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CTEPH: treatment

were studied for 16 weeks. Six minute walking distance (6MWD) increased from baseline by a mean of 39m in the riociguat group (95% confidence interval: 25 to 67; p<0.001). PVR decreased by 226 dyn.sec. cm-5 in the riociguat group (95% confidence interval: –303 to –190; p<0.001). Riociguat therapy was also associated with significant improvements in NT-proBNP level (p<0.001) and WHO functional class (p=0.003). This study became the first to show significant clinical efficacy in CTEPH and was pivotal for the approval by the US Food and Drug Administration and by the European Medicines Agency (EMA) for the treatment of patients with inoperable or persistent/recurrent PH after PEA. During CHEST-2, the clinical benefit and safety profile observed in CHEST-1 were maintained and patients previously treated with placebo improved to a similar extent as subjects on riociguat during the pivotal study.

Use of PAH-targeted treatment Off-label use of PAH-targeted medical therapy might have a role in the treatment of select CTEPH patients (level of evidence IIb B in 2015 Guidelines). There are several reasons for considering PAH-targeted therapies in CTEPH. In response to increased flow and shear stress through distal vascular segments that are not obstructed by proximal thrombotic material, patients develop a small vessel arteriopathy or ‘distal CTEPH’. Histopathologically, the distal arteries in CTEPH patients present vascular changes similar to those in patients with PAH.8

Furthermore, similar

to PAH, circulating endothelin-1 (ET-1) levels correlate with the haemodynamic and clinical severity of the disease in CTEPH patients.4,9

According to the CTEPH registry,1 after

PEA, a significant number of operated patients (16.7%) have persistent pulmonary hypertension defined by a mean pulmonary arterial pressure (mPAP) ≥ 25mmHg at the last measurement in the intensive care unit, and 37% were inoperable due to inaccessible peripheral disease, comorbidities, and discrepancy between pulmonary hypertension severity and morphological lesions. All these patients need effective therapy because untreated CTEPH has a poor outcome, with over half of the patients with a mPAP >50mmHg not surviving beyond one year after diagnosis.10

Different open-label and randomised controlled trials (RCTs) have

shown varying degrees of clinical effect with medical treatment.


A retrospective analysis of 23 inoperable CTEPH patients showed after three months of epoprostenol treatment a significant increase of six minute walking distance (+66m; p<0.005) and a significant improvement of haemodynamic profile as evidenced by a 21% decrease in indexed pulmonary vascular resistance (p<0.005).12

Epoprostenol is a potent short-acting vasodilator and inhibitor of platelet aggregation that is produced by the vascular endothelium. Short-term infusions of epoprostenol decrease pulmonary vascular resistance in a dose-dependent manner in patients with PAH.11

Limitations of the study are

the design and the small number of patients.

Treprostinil Treprostinil, a stable prostacyclin analogue, shares pharmacological actions similar to epoprostenol, with similar acute haemodynamic effects. However, in contrast to epoprostenol, treprostinil is chemically stable at room temperature and neutral pH and has a longer half-life (three to four hours) permitting continuous subcutaneous infusion rather than continuous infusion.13

A small open label uncontrolled study, including 25 patients, demonstrated

significant improvements in 6MWD, World Health Organization (WHO) functional class and brain natriuretic peptide plasma levels.14

However, the

small patient numbers and the uncontrolled nature of the investigation were limitations of this study.


Iloprost is a stable analogue of prostacyclin that is associated with a longer duration of vasodilatation. Inhaled iloprost has shown its efficacy in severe pulmonary hypertension.15

This RCT included 203

patients, 56 of whom had CTEPH. There are no separate data available on the CTEPH group.


Sildenafil is a selective inhibitor of cyclic guanosine monophosphate (cGMP)- specific phosphodiesterase-5, an enzyme that metabolises cGMP, thereby enhancing the cGMP-mediated relaxation and growth inhibition of vascular smooth-muscle cells. It has proven efficacy in idiopathic PAH.16 An open-label uncontrolled clinical trial included 104 inoperable CTEPH patients.17 After three months of treatment with sildenafil three times a day, there was a significant haemodynamic improvement, with reduction of pulmonary vascular resistance from 863±38 to 759±62 6MWD increased significantly from 310±11m to 361±15m after three months of therapy. However, the major limitation of this study is the single-centre uncontrolled design, with a lack of a control group. The results could not be confirmed in a small RCT including 19 patients randomised to placebo or sildenafil for 12 weeks.18

This RCT failed to

achieve its primary end-point: there was no significant change in 6MWD.


ET-1 is a potent vasoconstrictor and smooth-muscle mitogen and ET-1 plasma levels are increased in PAH and CTEPH patients. Bosentan is an oral ET receptor antagonist, blocking both endothelin receptors A (ETA) and B (ETB) and is effective in PAH treatment.19 The first large RCT in CTEPH was the BENEFIT (Bosentan Effects in iNopErable Forms of chronIc Thromboembolic Pulmonary Hypertension) study with bosentan.20

The BENEFIT trial included

157 patients with inoperable CTEPH, including 28% with previous PEA. Patients were randomised to receive either placebo or bosentan and were studied for 16 weeks.


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