General measures aim to limit any potentially deleterious effects of the patient's external circumstances on their PAH disease. These recommendations are largely based on expert opinion rather than controlled trials, and include measures such as avoiding pregnancy, prevention and prompt treatment of chest infections, and awareness of the potential effects of altitude.1,5,6
There has been considerable research into the causes of pulmonary arterial hypertension (PAH) over the past decade, and recent advances in our understanding of the mechanisms behind the development of the disease (see section: Why does PAH develop?) have led to major progress in treatment options for patients. While there is currently no cure for the disease, modern advanced PAH therapies can markedly improve a patient's symptoms and slow the rate of clinical deterioration.1,2 Research into therapies for PAH continues, and as clinical experience continues to grow, it is important to be aware of developments and recommendations in the field, including international guidlines (Fourth World Symposium, Dana Point Classification, 2008) and regional guidelines such as those provided by the European Society of Cardiology and European Respiratory Society (ESC/ERS), the American College of Chest Physicians (ACCP) and the American College of Cardiology Foundation and American Heart Association (ACCF/AHA).1,3-6
The aims of treatment in patients with PAH are several-fold and range from symptomatic relief to improvement in the physical limitations imposed by their disease (such as improving functional class; see section: Assessing the severity of PAH), and delaying disease progression.1,3
The management of PAH is complex and involves the use of a range of treatment options, including supportive and general measures, the assessment of vasoreactivity, and the optimal use of different drugs and interventions. Treatment options for PAH can be broadly broken down into four main categories:
Conventional or supportive therapy
A range of treatment approaches have been shown to provide some degree of symptomatic benefit to PAH patients. However, there is no evidence that they have an effect on the disease process or prognosis. Such measures include:
- Oxygen: For patients with dyspnoea associated with PAH, supplemental oxygen provides symptomatic relief and improves patient comfort, although there is no consistent evidence supporting any long-term benefit.1 It is generally considered important to maintain oxygen saturation above 90% at all times, and oxygen may be indicated in some patients1,5,6
- Anticoagulants: clinical data supportive of the use of anticoagulant therapy in PAH are limited; however, improved survival has been reported with oral anticoagulation in patients with idiopathic PAH (IPAH),5,6 and because of high risk of in situ thrombosis within the small pulmonary arteries, there is a rationale for the use of oral anticoagulants in PAH patients.1
- Diuretics: there are no randomised controlled trials (RCTs) of diuretics in PAH, however clinical experience shows clear symptomatic benefit in fluid-overloaded patients with decompensated right heart failure associated with PAH1,5
- Calcium channel blockers (CCBs): CCBs may be of benefit in a small proportion of patients with PAH. Suitable patients are detected by acute vasoreactivity testing during right heart catheterisation (see section: How is PAH diagnosed?).7 A positive vasoreactive response indicating potential suitability for CCB therapy is shown by around 10% of patients,1 and approximately 7% of these patients have a sustained response.7,8 Patients who respond to vasoreactivity testing and are subsequently treated with CCBs need regular assessment and repeat testing, as the vasoreactivity status may change.4,6
Advanced therapy (also termed PAH-specific therapy)
PAH-specific therapies have been developed specifically to target one of three major pathways known to be involved in the development of PAH8 (see section: Why does PAH develop?) and have, to varying degrees, been shown to affect the disease process:
- Endothelin receptor antagonists (ERAs): endothelin is implicated in the pathogenesis of PAH through its actions on the pulmonary vasculature. Endothelin is elevated in patients with PAH and levels are directly related to disease severity and prognosis. Endothelin receptor antagonists are oral treatments that act by blocking the binding of endothelin to either one (single antagonist) or both (dual antagonist) of its receptors (see section: Why does PAH develop?).8 Clinical trials have shown that treatment with ERAs has a beneficial effect on exercise capacity, WHO Functional Class (FC), haemodynamics and time to clinical worsening in patients with PAH.8-13
- Prostacyclin therapy: synthetic prostacyclins and prostacyclin analogues act by helping to correct the deficiency of endogenous prostacyclin seen in patients with PAH (see section: Why does PAH develop?). The clinical use of prostacyclins in patients with PAH has been extended by the synthesis of more stable anologs for intravenous infusion,14 as well as those that can be given by subcutaneous infusion,15,16 or by inhalation.17
- Phosphodiesterase-5 (PDE-5) inhibitors: these oral agents act on the nitric oxide (NO) pathway to induce vasodilation and also have antiproliferative effects on vascular smooth muscle cells (see section: Why does PAH develop?). Clinical trials have shown that treatment with PDE-5 inhibitors has a beneficial effect on exercise capacity, haemodynamic parameters, and symptoms in patients with PAH.18,19
For patients with severe PAH, for example those in WHO FC IV (see section: Assessing the severity of PAH), who do not respond satisfactorily to treatment with advanced therapies, surgery may be the only option.
- Balloon atrial septostomy: atrial septostomy creates a small hole between the right and left atria, allowing blood to pass from the right atrium directly to the left, bypassing the restricted pulmonary circulation. This aims to increase the left ventricular preload and the systemic blood flow (cardiac output), resulting in an improved systemic oxygen transport, and to reduce the pressure and therefore the stress on the right heart, but at the cost of lower oxygen levels in the blood (hypoxaemia).1,6
- Transplantation: lung transplantation or heart and lung transplantation are considered for patients who have failed medical therapy. Given the time needed to complete a transplant evaluation and the time spent on the transplant list awaiting suitable organs, it is currently recommended that patients with WHO FC III or IV symptoms (see section: Assessing the severity of PAH) should be referred for evaluation for transplantation while their response to therapy is being evaluated in order to avoid delays.1,20 Recent long-term survival studies have reported 10-year post-transplant survival rates of 42-66% in patients with IPAH and 70% in other groups of PAH patients.21,22
- Galiè N, Hoeper MM, Humbert M, et al. Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J 2009;30:2493–537.
- Humbert M, Sitbon O, Chaouat A, et al. Survival in patients with idiopathic, familial, and anorexigen-associated pulmonary arterial hypertension in the modern management era. Circulation 2010;122:156–63.
- Barst RJ, Gibbs JS, Ghofrani HA, et al. Updated evidence-based treatment algorithm in pulmonary arterial hypertension. J Am Coll Cardiol 2009;54:S78–84.
- Badesch DB, Abman SH, Simonneau G, et al. Medical therapy for pulmonary arterial hypertension: updated ACCP evidence-based clinical practice guidelines. Chest 2007;131:1917–28.
- Badesch DB, Abman SH, Ahearn GS, et al. Medical therapy for pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines. Chest 2004 Jul;126(1 Suppl):35S–62S.
- McLaughlin VV, Archer SL, Badesch DB, et al; ACCF/AHA. ACCF/AHA 2009 expert consensus document on pulmonary hypertension: a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association: developed in collaboration with the American College of Chest Physicians, American Thoracic Society, Inc., and the Pulmonary Hypertension Association. Circulation 2009;119:2250–94.
- Sitbon O, Humbert M, Jaïs X, et al. Long-term response to calcium channel blockers in idiopathic pulmonary arterial hypertension. Circulation 2005;11:3105–11.
- Humbert M, Sitbon O, Simonneau G. Treatment of pulmonary arterial hypertension. N Engl J Med 2004;351:1425–36.
- Channick RN, 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;358:1119–23.
- Rubin LJ, Badesch DB, Barst RJ, et al. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med 2002;346:896–903.
- Galiè N, Rubin LJ, Hoeper M, et al. Treatment of patients with mildly symptomatic pulmonary arterial hypertension with bosentan (EARLY study): a double-blind, randomised controlled trial. Lancet 2008;371:2093–100.
- Galiè N, Beghetti M, Gatzoulis MA, et al. Bosentan therapy in patients with Eisenmenger syndrome: a multicenter, double-blind, randomised, placebo-controlled study. Circulation 2006;114:48–54.
- Galiè N, Olschewski H, Oudiz RJ, 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. Circulation 2008;117:3010–9.
- Nicolas LB, Gutierrez MM, Galitz L, Dingemanse J. Epoprostenol with expanded stability has the same pharmacokinetic and pharmacodynamic profiles as epoprostenol in healthy subjects. Am J Respir Crit Care Med 2011;183:A5902.
- Simonneau G, Barst RJ, Galiè N, et al. Continuous subcutaneous infusion of treprostinil, a prostacyclin analogue, in patients with pulmonary arterial hypertension. A double-blind, randomised, placebo-controlled trial. Am J Respir Crit Care Med 2002;165:800–4.
- Barst RJ, Galiè N, Naeije R, et al. Long-term outcome in pulmonary arterial hypertension patients treated with subcutaneous treprostinil. Eur Respir J 2006;28:1195–203.
- Olschewski H, Simonneau G, Galiè N, et al. Inhaled iloprost in severe pulmonary hypertension. N Engl J Med 2002;347:322–9.
- Galiè N, Ghofrani HA, Torbicki A, et al. Sildenafil citrate treatment for pulmonary arterial hypertension. N Engl J Med 2005;353:2148–57.
- Galiè N, Brundage BH, Ghofrani HA, et al. Pulmonary Arterial Hypertension and Response to Tadalafil (PHIRST) Study Group. Tadalafil therapy for pulmonary arterial hypertension. Circulation 2009;119:2894–903.
- Orens JB, Estenne M, Arcasoy S, et al. International guidelines for the selection of lung transplant candidates: 2006 update--a consensus report from the Pulmonary Scientific Council of the International Society for Heart and Lung Transplantation. J Heart Lung Transplant 2006;25:745–55.
- de Perrot M, Granton JT, McRae K, et al. Outcome of patients with pulmonary arterial hypertension referred for lung transplantation: A 14-year single-center experience. J Thorac Cardiovasc Surg. 2012 Feb 3. Epublished ahead of print.
- Toyoda Y, Thacker J, Santos R, et al. Long-term outcome of lung and heart-lung transplantation for idiopathic pulmonary arterial hypertension. Ann Thorac Surg 2008;86:1116–22.