Developments in pulmonary arterial hypertension–targeted therapy for chronic thromboembolic pulmonary hypertension

Abstract

Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare disease characterised by the presence of organised chronic thromboembolic material occluding the proximal pulmonary arteries and a vasculopathy in the distal pulmonary arterial tree. Pulmonary endarterectomy (PEA) is a potential cure for many patients with CTEPH. However, PEA is not suitable for patients with a significant distal distribution of chronic thromboembolic material or with significant comorbidities. Also, a proportion of patients are left with residual CTEPH post PEA. Until recently, pulmonary arterial hypertension–targeted therapies have been used off licence to treat patients with inoperable or residual CTEPH. The CHEST1 study investigated the use of riociguat and was the first randomised controlled trial to show efficacy in inoperable or residual CTEPH. In this review, we explore the pathophysiology of CTEPH and review the current trial evidence for pulmonary arterial hypertension–targeted therapies. We also include a discussion of physiological considerations that require further investigation.

Keywords:

• chronic thromboembolic pulmonary hypertension
• clinical trials
• pathophysiology
• pulmonary arterial hypertension
• pulmonary arterial hypertension–targeted therapy
• riociguat

Financial & competing interests disclosure

This research has been funded/supported by the National Institute for Health Research Rare Diseases Translational Research Collaboration (NIHR RD-TRC). The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. J Pepke-Zaba has received research, educational grants and speaker’s honoraria from Bayer, Actelion and GlaxoSmithKline. C Hadinnapola has a PhD fellowship from NIHR Rare Diseases Translational Research Collaboration. C Hadinnapola has received educational grants from Actelion and has attended educational meetings organised by GlaxoSmithKline. The authors have no other relevant affiliations or financial involvement with any organisation or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Key issues

• The pathophysiology of chronic thromboembolic pulmonary hypertension (CTEPH) is incompletely understood. The lack of preclinical models has hindered progress on elucidating the cause of this disease.

• The two-compartment model of CTEPH describes proximal obstruction of the pulmonary arteries by organised chronic thromboembolic material and a distal vasculopathy histologically similar to pulmonary arterial hypertension (PAH).

• The histological similarities in the small vessel vasculopathy and the acute vasoreactive responses seen in both PAH and CTEPH suggest that PAH-targeted therapies would be effective in CTEPH. However, a lack of clinical trial data showing efficacy in CTEPH has led to many PAH-targeted therapies being used off licence.

• Riociguat is the only drug to show efficacy in a randomised controlled trial. The CHEST1 study showed improvement in pulmonary vascular resistance and 6 min walk distance following treatment with riociguat for 16 weeks, compared to placebo. On the basis of this, it has been licenced for use in CTEPH.

• The CHEST2 study showed that improvement in 6 min walk test was maintained during the open-label extension phase of the study.

• There is no conclusive evidence for the use of PAH-targeted therapy as bridging therapy to pulmonary endarterectomy. A large retrospective study looking at the use of bridging therapy did not show any long-term improvements in outcome. However, the use of bridging therapy was associated with a delay in referral for assessment of suitability for pulmonary endarterectomy.

• Further investigation of the effects of PAH-targeted therapies on the right ventricle is required.