Anticoagulants

Anticoagulants are a class of drugs that help prevent the formation of blood clots by interfering with the coagulation process. They are commonly used to treat and prevent thromboembolic disorders such as deep vein thrombosis (DVT), pulmonary embolism (PE), and atrial fibrillation (AF), and to prevent stroke in certain patients.

Types of Anticoagulants

Anticoagulants can be broadly classified into several categories based on their mechanisms of action and administration routes:

  1. Vitamin K Antagonists (VKAs)
  2. Heparins (including low molecular weight heparins)
  3. Direct Thrombin Inhibitors (e.g., Dabigatran, Argatroban, Bivalirudin)
  4. Direct Factor Xa Inhibitors (e.g., Rivaroxaban, Apixaban, Edoxaban)
  5. Fondaparinux
  6. Factor XI Inhibitors (e.g., Asundexian, Milvexian)
  7. Direct Oral Anticoagulants (DOACs)

1. Vitamin K Antagonists (e.g., Warfarin)

  • Mechanism of Action: Warfarin inhibits the enzyme vitamin K epoxide reductase, which is necessary for the activation of vitamin K-dependent clotting factors (II, VII, IX, and X). This reduces the ability of the blood to clot.
  • Indications:
    • Prevention and treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE)
    • Prevention of stroke in patients with atrial fibrillation
    • Mechanical heart valve prophylaxis
  • Typical Dose:
    • Warfarin: Initial dose is typically 5 mg once daily, adjusted based on the International Normalized Ratio (INR), with a target INR usually between 2-3 for most indications.
  • Side Effects:
    • Bleeding (major risk)
    • Skin necrosis
    • Teratogenic effects (contraindicated in pregnancy)
    • Drug and dietary interactions
  • Reversal Agent:
    • Vitamin K (oral or intravenous)
    • Fresh frozen plasma (FFP)
    • Prothrombin complex concentrates (PCC)
    • Recombinant factor VIIa (in severe cases)

2. Heparins (Unfractionated Heparin and Low Molecular Weight Heparins)

  • Mechanism of Action: Heparins activate antithrombin III, which inactivates thrombin (factor IIa) and factor Xa, preventing the conversion of fibrinogen to fibrin, a key step in blood clot formation.
    • Unfractionated Heparin (UFH): Inhibits both thrombin and factor Xa.
    • Low Molecular Weight Heparins (LMWH, e.g., Enoxaparin): Primarily inhibit factor Xa with less effect on thrombin.
  • Indications:
    • Prevention and treatment of DVT and PE
    • Acute coronary syndrome (ACS)
    • Perioperative anticoagulation
    • Anticoagulation during pregnancy (LMWH is preferred)
  • Typical Dose:
    • Unfractionated Heparin (UFH): IV bolus of 80 units/kg followed by an infusion of 18 units/kg/hour, adjusted based on aPTT.
    • Enoxaparin (LMWH): 1 mg/kg subcutaneously every 12 hours or 1.5 mg/kg subcutaneously once daily for treatment; for prophylaxis, 40 mg subcutaneously once daily.
  • Side Effects:
    • Bleeding
    • Heparin-induced thrombocytopenia (HIT)
    • Osteoporosis (with long-term use)
    • Hyperkalemia
  • Reversal Agent:
    • Unfractionated Heparin (UFH): Protamine sulfate (1 mg of protamine neutralizes 100 units of heparin).
    • LMWH: Protamine sulfate partially reverses the effects of LMWH; however, it is less effective compared to UFH.

3. Direct Thrombin Inhibitors (e.g., Dabigatran, Argatroban, Bivalirudin)

  • Mechanism of Action: Directly inhibit thrombin (factor IIa), preventing the conversion of fibrinogen to fibrin and thus inhibiting clot formation.
  • Indications:
    • Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation (Dabigatran)
    • Treatment and prevention of DVT and PE
    • Anticoagulation in patients with HIT (Argatroban, Bivalirudin)
  • Typical Dose:
    • Dabigatran: 150 mg orally twice daily for most indications; reduced to 75 mg twice daily in patients with renal impairment.
    • Argatroban: Continuous IV infusion with an initial dose of 2 mcg/kg/min, adjusted based on aPTT.
    • Bivalirudin: IV bolus of 0.75 mg/kg followed by an infusion of 1.75 mg/kg/hour.
  • Side Effects:
    • Bleeding (including gastrointestinal bleeding)
    • Dyspepsia (with Dabigatran)
    • Allergic reactions
    • No specific antidote (except for Dabigatran, which can be reversed with Idarucizumab)
  • Reversal Agent:
    • Dabigatran: Idarucizumab (Praxbind) specifically reverses Dabigatran.
    • Argatroban and Bivalirudin: No specific reversal agent; management is supportive, with potential use of hemodialysis for Dabigatran.

4. Direct Factor Xa Inhibitors (e.g., Rivaroxaban, Apixaban, Edoxaban)

  • Mechanism of Action: These drugs directly inhibit factor Xa, a crucial enzyme in the coagulation cascade that converts prothrombin to thrombin.
  • Indications:
    • Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation
    • Treatment and prevention of DVT and PE
    • Postoperative thromboprophylaxis after hip or knee replacement surgery
  • Typical Dose:
    • Rivaroxaban: 20 mg orally once daily with food for most indications.
    • Apixaban: 5 mg orally twice daily; reduced to 2.5 mg twice daily in patients with certain risk factors.
    • Edoxaban: 60 mg orally once daily; reduced to 30 mg once daily in patients with renal impairment or low body weight.
  • Side Effects:
    • Bleeding (major risk)
    • Liver enzyme elevation
    • Gastrointestinal disturbances
  • Reversal Agent:
    • Rivaroxaban and Apixaban: Andexanet alfa (Ondexxya) is the specific reversal agent.
    • Edoxaban: No specific reversal agent; supportive management is recommended.

5. Fondaparinux

  • Mechanism of Action: A synthetic pentasaccharide that selectively inhibits factor Xa by binding to antithrombin III, thereby preventing thrombin formation and clot development.
  • Indications:
    • Prevention and treatment of DVT and PE
    • Acute coronary syndrome (ACS)
  • Typical Dose:
    • Treatment of DVT/PE: 7.5 mg subcutaneously once daily (for patients 50-100 kg).
    • Prophylaxis: 2.5 mg subcutaneously once daily.
  • Side Effects:
    • Bleeding
    • Thrombocytopenia
    • No specific antidote
  • Reversal Agent:
    • No specific reversal agent; management is supportive, potentially using recombinant factor VIIa in severe cases.

6. Factor XI Inhibitors (e.g., Asundexian, Milvexian)

  • Mechanism of Action: These drugs are newer agents that inhibit factor XI, an upstream component of the intrinsic pathway of coagulation, reducing thrombin generation and clot formation.
  • Indications:
    • Currently under investigation for various thromboembolic disorders; potential future indications include stroke prevention and DVT/PE treatment.
  • Typical Dose:
    • Still under clinical trials; doses are being determined based on ongoing studies.
  • Side Effects:
    • Expected to have a lower bleeding risk compared to other anticoagulants, though studies are ongoing.
  • Reversal Agent:
    • No specific reversal agent is available yet; management would be supportive.

Direct Oral Anticoagulants (DOACs)

  1. Dabigatran (Pradaxa)
    • Mechanism: Direct thrombin inhibitor.
    • Uses: Prevention of stroke and systemic embolism in non-valvular AF, treatment and prevention of DVT and PE.
    • Dose: Typically 150 mg twice daily.
    • Adverse Effects: Bleeding, gastrointestinal upset.
    • Contraindications: Severe renal impairment, active bleeding, mechanical heart valves.
    • Monitoring: Routine monitoring is not required, but renal function should be assessed periodically.
    • Reversal Agent: Idarucizumab (Praxbind).
  2. Rivaroxaban (Xarelto)
    • Mechanism: Direct factor Xa inhibitor.
    • Uses: Prevention of stroke and systemic embolism in non-valvular AF, treatment and prevention of DVT and PE.
    • Dose: Typically 20 mg once daily with food.
    • Adverse Effects: Bleeding, anemia.
    • Contraindications: Active bleeding, severe renal impairment, hepatic disease with coagulopathy.
    • Monitoring: Routine monitoring not required.
    • Reversal Agent: Andexanet alfa (Ondexxya), activated charcoal if ingested recently.
  3. Apixaban (Eliquis)
    • Mechanism: Direct factor Xa inhibitor.
    • Uses: Prevention of stroke and systemic embolism in non-valvular AF, treatment and prevention of DVT and PE.
    • Dose: Typically 5 mg twice daily.
    • Adverse Effects: Bleeding, nausea.
    • Contraindications: Active bleeding, severe hepatic impairment.
    • Monitoring: Routine monitoring is not required.
    • Reversal Agent: Andexanet alfa (Ondexxya), activated charcoal if ingested recently.
  4. Edoxaban (Lixiana)
    • Mechanism: Direct factor Xa inhibitor.
    • Uses: Prevention of stroke and systemic embolism in non-valvular AF, treatment and prevention of DVT and PE.
    • Dose: Typically 60 mg once daily.
    • Adverse Effects: Bleeding, rash.
    • Contraindications: Active bleeding, severe renal impairment.
    • Monitoring: Routine monitoring is not required.
    • Reversal Agent: Andexanet alfa (Ondexxya), activated charcoal if ingested recently.

Clinical Use and Guidelines

In the UK, the use of anticoagulants is guided by clinical guidelines from authoritative bodies such as the National Institute for Health and Care Excellence (NICE) and the British Society for Haematology (BSH).

  1. Atrial Fibrillation:
    • Anticoagulation is recommended to prevent stroke and systemic embolism in patients with non-valvular AF. DOACs (e.g., apixaban, rivaroxaban) are preferred over warfarin for most patients.
  2. Venous Thromboembolism (VTE):
    • For the initial treatment of DVT and PE, LMWH or fondaparinux is often used, followed by long-term anticoagulation with a DOAC or warfarin.
  3. Mechanical Heart Valves:
    • Warfarin remains the anticoagulant of choice for patients with mechanical heart valves due to the lack of sufficient evidence supporting the use of DOACs in this population.
  4. Acute Coronary Syndromes (ACS):
    • Anticoagulation therapy is used in conjunction with antiplatelet agents to prevent thrombus formation. LMWH, UFH, or fondaparinux may be used depending on the clinical scenario.

Administration and Monitoring

Anticoagulants are administered through various routes depending on the specific drug and clinical context, including oral, intravenous, and subcutaneous routes. Regular monitoring is essential for certain anticoagulants to ensure therapeutic efficacy and safety:

  • Vitamin K Antagonists (VKAs): Regular INR monitoring is essential to adjust the dose and maintain therapeutic levels.
  • Heparins: UFH requires regular aPTT monitoring, while LMWH typically does not require routine monitoring, except in special populations (e.g., pregnant women, renal impairment).
  • Direct Oral Anticoagulants (DOACs): Routine monitoring is generally not required, but renal function should be periodically assessed.

References

  1. NICE Guidelines on Atrial Fibrillation
  2. British Society for Haematology: Guidelines on Anticoagulation
  3. British Heart Foundation: Anticoagulant Medications