There have been significant advances in the pharmacological treatment of PAH in the last decade, with improvements in survival and in safety of agents. These disease targeted therapies target one of three main pathways involved in the pathobiology of PAH.
- Prostacyclin pathway.
- Endothelin pathway.
- Nitric oxide pathway.
Disease targeted therapies are expensive and are potentially dangerous if prescribed inappropriately. Funding for these agents is only available through the Scottish Pulmonary Vascular Unit. All patients receiving disease targeted therapy will be followed up regularly at the SPVU.
Activation of the endothelin system has been demonstrated in the plasma and lung tissue of PAH patients. Endothelin (ET-1) exerts vasoconstrictor and mitogenic effects by binding to two receptors (Endothelin-A and B) in pulmonary vascular smooth muscle cells. Endothelin B receptors are also present in endothelial cells. Activation results in vasodilatory and anti-proliferative effects through release of NO and prostacyclin. Despite their different isoform activity, dual endothelin-A and B receptor antagonists (ERAs) are as effective as endothelin-A receptor antagonists.
Ambrisentan is an orally active, selective endothelin-A receptor antagonist. Two large RCTS (ARIES 1 and 2) demonstrated improved exercise capacity, haemodynamics and time to clinical worsening in patients with IPAH, HIV-PAH and CTD-PAH. It is currently approved for the treatment of WHO-FC II and III patients. The incidence of abnormal LFTs range from 0.8-3% with ambrisentan. Intermittent LFT monitoring is recommended. The most common side effects of ambrisentan include headache and peripheral oedema. It is prescribed at a dose of 5-10mg od (1).
Bosentan is an orally active dual endothelin-A and B receptor antagonist. Its efficacy has been assessed in IPAH, CTD-PAH and Eisenmerger’s syndrome in BREATHE-1, -2, -5 and EARLY RCTs. Improved exercise capacity, functional class, haemodynamics, time to clinical worsening and echo features have all been shown to improve on treatment. The most important adverse event associated with bosentan is hepatocellular injury. From trial data, increases in hepatic enzymes to > 3 times the upper limit of normal have been observed in approximately 11%. Other side effects include headache, flushing, lower extremity oedema and rarely, anaemia. Bosentan is teratogenic. Careful monitoring of therapy is required including LFTs on a monthly basis and regular FBC. Bosentan is introduced at 62.5mg bd and increased to 125mg bd at 4 weeks (LFTs permitting)(2).
Macitentan is the newest ERA. It demonstrates dual endothelin receptor antagonism with sustained receptor binding and enhanced tissue penetration. Its efficacy was demonstrated in the RCT SERAPHIN, which showed improved exercise capacity and significant reduction in the composite end-point of death, atrial septostomy, lung transplantation, initiation of treatment with IV/SC prostanoid or clinical worsening of PAH. The most common side effects are nasopharyngitis, headache and anaemia. Full blood count should be checked every 3-4 months. No liver toxicity was seen in SERAPHIN, however intermittent monitoring of liver function tests is still conducted. Dosing is 10mg once daily(3).
Sitaxsentan was withdrawn globally from the market in 2011 due to cases of severe hepatotoxicity and an unacceptable side-effect profile compared with alternative ERAs.
NITRIC OXIDE AND CYCLIC GUANOSINE MONOPHOSPHATE PATHWAY
Impairment of Nitric Oxide (NO) synthesis and signalling through the NO-soluble guanylate cyclase (sGC) – guanosine monophosphate (cGMP) pathway is involved in the pathogenesis of PAH. This pathway is targeted therapeutically in three main ways with current treatment:
- Direct administration of inhaled NO.
- Enhanced effect of NO by increasing its enzymatic production: soluble guanylate cyclase (sGC) activators.
- Inhibition of NO metabolism: phosphodiesterase type 5 inhibitors (PDE5is).
Soluble guanylate cyclase activators
Riociguat has recently been approved by the SMC for treatment of PAH and CTEPH (inoperable and recurrent or persistent PH post-pulmonary endarterectomy). Riociguat has a dual mode of action; it directly stimulates sGC independently of NO availability and acts in synergy with endogenous NO. In PAH and CTEPH, two large RCTs (PATENT-1 and CHEST-1) have demonstrated improved exercise capacity, haemodynamics and WHO functional class, with reduced time to clinical worsening also in PAH. This is the first drug shown to improve exercise capacity in CTEPH. These two RCTs have been continued into long-term extension studies which are currently ongoing(4).
The most common side-effects reported in trial data were headache, hypotension, dizziness and dyspepsia. Regular blood pressure monitoring is recommended. The combination of riociguat and PDE5is is contraindicated due to the risk of profound hypotension.
Inhibition of the cGMP degrading enzyme PDE5 results in vasodilation through the NO/cGMP pathway at sites expressing this enzyme. Additionally PDE5is exert anti-proliferative effects.
Sildenafil is an orally active, selective PDE5i. Five RCTs have confirmed improved exercise capacity, symptoms and / or haemodynamics(5). Most side effects are related to vasodilation, such as headache, flushing and epistaxis. IV sildenafil is available as a potential bridge for patients temporarily unable to ingest tablets. The dose range is from 25mg TID up to 100mg TID and blood pressure should be closely monitored at initiation and with dose increases.
Tadalafil is a once daily, selective PDE5i. The randomised controlled trial PHIRST demonstrated improved exercise capacity, symptoms and haemodynamics with treatment. It has a similar side effect profile to sildenafil. Tadalafil has recently been assessed with ambrisentan in the AMBITION study of upfront combination therapy (see below). Tadalafil is prescribed as 40mg once daily(6).
This drug is currently not approved for PAH. It was assessed in the small RCT EVALUATION, which demonstrated improved exercise capacity, haemodynamics and time to clinical worsening, with a similar side-effect profile to sildenafil(7).
Prostacyclin is produced predominantly by endothelial cells. It induces potent vasodilation of all vascular beds and inhibits platelet aggregation. Additionally, it has some cytoprotective and antiproliferative effects. Reduced expression of prostacyclin synthase occurs in the pulmonary arteries of patients with PAH.
Epoprostenol is a potent, short acting vasodilator and antiproliferative agent whose efficacy and safety have been well documented in numerous short and long term clinical trials and observational studies(8). Intravenous epoprostenol improves WHO functional class, 6 minute walk distance, haemodynamics and survival in IPAH. It is the only medication in PAH that has shown a survival benefit in a randomised controlled trial. Epoprostenol is widely considered to be the most potent and efficacious treatment for PAH
Epoprostenol (Veletri and Flolan-12) have a short half-life (3-5 min) and require continuous administration by means of an infusion pump and delivery via a tunnelled catheter. Each patient must learn the techniques of sterile preparation of the medication, operation of the portable infusion pump, and care of the central venous catheter.
Intravenous epoprostenol is usually started at a dose of 2ng/kg/min and the dose uptitrated on the basis of symptoms and side effects of the drug. In critical illness, dose titration can be more rapid under specialist instruction. Common side effects include headache, jaw pain, flushing, nausea, diarrhoea, skin rash and musculoskeletal pain. Infections and infusion interruptions can be life threatening.
loprost is a chemically stable prostanoid that can be delivered by a nebuliser 6 to 9 times per day, with each inhalation lasting 5 to 10 minutes. Iloprost has a plasma half life of around 30 minutes. The RCT AIR showed improved exercise capacity, haemodynamics and reduced clinical events. However Iloprost as an add on therapy has shown variable results(9). Most of the attention has focused on iloprost as an inhalation drug.
The nebulised route of iloprost allows it to promote selectively vasodilation in the pulmonary artery circulation whilst minimising the systemic effects commonly associated with intravenous prostacyclin. Common side effects of inhaled iloprost include cough, headache, flushing and jaw pain.
Treprostinil is an epoprostenol analogue and is chemically stable at room temperature. Intravenous, sub-cutaneous and oral preparations are available. Treprostinil is not currently licenced in the UK. There have been multiple RCTs evaluating treprostinil in various forms. SC treprostinil is effective in improving exercise capacity, haemodynamics and symptoms but is poorly tolerated due to erythema and pain at the infusion site.
The RCT TRIUMPH demonstrated improved exercise capacity and quality of life with inhaled treprostinil. IV treprostinil appears to be as effective as epoprostenol but RCT data are not as robust and with a high incidence of pain at infusion site(10). There are still ongoing trials evaluating oral treprostinil but the RCT FREEDOM showed no significant improvement in exercise capacity.
Beraprost was the first chemically stable, orally active prostacyclin analogue. It is not licenced in the UK and is only available in Japan and South Korea. The only RCT conducted with Beraprost showed improved exercise capacity. However this lasted only 3-6 months and no haemodynamic benefits were seen. The most common side effects are headache, flushing, jaw pain and diarrhoea(11) .
Selexipag is a novel orally active, selective prostacyclin receptor agonist(12). It is now available as a licenced drug and trial data from the event driven RCT GRIPHON are published, showing improvements in clinical outcome measures. However, PH units in the UK have recently received permission to introduce it to clinical use.
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(2) Channick R.N., Simonneau G., Sitbon O., et al; Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: a randomised placebo-controlled study. Lancet. 2001;358:1119-1123.
(3) Pulido T., Adzerikho I., Channick R.N., et al; Macitentan and morbidity and mortality in pulmonary arterial hypertension. N Engl J Med. 2013;369:809-818.
(4) Ghofrani H.A., Galie N., Grimminger F., et al; Riociguat for the treatment of pulmonary arterial hypertension. N Engl J Med. 2013;369:330-340.
(5) Galie N., Ghofrani H.A., Torbicki A., et al; Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med. 2005;353:2148-2157.
(6) N Galie et al. Tadalafil therapy for Pulmonary Artery Hypertension. Circulation. 2009; 119: 2894-2903.
(7) Jing Z.C., Yu Z.X., Shen J.Y., et al; Vardenafil in pulmonary arterial hypertension: a randomized, double-blind, placebo-controlled study. Am J Respir Crit Care Med. 2011;183:1723-1729.
(8) Barst R.J., Rubin L.J., Long W.A., et al;Primary Pulmonary Hypertension Study Group A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. N Engl J Med. 1996;334:296-302.
(9) Olschewski H., Simonneau G., Galie N., et al; Inhaled iloprost in severe pulmonary hypertension. N Engl J Med. 2002;347:322-329.
(10) Tapson V.F., Jing Z.C., Xu K.F., et al; Oral treprostinil for the treatment of pulmonary arterial hypertension in patients on background endothelin receptor antagonist and/or phosphodiesterase type 5 inhibitor therapy (The FREEDOM-C2 Study): a randomized controlled trial. Chest. 2013;142:1363-1364.
(11) Galie N., Humbert M., Vachiery J.L., et al; Effects of beraprost sodium, an oral prostacyclin analogue, in patients with pulmonary arterial hypertension: a randomised, double-blind placebo-controlled trial. J Am Coll Cardiol. 2002;39:1496-1502.
(12) Sitbon O., Channick R., Chin K.M., et al; Selexipag for the treatment of pulmonary arterial hypertension. NEJM 2015;373:2522-2533.