Idiopathic pulmonary arterial hypertension (PAH), formerly known as primary pulmonary hypertension, is characterised by raised pulmonary artery pressure and pulmonary vascular resistance in the absence of underlying significant cardiopulmonary or other medical disease. Idiopathic PAH is a progressive disorder that usually culminates in right ventricular failure and death. Moreover, patients with idiopathic PAH are often severely limited on exertion by dyspnoea and fatigue, and thus suffer from a poor quality of life.

Despite clinical recognition of idiopathic PAH for more than 100 years, there have been few effective therapeutic options until recently. Given the previous absence of effective pharmacological therapy, surgical removal of the disease by lung transplantation has been an important therapeutic option for patients with idiopathic PAH. Lung transplantation is associated with rapid and sustained improvement in pulmonary haemodynamics.¹ Moreover, in individual patients with idiopathic PAH who do not respond to medical treatment, timely lung transplantation will often be associated with improved survival even though long term survival after lung transplantation remains poor.^2,3

One of the first long term pharmacological approaches used for treating idiopathic PAH was systemic anticoagulation. In patients with idiopathic PAH, pulmonary microvascular thrombosis is present histologically and there is laboratory evidence of a procoagulant haematological state.^4,5 Moreover, both retrospective and non-randomised cohort studies have suggested a survival benefit of systemic anticoagulation in idiopathic PAH.^6,7 Although not formally studied in a randomised controlled trial, systemic anticoagulation is recommended for the majority of patients with PAH in the absence of a clear contraindication based on assessment of individual bleeding risk.⁸

SURVIVAL BENEFIT OF NEW TREATMENTS IN IDIOPATHIC PAH

Ongoing basic biological and clinical research has led to tremendous advances in our understanding of the pathobiology of idiopathic PAH. Moreover, an increasing number of novel therapeutic agents targeting these pathobiological features have been studied in randomised clinical trials and many are available and recommended for clinical use in patients with idiopathic PAH. These include prostacyclin derivatives such as intravenous epoprostenol, subcutaneous treprostinil, inhaled iloprost, and oral beraprost, as well as other novel oral pulmonary hypertension treatments such as the non-selective endothelin receptor antagonist bosentan and the phosphodiesterase V inhibitor sildenafil.^{8,9,10,11,12,13}

These new treatments for pulmonary hypertension have been shown to improve pulmonary haemodynamics as well as clinically relevant end points such as symptoms and functional capacity, objectively measured exercise capacity, and quality of life in many patients with idiopathic PAH. But are such improvements in the morbidity associated with idiopathic PAH enough? Most would agree that improvements in symptoms and functional capacity should not be the only goals. Patients with idiopathic PAH, a disease which is usually fatal, have been suggested to live in a “kingdom of the near-dead”.¹⁴ An improvement in survival has therefore always been an important goal of treatment for both patients and their caregivers.

A significant survival benefit has been suggested in patients with idiopathic PAH treated with several agents including oral calcium channel blockers, intravenous epoprostenol, oral beraprost, and oral bosentan (table 1). Chronic treatment with high dose calcium channel blockers was the first to show a survival benefit in these patients.⁷ Although treatment of idiopathic PAH with calcium channel blockers has not been assessed in a randomised controlled trial, high dose calcium channel blockers are accepted as first line oral treatment for some patients with idiopathic PAH based on the dramatic survival benefit observed in a non-randomised cohort trial and long term clinical experience.^7,15 Unfortunately, only a minority of patients with idiopathic PAH (13–27%) demonstrate acute vasodilator responsiveness.^7,15 Moreover, sustained long term reductions in pulmonary arterial pressure may only be achieved with high dose calcium channel blockers in perhaps half of acute vasodilator responders,¹⁵ so only 7–15% of patients with idiopathic PAH may have improved survival with chronic calcium channel blocker treatment.

For the large majority of idiopathic PAH patients who are not candidates for long term treatment with calcium channel blockers, an increasing number of therapeutic agents are becoming available. In such patients the first alternative was continuous intravenous delivery of epoprostenol. In a landmark study,⁹ intravenous epoprostenol treatment was associated with a significant survival benefit compared with standard treatment, although survival was not the primary end point. Several groups have recently published their long term experience confirming a survival benefit of intravenous epoprostenol treatment.^16–18 A small retrospective study suggests a survival benefit of an oral prostacyclin derivative, beraprost.¹⁹

The report by Sitbon and colleagues in this issue of Thorax supports a long term survival benefit of treatment with bosentan, the first drug in a new class of pharmacological agents, the endothelin receptor antagonists.²⁰ Bosentan is the first oral agent specifically approved for treatment of idiopathic PAH in North America, Europe, and other parts of the world. The study by Sitbon et al confirms the survival benefit suggested by an analysis of long term, open label bosentan treatment in idiopathic PAH patients enrolled in the original two randomised controlled trials.²¹

It is apparent that none of the studies of pulmonary hypertension specific treatments were placebo controlled, double blind randomised controlled trials and all suffer from several methodological limitations, some major (table 1). These include a lack of randomisation, non-blinding of patients and investigators to the active treatment, and limited power as many studies assessed fewer than 50 patients. In addition, all studies are limited by either a complete absence of a control group or the use of a control group other than a placebo treated cohort. Moreover, the basis of the survival advantage in several studies is a comparison of observed survival in a treated cohort of patients with idiopathic PAH with their expected survival which is based on haemodynamic severity of pulmonary hypertension and calculated from a reference equation derived from patients with idiopathic PAH in the National Institutes of Health (NIH) Registry.^22,23 Since patients in the NIH Registry were managed at recognized US pulmonary hypertension centres between 1981 and 1985, other differences and advances in the quality of care—both recognised (such as more widespread current use of systemic anticoagulation) and unrecognised—may bias in favour of the survival of contemporary cohorts, independent of the treatment under study.

Despite the above limitations, most would accept that several of the new treatments do indeed increase survival of patients with idiopathic PAH. It is noteworthy that trials of new treatments for pulmonary hypertension have largely enrolled idiopathic PAH patients with the most advanced disease (WHO functional class III and IV). Thus, survival benefit with the newer treatments may not necessarily be seen in idiopathic PAH patients with earlier WHO class I and II functional status and will clearly be harder to demonstrate, given the longer natural history of disease in such patients. Furthermore, all trials have included patients on other treatments that may independently modify survival, including systemic anticoagulation.²⁴ This approach of concomitant treatment with two or more agents addressing different pathobiological pathways is the future of pulmonary hypertension treatment and several formal combination treatment trials are in progress.

FUTURE THERAPEUTIC DIRECTIONS IN PAH

Unfortunately, the limitations in the studies described will probably be propagated in future studies. It would clearly be unethical to perform a placebo controlled trial of a new treatment for pulmonary hypertension with survival as an end point. Moreover, the increasing availability of effective oral treatment will make recruitment more difficult for future placebo controlled trials. Studies will increasingly compare the effects of new agents with those of established agents, as in the study by Sitbon et al in this issue which compared survival in bosentan treated and epoprostenol treated patients.

The focus of clinical trials of new PAH treatments is also broadening to include increasing numbers of patients with other types of pulmonary hypertension such as PAH secondary to connective tissue disease or congenital heart disease. However, large groups of patients with pulmonary hypertension remain unstudied and largely untreated, such as those with inoperable chronic thromboembolic pulmonary hypertension and pulmonary hypertension due to underlying cardiac or pulmonary disease.

Finally, given the difficulty in assessing a survival benefit, what other end points should we assess in future trials of new treatments for pulmonary hypertension? Quality of life is an important end point as pulmonary hypertension is associated with severe symptoms and functional limitation, and objective measurement tools are being developed. The symptoms, exercise limitation, and poor prognosis in pulmonary hypertension relate closely to the impairment of right ventricular function. Direct assessment of right ventricular size and function with new imaging approaches (such as three-dimensional echocardiography or MRI) and haemodynamic measurements (such as during exercise) will facilitate assessment of the severity of idiopathic PAH and quantify the decline over time or response to treatment. Moreover, new biological and genetic markers related to the pathobiology of pulmonary hypertension are currently being studied and may be useful parameters for diagnosis, assessment of severity, and guiding therapeutic decisions.

Patients with idiopathic PAH have clearly benefited from tremendous advances in the science and practice of pulmonary hypertension. However, many other patients with pulmonary hypertension have yet to benefit from the new treatments. We expect that treatments for pulmonary hypertension currently available and being developed will also lead to improvements in the quality of life, right ventricular function, and improved survival for patients with many other types of pulmonary hypertension.