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Acute ST-elevation myocardial infarction: Management of anticoagulation

Acute ST-elevation myocardial infarction: Management of anticoagulation
Authors:
A Michael Lincoff, MD
Donald Cutlip, MD
Section Editors:
Freek Verheugt, MD, FACC, FESC
Christopher P Cannon, MD
Deputy Editor:
Todd F Dardas, MD, MS
Literature review current through: Nov 2022. | This topic last updated: Sep 13, 2022.

INTRODUCTION — Acute myocardial infarction (MI) results from rupture or erosion of an atherosclerotic plaque, which leads to intraluminal thrombosis, reduced distal blood flow, and myocardial ischemia or infarction. Intraluminal hemostasis is a dynamic process involving both clot formation and fibrinolysis. The goal of antithrombotic therapy (the combination of anticoagulant and antiplatelet therapy) is to prevent clot extension and clot reformation. (See "Overview of hemostasis" and "Mechanisms of acute coronary syndromes related to atherosclerosis".)

This topic will review the approach to anticoagulation in patients with acute ST-elevation MI (STEMI) and will provide recommendations for the use of specific anticoagulants according to whether the patient will receive primary percutaneous coronary intervention (PCI), primary fibrinolysis, or no reperfusion therapy.

Information regarding anticoagulant agents in non-ST-elevation acute coronary syndromes (unstable angina or non-STEMI) and the role of antiplatelet therapy in STEMI is discussed separately. (See "Anticoagulant therapy in non-ST elevation acute coronary syndromes" and "Acute ST-elevation myocardial infarction: Antiplatelet therapy".)

CLASSIFICATION OF ANTICOAGULANT AGENTS — There are three classes of anticoagulants that are used to treat acute coronary syndromes:

Heparins – The heparins, including unfractionated heparin (UFH) and the low molecular weight heparins (LMWHs), form complexes with antithrombin (AT, formerly known as AT III) that convert AT from a slow to a rapid inactivator of thrombin (ie, indirect thrombin inhibition) and factor Xa. To a lesser extent, the heparins also inactivate factors XIIa, XIa, and IXa. (See "Overview of hemostasis" and "Heparin and LMW heparin: Dosing and adverse effects".)

Unfractionated heparin – Intravenous UFH induces rapid anticoagulation but binds to circulating plasma proteins, which results in variable inter- and intrapatient effects that require frequent monitoring and dose adjustments. UFH is more likely to cause heparin-induced thrombocytopenia compared with other anticoagulants. (See "Clinical presentation and diagnosis of heparin-induced thrombocytopenia".)

Low molecular weight heparin – Similar to UFH, LMWH inactivates factor Xa but has less effect on thrombin (figure 1). LMWH has a more predictable anticoagulant effect when compared with UFH and is less likely to cause immune-mediated thrombocytopenia. The anticoagulant effect of LMWH is more difficult to monitor; LMWH does not prolong the activated partial thromboplastin time in a predictable fashion.

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

Direct thrombin inhibitors – The direct thrombin inhibitors (eg, argatroban, inogatran, efegatran, lepirudin, hirudin, and bivalirudin [Hirulog]) directly bind to and inactivate one or more of the active sites on the thrombin molecule [1]. (See "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects", section on 'Direct thrombin inhibitors'.)

PRIMARY PERCUTANEOUS CORONARY INTERVENTION

Anticoagulation prior to PCI — Patients with STEMI whose reperfusion strategy is primary percutaneous coronary intervention (PCI) (algorithm 1) require prompt anticoagulation (algorithm 2). The only exceptions to immediate anticoagulation are cases in which the process of starting anticoagulation would delay primary PCI (eg, delay transfer to a PCI-capable center, delay the PCI procedure).

For most patients with STEMI who will undergo primary PCI, we suggest initial anticoagulation with unfractionated heparin (UFH) rather than other agents (eg, enoxaparin, fondaparinux, bivalirudin).

Other factors that affect the approach to anticoagulation include:

Chronic oral anticoagulation – In patients who take oral anticoagulants, we typically anticoagulate with an intravenous (IV) agent. There are no data to suggest that outpatient anticoagulation (eg, warfarin, direct oral anticoagulants) is sufficient anticoagulation for PCI in patients with STEMI.

Heparin-induced thrombocytopenia – In patients with a history of heparin-induced immune thrombocytopenia, we anticoagulate with bivalirudin, which is started in the catheterization suite. (See 'Anticoagulation during PCI' below.)

In brief, this approach to anticoagulation prior to PCI is based on the requirement for anticoagulation during PCI to prevent catheter-associated thrombi, the desire to slow the progression of thrombus formation without specific evidence of efficacy during the typically short interval between initiating anticoagulation and undergoing PCI, the available trial data that suggest a similar effect of the available anticoagulants, and the safety of UFH in terms of dosing and monitoring during PCI. Further details of the rationale and supporting trials are described elsewhere in this topic. (See 'Evidence in primary PCI' below.)

Anticoagulation during PCI — All patients who undergo PCI require anticoagulation to prevent intraarterial thrombus formation. During PCI for STEMI, we suggest anticoagulation with UFH rather than with other agents (eg, enoxaparin, fondaparinux, bivalirudin) (algorithm 2). If enoxaparin was given >6 hours prior to PCI, we initiate UFH during PCI rather than maintain anticoagulation with enoxaparin.

If not given prior to PCI, the chosen agent is either started or additional doses are given to achieve appropriate levels of anticoagulation in the catheterization suite. (See 'Dosing and monitoring' below.)

In summary, this approach is based on the need to prevent intraarterial thrombi associated with the catheters and equipment used during PCI. Our preference for UFH is based on trials that show no clinically significant differences between the anticoagulants and the ease of dosing and monitoring with UFH when compared with other anticoagulants. We do not use fondaparinux in this setting; low-quality data suggest that fondaparinux may increase the risk of catheter thrombi and adverse coronary artery events (eg, acute vessel closure). The details on the trials of anticoagulation are discussed elsewhere in this topic. (See 'Evidence in primary PCI' below.)

Anticoagulation after PCI — For patients with acute coronary syndrome who undergo PCI, including patients with STEMI, the role of routine use of anticoagulant therapy after PCI is unclear. The duration of anticoagulation is influenced by the agent used, whether complications occurred during PCI, and whether there is a clear indication for long-term anticoagulation:

Patients without complications or other indications for anticoagulation – In patients who have an uncomplicated PCI and who do not have another indication for anticoagulation (eg, atrial fibrillation, mechanical heart valve), UFH or enoxaparin can be stopped immediately following the procedure, while bivalirudin is typically continued for four hours after PCI.

This approach is based on the use of UFH and low molecular weight heparin (LMWH) in large randomized trials and from the results of a trial that compared no bivalirudin after PCI with four hours of bivalirudin infusion after PCI; the latter trial found similar rates of the primary outcome [2].

Patients with complications of PCI In patients who have evidence of bleeding or thrombosis or who are at risk of these complications, anticoagulation is managed as follows:

Bleeding complications – In patients with major access site bleeding or other clinically significant bleeding (eg, intracerebral hemorrhage, hemorrhagic pericardial effusion) that may be worsened by continued anticoagulation, additional management of anticoagulation and bleeding may be required. The management of these patients is discussed separately. (See "Periprocedural complications of percutaneous coronary intervention".)

Thrombotic complications – Thrombotic complications of STEMI that would require extending the duration of anticoagulation are rare. In cases of residual intracoronary thrombus or other thrombotic complications, treatment with additional anticoagulation or antiplatelet therapy is individualized.

Other indications for long-term anticoagulation In patients who have other indications for anticoagulation (eg, evidence of left ventricular thrombus, atrial fibrillation), we continue parenteral anticoagulation until the patient can be transitioned to an anticoagulant appropriate for outpatient use. The disease or condition under treatment determines the agent of choice. Common conditions that may require anticoagulation in patients with STEMI include:

Left ventricular thrombus. (See "Left ventricular thrombus after acute myocardial infarction".)

Atrial fibrillation. (See "Atrial fibrillation in adults: Selection of candidates for anticoagulation".)

Deep vein thrombosis. (See "Overview of the treatment of proximal and distal lower extremity deep vein thrombosis (DVT)".)

Mechanical valve prosthesis. (See "Anticoagulation for prosthetic heart valves: Management of bleeding and invasive procedures".)

Dosing and monitoring — The dosing and monitoring of the most used anticoagulants are as follows:

Unfractionated heparin The dosing and monitoring of UFH therapy depends on the venue of care and the proximity to the PCI procedure:

Initiating and monitoring UFH – For patients who will undergo PCI without use of a glycoprotein (GP) IIb/IIIa inhibitor, which is our preferred approach, we use an initial IV bolus of UFH of 70 to 100 units/kg up to a maximum of 10,000 units (with additional boluses if needed to achieve an activated clotting time [ACT] target >250 s).

For patients who will undergo PCI with a GP IIb/IIIa inhibitor, which is not our usual approach, we use an initial UFH bolus of 50 to 70 units/kg up to a maximum of 7000 units (with additional boluses if needed to achieve an ACT target >200 s).

Managing UFH in the emergency department or after PCI – For most patients, the expected interval between initiation of UFH and transfer to the catheterization laboratory is short (eg, less than 90 minutes) and accordingly, monitoring is not required prior to PCI. However, if there is a longer delay prior to PCI or if UFH is continued after PCI, UFH should be dosed and monitored in accordance with local protocols (eg, nomograms) specific to the indication for treatment. (See "Heparin and LMW heparin: Dosing and adverse effects", section on 'Unfractionated heparin'.)

Bivalirudin – We use an initial bolus of 0.75 mg/kg followed by an IV infusion of 1.75 mg/kg/hour. The maintenance dose is decreased to 1.0 mg/kg/hour in patients with an estimated glomerular filtration rate (eGFR) <30 mL/1.73 m2.

Bivalirudin is not typically monitored during the PCI procedure, though one contributor to this topic obtains a single activated clotting time assay to ensure that delivery of bivalirudin was effective.

Enoxaparin LMWHs are managed by weight-based dosing, and monitoring is typically not required. Enoxaparin is the LMWH of choice for use in acute coronary syndrome.

Initiating enoxaparin in the emergency department – The initial dose of enoxaparin is adjusted for age and renal function, specifically creatinine clearance. However, PCI should not be delayed by blood sampling or waiting for the return of a creatinine level.

-Age less than 75 years In patients who are <75 years of age with creatinine clearance ≥30 mL/minute using the Cockcroft-Gault formula (calculator 1 and calculator 2), we use a loading dose of 30 mg IV bolus followed by 1 mg/kg subcutaneously every 12 hours (maximum of 100 mg for the first two doses only). The first subcutaneous dose should be administered with the IV bolus.

For patients who are <75 years of age with a creatinine clearance <30 mL/minute using the Cockcroft-Gault formula, we use a 30 mg IV bolus given with the first dose of the subcutaneous maintenance regimen, which is adjusted to 1 mg/kg subcutaneously every 24 hours.

-Age ≥75 years In patients ≥75 years of age with creatinine clearance ≥30 mL/minute, we do not use a loading dose and administer a maintenance dose of 0.75 mg/kg subcutaneously every 12 hours (maximum of 75 mg for the first two doses only).

For patients who are 75 years of age or older with a creatinine clearance <30 mL/minute, we do not use a loading dose and administer a maintenance subcutaneous dose of 1 mg/kg every 24 hours.

Dosing enoxaparin during PCI – Due to the complexity of enoxaparin dosing, for most patients who were initially treated with enoxaparin and in whom the last dose was given more than six hours prior to PCI, we change from enoxaparin- to UFH-based anticoagulation at the beginning of PCI.

In patients who will continue with enoxaparin anticoagulation, several factors influence the choice of dosing of enoxaparin during PCI:

-Last dose given less than eight hours prior to PCI If the last dose of subcutaneous enoxaparin was given within the prior eight hours, no additional enoxaparin should be given prior to PCI.

-Last dose given 8 to 12 hours before PCI If enoxaparin will be continued and the last subcutaneous dose was given 8 to 12 hours prior to PCI, an IV dose of 0.3 mg/kg of enoxaparin should be given prior to PCI [3].

-Last dose given more than 12 hours prior to PCI – If the last dose of subcutaneous enoxaparin was given more than 12 hours prior to PCI, another full dose of enoxaparin is given immediately prior to PCI.

-Dosing for prolonged PCI procedures – For patients undergoing primary PCI whose PCI procedure has extended over 120 minutes, an IV bolus of 0.25 mg/kg should be given.

Evidence in primary PCI — It is standard practice to give anticoagulation during PCI to prevent thrombus formation on intravascular devices (eg, arterial sheaths, catheters, stents). Our preference for the use of UFH in most patients is based on clinical trial evidence that shows similar efficacy between UFH and other anticoagulants and our experience with the dosing and monitoring of UFH, which is simpler than that of other anticoagulants. In addition, lower-quality data (eg, subgroup analyses, secondary endpoint analyses) suggest that UFH may be associated with a higher rate of bleeding and a lower rate of definite stent thrombosis when compared with bivalirudin and with a lower rate of equipment thrombosis when compared with fondaparinux.

Our approach to the timing of anticoagulation, dosing, and duration of therapy is derived from trial protocols and agrees with the American College of Cardiology/American Heart Association and the European Society of Cardiology guidelines [3-5].

The evidence includes the following:

UFH compared with bivalirudin – In trials that examined the efficacy of anticoagulation under conditions similar to our practice (ie, rare treatment with a GP IIb/IIIa inhibitor, routine use of prasugrel or ticagrelor, and routine use of radial access), UFH has either similar or better efficacy than bivalirudin, and UFH may have lower rates of bleeding and stent thrombosis. Trials that evaluated anticoagulant regimens under these conditions include:

In the 2017 SWEDEHEART trial, 6006 patients with STEMI or non-STEMI undergoing urgent PCI and receiving treatment with ticagrelor, prasugrel, or cangrelor were randomly assigned to bivalirudin or heparin [6]. Most patients received radial artery access. The use of GP IIb/IIIa inhibitors was rare (2.4 and 2.8 percent of patients in the bivalirudin and heparin groups, respectively).

The primary composite endpoint (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). While not powered to assess the individual endpoints that composed the composite outcome, the trial did not find large differences between the two anticoagulants for the individual components. The rate of stent thrombosis was similar between the two groups (1.7 versus 1.8 in the UFH group). The rates of the primary outcome were similar in patients with radial or femoral access.

In the 2014 HEAT-PPCI single-center trial, 1829 patients undergoing emergency angiography were randomly assigned to heparin (70 units/kg) or bivalirudin (bolus 0.75 mg/kg; infusion 1.75 mg/kg/hour) [7]. The rate of GP IIb/IIIa inhibitor use was similar between the two groups (13 and 15 percent, respectively). Ticagrelor or prasugrel was used in nearly 90 percent of patients. Approximately 80 percent of patients received a radial artery approach for vascular access.

The primary outcome included all-cause mortality, cerebrovascular accident, reinfarction, or additional unplanned target lesion revascularization and occurred more often in the bivalirudin group (8.7 versus 5.7 percent; relative risk [RR] 1.52, 95% CI 1.1-2.1). Rates of major bleeding were similar in the bivalirudin and heparin groups (3.5 versus 3.1 percent, respectively; RR 1.2, 95% CI 0.7-1.9). Definite or probable stent thrombosis occurred more often with bivalirudin (3.4 versus 0.9 percent; RR 3.91, 95% CI 1.6-9.5). In a prespecified subgroup analysis, radial and femoral access had a similar risk of the primary outcome.

While there are older trials that compared the efficacy of UFH with bivalirudin, their results are less pertinent to modern practice, in which radial access is common, prasugrel or ticagrelor are used more commonly than clopidogrel, and GP IIb/IIIa inhibitor use is rare [2,8,9]. In aggregate, these older trials suggested that the risk of mortality and recurrent MI were similar with UFH and bivalirudin, while secondary analyses suggested that bivalirudin may be associated with less bleeding and a higher risk of stent thrombosis.

UFH compared with enoxaparin – There are few high-quality trials that compared UFH with enoxaparin:

In the only trial (ATOLL) of patients with STEMI that compared UFH with intravenous enoxaparin, 80 percent of patients received a GP IIb/IIIa inhibitor, 93 percent received clopidogrel, and 67 percent of patients underwent radial access [10]. At 30 days, the group assigned to enoxaparin had a nonsignificantly lower risk of death, complications of MI, procedure failure, or major bleeding (28 versus 34 percent; RR 0.83, 95% CI 0.68-1.01); the rates of major bleeding were similar between the two groups.

Two meta-analyses (one of which included ATOLL) concluded that the use of LMWH (generally enoxaparin) compared with UFH leads to lower rates of mortality and major bleeding [11,12]. However, important limitations of these meta-analyses limit their application to practice and include pooling of trials and observational studies, absence of patient level data, and variation in the timing, dose, and route of administration of enoxaparin across studies.

UFH compared with fondaparinux – Our preference for UFH rather than fondaparinux is based on subgroup analyses of the OASIS-6 trial [13]. In the subgroup of patients in the trial who underwent PCI, random assignment to fondaparinux or UFH was associated with similar rates of death and reinfarction, but patients who received fondaparinux had higher rates of guiding catheter thrombosis (22 versus 0; p<0.001) and higher rates of coronary complications such as abrupt coronary artery closure, new angiographic thrombus, catheter thrombus, no reflow, dissection, or perforation (270 versus 225; p = 0.04). Though these analyses are not conclusive, the similar efficacy of fondaparinux and UFH in patients undergoing PCI and the possibility of higher equipment thrombus rates and coronary artery complications lead us to favor UFH over fondaparinux.

The full results of the complex OASIS-6 trial and its subsequent analyses are discussed elsewhere in this topic. (See 'Rationale and evidence in primary fibrinolysis' below.)

FIBRINOLYTIC THERAPY WITH OR WITHOUT PLANNED PCI

Choice of anticoagulant — In patients with STEMI who undergo reperfusion with fibrinolysis, and regardless of the specific fibrinolytic agent chosen, the approach to anticoagulation is influenced by the likelihood of angiography and/or percutaneous coronary intervention (PCI) following fibrinolysis (algorithm 1 and algorithm 2), as follows:

Fibrinolysis followed by PCI – In patients who undergo primary fibrinolysis and who are likely to have PCI thereafter (ie, pharmacoinvasive strategy), we suggest the use of unfractionated heparin (UFH) rather than other agents (eg, enoxaparin, bivalirudin, or fondaparinux).

This approach is influenced by the similar efficacy of the anticoagulants in fibrinolysis and our preference for UFH in patients undergoing PCI. (See 'Anticoagulation during PCI' above and 'Rationale and evidence in primary fibrinolysis' below.)

Fibrinolysis without planned PCI – For patients who are unlikely to undergo angiography or PCI, we suggest anticoagulation with enoxaparin or fondaparinux rather than other agents or no anticoagulation. However, fondaparinux is not approved for use in patients with STEMI by the US Food and Drug Administration.

Our approach is supported by evidence that suggest that enoxaparin and fondaparinux have favorable effects when compared with no anticoagulation and that these agents are superior to UFH. The rationale and evidence for this approach are discussed elsewhere in this topic. (See 'Rationale and evidence in primary fibrinolysis' below.)

Dosing and duration of therapy — In patients who will undergo primary fibrinolysis, the dosing and duration of anticoagulant therapy is as follows:

UFH – For patients receiving fibrinolysis, we suggest an initial intravenous (IV) bolus dose of UFH of 60 units/kg (maximum of 4000 units) followed by an IV infusion of 12 units/kg/hour (maximum 1000 units/hour) to achieve an activated partial thromboplastin time of 50 to 70 s.

The infusion is maintained with periodic monitoring according to local protocols until PCI is complete or for 48 hours, whichever comes first.

Enoxaparin – The dose of enoxaparin is based on age and kidney function, but assessment of kidney function should not delay the delivery of anticoagulation and fibrinolysis:

Age less than 75 years In patients who are <75 years of age with creatinine clearance ≥30 mL/minute using the Cockcroft-Gault formula (calculator 1 and calculator 2), we use a loading dose of 30 mg plus 1 mg/kg (maximum of 100mg). The maintenance dose is 1 mg/kg given subcutaneously every 12 hours (maximum of 100 mg for the first maintenance dose).

For patients who are <75 years of age with a creatinine clearance <30 mL/minute using the Cockcroft-Gault formula, we use a 30 mg IV bolus given with the first dose of the subcutaneous maintenance regimen, which is adjusted to 1 mg/kg subcutaneously every 24 hours.

Age ≥75 years – In patients ≥75 years with creatinine clearance ≥30 mL/minute, we do not use a loading dose and administer a maintenance dose of 0.75 mg/kg subcutaneously every 12 hours (maximum of 75 mg for the first two doses only).

For patients who are 75 years or older with a creatinine clearance <30 mL/minute, we do not use a loading dose and administer a maintenance subcutaneous dose of 1 mg/kg every 24 hours.

Enoxaparin therapy is continued until PCI occurs, until discharge, or for eight days, whichever comes first. At the time of PCI, enoxaparin is typically switched to UFH (see 'Anticoagulation during PCI' above). After PCI, enoxaparin is discontinued unless there is another indication for ongoing anticoagulation (eg, left ventricular thrombus, atrial fibrillation).

Fondaparinux – For patients receiving fibrinolytic therapy who have a creatinine clearance >30 mL/minute, we give fondaparinux 2.5 mg intravenously as a bolus followed by a subcutaneous dose of 2.5 mg once daily. Fondaparinux should not be used in patients with an estimated creatinine clearance <30 mL/minute.

Fondaparinux should be continued until discharge or for eight days, whichever comes first.

Rationale and evidence in primary fibrinolysis — In patients undergoing primary fibrinolysis, the rationale and evidence for anticoagulation depend on whether PCI is likely or unlikely after fibrinolysis:

PCI following fibrinolysis – Our preference for UFH in patients undergoing PCI is supported by the similar clinical effect of UFH compared with other anticoagulants in fibrinolysis and its advantages in patients treated with primary PCI. (See 'Evidence in primary PCI' above.)

Fibrinolysis without PCI In patients with STEMI who are primarily treated with fibrinolysis without subsequent PCI, the available evidence suggests that anticoagulation with enoxaparin or fondaparinux have a greater effect than no anticoagulation or anticoagulation with other agents. Bivalirudin is not well studied in this setting and may be associated with greater rates of intracerebral hemorrhage. Trials that describe the effects of the various anticoagulants compared with no anticoagulation or with other agents include the following:

Effect of anticoagulation versus no anticoagulation The trials and studies that compare anticoagulation with no anticoagulation include:

UFH compared with placebo – In trials of patients with STEMI who underwent primary fibrinolysis, treatment with heparin was associated with minimal or no benefit on mortality when compared with placebo, and the effect of heparin on vessel patency varied between trials. There are no randomized trials that directly compare heparin with placebo in patients optimally treated with aspirin plus a platelet P2Y12 inhibitor, which is a major limitation of the available data. (See "Acute ST-elevation myocardial infarction: Antiplatelet therapy", section on 'Patients receiving fibrinolytic therapy'.)

The data that support the use of heparin as an adjunctive therapy in patients undergoing fibrinolysis include:

-In a 2005 meta-analysis of four trials that studied the relative effect of UFH with placebo, there were similar rates of mortality (4 versus 5 percent in the placebo group; pooled odds ratio [OR] 1.04, 95% CI 0.62-1.8) and reinfarction (3.5 versus 3.2 percent, pooled OR 1.1, 95% CI 0.6-2.0) [14].

-Though fibrin-specific agents (eg, tenecteplase, reteplase) might result in more circulating fibrin and thrombosis when compared with non-fibrin-specific agents (eg, streptokinase), the effect of UFH on mortality and vessel patency was minimal or none for both types of agents [15-20].

LMWH compared with placebo The effect of low molecular weight heparin (LMWH) has been evaluated in clinical trials of patients with STEMI who were predominantly treated with streptokinase; it is unclear whether the results of LMWH extend to patients treated with tenecteplase and reteplase (ie, the preferred agents for thrombolysis) (table 1).

-In a meta-analysis of trials that compared UFH and LMWH with placebo, LMWH was associated with a lower risk of death at 30 days (10 versus 11 percent; pooled OR 0.86, 95% CI 0.78-0.95) and reinfarction (1.6 versus 2.1 percent; pooled OR 0.72, 95% CI 0.58-0.90) [14].

-In the largest trial included in the meta-analysis, the CREATE trial, patients with an acute STEMI were randomly assigned to reviparin or placebo [21]. Streptokinase was the most administered agent in this trial (73 percent of patients). At seven days, the rate of the primary composite outcome (death, MI, or stroke) was significantly reduced with reviparin (9.6 versus 11.0 percent; hazard ratio [HR] 0.87, 95% CI 0.79-0.95), and this benefit persisted at 30 days. Reviparin treatment was significantly better when started within two hours after symptom onset.

Fondaparinux compared with placebo – The efficacy of fondaparinux in STEMI was evaluated in the OASIS-6 trial [13]. The trial was designed to assess the effect of fondaparinux relative to "usual care" in a group of patients without an indication for anticoagulation (eg, non-fibrin-specific fibrinolytic agent, no PCI) and in another group of patients with an indication for anticoagulation (eg, fibrin-specific thrombolytic agent, reperfusion with primary PCI):

-Stratum 1 consisted of 5658 patients who did not have an indication for anticoagulation as determined by the treating clinician. These patients mostly received primary reperfusion with streptokinase (78 percent) and were randomly assigned to subcutaneous fondaparinux (initial dose intravenously and then 2.5 mg/day given subcutaneously) or placebo for up to eight days or hospital discharge, whichever occurred first. In this arm of the trial, fondaparinux was associated with a lower rate of the primary endpoint of death or reinfarction (11.2 versus 14.0 percent; HR 0.79, 95% CI 0.68-0.92). The results of stratum 2 are described below.

Relative efficacy of the anticoagulants – Among agents used as adjunctive therapy in fibrinolysis, enoxaparin may be the most effective but is more difficult to manage in patients who will undergo PCI as part of a pharmacoinvasive strategy (algorithm 1). In the absence of a large benefit of anticoagulation, the complications of dosing enoxaparin, and sheath thrombus associated with fondaparinux, UFH has several advantages over other anticoagulants and can be used among patients who will undergo a pharmacoinvasive strategy. In patients who will not undergo PCI, fondaparinux and enoxaparin have greater efficacy when compared with UFH.

UFH compared with LMWH – Trials and studies that compared the relative efficacy of UFH and LMWH (enoxaparin) in patients with STEMI treated with fibrinolytic agents have generally found that enoxaparin is superior to UFH [22-27]:

-A 2007 meta-analysis of trials comparing UFH to enoxaparin in over 27,000 STEMI patients receiving fibrinolytic therapy found that the primary outcome of death, MI, or major bleeding at 30 days occurred less often in patients receiving enoxaparin (11.1 versus 12.9 percent, OR 0.84, 95% CI 0.73-0.97), with most of the benefit attributable to a reduction in MI [28]. However, major bleeding occurred significantly more often in patients receiving enoxaparin (2.6 versus 1.8 percent).

-A substudy of ExTRACT-TIMI 25, which was published after the meta-analysis, included 4676 patients who underwent fibrinolysis, some of whom underwent subsequent PCI [29]. Compared with patients assigned to UFH, patients who were randomly assigned to enoxaparin had a lower rate of provisional PCI (an indicator of failed fibrinolysis; 23 versus 24 percent) and, among those who underwent PCI, a lower rate of the primary endpoint (11 versus 14 percent). There were no differences in major bleeding.

Fondaparinux compared with UFH – In stratum 2 of the OASIS-6 trial, 6434 patients who had an indication for heparin (eg, fibrinolytic therapy with a fibrin-specific agent, planned PCI) as determined by the treating clinician were randomly assigned to fondaparinux (initial dose intravenously and then 2.5 mg/day given subcutaneously) for up to eight days or hospital discharge, or to UFH 60 units/kg bolus followed by infusion of 12 units/kg/hour for 24 to 48 hours [13]. In patients assigned to fondaparinux, there was a small decrease in the rate of the primary outcome (8.3 versus 8.7 percent; HR 0.96, 95% CI 0.76-0.99).

In prespecified subgroup analyses that included all patients enrolled in OASIS-6, fondaparinux was beneficial in patients who received fibrinolytic therapy with PCI or who received no reperfusion therapy. However, in patients who received fondaparinux and who underwent PCI, there was a higher rate of the primary outcome and sheath thrombosis [30,31].

Bivalirudin compared with UFHBivalirudin was compared with UFH in the HERO-2 trial of 17,073 STEMI patients treated with streptokinase [32]. At 30 days, the rates of mortality were similar between the two groups (11 percent) and there was a small reduction in reinfarction at 96 hours with bivalirudin (1.6 versus 2.3 percent). In addition, there was some evidence that the risk of severe bleeding (0.7 versus 0.5 percent) and intracerebral bleeding (0.6 versus 0.4 percent) were higher with bivalirudin, and moderate and mild bleeding were increased with bivalirudin.

Other anticoagulants – There are only limited data assessing the role of argatroban or lepirudin [33]; these drugs are not used in acute STEMI due to the absence of large-scale trials showing benefit and concerns of an increased rate of bleeding compared with other anticoagulants.

NO REPERFUSION THERAPY

Choice of agent — For patients who do not undergo reperfusion with primary percutaneous coronary intervention (PCI) or fibrinolysis and who do not have contraindications to anticoagulation or another indication for long-term anticoagulation (eg, mechanical valve), we suggest treatment with unfractionated heparin (UFH) for 48 hours or with enoxaparin for eight days or until discharge, whichever comes first (algorithm 2). We do not use bivalirudin or fondaparinux in this setting.

The American College of Cardiology/American Heart Association guidelines suggest that the approach to anticoagulation for patients not undergoing reperfusion is generally the same as that for patients undergoing reperfusion [3,4]. The European Society of Cardiology guidelines note that anticoagulation should be given to patients who will not undergo reperfusion and contains a weak recommendation for fondaparinux rather than UFH or enoxaparin [34].

Dosing and monitoring — The dosing and monitoring of each agent are as follows:

UFH – For patients treated with medical therapy (no reperfusion), we suggest an intravenous (IV) bolus of 50 to 70 units/kg up to a maximum of 5000 units, to be followed by an IV drip of 12 units/kg/hour, with a goal activated partial thromboplastin time of 1.5 to 2 times control or approximately 50 to 75 s.

Enoxaparin – The dosing of enoxaparin is based on age and kidney function, and monitoring is not typically required:

Age less than 75 years In patients who are <75 years of age with creatinine clearance ≥30 mL/minute using the Cockcroft-Gault formula (calculator 1 and calculator 2), we use a loading dose of 30 mg IV bolus followed by 1 mg/kg subcutaneously every 12 hours (maximum of 100 mg for the first two doses only). The first subcutaneous dose should be administered with the IV bolus.

For patients who are <75 years of age with a creatinine clearance <30 mL/minute using the Cockcroft-Gault formula, we use a 30 mg IV bolus given with the first dose of the subcutaneous maintenance regimen, which is adjusted to 1 mg/kg subcutaneously every 24 hours.

Age ≥75 years – In patients ≥75 years with creatinine clearance ≥30 mL/minute, we do not use a loading dose and administer a maintenance dose of 0.75 mg/kg subcutaneously every 12 hours (maximum of 75 mg for the first two doses only).

For patients who are 75 years or older with a creatinine clearance <30 mL/minute, we do not use a loading dose and administer a maintenance subcutaneous dose of 1 mg/kg every 24 hours.

Evidence — Our recommendation for anticoagulant use in this setting is largely based on the pathophysiology of thrombus formation in acute MI and from extrapolation of the experience with patients who undergo reperfusion to patients who will not undergo reperfusion. The available studies of anticoagulation versus no anticoagulation in this population have conflicting results. Only one relatively small trial directly compared UFH with enoxaparin and found similar event rates between the two groups:

From subgroup analyses of trials designed to assess the efficacy of fibrinolysis, patients treated with heparin alone (eg, did not receive a thrombolytic) did not clearly have a lower risk of adverse outcomes when compared with placebo.

For example, in a subgroup analysis of 3325 patients who did not undergo thrombolysis as intended in the CREATE trial, therapy with reviparin was associated with a significant reduction in the incidence of death, MI, or stroke compared with placebo (15 versus 18 percent) [21], while the results of other studies showed conflicting results [35,36].

The TETAMI trial compared the efficacy of UFH (with or without tirofiban) with enoxaparin (with or without tirofiban) in 1224 patients who were ineligible for reperfusion therapy [37]. At 30 days, the incidence of the combined endpoint of death, reinfarction, or recurrent angina for patients treated with enoxaparin was similar to UFH (16 versus 17 percent).

In patients who did not receive reperfusion, bivalirudin has not been studied and the only evidence for the efficacy of fondaparinux is from a subgroup analysis:

The role of fondaparinux in patients with STEMI not treated with reperfusion was evaluated in a prespecified subgroup analysis of the OASIS-6 trial (see 'Rationale and evidence in primary fibrinolysis' above). Among the 2867 in the trial who did not undergo reperfusion therapy, fondaparinux reduced the rate of the primary efficacy outcome (death and MI at 30 days) compared with UFH or placebo (12.2 versus 15.1 percent; hazard ratio 0.80, 95% CI 0.65-0.98) [30].

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: ST-elevation myocardial infarction (STEMI)".)

SUMMARY AND RECOMMENDATIONS

Anticoagulation for primary PCI

Anticoagulation prior to PCI – Patients with ST-elevation myocardial infarction (STEMI) whose reperfusion strategy is primary percutaneous coronary intervention (PCI) (algorithm 1) require prompt anticoagulation (algorithm 2). The only exceptions to immediate anticoagulation are cases in which the process of starting anticoagulation would delay primary PCI (eg, delay transfer to a PCI-capable center, delay the PCI procedure).

For most patients with STEMI who will undergo primary PCI, we suggest initial anticoagulation with unfractionated heparin (UFH) rather than other agents (eg, enoxaparin, fondaparinux, bivalirudin) (algorithm 2) (Grade 2C). We prefer UFH over enoxaparin because UFH has simpler dosing and monitoring. Bivalirudin has not been studied in this setting. (See 'Anticoagulation prior to PCI' above.)

Anticoagulation during PCI – All patients who undergo PCI require anticoagulation to prevent intraarterial thrombus formation. During PCI for STEMI, we suggest anticoagulation with UFH rather than with other agents (eg, bivalirudin, enoxaparin, or fondaparinux) (algorithm 2) (Grade 2C). We prefer UFH in this setting for the same reasons outlined above (ie, simpler dosing and monitoring). We do not use fondaparinux because it is associated with increased risk of catheter thrombosis. If enoxaparin was given >6 hours prior to PCI, we initiate UFH during PCI rather than maintain anticoagulation with enoxaparin. (See 'Anticoagulation during PCI' above.)

Anticoagulation after PCI The duration of anticoagulation is influenced by the agent used, whether complications occurred during PCI, and whether there is an indication for long-term anticoagulation. (See 'Anticoagulation after PCI' above.)

Anticoagulation for fibrinolysis with or without PCI – In patients with STEMI who undergo reperfusion with fibrinolysis regardless of the specific fibrinolytic agent (algorithm 1), the approach to anticoagulation is influenced by the likelihood of angiography and/or PCI following fibrinolysis as follows:

Fibrinolysis followed by PCI – In patients who undergo primary fibrinolysis and who are likely to have PCI thereafter (ie, pharmacoinvasive strategy), we suggest the use of UFH rather than other agents (eg, enoxaparin, bivalirudin, or fondaparinux) (algorithm 2) (Grade 2C). (See 'Choice of anticoagulant' above.)

Fibrinolysis without planned PCI For patients who are unlikely to undergo angiography and/or PCI, we suggest anticoagulation with enoxaparin or fondaparinux rather than other agents or no anticoagulation (algorithm 2) (Grade 2B). However, fondaparinux is not approved for use in patients with STEMI by the US Food and Drug Administration. (See 'Choice of anticoagulant' above.)

Duration of therapy – The duration of therapy is determined by the agent:

-UFH – UFH therapy should continue with periodic monitoring according to local protocols until PCI is complete or for 48 hours, whichever comes first. (See 'Dosing and duration of therapy' above.)

-Enoxaparin – For patients who will undergo PCI and who are treated with enoxaparin, therapy with enoxaparin should continue until PCI. For patients who will not undergo PCI, therapy with enoxaparin should continue for eight days or until discharge, whichever comes first. (See 'Dosing and duration of therapy' above.)

Anticoagulation if no reperfusion therapy – For patients who do not undergo reperfusion with primary PCI or fibrinolysis and who do not have contraindications to anticoagulation or another indication for long-term anticoagulation (eg, mechanical valve), we suggest treatment with UFH for 48 hours or with enoxaparin for eight days or until discharge, whichever comes first (algorithm 2) (Grade 2C). We do not use bivalirudin or fondaparinux in this setting. (See 'No reperfusion therapy' above.)

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References