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CTEPH: medical treatment

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.7

Different open-label and

randomised controlled trials (RCTs) have shown varying degrees of clinical effect with medical treatment.

PAH-targeted treatment Epoprostenol

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.8


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.12

This RCT

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).9 Limitations of the study are the design and the small number of patients.


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.10

A small open label uncontrolled study, including 25 patients, demonstrated significant improvements in six minute walking distance, World Health Organization (WHO) functional class and brain natriuretic peptide plasma levels.11 However, the small patients numbers and the uncontrolled nature of the investigation are limitations of this study.

included 203 patients of whom 56 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.13

An open-label

uncontrolled clinical trial included 104 inoperable CTEPH patients.14

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 The six minute walking distance 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.15

This RCT failed

to achieve its primary end-point: there was no significant change in six minute walking distance.


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.16

The first large RCT in CTEPH was the BENEFIT (Bosentan Effects in iNopErable Forms of chronIc Thromboembolic Pulmonary Hypertension) study with bosentan.17


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. The study demonstrated a significant pulmonary vascular resistance reduction of -24% (95% confidence interval: -32 to -16; p<0.0001). However, 6 min walk distance in meters remained unchanged, with a treatment effect of 2m (95% confidence interval: –22 to 27; p=0.5449). Because of the lack of efficacy in both primary endpoints, bosentan is not approved for CTEPH in any country in the world.

CTEPH treatment Riociguat

Riociguat belongs to a new class of vasodilating drugs directly stimulating soluble guanylate cyclase (sGC).18,19

sGC is

a key signal-transduction enzyme activated by nitric oxide and it catalyses the conversion of guanosine-5’- triphosphate (GTP) into the second


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