxaban, apixaban, and otamixaban) and indirect (fondaparinux) inhibitors. DTI—direct thrombin inhibitor; LMH—low molecular weight heparin; UFH—unfractionated heparin; VKA—vitamin K antagonist; XaI—factor Xa inhibitor

Factor Xa is an attractive target for inhibition of the coagulation cascade as it is a common step for both the intrinsic and extrinsic pathways [2]. Furthermore factor Xa is the amplification site of the coagulation cascade where one molecule of factor Xa catalyzes the formation of 1000 molecules of thrombin [3]. Factor Xa and thrombin are both inflammatory mediators and inhibition may produce pleiotropic effects that could be potentially beneficial in ACS. In ACS patients treated with enoxaparin, anti-Xa activity independently correlates with 30-day mortality [4]. Finally, although direct factor Xa inhibitors inhibit thrombin generation they may allow established thrombin to continue its vital functions in maintaining hemostasis, thereby potentially reducing hemorrhagic complications arising from administration during ACS [2].

Indirect Factor Xa Inhibitors

Indirect inhibition of factor Xa is achieved via the potentiation of anti-thrombin III (AT-III) activity. Indirect factor Xa inhibitors are currently only available for parenteral administration. Unfractionated heparin (UFH) and low molecular weight heparin (LMWH) are the most established indirect anti-Xa drugs, but recently fondaparinux is gaining prominence as an alternative to heparin.

Unfractionated and Low Molecular Weight Heparin

Heparin is a naturally occurring polysaccharide, the therapeutic form of which (UFH) is typically porcine or bovine in origin. Heparin induces an allosteric conformational change in AT-III leading to factor Xa inactivation and promotes the inactivation of thrombin and other target coagulation proteinases by a ternary complex bridging mechanism [5].

LMWH is a synthetic form of heparin comprising short polysaccharide chains and has a more specific action on the coagulation cascade than UFH. There is significant variability in response to UFH that necessitates monitoring of its anticoagulant effect and is usually administered by continuous intravenous infusion. LMWH, conversely, is advantageous in that it has more favorable pharmacokinetics, produces greater proximal inhibition of the coagulation cascade in particular factor Xa [6], and does not require continuous monitoring. The most commonly used LMWH in ACS, enoxaparin, is administered at a dose of 1 mg/kg twice daily (which is usually halved in the presence of renal failure).

Fondaparinux

Fondaparinux is a synthetic pentasaccharide chemically related to heparin but binds specifically to AT-III and has no direct effect on thrombin. It has no direct action on factor Xa but increases the ability of AT-III to inhibit factor Xa approximately 300-fold [7]. Due to exclusive renal excretion, it is contraindicated in renal failure. Putative advantages of fondaparinux over heparin include once-daily fixed-dose subcutaneous administration without the need for monitoring, less bleeding due to its more specific mode of action, and very low (possibly negligible) incidence of heparin-induced thrombocytopenia [8]. The dose-determining PENTUA study suggests a dose of 2.5 mg daily of fondaparinux is sufficient for treatment of ACS, which was also the dose used in the OASIS-5 study [9, 10].

Direct Factor Xa Inhibitors

Direct factor Xa inhibitors (the “xabans”) are a new class of synthetic drugs that specifically inhibit factor Xa without the need for AT-III as a mediator. Currently available xabans that have been investigated in ACS include apixaban (Pfizer, New York, NY; Bristol-Myers Squibb, New York, NY), rivaroxaban (Johnson & Johnson, New Brunswick, NJ), and otamixaban (Sanofi-Aventis, Bridgewater, NJ). Edoxaban (Daiichi-Sankyo, Parsippany, NJ) has been investigated in deep vein thrombosis prophylaxis and stroke prevention in atrial fibrillation in phase 2 trials. Darexaban (YM150) is a newly developed direct factor Xa inhibitor and was recently investigated in a phase 2 clinical trial RUBY-1 that showed a dose-dependent increased bleeding risk when used with dual antiplatelet therapy in ACS [11]. This study was not powered for efficacy and darexaban has yet to be investigated in a phase 3 trial in ACS.

Apixaban

Apixaban is a potent inhibitor of factor Xa and is administered orally twice daily. It is excreted through multiple pathways and has low drug interactions [2]. The optimal dosing of apixaban in ACS was studied in the phase 2 APPRAISE trial [12], which led to the selection of 5 mg twice daily as the dose for further investigation in the APPRAISE 2 trial [13•].

Rivaroxaban

Rivaroxaban is an oral direct factor Xa inhibitor with a rapid onset (within 4 h) and half-life of 5–9 h. It is eliminated both fecally and renally, and has few interactions with other drugs [2]. The ATLAS-ACS TIMI-46 trial found a dose-dependent increased risk of bleeding [14•]. The optimal dosage in ACS is therefore the subject of further study in an ongoing trial ATLAS-2 ACS TIMI-51, which compares 2.5 and 5 mg twice-daily dosages with placebo [15].

Otamixaban

Otamixaban is a novel xaban in that it is administered intravenously, it has a short half-life, and it has a rapid onset of action. It is exclusively hepatically metabolized and the results of the study SEPIA-ACS 1 TIMI-42 suggested intermediate doses (0.105–0.140 mg/kg/h) be used for subsequent study [16•].

Factor Xa Inhibition in Non-ST-Segment Elevation ACS

The utility of heparin in ACS is well established. Eikelboom et al. [17] conducted a meta-analysis of trials comparing treatment with UFH versus placebo in ACS where the odds ratio (OR) of short-term death or myocardial infarction (MI) was 0.53 (95% CI, 0.38–0.73; P = 0.0001) in favor of UFH, driven predominantly by a marked reduction in MI rate.

In a meta-analysis of 12 randomized studies comparing enoxaparin and UFH in ACS (n = 49,088), treatment with enoxaparin was associated with a statistically significant lower rate of 30-day death or MI (LMWH 9.8% vs UFH 11.4%; OR, 0.84; P < 0.001) [18]. Although there was a higher rate of major bleeding in the enoxaparin groups (LMWH 4.3% vs UFH 3.4%; OR, 1.25; P = 0.019), there was an overall lower incidence of the net clinical end point of death, MI, or major bleeding at 30 days in the enoxaparin group, although this did not reach statistical significance (LMWH 12.5% vs UFH 13.5%; OR, 0.90; P = 0.051).

The effect of fondaparinux on non-ST-segment elevation ACS (NSTEACS) was investigated in the PENTUA study, which compared once-daily doses of 2.5, 4, 8, and 12 mg against the LMWH enoxaparin (1 mg/kg twice daily) in 1138 patients with ACS [9]. The 9-day primary end point of death, MI, or recurrent ischemia occurred in 27.9%, 35.9%, 34.7%, 30.3%, and 35.7%, respectively. Despite the high event rates there was no statistical significance between all groups, although the lowest rate was observed in the 2.5-mg fondaparinux group. Interestingly there was also no difference in bleeding rates.

The large multicenter randomized controlled trial OASIS-5 compared 2.5 mg daily of fondaparinux (double-dummy administration) with enoxaparin (1 mg/kg twice daily) administered for a mean of 6 days in 20,078 patients with NSTEACS [10]. No significant difference was observed in the primary end point of death, MI, or refractory ischemia at 9 days (fondaparinux 5.8% vs enoxaparin 5.7%) but a trend toward fewer events in the fondaparinux group (fondaparinux, n = 1222, vs enoxaparin, n = 1308; P = 0.06) was observed at the end of the study. However, there was a markedly lower rate of major bleeding in the fondaparinux group at 9 days (2.2% vs 4.1%; P < 0.001) leading to a lower rate of the composite end point of death, MI, refractory ischemia, or major bleeding at 9 days in the fondaparinux group (7.3% vs 9.0%; P < 0.001). There were also significantly fewer deaths at 30 days in the fondaparinux group (295 vs 352; P = 0.02).

The potential for direct anti-Xa inhibition in ACS has been investigated recently in phase 2 and phase 3 clinical trials. The phase 2 multicenter, randomized, controlled, APPRAISE study enrolled 1715 patients with ACS (~ 38% with NSTEACS) who were randomly assigned to receive 2.5 mg twice daily, 10 mg once or twice daily, or 20 mg once daily of apixaban or placebo [12]. The primary end point was the incidence of major bleeding as defined by the International Society of Thrombosis and Hemostasis (ISTH) [19] or clinically relevant non-major bleeding. The main efficacy outcome was the composite of cardiovascular death, MI, severe recurrent ischemia, or ischemic stroke. There was a dose-dependent increase in the primary safety end point of ISTH-defined major bleeding or clinically relevant bleeding in the apixaban group. The primary safety end point occurred in 3.0% of the placebo group (95% CI, 1.8–4.7), 5.7% in the apixaban 2.5-mg twice-daily group (95% CI, 3.4–8.9), and 7.9% in 10-mg once-daily group (95% CI, 5.2–11.5).The efficacy end point of cardiovascular death, MI, severe recurrent ischemia, or ischemic stroke was nonsignificantly lower in patients assigned to apixaban 2.5 mg twice daily (7.6%) and 10 mg once daily (6.0%) compared with placebo (8.7%). The addition of clopidogrel therapy was left to the discretion of treating physicians with 73% of the 2.5-mg twice-daily apixaban group receiving clopidogrel in addition to aspirin. Bleeding tended to occur more frequently in patients receiving concomitant clopidogrel therapy, whereas the dose-dependent reduction in ischemic events tended to be more pronounced in the apixaban groups not receiving clopidogrel. These data need to be interpreted with caution, as the study population was heterogeneous with many patients not receiving contemporaneous treatment for ACS and it is unclear if the addition of clopidogrel occurred pre- or post-randomization.

The follow-on APPRAISE-2 study randomizing 7392 patients with high-risk ACS (~ 60% NSTEACS) to apixaban (5 mg twice daily) or placebo in addition to standard antiplatelet has recently been published [13•]. The study was discontinued prematurely by the Data and Safety Monitoring Board due to excess in major bleeding events with apixaban over placebo without a concomitant improvement in ischemic events. The primary safety end point of Thrombolysis in Myocardial Infarction (TIMI) major bleeding occurred in 1.3% of patients receiving apixaban and 0.5% of patients receiving placebo after a median follow-up of 241 days (hazard ratio [HR] 2.59; 95% CI, 1.50–4.46; P = 0.001), with more intracranial and fatal bleeds in the apixaban group. There was no differences in the primary end point of cardiovascular death, MI, or ischemic stroke (apixaban 7.5% vs placebo 7.9%; HR, 0.95; 95% CI, 0.80–1.11; P = 0.51). The excessive bleeding observed could be related to the high number of patients (~ 80%) also receiving “parenteral antithrombotic agents” (presumably heparin). On the basis of currently published data, apixaban cannot be recommended for routine clinical use in NSTEACS in combination with dual-antiplatelet therapy.

The utility of rivaroxaban for ACS was investigated in the double-blind phase 2 study ATLAS-ACS TIMI-46 study, which recruited 3491 patients with ACS [14•]. Patients in this study were stratified into two strata. Stratum 1 received aspirin only (n = 761), whereas stratum 2 received both aspirin and a thienopyridine (n = 2730). Each strata were further block randomized in a 1:1:1 manner to either placebo or rivaroxaban (at doses of 5–20 mg) once daily or the same total daily dose of rivaroxaban given twice daily. There was a significant dose-dependent increase in bleeding in the rivaroxaban groups compared with placebo (rivaroxaban 5 mg, HR 2.21; 95% CI, 1.25–3.91; rivaroxaban 10 mg, HR, 3.5; 95% CI, 2.31–4.87; rivaroxaban 15 mg, HR, 3.60; 95% CI, 2.32–5.58; and rivaroxaban 20 mg, HR, 5.06; 95% CI, 3.45–7.42; P < 0.0001). The rate of clinically significant bleeding in the placebo group was 3.3%. The rates of the primary efficacy end point (a composite of death, MI, stroke, and severe recurrent ischemia) were 5.6% in the pooled rivaroxaban group versus 7.0% in the placebo group. Although the primary efficacy end-point rate was lower in the rivaroxaban group this did not reach statistical significance (P = 0.10). However, there was a significantly lower rate of the secondary efficacy end point (death, MI, or stroke) in the rivaroxaban group (rivaroxaban 3.9% vs placebo 5.5%; HR, 0.69; 95% CI, 0.50–0.96; P = 0.0270). The results were reproduced in both study strata.

A large phase 3 trial ATLAS-2 ACS TIMI-51 investigating the use of rivaroxaban in combination with aspirin and/or clopidogrel in ACS is currently underway [15]. This is a multicenter randomized double-blind trial recruiting more than 15,570 ACS patients who will once again be separated into two strata depending on antiplatelet therapy (stratum 1: aspirin alone; stratum 2: aspirin and a thienopyridine). Patients in both strata will be randomized to receive rivaroxaban 2.5 mg twice daily, rivaroxaban 5 mg twice daily, or placebo. The primary efficacy end point is the composite of cardiovascular death, MI, or stroke, whereas the primary safety end point is thrombolysis in MI, noncardiac surgery-related major bleeding.

Otamixaban was investigated in the SEPIA-ACS 1 TIMI-42 trial, which recruited 3241 patients with high-risk NSTEACS who were randomly assigned to receive otamixaban at five different doses (0.08-mg/kg bolus followed by infusions of 0.035 [n = 125], 0.070 [n = 676], 0.105 [n = 662], 0.140 [n = 658], or 0.175 [n = 671] mg/kg/h) or to the control group who received UFH with eptifibatide (n = 449) [16•]. The primary efficacy end point was a composite of death, MI, urgent revascularization, or bailout glycoprotein IIb/IIIa inhibitor use at 7 days. The rates of the primary efficacy end point were as follows: 6.2% in the control group, 7.2% (relative risk [RR], 1.16; 95% CI, 0.56–2.38) in the 0.035-mg/kg/h otamixaban group, 4.6% (RR, 0.74; 95% CI, 0.45–1.21) in the 0.070-mg/kg/h group, 3.8% (RR, 0.61; 95% CI, 0.36–1.02) in the 0.105-mg/kg/h group, 3.6% (RR, 0.58; 95% CI, 0.34–1.00) in the 0.140-mg/kg/h group, and 4.3% (RR, 0.69; 95% CI, 0.42–1.15) in the 0.175-mg/kg/h group. The primary safety efficacy end point was noncardiac surgery-related TIMI major or minor bleeding and occurred in 2.7% of the control group, 0.6% of the 0.035-mg/kg/h otamixaban group, 1.6% of the 0.070-mg/kg/h group, 3.1% of the 0.105-mg/kg/h group, 3.4% of the 0.140-mg/kg/h group, and 5.4% of the 0.175-mg/kg/h group (P = 0.0001 for trend). A combined analysis of the intermediate-dose (0.105 and 0.140 mg/kg/h) groups showed a significant 46% reduction (P = 0.0198) in the primary efficacy end point with no significant difference in the primary safety end point (RR, 1.20; 95% CI, 0.64–2.27; P = 0.5634) when compared with the UFH/eptifibatide group. This data, although promising, has yet to be confirmed in a large phase 3 clinical trial.

Factor Xa Inhibition in ST-Segment Elevation MI

Thrombolytic therapy is the most commonly used treatment for ST-segment elevation MI (STEMI) worldwide and is frequently administered with heparin. The large multicenter randomized controlled trial EXTRACT-TIMI 25 demonstrated the superiority of enoxaparin over UFH in 20,506 patients receiving thrombolysis for STEMI [20]. The primary composite end point of death or nonfatal recurrent MI occurred in 12.0% of patients in the UFH group and 9.9% of patients in the LMWH group (17% RR reduction; P < 0.001). There was also a reduction of the secondary end point of composite of death, nonfatal recurrent MI, or urgent revascularization in the LMWH group (UFH 14.5% vs LMWH 11.7%; P < 0.001). However, major bleeding occurred more frequently in the LMWH group (UFH 1.4% vs LMWH 2.1%; P < 0.001). Despite the higher bleeding rate in the LMWH group there was an overall lower rate of the net clinical benefit end point (composite of death, nonfatal reinfarction, or nonfatal intracranial hemorrhage) in the LMWH group (UFH 12.2% vs LMWH 10.1%; P < 0.001).

The role of fondaparinux in STEMI was assessed by the double-blind multicenter randomized controlled OASIS-6 study, which compared fondaparinux with UFH and placebo in 12,092 patients with acute STEMI [21]. The trial had a complex design and stratified patients according to those in whom UFH was contraindicated (stratum 1) and patients who could receive UFH for STEMI (stratum 2). Patients were randomized to receive fondaparinux 2.5 mg once daily or placebo for up to 8 days in stratum 1. In stratum 2, patients were randomized to fondaparinux or 48 h of UFH followed by placebo in a double-dummy fashion with sham activated partial thromboplastin time measurements in the fondaparinux group for up to 8 days. There was a significant reduction in the primary end point of death or reinfarction at 30 days in the fondaparinux group (control group 11.2% vs fondaparinux group 9.7%; HR, 0.86; 95% CI, 0.77–0.96; P = 0.008). There was a lower incidence of 30-day death or reinfarction in stratum 2 but this did not reach statistical significance (HR, 0.82; 95% CI, 0.66–1.02; P = 0.08). Patients in the fondaparinux group who received thrombolytic therapy fared better than the control groups (HR, 0.79; P = 0.003) as did those who received fondaparinux but not reperfusion therapy (HR, 0.80; P = 0.03). There was a trend toward fewer severe bleeds in the fondaparinux groups that did not reach statistical significance (control 1.3% vs fondaparinux 1.0%).

The role of direct factor Xa inhibition with xabans in STEMI has yet to be determined. To date there has been no “head-to-head” randomized clinical trial investigating the utility of this group of drugs in STEMI only. The APPRAISE study comparing apixaban with placebo included approximately 62% of patients with STEMI, 14% of whom were treated with thrombolysis [12]. The results of this study with respect to STEMI need to be interpreted with caution due to the high proportion of patients with NSTEACS and who also received concomitant UFH (70.6–77.8%) and LMWH (39.7–45%) therapy. The prematurely discontinued APPRAISE-2 also recruited approximately 40% of patients with STEMI (n = 2927) and there was a trend toward fewer ischemic events in the apixaban group in this cohort but more bleeding [13•]. Again these results must be interpreted with caution due to the heterogeneous nature of the groups. The currently ongoing ATLAS-2 ACS TIMI-51 investigating rivaroxaban in ACS will also recruit patients with STEMI [15].

Factor Xa Inhibition in Percutaneous Coronary Intervention

Effective anticoagulation during percutaneous coronary intervention (PCI) is of considerable importance for the prevention of thrombus formation on guiding catheters, coronary wires, and stents. UFH has been the gold-standard anticoagulant used in the cardiac catheterization laboratory for many years. Putative advantages of UFH over other anticoagulants include ease of administration, rapid onset of action, measurable anticoagulant effect, and reversibility. However, mortality following PCI in ACS is closely related to bleeding [22]. The introduction of new anticoagulants for PCI should therefore not only exhibit effective antithrombotic properties but also have low bleeding rates.

The randomized controlled SYNERGY trial compared enoxaparin to UFH in 10,027 patients with high-risk NSTEACS treated with an early invasive (PCI) strategy [23]. There was no significant difference between the two groups for the primary end point of 30-day death or nonfatal MI (LMWH 14.0% vs UFH 14.5%). There was no difference in PCI-related ischemic events between both groups but an excess of TIMI-defined major bleeding (LMWH 9.1% vs UFH 7.6%; P = 0.008), but not by GUSTO-defined severe bleeding (LMWH 2.7% vs UFH 2.2%; P = 0.08) or transfusions (LMWH 17.0% vs UFH 16.0%; P = 0.16).

The recently published ATOLL study randomized 910 patients treated with primary PCI for STEMI to an intravenous bolus of 0.5 mg/kg of enoxaparin or UFH prior to PCI in an open-label fashion [24••]. The 30-day incidence of death, complication of MI, procedure failure, or major bleeding was lower in the LMWH group but did not reach statistical significance (28% in the LMWH group vs 34% in the UFH group; RR, 0.83; 95% CI, 0.68–1.01; P = 0.06). However, enoxaparin did significantly reduce the secondary composite end point of death, recurrent ACS, or urgent revascularization (LMWH 7% vs UFH 11%; RR, 0.59; 95% CI, 0.38–0.91; P = 0.015). There was no difference in procedural success rate or major bleeding in both groups.

Navarese et al. [25] recently conducted a meta-analysis of 10 randomized trials comparing LMWH to UFH in STEMI patients (n = 16,286) treated with primary PCI or with PCI after thrombolysis. In the primary PCI group, LMWH treatment was associated with a reduction in mortality (RR, 0.51; 95% CI, 0.41–0.64; P < 0.001) and major bleeding (RR, 0.68; 95% CI, 0.49–0.94; P = 0.02) when compared with UFH use during PCI. There was no benefit of LWMH over UFH in the group treated with PCI after thrombolysis in this meta-analysis. However, in a substudy of EXTRACT-TIMI 25 in which 4676 STEMI patients underwent PCI post thrombolysis for STEMI, patients receiving periprocedural LMWH had a lower incidence of 30-day death or recurrent MI when compared with UFH (LMWH 10.7% vs UFH 13.8%; RR, 0.77; P < 0.001) with no differences in bleeding [26]. Current evidence would therefore suggest enoxaparin as a potentially safe and effective alternative to UFH in patients with STEMI managed with PCI.

The role of fondaparinux in PCI is controversial. Among the patients with NSTEACS recruited into the OASIS-5 study, which found a net benefit for fondaparinux over enoxaparin, 34.3% had received in-hospital PCI [10]. However, in the OASIS-6 study in which 36.9% of patients in the fondaparinux groups were treated with in-hospital PCI for STEMI, there was an excess of catheter thrombosis in the fondaparinux group (22 events vs 0; P < 0.001) and more PCI complications (abrupt coronary artery closure, new angiographic thrombus, catheter thrombus, no reflow, dissection, or perforation; fondaparinux 270 events vs control 225 events; P = 0.04) with fondaparinux [21]. The subsequently conducted FUTURA/OASIS 8 study suggests that the addition of heparin during PCI in ACS patients treated with fondaparinux is associated with low rates of catheter thrombosis [27]. However, on the basis of currently published data the routine use of fondaparinux in STEMI patients treated with primary PCI cannot be recommended.

The role of otamixaban in elective PCI was investigated in the SEPIA-PCI trial [28]. This was a dose-finding study in which the primary end points were change in prothrombin fragments 1 and 2, and anti-factor Xa activity. Although not powered to address clinical end points there was a lower incidence of 30-day death, MI, and urgent target vessel revascularization in the intermediate-dose group of 0.120-mg/kg bolus followed by 0.160-mg/kg/h infusion (4% vs 9% in the UFH group). In the SEPIA-ACS 1 TIMI 42 study, 63% of patients with NSTEACS were managed with PCI [16•]. In the PCI subset, there was a higher rate of thrombotic complications (defined as abrupt or side branch closure, distal embolization or no/slow reflow, or new thrombus) in the low-dose otamixaban group but no difference between the intermediate-dose group and the UFH/eptifibatide group. Doses of otamixaban of 0.105–0.140 mg/kg/h, therefore, deserve further study to determine its role in PCI for ACS.

Conclusions

Factor Xa inhibition has been demonstrated to be an effective treatment strategy for ACS. Table 1 provides a summary of the agents reviewed. In the clinical setting, factor Xa inhibition is currently usually achieved indirectly with administration of heparin (UFH or LMWH) or fondaparinux. Enoxaparin has emerged as a safe and effective alternative to UFH both in medically and invasively managed ACS. Fondaparinux, conversely, appears to have advantages in causing less bleeding in NSTEACS. Direct factor Xa inhibition has potential theoretic advantages, although more evidence is required before it can be recommended for elective use in ACS.
Table 1

Summary of factor Xa agents reviewed

 

Unfractionated heparin

Low molecular weight heparin

Fondaparinux

Apixaban

Rivaroxaban

Otamixaban

Mean molecular weight (daltons)

15,000

5000

1728

460

436

446

Mode of factor Xa inhibition

Indirect (via AT-III)

Indirect (via AT-III)

Indirect (via AT-III)

Direct

Direct

Direct

Half-life (minutes)

60

240

1020–1260

540–840

300–720

90–120

Route of administration

Parenteral

Parenteral

Parenteral

Oral

Oral

Parenteral

Clearance

Renal

Renal

Renal

Fecal and renal

Fecal and renal

Hepatic

Effect on APTT

+++

+/−

+/−

+

+

+

Key clinical trials in ACS

Eikelboom et al. [17]

ESSENCE, TIMI-2B, Navarese et al. meta-analysis [25], EXTRACT-TIMI 25, SYNERGY, ATOLL

PENTUA, OASIS-5, OASIS-6

APPRAISE, APPRAISE-2

ATLAS-ACS TIMI-46

SEPIA-ACS 1 TIMI-42

Potential advantages

Established, rapid onset, short half-life, reversible

Predictable pharmacokinetics, does not require monitoring, appears superior to UFH (including during PCI for STEMI)

Less bleeding, more specific indirect factor Xa inhibition, negligible HIT rates

Oral administration, potent direct factor Xa inhibition, no monitoring required

Oral administration, potent direct factor Xa inhibition, no monitoring required

Evidence of benefit with intermediate doses particularly with PCI, short acting

Potential disadvantages

Variable response, high bleeding rates, HIT, requires monitoring

Localized injection site hematoma, HIT

Catheter thrombosis in OASIS-6, role in PCI uncertain

High bleeding rates in APPRAISE-2, role with PCI unestablished

Optimal dosage uncertain, phase 3 trial still underway

More evidence is still required

ACS acute coronary syndromes; APPRAISE Apixaban for Prevention of Acute Ischemic and Safety Events; APTT activated partial thromboplastin time; AT-III anti-thrombin III; ATLAS-ACS TIMI-46 Rivaroxaban in Combination with Aspirin Alone or with Aspirin and a Thienopyridine in Patients with Acute Coronary Syndromes; ATOLL Intravenous Enoxaparin or Unfractionated Heparin in Primary Percutaneous Coronary Intervention for ST-Elevation Myocardial Infarction; ESSENCE Evaluation of the Safety and Efficacy of Enoxaparin in Non-ST Elevation Coronary Events; EXTRACT-TIMI 25 Enoxaparin and Thrombolysis Reperfusion for Acute Myocardial Infarction Treatment Thrombolysis in Myocardial Infarction - Study 25; HIT heparin-induced thrombocytopenia; OASIS-5 Efficacy and Safety of Fondaparinux Versus Enoxaparin in ACS Patients; OASIS-6 Fondaparinux in ST Elevation Myocardial Infarction; PCI percutaneous coronary intervention; PENTUA Pentasaccharide in Unstable Angina; SEPIA-ACS 1 TIMI-42 Otamixaban for the Treatment of Patients with non-ST-Elevation Acute Coronary Syndromes; STEMI ST-segment elevation myocardial infarction; SYNERGY Superior Yield of the New Strategy of Enoxaparin, Revascularization, and Glycoprotein (GP) IIb/IIIa Inhibitors; TIMI-2B Thrombolysis in Myocardial Infarction 2B; UFH unfractionated heparin.

Many ACS patients are managed with PCI and subsequent studies on the utility of factor Xa inhibitors must also address the use of these agents in the context of the cardiac catheterization laboratory. Fondaparinux, although demonstrating favorable results in OASIS-5, cannot be recommended for first-line use in STEMI managed with primary PCI on the basis of results from OASIS-6. Otamixaban offers considerable promise, as it appears to be safe during cardiac catheterization as well as being clinically effective when administered in intermediate doses.

The use of an oral direct factor Xa inhibitor such as rivaroxaban or apixaban is attractive but the contradictory results of the two APPRAISE studies raise concerns about this approach. A possible explanation for the increased bleeding rates observed in APPRAISE-2 could reside in the fact that many of the recruited patients were also receiving concomitant heparin treatment as well as antiplatelet therapy. The recently published ARISTOTLE study, which used dosing of 5 mg twice daily (identical to APPRAISE-2), found that apixaban was superior to warfarin when used for stroke prevention in patients with atrial fibrillation [29]. In a similar cohort of patients, rivaroxaban was noninferior to warfarin with regard to stroke prevention and bleeding in the ROCKET-AF study [30]. Whether these results will translate to patients with ACS remains to be seen and we eagerly await future studies on the subject, in particular ATLAS-2 ACS TIMI-51.

Disclosure

Conflicts of interest: L. Lee: has received funding for an interventional fellowship from Cordis, and has received grant support from Abbott Vascular; D. Chew: has been on the advisory boards for AstraZeneca Australia and Eli Lilly Australia; has been a consultant for Abbott Vascular; and has received payment from AstraZeneca Australia for a lecture.

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© Springer Science+Business Media, LLC 2011