This Article Full Text Full Text (PDF) All Versions of this Article: 200603-358OCv1 174/11/1257    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by McLaughlin, V. V. Articles by Rubin, L. J. Search for Related Content PubMed PubMed Citation Articles by McLaughlin, V. V. Articles by Rubin, L. J.

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

The University of Michigan Health System, Ann Arbor, Michigan; LA Biomedical Research Institute at Harbor–UCLA Medical Center, Torrance; University of California at San Diego, San Diego; CoTherix, Inc., South San Francisco, California; Baylor University, Houston, Texas; Duke University Medical Center, Durham, North Carolina; University of Pittsburgh, Pittsburgh, Pennsylvania; University of Colorado Health Sciences Center, Denver, Colorado; and Columbia University College of Physicians and Surgeons, New York, New York

Correspondence and requests for reprints should be addressed to Vallerie V. McLaughlin, M.D., Associate Professor of Medicine, Director, Pulmonary Hypertension Program, University of Michigan, 1500 East Medical Center Drive, Women's Hospital–Room L3119, Ann Arbor, MI 48109-0273. 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 analog, to the endothelin receptor antagonist bosentan in patients with PAH.

Methods: In a randomized, multicenter, double-blind trial, inhaled iloprost (5 µg) or placebo was added to stable monotherapy with bosentan for 12 wk. Efficacy endpoints included change from baseline in 6-min-walk distance (6-MWD), modified New York Heart Association (NYHA) functional class, 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 of 335 m) were randomized. At Week 12, patients receiving iloprost had a mean increase in 6-MWD of 30 m (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% of iloprost versus 6% of placebo patients (p = 0.002). Iloprost delayed the time to clinical worsening (p = 0.0219). Improvements were noted in postinhalation placebo-adjusted change in mean pulmonary artery pressure (–8 mm Hg; p < 0.001) and pulmonary vascular resistance (–254 dyn · s · cm^–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 patients with PAH with reduced exercise capacity on bosentan monotherapy is safe and efficacious.

Key Words: bosentan • iloprost • pulmonary arterial hypertension

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Very few controlled data regarding combination therapy for pulmonary arterial hypertension are available. What This Study Adds to the Field This study demonstrates the safety and efficacy of the addition of iloprost in patients with pulmonary arterial hypertension who remain symptomatic while on bosentan.

 

This article has been cited by other articles:

				R. Spence, A. Mandagere, C. Dufton, and J. Venitz Pharmacokinetics and Safety of Ambrisentan in Combination With Sildenafil in Healthy Volunteers J. Clin. Pharmacol., December 1, 2008; 48(12): 1451 - 1459. [Abstract] [Full Text] [PDF]

				H. H. Leuchte, C. Baezner, R. A. Baumgartner, D. Bevec, G. Bacher, C. Neurohr, and J. Behr Inhalation of vasoactive intestinal peptide in pulmonary hypertension Eur. Respir. J., November 1, 2008; 32(5): 1289 - 1294. [Abstract] [Full Text] [PDF]

				G. Simonneau, L. J. Rubin, N. Galie, R. J. Barst, T. R. Fleming, A. E. Frost, P. J. Engel, M. R. Kramer, G. Burgess, L. Collings, et al. Addition of Sildenafil to Long-Term Intravenous Epoprostenol Therapy in Patients with Pulmonary Arterial Hypertension: A Randomized Trial Ann Intern Med, October 21, 2008; 149(8): 521 - 530. [Abstract] [Full Text] [PDF]

				D. B. Taichman Therapy for Pulmonary Arterial Hypertension: The More, the Merrier? Ann Intern Med, October 21, 2008; 149(8): 583 - 585. [Full Text] [PDF]

				R. L. Benza, R. J. Barst, N. Galie, A. Frost, R. E. Girgis, K. B. Highland, C. Strange, C. M. Black, D. B. Badesch, L. Rubin, et al. Sitaxsentan for the Treatment of Pulmonary Arterial Hypertension: A 1-Year, Prospective, Open-Label Observation of Outcome and Survival Chest, October 1, 2008; 134(4): 775 - 782. [Abstract] [Full Text] [PDF]

				K. Kuwano, A. Hashino, K. Noda, K. Kosugi, and K. Kuwabara A Long-Acting and Highly Selective Prostacyclin Receptor Agonist Prodrug, 2-{4-[(5,6-Diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}-N-(methylsulfonyl)acetamide (NS-304), Ameliorates Rat Pulmonary Hypertension with Unique Relaxant Responses of Its Active Form, {4-[(5,6-Diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}acetic Acid (MRE-269), on Rat Pulmonary Artery J. Pharmacol. Exp. Ther., September 1, 2008; 326(3): 691 - 699. [Abstract] [Full Text] [PDF]

				K. Boutet, D. Montani, X. Jais, A. Yaici, O. Sitbon, G. Simonneau, and M. Humbert Review: Therapeutic advances in pulmonary arterial hypertension Therapeutic Advances in Respiratory Disease, August 1, 2008; 2(4): 249 - 265. [Abstract] [PDF]

				N. S. Hill, I. R. Preston, and K. E. Roberts Patients with Pulmonary Arterial Hypertension in Clinical Trials: Who Are They? Proceedings of the ATS, July 15, 2008; 5(5): 603 - 609. [Abstract] [Full Text] [PDF]

				R. L. Benza, B. K. Rayburn, J. A. Tallaj, S. V. Pamboukian, and R. C. Bourge Treprostinil-Based Therapy in the Treatment of Moderate-to-Severe Pulmonary Arterial Hypertension: Long-term Efficacy and Combination With Bosentan Chest, July 1, 2008; 134(1): 139 - 145. [Abstract] [Full Text] [PDF]

				N. Galie, H. Olschewski, R. J. Oudiz, F. Torres, A. Frost, H. A. Ghofrani, D. B. Badesch, M. D. McGoon, V. V. McLaughlin, E. B. Roecker, et al. Ambrisentan for the Treatment of Pulmonary Arterial Hypertension: Results of the Ambrisentan in Pulmonary Arterial Hypertension, Randomized, Double-Blind, Placebo-Controlled, Multicenter, Efficacy (ARIES) Study 1 and 2 Circulation, June 10, 2008; 117(23): 3010 - 3019. [Abstract] [Full Text] [PDF]

				B. MacKnight, E. A. Martinez, and B. A. Simon Anesthetic Management of Patients With Pulmonary Hypertension Seminars in Cardiothoracic and Vascular Anesthesia, June 1, 2008; 12(2): 91 - 96. [Abstract] [PDF]

				K. M. Chin and L. J. Rubin Pulmonary arterial hypertension. J. Am. Coll. Cardiol., April 22, 2008; 51(16): 1527 - 1538. [Abstract] [Full Text] [PDF]

				M. Gomberg-Maitland and H. Olschewski Prostacyclin therapies for the treatment of pulmonary arterial hypertension Eur. Respir. J., April 1, 2008; 31(4): 891 - 901. [Abstract] [Full Text] [PDF]

				M. Humbert Update in Pulmonary Arterial Hypertension 2007 Am. J. Respir. Crit. Care Med., March 15, 2008; 177(6): 574 - 579. [Full Text] [PDF]

				M. A. Mathier, J. Zhang, and R. C. Ramanathan Dramatic Functional Improvement Following Bariatric Surgery in a Patient With Pulmonary Arterial Hypertension and Morbid Obesity Chest, March 1, 2008; 133(3): 789 - 792. [Abstract] [Full Text] [PDF]

				National Pulmonary Hypertension Centres of the UK Consensus statement on the management of pulmonary hypertension in clinical practice in the UK and Ireland Heart, March 1, 2008; 94(Suppl_1): i1 - i41. [Full Text] [PDF]

				National Pulmonary Hypertension Centres of the UK Consensus statement on the management of pulmonary hypertension in clinical practice in the UK and Ireland Thorax, March 1, 2008; 63(Suppl_2): ii1 - ii41. [Full Text] [PDF]

				J. Dupuis and M. M. Hoeper Endothelin receptor antagonists in pulmonary arterial hypertension Eur. Respir. J., February 1, 2008; 31(2): 407 - 415. [Abstract] [Full Text] [PDF]

				R. Souza, M. Humbert, B. Sztrymf, X. Jais, A. Yaici, J. Le Pavec, F. Parent, P. Herve, F. Soubrier, O. Sitbon, et al. Pulmonary arterial hypertension associated with fenfluramine exposure: report of 109 cases Eur. Respir. J., February 1, 2008; 31(2): 343 - 348. [Abstract] [Full Text] [PDF]

				D. D. Ivy, A. K. Doran, K. J. Smith, G. B. Mallory Jr, M. Beghetti, R. J. Barst, D. Brady, Y. Law, D. Parker, L. Claussen, et al. Short- and Long-Term Effects of Inhaled Iloprost Therapy in Children With Pulmonary Arterial Hypertension J. Am. Coll. Cardiol., January 15, 2008; 51(2): 161 - 169. [Abstract] [Full Text] [PDF]

				M. M. Hoeper, H. J. Seyfarth, G. Hoeffken, H. Wirtz, E. Spiekerkoetter, M. W. Pletz, T. Welte, and M. Halank Experience with inhaled iloprost and bosentan in portopulmonary hypertension Eur. Respir. J., December 1, 2007; 30(6): 1096 - 1102. [Abstract] [Full Text] [PDF]

				G. V. Ramani, L. Cadaret, J. Zhang, R. Ramanathan, and M. A. Mathier DRAMATIC FUNCTIONAL IMPROVEMENT FOLLOWING BARIATRIC SURGERY IN A MORBIDLY OBESE PATIENT WITH PULMONARY ARTERIAL HYPERTENSION Chest Meeting Abstracts, October 1, 2007; 132(4): 730 - 730. [Abstract] [PDF]

				G. Tino Clinical Year in Review I: Lung Cancer, Interventional Pulmonology, Pediatric Pulmonary Disease, and Pulmonary Vascular Disease Proceedings of the ATS, September 15, 2007; 4(6): 478 - 481. [Full Text] [PDF]

				D. L. Helman Jr, A. W. Brown, J. L. Jackson, and A. F. Shorr Analyzing the Short-term Effect of Placebo Therapy in Pulmonary Arterial Hypertension: Potential Implications for the Design of Future Clinical Trials Chest, September 1, 2007; 132(3): 764 - 772. [Abstract] [Full Text] [PDF]

				D. B. Badesch, S. H. Abman, G. Simonneau, L. J. Rubin, and V. V. McLaughlin Medical Therapy for Pulmonary Arterial Hypertension: Updated ACCP Evidence-Based Clinical Practice Guidelines Chest, June 1, 2007; 131(6): 1917 - 1928. [Abstract] [Full Text] [PDF]

				M. M. Hoeper Observational trials in pulmonary arterial hypertension: low scientific evidence but high clinical value Eur. Respir. J., March 1, 2007; 29(3): 432 - 434. [Full Text] [PDF]