RARE DISEASE
Chronic thromboembolic pulmonary hypertension
Chronic thromboembolic pulmonary hypertension
Chronic thromboembolic pulmonary hypertension
Synonyms: CTEPH
Synonyms: CTEPH
Synonyms: CTEPH
Drug discovery
17
drugs
With orphan designations
Overview
Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare, progressive form of pulmonary hypertension caused by unresolved thromboemboli and fibrotic vascular remodeling, leading to pulmonary artery obstruction and elevated pressures. Diagnosis requires right heart catheterization (mean PAP ≥25 mmHg) and imaging (V/Q scan, CT angiography). It arises in 0.4–4.8% of acute pulmonary embolism survivors, with risks including splenectomy, non-O blood type, and chronic inflammation. Treatment involves surgery, interventional procedures, or targeted therapy [1][2][4][7][12].
Population
Incidence: ~5 cases per million annually (up to 30 in some reports), with median age of 63 years [1][2][4][12].
Predisposing factors: History of pulmonary embolism, anti-phospholipid antibodies, chronic inflammatory conditions, and splenectomy [1][4][16].
No gender predominance; ~50–75% of patients lack prior symptomatic embolism history [7][17].
Therapies
Pulmonary endarterectomy (PEA): First-line curative surgery for operable proximal lesions, with <2% mortality in expert centers [3][13][18].
Balloon pulmonary angioplasty (BPA): Percutaneous intervention for distal disease or inoperable cases, improving hemodynamics and exercise tolerance [3][8][17].
Medical therapy: Riociguat (sGC stimulator) is approved for inoperable cases; anticoagulation is lifelong [8][12][13].
Categories: rare respiratory diseases
Research Papers
1,770 drug discovery papers about Chronic thromboembolic pulmonary hypertension, with 2 first-in-class and 24 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
1,770 drug discovery papers about Chronic thromboembolic pulmonary hypertension, with 2 first-in-class and 24 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-08-08 | STOP-RIO study: protocol for a randomised, controlled, open-label non-inferiority trial to test the safety of discontinuation of riociguat after balloon pulmonary angioplasty in chronic thromboembolic pulmonary hypertension.
Balloon pulmonary angioplasty (BPA) improves haemodynamics and outcomes in patients with inoperable chronic thromboembolic pulmonary hypertension (CTEPH). Riociguat is frequently initiated before BPA to reduce procedural risks. However, evidence supporting continuation after successful BPA is lacking and current guidelines provide no criteria for treatment discontinuation. Consequently, many patients remain on long-term riociguat despite uncertain benefit, potential adverse effects and high costs. STOP-RIO is a multicentre, open-label, randomised, non-inferiority (NI) trial conducted in the two Dutch CTEPH expert centres. Seventy-four adult CTEPH patients treated with riociguat monotherapy with a mean pulmonary artery pressure (mPAP) <30 mmHg post-BPA will be randomised (1:1) to stop or continue the medication. The primary endpoint is the between-group difference in baseline-adjusted mPAP at rest measured by right heart catheterisation at 16 weeks. NI will be tested for the primary endpoint and for the two secondary endpoints highest in hierarchy N-terminal pro-B-type natriuretic peptide and 6-min walk distance. Additional secondary endpoints include haemodynamic parameters, safety outcomes, patient-reported outcomes and healthcare use. The primary analysis will be performed in a per-protocol population with secondary intention-to-treat and exploratory analyses. A prospective health economic evaluation will be conducted from a societal perspective. The study is conducted in accordance with the Declaration of Helsinki and Good Clinical Practice and has received ethical approval. Written informed consent will be obtained from all participants. Results will be disseminated through peer-reviewed publication and shared with patient organisations and scientific congress. EU Clinical Trials Register: 2024-5 19 225-38-00.
2026-08-02 | The Role of Medical Therapy Before and After Balloon Pulmonary Angioplasty: CTEPH AC Registry Across Japan.
We aimed to evaluate the role of medical therapy before and after balloon pulmonary angioplasty (BPA) for non-operable chronic thromboembolic pulmonary hypertension (CTEPH) in the modern management era. This Japanese nationwide, multicenter, prospective observational registry, including 37 centers, analyzed data newly registered from August 2018-December 2023. Pretreatment before BPA was analyzed in patients who were treatment naïve or received medical therapy only at registration (n = 557). De-escalation or escalation of medical therapy after BPA was analyzed in patients who underwent BPA (n = 966). The BPA pretreatment analysis in 557 patients showed that approximately 70% of the patients received medical therapy, of which 18% received combination therapy. Patients who received monotherapy or combination therapy had more severe baseline hemodynamics than those who did not. The 3-year survival did not significantly differ between the no, mono, and combination pretreatment groups (94%, 98%, and 97%, respectively; p = 0.852). The BPA post-treatment analysis in 966 patients showed that 20% of patients underwent de-escalation of medical therapy. Patients with de-escalation of medical therapy had lower mean pulmonary artery pressure (PAP) (20.9 ± 5.8 vs. 24.1 ± 7.3 mmHg, p < 0.01); however, they had a lower cardiac index at last follow-up compared to patients without de-escalation (2.66 ± 0.61 vs. 2.84 ± 0.70 L/min/m2, p = 0.01). Patients with severe disease tended to undergo pre-treatment before BPA; however, patient survival did not differ across pretreatment types. De-escalation of medical therapy after BPA can affect cardiac index. Therefore, de-escalation or continuation of medical therapy should be carefully considered even after mean PAP normalizes after BPA.
2026-07-30 | Riociguat pretreatment in patients with chronic thromboembolic pulmonary hypertension
Question Whether pretreatment with vasodilators reduces balloon pulmonary angioplasty (BPA)-related complications and achieves better outcomes in patients with inoperable chronic thromboembolic pulmonary hypertension (CTEPH) is unknown. We evaluated the effects of riociguat pretreatment on BPA-related complications and outcomes in patients with inoperable CTEPH. Patients and Methods We retrospectively identified 242 patients with CTEPH who underwent BPA between May 2014 and December 2022. Patients were subdivided according to the presence or absence of riociguat pretreatment, procedure-related complications, and overall survival. Results After baseline haemodynamic evaluation, 52 patients (21%) received riociguat prior to BPA (median dose, 6.0 [4.5–7.5] mg), while the remaining 190 patients (79%) underwent BPA as first-line treatment. At diagnosis, the mean pulmonary arterial pressure (PAP) and pulmonary vascular resistance (PVR) were similar between the groups, whereas the riociguat pretreatment group showed a lower mean PAP and PVR at the first BPA session. The prevalence of serious BPA-related complications throughout all BPA procedures was similar in both groups. After a median of four BPA sessions, improvements in haemodynamic parameters were comparable between the groups. During a median follow-up period of 76 months (interquartile range: 48–106) after BPA, 32 patients experienced all-cause death, and riociguat pretreatment did not influence survival (hazard ratio: 0.86, 95% confidence interval: 0.33–2.25). Conclusions Pretreatment with riociguat was not associated with risk reduction or overall survival after BPA. In patients with inoperable CTEPH who consider undergoing BPA, riociguat pretreatment is not mandatory for risk reduction.
2026-07-29 | Pulmonary Hypertension Under the Microscope: What Histopathology Means for Diagnosis and Treatment.
Pulmonary hypertension (PH) comprises a heterogeneous group of conditions characterised by elevated mean pulmonary artery pressure and classified into five groups according to underlying aetiology. Across PH subtypes, pathological remodelling of the pulmonary microvasculature, including arterioles, capillaries, and venules, drives hemodynamic burden, right ventricular dysfunction, and clinical outcomes. While certain structural features are conserved, distinct histopathological patterns shape group-specific pathophysiology, treatment responses, and prognosis. Experimental models such as monocrotaline and hypoxia have revealed key mechanisms of medial hypertrophy, distal neomuscularization, intimal fibrosis, and recanalization, but also highlight differences in cellular pathways and vascular compartments involved. Human histological studies confirm these changes and demonstrate group-specific signatures: venule-predominant remodelling in Group 2 PH, dense occlusive venous fibrosis in PVOD, arterial-dominant lesions in Group 1 PAH, and mixed arterial-venous changes in CTEPH. These structural differences help explain variable therapeutic responses; for example, vasodilators are effective in pre-capillary arteriolar predominant disease but may precipitate pulmonary oedema in venous-predominant PH phenotypes. In CTEPH, distal arteriolar pathology is a therapeutic target, though venous remodelling may underlie heterogeneity of outcomes. Emerging non-invasive markers, including echocardiographic indices such as TAPSE/RVSP and exercise hemodynamics, may provide physiological surrogates of microvascular disease, although direct correlations with histopathology remain limited. Pulmonary vascular remodelling varies substantially across PH groups, with distinct arterial and venous signatures that influence hemodynamics, treatment response, and outcomes. Integrating histopathological insights with hemodynamic phenotyping and non-invasive assessments may enable earlier detection of pulmonary vascular disease and support more precise, mechanism-directed therapeutic strategies.
2026-07-28 | Polycythemia Vera, Thrombophilia, CTEPH, Cerebral Venous Sinus Thrombosis and Vertebral Artery Occlusion: A Case-Illustrated Narrative Review of Competing Thrombotic and Hemorrhagic Risks.
The coexistence of systemic prothrombotic disorders, chronic thromboembolic pulmonary hypertension (CTEPH), chronic hypoxia, and cerebrovascular thrombosis creates complex diagnostic and therapeutic challenges. We report the case of a 52-year-old woman with JAK2V617F-positive polycythemia vera, inherited thrombophilic abnormalities, recurrent pulmonary thromboembolism progressing to severe CTEPH, chronic hypoxemia, cerebral venous sinus thrombosis, and right vertebral artery occlusion. Management challenge: The case illustrates persistent thrombotic risk despite anticoagulation, the need for disease-directed cytoreduction, limited access to CTEPH-directed interventional treatment, neurological vulnerability despite preserved brain parenchymal integrity, and the narrow therapeutic margin created by the combined use of anticoagulant, cytoreductive, and pulmonary vasodilator therapy. Particular emphasis is placed on the competing risks of recurrent thrombosis and hemorrhagic complications, especially in the cerebrovascular territory. This case highlights the need for repeated multidisciplinary reassessment in patients with overlapping hematological, pulmonary, and neurological vascular disease. Improved survival in patients with severe multisystemic conditions may increase the clinical relevance of complex presentations requiring coordinated management. Further evidence is needed to support safer, more standardized treatment strategies for patients requiring simultaneous control of thrombosis, pulmonary vascular disease, myeloproliferation, hypoxia, and treatment-related bleeding risk.
2026-08-08 | STOP-RIO study: protocol for a randomised, controlled, open-label non-inferiority trial to test the safety of discontinuation of riociguat after balloon pulmonary angioplasty in chronic thromboembolic pulmonary hypertension.
Balloon pulmonary angioplasty (BPA) improves haemodynamics and outcomes in patients with inoperable chronic thromboembolic pulmonary hypertension (CTEPH). Riociguat is frequently initiated before BPA to reduce procedural risks. However, evidence supporting continuation after successful BPA is lacking and current guidelines provide no criteria for treatment discontinuation. Consequently, many patients remain on long-term riociguat despite uncertain benefit, potential adverse effects and high costs. STOP-RIO is a multicentre, open-label, randomised, non-inferiority (NI) trial conducted in the two Dutch CTEPH expert centres. Seventy-four adult CTEPH patients treated with riociguat monotherapy with a mean pulmonary artery pressure (mPAP) <30 mmHg post-BPA will be randomised (1:1) to stop or continue the medication. The primary endpoint is the between-group difference in baseline-adjusted mPAP at rest measured by right heart catheterisation at 16 weeks. NI will be tested for the primary endpoint and for the two secondary endpoints highest in hierarchy N-terminal pro-B-type natriuretic peptide and 6-min walk distance. Additional secondary endpoints include haemodynamic parameters, safety outcomes, patient-reported outcomes and healthcare use. The primary analysis will be performed in a per-protocol population with secondary intention-to-treat and exploratory analyses. A prospective health economic evaluation will be conducted from a societal perspective. The study is conducted in accordance with the Declaration of Helsinki and Good Clinical Practice and has received ethical approval. Written informed consent will be obtained from all participants. Results will be disseminated through peer-reviewed publication and shared with patient organisations and scientific congress. EU Clinical Trials Register: 2024-5 19 225-38-00.
2026-08-02 | The Role of Medical Therapy Before and After Balloon Pulmonary Angioplasty: CTEPH AC Registry Across Japan.
We aimed to evaluate the role of medical therapy before and after balloon pulmonary angioplasty (BPA) for non-operable chronic thromboembolic pulmonary hypertension (CTEPH) in the modern management era. This Japanese nationwide, multicenter, prospective observational registry, including 37 centers, analyzed data newly registered from August 2018-December 2023. Pretreatment before BPA was analyzed in patients who were treatment naïve or received medical therapy only at registration (n = 557). De-escalation or escalation of medical therapy after BPA was analyzed in patients who underwent BPA (n = 966). The BPA pretreatment analysis in 557 patients showed that approximately 70% of the patients received medical therapy, of which 18% received combination therapy. Patients who received monotherapy or combination therapy had more severe baseline hemodynamics than those who did not. The 3-year survival did not significantly differ between the no, mono, and combination pretreatment groups (94%, 98%, and 97%, respectively; p = 0.852). The BPA post-treatment analysis in 966 patients showed that 20% of patients underwent de-escalation of medical therapy. Patients with de-escalation of medical therapy had lower mean pulmonary artery pressure (PAP) (20.9 ± 5.8 vs. 24.1 ± 7.3 mmHg, p < 0.01); however, they had a lower cardiac index at last follow-up compared to patients without de-escalation (2.66 ± 0.61 vs. 2.84 ± 0.70 L/min/m2, p = 0.01). Patients with severe disease tended to undergo pre-treatment before BPA; however, patient survival did not differ across pretreatment types. De-escalation of medical therapy after BPA can affect cardiac index. Therefore, de-escalation or continuation of medical therapy should be carefully considered even after mean PAP normalizes after BPA.
2026-07-30 | Riociguat pretreatment in patients with chronic thromboembolic pulmonary hypertension
Question Whether pretreatment with vasodilators reduces balloon pulmonary angioplasty (BPA)-related complications and achieves better outcomes in patients with inoperable chronic thromboembolic pulmonary hypertension (CTEPH) is unknown. We evaluated the effects of riociguat pretreatment on BPA-related complications and outcomes in patients with inoperable CTEPH. Patients and Methods We retrospectively identified 242 patients with CTEPH who underwent BPA between May 2014 and December 2022. Patients were subdivided according to the presence or absence of riociguat pretreatment, procedure-related complications, and overall survival. Results After baseline haemodynamic evaluation, 52 patients (21%) received riociguat prior to BPA (median dose, 6.0 [4.5–7.5] mg), while the remaining 190 patients (79%) underwent BPA as first-line treatment. At diagnosis, the mean pulmonary arterial pressure (PAP) and pulmonary vascular resistance (PVR) were similar between the groups, whereas the riociguat pretreatment group showed a lower mean PAP and PVR at the first BPA session. The prevalence of serious BPA-related complications throughout all BPA procedures was similar in both groups. After a median of four BPA sessions, improvements in haemodynamic parameters were comparable between the groups. During a median follow-up period of 76 months (interquartile range: 48–106) after BPA, 32 patients experienced all-cause death, and riociguat pretreatment did not influence survival (hazard ratio: 0.86, 95% confidence interval: 0.33–2.25). Conclusions Pretreatment with riociguat was not associated with risk reduction or overall survival after BPA. In patients with inoperable CTEPH who consider undergoing BPA, riociguat pretreatment is not mandatory for risk reduction.
2026-07-29 | Pulmonary Hypertension Under the Microscope: What Histopathology Means for Diagnosis and Treatment.
Pulmonary hypertension (PH) comprises a heterogeneous group of conditions characterised by elevated mean pulmonary artery pressure and classified into five groups according to underlying aetiology. Across PH subtypes, pathological remodelling of the pulmonary microvasculature, including arterioles, capillaries, and venules, drives hemodynamic burden, right ventricular dysfunction, and clinical outcomes. While certain structural features are conserved, distinct histopathological patterns shape group-specific pathophysiology, treatment responses, and prognosis. Experimental models such as monocrotaline and hypoxia have revealed key mechanisms of medial hypertrophy, distal neomuscularization, intimal fibrosis, and recanalization, but also highlight differences in cellular pathways and vascular compartments involved. Human histological studies confirm these changes and demonstrate group-specific signatures: venule-predominant remodelling in Group 2 PH, dense occlusive venous fibrosis in PVOD, arterial-dominant lesions in Group 1 PAH, and mixed arterial-venous changes in CTEPH. These structural differences help explain variable therapeutic responses; for example, vasodilators are effective in pre-capillary arteriolar predominant disease but may precipitate pulmonary oedema in venous-predominant PH phenotypes. In CTEPH, distal arteriolar pathology is a therapeutic target, though venous remodelling may underlie heterogeneity of outcomes. Emerging non-invasive markers, including echocardiographic indices such as TAPSE/RVSP and exercise hemodynamics, may provide physiological surrogates of microvascular disease, although direct correlations with histopathology remain limited. Pulmonary vascular remodelling varies substantially across PH groups, with distinct arterial and venous signatures that influence hemodynamics, treatment response, and outcomes. Integrating histopathological insights with hemodynamic phenotyping and non-invasive assessments may enable earlier detection of pulmonary vascular disease and support more precise, mechanism-directed therapeutic strategies.
2026-07-28 | Polycythemia Vera, Thrombophilia, CTEPH, Cerebral Venous Sinus Thrombosis and Vertebral Artery Occlusion: A Case-Illustrated Narrative Review of Competing Thrombotic and Hemorrhagic Risks.
The coexistence of systemic prothrombotic disorders, chronic thromboembolic pulmonary hypertension (CTEPH), chronic hypoxia, and cerebrovascular thrombosis creates complex diagnostic and therapeutic challenges. We report the case of a 52-year-old woman with JAK2V617F-positive polycythemia vera, inherited thrombophilic abnormalities, recurrent pulmonary thromboembolism progressing to severe CTEPH, chronic hypoxemia, cerebral venous sinus thrombosis, and right vertebral artery occlusion. Management challenge: The case illustrates persistent thrombotic risk despite anticoagulation, the need for disease-directed cytoreduction, limited access to CTEPH-directed interventional treatment, neurological vulnerability despite preserved brain parenchymal integrity, and the narrow therapeutic margin created by the combined use of anticoagulant, cytoreductive, and pulmonary vasodilator therapy. Particular emphasis is placed on the competing risks of recurrent thrombosis and hemorrhagic complications, especially in the cerebrovascular territory. This case highlights the need for repeated multidisciplinary reassessment in patients with overlapping hematological, pulmonary, and neurological vascular disease. Improved survival in patients with severe multisystemic conditions may increase the clinical relevance of complex presentations requiring coordinated management. Further evidence is needed to support safer, more standardized treatment strategies for patients requiring simultaneous control of thrombosis, pulmonary vascular disease, myeloproliferation, hypoxia, and treatment-related bleeding risk.
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Drug Discovery Landscape
17 orphan drug designations for Chronic thromboembolic pulmonary hypertension, including 2 approved therapies.
17 orphan drug designations for Chronic thromboembolic pulmonary hypertension, including 2 approved therapies.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Macitentan [Opsumit] | small molecules | EMA | 2021-12-10 | — | Janssen Cilag International |
selexipag | small molecules | FDA | 2018-10-02 | — | Janssen Research & Development LLC |
macitentan | small molecules | FDA | 2017-06-15 | — | Actelion Pharmaceuticals Ltd. (a Janssen Pharmaceutical Company of Johnson and Johnson) |
riociguat [Adempas] | small molecules | FDA | 2013-09-19 | 2013-10-08 | Bayer HealthCare Pharmaceuticals, Inc. |
Treprostinil sodium [Trepulmix] | small molecules | EMA | 2013-02-08 | 2020-04-07 | SciPharm Sàrl |
Lisuride hydrogen maleate | small molecules | EMA | 2011-05-13 | — | Sinoxa Pharma GmbH |
Riociguat [Adempas] | small molecules | EMA | 2007-12-20 | — | Bayer AG |
Treprostinil diethanolamine (oral use) | small molecules | EMA | 2005-08-26 | — | Ferrer Internacional S.A. |
Selexipag [Uptravi] | small molecules | EMA | 2005-08-26 | — | [INACTIVE] Actelion Registration Limited |
Ambrisentan [Volibris] | small molecules | EMA | 2005-04-11 | — | [INACTIVE] Glaxo Group Limited |
Sitaxentan sodium [Thelin] | small molecules | EMA | 2004-10-21 | — | Pfizer Limited |
Treprostinil sodium (inhalation use) | small molecules | EMA | 2004-04-14 | — | United Therapeutics Ireland Limited |
Sildenafil citrate [Revatio] | small molecules | EMA | 2003-12-12 | — | Pfizer Limited |
Beraprost sodium [Beradrak] | small molecules | EMA | 2001-09-18 | — | Laboratoire Aventis |
Bosentan monohydrate [Tracleer] | small molecules | EMA | 2001-02-14 | — | [INACTIVE] Actelion Registration Limited |
Iloprost [Ventavis] | small molecules | EMA | 2000-12-29 | — | [INACTIVE] Bayer Pharma AG |
Neutrophil-endothelial interaction inhibitor | small molecules | FDA | 1993-12-22 | — | Cytel Corporation |
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