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Published ahead of print on August 31, 2006, doi:10.1164/rccm.200603-358OC

Am. J. Respir. Crit. Care Med., Volume 174, Number 11, December 2006, 1257-1263

A more recent version of this article appeared on December 1, 2006
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Submitted on March 10, 2006
Accepted on August 31, 2006

Randomized Study of Adding Inhaled Iloprost to Existing Bosentan in Pulmonary Arterial Hypertension

Vallerie V McLaughlin1*, Ronald J Oudiz2, Adaani Frost3, Victor F Tapson4, Srinivas Murali5, Richard N Channick6, David B Badesch7, Robyn J Barst8, Henry H Hsu9, and Lewis J Rubin6

1 Internal Medicine, The University of Michigan Health System, Ann Arbor, MI, USA, 2 Internal Medicine, LA Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA, 3 Internal Medicine, Baylor University, Houston, TX, USA, 4 Internal Medicine, Duke University Medical Center, Durham, NC, USA, 5 Internal Medicine, University of Pittsburgh, Pittsburgh, Pa, USA, 6 Internal Medicine, University of California at San Diego, San Diego, CA, USA, 7 Internal Medicine, University of Colorado Health Sciences Center, Denver, CO, USA, 8 Pediatrics, Columbia University College of Physicians & Surgeons, New York City, NY, USA, 9 CoTherix, Inc, South San Francisco, CA, USA

* To whom correspondence should be addressed. E-mail: vmclaugh{at}umich.edu.

Rationale: Small, open-label studies suggest that combinations of existing therapies may be effective for pulmonary arterial hypertension (PAH). Objective: To evaluate the safety and efficacy of adding inhaled iloprost, a prostacyclin analogue, to the endothelin receptor antagonist bosentan in PAH patients. Methods: In a randomized, multicenter, double-blind trial, inhaled iloprost (5µg) or placebo, was added to stable monotherapy with bosentan for 12 weeks. Efficacy endpoints included change from baseline in 6-minute walk distance (6-MWD), modified New York Heart Association (NYHA) functional class, and hemodynamic parameters, and time to clinical worsening. Measurements and Main Results: A total of 67 patients with PAH (55% idiopathic PAH, 45% associated PAH, 94% NYHA class III, and mean baseline 6-MWD 335 m) were randomized. At Week 12, patients receiving iloprost had a mean increase in 6-MWD of 30m (p = 0.001); placebo patients had a mean 6-MWD increase of 4 m (p = 0.69), with a placebo-adjusted difference of +26 m (p = 0.051). NYHA status improved by one class in 34% iloprost versus 6% placebo patients (p = 0.002). Iloprost delayed the time to clinical worsening (p = 0.022). Improvements were noted in post-inhalation placebo-adjusted change in mean pulmonary artery pressure (-8 mmHg; p <0.001) and pulmonary vascular resistance (-254 dynesxsecxcm-5; p <0.001). Combination therapy was well-tolerated.Conclusions: Within the limitations of a relatively small sample size, results of this study demonstrate that the addition of inhaled iloprost in PAH patients with reduced exercise capacity on bosentan monotherapy is safe and efficacious. http://www.clinicaltrials.gov/ct/show/NCT00086463?order=3
Key words: iloprost, bosentan, pulmonary arterial hypertension




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