Chronic Thromboembolic Disease Without Pulmonary Hypertension

Chronic thromboembolic pulmonary disease without pulmonary hypertension (CTED) is persistent organised obstruction of pulmonary arteries after pulmonary embolism, with symptoms such as exertional dyspnoea and a normal or only mildly raised resting pulmonary artery pressure (mean below 20 mmHg).

About 10 to 30% of patients with a past pulmonary embolism have residual perfusion defects at 3 to 12 months, and 2 to 4% progress to chronic thromboembolic pulmonary hypertension. CTED is a spectrum of that disease, defined by imaging evidence of chronic clots with symptoms but normal resting haemodynamics. It is probably under recognised.

Pathophysiology. Incomplete resolution of thrombus leads to fibrous organisation, with recanalisation and bands, webs and narrowings in the vessels. Dead space and ventilation perfusion mismatch limit exercise. Pulmonary pressure may rise only with exercise, and microvasculopathy in unobstructed areas can later cause pulmonary hypertension.

Persistent or new exertional dyspnoea, reduced exercise tolerance, fatigue and sometimes chest discomfort, palpitations or syncope on exertion, 3 months or more after a pulmonary embolism. Signs are usually absent at rest, and right heart failure is unusual. Other patients are found on a scan with no known embolism.

Syncope, chest pain with exertion or new right heart failure needs urgent assessment for progression to pulmonary hypertension.

• Persistent symptoms after at least 3 months of effective anticoagulation.
• Ventilation perfusion scan: persistent mismatched segmental or larger perfusion defects, the most sensitive screening test (sensitivity over 95%), and a normal scan excludes the disease.
• CT pulmonary angiography: webs, bands, eccentric wall adherent thrombus, vessel occlusion, abrupt vessel narrowing, mosaic perfusion, bronchial artery enlargement. Digital subtraction angiography or dual energy CT for operability.
• Echocardiography and right heart catheterisation: resting mean pulmonary artery pressure of 20 mmHg or less (pulmonary vascular resistance below 2 Wood units), to separate from pulmonary hypertension. Exercise right heart catheterisation may show a high pressure flow slope.
• Cardiopulmonary exercise test: reduced peak oxygen uptake, high dead space ventilation (ventilatory equivalents raised), and reduced end tidal carbon dioxide.
• Look for causes of persistent symptoms: lung disease, heart disease, deconditioning, anaemia, and thrombophilia (antiphospholipid antibodies, with testing before warfarin if possible).

Differential diagnosis.

• Chronic thromboembolic pulmonary hypertension
• Deconditioning after pulmonary embolism
• Left heart disease and heart failure with preserved ejection fraction
• Chronic lung disease and asthma
• Pulmonary artery sarcoma or vasculitis

• Indefinite anticoagulation: apixaban 5 mg twice daily (or 2.5 mg twice daily after 6 months in selected patients), rivaroxaban 20 mg daily with food (or 10 mg daily), or warfarin to an INR of 2 to 3. Antiphospholipid syndrome (triple positive) needs warfarin (INR 2 to 3), not a direct oral anticoagulant.
• Supervised exercise training and pulmonary rehabilitation for 8 to 12 weeks, which improves exercise capacity.
• Interventions for symptomatic patients with accessible, lobar or segmental disease and impaired function, at expert centres: balloon pulmonary angioplasty (several sessions at 4 to 6 weeks, with improved dyspnoea and exercise tolerance), or pulmonary endarterectomy for proximal disease, with the decision made by a multidisciplinary team.
• Medical therapy: riociguat 1 mg three times daily, titrated every 2 weeks to a maximum of 2.5 mg three times daily, has been studied in small groups, but benefit is unproven in the absence of pulmonary hypertension. Pulmonary vasodilators are not used routinely.
• Oxygen for exertional desaturation (saturation under 90% on exercise), and treatment of coexisting heart and lung disease.
• Avoid oestrogen containing contraception and hormone therapy, and counsel on travel and immobility.

Complications and prognosis. Progression to pulmonary hypertension in a minority (a few in every 100 patients each year), recurrent embolism, and bleeding on anticoagulation. Prognosis is good in the absence of pulmonary hypertension.

Monitoring. Review at 3, 6 and 12 months, then yearly, with echocardiography, six minute walk test and natriuretic peptide, and repeat right heart catheterisation if function worsens.

Referral and escalation. Refer to a pulmonary hypertension or chronic thromboembolic disease centre for assessment of intervention.