Can anticoagulation alone improve prognosis in patients with severe pulmonary hypertension due to chronic thromboembolic pulmonary hypertension (CTEPH)?

Anticoagulation Alone is Insufficient for Severe CTEPH

Anticoagulation alone cannot improve prognosis in patients with severe pulmonary hypertension due to CTEPH—pulmonary endarterectomy (PEA) is the only potentially curative treatment and must be pursued as first-line therapy. 1, 2

Why Anticoagulation Alone Fails in Severe CTEPH

The fundamental pathophysiology of CTEPH involves organized, fibrotic thromboembolic material incorporated into the pulmonary arterial wall, not fresh thrombus that can be dissolved. 1 This organized material causes:

• Mechanical obstruction at the main, lobar, and segmental pulmonary artery levels 1
• Progressive small vessel vasculopathy in unobstructed vessels 3
• Right ventricular failure from chronic pressure overload 1

Anticoagulation prevents new thrombotic events but does nothing to remove existing organized thrombus or reverse pulmonary vascular remodeling. 1, 4

The Evidence on Anticoagulation Alone

While lifelong anticoagulation is mandatory for all CTEPH patients, the evidence shows it is supportive, not curative:

• The prognosis of medically treated CTEPH patients (anticoagulation alone) is poor and worsens as pulmonary hypertension progresses 5
• Patients who do not undergo PEA or suffer from persistent post-PEA pulmonary hypertension face a poor prognosis 1
• Historical data demonstrate that without definitive intervention, CTEPH carries significant mortality risk 1

The Treatment Algorithm for Severe CTEPH

Step 1: Immediate Referral for PEA Evaluation

• All patients with severe CTEPH must be referred to an experienced PEA center immediately, even if symptoms seem stable 2
• PEA achieves near-normalization of hemodynamics in most patients with in-hospital mortality as low as 4.7% 1, 2
• Long-term survival after PEA is 75-92.3% at 6 years, with 93% of patients achieving NYHA class I or II 2
• There is no PVR threshold or degree of RV dysfunction that absolutely precludes PEA 1, 2

Step 2: Lifelong Anticoagulation (Regardless of Other Treatments)

• Start warfarin targeting INR 2-3 immediately upon diagnosis 1, 2, 6
• Continue anticoagulation even after successful PEA to prevent recurrent venous thromboembolism 1, 2, 6
• Direct oral anticoagulants (DOACs) may be considered as alternatives to warfarin, though warfarin remains the traditional standard 7, 8
• Recent meta-analysis shows DOACs associated with higher risk of recurrent PE in CTEPH (RR 3.80,95% CI 1.93-7.50), making warfarin preferable in severe disease 9

Step 3: If Truly Inoperable

Only after multidisciplinary assessment at an experienced center determines the patient is technically inoperable should alternatives be considered:

• Riociguat is the only FDA-approved medication for inoperable CTEPH or persistent/recurrent PH after PEA 2, 6
• Balloon pulmonary angioplasty (BPA) for distal disease not amenable to surgery 2, 6
• Other PAH-targeted therapies are used off-label but lack robust evidence for mortality benefit 1

Critical Pitfalls to Avoid

Pitfall #1: Accepting "Inoperability" Without Expert Assessment

• Operability determination requires evaluation by an experienced multidisciplinary CTEPH team at a high-volume center 1, 2
• Many patients deemed "inoperable" at non-expert centers are successfully treated with PEA at specialized centers 2

Pitfall #2: Delaying Surgical Referral

• Early intervention is crucial before irreversible hypertensive vasculopathy develops 5
• Even patients with mild symptoms should be referred promptly 2

Pitfall #3: Relying on Anticoagulation Alone for Severe Disease

• Anticoagulation is supportive care, not definitive treatment 1, 4
• Patients with severe pulmonary hypertension will continue to deteriorate on anticoagulation alone 5

Pitfall #4: Using DOACs Without Understanding the Risks

• DOACs show higher recurrent PE rates compared to warfarin in CTEPH 9
• Warfarin should be preferred in severe disease, especially pre-operatively 7, 9
• DOACs are contraindicated in severe renal impairment (CrCl <25 mL/min) and hepatic dysfunction 7

The Bottom Line

For severe CTEPH, anticoagulation alone is palliative, not therapeutic. The treatment paradigm must be: (1) immediate referral for PEA evaluation, (2) lifelong anticoagulation with warfarin as the backbone, and (3) consideration of medical therapy or BPA only for truly inoperable patients as determined by expert centers. 1, 2, 6