Anticoagulant therapy in non-ST-elevation acute coronary syndromes

INTRODUCTION — Type I acute myocardial infarction (MI) results from intraluminal thrombosis that impairs distal blood flow and 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. (See "Overview of hemostasis" and "Mechanisms of acute coronary syndromes related to atherosclerosis".)

This topic will review the evidence that supports use of parenteral anticoagulant therapy in patients with acute non-ST-elevation acute coronary syndromes (NSTEACS), which include both unstable angina and acute non-ST-elevation myocardial infarction (NSTEMI). The topic will provide recommendations for its use according to whether the patient undergoes an invasive or noninvasive management strategy.

Other aspects of NSTEACS management are discussed elsewhere and include:

●Overview of acute management. (See "Overview of the acute management of non-ST-elevation acute coronary syndromes".)

●Choice of management strategy (algorithm 1). (See "Non-ST-elevation acute coronary syndromes: Selecting an approach to revascularization".)

●Acute antiplatelet therapy. (See "Acute non-ST-elevation acute coronary syndromes: Initial antiplatelet therapy".)

ROLE OF ANTICOAGULATION — In patients with NSTEACS, we recommend anticoagulation rather than no anticoagulation. Anticoagulation should begin immediately after the diagnosis of NSTEACS (NSTEMI, unstable angina) is established. The strategy chosen for management (invasive versus noninvasive strategy) and features of the patient determine the specific agent and the duration of therapy. (See 'Selecting an agent, dosing, and duration of therapy' below and 'Special circumstances' below.)

Other components of the antithrombotic regimen typically used to treat NSTEACS are discussed separately. (See "Overview of the acute management of non-ST-elevation acute coronary syndromes".)

This approach is consistent with European and North American guidelines [1,2].

This recommendation is based on trials that showed a reduction in the combined outcome of recurrent MI or death with anticoagulation (unfractionated heparin [UFH], low molecular weight heparin [LMWH]) compared with no anticoagulation. In a meta-analysis of eight trials composed of 2919 patients with NSTEACS, the rate of death or recurrent MI was lower with short-term (ie, seven days or fewer) anticoagulation with either UFH (7.9 versus 10.5 percent; odds ratio [OR] 0.67, 95% CI 0.45-0.99) or LMWH (1.6 versus 5.2 percent; OR 0.34, 95% CI 0.2-0.58); the largest effect was on recurrent MI [3]. Notably, these trials predate the routine use of dual antiplatelet therapy (ie, aspirin plus a P2Y₁₂ inhibitor), radial access, and drug-eluting stents.

SELECTING AN AGENT, DOSING, AND DURATION OF THERAPY

Invasive approach — In patients with NSTEACS managed with an invasive approach (ie, angiography and possible revascularization within 48 hours of diagnosis without prior imaging), we suggest initial anticoagulation with unfractionated heparin (UFH) rather than enoxaparin (algorithm 2). UFH is easier to dose when compared with enoxaparin. Bivalirudin is not used prior to percutaneous coronary intervention (PCI).

In patients with NSTEACS who will undergo PCI, we suggest intraprocedural anticoagulation with UFH or bivalirudin rather than use of enoxaparin. In this scenario, we prefer UFH due to its lower cost compared with bivalirudin. Enoxaparin is a reasonable option for anticoagulation in this setting, but UFH and bivalirudin are simpler to dose and monitor.

We do not use fondaparinux for anticoagulation during PCI due to a higher risk of catheter-related thrombi.

The dosing and duration of UFH, bivalirudin, and enoxaparin in patients with NSTEACS who will undergo an invasive management strategy are as follows:

●UFH – Initial therapy is a weight-based intravenous bolus of 60 units/kg (maximum dose 5000 units) followed by 12 units/kg/hour intravenously (maximum dose 1000 units per hour) to achieve an activated partial thromboplastin time of 50 to 75 seconds.

In the catheterization laboratory, additional UFH is given to achieve adequate anticoagulation.

After catheterization, UFH can be discontinued unless there are other indications for ongoing anticoagulation (eg, mechanical heart valve).

●Bivalirudin – In most circumstances, use of bivalirudin is limited to anticoagulation during PCI and immediately thereafter. For infusion in the catheterization laboratory, we give an intravenous bolus of 0.75 mg/kg and an infusion of 1.75 mg/kg/hour.

Bivalirudin can be stopped immediately after PCI is complete or continued for up to four hours following PCI. In cases where bivalirudin infusion will be extended after PCI, it is reasonable to continue bivalirudin infusion at 1.75 mg/kg/hour [4-8]. (See "Acute ST-elevation myocardial infarction: Management of anticoagulation", section on 'Anticoagulation after PCI'.)

●Enoxaparin – The dosing for enoxaparin is discussed elsewhere in this topic. (See 'Noninvasive approach' below.)

Our approach is consistent with North American guidelines; European guidelines do not mention bivalirudin as an option for anticoagulation in this setting [1,2].

All patients with NSTEACS managed with an invasive strategy should receive initial anticoagulation and anticoagulation appropriate for angiography or PCI to mitigate thrombosis and prevent catheter-related thrombotic complications, respectively. There are no trials that specifically address anticoagulation prior to PCI. In trials that addressed anticoagulation during PCI, heparin, bivalirudin, and enoxaparin had similar efficacy for the outcomes of mortality and recurrent MI. Thus, differences in safety, ease of dosing, and cost influence the choice of agent among these agents.

Compared with bivalirudin, UFH has similar efficacy and is less costly. In a meta-analysis that included 12,155 patients with NSTEMI who underwent PCI, heparin and bivalirudin had similar rates of all-cause mortality (1.1 versus 1.2 percent), recurrent MI (7.9 versus 8.0 percent), and stent thrombosis (0.9 percent) at 30 days [9]. Rates of mortality were similar when bivalirudin was compared with either heparin alone or with heparin plus infusion of a glycoprotein IIb/IIIa inhibitor. The rate of major bleeding events was lower in patients assigned to bivalirudin, but the clinical significance of this finding is unclear; most patients in the analysis underwent femoral arterial access while most patients in modern practice undergo radial arterial access, which reduces the risk of bleeding regardless of the anticoagulant used for PCI.

Compared with enoxaparin, UFH is easier to dose, and, in trials conducted before routine use of radial artery access for PCI, UFH had either a similar or lower risk of bleeding:

●In the SYNERGY trial, 10,027 patients with NSTEACS intended for management with an invasive strategy were randomly assigned to anticoagulation with enoxaparin or UFH [10,11]. Coronary angiography was performed in 92 percent of the SYNERGY patients, 47 percent underwent PCI, and 19 percent underwent surgical revascularization. At 30 days, there were similar rates of death (3.2 versus 3.1 percent in the UFH group; odds ratio [OR] 1.04, 95% CI 0.84-1.3) and nonfatal MI (11.7 versus 12.7 percent; OR 0.92, 95% CI 0.82-1.03). Depending on the definition of bleeding, rates of bleeding were either nominally higher in the enoxaparin group or similar between groups.

●In Phase A of the A to Z trial, 3987 patients with NSTEACS who were treated with tirofiban were randomly assigned to enoxaparin or UFH anticoagulation [12]. At the discretion of the treating physician, an invasive strategy was pursued in 55 percent of the study subjects. At seven days, the rates of death (1.1 versus 0.9 percent in the UFH group) and recurrent MI (3.6 versus 4.6 percent) were similar between the two groups. The incidence of major bleeding was nominally higher with enoxaparin (0.9 versus 0.4 percent with UFH).

There are no direct comparisons between bivalirudin and enoxaparin.

We do not use fondaparinux for anticoagulation during PCI due to a higher risk of catheter-related thrombi. In the OASIS-5 trial, 20,078 patients with NSTEACS were randomly assigned to fondaparinux (2.5 mg/day) or enoxaparin (1 mg/kg twice daily) for a mean of six days [13-16]. In patients in whom PCI was performed, anticoagulation was generally stopped after PCI. In those who did not undergo PCI, anticoagulation was stopped at discharge or after 48 hours. Over 60 percent of patients underwent catheterization, and over 30 percent of patients who underwent catheterization had PCI. At 30 days, patients assigned to enoxaparin or fondaparinux had similar rates of death (1.9 versus 1.8 in the fondaparinux group) and recurrent MI (2.7 versus 2.6). At 180 days, patients assigned to fondaparinux had a rate of death that was probably lower than patients assigned to enoxaparin (5.8 versus 6.6 percent; hazard ratio [HR] 0.89, 95% CI 0.80-1.00); the rate of MI was also similar (6.3 versus 6.6 percent; HR 0.95, 95% CI 0.85-1.06). In the subgroup of patients who underwent revascularization by day 9, the efficacy of fondaparinux and enoxaparin were similar. At nine days, the group assigned to enoxaparin had a higher rate of major bleeding (5.4 versus 2.8 percent; HR 0.51, 95% CI 0.4-0.66). Despite a protocol amendment that allowed for the addition of open-label UFH in patients receiving fondaparinux, fondaparinux was associated with a small but significant increase in the rate of catheter-related thrombi in patients undergoing PCI (0.9 versus 0.4 percent).

Noninvasive approach — In patients with NSTEACS managed with a noninvasive approach (ie, angiography is only performed after noninvasive imaging), we suggest anticoagulation with UFH, fondaparinux, or enoxaparin rather than other agents. The choice of agent differs among the contributors to this topic and is generally based on ease of dosing, familiarity with specific agents, likelihood of eventual coronary angiography, and cost.

●Dosing and duration for a noninvasive strategy

•Fondaparinux – The dose of fondaparinux for a noninvasive strategy is 2.5 mg subcutaneously once daily.

In patients undergoing a noninvasive strategy, anticoagulation is given for at least 48 hours, until stress testing occurs, or until discharge. This approach to dosing and duration of therapy is based on protocols used in older trials of anticoagulation [13].

•Unfractionated heparin – Initial therapy consists of a weight-based intravenous bolus of 60 units/kg (maximum dose 4000 to 5000 units) followed by 12 units/kg/hour intravenously (maximum dose 1000 units per hour) to achieve an activated partial thromboplastin time of 50 to 75 seconds.

Therapy should be continued for a minimum of 48 hours or until discharge. In patients who will undergo stress testing, it is reasonable to stop UFH infusion prior to stress testing.

•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.

In patients undergoing a noninvasive strategy, anticoagulation is continued for 48 hours, until stress testing, or until discharge.

●Approach if converting to an invasive strategy – In patients who were initially treated with enoxaparin or fondaparinux as part of a noninvasive strategy but who will undergo PCI (eg, patients with inducible ischemia or obstructive coronary artery disease on anatomic imaging), anticoagulation is typically converted to UFH or bivalirudin prior to angiography. However, one contributor to this topic continues enoxaparin in this setting.

The approach to converting between anticoagulants depends on the type of anticoagulant:

•Enoxaparin given prior to angiography – If enoxaparin was initiated prior to angiography, two or more doses were given, and the last dose was given less than eight hours earlier, we proceed to angiography without additional enoxaparin.

If the patient received only one dose of enoxaparin prior to angiography or the last dose was more than eight hours earlier, we give an additional intravenous bolus of enoxaparin (0.3 mg/kg) prior to angiography.

The available data suggest that the efficacy of UFH, bivalirudin, and enoxaparin are similar in this setting. However, one contributor favors continuation of enoxaparin based on a secondary analysis suggesting lower rates of death or MI in patients who continued to receive enoxaparin (ie, did not crossover to UFH) [11].

•Fondaparinux given prior to angiography – If fondaparinux was initiated before arrival in the catheterization laboratory, we give UFH 85 units/kg bolus immediately prior to angiography with additional boluses based on an activated clotting time dosing algorithm.

Our approach is consistent with European and North American guidelines [1,2].

The evidence does not suggest that one anticoagulant is clearly superior to another for noninvasive management of NSTEACS. As such, the decision of which anticoagulant to use is often based on familiarity with specific agents, cost, and ease of dosing. Our contributors differ in their approach to selection of an anticoagulant. One contributor to this topic prefers fondaparinux if coronary angiography is unlikely to occur. Other contributors to this topic rarely use fondaparinux or enoxaparin and prefer UFH given the familiarity with its use, low cost, and the high likelihood of coronary angiography even in patients initially managed with a noninvasive approach.

Older evidence suggests that enoxaparin may have a nominally lower rate of recurrent MI compared with UFH and that fondaparinux likely has similar efficacy compared with enoxaparin. In a meta-analysis of two trials that included patients with NSTEACS who received noninvasive management, patients assigned to anticoagulation with enoxaparin had lower rates of recurrent MI compared with UFH (7.1 versus 8.6 percent; OR 0.82, 95% CI 0.69-0.97) and similar rates of death (3.3 versus 3.9 percent; OR 0.84, 95% CI 0.66-1.08) [17]. There are no direct comparisons between UFH and fondaparinux, and bivalirudin has not been studied in this population. The data on fondaparinux and the approach in patients who will undergo PCI are discussed elsewhere in this topic [13-16]. (See 'Invasive approach' above.)

SPECIAL CIRCUMSTANCES

Heparin-induced thrombocytopenia — Patients with NSTEACS who have a history of immune-mediated heparin-induced thrombocytopenia (HIT) should be treated with bivalirudin, fondaparinux, or argatroban (algorithm 2). The choice of agent depends on local familiarity with agents used to anticoagulate patients with HIT. There are no large studies in patients with HIT to guide practice, though bivalirudin and fondaparinux are well-studied in acute coronary syndromes compared with argatroban. Further details on the management of patients with HIT can be found separately. (See "Management of heparin-induced thrombocytopenia".)

Prior oral anticoagulation — In patients who receive anticoagulation in the outpatient setting, anticoagulation should be switched to a parenteral agent appropriate for the management of NSTEACS. Anticoagulation with either warfarin or an oral direct-acting anticoagulant alone is insufficient for the treatment of NSTEACS.

Glycoprotein IIb/IIIa inhibitor treatment for PCI — In patients with NSTEACS in whom the plan is to perform PCI after administering aspirin, a P2Y₁₂ inhibitor, and a glycoprotein IIb/IIIa inhibitor, which is an uncommon approach, a lower dose of anticoagulation may be used to mitigate the risk of bleeding. However, there are few data to guide practice; targets for anticoagulation are typically determined by local protocols. Details on the use of glycoprotein IIb/IIIa inhibitors in patients with NSTEACS are discussed separately. (See "Acute non-ST-elevation acute coronary syndromes: Initial antiplatelet therapy".)

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 – In patients with non-ST-elevation acute coronary syndromes (NSTEACS), we recommend anticoagulation therapy rather than no anticoagulation (Grade 1B). Anticoagulation therapy should be given as soon as possible after diagnosis in conjunction with other antiplatelet therapies. (See 'Role of anticoagulation' above.)

The specific agent used for anticoagulation is based on the strategy chosen:

•Invasive strategy – In patients with NSTEACS managed with an invasive approach (ie, angiography and possible revascularization within 48 hours of diagnosis without prior imaging), we suggest initial anticoagulation with unfractionated heparin (UFH) rather than enoxaparin (Grade 2C) (algorithm 2). Bivalirudin and fondaparinux are not used for anticoagulation prior to percutaneous coronary intervention (PCI).

In patients with NSTEACS who will undergo PCI, we suggest intraprocedural anticoagulation with UFH or bivalirudin rather than use of enoxaparin (Grade 2C). UFH is easier to dose compared with enoxaparin in patients who will undergo PCI.

We do not use fondaparinux for anticoagulation during PCI due to a higher risk of catheter-related thrombi.

In patients who undergo angiography either with or without PCI, the duration of anticoagulation after the procedure depends on the anticoagulant; UFH is typically stopped after the procedure, while bivalirudin may be discontinued immediately or continued for up to four hours after the procedure. (See 'Invasive approach' above.)

•Noninvasive strategy – In patients with NSTEACS managed with a noninvasive approach (ie, angiography is only performed after noninvasive imaging), we suggest anticoagulation with UFH, fondaparinux, or enoxaparin rather than other agents (Grade 2C). The choice of a specific agent differs among the contributors to this topic and is generally based on ease of dosing, familiarity with specific agents, likelihood of eventual coronary angiography, and cost. (See 'Noninvasive approach' above.)

The subsequent management of anticoagulation depends on whether the patient proceeds to angiography or not:

-Duration of therapy for noninvasive management – In patients undergoing a noninvasive strategy, anticoagulation should continue for a minimum of 48 hours, until stress testing, or until discharge.

-Conversion to angiography – In patients who were initially treated with enoxaparin or fondaparinux as part of a noninvasive strategy but who will undergo PCI (eg, patients with inducible ischemia or obstructive coronary artery disease on anatomic imaging), anticoagulation should be converted to UFH or bivalirudin prior to PCI (algorithm 2). Enoxaparin is also a reasonable option. (See 'Noninvasive approach' above.)

●Special populations

•Heparin-induced thrombocytopenia – Patients with NSTEACS and history of immune-mediated heparin-induced thrombocytopenia (HIT) should be treated with either bivalirudin, fondaparinux, or argatroban (algorithm 2). (See "Management of heparin-induced thrombocytopenia".)

•Management of oral anticoagulation – In patients who receive anticoagulation in the outpatient setting, anticoagulation should be switched to a parenteral agent appropriate for the management of NSTEACS. (See 'Prior oral anticoagulation' above.)

•Glycoprotein IIb/IIIa inhibitor treatment for PCI – In patients with NSTEACS in whom the plan is to perform PCI after administering aspirin, a P2Y₁₂ inhibitor, and a glycoprotein IIb/IIIa inhibitor, which is an uncommon approach, a lower dose of anticoagulation may be used to mitigate the risk of bleeding. However, there are few data to guide practice. (See 'Glycoprotein IIb/IIIa inhibitor treatment for PCI' above.)

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