The place of fondaparinux in the ESC and ACC/AHA guidelines for anticoagulation in patients with non-ST elevation acute coronary syndromes
Department of Cardiology, University Hospital Jean Minjoz, Boulevard Fleming, 25000 Besançon, France
*Corresponding author. Tel: + 33 381 668 539; fax: + 33 381 668 582. E-mail address: jpbassan{at}univ-fcomte.fr
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Abstract |
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The European Society of Cardiology (ESC) and American College of Cardiology/ American Heart Association (ACC/AHA) Practice Guidelines Committees recently published new guidelines on the management of patients with non-ST elevation acute coronary syndromes (NSTE-ACS). In both guidelines, the use of an anticoagulant drug (unfractionated heparin, enoxaparin, bivalirudin, or fondaparinux) became a class IA recommendation. As bleeding events impact survival prognosis, the main focus of new anticoagulant strategies has been on limiting major bleeding complications associated with their use, while maintaining a high level of efficacy. In patients with NSTE-ACS, fondaparinux, the first selective factor Xa inhibitor approved for use in this setting, exhibited similar short-term efficacy compared with enoxaparin, but reduced major bleeding and 30 day mortality. Therefore, in the context of early invasive or conservative strategy, fondaparinux was given a prominent place (class I recommendation) by both societies, notably in patients at risk of bleeding. Fondaparinux was preferred over enoxaparin (class IA vs. IIa-B) in the ESC guidelines, regardless of initial strategy (excluding urgent revascularization for life-threatening conditions). In the ACC/AHA guidelines, fondaparinux was considered the drug of choice in conservative strategy. In fondaparinux patients undergoing invasive procedures, it was recommended to add unfractionated heparin. Fondaparinux was proposed as a drug of choice in patients with renal dysfunction.
Key Words: Acute coronary syndromes • Anticoagulant • Fondaparinux • Guidelines • Low-molecular-weight heparins • Unstable angina
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Introduction |
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The goal of the treatment for non-ST elevation acute coronary syndromes (NSTE-ACS) is to immediately relieve myocardial ischaemia and prevent the occurrence of severe adverse outcomes [i.e. death or myocardial (re)infarction].1,2 In the short-term, it includes the administration of anti-ischaemic and antithrombotic agents; the use of invasive procedures (i.e. angiography, potentially followed by percutaneous coronary intervention for coronary revascularization) is optional depending on the medical status of the patient. In practice, the optimal use of the various available therapeutic options is based on guidelines established through a consensus of expert opinion after a thorough review of all published evidence. Recently, the European Society of Cardiology (ESC) and the American College of Cardiology/American Heart Association (ACC/AHA) published new recommendations on the diagnosis and treatment of patients with NSTE-ACS.1,2 The strength of evidence for, or against, particular procedures or treatments was weighted according to pre-defined scales of grading recommendations in classes and levels of evidence (Table 1). The classes of recommendation correspond to the scale of treatment’s clinical benefit, from high (class I) to low, nil, or even adverse (class III). The levels of recommendation, ranked high (A) to low (C), correspond to the estimate of certainty of treatment effect on the basis of the quality and quantity of evidence. However, there are discrepancies between the level definitions in the ESC and ACC/AHA guidelines. In particular, the quality of the methodology is prominent in the ESC guidelines (e.g. one double-blind, large trial weighs more than meta-analyses of several trials), whereas the number of population risk strata evaluated in registries (along with that evaluated in clinical trials) is key in the ACC/AHA guidelines.1,2 Another substantial difference between the two societies is that the recommendations in the ESC guidelines were based on the efficacy–safety profile of the drugs/treatments, and not simply on the efficacy alone.
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In patients with NSTE-ACS, a combination of antiplatelet and anticoagulant drugs is required to achieve an optimal antithrombotic effect. Recent registries and large trials in patients with ACS have consistently shown that bleeding events significantly impact survival prognosis.3,4 Therefore, in the development of new anticoagulant dosing regimens or new anticoagulant agents in this setting, the main focus has been on limiting major bleeding complications associated with their use, while maintaining their efficacy and, thus, their capacity to reduce mortality. Since the previous ESC and ACC/AHA guidelines, both published in 2002,5,6 two important positive, large, non-inferiority trials testing new synthetic anticoagulant drugs have been published and taken into consideration: the ACUITY trial comparing bivalirudin, a selective direct inhibitor of factor IIa, with unfractionated heparin (UFH)7 and the OASIS-5 trial comparing fondaparinux, the first selective inhibitor of factor Xa, with enoxaparin.8 In the latter, fondaparinux 2.5 mg once daily exhibited similar short-term efficacy compared with enoxaparin 1 mg/kg twice daily, but showed a remarkable and unique effect by reducing major bleeding by 48% and 30 day mortality by 17%.
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Anticoagulant drugs in patients with non-ST elevation acute coronary syndromes |
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Activation of coagulation mechanisms plays a central role in the occurrence of NSTE-ACS, as illustrated by the fact that patients with this disorder exhibit high levels of thrombin generation markers and are effectively treated with anticoagulant drugs.2 The ultimate aim of anticoagulant drugs is to inhibit thrombin generation and/or activity. Several anticoagulants, which act at different levels of the coagulation cascade, have been investigated in the initial management of patients with NSTE-ACS, including UFH, low-molecular-weight heparins, direct thrombin inhibitors, and fondaparinux (Table 2).
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Heparins: unfractionated heparin and enoxaparin
UFH inhibits several activated coagulation factors (including factor IIa) via plasma antithrombin. Its main limitations are related to its pharmacokinetic profile.1 Continuous intravenous infusion is needed in patients with NSTE-ACS due to its poor bioavailability at low doses and short half-life via the subcutaneous route. Moreover, after treatment discontinuation, reactivation of the coagulation process may increase the risk of the recurrence of clinical events.
Enoxaparin is the low-molecular-weight heparin of choice in NSTE-ACS. It mainly inhibits factor Xa and factor IIa. It is effectively administered via the subcutaneous route, with a predictable dose–effect relationship.1 However, maximum plasma levels occur 3 to 5 h after subcutaneous injection, indicating that intravenous administration is necessary in urgent situations.9 In the treatment of patients with NSTE-ACS, dosages are body-weight-adapted with two daily injections every 12 h to avoid the risk of inadequate plasma levels during treatment. The monitoring of plasma levels may be useful in special populations, e.g. obese patients or patients with renal failure. The administration of both UFH and enoxaparin is associated with a non-negligible risk of immunoallergic thrombocytopenia.
Direct thrombin inhibitors: bivalirudin
Bivalirudin is a synthetic analogue of hirudin that inhibits thrombin by binding directly to the molecule.1 The drug is administered via the intravenous route, and the anticoagulant activity may be monitored using the activated partial thromboplastin time or the activated clotting time. However, contrary to UFH, the anticoagulant effect of bivalirudin is more predictable, as the drug does not bind to plasma protein. Currently, its use is only proposed in the context of urgent or elective percutaneous coronary intervention.
Factor Xa inhibitors: fondaparinux
Fondaparinux is the first pure factor Xa inhibitor available for clinical use. This synthetic pentasaccharide selectively inhibits factor Xa via plasma antithrombin. Factor Xa plays a pivotal role upstream in the coagulation cascade at the cross-link of contact and extrinsic pathways. Administered subcutaneously at the dose of 2.5 mg, fondaparinux exhibits a 100% bioavailability with a very rapid onset of action (half of the peak plasma concentration being reached in 25 min after dosing, and peak plasma concentration in 2 h) and a 17 h elimination half-life, optimal for once-daily administrations.10 Maximum plasma concentrations are achieved even more rapidly following intravenous bolus administration, but the half-life is unchanged compared with subcutaneous administration.11 Fondaparinux does not bind to plasma proteins other than antithrombin, explaining the low intra- and inter-subject variabilities and the absence of drug interactions. At therapeutic doses, fondaparinux exerts very limited effects on routine haemostasis tests, including activated partial thromboplastin time and activated clotting time. Moreover, the drug exhibits no effect on platelets and there is no need to monitor platelet count, as the risk of immunoallergic thrombocytopenia is negligible, if not nil.12 Overall, the use of fondaparinux is simple: the once-daily 2.5 mg dose is recommended in all patients with ACS, with no dose-adjustment and no laboratory monitoring, regardless of patient type.
Of note, enoxaparin, bivalirudin, and fondaparinux are all eliminated by the renal route and contraindicated in patients with severe renal impairment.
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Recommendations for anticoagulation in patients with non-ST elevation acute coronary syndromes |
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Because patients with NSTE-ACS are a heterogeneous group in terms of risk of cardiac death and non-fatal ischaemic events, their therapeutic management is tailored according to the risk of subsequent events. Consequently, more intensive antithrombotic therapy, notably with respect to antiplatelet agents, is generally recommended for patients most at risk of ischaemic complications. However, this may be problematic, as this strategy is generally associated with an increased risk of bleeding complications, and patients at high risk of ischaemic events are also at high risk of bleeding complications, particularly the elderly and those with renal dysfunction.1,2 Moreover, recent data have indicated that bleeding events have a major impact on survival prognosis.7,8 For example, major bleeding was an independent predictor for the long-term risk of death, myocardial infarction, and stroke in the OASIS-5 trial in patients with NSTE-ACS (Figure 1).13 This finding may be related to the need to discontinue antithrombotic treatments in patients who bleed. Other factors include inflammatory reactions and activation of coagulation triggered by bleeding, haemodynamic consequences of the bleed, and potential deleterious effects of blood transfusions. Anaemia, present in 5–10% of patients with NSTE-ACS, is also associated with a less favourable prognosis.1 Consequently, the experts of the ESC guidelines have emphasized the fact that, besides assessing the ischaemic risk, bleeding risk assessment should be an important component of the decision-making process. In addition, they have recommended the implementation of all measures necessary to avoid the deterioration of anaemia by bleeding (I-B). Bleeding prevention is equally as important as the prevention of ischaemic events and may result in a significant risk reduction for death, myocardial infarction, and stroke. Thus, their recommendations for the use of anticoagulant drugs were established by taking into account both their efficacy and safety profile in terms of bleeding risk; they proposed a preference for anticoagulant drugs with a reduced risk of bleeding (I-B).
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Management strategies
The type of therapeutic strategy, and particularly the need for and timing of invasive strategy, influences both the choice and the dosage regimen of anticoagulant drugs (Table 3). Several risk tools (e.g. the TIMI risk calculator, the PURSUIT risk score, or the GRACE calculator) may help the physician in choosing the most adequate therapeutic strategy. A conservative strategy is generally recommended for low-risk patients, whereas invasive strategy is proposed for higher risk patients. Regarding the latter, the ESC guidelines distinguished between ‘urgent invasive strategy’ to be performed within 2 h of symptom onset and ‘early invasive strategy’ to be performed within 72 h of symptom onset, depending on the medical status of the patient. In this latter context, decisions about the timing of catheterization are continuously re-evaluated and modified according to clinical evolution and occurrence of new clinical findings. The ACC/AHA guidelines distinguished ‘invasive strategy’ (regrouping ‘initial’ and ‘early’ invasive strategy) from ‘initial conservative strategy’ or ‘selective invasive management’. In the latter case, an invasive evaluation is proposed only for patients who failed medical therapy, or in whom objective evidence of ischaemia is identified.
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ESC guidelines for anticoagulation
In the ESC guidelines, anticoagulation was recommended for all patients, in addition to antiplatelet therapy, with the highest level of recommendation (I-A). It was specified, though, that the type of drug be selected according to the risk of both bleeding and ischaemic events (I-B) (Table 4).1
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In early invasive or conservative strategy (non-urgent situations), fondaparinux was preferred on the basis of its having the most favourable efficacy/safety profile (I-A). Enoxaparin, with a less favourable efficacy/safety profile, was proposed only if the bleeding risk was low (IIa-B). Concerning the duration of treatment, it was recommended that fondaparinux or enoxaparin be continued up to hospital discharge (I-B). The ESC experts considered that other available low-molecular-weight heparins, or UFH, could not be recommended over fondaparinux in this setting, since their efficacy/profile relative to fondaparinux was unknown.
In patients who undergo percutaneous coronary intervention in the context of early invasive strategy, the experts considered that the anticoagulant drug started before the procedure should be maintained during the procedure, whether this treatment was enoxaparin (IIa-B), UFH (I-C), or bivalirudin (I-B). For fondaparinux, they recommended an additional 50–100 U/kg intravenous bolus of UFH during the procedure (IIa-C).
In the context of urgent invasive strategy (i.e. performed within 2 h of symptom onset and which only concerns <5% of patients), the ESC experts recommended bivalirudin (I-B), UFH (I-C), or enoxaparin (IIa-B), to be started immediately. Fondaparinux was not recommended in this setting. Anticoagulation can be stopped within 24 h after the invasive procedure (IIa-C).
ACC/AHA guidelines for anticoagulation
In the ACC/AHA guidelines, the experts recommended that anticoagulant therapy should be added to antiplatelet therapy as soon as possible after presentation (I-A) (Table 4).2
For patients in whom a conservative strategy was selected, the ACC/AHA experts noted that enoxaparin or UFH (I-A) or fondaparinux (I-B) has established efficacy. However, they considered that enoxaparin or fondaparinux was preferable to UFH, unless a coronary artery bypass graft was planned within 24 h (IIa-B). They also stated that fondaparinux was preferable to enoxaparin or UFH in patients with an increased risk of bleeding (I-B). They did not recommend bivalirudin, as this drug had not been tested in a non-invasive strategy setting. For patients who did not undergo angiography or stress testing, they recommended the continuation of UFH for 48 h, and fondaparinux or enoxaparin for the duration of hospitalization, up to 8 days (I-A).
For patients in whom an invasive strategy was selected, the experts of the ACC/AHA guidelines recommended a number of anticoagulant strategies with a class I grade, but they emphasized the fact that a preference for a particular strategy was far from clear since many confounding factors made the comparison of these various antithrombotic strategies difficult. The recommended drug were UFH (I-A), enoxaparin (I-A), fondaparinux (I-B), or bivalirudin (I-B). An additional bolus of UFH (
50 U/kg) was recommended if fondaparinux was used. If no significant obstructive coronary artery disease was observed upon angiography, they indicated that anticoagulant therapy should be administered at the discretion of the clinician (I-C). If any coronary artery disease was present upon angiography, they recommended the continuation of the anticoagulant drug used before diagnostic angiography, i.e. either UFH for 48 h or until discharge (I-A), or enoxaparin (I-A) or fondaparinux (I-B) for the duration of hospitalization, up to 8 days. If bivalirudin was given prior to diagnostic angiography, the experts indicated that the drug could be discontinued, or continued for 72 h at the physician’s discretion (I-B). If the patient underwent percutaneous coronary intervention, they recommended the discontinuation of anticoagulant therapy after the procedure in uncomplicated cases (I-B).
If coronary artery bypass graft surgery was selected after diagnostic angiography, UFH could be continued (I-B). On the other hand, they recommended the discontinuation of enoxaparin, fondaparinux, or bivalirudin 12–24 h, 24 h, or 3 h before the procedure, respectively, and the administration of UFH as per institutional practice (I-B).
Specific issues for anticoagulation
Renal dysfunction, frequently observed in patients with coronary artery disease, notably the elderly, has a major impact on prognosis.1 It is also an independent predictor of bleeding risk—the more severe the dysfunction, the higher the bleeding risk.1 Furthermore, its presence complicates the use of drugs with exclusive or substantial renal elimination. Thus, the ESC experts noted that a better definition of the appropriate dose of antithrombotic agents, according to the level of renal dysfunction, was needed (Table 5).1 Concerning anticoagulant drugs, they recommended that the use of UFH be adjusted according to activated partial thromboplastin time in patients with a creatinine clearance <30 mL/min, since the renal route is not the main route of elimination of this drug (I-C).1 However, at high doses, UFH is cleared via the kidneys, and, in both the ESC and ACC/AHA guidelines, it was noted that, according to registry data, the use of UFH did not avoid bleeding complications in patients with renal dysfunction.1,2 In patients with severe renal failure (creatinine clearance <30 mL/min), low-molecular-weight heparins, fondaparinux, and bivalirudin are generally contra-indicated, or down-titrated according to country-specific labelling. However, the ESC experts noted that, because of its greater safety in terms of bleeding risk compared with enoxaparin, including patients with renal impairment, fondaparinux might be the anticoagulant of choice in this situation. Indeed, in the OASIS-5 trial, fondaparinux 2.5 mg once daily was safer in terms of bleeding risk than enoxaparin in patients with severe renal failure, despite the use of reduced enoxaparin doses in these patients (1 mg/kg once daily instead of 1 mg/kg twice daily according to the US labelling of enoxaparin).8,9,14 Fondaparinux also reduced mortality in these patients (Table 6).14
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Thrombocytopenia may occur in the course of treatment of NSTE-ACS. This event may be related to the use of UFH or low-molecular-weight heparins in the context of immunoallergic heparin-induced thrombocytopenia. In this case, the ESC experts recommended the immediate discontinuation of heparin administration (I-C).1 Likewise, the ACC/AHA experts stated that a high clinical suspicion of heparin-induced thrombocytopenia mandated the immediate cessation of all heparin therapy (included that used to flush intravenous lines).2 Importantly, the ESC experts noted that prevention of heparin-induced thrombocytopenia could be achieved by using anticoagulants devoid of this risk, e.g. fondaparinux or bivalirudin, or by administering heparins for only a brief period (I-B).1
Place of fondaparinux in the ESC and ACC/AHA guidelines
Fondaparinux has a prominent place with a class I recommendation in both the ESC and ACC/AHA NSTE-ACS guidelines.1,2 In the ESC guidelines, when a decision between early invasive or conservative strategy is pending, fondaparinux was preferred (I-A) over the other available anticoagulant drugs on the basis of its more favourable efficacy/safety profile, regardless of the patient.1 In the ACC/AHA guidelines, this preference for fondaparinux was given for patients at risk of bleeding, particularly in the setting of non-invasive strategy, as available trials ‘suggest an anticoagulant preference in the order of fondaparinux, enoxaparin, and UFH (least preferred)’.2
Concerning invasive procedures, fondaparinux was recommended with the adjunction of an intravenous bolus of UFH at the dose of 50–100 U/kg (I-B) in the ACC/AHA guidelines and in the ESC guidelines (IIa-C).1,2 Both societies noted that, although adding UFH to fondaparinux in this setting did not increase bleeding risk in the OASIS-5 study,8,15 a larger data set of patients was needed to confirm the safety of the association.1
The ESC guidelines did not recommend fondaparinux in the setting of urgent revascularization requested within 2 h after symptom onset for life-threatening conditions.1
Finally, the ESC experts also underlined the value of fondaparinux in patients with renal dysfunction, or with a suspicion or a risk of heparin-induced thrombocytopenia.1
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Conclusion |
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The choice of anticoagulant drugs in patients with NSTE-ACS is critical. Since the publication of the previous ESC and ACC/AHA guidelines, two important new sets of data have been published, the first concerning the link between the risk of bleeding and the risk of ischaemic events and death, the second being the publication of the ACUITY and OASIS-5 trials. As a consequence, the patient risk profile is recognized as being a crucial factor when selecting the best anticoagulation therapy, and, along with UFH and enoxaparin, bivalirudin and fondaparinux are two new anticoagulant drugs to be considered during this selection process. In OASIS-5, fondaparinux was as effective as enoxaparin in the short term, but significantly reduced bleeding risk and mortality at 30 days. Furthermore, contrary to what was observed with previous anticoagulants, the overall benefit obtained in fondaparinux-treated patients was maintained on a long-term basis. Consequently, fondaparinux 2.5 mg once daily was given a class I recommendation in the management of patients with NSTE-ACS in both the ESC and ACC/AHA guidelines. Moreover, both the ESC and ACC/AHA experts considered that, compared with other available anticoagulant drugs, fondaparinux was an appealing choice in NSTE-ACS patients, especially in patients at higher risk for bleeding. Thus, it may be expected that with the implementation of these new guidelines in practice, and in particular the use of effective and safe anticoagulant drug such as fondaparinux, the prognosis of patients with NSTE-ACS will continue to improve.
Conflict of interest: Speakers' Bureau: Sanofi-aventis, GlaxoSmithKline, Lilly, Servier; Consultancy: Sanofi-aventis; Shares: Sanofi-aventis, GlaxoSmithKline, Lilly.
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