Treprostinil in Pulmonary Arterial Hypertension

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Citation
European Cardiovascular Disease 2006 - Issue 2;2006:2(2):31-32
DOI
http://dx.doi.org/10.15420/ecr.2006.0.2.31
Prostacyclins in PAH - Pathobiological Rationale

Endothelial dysfunction is the cornerstone event in the pathobiology of pulmonary arterial hypertension (PAH), a rapidly evolving clinical syndrome of dyspnoea and fatigue eventually leading to right ventricular failure and death.1 In the pulmonary vascular bed, endothelial cells are the major source of mediators modulating pulmonary vascular tone, platelet aggregation and muscular cell growth. These mediators include endothelin-1 (ET-1), nitric oxide (NO) and prostacyclin (PGI2). PGI2 induces relaxation of vascular smooth muscle, inhibits the growth of smooth-muscle cells and has cytoprotective effects. In addition, it is a powerful inhibitor of platelet aggregation. In lungs from patients with PAH, the PGI2 pathway is dysregulated. Moreover, reduced PGI2 release is associated with symptoms severity and haemodynamic deterioration in idiopathic PAH.2 These findings provide a convincing rationale for the use of prostacyclins in the therapy of PAH.

Clinical Benefit of Subcutaneous Treprostinil

Treprostinil is a tricyclic benzindene analogue of prostacyclin with similar antiplatelet and vasodilatory actions.3 Treprostinil is chemically stable in either sterile water or 0.9% sodium chloride and 5% dextrose solutions at room temperature. These characteristics and relatively long half-life, in the range of two to four hours, make this drug suitable for subcutaneous (SC) infusion.

The effects of SC treprostinil were studied in the largest trial to date of PAH.3 In this 12-week study, 470 patients with PAH were randomly assigned to SC treprostinil or placebo. Compared with placebo, treprostinil improved exercise tolerance (assessed by six-minute walking distance (SMWD)), Borg Dyspnoea Scale, clinical state and haemodynamics.3 The between-treatment group difference in median SMWD was 16m (p 0.006). Improvement in exercise capacity was greater in the sicker patients and was dose-related but independent of disease aetiology. An analysis by quartile revealed that an improvement of +37m was present in patients receiving doses >16ng/kg/min, similar to previously reported results in drug therapy for PAH.3

Long-term observations on SC treprostinil therapy confirm these improvements. In a retrospective multicentre study,4 99 patients with PAH and 23 with distal chronic thromboembolic pulmonary hypertension were followed for a mean of 26 months. After three years of treprostinil therapy, SMWD improved (+100m) and New York Heart Association (NYHA) functional class improved (3.2 to 2.1 on average). Survival was 88.6% and 70.6% at one and three years, respectively. In addition, safe transitioning from intravenous (IV) epoprostenol to SC treprostinil was proved feasible within 48 hours in patients presenting severe complications of IV therapy.3

Although user-friendly, pain at infusion site has been a major drawback of SC tresprostinil, hampering the dose titration strategy and leading to an 8% discontinuation rate. Long-term practice reveals that a more aggressive titration regimen is desirable feasible and does not lead to premature discontinuation. In a long-term analysis, pain at infusion site accounted for only 4% of treatment interruption.4 Moreover, most patients were able to reach an effective dose >15ng/kg/min within one month. Pain appeared to decrease over time and when patients were keeping the same site for an average of seven days. Topical ointment, cooling or cold, also appeared to be helpful.

Experience with IV Treprostinil

Treprostinil can be administered intravenously, which may provide an alternative to epoprostenol for patients who benefit from SC treprostinil but have to withhold therapy due to site pain.

A 12-week multicentre, prospective, open-label study was performed to assess the safety and efficacy of IV treprostinil after transition from IV epoprostenol.5 Stable NYHA II-III PAH patients (n=31) receiving epoprostenol therapy were switched in 24-48 hours to IV treprostinil. The safety profile was consistent with previously reported data on SC treprostinil and prostanoid therapy. In addition, the ability to safely transition back to epoprostenol in case of failure was demonstrated. The clinical efficacy of epoprostenol was maintained in all patients, as assessed by walking distance, Borg scale and NYHA class. In contrast, changes in pulmonary haemodynamics were observed with a significant increase in mean pulmonary pressure and a decrease in cardiac output, resulting in increased pulmonary vascular resistance. These effects were observed at a dose of treprostinil required to maintain efficacy that was twice as high as the dose of epoprostenol. Interestingly, a great inter-individual variability of effective dosing was in keeping with previous observations on prostacyclin therapy. Finally, the safety and efficacy of IV treprostinil in patient treated de novo has recently been demonstrated in a small population.6

Summary

Treprostinil is effective and safe in the treatment of patients suffering from PAH. Although pain at infusion site complicates management, this drawback can be overcome and patients may be succesfully treated for years. SC treprostinil has been approved for treating PAH by many regulatory agencies worldwide and is part of the European Society of Cardiology therapeutic algorithm for patients in NYHA III-IV. IV treprostinil recently received US Food and Drug Administration approval.

Preliminary reports suggest that the drug can be efficacious by inhalation and an oral analogue is currently under development.

References
  1. Galie N, Torbicki A, Barst R, et al., Guidelines on diagnosis and treatment of pulmonary arterial hypertension. The Task Force on Diagnosis and Treatment of Pulmonary Arterial Hypertension of the European Society of Cardiology , Eur Heart J (2004);25: pp. 2243-2278.
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  2. Faber H, Loscalzo, Mechanism of disease: pulmonary arterial hypertension , New Engl J Med (2004);351: pp. 1655-1665.
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  3. Vachi JL, Naeije R, Treprostinil for pulmonary hypertension , Expert Rev Cardiovasc Ther (2004);2: pp. 89-97.
  4. Lang I, Gomez-Sanchez M, Kneussl M, et al., Efficacy of long-term subcutaneous treprostinil sodium therapy in pulmonary hypertension , Chest (2006);129: pp. 1636-1643.
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  5. Gomberg-Maitland M, Tapson VF, Benza RL, et al., Transition from intravenous epoprostenol to intravenous treprostinil in pulmonary hypertension , Am J Respir Crit Care Med (2005);Dec 15;172(12): pp.1586-1589.
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  6. Tapson V, Gomberg-Maitland M, McLaughlin V, et al., Safety and efficacy of IV treprostinil for pulmonary arterial hypertension: a prospective, multicenter, open-label, 12-week trial , Chest (2006);129: pp. 683-688.
    Crossref | PubMed