In the past 15-20 years enormous progress has been made in the treatment of pulmonary arterial hypertension, one of the five subtypes of pulmonary hypertension (WHO group 1), with nine drugs approved by the EU regulatory authorities. The new treatments have led to significant improvements for patients in terms of symptoms, disease progression and survival. One of these nine drugs has shown benefits also in the form of pulmonary hypertension known as CTEPH (chronic thromboembolic pulmonary hypertension, WHO group 4). Currently there are no approved PH drugs for the other three classes of pulmonary hypertension.

Please scroll through the next sections for further details.

Further information and educational materials on PH therapies can also be found in the section ‘PH. It’s personal’ and drug information.

Approved drugs for pulmonary arterial hypertension fall under four main types:

1. Endothelin receptor antagonists (“ERA’s”) These drugs aim to counterbalance the deleterious effects of endothelin, a substance which is thought to be produced in excess in PAH patients and which causes vasoconstriction (narrowing) of the blood vessels.Three ERA’s are approved for use in PAH in Europe:
   • ambrisentan
   • bosentan
   • macintentan

   ERA’s are oral drugs.

2. Phosphodiesterase type-5 (“PDE-5”) inhibitors Inhibition of the PDE-5 enzyme results in vasodilatation through the nitric oxide pathway. In addition, PDE-5 inhibitors exert anti-proliferative effects. Two PDE-5 inhibitors are approved for use in PAH in Europe:
   • sildenafil
   • tadalafil

   PDE-5 inhibitors’s are oral drugs.

3. Prostanoids Prostacyclin has very strong vasodilator effects on the blood vessels. In people with PAH an insufficient production of prostacyclin has been shown. The clinical use of prostacyclin has been made possible by synthetic analogues. Four drugs targeting the prostacyclin pathway are currently approved in Europe:
   • epoprostenol
   • iloprost
   • selexipag
   • treprostinil

   Drugs targeting the prostacycin pathway have different systems of delivery: oral (selexipag), inhaled (iloprost) and intravenous (epoprostenol), the latter two by 24/7 infusion with small portable pumps. In some countries the oral prostanoid beraprost is available as well as inhaled, intravenous and subcutaneous treprostinil.

4. Soluble guanylate cyclase stimulators (SGCs)¹ Soluble guanylate cyclase stimulators, which work on the nitric oxide pathway (please see detailed description under PDE5 inhibitors), help arteries relax to increase blood flow and decrease blood pressure. One soluble guanylate cyclase stimulator has been approved in Europe for two forms of pulmonary hypertension. CTEPH and PAH:
   • riociguat

   Riociguat is an oral drug.

Lung or heart/lung transplant surgery

Transplant surgery is normally indicated for patients with PAH who do not respond appropriately to maximal drug therapy and are deteriorating despite being on the most powerful form of treatment, including prostanoids (usually intravenous). In the case of pulmonary hypertension surgery typically involves replacing both lungs, but sometimes requires replacing the heart and lungs. Both single and bilateral procedures have been performed, apparently with similar survival.

In order to be listed for surgery patients must undergo a complex assessment procedure. Factors that are considered in this assessment include: age, life expectancy, other co-morbidities, psychological state and lifestyle. Not all PH patients are eligible for transplant. Transplant surgery can considerably improve quality of life and life expectancy. Risks include organ rejection, even long term, and infection. After transplant patients will be on anti-rejection therapy for the rest of their lives and must undergo periodic check-ups.

The reduced availability of donor organs is a very serious issue and this is a key limiting factor for surgery. Much remains to be done in terms of raising awareness to encourage organ donation. In some European countries, such as Austria, there is a so-called “opt-out” system whereby everyone is automatically a donor unless they explicitly say they do not wish to be. Easier access to transplant could be ensured by enacting more favourable donor legislation in Europe.

Pulmonary endarterectomy

CTEPH is the only cause of severe pulmonary hypertension which is potentially curable without the need to resort to lung transplantation. Pulmonary endarterectomy (PEA) is the surgical procedure which removes the obstructing thromboembolic material, resulting in significant improvements (and in many cases normalisation) in right ventricular haemodynamics and function. Detailed pre-operative patient evaluation and selection, surgical technique and experience, and meticulous post-operative management are essential prerequisites for success after this intervention.

The selection of patients for surgery depends on the extent and location of the organized thrombi in relation to the degree of PH and taking into consideration age and co-morbidities. Proximal organized thrombi represent the ideal indication while more distal obstructions may prevent a successful procedure. Many people can be completely cured of with CTEPH with surgery. They will still need to undergo regular medical tests and patients will be on anticoagulant therapy for the rest of their lives.

Reviewed by Prof. Simon J Gibbs

Last medical update: 05/30/2020

Sources

1. Galiè N, Channick RN, Frantz RP, et al. . Risk stratification and medical therapy of pulmonary arterial hypertension. Eur Respir J 2019; 53: 1801889