Pulmonary arterial hypertension: a new era in management

Anne M Keogh, Keith D McNeil, Trevor Williams, Eli Gabbay and Leslie G Cleland
Med J Aust 2003; 178 (11): 564-567. || doi: 10.5694/j.1326-5377.2003.tb05360.x
Published online: 2 June 2003


  • Pulmonary arterial hypertension (PAH) is a heterogeneous condition with a wide range of causes.

  • The diagnosis is often delayed or missed.

  • PAH is covert in its early stages, when its detection and treatment should have the most impact.

  • Access in Australia to effective PAH therapies has lagged behind that in other affluent countries.

  • New agents for PAH, now becoming available, improve symptoms and reduce pulmonary resistance, with some demonstrating an ability to reverse remodelling of the right ventricle.

  • Best management of PAH is comprehensive and multidisciplinary. Centres of excellence are needed in geographically strategic areas.

  • Aggressive efforts must be made to diagnose PAH and to facilitate access to effective therapies.

Pulmonary arterial hypertension (PAH) is generally considered a rare and rapidly lethal condition with poor prognosis and few or no treatment options.1,2 However, PAH is a generic term that includes elevated pulmonary vascular resistance due to a wide range of causes (Box 1).3 PAH is defined as a mean pulmonary arterial pressure of >25 mmHg at rest and >30 mmHg with exercise. Primary pulmonary hypertension has an estimated incidence of 2 per million population (possibly higher), with PAH associated with other diseases showing a higher incidence.3 PAH is often not detected until the late and highly symptomatic stage. There is increasing recognition that PAH associated with other diseases (eg, connective tissue diseases such as scleroderma, airways diseases, interstitial lung disease and sleep apnoea) contributes to exercise intolerance and is a threat to survival. Perhaps in the past, with few treatment options, late diagnosis of PAH was not critical. With new drugs demonstrating efficacy in PAH, an active effort is required to diagnose its presence early, when these treatments may have greater effect.


Patients with family history of primary PAH may have a genetic predisposition to PAH, although the predictive value of the BMPR2 gene, which has been associated with the disease, is not yet well defined.6 Up to 15% of patients with scleroderma (especially limited scleroderma) ultimately develop PAH, and annual screening with DLCO measurement and echocardiography is advisable.


PAH can be treated specifically (pulmonary thromboendarterectomy) or generically. Chronic thromboembolic pulmon-ary hypertension is increasingly recognised as an important cause of secondary PAH, for which pulmonary thrombo-endarterectomy may provide definitive treatment.7 PAH secondary to sleep apnoea may respond to continuous positive airway pressure.8 PAH complicating connective tissue disease is recognised as an independent predictor of poorer prognosis in these conditions.9 Treatment here should be along similar lines to that used in primary pulmonary hypertension.

Until recently, access to effective drug treatment for severe PAH has been very limited in Australia. Heart–lung transplantation for primary pulmonary hypertension was first performed at St Vincent's Hospital, Sydney, in 1986. This was the first putative "curative" therapy for this condition, but is now appropriate only for patients with advanced disease for whom medical therapy has failed. There is, however, an increasing selection of vasodilator and remodelling agents becoming available, providing promise of effect-ive long term medical alternatives.10-14 British guidelines for the diagnosis and treatment of PAH were recently published and treatment algorithms are under development internationally.15

Medical therapies

The pathophysiological basis of PAH is an increase in vasoconstrictor substances (thromboxane, endothelin) and a reduction in vasodilatory substances (nitric oxide, prostacyclin) with smooth muscle cell proliferation and in situ thrombosis, resulting in structural reduction in pulmonary arterial lumen size and, ultimately, plexigenic arteriopathy.

Medical therapies for PAH (Box 3) consist of agents which modify one or more of these pathogenetic mechanisms:

  • anticoagulation (to prevent in situ thrombosis or thromboembolism; eg, warfarin, prostacyclin analogues);

  • vasodilators (eg, prostacyclin analogues, which increase intracellular cyclic AMP, calcium antagonists, endothelin antagonists, bosentan, and phosphodiesterase 5 inhibitors, which increase cyclic GMP); and

  • long term antifibrotic and remodelling agents (prostacyclin analogues and bosentan).

Natural history

PAH is often a lethal condition or contributes to a poor outlook, with the prognosis directly related to the severity of the associated right ventricular dysfunction.2 Once right ventricular failure ensues, the median survival for patients without treatment is short. PAH, arising secondary to other disorders, contributes to exercise intolerance and reduces survival.


Historically, Australia has been unable to offer patients with PAH adequate treatment, largely because of the high cost of therapy. The performance of pulmonary thromboendarterectomy in Australia was recently shown to achieve success rates similar to international practice. Transplantation continues to be limited by donor availability.

Now, with the availability of new and effective oral agents, we can abandon the therapeutic nihilism of past decades, and offer patients effective therapies. Some of these agents allow reverse remodelling of the right ventricle within very short periods. Reverse remodelling of the pulmonary artery and the potential to reverse the entire disease process are realistic targets.

This new era of effective agents gives clinicians a sound reason to diagnose PAH, to tease out all contributing elements and to detect cases early. Trials to date have been performed in moderately to severely affected patients, but are now in progress in less ill patients. As with most cardiovascular diseases, earlier detection and intervention is likely to be rewarded with better outcomes.

3: Medical therapies for pulmonary arterial hypertension

Drug class: trial results



Level of evidence*

Administration and dosage

Limitations in Australia

Anticoagulants: Associated with improved survival in primary pulmonary hypertension in responders and nonresponders to calcium-channel blockers




To keep international normalised ratio (INR) in the range 2.5–4.0

Calcium-channel blockers: Improved survival and reduced symptoms in 10% of primary pulmonary hypertension patients

Diltiazem, amlodipine, nifedipine



Oral; high dose, eg, diltiazem 900 mg daily

Restricted to patients with preserved right ventricular function

Prostacyclin analogues: Increased survival, reduced symptoms, improved functional class, haemodynamics and walk distance, reduced pulmonary vascular resistance




Continuous intravenous infusion (because of very short half-life); 22–45 ng/kg per minute

Not reimbursed




Inhaled; 20 μg 5–12 times per day

Not reimbursed




Oral; ≥ 40 μg four times per day

Not available




Subcutaneous infusion; >10 ng/kg per minute

Injection site pain, not reimbursed

Endothelin receptor antagonists: Improved walk distance and haemodynamics, delayed clinical worsening, improved echo parameters




Oral; initial, 62.5 mg twice daily; target, 125 mg twice daily

Currently available in an open label study

Elevated serum transaminase levels in 3%–5% of patients

Phosphodiesterase 5 inhibitors: Improved functional class and walk distance, reduced pulmonary arterial pressure


20, 21


Oral; uncertain dose, 25–100 mg three times per day

Currently in trial, possible retinal toxicity

Medical foods: Acute reduction in pulmonary vascular resistance




Oral (powder, capsules); 6 g per day

Gastrointestinal side effects

* Level of evidence according to National Health and Medical Research Council grades.23

  • Anne M Keogh1
  • Keith D McNeil2
  • Trevor Williams3
  • Eli Gabbay4
  • Leslie G Cleland5

  • St Vincent's Hospital, Darlinghurst, NSW.
  • 1 Prince Charles Hospital, Chermside, QLD.
  • 2 Alfred Hospital, Prahran, VIC.
  • 3 Royal Perth Hospital, Perth, WA.
  • 4 Royal Adelaide Hospital, Adelaide, SA.


Competing interests:

All the authors are members of the Australian Advisory Board, Actelion Pharmaceut-icals, Australia (manufacturer of bosentan).

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