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CLINICAL STATEMENTS AND GUIDELINES

Circulation. 2025;151:e771–e862. DOI: 10.1161/CIR.0000000000001309 April 1, 2025 e795

a predictable dose response and risk of heparininduced thrombocytopenia.33 In unstable angina, a meta-analysis including 1353 patients enrolled from 6 randomized studies showed that, in comparison to patients treated with aspirin alone, those treated with aspirin and heparin were at lower, albeit nonstatistically significant, risk for MI or death during the randomized treatment period (relative risk, 0.67 [95% CI, 0.44-1.02]).3 Its efficacy compared with placebo has not been evaluated in the current era of dual antiplatelet therapy (DAPT) and early revascularization.33

2 Fondaparinux, a synthetic pentasaccharide that

selectively binds antithrombin and causes rapid and predictable inhibition of Factor Xa, was evaluated in patients with high-risk NSTE-ACS in the OASIS-5 (Fifth Organization to Assess Strategies in Acute Ischemic Syndromes) trial.5 Fondaparinux was similar to enoxaparin in the risk for ischemic events at 9 days, but it reduced major bleeding. About 40% of the patients underwent PCI, and an increase was observed in the rate of guidingcatheter thrombus formation with fondaparinux (0.9% versus 0.3%) compared with enoxaparin. In NSTE-ACS, despite some data favoring the use of enoxaparin over UFH,11 multiple meta-analyses have not demonstrated compelling superiority in efficacy over UFH.7,26,36 A meta-analysis comparing low-molecular-weight heparin to UFH in 12 171 patients with ACS without ST-segment elevation across 5 randomized trials showed no significant difference in death or MI (2.2% versus 2.3%) or in the risk of major bleeding.36

3 For patients with ACS undergoing coronary revas-

cularization (CABG or PCI), parenteral anticoagulation is indicated until revascularization. The premature discontinuation of anticoagulation is associated with a transient rebound increase in thrombin activity and activated protein C and the reactivation of ischemic events,12,13 with the greatest risk for reinfarction in the first 4 to 8 hours after the discontinuation of anticoagulation. 4.	 UFH has traditionally been the preferred anticoagulant to support PCI in patients with NSTE-ACS. Activated clotting time is used to guide dosing during PCI.37 Although its pharmacokinetic effects are not always predictable, its anticoagulant effect is reversible with the administration of protamine. 5.	 Bivalirudin is a direct thrombin inhibitor evaluated

in both NSTE-ACS and STEMI that can be used to support PCI. In the BRIGHT-4 (Bivalirudin with Prolonged Full-Dose Infusion during PPCI versus Heparin) trial,15 which enrolled patients with STEMI undergoing PPCI using radial access (93%), bivalirudin was compared with heparin monotherapy in an open-label design. The bivalirudin regimen used included the standard bolus and dosing (0.75 mg/kg, then 1.75 mg/kg per hour) plus a post-PCI infusion at the full dose (1.75 mg/kg per hour) for 2 to 4 hours. Bivalirudin with the full dose post- PCI infusion was superior to UFH in reducing the 30-day composite of all-cause death or BARC

Table 10.  Dosing of Parenteral Anticoagulation in ACS Drug Dosing UFH Initial therapy: Loading dose 60 IU/kg (max 4000 IU), with initial infusion 12 IU/kg per h (max 1000 IU/h) adjusted to therapeutic aPTT range of 60-80 s.

To support PCI: In patients who have received prior anticoagulant therapy, additional UFH as needed to achieve an ACT 250-300 s. In patients who have not received prior anticoagulant therapy, 70-100 U/kg initial bolus to achieve target ACT of 250-300 s. With fibrinolytic therapy: Loading dose 60 IU/kg (maximum 4000 IU) with initial infusion 12 IU/kg per h (maximum 1000 IU/h) adjusted to therapeutic aPTT range.*

Bivalirudin To support PCI: 0.75 mg/kg bolus, 1.75 mg/kg per h IV infusion during the PCI procedure.

Post-PCI infusion for PPCI: 1.75 mg/kg per h for 2-4 h post-PCI. In patients with CrCl <30 mL/min, reduced infusion to 1 mg/kg per h.

Enoxaparin Initial therapy: 1 mg/kg subcutaneous every 12 h. Reduce dose to 1 mg/kg per d subcutaneous if CrCl <30 mL/min.

To support PCI: For previous treatment with enoxaparin, if the last subcutaneous dose was administered 8-12 h earlier or if only 1 subcutaneous dose of enoxaparin has been administered, an IV dose of 0.3 mg/kg of enoxaparin should be given. If the last dose was administered within the previous 8 h, no additional enoxaparin should be given. For patients who have not received prior anticoagulant therapy, 0.5-0.75 mg/kg IV bolus. With fibrinolytic therapy: If age <75 y, 30 mg IV bolus, followed in 15 min by 1 mg/kg subcutaneous every 12 h (maximum 100 mg for the first 2 doses). If age ≥75 y: no bolus, 0.75 mg/kg subcutaneous every 12 h (maximum 75 mg for the first 2 doses). Regardless of age, if CrCl <30 mL/min: 1 mg/kg subcutaneous every 24 h.

Fondaparinux Initial therapy: 2.5 mg subcutaneous daily.

With fibrinolytic therapy: 2.5 mg IV, then 2.5 mg subcutaneous daily starting the following day. Contraindicated if CrCl <30 mL/min. Fondaparinux should not be used to support PCI because of the risk of catheter thrombosis.

*Therapeutic aPTT range in setting of fibrinolytic therapy is 50-70 s. ACS indicates acute coronary syndromes; ACT, activated clotting time; aPTT, activated partial thromboplastin time; CrCl, creatinine clearance; PCI, percutaneous coronary intervention; PPCI, primary percutaneous coronary intervention; and UFH, unfractionated heparin.

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