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© The European Society of Cardiology 2007. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Antithrombin treatment in patients with non-ST-elevation acute coronary syndromes undergoing percutaneous coronary intervention

Jean-Philippe Collet1,2, Raphaëlle Dumaine1,2 and Gilles Montalescot1,2,*

1 Institut de Cardiologie, Pitié-Salpêtrière University Hospital, Bureau 2-236, 47 Boulevard de l'Hopital, 75013 Paris, France
2 Institut de Cardiologie (APHP) and INSERM unit#856, Pitié-Salpêtriére University Hospital, 47 Boulevard de l'Hopital, 75013 Paris, France

* Corresponding author. Tel: +33 1 42 16 30 07; fax: +33 1 42 16 29 31. E-mail address: gilles.montalescot{at}psl.aphp.fr


   Abstract
Top
 Abstract
Introduction
 Mechanisms of action of...
 LMWH in ACS
 Direct anti-XA inhibitor:...
 Direct thrombin inhibitors
 Comments
 References
 
Unfractionated heparin (UFH) has long been the only thrombin inhibitor used in non ST-elevation ACS (NSTE-ACS) patients undergoing percutaneous coronary intervention. Better anticoagulation regimens have been developed given the limitations of UFH which include its sometimes difficult-to-manage effects on coagulation, the need for repeated monitoring of coagulation, the narrow therapeutic window, the potential induction of platelet activation, and the risk of thrombocytopenia. The three new anticoagulants, enoxaparin, fondaparinux, and bivalirudin have demonstrated improvements, against UFH and represent new alternative therapies. We have reviewed the major challenges for each of them to become ideal. Additional data are needed for enoxaparin when accumulation of the drug is likely to occur (obese patients, renal insufficiency) given the risk of subsequent bleeding. Fondaparinux and bivalirudin represent an opportunity to improve safety. However, cost is a real concern for bivalirudin especially when access to the catheterization laboratory is delayed. In addition, whether bivalirudin can replace selective procedural abciximab use in the catheterization laboratory in high-risk ACS patients also remains to be established. Catheter thrombosis is a concern for fondaparinux and the need for combining UFH with fondaparinux to overcome this potential detrimental side effect is an unexpected limitation that needs re-appraisal.

Key Words: Unfractionated heparin • Direct thrombin inhibitor • Low molecular weight heparin • Acute coronary syndrome • Percutaneous coronary intervention


   Introduction
Top
 Abstract
 Introduction
Mechanisms of action of...
 LMWH in ACS
 Direct anti-XA inhibitor:...
 Direct thrombin inhibitors
 Comments
 References
 
Acute coronary syndromes (ACS) are, in most cases, the clinical manifestation of intracoronary thrombosis following the disruption of an atherosclerotic plaque. The plaque disruption results in platelet activation and aggregation as well as tissue factor and coagulation factors activation. Thrombin is a key enzyme of the coagulation cascade, as it controls the ultimate step: the conversion of fluid-phase fibrinogen into fibrin, which is the scaffold of the clot. Furthermore, thrombin sustains the clotting process by two mechanisms: amplification of its own production by activating the intrinsic pathway, particularly factors XI, IX, VIII, and X, and platelet activation. Thrombin binds to fibrin, fibrin degradation products, as well as subendothelial matrix, and remains active once bound. However, bound-thrombin cannot be inactivated by antithrombin/heparin complex.1 Thus, thrombin-rich clot represents a powerful reservoir of prothrombotic thrombin.

Unfractionated heparin (UFH) has long been the only thrombin inhibitor used in unstable angina patients, despite the lack of definitive proven benefit over placebo in ACS patients treated with aspirin.2 In addition, several pharmacological characteristics limit the antithrombin activity of UFH. This, associated with the necessity of close monitoring of anticoagulant activity, as well as a high incidence of heparin-induced thrombocytopenia,3 encouraged the development of alternative antithrombin strategies.

Low-molecular-weight heparins (LMWH), synthetic pentasaccharide, as well as direct thrombin inhibitors (DTIs) have proved some benefit in non-ST-elevation ACS (NSTE-ACS) patients. However practical issues such as transfer from the CCU to the cathlab and dose adjustment for PCI remained to be clarified for DTIs and pentasaccharide.


   Mechanisms of action of the different thrombin inhibitors
Top
 Abstract
 Introduction
 Mechanisms of action of...
LMWH in ACS
 Direct anti-XA inhibitor:...
 Direct thrombin inhibitors
 Comments
 References
 
Thrombin has an active site and two exosites, one of which—exosite 1—binds to its fibrin substrate, orientating it towards the active site. Figure 1 displays the mechanisms of action of the different thrombin inhibitors.


Figure 0701
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  		Figure 1 Mechanisms of action of the different thrombin inhibitors. Adapted in part from Weitz and Buller.8

 
UFH binds to exosite 2 on thrombin, as well as to antithrombin, forming a ternary complex. This ternary complex is necessary for the inhibition of thrombin by antithrombin (Figure 1A, left). In contrast to thrombin inhibition, inactivation of factor Xa does not require the formation of a ternary complex. UFH inhibits thrombin and factor Xa in the same proportion (the ratio antiXa/IIa activity equals 1) (Figure 1A, right). The interaction of the heparins (UFH as well as LMWH) with antithrombin is mediated by a unique pentasaccharide sequence present in approximately one-third of the UFH chains. In addition, UFH also binds simultaneously to fibrin and thrombin. The heparin/thrombin/fibrin complex lessens the ability of the heparin–antithrombin complex to inhibit thrombin and increases the affinity of thrombin for its fibrin substrate. This results in protection of fibrin-bound thrombin from inactivation by the heparin–antithrombin complex1 (Figure 1B). The antithrombin action of UFH is limited by variable efficacy and stability, mainly due to poor bioavailability, non-specific protein binding, neutralization by platelet factor-4, and a lack of efficacy on fibrin-bound thrombin. Moreover, UFH exhibits prothrombotic properties related to a poor control of von Willebrand factor release, as well as platelet activation, platelet aggregation through binding and upregulation of the platelet GP IIb–IIIa receptor, and thrombin generation rebound after discontinuation.4–7

LMWH result from the depolymerization of UFH chains and contain, in approximatively 20% of the chains, the critical pentasaccharide unit needed for their interaction with antithrombin.1 Conversely to UFH, LMWH action is primarily directed against factor Xa, because most of the chains are not sufficiently long to form the ternary complex necessary for the inactivation of thrombin (<50% of the chains contain at least the 18 saccharide units needed for the formation of the ternary heparin/thrombin/antithrombincomplex) (Figure 1C). Depending on the LMWH, the anti-thrombin/anti-Xa activity ratio varies from 1.9 (tinzaparin) to 3.8 (enoxaparin).1 Fractionated LMWH have a more predictable pharmacological profile than UFH, eleminating the need for therapeutic drug monitoring (dose adjustment are required among obese, elderly, as well as patients with renal failure). This is mainly due to reduced non-specific protein binding and reduced neutralization by platelet factor-4. Other properties such as reduced induction of von Willebrand factor release and reduced platelet activation are of crucial importance in the setting of ACS.4–6 Furthermore, LMWH produce enhanced release of tissue factor pathway inhibitor, a glycoprotein that forms a quaternary complex with factor VIIa-tissue factor complex and factor Xa, thus inhibiting the factor VIIa-tissue factor complex. This action on the coagulation cascade upstream from thrombin is a theoretical advantage over UFH, especially in the setting of ACS, where limiting the amplification of clotting formation by inhibiting thrombin generation is a key element of the treatment strategy. Heparin-induced thrombocytopenia is also much less common with LMWH than UFH.3

Fondaparinux is a synthetic pentasaccharide that selectively inhibits factor Xa. This analogue of the pentasaccharide sequence of heparin, which mediates its interaction with antithrombin, catalyses factor Xa inhibition by antithrombin (Figure 1D). The action on the coagulation cascade upstream from thrombin has the same theoretical advantages over UFH as mentioned earlier for LMWH.

DTIs studied in the setting of ACS, such as hirudin and bivalirudin, bind both the active site of thrombin and exosite 1 (bivalent inhibitors). They remove thrombin from its fibrin substrate8 (Figure 1E). DTIs do not bind to plasma proteins, providing a more predictable pharmacological response than UFH. They are not affected by platelet factor-4, have a low immunogenic propensity, and thus are very unlikely to induce thrombocytopenia. Other safety characteristics are the short plasma half-life, 25 min for bivalirudin, and the absence of necessity for anticoagulation monitoring. Furthermore, bivalirudin blocks thrombin signalling to the protease-activated receptor, thus limiting platelet activation. Conversely to heparins, DTIs are active against fibrin-bound thrombin. However, because they exert a direct action on thrombin in a 1:1 stoichiometric fashion, the amount of thrombin inhibited is parallel to the concentration of DTI. If a single molecule of heparin (UFH or LMWH) catalyses the action of multiple molecules of antithrombin, in contrast, a single molecule of DTI binds to one molecule of thrombin in both the fluid phase and the clot-bound phase. This might ‘exhaust’ the supply of DTI, allowing thrombin molecules to remain enzymatically active. The increase of their concentration to achieve a greater inhibition of thrombin has been associated with prohibitive bleeding rates.


   LMWH in ACS
Top
 Abstract
 Introduction
 Mechanisms of action of...
 LMWH in ACS
Direct anti-XA inhibitor:...
 Direct thrombin inhibitors
 Comments
 References
 
Head-to-head comparison of LMWH with UFH without IIb/IIIa inhibitors and without catheterization
Several randomized clinical trials have compared the efficacy and safety of LMWH and UFH among initially medically managed patients presenting with ACS.9–11 Among those, enoxaparin was the only LMWH to demonstrate a significant and sustained benefit over UFH; in the meta-analysis of the TIMI 11B and ESSENCE trials, enoxaparin was associated with a significant reduction of death and MI at 8, 14, and 43 days (OR 0.77; 95% CI 0.62–0.95; OR 0.79; 95% CI 0.65–0.96; and OR 0.82; 95% CI 0.69–0.97, respectively).9

Head-to-head comparison of LMWH with UFH in combination with IIb/IIIa inhibitors and catheterization
More recently, safety and efficacy of these two antithrombin regimens have been compared among patients receiving up-to-date anthrombotic regimens including glycoprotein IIb/IIIa inhibitor (GPI). A pooled analysis was performed among the 21 946 patients included in the six randomized trials comparing UFH and enoxaparin in non-ST-segment elevation ACS.12 Enoxaparin treatment was associated with lower incidence of death/MI at 30 days than UFH (10.1 vs. 11.0%; OR 0.91; 95% CI 0.83–0.99; number needed to treat 107). The benefit of enoxaparin was even higher among patients receiving no pre-randomization antithrombin therapy (8.0 vs. 9.4%; OR 0.81; 95% CI 0.70–0.94; number needed to treat 72). No significant difference was found in blood transfusion (OR 1.01; 95% CI 0.89–1.14) and there was no major bleeding (OR 1.04; 95% CI 0.83–1.30) at 7 days after randomization. In all these trials, enoxaparin dose of 1 mg/kg [subcutaneous (SC)] was administered every 12 h in order to achieve therapeutic anti-Xa levels. This is of importance, as it has been demonstrated that low anti-Xa activity (<0.5 IU/mL) was an independent predictor of poor outcome among ACS patients; conversely, anti-Xa activity, within the target range of 0.5–1.2 IU/mL, is not related to bleeding events.13 Among patients with impaired creatinine clearance, the therapeutic range is safely achieved by reducing enoxaparin dose.14

PCI in patients with upstream SC LMWH
Collet et al.15 reported on the safety and efficacy of PCI in ACS patients who received the last SC injection of enoxaparin < 8 h before catheterization without additional anticoagulation and without coagulation monitoring. Of the 451 consecutive patients with NSTE-ACS who received at least 48 h treatment with SC enoxaparin (1 mg/kg/12 h), 132 (28%) underwent immediate PCI following angiography with no further enoxaparin. The mean anti-Xa activity at the time of catheterization was > 0.5 IU/mL in 97.6% patients. There were no instances of in-hospital acute vessel closure or urgent revascularization following PCI. Death/myocardial infarction (MI) at 30 days occurred in 3.0% in the PCI group, but 6.2% in the whole population, and 10.8% in patients not undergoing catheterization. The 30 day major bleeding rate was 0.8% in the PCI group and was comparable with that of patients medically managed (1.3%). Similar results have been obtained in an even larger Chinese population of ACS.16 Recent data drawn from more than 350 patients also indicate that similar anti-Xa levels to those found after 48 h of SC treatment are achieved after just two SC doses of enoxaparin.17 Finally, the same favourable results were obtained in the NICE-3 study.18 A total of 661 ACS patients were treated with enoxaparin SC 1 mg/kg plus abciximab, eptifibatide, or tirofiban at standard doses and both strategies were combined for the transition from the ward to the catheter laboratory: no interruption and no addition of enoxaparin for PCI within 8 h of the last SC injection and an additive IV bolus of 0.3 mg/kg when PCI was performed between 8 and 12 h of the last SC injection. The major bleeding rate was 4.5%, and the in-hospital death/MI/urgent target vessel revascularization rate was 5.7%.

The Superior Yield of the New Strategy of Enoxaparin Revascularization and Glycoprotein IIb/IIIa Inhibitors (SYNERGY) trial was the largest randomized, open-label, international trial comparing enoxaparin and UFH among 10 027 high-risk patients with non-ST-segment elevation ACS to be treated with an intended early invasive strategy. The incidence of the composite primary efficacy endpoint (death/MI at 30 days) was similar in enoxaparin- and UFH-treated patients (14.0 vs. 14.5% respectively; OR 0.96; 95% CI 0.86–1.06). Of the 9978 patients, 2440 did not receive pre-randomization therapy and 6138 received consistent therapy through randomization. Patients who received consistent therapy with enoxaparin had significantly less death or MI than patients randomized to UFH (13.3 vs. 15.9%, respectively; HR 0.82; 95% CI 0.72–0.94; P = 0.004, adjusted P = 0.041), with a trend towards increased bleeding (2.4 vs. 2.3%, respectively, P = 0.894).19 The authors stated that as a first-line agent in the absence of changing antithrombin therapy during treatment, enoxaparin appears to be superior to UFH without an increased bleeding risk. The SYNERGY PCI study included 4687 high-risk patients undergoing PCI after randomization to UFH (60 U/kg bolus, then 12 U/kg per hour adjusted to an activated partial thromboplastin time of 50–70 s) or enoxaparin (1 mg/kg SC every 12 h plus an additional 3 mg/kg IV at the time of PCI if the procedure was performed more than 8 h after last SC dose). Similar to the primary SYNERGY trial, the primary endpoint death/MI at 30 days was not significantly different between the enoxaparin and UFH (13.1 vs. 14.2%; HR 0.92; 95% CI 0.79–1.08). There was also no difference in death alone or MI alone. Although GUSTO (Global Use of Strategies To Open Occluded Coronary Arteries) severe bleeding (severe bleeding leading to haemodynamic compromise or intracranial haemorrhage) was not significantly different between the two groups (1.5 vs. 1.6%; HR 0.91; 95% CI 0.57–1.45), there was an increase in TIMI major bleeding with enoxaparin (3.7 vs. 2.5%; HR 1.46; 95% CI 1.04–2.04).

These consistent data further support the efficacy and the safety of SC enoxaparin to anticoagulate PCI in NSTE-ACS patients. Dose adjustment is warranted in obese, elderly, and renal failure patients, and switching to another anticoagulant during PCI, namely UFH, seems to be associated with increased risk of bleeding. It appears, furthermore, that LMWH and GPI can be safely used in combination, without any apparent increase in the risk of major bleeding.20 The algorithm on how to transfer patients pre-treated with subcutaneous (SQ) LMWH from the CCU to the cathlab is summarized in Figure 2.


Figure 0702
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  		Figure 2 Algorithm on how to transfer patients pre-treated with SQ LMWH from the CCU.20

 

   Direct anti-XA inhibitor: fondaparinux
Top
 Abstract
 Introduction
 Mechanisms of action of...
 LMWH in ACS
 Direct anti-XA inhibitor:...
Direct thrombin inhibitors
 Comments
 References
 
In the international, multicentre, randomized, double-blind, double-dummy Fifth Organization to Assess Strategies in Acute Ischaemic Syndromes (OASIS-5) trial, 20 078 patients with NSTE-ACS were randomized to either fondaparinux (2.5 mg per day, SC) or enoxaparin (1 mg/kg/12 h SC). In patients with severe renal dysfunction (creatinine clearance < 30 mL/min), enoxaparin dose was reduced to 1 mg/kg/24 h. Creatinine levels under median were observed among 8871/19 995 patients (44.4%), with data available. Angiography could be performed at any time. To perform a PCI, no anticoagulant switch was done with fondaparinux; additional IV boluses were administered depending on both the timing of the last SC injection and concomitant administration of GPI21(Figure 3). Among patients receiving enoxaparin, a switch to UFH was to be done if a PCI was performed 6 h after the last SC enoxaparin injection, a strategy described as non-optimal in SYNERGY (results of which were not known when OASIS 5 started enrolment). Overall, 55% of patients in the enoxaparin group received UFH, and 21% in the fondaparinux group. Angiography was performed among 63% of the patients, and 34% underwent PCI during hospitalization. The triple ischaemic primary endpoint of death/MI/recurrent ischaemia at 9 days was similar in both treatment groups (5.8% in the fondaparinux group vs. 5.7% in the enoxaparin group; HR 1.01; 95% CI 0.90–1.13), meeting the criteria of non-inferiority. The incidence of major bleedings at 9 days was significantly reduced with fondaparinux (2.2 vs. 4.1%; HR 0.52; 95%CI 0.44–0.61). This reduction in bleeding incidence was associated with a reduction in mortality (HR 0.89; 95% CI 0.80–1.00; P = 0.05) as well as the composite of death/MI/stroke through 180 days (HR 0.89; 95% CI 0.82–0.97). A total of 6207 patients underwent PCI. A significant increase rate of catheter thrombus was reported in fondaparinux-treated patients compared with enoxaparin-treated patients (1.3 vs. 0.5%, P < 0.001), although acute coronary complications remained similar (9.6 vs. 8.6%, P = 0.18). This serious drawback for PCI was also found in the ASPIRE and OASIS 6 studies.22,23 The adjunct of a full dose of UFH has been recommended on top of the fondaparinux treatment to perform PCI to avoid this excess of risk in catheter thrombosis.


Figure 0703
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  		Figure 3 Study design of the OASIS-5 trial.21

 

   Direct thrombin inhibitors
Top
 Abstract
 Introduction
 Mechanisms of action of...
 LMWH in ACS
 Direct anti-XA inhibitor:...
 Direct thrombin inhibitors
Comments
 References
 
Phase III ACS trials with DTIs are limited to hirudin and bivalirudin.

Recombinant hirudin
The GUSTO-IIb24 randomized 8011 patients with NSTE-ACS between UFH (5000 U bolus, followed by a 1000 U/h infusion) and hirudin (0.1 mg/kg bolus, followed by a 0.1 mg/kg/h infusion) during 3–5 days. Coronary angiography was performed among 58 and 57% of the patients in the hirudin and UFH arms, respectively, and PTCA in 22 and 23% patients, respectively. Incidence of the composite of death/MI at 30 days was similar within the two groups (9.1 vs. 8.3%, P = NS), but hirudin was associated with a strong trend towards an increased risk of severe bleeding (1.3 vs. 0.9%, P = 0.06) and intracranial bleeding (0.2 vs. 0.02%, P = 0.06). In the global population of the study (including an additional group of 4131 patients with ST-elevation MI), the authors noted that there was nonetheless a significant benefit of hirudin therapy compared with heparin within the first 48 h; this benefit was not maintained at 30 days. Hypotheses of rebound coagulation activation after discontinuation of hirudin therapy or a lack of passivation of the vascular injury were raised. Indeed, haemostatic marker studies demonstrated that hirudin as well as UFH failed to prevent thrombin generation. Moreover, elevation of thrombotic markers after drug discontinuation was associated with death and reinfarction at 30 days.25 The mightiness of better outcomes through more optimal blockade of platelet activation, using GP IIb-IIIa blockage agents in addition to hirudin, was hypothesized.

After the OASIS (Organization to Assess Strategies for Ischemic Syndromes) pilot dose-finding study,26 the OASIS-2 was a double-blind randomized trial comparing UFH (5000 U bolus, then 15 U/kg/h; n = 5058) and hirudin (0.4 mg/kg bolus, then 0.15 mg/kg/h, n = 5083) for 72 h among ACS patients.27 The composite of cardiovascular death or new MI at 7 days (primary endpoint) tended to be less frequent among hirudin-treated patients than among UFH-treated patients [3.6 vs. 4.2%, relative risk (RR) 0.84 (95% CI 0.69–1.02); P = 0.077). Hirudin was associated with lower rate of cardiovascular death/new MI/refractory angina at 7 zdays compared with UFH [5.6 vs. 6.7%; RR 0.82 (0.70–0.96); P = 0.0125]. The vast majority of the patients were treated medically, and only 15.4% of the patients (n = 1565) underwent PCI during the first 6 month trial period. Of those, 7.5% (n = 117) underwent early PCI within the first 72 h. In this small subgroup, hirudin was associated with a significantly lower incidence of death or MI at 96 h (6.4 vs. 21.4%, OR 0.30; 95% CI 0.10–0.88) and 35 days (6.4 vs. 22.9%; OR 0.25; 95% CI 0.07–0.86) compared with UFH. In the overall population, these efficacy results were however balanced by an excess of major bleeding requiring transfusion with hirudin (1.2 vs. 0.7%, P = 0.01). The safety concerns were then raised against the use of hirudin and probably caused the interruption of further development of this agent.

Bivalirudin (or hirulog)
Bivalirudin has been investigated more than 10 years ago as an adjunctive therapy for high-risk PCI and is now the only DTI labelled for PCI. After the dose-ranging studies,28 the recent REPLACE-1 and -2 trials29,30 have shown that bivalirudin provided similar protection from ischaemic events as UFH/enoxaparin + GP IIb/IIIa inhibitors, with markedly reduced bleeding (Figure 4).


Figure 0704
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  		Figure 4 Bleeding and ischaemia in the three trials of bivalirudin during PCI.

 
After the dose-finding, randomized, double-blind TIMI 7 trial,31 a comparison between bivalirudin and UFH was performed in the Bivalirudin (Hirulog) Angioplasty Study.32 A total of 4098 patients undergoing PCI for unstable or post-infarction angina were randomly allocated to UFH or bivalirudin, as given in Table 1. The primary endpoint of in-hospital death/MI/abrupt vessel closure or clinical deterioration of cardiac origin was similar with both therapies by on-treatment analysis (bivalirudin 11.4%, UFH 12.2%, P = NS); however major bleeding was significantly reduced with bivalirudin (3.8 vs. 9.8%, P < 0.001). Re-analysis of the Bivalirudin Angioplasty Study33 including the entire intention-to-treat cohort of 4312 patients, and not only the 4098 patients treated as per protocol, indicated a significant benefit of bivalirudin in the new endpoint of death/MI/repeat revascularization at 7 (6.2 vs. 7.9%, P = 0.04) and 90 days (15.7 vs. 18.5%, P = 0.01). At 180 days, the absolute risk reduction was maintained, but this was not significant (23.0 vs. 24.7%, P = 0.15). Major bleeding was again less frequent with bivalirudin than with UFH (3.5 vs. 9.3% P < 0.001). On the basis of these trials (Figure 4), bivalirudin appears to be more effective and safer than UFH in ACS patients undergoing PCI. However, the high dose of heparin described earlier resulted in a median activated clotting time (ACT) of 383 s in the UFH group (compared with 346 s in the bivalirudin group, P < 0.001), which is higher than the recommended ACT, and this might have handicapped the UFH arm.


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  		Table 1 Major characteristics of the different anticoagulants

 
The PROTECT-TIMI 30 randomized, open label, multicentre trial compared eptifibatide in combination with heparin (UFH or enoxaparin) with bivalirudin plus provisional eptifibatide in 857 high-risk ACS patients undergoing PCI.34 The primary endpoint of coronary flow reserve (angiographic endpoint) was similar in both groups. The myocardial perfusion after PCI, as assessed by TIMI myocardial perfusion grade, was significantly improved in eptifibatide-treated patients (grade 3 in 57.9% eptifibatide-treated patients vs. 50.9% bivalirudin-treated patients, P = 0.048). In addition, duration of ischaemia among patients with an event was significantly reduced in the eptifibatide groups (36 vs. 169 min in the bivalirudin group, P = 0.013). No major bleeding occurred in the bivalirudin group compared with 0.7% in the eptifibatide group (P = NS); minor bleedings were less frequent among bivalirudin-treated patients (0.4 vs. 2.5%, P = 0.027).

On the basis of these preliminary studies, it appears that bivalirudin has the safety and efficacy potential to replace UFH in the treatment of ACS. Additional information in the contemporary setting of ACS was brought by the results of the large, phase III, randomized, open-label ACUITY trial at the American College of Cardiology (2006). The study was designed to test the hypotheses that in moderate-to-high-risk patients with ACS undergoing an invasive strategy, compared with UFH or LMWH + GP IIb/IIIa inhibitors, (i) bivalirudin + GP IIb/IIIa inhibitors will result in less adverse ischaemic events and less bleeding and (ii) bivalirudin alone will result in similar rates of ischaemic events and markedly reduced bleeding. More than 13 800 patients were randomized into three treatment arms: UFH or enoxaparin + GPI (n = 4603); bivalirudin + GPI (n = 4604); bivalirudin alone (n = 4612). A second randomization was then performed within the GPI groups: routine upstream GPI in all patients or beginning of GPI infusion in the catheterization laboratory if a PCI was to be performed (Figure 5). Angiography was to be performed among all patients within 72 h.35 Table 2 shows study drugs regimen and main endpoint results. The three primary endpoints at 30 days were the following: a triple ischaemic endpoint (death/MI/urgent revascularization), major bleeding, and net clinical outcome combining the triple ischaemic and bleeding endpoints. By intent to treat, the triple ischaemic endpoint occurred similarly among the three treatment arms, satisfying the criteria of non-inferiority of bivalirudin alone or with GPI compared with UFH/enoxaparin + GPI (7.8 vs. 7.7 vs. 7.3%, P-value for non-inferiority < 0.05). Tirofiban and eptifibatide were used as upstream therapy in > 95% of the patients to reduce ischaemic events with a significant excess of major bleeds compared with deferred use of IIb/IIIa inhibitors (6.1 vs. 4.9%, P = 0.009). Major bleedings were observed as among the two GPI arms, reaching significance for non-inferiority of bivalirudin + GPI (5.7% in the heparin + GPI group and 5.3% in the bivalirudin + GPI group, P-value for non-inferiority 0.001). Bivalirudin alone was found superior to heparin + GPI in reducing the incidence of major bleedings (3 vs. 5.7%, P-value for superiority < 0.001). In terms of net clinical outcome, bivalirudin was superior to heparin + GPI (10.1% in the bivalirudin-only group, 11.8% in the bivalirudin + GPI, 11.7% in the UFH/enoxaparin + GPI group, P-value for superiority 0.015).


Figure 0705
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  		Figure 5 Design of the ACUITY trial.35 CCL, cardiac Catheterization laboratory.

 

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  		Table 2 Doses of bivalirudin used in different ACS trials

 
After the ACUITY trial, among the moderate-to-high-risk ACS patients in whom an early invasive strategy with use of GPI is planned, bivalirudin appears as efficient as UFH or enoxaparin therapy. However, bivalirudin alone significantly reduces the risk of major bleedings, resulting in a greater efficiency in reducing the risk of events (ischaemic or bleeding) at 30 days compared with UFH/enoxaparin + GPI or bivalirudin + GPI. However, it must be pointed out that GPI are the real triggers of bleedings in this study as in other trials, and when used symmetrically in the control arm with heparin and in the bivalirudin arm, the safety benefit of bivalirudin is lost. Moreover, the intermediate risk of the population and the short-time window of upstream therapy with GPI left little chance to these drugs to be effective at preventing ischaemic events. Whether a more selective use of these drugs would provide a different result remains unknown. The randomized ISAR-REACT 2 trial36 reported very convincing results of procedural abciximab compared with placebo to reduce ischaemic events in a population of high-risk ACS patients undergoing PCI, without any excess of major bleeding complications (1.4 vs. 1.4%) (Figure 6). In addition, it has been demonstrated that bleeding events are associated with a higher mortality and increased ischaemic risk, mainly within 30 days of hospitalization for ACS.37 Procedures (radial approach) as well as medications (new antithrombin agents) reducing the risk of bleeding should be encouraged and cost effectiveness studies conducted.


Figure 0706
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  		Figure 6 Design and results of the ISAR-REACT-2 trial.36

 

   Comments
Top
 Abstract
 Introduction
 Mechanisms of action of...
 LMWH in ACS
 Direct anti-XA inhibitor:...
 Direct thrombin inhibitors
 Comments
References
 
The largest body of evidence has been obtained with LMWH and, more specifically, enoxaparin, showing superiority or at least equivalence to UFH in ACS patients undergoing currently recommended early invasive strategy. This anticoagulant strategy can be used in patients at first presentation in the ER or in the CCU with a seamless transition to the catheterization laboratory. Enoxaparin use has been shown to be simple and safe without the need for monitoring or dose adjustment when combined with GP IIb/IIIa receptor inhibitors. However, biological monitoring (anti-Xa measurement) may be needed in special situations such as prolonged treatments in obese patients (BMI > 30) or in patients with renal insufficiency (creatinine clearance < 60 mL/min) when accumulation of the drug is likely to occur; additional data are needed in these situations. Indeed, the risk of severe bleeding following treatment with an unadjusted dose of LMWH has been shown to be greater in patients with severe renal impairment (creatinine clearance < 30 mL/min) than in those without, and reducing the LMWH dose may prevent this excess of major bleeding.14,38

There is evidence suggesting that bivalirudin is as effective and safer than heparin + GPI for ACS patients rapidly managed in the catheterization laboratory, but a systematic use of GPI (as tested in the control arm of ACUITY) probably does not reflect the current European practice in an ACUITY-type population of ACS. Cost is also a concern when compared with the other anticoagulant alternatives, especially when access to the catheterization laboratory is delayed. Another challenge is whether bivalirudin can replace selective procedural abciximab use in the catheterization laboratory in high-risk ACS patients with positive troponin undergoing PCI. Indeed, this strategy was effective in ISAR REACT II, and ACUITY failed to show superiority of upstream therapy with small molecules in a heterogeneous population with a large proportion of patients which did not undergo PCI and/or was at low risk of ischaemic events, situations where the risk/benefit ratio of GPI is low. High-risk ACS patients eligible for immediate catheterization and PCI are ideal candidates for procedural abciximab. As in REPLACE 2 for scheduled PCI, the practicality and benefit of bivalirudin in ACS patients may be more for the low-risk patients having a fast access to the catheterization laboratory. Indeed, patients who required a prolonged upstream treatment (>24 h) because of the impossibility of immediate transfer are not ideal candidates given the cost of bivalirudin and the lack of data.

Fondaparinux deserves great attention given the recent impressive results of the OASIS-5 trial, especially on long-term survival and safety of the drug. However, although the impressive efficacy and low incidence of bleeding complications with fondaparinux are well accepted, many cardiologists have voiced uncertainty about using the drug routinely instead of UFH or enoxaparin in ACS patients because of concerns about catheter thrombosis in patients undergoing PCI. The need for combining UFH with fondaparinux to overcome this potential detrimental side effect is an unexpected limitation that needs re-appraisal. Indeed, combination of anticoagulants has been shown to be harmful in the SYNERGY trial and there may be some reluctance in adopting this strategy for PCI.

There is no doubt that safety has become a critical issue as outlined by recent randomized studies providing evidence that severe bleeding and transfusion are associated with poorer prognosis, increase in mortality, and cost. The recent data from OASIS 5 and STEEPLE39 trials showed that the excess of bleeding events could be significantly reduced by decreasing the anticoagulation regimen either during upstream medical management or during PCI. Obviously, fondaparinux and bivalirudin represent an opportunity to improve safety. The three new anticoagulants, enoxaparin, fondaparinux, and bivalirudin have demonstrated improvements, against UFH. This will certainly lead to changes in recommendations of anticoagulation in ACS. The first step now might be to downgrade UFH in the scale of recommendations to reflect the advantages of these new treatments.

Conflict of interest: G.M. has received consultant and/or speaker fees and research grants from Sanofi-Aventis, EliLilly, the Medicines Company, GSK.


   References
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 Abstract
 Introduction
 Mechanisms of action of...
 LMWH in ACS
 Direct anti-XA inhibitor:...
 Direct thrombin inhibitors
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 References
 

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