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should be considered: (1) if radiological signs (detailed in Section 5.1.7) suggest CTEPH on the CTPA performed to diagnose PE,112 and/or if estimated sPAP is .60 mmHg112 on echocardiogram; (2) when dyspnoea or functional limitations persist in the clinical course post-PE;754 and (3) in asymptomatic patients with risk factors for CTEPH or a high CTEPH prediction score.755 Clinical conditions such as permanent intravascular devices (pacemaker, long-term central lines, ventriculoatrial shunts), inflammatory bowel diseases, essential thrombocythaemia, polycythaemia vera, splenectomy, antiphospholipid syndrome, high-dose thyroid hormone replacement, and malignancy are risk factors for CTEPH.54,103,756 Alternative causes of PA obstructions (also included in group 4 of the PH classification)—including PA sarcomas, other malignant tumours (e.g. renal carcinoma, uterine carcinoma, and germ-cell tumours of the testis), non-malignant tumours (e.g. uterine leiomyoma), arteriitis without CTD, congenital or acquired PA stenoses, parasites (hydatid cyst), and foreign-body embolism—have to be considered in the differential diagnosis of CTEPD.757 They can be explored by specific additional imaging such as 18F-2-fluoro-2-deoxy-D-glucose-positron emission tomography (PET) scan, which can provide additional information when PA sarcoma is suspected.758 Ventilation/perfusion scintigraphy207 remains the most effective tool in excluding CTEPD. Alternative perfusion imaging techniques —such as iodine subtraction mapping, DECT, and MRI perfusion— have numerous theoretical advantages over V/Q but are more technically challenging and expensive, have limited availability, and currently lack multicentre validation. Computed tomography pulmonary angiography with bi-planar reconstruction is broadly used for diagnosing CTEPD and assessing operability, but a negative CTPA, even if high quality, does not exclude CTEPD, as distal disease can be missed. Digital subtraction angiography is still used to assess treatment options when CTPA is inconclusive. Selective segmental angiography, cone-beam CT, and area detector CT allow for more accurate visualization of subsegmental vasculature and are useful for procedural guidance for BPA. The benefits of the new technologies require validating in prospective trials before being recommended for routine clinical use; a large, European, multicentre study is currently ongoing.759

10.2 Therapy

The CTEPH treatment algorithm includes a multimodal approach of combinations of pulmonary endarterectomy (PEA), BPA, and medical therapies to target the mixed anatomical lesions: proximal, distal, and microvasculopathy, respectively (Figures 14 and 15). General measures recommended for PAH also apply to CTEPH, including supervised exercise training, which is effective and safe in inoperable CTEPH patients,760 as well as early after PEA.761 Lifelong therapeutic anticoagulation is recommended for patients with CTEPH, as recurrent pulmonary thrombo-embolism accompanied by insufficient clot resolution are key pathophysiological features of this disease. There are no RCTs in CTEPH with any of the approved anticoagulants; however, despite this lack of evidence, VKAs are recommended by experts, and are most widely used as background therapy for patients with CTEPH. More recently, NOACs have more frequently been used as alternatives to VKAs, again, lacking evidence from RCTs. A retrospective case series from the UK and a multicentre prospective registry (EXPERT) showed comparable bleeding rates for VKAs and NOACs in CTEPH, but recurrent venous thrombo-embolism rates were higher in those receiving NOACs.762,763 In patients with antiphospholipid syndrome (10% of the CTEPH population), VKAs are recommended.103,764,765 Screening for antiphospholipid syndrome should be performed at CTEPH diagnosis. In the absence of any evidence in favour or against prolonged anticoagulation in patients with CTEPD without PH, long-term anticoagulant therapy is based on individual decisionmaking. It is recommended when the risk of PE recurrence is intermediate or high, thereby following the 2019 ESC/ERS Guidelines for the diagnosis and management of acute pulmonary embolism (Table 11).103

10.2.1 Surgical treatment

Surgical PEA is the treatment of choice for patients with accessible PA lesions.102 As surgery may normalize pulmonary haemodynamics (65% decrease in PVR)766 and functional capacity, an expert multidisciplinary team including an experienced PEA surgeon (on-site or closely collaborating) is mandatory for evaluating operability and deciding final treatment.102 Operability is based on team experience, accessibility of PA lesions, correlation between severity of PH and degree of PA obstructions, and comorbidities.767 The surgical technique is complex but well standardized with .30 years of experience. It consists of a complete bilateral endarterectomy of the PAs down to segmental and subsegmental levels in phases of deep hypothermic circulatory arrest (Figure 15).767,768 In CTEPH centres, surgical outcomes are favourable, with peri-operative mortality rates ,2.5% due to improved management of cardiac and pulmonary complications and wellestablished use of ECMO.768 Post-operative PH is frequently observed (≏25%),766 but long-term outcomes after PEA surgery are excellent regarding survival (averaging 90% at 3 years) and quality of life,769–771 even in patients with distal PA obstructions.772 On the other hand, patients with proximal operable disease declining surgery have a poor long-term outcome, with a 5 year survival of 53% compared with 83% in patients undergoing PEA.773 Therefore, PEA should be offered to all operable patients with a favourable risk:benefit ratio, ideally during a personal consultation between the patient and the PEA surgeon.102 Selected symptomatic patients with CTEPD without PH can be successfully treated by PEA, with clinical and haemodynamic improvements at rest and exercise.135,774 Those patients would require careful discussion to balance risk and benefit.

10.2.2 Medical therapy

To manage the microvascular component of CTEPH (Figure 15), medical therapies have been used off-label based on uncontrolled studies and/or regional approvals. Meanwhile, three RCTs have successfully been conducted. The first phase 3 RCT investigated the efficacy of riociguat in patients with inoperable CTEPH or those with persistent/recurrent PH after PEA.775 Riociguat, after 16 weeks of therapy, improved 6MWD and reduced PVR by 31% compared with placebo, and is approved for this indication. Treprostinil s.c. was investigated in a phase 3 RCT, which showed improved 6MWD at week 24 in patients with inoperable CTEPH or those with persistent/recurrent PH after PEA receiving a high dose compared with a low dose;776 s.c. treprostinil is approved for this indication. In a phase 2 study including only patients with inoperable CTEPH, macitentan 10 mg improved PVR and 6MWD vs. placebo Downloaded from academic.oup.com/eurheartj/article/43/38/3618/6673929 by guest on 07 October 2026