1. Introduction and Clinical Imperative

Acute coronary syndrome (ACS) management hinges on prompt anticoagulation to prevent thrombus propagation while minimizing hemorrhagic complications. Risk stratification (e.g., using TIMI or CRUSADE scores) and patient-specific factors such as renal function, age, and bleeding history are crucial in guiding the selection of anticoagulant agents and their appropriate dosing.

• Therapeutic goal: The primary aim is to effectively suppress thrombosis and prevent further ischemic events without causing excessive bleeding.
• Impact of bleeding: Major bleeding events occurring after ACS are independently associated with an increased risk of mortality.

2. Weight-Based Protocols

2.1 Unfractionated Heparin (UFH)

Unfractionated Heparin (UFH) offers the advantages of rapid onset and offset of action, along with full reversibility. However, its variable pharmacokinetics necessitate frequent monitoring to maintain therapeutic levels.

2.2 Low-Molecular-Weight Heparin (Enoxaparin)

Enoxaparin provides more predictable anti-Xa activity compared to UFH, generally requiring less monitoring. However, it can accumulate in patients with renal impairment and is only partially reversible with protamine.

3. Monitoring Strategies: aPTT vs Anti-Xa Assays

Effective anticoagulation requires appropriate monitoring. The activated partial thromboplastin time (aPTT) is widely available but can be influenced by various factors. Anti-Xa assays offer more specific measurement of heparin activity but are less universally accessible and may have longer turnaround times.

• aPTT: Offers rapid turnaround time. However, results can be influenced by pre-analytical variables (e.g., sample collection, processing), instrument and reagent variability, and the presence of lupus anticoagulants or elevated Factor VIII levels.
• Anti-Xa Assay: Provides a more specific measure of Xa inhibition by heparins. It is less affected by reagent variability and other coagulation factors. However, it is generally more expensive and may not be available in all institutions with rapid turnaround.
• Activated Clotting Time (ACT): Primarily used for intra-procedural monitoring of UFH during PCI, with a target range typically between 250–300 seconds (or 200-250 seconds if a GP IIb/IIIa inhibitor is used).

4. Special Indications and High-Risk Scenarios

4.1 Heparin-Induced Thrombocytopenia (HIT)

HIT is a prothrombotic, immune-mediated adverse drug reaction to heparin.

• Diagnosis: Suspect HIT based on clinical criteria (e.g., 4Ts score: Thrombocytopenia, Timing of platelet count fall, Thrombosis or other sequelae, oTher causes for thrombocytopenia not evident). Confirm with a PF4-heparin antibody enzyme-linked immunosorbent assay (ELISA) and/or functional assays like the serotonin release assay (SRA).
• Management: Immediately stop all forms of heparin (UFH and LMWH). Initiate a non-heparin anticoagulant, such as argatroban (a direct thrombin inhibitor) or bivalirudin. Do not use LMWH as it has cross-reactivity. Warfarin should only be started once platelet counts have recovered significantly (e.g., >150,000/µL) and must overlap with the non-heparin anticoagulant.

4.2 High Bleeding Risk

Patients with a high baseline bleeding risk require careful selection and dosing of anticoagulants.

• Identification: Utilize validated bleeding risk scores such as CRUSADE (Can Rapid risk stratification of Unstable angina patients Suppress ADverse outcomes with Early implementation of the ACC/AHA guidelines) score ≥50 or PRECISE-DAPT (PREdicting bleeding Complications In patients undergoing Stent implantation and subsEquent Dual Anti Platelet Therapy) score ≥25.
• Strategies:
  • Consider dose reduction (e.g., UFH initial bolus 50 U/kg, enoxaparin 1 mg/kg SC q24h if CrCl <30 mL/min or for elderly with borderline renal function).
  • Shorten the duration of anticoagulation (e.g., UFH for 24-48 hours, enoxaparin for a maximum of 5-8 days depending on clinical scenario).
  • Avoid overlapping different parenteral anticoagulants and use glycoprotein IIb/IIIa inhibitors judiciously, only when a clear, high ischemic benefit outweighs the bleeding risk.
  • Prioritize radial access for PCI.

5. Transitioning and Bridging Strategies

Transitioning from parenteral to oral anticoagulation or bridging anticoagulation around procedures is rarely needed for the primary indication of ACS itself but may be required for comorbid conditions (e.g., atrial fibrillation, mechanical heart valves).

• Warfarin: If long-term warfarin is indicated for a concomitant condition, initiate it concurrently with the parenteral anticoagulant. Continue both until the International Normalized Ratio (INR) is within the therapeutic range (typically 2.0–3.0) for at least two consecutive days, after which the parenteral agent can be discontinued. A typical overlap is 3-5 days.
• Direct Oral Anticoagulants (DOACs): DOACs are primarily indicated for comorbid conditions like non-valvular atrial fibrillation or venous thromboembolism (VTE). De novo initiation of DOACs in the acute phase of STEMI, particularly outside of established guideline recommendations or clinical trial protocols, should be approached with caution. Transitioning from parenteral anticoagulation to a DOAC usually involves stopping the parenteral agent and starting the DOAC at the time the next parenteral dose would have been due, or as per specific drug recommendations.
• Bridging Anticoagulation: For most ACS patients, bridging anticoagulation is generally unnecessary, as DAPT provides sufficient antithrombotic effect. If bridging is required for a high-risk patient with a mechanical valve or other compelling long-term anticoagulation indication undergoing a procedure, follow specific peri-procedural protocols, often involving stopping warfarin and using shorter-acting LMWH or UFH.

6. Duration of Anticoagulation

The duration of parenteral anticoagulation in ACS is tailored to the clinical presentation, revascularization strategy, and individual patient factors.

• Medical Management (No Revascularization or Delayed Revascularization):
  • UFH: Typically administered for 48 hours or until revascularization if planned.
  • Enoxaparin: Continued until hospital discharge or for up to 8 days (whichever comes first), or until revascularization.
• Post-PCI:
  • If UFH was used for PCI, it is generally discontinued immediately after the procedure unless there’s a compelling reason to continue (e.g., high thrombus burden, suboptimal stent deployment).
  • If enoxaparin was used leading up to PCI, the need for post-PCI doses depends on the timing of the last SC dose relative to the procedure. Generally, parenteral anticoagulation is not continued long-term post-PCI if DAPT is adequate. Some protocols may continue for 24–48 hours post-sheath removal in specific high-risk situations, but this is not routine.
• Individualization: The decision on duration should always be individualized, considering factors such as patient frailty, renal function, bleeding history, thrombotic risk, and the specifics of the ACS event and intervention.

7. Clinical Algorithm and Flowchart

A stepwise approach helps standardize and optimize anticoagulation in ACS:

8. Pearls, Pitfalls, and Controversies