6.4: Anticoagulation & Antiplatelet Therapy

Anticoagulation & Antiplatelet Therapy in Australian Practice

In Australian clinical pharmacy, managing antithrombotic therapy requires a deep understanding of the differences between Direct Oral Anticoagulants (DOACs), vitamin K antagonists (warfarin), and antiplatelet agents. Pharmacists must navigate initiation, switching, monitoring, perioperative cessation, and reversal protocols, referencing resources like the Australian Medicines Handbook (AMH) and national consensus guidelines.

1. Direct Oral Anticoagulants (DOACs) vs. Warfarin

DOACs have become the standard of care for stroke prevention in non-valvular atrial fibrillation (NVAF) and the treatment/prevention of venous thromboembolism (VTE) due to their predictable pharmacokinetics, lack of routine monitoring, and fewer drug-food interactions. However, warfarin remains indicated in specific patient groups.

Pharmacological Profiles and Comparisons

Key Clinical Pearl: Apixaban Dose Reduction in NVAF

In NVAF, the standard apixaban dose is 5 mg BD. Reduce to 2.5 mg BD only if the patient meets at least two of the following criteria:

• Age ≥ 80 years
• Body weight ≤ 60 kg
• Serum creatinine ≥ 133 micromol/L

Mandated Warfarin Indications (DOAC Contraindications)

DOACs are contraindicated, and warfarin must be used, in:

1. Mechanical Heart Valves: Increased thromboembolic and bleeding risks with DOACs (demonstrated in the RE-ALIGN trial for dabigatran).
2. Moderate-to-Severe Mitral Stenosis: Rheumatic heart disease-associated AF.
3. Antiphospholipid Syndrome (APS): Particularly 'triple-positive' patients (positive for lupus anticoagulant, anticardiolipin, and anti-beta-2-glycoprotein I antibodies), where DOACs carry a higher rate of arterial thrombotic events than warfarin.

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2. Warfarin Monitoring, INR, and Reversal Guidelines

Warfarin therapy requires frequent monitoring of the International Normalised Ratio (INR). In Australia, the management of supratherapeutic INR is standardized to minimize bleeding risk while preventing thrombosis.

Management of High INR (No Bleeding)

• INR 3.0-4.5: Reduce or withhold the next 1-2 doses of warfarin. Monitor INR and restart at a lower dose when the INR returns to the therapeutic range.
• INR 4.5-10.0: Withhold 1-2 doses of warfarin. Measure INR daily. If the patient has a high bleeding risk, consider giving oral phytomenadione (Vitamin K1) 1-2 mg. Restart at an adjusted dose when INR is within target.
• INR > 10.0: Stop warfarin. Give oral phytomenadione 2.5-5 mg. Monitor INR and give further oral Vitamin K1 if necessary. Restart warfarin at a lower dose once the INR is therapeutic.

Management of Bleeding (Any INR)

• Clinically Significant / Major Bleeding: Stop warfarin immediately. Administer Prothrombinex-VF (human coagulation factors II, IX, X) at a dose of 25-50 units/kg via slow IV infusion. Concurrently, administer phytomenadione 5-10 mg IV (infuse slowly over 20 minutes to prevent anaphylaxis).
  • Note: Prothrombinex-VF contains low levels of Factor VII. If there is life-threatening bleeding, Fresh Frozen Plasma (FFP) (150-300 mL) may be co-administered to supply Factor VII, though Prothrombinex-VF remains the primary rapid reversal agent in Australia.

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3. Initiation, Switching, and Bridging Therapy

Warfarin Initiation

Warfarin takes 4-5 days to achieve full therapeutic antithrombotic effect because of the long half-lives of Factor II (prothrombin, ~60-72 hours) and Factor X (~40 hours). During the first 24-48 hours of initiation, a transient prothrombotic state exists because anticoagulant Protein C (~8 hours half-life) and Protein S (~30 hours half-life) are depleted first.

• Bridging: For acute VTE, patients must receive concurrent therapeutic-dose Low Molecular Weight Heparin (LMWH, e.g. enoxaparin 1.5 mg/kg daily or 1 mg/kg BD) for at least 5 days and until the INR is ≥ 2.0 for two consecutive days.
• Dosing: Avoid loading doses > 10 mg. In elderly, frail, or hepatic-impaired patients, start with a conservative dose of 2-5 mg daily.

Switching Protocols (AMH Guidelines)

• Warfarin to DOAC: Stop warfarin. Start apixaban or dabigatran when INR < 2.0. Start rivaroxaban when INR < 3.0.
• DOAC to Warfarin: Overlap DOAC and warfarin. Start warfarin while continuing the DOAC. Monitor INR (measure just before the next scheduled DOAC dose to minimize the DOAC's effect on the INR assay). Stop the DOAC once the INR is ≥ 2.0.
• LMWH to DOAC: Stop LMWH and start the DOAC when the next dose of LMWH would have been due.

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4. Perioperative Management of Anticoagulants

Cessation times before elective surgery depend on the bleeding risk of the procedure and the patient's renal function.

DOAC Perioperative Interruption

• Warfarin: Stop warfarin 5 days prior to surgery. Check the INR the day before surgery. If INR ≥ 1.5, administer oral phytomenadione 1-2 mg.
• Bridging in Warfarin Patients: Bridging with therapeutic LMWH is indicated only for patients at high risk of thromboembolism (e.g., mechanical heart valve, AF with CHA2DS2-VA score ≥ 5 or recent stroke/TIA within 3 months, or VTE within the past 3 months). Stop LMWH 24 hours before surgery.

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5. Specific Reversal Agents

• Idarucizumab (Praxbind): A humanised monoclonal antibody fragment that binds specifically to dabigatran (both free and thrombin-bound) with an affinity 350 times higher than that of dabigatran for thrombin. Dose: 5 g IV (administered as two separate 2.5 g/50 mL vials, back-to-back as a bolus or rapid infusion).
• Andexanet alfa (Ondexxya): A recombinant modified human Factor Xa decoy protein that binds and sequesters factor Xa inhibitors (apixaban, rivaroxaban). Dose depends on the specific DOAC, dose, and time since last ingestion.
• Protamine Sulfate: Used to reverse unfractionated heparin (1 mg protamine neutralises 100 units of heparin; max dose 50 mg). It only partially reverses LMWH (approximately 60% of anti-Xa activity).

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6. Antiplatelet Management

Antiplatelets are critical for secondary prevention of cardiovascular events. Dual Antiplatelet Therapy (DAPT) consisting of aspirin (100 mg daily) and a P2Y12 inhibitor (clopidogrel, prasugrel, or ticagrelor) is standard after acute coronary syndrome (ACS) or percutaneous coronary intervention (PCI).

Clinical Profiles of P2Y12 Inhibitors

• Clopidogrel: Irreversible prodrug; requires two-step hepatic activation (CYP2C19). PPIs like omeprazole or esomeprazole inhibit CYP2C19 and may decrease clopidogrel's efficacy; pantoprazole is the preferred PPI if co-prescribing is necessary.
• Prasugrel: Irreversible prodrug; faster and more consistent activation than clopidogrel. Contraindicated in patients with a history of stroke or TIA; caution in patients ≥ 75 years or weight < 60 kg due to high bleeding risk.
• Ticagrelor: Reversible inhibitor; does not require metabolic activation. Twice-daily dosing. Common side effects include transient dyspnoea (usually self-limiting) and bradyarrhythmias.

Perioperative Antiplatelet Cessation

For elective surgeries carrying high bleeding risk:

• Stop clopidogrel 5 days before surgery.
• Stop ticagrelor 5 days before surgery.
• Stop prasugrel 7 days before surgery.
• Aspirin: Usually continued throughout the perioperative period for secondary prevention, unless the surgery carries an exceptionally high risk of localized bleeding in closed spaces (e.g., neurosurgery or posterior eye surgery).
• Resumption: Resume antiplatelets as soon as haemostasis is secured post-operatively (usually within 24-48 hours).