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Anticoagulant therapy in non-ST elevation acute coronary syndromes

Anticoagulant therapy in non-ST elevation acute coronary syndromes
Literature review current through: Jan 2024.
This topic last updated: Dec 08, 2022.

INTRODUCTION — Acute myocardial infarction results from rupture of an atherosclerotic plaque, which leads to intraluminal thrombosis. Intraluminal thrombus impairs distal blood flow and may lead to myocardial ischemia or infarction. Intraluminal hemostasis is a dynamic process involving both clot formation and intrinsic fibrinolysis. The goal of antithrombotic therapy (the combination of anticoagulant and antiplatelet therapy) is to prevent clot extension and reformation in cases where the clot has undergone fibrinolysis either by intrinsic mechanisms, fibrinolytic treatment, or mechanical means. (See "Overview of hemostasis" and "Mechanisms of acute coronary syndromes related to atherosclerosis".)

This topic will review the evidence that supports the use of parenteral anticoagulant therapy in all patients with acute non-ST elevation acute coronary syndromes (NSTEACS), which include both unstable angina and acute non-ST elevation myocardial infarction. The topic will provide recommendations for its use according to whether the patient receives reperfusion with percutaneous coronary intervention or no reperfusion therapy. Information regarding anticoagulant agents in ST-elevation myocardial infarction and the role of antiplatelet therapy in NSTEACS is found elsewhere. (See "Acute ST-elevation myocardial infarction: Management of anticoagulation" and "Acute non-ST-elevation acute coronary syndromes: Early antiplatelet therapy".)

CLASSIFICATION OF ANTICOAGULANT AGENTS — There are three classes of anticoagulants that have been evaluated in the management of acute coronary syndromes:

The heparins, including unfractionated heparin (UFH) and the low molecular weight heparins (LMWH), are indirect thrombin inhibitors that complex with antithrombin (AT, formerly known as AT III) and convert AT from a slow to a rapid inactivator of thrombin, factor Xa, and to a lesser extent, factors XIIa, XIa, and IXa. (See "Overview of hemostasis" and "Heparin and LMW heparin: Dosing and adverse effects".)

There are a few limitations to UFH therapy in patients with acute myocardial infarction. One potential issue is binding to circulating plasma proteins, which renders inter- and intra-patient dosing unpredictable and requires continuous intravenous rather than subcutaneous dosing for consistent anticoagulant effect. The propensity to develop heparin-induced thrombocytopenia is another limitation. (See "Clinical presentation and diagnosis of heparin-induced thrombocytopenia".)

LMWH inactivates factor Xa, like UFH, but has a lesser effect on thrombin (figure 1). LMWH does not prolong the aPTT in a predictable fashion. They have a number of advantages over UFH, including a more predictable anticoagulant effect and a reduced likelihood of inducing immune-mediated thrombocytopenia.

LMWHs include enoxaparin, nadroparin, tinzaparin, and dalteparin. The last three have been compared with placebo, UFH, or enoxaparin [1-5]. These three seem to be as effective as UFH, may be less effective than enoxaparin, and may be associated with higher rates of major bleeding.

The synthetic heparin pentasaccharide fondaparinux acts through antithrombin to exclusively neutralize factor Xa. Fondaparinux is the only non-heparin factor Xa inhibitor that has been evaluated for efficacy and safety in patients with NSTEACS and is available for clinical use. (See "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects", section on 'Direct factor Xa inhibitors'.)

The direct thrombin inhibitors (eg, argatroban, inogatran, efegatran, lepirudin, hirudin, and bivalirudin [Hirulog]) bind to and inactivate one or more of the active sites on the thrombin molecule [6]. While early studies suggested benefit from many of them when compared with heparin [7], only bivalirudin is clinically used. (See "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects", section on 'Direct thrombin inhibitors'.)

OUR APPROACH — Anticoagulant therapy should be given as soon as possible after diagnosis to all patients with NSTEACS. The recommendation for use in all patients is based on early studies with unfractionated heparin (UFH) and dalteparin (a low molecular weight heparin), which found that anticoagulant therapy leads to better outcomes, such as a reduction in the rate of myocardial infarction, than no therapy [8,9]. The recommendation for early use is based on the fact that this therapy was started within a few hours of diagnosis in all randomized trials.

The choice between UFH, enoxaparin, bivalirudin, or fondaparinux is determined by whether the patient is managed by an early invasive or a conservative approach, as well as local practice (see "Non-ST-elevation acute coronary syndromes: Selecting an approach to revascularization"):

For patients managed with a conservative approach, we prefer either fondaparinux or enoxaparin given at the time of diagnosis.

For patients managed with an invasive strategy (angiography, usually within 48 hours), we prefer UFH given at the time of diagnosis in most cases. This recommendation also applies to patients who will undergo angiography within four hours, referred to as the immediate angiography approach. Fondaparinux makes less sense in this setting, as heparin or bivalirudin would need to be added to fondaparinux soon after starting the latter.

We prefer UFH to bivalirudin in patients receiving ticagrelor or prasugrel for reasons of a possibly lower rate of stent thrombosis and lower cost. For patients receiving clopidogrel, either bivalirudin or UFH is reasonable as a procedural anticoagulant if percutaneous coronary intervention is performed. Although bivalirudin was used upstream of cardiac catheterization in one trial, we rarely use bivalirudin outside of the cardiac catheterization laboratory. For patients with femoral artery access and concern for higher risk of bleeding, bivalirudin is a reasonable choice.

For patients who undergo an invasive approach, and who were started on fondaparinux, switching to heparin or bivalirudin is mandatory, as the risk of intracoronary catheter thrombosis appears to be increased with fondaparinux treatment alone. (See 'Invasive approach' below.)

CONSERVATIVE APPROACH — For patients managed with a conservative approach (revascularization not intended), we prefer either fondaparinux or enoxaparin to bivalirudin or unfractionated heparin (UFH). The choice between fondaparinux and enoxaparin should be determined by issues of cost and local practice. For patients at increased risk of bleeding (table 1), based on the findings in OASIS-5, some of our experts prefer fondaparinux to enoxaparin. (See 'Invasive approach' below.)

In patients managed conservatively, enoxaparin leads to fewer adverse cardiovascular events when compared with UFH. In addition, enoxaparin is easier to administer (subcutaneous as opposed to the intravenous route with UFH) and requires no laboratory monitoring. Bivalirudin has not been adequately assessed in this population.

In the following three trials, all or most of the patients were approached with a conservative strategy. These trials had differing populations and cointerventions:

The ESSENCE trial compared the effectiveness of enoxaparin with continuous UFH in 3171 aspirin-treated patients with unstable angina (angina at rest) or acute non-ST elevation myocardial infarction (NSTEMI); therapy was given for a minimum of 48 hours to a maximum of eight days [10]. Revascularization was not intended in this trial. At 30 days, enoxaparin therapy had a significant lower rate of a combined end point of death, MI, and recurrent angina (19.8 versus 23.3 percent with UFH) or a revascularization procedure (27.0 versus 32.2 percent). There was no difference between the two groups in the rates of major bleeding (6.5 versus 7.0 percent) or severe thrombocytopenia (0.4 versus 0.6 percent) [11]. These benefits were maintained at one year [12].

The benefits of enoxaparin compared with UFH in NSTEACS patients were confirmed in the TIMI 11B trial of 3910 aspirin-treated patients for whom revascularization was not intended [13]. The incidence of the primary end point (death, MI, or urgent revascularization) was significantly lower with enoxaparin at eight days (12.4 versus 14.5 for heparin). The benefit of enoxaparin was limited to patients with elevated levels of troponin I [14].

In Phase A of the A to Z trial, 3987 patients with an NSTEACS (74 percent NSTEMI) were randomly assigned to enoxaparin or UFH [15]. An early invasive strategy was declared in 55 percent of the study subjects, at the discretion of the physician. At seven days, there was no significant difference in the incidence of the primary end point (death, MI, or refractory ischemia) between the enoxaparin and UFH arms (8.4 versus 9.4 percent, respectively; hazard ratio 0.88; 95% CI 0.71-1.08). However, in the subgroup of patients who were treated with an intended early conservative strategy, there was a significant reduction in the primary end point with enoxaparin (7.7 versus 10.6 percent). The incidence of major bleeding was greater with enoxaparin (0.9 versus 0.4 percent with UFH; p = .05), but there was no increase in transfusion rates.

INVASIVE APPROACH — For NSTEACS patients managed with an invasive approach (angiography and possible revascularization within 48 hours), we prefer unfractionated heparin (UFH; given as soon as possible after diagnosis) to bivalirudin, enoxaparin, or fondaparinux. While UFH and bivalirudin have similar efficacy and safety outcomes, there is a significant cost advantage to UFH.

Unfractionated heparin compared with enoxaparin — For most NSTEACS patients undergoing an invasive strategy, we prefer UFH to enoxaparin based on an increased rate of bleeding with the latter. There is no evidence to support the use of other low molecular weight heparins.

The SYNERGY trial provides the best evidence with which to compare UFH with enoxaparin in patients who receive contemporary antiplatelet therapy [16,17]. This trial randomly assigned 10,027 patients with an NSTEACS to open label enoxaparin or UFH. Coronary angiography was performed in 92 percent of the SYNERGY patients; 47 percent underwent percutaneous coronary intervention (PCI), and 19 percent underwent surgical revascularization.

There was no significant difference in the rate of the primary end point of death or nonfatal myocardial infarction (MI) at 30 days or at six months with enoxaparin (14.0 versus 14.5 percent and 17.6 versus 17.8 percent, enoxaparin compared with UFH). There was also no difference in death or nonfatal MI or in all-cause mortality at one year (7.4 versus 7.8 percent). However, there was a significant increase in in-hospital major bleeding with enoxaparin (9.1 versus 7.6 percent for UFH).

Unfractionated heparin compared with bivalirudin — For most NSTEACS patients undergoing an invasive strategy, we prefer UFH to bivalirudin for reasons of cost and a possibly higher rate of stent thrombosis with bivalirudin. For patients who have undergone coronary angiography, bivalirudin is a reasonable alternative to heparin plus a glycoprotein (GP) IIb/IIIa inhibitor. The most contemporary study that compared bivalirudin with UFH was the 2017 open-label VALIDATE-SWEDEHEART randomized trial. In this trial, 6006 patients with ST-elevation MI or non-ST elevation MI (NSTEMI) undergoing urgent PCI and receiving treatment with ticagrelor, prasugrel, or cangrelor were randomly assigned to bivalirudin or heparin [18]. Most patients received radial artery access, and the use of GP IIb/IIIa inhibitors was not intended. The primary composite end point (death from any cause, MI, or major bleeding at 180 days) occurred in 12.3 percent in the bivalirudin group and 12.8 percent in the heparin group (hazard ratio 0.96, 95% CI 0.83-1.10). In addition, no significant difference in the rate of definite stent thrombosis was found. While not powered to assess the individual end points in the composite, the trial did not find any apparent difference between the two anticoagulants for the individual components, including major bleeding, which was 8.6 percent in each group. The observed event rates were lower than those predicted.

Before VALIDATE-SWEDEHEART, bivalirudin had been compared with heparin in three large randomized trials performed before the routine use of ticagrelor or prasugrel or before the routine use of the radial artery for access. These trials presented below suggested similar outcomes with the two anticoagulants, with the exception that major bleeding was increased in the two trials that planned combination of heparin with GP IIb/IIIa inhibitor. Since we do not recommend routine use of a GP IIb/IIIa inhibitor, there is no advantage to bivalirudin in most patients. (See "Acute non-ST-elevation acute coronary syndromes: Early antiplatelet therapy", section on 'Glycoprotein IIb/IIIa inhibitors'.)

In the ACUITY trial, nearly 14,000 patients with moderate- to high-risk ACS undergoing PCI were randomly assigned to bivalirudin (alone or with a GP IIb/IIIa inhibitor) or UFH or enoxaparin (both with a GP IIb/IIIa inhibitor) [19,20]. Prior to randomization, about 64 percent of patients were receiving either UFH or enoxaparin, while about 36 percent were receiving neither. Primary end points included a composite of ischemic complications (death, MI, or unplanned revascularization for ischemia at 30 days) and major bleeding. Bivalirudin alone was noninferior to UFH or enoxaparin for the rate of ischemic complications (7.8 versus 7.3 percent, relative risk 1.08, 95% CI 0.93-1.24), while the rate of major bleeding was significantly lower with bivalirudin monotherapy (3.0 versus 5.7 percent, relative risk 0.53, 95% CI 0.43-0.65).

In the ISAR-REACT 4 trial, 1721 patients with NSTEMI were randomly assigned to heparin plus GP IIb/IIIa inhibitor or bivalirudin monotherapy immediately before PCI [21]. At 30 days, there was no significant difference in the rate of the primary composite end point (death, large recurrent MI, urgent target–vessel revascularization, or major bleeding) between heparin plus GP IIb/IIIa inhibitor and bivalirudin (10.9 versus 11.0 percent; relative risk 0.99, 95% CI 0.74-1.32). There was significantly more major bleeding with UFH plus GP IIb/IIIa inhibitor (4.6 versus 2.6 percent).

The 2015 MATRIX trial randomly assigned 7213 patients with an ACS (NSTEACS in 44 percent) to receive either bivalirudin or UFH [22]. In patients receiving bivalirudin, GP IIb/IIIa inhibitors could only be given to patients with periprocedural ischemic complications; in patients receiving heparin, GP IIb/IIIa inhibitor (at the discretion of treating physician) could be given before PCI. GP IIb/IIIa inhibitor was given in 4.6 percent of patients in the bivalirudin group and 25.9 percent of patients in the heparin group. At 30 days, comparing bivalirudin with heparin, there was no difference in the rates of the primary end points of major adverse cardiovascular events, a composite of death, MI, or stroke; or net adverse clinical events, a composite of major bleeding or major adverse cardiovascular event (10.3 versus 10.9 percent; relative risk 0.94, 95% CI 0.81-1.09 and 11.2 versus 12.4 percent; relative risk 0.89, 95% CI 0.78-1.03, respectively).

The rate of definite stent thrombosis was borderline higher with bivalirudin (1.0 versus 0.6 percent; rate ratio 1.71, 95% CI 1.00-2.93). However, there was no significant difference in the rate of definite or probable stent thrombosis.

The rate of Bleeding Academic Research Consortium 3 or 5 bleeding (table 2) was lower in the bivalirudin group (1.4 versus 2.5 percent; rate ratio 0.55, 95% CI 0.39-0.78), but the relevance of this finding is unclear given the marked asymmetry in the use of GP IIb/IIIa inhibitors in the two treatment groups (4.6 percent with bivalirudin versus 25.9 percent with heparin).

At one year, comparing bivalirudin with heparin, there was no difference in the rates of the primary end points of major adverse cardiovascular events or net adverse clinical events (15.8 versus 16.8 percent; relative risk 0.94, 95% CI 0.83-1.05 and 17.0 versus 18.4 percent; relative risk 0.91, 95% CI 0.81-1.02, respectively) [23].

Fondaparinux — For most patients with NSTEACS managed with an invasive strategy, we prefer anticoagulation with UFH (see 'Unfractionated heparin compared with bivalirudin' above). We do not routinely use fondaparinux due to the possibility of an increased rate of stent thrombosis and thus a requirement to use heparin at the same time. Fondaparinux may be a reasonable anticoagulant choice in ACS patients at increased risk of bleeding (table 1), based principally on the results of the OASIS-5 trial discussed below.

However, some patients will have been started on fondaparinux for reasons such as a concern for bleeding. For those individuals undergoing PCI in whom fondaparinux was chosen as the initial anticoagulant, we strongly recommend switching to standard-dose UFH (see 'Anticoagulant Use' below), with further dosing of the latter based on the activated clotting time, as was done in the FUTURA/OASIS 8 trial (discussed below). Although bivalirudin has not been evaluated in patients started on fondaparinux, we believe that switching to bivalirudin is also a reasonable anticoagulant strategy.

In OASIS-5, 20,078 NSTEACS patients were randomly assigned to fondaparinux (2.5 mg/day) or enoxaparin (1 mg/kg twice daily) for a mean of six days (anticoagulant was generally stopped after PCI, if it was performed) [24-27]. Over 60 percent of patients underwent catheterization and over 30 percent had PCI. Patients received weight-adjusted UFH during PCI if the last dose of enoxaparin was greater than six hours before the procedure. For patients who received an initial dose of subcutaneous fondaparinux and then underwent PCI, an additional dose was given intravenously (table 3). After isolated reports of catheter thrombosis, a protocol amendment allowed for the addition of open-label UFH in patients receiving fondaparinux at the discretion of the investigator.

The following findings were noted:

The two groups had similar rates of the primary end point, defined as death, MI, or refractory ischemia at nine days (5.8 versus 5.7 percent with enoxaparin), and the secondary end point of death or MI (4.1 percent in both groups).

At longer-term follow-up, there was a reduction in the primary end point with fondaparinux at 30 days (2.9 versus 3.5 percent, hazard ratio 0.83, 95% CI 0.71-0.97) and six months (5.8 versus 6.5 percent, hazard ratio 0.89, 95% CI 0.81-1.00). These differences were entirely due to a significantly lower rate of death.

The rate of major bleeding was significantly reduced with fondaparinux (2.2 versus 4.1 percent, hazard ratio 0.52, 95% CI 0.44-0.61). The benefits and risks were consistent among various subgroups, including age and sex, the spectrum of renal function, and whether or not revascularization was performed within nine days [24,25].

The safety of fondaparinux relative to enoxaparin was confirmed in two important prespecified subgroups: those who underwent PCI [26], and those in patients who received GP IIb/IIIa inhibitors [27].

However, fondaparinux was associated with a small but significant increase in the rate of catheter-related thrombi (in patients undergoing PCI) compared with enoxaparin (0.9 versus 0.4 percent). The frequency of catheter-related thrombi was significantly reduced in both groups in those patients who received open-label UFH before the procedure.

The observation in the OASIS-5 trial of a small but significant increase in catheter-related thrombi, which was mitigated by the use of UFH, raises the question as to the optimal dose of UFH in such patients. This issue was directly addressed in the FUTURA/OASIS 8 trial in which 2026 high-risk patients with NSTEACS treated with fondaparinux and scheduled to undergo PCI within 72 hours were randomly assigned to either a standard-dose UFH regimen (85 units/kg bolus with additional boluses based on an activated clotting time dosing algorithm) or a fixed low dose (50 units/kg without activated clotting time) [28]. For patients receiving a GP IIb/IIIa inhibitor, the UFH bolus in the standard-dose group was lowered to 50 units/kg.

At 48 hours after PCI, there was no significant difference between low-dose and standard regimens in the rate of the primary composite end point of major bleeding, minor bleeding, or major vascular access-site complications (4.7 versus 5.8 percent, respectively). The composite secondary outcome of major bleeding at 48 hours with death, MI, or target vessel revascularization within 30 days occurred more often in the low-dose group, nearly attaining statistical significance (5.8 versus 3.9 percent; odds ratio 1.51, 95% CI 1.00-2.28). Catheter thrombus rates were very low and not statistically different in the two groups (0.5 and 0.1 percent, respectively). (See "Periprocedural bleeding in patients undergoing percutaneous coronary intervention".)

ANTICOAGULANT USE — The type and dose of anticoagulant depends on whether the patient will be undergoing a conservative or invasive approach and for the latter, whether it is started prior to arrival in the catheterization laboratory or in it. For all patients undergoing percutaneous coronary intervention (PCI), the use of an activated clotting time (ACT) goal is important in heparin management.

Conservative approach — We prefer fondaparinux or enoxaparin for these patients, using the following initial doses (see 'Conservative approach' above):

Fondaparinux – 2.5 mg subcutaneously once daily in patients managed with a noninvasive strategy. (See 'Fondaparinux' above.)

Enoxaparin – No loading dose is necessary. Dosing is 1 mg/kg subcutaneously every 12 hours or for patients with an estimated creatinine clearance less than 30 mL/min, 1 mg/kg subcutaneously daily.

Invasive approach — For patients who are being considered for an invasive approach, we prefer unfractionated heparin (UFH) in most cases. (See 'Invasive approach' above.)

Anticoagulant dosing will depend on the whether the anticoagulant is started before arrival to the catheterization laboratory or in it. If it started before arrival to the catheterization laboratory (for example in an emergency department), we prefer UFH or bivalirudin using the following dosing:

UFH – We give an intravenous bolus of 60 units/kg (maximum dose 4000 to 5000 units) followed by 12 units/kg per hour intravenously (maximum dose 1000 units per hour) to achieve an activated partial thromboplastin time of 50 to 75 seconds.

Bivalirudin – Intravenous bolus of 0.1 mg/kg and an infusion of 0.25 mg/kg per hour if started before angiography; if PCI is performed, an additional 0.5 mg/kg bolus is given, and the infusion rate is increased to 1.75 mg/kg per hour. If started in the catheterization laboratory at the time of PCI, intravenous bolus of 0.75 mg/kg and an infusion of 1.75 mg/kg per hour is appropriate.

For patients who ultimately undergo PCI, anticoagulant dosing depends on whether the patient arrives on anticoagulant and if so which one:

If no anticoagulant was given prior to PCI, we give an initial intravenous UFH bolus of 70 to 100 units/kg to achieve an ACT of 250 to 300 seconds if glycoprotein (GP) IIb/IIIa inhibitor is not intended to be used or 50 to 70 units/kg to achieve an ACT of 200 to 250 seconds if GP IIb/IIIa inhibitor is intended.

If UFH was administered, we give an additional bolus of UFH after sheath insertion if needed to target an ACT of 250 to 300 seconds if a GP IIb/IIIa inhibitor has not been given and is not planned during PCI. For such patients who will receive a GP IIb/IIIa inhibitor, we give additional UFH as needed to target an ACT of 200 to 250 seconds.

If enoxaparin was initiated and two or more doses were given, and the last dose was given less than eight hours earlier, we proceed without additional enoxaparin. If a patient was given only one dose or the last dose was more than eight hours earlier, we give an additional intravenous bolus of enoxaparin (0.3 mg per kg). It may be better to continue with enoxaparin rather than switching to UFH, especially if anticoagulation may be continued after the procedure, since extrapolation from SYNERGY suggests that switching to UFH may be associated with an increased risk of death or MI at 30 days. (See 'Unfractionated heparin compared with enoxaparin' above.)

If fondaparinux was initiated before arrival in the catheterization laboratory, we give UFH 85 units/kg bolus with additional boluses based on an ACT dosing algorithm. (See 'Fondaparinux' above.)

Duration — The duration of anticoagulant therapy depends on the initial management strategy. Although the optimal treatment length has not been determined, the following represent commonly employed regimens in clinical practice (which we consider reasonable):

For patients undergoing PCI, anticoagulant therapy is stopped at the end of the procedure in uncomplicated cases. Continuation of anticoagulation beyond the times suggested above should be undertaken only if:

The PCI is complicated and there is an ongoing risk of recurrent ischemia.

There is evidence of high risk for systemic or venous thromboembolism (anterior ST-elevation MI, severe left ventricular dysfunction, heart failure, history of systemic or pulmonary embolus, or echocardiographic evidence of mitral or left ventricular thrombus) or a preexistent rationale for long-term anticoagulation, such as patients with prosthetic heart valves or atrial fibrillation.

In cases where bivalirudin is used as the anticoagulation strategy and a platelet P2Y12 receptor blocker has been given just before or after PCI, it is reasonable to continue a full-infusion dose of bivalirudin (1.75 mg/kg/hour) for four hours after the procedure [20,29-32]. (See "Antithrombotic therapy for elective percutaneous coronary intervention: Clinical studies", section on 'Bivalirudin' and 'Unfractionated heparin compared with bivalirudin' above and "Acute ST-elevation myocardial infarction: Management of anticoagulation", section on 'Anticoagulation after PCI'.)

For patients undergoing a noninvasive (conservative) strategy who are receiving dual antiplatelet therapy, we suggest a minimum of 48 hours for the duration of anticoagulation.

Heparin-induced thrombocytopenia — The incidence of immune-mediated heparin-induced thrombocytopenia (HIT) is approximately 2.5 to 3.0 percent in patients exposed to UFH for more than four days [33]. The incidence is much lower in patients treated with UFH for less than four days (0.2 percent) and in those treated with LMWH (0.2 versus 2.6 percent with UFH in a meta-analysis of studies that mostly consisted of patients who had undergone orthopedic surgery) [33]. (See "Management of heparin-induced thrombocytopenia".)

Based upon these observations, we suggest that the platelet count be measured serially in patients treated with UFH. In patients with a history of HIT, or in whom HIT develops or is suspected while on UFH therapy, the preferred anticoagulant is bivalirudin if they are undergoing PCI. For HIT patients receiving a conservative approach, we prefer fondaparinux. (See "Management of heparin-induced thrombocytopenia" and 'Our approach' above.)

RECOMMENDATIONS OF OTHERS — Guidelines for the use of anticoagulant therapy in patients with NSTEACS are available from the American College of Cardiology/American Heart Association (2014) [34], and the European Society of Cardiology/European Association for Cardio-Thoracic Surgery (2014) [35]. Each of the guidelines makes a strong recommendation for the use of anticoagulant therapy in all patients with ACS.

The following are important points made by in these guidelines:

From the American College of Cardiology/American Heart Association:

Among patients in whom an invasive strategy is selected, a recommendation is made for the use of enoxaparin, unfractionated heparin (UFH), or bivalirudin.

Among patients in whom a conservative strategy is selected, a recommendation is made for the use enoxaparin, fondaparinux, or UFH, with the first two preferred to the latter.

In the 2015 European Society of Cardiology guideline for the management of ACS in patients without persistent ST-segment elevation, fondaparinux is recommended as having the most favorable efficacy-safety profile regardless of the management strategy. In patients undergoing percutaneous coronary intervention treated with fondaparinux, a single intravenous bolus of UFH is recommended during the procedure.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Non-ST-elevation acute coronary syndromes (non-ST-elevation myocardial infarction)".)

SUMMARY AND RECOMMENDATIONS

Anticoagulant therapy – We recommend anticoagulant therapy for all patients with NSTEACS (Grade 1A). This recommendation is made for patients irrespective of whether an invasive or a conservative approach is taken. Anticoagulant therapy should be given as soon as possible after diagnosis and should be given in conjunction with recommended antiplatelet therapy. (See 'Our approach' above.)

Type of therapy based on revascularization strategy

-Early invasive strategy – For NSTEACS patients managed with an early invasive strategy (angiography and possible revascularization within 48 hours), we recommend UFH rather than bivalirudin, enoxaparin, or fondaparinux (Grade 1A). (See 'Invasive approach' above.)

Bivalirudin is a reasonable alternative to heparin plus a glycoprotein IIb/IIIa inhibitor in patients who have undergone coronary angiography without an anticoagulant having been started. (See 'Unfractionated heparin compared with bivalirudin' above.)

Fondaparinux has little role in patients undergoing an invasive approach due to reasons of cost (when compared with UFH) and the requirement for the coadministration of UFH prior to percutaneous coronary intervention.

Enoxaparin has no role in patients undergoing an invasive approach due to a significant increase in the risk of bleeding.

-Conservative or noninvasive strategy – For NSTEACS patients in whom a conservative (noninvasive) strategy is planned, we recommend either fondaparinux or enoxaparin in preference to either UFH or bivalirudin (Grade 1B). (See 'Our approach' above and 'Conservative approach' above.)

The choice between fondaparinux and enoxaparin should be guided by issues of cost and local practice. For patients at higher risk of bleeding (table 1), we suggest fondaparinux (Grade 2B).

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Michael Simons, MD, who contributed to earlier versions of this topic review.

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Topic 93 Version 56.0

References

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