What are the classifications, mechanisms, and dosing of anticoagulants, including Direct Oral Anticoagulants (DOACs) like apixaban (apixaban) and rivaroxaban (rivaroxaban), vitamin K antagonists like warfarin (warfarin), and heparins, and how are they monitored?

Anticoagulant Classifications, Mechanisms, Doses, and Monitoring

Classification and Mechanisms of Action

Anticoagulants are classified into three major categories: vitamin K antagonists (warfarin), direct oral anticoagulants (DOACs), and heparins, each with distinct mechanisms targeting different points in the coagulation cascade. 1

Vitamin K Antagonists

• Warfarin inhibits vitamin K epoxide reductase complex 1 (VKORC1), preventing synthesis of vitamin K-dependent clotting factors (II, VII, IX, X) 1
• Bioavailability exceeds 95% with time to peak concentration of 2-6 hours 1
• Plasma half-life is 36-48 hours with duration of action approximately 5 days beyond INR normalization 1
• No renal clearance; metabolized hepatically 1

Direct Oral Anticoagulants (DOACs)

Factor Xa Inhibitors:

• Apixaban, rivaroxaban, and edoxaban directly inhibit factor Xa in the coagulation cascade 1
• Apixaban: 50% bioavailability, 3-4 hour peak, 9-14 hour half-life, 27% renal clearance 1
• Rivaroxaban: 100% bioavailability (66% without food), 2-4 hour peak, 6-9 hour half-life (11-13 hours in elderly), 33% renal clearance 1
• Edoxaban: 62% bioavailability, 1-2 hour peak, 10-14 hour half-life, 37-59% renal clearance 1

Direct Thrombin Inhibitor:

• Dabigatran directly inhibits factor IIa (thrombin) 1
• Low bioavailability (3-7%), 1.25-3 hour peak, 12-15 hour half-life 1
• 85% renal clearance (partially dialyzable) 1

Heparins

• Unfractionated heparin (UFH) and low-molecular-weight heparins (LMWH) potentiate antithrombin III activity 2
• UFH requires no dose adjustment for renal dysfunction 3
• LMWHs undergo renal clearance and require dose reduction in severe renal impairment 3

Standard Dosing Regimens

Warfarin Dosing

• Target INR 2.0-3.0 for atrial fibrillation and most thromboembolic conditions, aiming for midpoint of 2.5 4
• Target INR 2.5-3.5 for mechanical heart valves depending on valve type and location 4
• Initiate with 2-5 mg daily, adjusting based on INR response 1

DOAC Dosing

Apixaban:

• Standard dose: 5 mg twice daily 1
• Reduced dose: 2.5 mg twice daily for patients meeting dose-reduction criteria 1

Rivaroxaban:

• Atrial fibrillation: 20 mg once daily with evening meal 1
• Dose reduction required for creatinine clearance <50 mL/min 1

Edoxaban:

• Standard dose: 60 mg once daily 1
• Reduced dose: 30 mg once daily for specific criteria 1

Dabigatran:

• Standard dose: 150 mg twice daily 5
• Reduced dose: 110 mg twice daily for patients ≥80 years or receiving verapamil 5
• Individual dose reduction considered for ages 75-80 years, moderate renal impairment, or increased bleeding risk 5

Monitoring Techniques

Warfarin Monitoring

Weekly INR monitoring is mandatory during warfarin initiation, transitioning to monthly monitoring once stable. 4

• INR below 2.0 significantly increases thromboembolism risk 4
• INR above 3.0 increases major bleeding incidence 4
• INR above 3.5 markedly elevates intracranial hemorrhage risk 4
• Time in therapeutic range (TTR) must be ≥65-70% for adequate control; if TTR falls below 65%, switch to DOACs or implement intensive interventions 4

DOAC Monitoring

No routine laboratory monitoring is required for DOACs, but renal function monitoring is essential. 4

When DOAC level measurement is needed:

• Apixaban, rivaroxaban, edoxaban: Drug-specific calibrated anti-Xa assays 1
• Dabigatran: Ecarin clotting time (ECT) or diluted thrombin time (DTT) 1
• Standard coagulation tests (PT, aPTT) may be insensitive to exclude residual DOAC effect 1

Altered coagulation parameters:

• All DOACs affect PT, aPTT, and ACT to varying degrees 1
• Quantitative assessment requires drug-specific calibrators 1

Heparin Monitoring

• UFH: Monitor with aPTT ratio 1.5-3.0 (keeping aPTT <100 seconds) or anti-Xa levels 0.3-0.7 IU/mL 2
• LMWH: Generally no monitoring required; if needed, use anti-Xa levels 4 hours post-dose 2

Perioperative Management

DOAC Interruption Guidelines

For high bleeding risk procedures, interrupt rivaroxaban, apixaban, and edoxaban 3 days (72 hours) before surgery. 1

• This corresponds to 4-5 half-lives, resulting in minimal residual anticoagulant effect 1
• For low-to-moderate bleeding risk procedures, interrupt DOACs 1 full day (24-36 hours) before 1

Dabigatran requires longer interruption due to renal clearance:

• CrCl >50 mL/min: Interrupt 4 days before high-risk procedures 1
• CrCl 30-50 mL/min: Interrupt 5 days before high-risk procedures 1
• For low-risk procedures with CrCl >50 mL/min: 2 days interruption acceptable 1

Bridging with parenteral anticoagulation is NOT recommended for routine perioperative DOAC management 1

DOAC Resumption

Resume DOACs at least 6 hours after procedure completion in absence of ongoing bleeding 1

• Once daily evening regimen: Resume evening of procedure day 1
• Once daily morning regimen: Resume next morning 1
• Twice daily regimen: Resume evening of procedure day 1
• If ongoing bleeding or surgical contraindication exists, delay resumption and initiate venous thromboprophylaxis 1

Reversal Agents

DOAC-Specific Reversal

Idarucizumab (5 g IV bolus) specifically reverses dabigatran with median time to hemostasis of 2.5 hours in life-threatening bleeding 1

Andexanet alfa reverses factor Xa inhibitors (apixaban, rivaroxaban, edoxaban) 1

4-factor prothrombin complex concentrate (4F-PCC) serves as alternative reversal for all DOACs when specific agents unavailable 1

Warfarin Reversal

• Vitamin K for non-urgent reversal 1
• 4F-PCC or fresh frozen plasma for urgent reversal 1

Special Populations and Clinical Considerations

Renal Impairment

Warfarin is preferred for severe renal dysfunction (CrCl <15 mL/min or hemodialysis) as it requires no dose adjustment 4, 3

• Apixaban demonstrated safety in CrCl 25-30 mL/min with less bleeding than warfarin 6
• Dabigatran contraindicated in severe renal impairment due to 85% renal clearance 1

Absolute Indications for Warfarin Over DOACs

Warfarin is mandatory for all mechanical heart valves as DOACs are absolutely contraindicated 4, 7

• Moderate-to-severe mitral stenosis requires warfarin 4, 7

When DOACs Are Preferred

For all eligible patients with nonvalvular atrial fibrillation, DOACs are strongly recommended over warfarin due to superior safety profiles and equivalent efficacy 4

• Apixaban, edoxaban, or dabigatran 110 mg preferred for patients with prior bleeding or high bleeding risk 4
• Apixaban appears associated with lesser bleeding risk than rivaroxaban in comparative studies 8, 9

Drug Interactions

• Apixaban and rivaroxaban: CYP3A4 and P-glycoprotein interactions 1
• Edoxaban: Minimal CYP3A4 (<5%), P-glycoprotein interactions 1
• Dabigatran: P-glycoprotein interactions only 1

Critical Pitfalls to Avoid

Never use DOACs in patients with mechanical heart valves or moderate-to-severe mitral stenosis 4, 7

Avoid underdosing DOACs by ensuring full standard doses unless specific dose-reduction criteria are met, as underdosing leads to avoidable thromboembolic events 5

Do not routinely bridge DOACs perioperatively as bridging increases bleeding without reducing thromboembolism 1

When transitioning from DOAC to UFH, measure baseline anti-Xa in patients with renal impairment or recent DOAC exposure to detect interference, as DOAC residual levels can falsely elevate UFH-calibrated anti-Xa results 1

Never transfuse platelets in acute heparin-induced thrombocytopenia unless life-threatening bleeding occurs 1