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CTEPH: treatment

The first and only treatment approved for CTEPH

This review will provide a brief clinical overview of CTEPH, discuss the mechanism of action of riociguat and the evidence supporting its use in this condition

Lisa M Mielniczuk MD MSc FRCPC Associate Professor of Medicine, University of Ottawa, Canada

Riociguat is a member of a new class of therapeutic agents called soluble guanylate cyclase (sGC) stimulators and has recently been demonstrated to be an effective new therapy in the management of pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH).1–3


CTEPH is a serious disease characterised by obstruction of the pulmonary vasculature from unresolved thrombi. It is a ‘rare/orphan disease’ with an epidemiology comparable to PAH. CTEPH results in progressive PH and, in many, right ventricular failure.2


defined as a raised mean pulmonary artery pressure (greater than 25mmHg at rest) caused by persistent obstruction of pulmonary arteries after pulmonary embolism that has not resolved despite adequate anticoagulation for at least three months.4

It is estimated that the

prevalence of CTEPH after acute pulmonary embolism is 0.1–4% after two years. There are known risk factors predisposing to CTEPH development, in terms of both severity of PE as well as patient risk factors. The former includes patients with recurrent venous thromboembolism, large perfusion defects and those with echocardiographic signs of PH at the time of initial presentation. Patient-related risks include those with myeloproliferative disorders, inflammatory bowel disease and the presence of permanent central venous

lines, pacemakers or ventriculoatrial shunts.5–7

Central to all of these clinical

disorders is inflammation and/or infection – both of which likely predispose to the non-dissolution of thromboembolic material.4

Initial trigger for CTEPH development The initial trigger for CTEPH development is the occlusion of pulmonary arteries by thromoboembolic material. However, the non-dissolution of this thrombotic

for eligible patients. Unfortunately, a significant proportion of patients with CTEPH are not eligible for pulmonary endarterectomy because of either technical reasons or comorbidities. In addition, recurrent PH following endarterectomy surgery is not uncommon, and contributes significantly to long-term morbidity and mortality in these patients. In the large European/Canadian Registry, it was observed that 17% of patients had persistent PH (pulmonary artery pressure

“A significant proportion of patients with CTEPH are not eligible for pulmonary endarterectomy because of either technical reasons or comorbidities”

material results in the formation of organised scar tissue, or fibrous clots, and intraluminal webs and bands that can partially or completely obstruct pulmonary arteries. The resultant pulmonary blood flow is redirected to non-occluded blood vessels, which become exposed to high intravascular pressures and sheer stress, resulting in endothelial dysfunction, and vascular remodelling of precapillary arteries. These changes resemble findings demonstrated in PAH.8 In the absence of treatment, the

survival for patients with CTEPH is poor, with a median survival of less than two years in patients with a mean pulmonary artery pressure >30mmHg at diagnosis.9 Traditionally, the management of these patients included life-long anticoagulation and, in selected cases, insertion of inferior vena cava filters.4

However, pulmonary

endarterectomy is the only potentially curative strategy and the standard of care

>25mmHg following surgery) and at least 31% of patients referred to participating centres were considered inoperable, due either to inaccessibility with vascular obstruction distal to the segmental arteries or a discrepancy between pulmonary vascular resistance and vascular obstruction suggesting extensive small vessel arteriopathy.10

In this group of

patients, alternative therapies that reduce PH severity and improve functional capacity could significantly alter the prognosis.

The justification for the use of PAH- targeted therapies in this patient population has been taken from the observation of some shared pathophysiological features. The histopathological examination of distal, precapillary pulmonary arteries in patients with CTEPH demonstrates changes similar to those observed in patients with idiopathic PAH. In addition, plasma levels


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