How to decide the dose of antithrombotic (anti-clotting) therapy?

Antithrombotic Therapy Dosing Strategy

Dose antithrombotic therapy based on the specific agent class, renal function, body weight, indication, and bleeding risk—with vitamin K antagonists (VKAs) targeted to INR 2.0-3.0, direct oral anticoagulants (DOACs) adjusted for creatinine clearance and specific patient characteristics, low molecular weight heparins (LMWHs) weight-adjusted with renal dose reduction when CrCl <30 mL/min, and unfractionated heparin (UFH) weight-adjusted with aPTT monitoring. 1

Vitamin K Antagonist (VKA) Dosing

Initial Dosing

• Use a 10 mg loading dose of warfarin for most patients starting VKA therapy, as this approach is safe with recurrent VTE rates of 1.9% and major bleeding rates of 1.0% at 3 months. 1
• Start VKA simultaneously with parenteral anticoagulation (heparin/LMWH) rather than delaying, and overlap for at least 5 days until INR ≥2.0 for at least 24 hours. 2

Maintenance Dosing

• Target INR of 2.5 (range 2.0-3.0) for all standard indications including atrial fibrillation, VTE treatment, and stroke prevention. 1, 3
• Do not use more intensive INR ranges (higher targets) even for high-risk groups such as antiphospholipid syndrome or cancer, as standard intensity provides optimal benefit-risk balance. 1

Monitoring Strategy

• Use computer software or manual dosing algorithms rather than usual care to improve time in therapeutic range and reduce hemorrhagic/thromboembolic events. 1
• Monitor INR more frequently during initiation, then extend intervals once stable dosing is achieved. 1

Direct Oral Anticoagulant (DOAC) Dosing

Rivaroxaban Dosing by Indication

For atrial fibrillation:

• Standard dose: 20 mg once daily with food when CrCl >50 mL/min 4
• Reduced dose: 15 mg once daily with food when CrCl 15-50 mL/min 4
• Avoid use when CrCl <15 mL/min 4

For VTE treatment:

• Initial phase: 15 mg twice daily with food for first 21 days 4
• Continuation: 20 mg once daily with food for remaining treatment 4
• Recurrence prevention: 10 mg once daily (with or without food) after completing ≥6 months of standard anticoagulation 4

For coronary artery disease or peripheral artery disease:

• 2.5 mg twice daily (with or without food) plus aspirin 75-100 mg once daily 4
• No renal dose adjustment needed for this indication 4

Other DOAC Dose Adjustments

Apixaban:

• Standard: 5 mg twice daily 1
• Reduce to 2.5 mg twice daily if patient has ≥2 of: age ≥80 years, weight ≤60 kg, serum creatinine ≥1.5 mg/dL 1

Dabigatran:

• Standard: 150 mg twice daily 1
• Reduce to 75 mg twice daily if CrCl 15-30 mL/min 1

Edoxaban:

• 60 mg once daily if CrCl 51-95 mL/min (not recommended if CrCl >95 mL/min) 1
• 30 mg once daily if CrCl 15-50 mL/min 1

Low Molecular Weight Heparin (LMWH) Dosing

Standard Weight-Based Dosing

For therapeutic anticoagulation:

• Enoxaparin: 1 mg/kg subcutaneously twice daily (standard dose) 1
• Dalteparin: Weight-based dosing per indication 1
• Tinzaparin: 175 units/kg subcutaneously once daily 1

For prophylaxis:

• Enoxaparin: 40 mg subcutaneously daily 1
• Dalteparin: 5000 units subcutaneously daily 1
• Tinzaparin: 4500 units (fixed dose) or 75 units/kg subcutaneously daily 1

Critical Renal Dose Adjustments

When CrCl <30 mL/min, reduce enoxaparin dose to 0.5 mg/kg subcutaneously once daily (instead of 1 mg/kg twice daily) for therapeutic anticoagulation. 5

This recommendation is essential because:

• Patients with CrCl <30 mL/min have significantly higher major bleeding risk (5.0% vs 2.4%; OR 2.25) compared to those with CrCl >30 mL/min 5
• Standard therapeutic doses without adjustment increase major bleeding dramatically (8.3% vs 2.4%; OR 3.88) in severe renal insufficiency 5
• Empiric dose reduction decreases major bleeding substantially (0.9% vs 1.9%; OR 0.58) 5

Monitoring in Renal Impairment

• Monitor anti-Xa levels specifically when CrCl <30 mL/min 5
• Target anti-Xa ranges for therapeutic enoxaparin: 0.6-1.0 units/mL (measured 4 hours post-dose) for twice-daily dosing, >1.0 units/mL for once-daily dosing 5
• Consider switching to IV unfractionated heparin in severe renal insufficiency to avoid bioaccumulation issues 5

Special Populations

• Adjust doses for obese or significantly underweight patients receiving prophylaxis based on body weight 1
• Use caution in patients with renal dysfunction; dose adjustments and anti-Xa monitoring may be required 1
• Avoid tinzaparin in patients aged >70 years with renal insufficiency 1

Unfractionated Heparin (UFH) Dosing

Intravenous UFH

• Use weight-adjusted bolus and maintenance doses rather than fixed doses to optimize time in therapeutic range and reduce hemorrhagic/thromboembolic events. 1
• Monitor aPTT and adjust doses according to institutional protocols or ACCP recommendations. 1

Subcutaneous UFH

• Weight-adjust doses and monitor with aPTT for therapeutic anticoagulation 1
• For prophylaxis: 5000 units subcutaneously every 8-12 hours (no weight adjustment needed) 1

Fondaparinux Dosing

Standard Dosing

• Prophylaxis: 2.5 mg subcutaneously daily 1
• Therapeutic dosing: Weight-based (specific doses vary by weight category) 1

Renal Contraindications

• Contraindicated when CrCl <30 mL/min 1
• Use with caution when CrCl 30-50 mL/min, weight <50 kg, or age >75 years 1

Antiplatelet Therapy Dosing in Combination Regimens

Aspirin Dosing

• Loading dose: 325 mg for aspirin-naïve patients undergoing PCI 1
• Maintenance: 75-100 mg daily when combined with oral anticoagulation 1
• For primary prevention in moderate-risk patients: 75-162 mg daily 6

P2Y12 Inhibitor Selection and Dosing

Clopidogrel is the preferred P2Y12 inhibitor when combined with oral anticoagulation due to lower bleeding risk compared to prasugrel or ticagrelor. 1

• Loading dose: 600 mg 1
• Maintenance: 75 mg daily 1

Duration Considerations by Indication

VTE Treatment Duration

• Provoked VTE (transient risk factor): 3 months minimum 2
• Unprovoked VTE: At least 3 months, then evaluate for indefinite therapy based on bleeding risk 2
• Cancer-associated VTE: At least 3 months of LMWH, continue as long as cancer is active 2

Post-PCI Duration

• ACS with oral anticoagulation: P2Y12 inhibitor for 12 months 1
• Stable ischemic heart disease with oral anticoagulation: Clopidogrel for 6 months 1

Common Pitfalls to Avoid

• Never use standard LMWH doses without adjustment when CrCl <30 mL/min—this dramatically increases bleeding risk 5
• Do not target higher INR ranges (>3.0) for high-risk patients; standard intensity (2.0-3.0) is optimal 1
• Avoid combining more potent P2Y12 inhibitors (prasugrel, ticagrelor) with oral anticoagulation unless ischemic risk clearly outweighs bleeding risk 1
• Do not use fondaparinux when CrCl <30 mL/min 1
• Calculate creatinine clearance based on actual body weight for dosing decisions 1, 4