What are the recommended doses of anticoagulants, such as Direct Oral Anticoagulants (DOACs) like rivaroxaban (Xarelto), apixaban (Eliquis), or edoxaban (Savaysa), or Vitamin K Antagonists (VKAs) like warfarin (Coumadin), for long-term management of patients with Chronic Thromboembolic Pulmonary Hypertension (CTEPH) and Pulmonary Embolism (PE)?

Anticoagulant Dosing for Long-Term Management of PE and CTEPH

For long-term management of pulmonary embolism (PE), use therapeutic-dose anticoagulation for at least 3 months, then consider dose-reduced DOACs (apixaban 2.5 mg twice daily or rivaroxaban 10 mg once daily) for extended prophylaxis after 6 months of full-dose therapy; for chronic thromboembolic pulmonary hypertension (CTEPH), lifelong anticoagulation is mandatory with warfarin (INR 2.0-3.0) remaining the standard, though emerging evidence supports DOAC use. 1

Initial Treatment Phase (First 3 Months)

Direct Oral Anticoagulants (DOACs) - Preferred

Rivaroxaban:

• 15 mg orally twice daily with food for the first 21 days 1, 2
• Then 20 mg once daily with food for the remaining treatment 1, 2

Apixaban:

• 10 mg orally twice daily for the first 7 days 1, 3
• Then 5 mg orally twice daily 1, 3

Edoxaban:

• Requires 5-10 days of parenteral anticoagulation (LMWH, fondaparinux, or UFH) first 1
• Then 60 mg orally once daily 1

Dabigatran:

• Requires 5-10 days of parenteral anticoagulation first 1
• Then 150 mg orally twice daily 1

Vitamin K Antagonists (VKAs)

Warfarin:

• Target INR 2.0-3.0 (target 2.5) for all treatment durations 1
• Requires bridging with parenteral heparin initially 1

Extended Anticoagulation (After 6 Months)

Dose-Reduced DOAC Regimens (Preferred for Extended Prophylaxis)

The 2019 ESC Guidelines recommend dose reduction after 6 months of therapeutic anticoagulation for patients without cancer: 1

Apixaban:

• 2.5 mg orally twice daily (Class IIa, Level A recommendation) 1, 4

Rivaroxaban:

• 10 mg orally once daily with or without food (Class IIa, Level A recommendation) 1, 5

Dabigatran and Edoxaban:

• Dose should remain unchanged at therapeutic levels (150 mg twice daily for dabigatran, 60 mg once daily for edoxaban), as reduced-dose regimens were not investigated in dedicated extension trials 1

Duration Decisions

Discontinue after 3 months (Class I, Level B):

• First PE/VTE secondary to major transient/reversible risk factor 1

Extended anticoagulation of indefinite duration recommended (Class I, Level B):

• Recurrent VTE (at least one previous episode of PE or DVT) not related to major transient/reversible risk factor 1

Extended anticoagulation should be considered (Class IIa, Level A-C):

• First episode of PE with no identifiable risk factor 1, 4
• First episode of PE associated with persistent risk factor other than antiphospholipid syndrome 1
• First episode of PE associated with minor transient/reversible risk factor 1

CTEPH-Specific Management

Lifelong anticoagulation is mandatory for all CTEPH patients (Class I, Level B recommendation): 1

Current Standard of Care

Warfarin remains the established standard:

• Target INR 2.0-3.0 1
• Based on historical experience and evidence 6

Emerging DOAC Evidence for CTEPH

Recent meta-analysis findings suggest caution with DOACs in CTEPH: 7

• DOACs associated with lower mortality (RR 0.54,95% CI: 0.37-0.79) 7
• However, higher risk of recurrent PE observed (RR 3.80,95% CI: 1.93-7.50) 7
• No significant difference in major bleeding or all bleeding events 7

Clinical implication: While DOACs are being investigated for CTEPH (ongoing KABUKI trial with edoxaban), warfarin remains the recommended anticoagulant until definitive evidence establishes DOAC safety and efficacy in this population 6, 7

Special Populations and Contraindications

Antiphospholipid Antibody Syndrome

VKA for indefinite period is mandatory (Class I, Level B):

• DOACs are NOT an alternative to VKAs in antiphospholipid syndrome 1, 4

Cancer-Associated PE

Preferred agents:

• LMWH (dalteparin 200 units/kg daily for 1 month, then 150 units/kg daily for months 2-6) 1
• Edoxaban 60 mg once daily 1
• Rivaroxaban 20 mg once daily (after initial 15 mg twice daily for 21 days) 1

Renal Impairment

Rivaroxaban:

• CrCl ≥30 mL/min: standard dosing 5
• CrCl 15-29 mL/min: consider dose reduction or alternative anticoagulation 5
• Requires annual renal function reassessment, more frequently in elderly (≥75 years) 5

Apixaban:

• Safer in severe CKD (CrCl <30 mL/min) due to only 27% renal clearance 5
• Can be used with dose reduction (2.5 mg twice daily) even in dialysis patients 5

Critical Monitoring Requirements

For all patients receiving extended anticoagulation (Class I, Level C):

• Reassess drug tolerance and adherence at regular intervals (e.g., annually) 1
• Monitor hepatic and renal function regularly 1
• Assess bleeding risk using validated prediction models 1
• Identify and treat modifiable bleeding risk factors 1

Common Pitfalls to Avoid

Do not use therapeutic-dose DOACs indefinitely when dose-reduced regimens are appropriate: After 6 months of therapeutic anticoagulation for PE without cancer, transition to reduced-dose apixaban (2.5 mg twice daily) or rivaroxaban (10 mg once daily) rather than continuing full therapeutic doses 1, 4, 5

Do not use DOACs in antiphospholipid syndrome: This is an absolute contraindication; use VKA instead 1, 4

Do not assume all DOACs have validated dose-reduced regimens: Only apixaban and rivaroxaban have evidence supporting reduced-dose extended prophylaxis; dabigatran and edoxaban should remain at therapeutic doses if used for extended therapy 1

Do not use DOACs as first-line in CTEPH: Warfarin remains the standard until more definitive evidence establishes DOAC safety, given the concerning signal for increased recurrent PE risk 6, 7