In an adult with chronic thromboembolic pulmonary hypertension diagnosed after a delayed interval and without contraindications, does initiating a direct oral anticoagulant (e.g., rivaroxaban or apixaban) improve prognosis?

Anticoagulation in Late-Diagnosed CTEPH

Lifelong anticoagulation is mandatory in CTEPH regardless of when diagnosis occurs, and while vitamin K antagonists remain the guideline-recommended standard, DOACs can be considered as an alternative despite limited evidence and a potentially higher risk of VTE recurrence. 1

Guideline-Based Recommendations

Standard Anticoagulation Approach

• Lifelong anticoagulation is recommended for all CTEPH patients, even after pulmonary endarterectomy (PEA), and this applies regardless of diagnostic delay. 1

• Vitamin K antagonists (VKAs) remain the guideline-recommended anticoagulant for CTEPH, as no data exist on the efficacy and safety of DOACs in this specific population according to European Society of Cardiology guidelines. 1

• The recommendation for lifelong anticoagulation is based on preventing recurrent venous thromboembolism, which remains a risk even years after initial diagnosis. 1

DOAC Use: Off-Guideline but Increasingly Common

• DOACs are not specifically recommended in CTEPH guidelines due to lack of evidence at the time of guideline publication, but they are increasingly used in clinical practice. 1

• When DOACs are used for general VTE (not specifically CTEPH), apixaban, rivaroxaban, edoxaban, or dabigatran are recommended over VKAs for standard venous thromboembolism. 1

Evidence from Clinical Studies

Efficacy Concerns with DOACs

• A 2024 retrospective cohort study of 321 CTEPH patients found that DOACs had similar survival and bleeding rates compared to warfarin, but significantly higher VTE recurrence rates (1.5%/person-year vs 0.3%/person-year, p=0.030). 2

• A 2020 multicenter study of 1,000 post-PEA patients demonstrated that DOACs were associated with significantly higher VTE recurrence (4.62%/person-year vs 0.76%/person-year, p=0.008) compared to VKAs, though bleeding rates were equivalent. 3

• A 2023 meta-analysis of 2,969 CTEPH patients showed DOACs were associated with lower mortality (RR 0.54) but higher risk of recurrent PE (RR 3.80) compared to VKAs. 4

Safety Profile

• Major bleeding rates appear similar between DOACs and VKAs in CTEPH patients across multiple studies (0.3-0.68%/person-year for both groups). 2, 5, 3

• A 2023 observational study of 205 CTEPH patients found identical total bleeding rates (2.52%/person-year) for both DOAC and VKA groups. 5

Clinical Decision Algorithm

When to Use VKAs (Preferred)

• Use VKAs as first-line anticoagulation in CTEPH patients who can tolerate INR monitoring and have no contraindications to warfarin. 1

• VKAs are mandatory in patients with antiphospholipid antibody syndrome, as DOACs are contraindicated in this population. 1

• Target INR of 2.5 (range 2.0-3.0) should be maintained for CTEPH patients on VKAs. 1

When DOACs May Be Considered

• DOACs may be considered in CTEPH patients who cannot tolerate VKA therapy due to difficulty maintaining therapeutic INR, significant drug-food interactions, or patient preference after thorough counseling about potentially higher VTE recurrence risk. 2, 5, 3

• Among DOACs, rivaroxaban has the most clinical experience in CTEPH patients based on available studies. 6, 3

• Patients switched to DOACs require close monitoring for signs of recurrent VTE, particularly in the first year after transition. 2, 3

Contraindications to DOACs in CTEPH

• Do not use DOACs in CTEPH patients with severe renal impairment (creatinine clearance <30 mL/min), antiphospholipid antibody syndrome, pregnancy, or lactation. 1, 7

• Avoid DOACs in patients with significant liver disease and coagulopathy. 8

Critical Pitfalls and Caveats

The VTE Recurrence Signal

• The consistent finding of higher VTE recurrence with DOACs across multiple studies (ranging from 3-5 fold higher) is concerning and suggests DOACs may be less effective than VKAs in preventing recurrent thromboembolism in CTEPH. 2, 3, 4

• This higher recurrence rate did not translate to increased mortality in most studies, but the clinical significance of recurrent VTE in an already compromised pulmonary vascular bed should not be underestimated. 2, 4

Timing of Anticoagulation Initiation

• Late diagnosis does not change the fundamental need for anticoagulation—start immediately upon CTEPH diagnosis regardless of how long symptoms have been present. 1

• There is no evidence that delayed initiation of anticoagulation (due to late diagnosis) affects the choice between VKAs and DOACs. 1

Post-PEA Considerations

• Anticoagulation must continue lifelong even after successful PEA, as residual thrombotic material and endothelial dysfunction persist. 1

• The higher VTE recurrence rate with DOACs was observed in post-PEA patients, suggesting this population may be particularly vulnerable to inadequate anticoagulation with DOACs. 3

Monitoring and Follow-Up

• All CTEPH patients should undergo routine clinical evaluation 3-6 months after diagnosis and regularly thereafter to assess for disease progression or recurrent VTE. 1, 7

• Patients on DOACs require assessment of renal function, hepatic function, drug adherence, and tolerance at regular intervals. 7, 8

• Any symptomatic deterioration should prompt evaluation for recurrent VTE, particularly in patients on DOACs given the higher recurrence signal. 2, 3