Treatment of pulmonary hypertensionBMJ 2003; 326 doi: https://doi.org/10.1136/bmj.326.7394.835 (Published 19 April 2003) Cite this as: BMJ 2003;326:835
Several options exist, but they are expensive and necessitate specialist care
For understandable reasons, the pulmonary circulation remains an enigma to most doctors. This is because the cardinal symptom, dyspnoea, is shared with many more common diseases, and the signs of pulmonary hypertension are difficult to elicit for the non-specialist. Consequently, the delay between onset of symptoms and diagnosis is two years, and the mean survival from the time of diagnosis is only another two years in untreated patients with severe hypertension of the pulmonary artery. In the past, pulmonary hypertension was not treatable, but now several treatments are available.
Severe pulmonary hypertension, with a total prevalence of about 30-50/million, can be primary or associated with apparently disparate conditions including connective tissue disease, congenital heart disease, chronic pulmonary thromboembolism, HIV infection, use of an appetite suppressant, and liver disease. Surprisingly, nearly all these conditions have a similar histological picture of vascular remodelling. The pathobiology of pulmonary artery hypertension is now better understood. A gene for familial pulmonary arterial hypertension, which codes for BMPR2 a receptor in the transforming growth factor β (TGF-β) family, has been discovered. 1 2 This gene is also found in up to 26% of patients with so called sporadic pulmonary hypertension. The genetic abnormality perhaps must be accompanied by some additional environmental factor to cause pulmonary artery hypertension (“the double hit hypothesis”), and the remodelling occurs because that factor (or factors) acts in concert with disturbed BMPR signalling to cause an increase in production of cytokines and other factors.
In the past pulmonary artery hypertension was considered untreatable unless the underlying cause could be treated (for example, HIV infection), and patients could be offered only oxygen and transplantation. It was later realised that oral anticoagulants alone improved survival, which implies a thrombotic component to the cause or progression of the disease. Furthermore, in patients with an acute response to vasodilators, a high dose of calcium channel blockers resulted in a five year survival of more than 90%.3 Unfortunately only 10-15% of patients fall into this “responder” category, and therefore a need for other forms of treatment existed.
The breakthrough came in the early 1980s when it was shown that patients could be maintained on continuous intravenous epoprostenol, which improves both exercise capacity and haemodynamics.4 Subsequently it was also shown that long term treatment with intravenous epoprostenol improved survival.5 Unfortunately, because of its short half life, epoprostenol must be given continuously intravenously, with the attendant risks of air embolism and sepsis. This difficulty and the need for treatments working through alternative mechanisms prompted several trials. No placebo controlled trials were conducted before 1999, but since 2000 over 1000 patients worldwide have been enrolled in trials, all of which have examined similar end points and studied similar patients. Most of the trials studied patients in WHO functional classes 2-4 and lasted between 12 and 16 weeks. Their primary end point was a measurement of exercise capacity as defined by the six minute walk test (which measures how far someone can walk in six minutes), and the main secondary end points were improvements in pulmonary haemodynamics and breathlessness.
Three epoprostenol analogues were studied—treprostinol, beraprost, and iloprost. Treprostinol is a stable analogue of epoprostenol, which is given continuously subcutaneously. Escalation of dosage was limited by the protocol to avoid pain at the site of infusion. Thus many patients did not receive therapeutic doses, but a significant improvement was found in the six minute walk test, which was greater in those taking the higher doses.6 Beraprost is active orally and was given to generally less sick patients (WHO classes 2-3). An improvement in the six minute walk test occurred in all patients, but, patients with primary pulmonary hypertension improved more.7 Iloprost can be given intravenously or by nebuliser, but in this trial it was given by inhalation. The rationale for this method of delivery is that less of the substance reaches the systemic circulation (a “pseudoselective” pulmonary vasodilator). The six minute walk test improved in all categories, but once again improvement was greater in those with primary pulmonary hypertension. An improvement in haemodynamics also occurred.8 Iloprost must be given six to nine times a day, which may disrupt the patient's lifestyle, but this may be helped by the new portable nebulisers.
The other main approach to pulmonary hypertension has been the blockade of endothelin receptors, the rationale being that plasma endothelin is raised in patients with various types of pulmonary hypertension. Two placebo controlled trials of bosentan (an endothelin receptor A and B antagonist) have been conducted. 9 10 The six minute walk test improved in the whole group, but the improvement was greater when the drug was used in higher doses. However, problems with liver function occurred with the higher dose. There is an argument for using a pure endothelin A antagonist, and sitaxsentan has been used in an open pilot study. This showed an improvement in the six minute walk test and a decrease in pulmonary vascular resistance of 30%.11
Endothelial production of nitric oxide is diminished with pulmonary hypertension, prompting attempts to reverse this defect either by giving continuous inhaled nitric oxide, which is effective but difficult to administer, or by increasing the substrate for nitric oxide L—arginine.12 A trial of supplementation with L—arginine is currently under way. In addition to increasing the supply of nitric oxide, attempts to increase directly cyclic GMP in the smooth muscle cells have been made. Sildenafil used for erectile dysfunction blocks the enzyme phosphodiesterase type 5 present in the corpus cavernosum of the penis and also the lungs. This raises the possibility that a phosphodiesterase type 5 inhibitor such as sildenafil could be a relatively selective pulmonary vasodilator. There is some evidence for this belief. 13 14 A large placebo controlled trial of sildenafil is now in progress.
Several treatments are now available for severe pulmonary arterial hypertension. Most of the experience concerns adults, but the same principles of management apply even to very young children. We have good evidence that these drugs improve exercise tolerance and haemodynamics, but we must await evidence for an improvement in survival, which so far has been shown only with epoprostenol. These drugs are expensive, the patients sick, and the appropriate investigations difficult and potentially dangerous. For these reasons, the care in the United Kingdom and Ireland has been organised into designated pulmonary hypertension units with published standards of care. Currently only epoprostenol and bosentan are licensed treatments for pulmonary arterial hypertension, but we hope that other drugs will be licensed shortly. If these drugs show synergy, they may be used in combination in the future. Eventually with greater understanding of the genetics and pathobiology of pulmonary hypertension we may even have a series of drugs, which attack the problem at its molecular roots.
On behalf of the National Pulmonary Hypertension Services of UK and Ireland: Ireland, Dublin, Sean Gaine (Mater Misericordiae); London, Gerry Coghlan and Carol Black (Royal Free); London, Simon Gibbs (Hammersmith, Royal Brompton, and Harefield), and Michael Gatzoulis and Timothy Evans (Royal Brompton and Harefield); London (children) Glennis Haworth (Great Ormond Street); Sheffield, David Kiely (Royal Hallamshire); Newcastle, Paul Corris (Freeman Hospital); Cambridge, Joanna Pepke-Zaba and Nicholas Morell (Papworth); Scotland, Glasgow, Andrew Peacock (Western Infirmary).
Competing interests AJP has received support to attend conferences and occasional consultation fees from Glaxo (UK), Actelion (UK), and Schering (Germany).