TREATMENT : DISEASE TARGETED THERAPY

A number of new agents have become available for the treatment of pulmonary arterial hypertension. These are expensive agents and can be difficult to use. Currently treatment with them is only funded in Scotland through the SPVU.

These therapies target one of three pathways involved in the pathobiology of PAH; the prostacyclin pathway, the endothelin pathway, and the nitric oxide pathway.

PROSTANOIDS

Epoprostenol Therapy

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. 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.

Intravenous epoprostenol must be delivered by continuous (due to a short half life of < 5 minutes) intravenous infusion, usually through a Hickman line. 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. Common side effects include headache, jaw pain, flushing, nausea, diarrhoea, skin rash and musculoskeletal pain. Infections and infusion interruptions can be life threatening. Given its considerable complexity, epoprostenol use should be limited to specialist centres.

1. Rubin LJ, Mendoza J, Hood M, McGoon M, Barst R, Williams WB, et al. Treatment of primary pulmonary hypertension with continuous intravenous prostacyclin (epoprostenol). Results of a randomized trial. Annals of internal medicine. 1990 Apr 1;112(7):485-91.

2. Barst RJ, Rubin LJ, Long WA, McGoon MD, Rich S, Badesch DB, et al. A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. The Primary Pulmonary Hypertension Study Group. The New England journal of medicine. 1996 Feb 1;334(5):296-302.

3. Badesch DB, Tapson VF, McGoon MD, Brundage BH, Rubin LJ, Wigley FM, et al. Continuous intravenous epoprostenol for pulmonary hypertension due to the scleroderma spectrum of disease. A randomized controlled trial. Annals of internal medicine. 2000 Mar 21;132(6):425-34.

4. Higenbottam T, Butt AY, McMahon A, Westerbeck R, Sharples L. Long-term intravenous prostaglandin (epoprostenol or iloprost) for treatment of severe pulmonary hypertension. Heart (British Cardiac Society). 1998 Aug;80(2):151-5.

Treprostinil Therapy

Treprostinil is a stable prostanoid with a half life of 4 hours that was first developed for continuous subcutaneous use. Unfortunately, approximately 85% of patients experience pain or erythema at the site of the subcutaneous infusion. Other common side effects include headache, diarrhoea, rash and nausea. Investigational trials with both inhaled and oral formulations of treprostinil are ongoing. Treprostinil can also be delivered as a continuous intravenous infusion. Therapy with this agent is not yet formally licensed in the UK.

5. Simonneau G, Barst RJ, Galie N, Naeije R, Rich S, Bourge RC, et al. Continuous subcutaneous infusion of treprostinil, a prostacyclin analogue, in patients with pulmonary arterial hypertension: a double-blind, randomized, placebo-controlled trial. American journal of respiratory and critical care medicine. 2002 Mar 15;165(6):800-4.

Iloprost Therapy

Iloprost is a chemically stable prostanoid that can be delivered by a nebuliser 6 to 9 times per day, with each inhalation lasting between 5 ? 10 minutes. Iloprost has a plasma half life of almost 30 minutes. Most of the attention has focused on iloprost as an inhalation drug. This route allows it to selectively promote 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.

6. Olschewski H, Simonneau G, Galie N, Higenbottam T, Naeije R, Rubin LJ, et al. Inhaled iloprost for severe pulmonary hypertension. The New England Journal of Medicine. 2002 Aug 1;347(5):322-9.

ENDOTHELIN RECEPTOR ANTAGONISTS

Endothelin (ET-1) was characterised in 1988 as a potent vasoconstrictor and antagonism of ET receptors is now firmly established as a therapeutic target for patients with PAH.

Bosentan Therapy

Bosentan is an orally active, nonselective ET receptor antagonist. Its efficacy for the treatment of PAH has been proven in two randomised controlled trials. The most important adverse effect associated with bosentan is hepatocellular injury. Increases in hepatic enzymes to > 3 times the upper limit of normal have been observed in approximately 11% of patients treated with bosentan in clinical trials. Other side effects include headache, flushing, lower extremity oedema and rarely, anaemia. Bosentan is teratogenic. Careful monitoring of therapy is required including liver function tests on a monthly basis and a regular full blood count analysis. Bosentan is introduced at 62.5mg bd and increased to 125mg bd at 4 weeks (liver function tests permitting).

Click here to download a list of Bosentan and possible drug interactions

7. Channick, R.N., et al., Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: a randomised placebo-controlled study. Lancet, 2001. 358(9288): p. 1119-23.

8. Rubin, L.J., et al., Bosentan therapy for pulmonary arterial hypertension. N Engl J Med, 2002. 346(12): p. 896-903.

9. Galie, N., et al., Bosentan therapy in patients with Eisenmenger syndrome: a multicenter, double-blind, randomized, placebo-controlled study. Circulation, 2006. 114(1): p. 48-54.

10. Denton, C.P., et al., Bosentan treatment for pulmonary arterial hypertension related to connective tissue disease: a subgroup analysis of the pivotal clinical trials and their open-label extensions. Ann Rheum Dis, 2006. 65(10): p. 1336-40.

Ambrisentan Therapy

Ambrisententan is a selective ETA antagonist. Its efficacy has been shown in the ARIES trials 1 & 2 which demonstrated improvements in time to clinical worsening, 6 minute walk test distance, functional class, and haemodynamic parameters. Liver function tests require to be monitored regularly. The most common side effects of ambrisentan include headache and peripheral oedema. Ambrisentan is prescribed at a dose of 5-10mg od.

11. Galie N et al., Ambrisentan for the treatment of  pulmonary arterial hypertension.  Results of the ambrisentan in pulmonary arterial hypertension, randomised, double-blind, placebo-controlled, multicenter, efficacy (ARIES) study 1 and 2.  Circulation2008; 117:3010-3019  

PHOSPHODIESTERASE TYPE 5 (PDE-5) INHIBITORS

Sildenafil Therapy

Sildenafil is a potent and highly selective PDE-5 inhibitor. It was demonstrated to improve exercise capacity, WHO functional class, and haemodynamics in patients with symptomatic pulmonary hypertension in the Sildenafil Use in Pulmonary Hypertension (SUPER) trial. Sildenafil is usually prescribed at a dose of 20mg tid. Introduction of sildenafil requires close monitoring of blood pressure. Side effects of sildenafil include headache, flushing, dyspepsia, and epistaxis. No specific laboratory monitoring is recommended. The use of sildenafil is contraindicated in patients taking nitrate medications because of potential hypotensive effects.

Click here to download a list of Sildenafil and possible drug interactions

12. Galie N, Ghofrani HA, Torbicki A, Barst RJ, Rubin LJ, Badesch D, et al. Sildenafil citrate therapy for pulmonary arterial hypertension. The New England journal of medicine. 2005 Nov 17;353(20):2148-57.

COMBINATION TREATMENT

The role of combination therapy is currently unproven and the subject of several current randomised controlled trials.

13. Humbert, M., et al., Combination of bosentan with epoprostenol in pulmonary arterial hypertension: BREATHE-2. Eur Respir J, 2004. 24(3): p. 353-9.

14. McLaughlin, V.V., et al., Randomized Study of Adding Inhaled Iloprost to Existing Bosentan in Pulmonary Arterial Hypertension. Am J Respir Crit Care Med, 2006.