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Addition of Sildenafil to Long-Term Intravenous Epoprostenol Therapy in Patients with Pulmonary Arterial Hypertension: A Randomized Trial

Gérald Simonneau, MD; Lewis J. Rubin, MD; Nazzareno Galiè, MD; Robyn J. Barst, MD; Thomas R. Fleming, PhD; Adaani E. Frost, MD; Peter J. Engel, MD; Mordechai R. Kramer, MD; Gary Burgess, MD; Lorraine Collings, MSc; Nandini Cossons, MD, PhD; Olivier Sitbon, MD; David B. Badesch, MD, PACES Study Group
[+] Article and Author Information

For members of the PACES (Pulmonary Arterial Hypertension Combination Study of Epoprostenol and Sildenafil) Study Group, see the Appendix.

ClinicalTrials.gov registration number: NCT00159861.


From Hôpital Antoine Béclère, Université Paris-Sud, Clamart, France; University of California at San Diego, La Jolla, California; Institute of Cardiology, University of Bologna, Bologna, Italy; Columbia University, New York, New York; University of Washington, Seattle, Washington; Baylor College of Medicine, Houston, Texas; Ohio Heart and Vascular Center/Lindner Clinical Trial Center, Cincinnati, Ohio; Rabin Medical Center, Petah Tiqva, Israel; Pfizer Global Research and Development, Pfizer, Sandwich, United Kingdom; and University of Colorado Health Sciences Center, Denver, Colorado.


Acknowledgment: The authors acknowledge the contributions of the following investigators: Marion Delcroix (Belgium); John T. Granton, David Langleben, Sanjay Mehta, Evangelos Michelakis, David G. Ostrow, and Sidney M. Viner (Canada); Michael Aschermann (Czech Republic); Jorn Carlsen (Denmark); Ari Chaouat and Christophe Pison (France); Alessandra Manes and L. Negro (Italy); Anko Boonstra and Repke J. Snijder (Netherlands); Joan A. Barbera and Miguel A. Gomez-Sanchez (Spain); Andrew J. Peacock and Joanna Pepke-Zaba (United Kingdom); and Murali M. Chakinala, Bennett P. Deboisblanc, Greg C. Elliot, Robert P. Frantz, Reda E. Girgis, Mardi Gomberg-Maitland, Nicholas S. Hill, Dean J. Kereiakes, James R. Klinger, James P. Maloney, Michael A. Mathier, Omar A. Minai, Srinivas C. Murali, Ronald J. Oudiz, Marc R. Pritzker, Ivan M. Robbins, David J. Ross, Melvyn Rubenfire, Shelley M. Shapiro, F. Soto, Steven W. Stites, Victor F. Tapson, Austin B. Thompson III, Aaron Waxman, and Dianne L. Zwicke (United States). The authors also acknowledge the editorial assistance provided by Mukund Nori, PhD, MBA, in the preparation of this manuscript.

Grant Support: By Pfizer, Sandwich, United Kingdom.

Potential Financial Conflicts of Interest:Employment: G. Burgess (Pfizer), L. Collings (Pfizer), N. Cossons (Pfizer). Consultancies: G. Simonneau (Pfizer), L.J. Rubin (Pfizer), N. Galiè (Pfizer), R.J. Barst (Pfizer), T.R. Fleming (Pfizer), A.E. Frost (Pfizer, Actelion, Encysive, Gilead), P.J. Engel (Actelion, Encysive, Myogen, Gilead), O. Sitbon (Pfizer, Actelion, GlaxoSmithKline), D.B. Badesch (Pfizer). Honoraria: G. Simonneau (Pfizer), L.J. Rubin (Pfizer), N. Galiè (Pfizer), R.J. Barst (Pfizer), T.R. Fleming (Pfizer), A.E. Frost (Gilead, Encysive, Pfizer, Actelion), O. Sitbon (GlaxoSmithKline, Actelion, Pfizer), D.B. Badesch (Pfizer). Stock ownership or options (other than mutual funds): G. Burgess (Pfizer). Grants received: G. Simonneau (Pfizer), L.J. Rubin (Pfizer), N. Galiè (Pfizer), R.J. Barst (Pfizer), A.E. Frost (Gilead, Encysive, Pfizer, Actelion), O. Sitbon (Pfizer, Actelion, United Therapeutics, Encysive, Schering), D.B. Badesch (Pfizer).

Reproducible Research Statement:Study protocol, statistical code, and data set: Not available.

Requests for Single Reprints: Gérald Simonneau, MD, Service de Pneumologie, Hôpital Antoine Béclère, 157 Rue de la Porte de Trivaux, Clamart, 92140 France; e-mail, gerald.simonneau@abc.ap-hop-paris.fr.

Current Author Addresses: Drs. Simonneau and Sitbon: Service de Pneumologie, Hôpital Antoine Béclère, 157 Rue de la Porte de Trivaux, Clamart, 92140 France.

Dr. Rubin: Division of Pulmonary and Critical Care Medicine, University of California at San Diego, 9300 Campus Point Drive, 7372, La Jolla, CA 92037.

Dr. Galiè: Institute of Cardiology, University of Bologna, Via Massarenti, 9, Bologna 40138 Italy.

Dr. Barst: Department of Pediatric Cardiology, Columbia Presbyterian Medical Center, 3959 Broadway, BH262N, New York, NY 10032-1551.

Dr. Fleming: Department of Biostatistics, F-600 Health Sciences, Box 357232, University of Washington, Seattle, WA 98195-7232.

Dr. Frost: Division of Pulmonary and Critical Care, Baylor College of Medicine, 1239 Smith Tower, 6550 Fannin Street, Houston, TX 77030.

Dr. Engel: Cincinnati Pulmonary Hypertension Clinic, Ohio Heart and Vascular Center, 2123 Auburn Avenue, Cincinnati, OH 45219.

Dr. Kramer: Pulmonary Institute, Rabin Medical Center, Beilinson Campus, Petah Tiqva 49100, Israel.

Drs. Burgess and Cossons and Ms. Collings: PGRD, Pfizer, Ramsgate Road, Sandwich, Kent CT13 9NJ, United Kingdom.

Dr. Badesch: Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Sciences Center, 4200 East Ninth Avenue, Denver, CO 80262.

Author Contributions: Conception and design: G. Simonneau, L.J. Rubin, N. Galiè, R.J. Barst, G. Burgess, L. Collings, D.B. Badesch.

Analysis and interpretation of the data: L.J. Rubin, N. Galiè, R.J. Barst, T.R. Fleming, A.E. Frost, P.J. Engel, M.R. Kramer, G. Burgess, L. Collings, N. Cossons, O. Sitbon, D.B. Badesch.

Drafting of the article: G. Simonneau, L.J. Rubin, N. Galiè, R.J. Barst, T.R. Fleming, A.E. Frost, P.J. Engel, M.R. Kramer, G. Burgess, L. Collings, N. Cossons, O. Sitbon, D.B. Badesch.

Critical revision of the article for important intellectual content: G. Simonneau, L.J. Rubin, N. Galiè, R.J. Barst, T.R. Fleming, A.E. Frost, P.J. Engel, M.R. Kramer, G. Burgess, L. Collings, N. Cossons, O. Sitbon, D.B. Badesch.

Final approval of the article: G. Simonneau, L.J. Rubin, N. Galiè, R.J. Barst, T.R. Fleming, A.E. Frost, P.J. Engel, M.R. Kramer, G. Burgess, L. Collings, N. Cossons, O. Sitbon, D.B. Badesch.

Provision of study materials or patients: G. Simonneau, L.J. Rubin, N. Galiè, R.J. Barst, A.E. Frost, P.J. Engel, M.R. Kramer, G. Burgess, O. Sitbon, D.B. Badesch.

Statistical expertise: T.R. Fleming, L. Collings.

Obtaining of funding: G. Burgess.

Administrative, technical, or logistic support: G. Burgess.

Collection and assembly of data: L.J. Rubin, N. Galiè, R.J. Barst, A.E. Frost, P.J. Engel, M.R. Kramer, G. Burgess, L. Collings, N. Cossons, O. Sitbon, D.B. Badesch.


Ann Intern Med. 2008;149(8):521-530. doi:10.7326/0003-4819-149-8-200810210-00004
Text Size: A A A

Background: Oral sildenafil and intravenous epoprostenol have independently been shown to be effective in patients with pulmonary arterial hypertension.

Objective: To investigate the effect of adding oral sildenafil to long-term intravenous epoprostenol in patients with pulmonary arterial hypertension.

Design: A 16-week, double-blind, placebo-controlled, parallel-group study.

Setting: Multinational study at 41 centers in 11 countries from 3 July 2003 to 27 January 2006.

Patients: 267 patients with pulmonary arterial hypertension (idiopathic, associated anorexigen use or connective tissue disease, or corrected congenital heart disease) who were receiving long-term intravenous epoprostenol therapy.

Intervention: Patients were randomly assigned to receive placebo or sildenafil, 20 mg three times daily, titrated to 40 mg and 80 mg three times daily, as tolerated, at 4-week intervals. Of 265 patients who received treatment, 256 (97%) patients (123 in the placebo group and 133 in the sildenafil group) completed the study.

Measurements: Change from baseline in exercise capacity measured by 6-minute walk distance (primary end point) and hemodynamic measurements, time to clinical worsening, and Borg dyspnea score (secondary end points).

Results: A placebo-adjusted increase of 28.8 meters (95% CI, 13.9 to 43.8 meters) in the 6-minute walk distance occurred in patients in the sildenafil group; these improvements were most prominent among patients with baseline distances of 325 meters or more. Relative to epoprostenol monotherapy, addition of sildenafil resulted in a greater change in mean pulmonary arterial pressure by −3.8 mm Hg (CI, −5.6 to −2.1 mm Hg); cardiac output by 0.9 L/min (CI, 0.5 to 1.2 L/min); and longer time to clinical worsening, with a smaller proportion of patients experiencing a worsening event in the sildenafil group (0.062) than in the placebo group (0.195) by week 16 (P = 0.002). Health-related quality of life also improved in patients who received combined therapy compared with those who received epoprostenol monotherapy. There was no effect on the Borg dyspnea score. Of the side effects generally associated with sildenafil treatment, the most commonly reported in the placebo and sildenafil groups, respectively, were headache (34% and 57%; difference, 23 percentage points [CI, 12 to 35 percentage points]), dyspepsia (2% and 16%; difference, 13 percentage points [CI, 7 to 20 percentage points]), pain in extremity (18% and 25%; difference, 8 percentage points [CI, −2 to 18 percentage points]), and nausea (18% and 25%; difference, 8 percentage points [CI, −2 to 18 percentage points]).

Limitations: The study excluded patients with pulmonary arterial hypertension associated with other causes. There was an imbalance in missing data between groups, with 8 placebo recipients having no postbaseline walk assessment compared with 1 sildenafil recipient. These patients were excluded from the analysis.

Conclusion: In some patients with pulmonary arterial hypertension, the addition of sildenafil to long-term intravenous epoprostenol therapy improves exercise capacity, hemodynamic measurements, time to clinical worsening, and quality of life, but not Borg dyspnea score. Increased rates of headache and dyspepsia occurred with the addition of sildenafil.

Figures

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Figure 1.
Study flow diagram.

6MWD = 6-minute walk distance.

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Figure 2.
Changes from baseline in 6-minute walk distance.

A. Change from baseline in 6-minute walk distance, by treatment group (model-adjusted estimates). B. Relative change from baseline in 6-minute walk distance (model-adjusted estimates). C. Change from baseline in 6-minute walk distance for patients with distances <325 meters at baseline, by treatment group (model-adjusted estimates). D. Change from baseline in 6-minute walk distance for patients with distances ≥325 meters at baseline, by treatment group (model-adjusted estimates).

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Appendix Figure 1.
Mean change from baseline in 6-minute walk distance, stratified by baseline walk (model-adjusted estimates).
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Appendix Figure 2.
Change from baseline in 6-minute walk distance (6MWD), by baseline walk and treatment group.
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Appendix Figure 3.
Change from baseline in 6-minute walk distance, by baseline epoprostenol dose and treatment group.
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Figure 3.
Kaplan–Meier plot of time to clinical worsening.

* The number censored between days 0 and 27.

† The number censored between days 28 and 55.

‡ The number censored between days 56 and 83.

§ The number censored between days 84 and 111.

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Summary for Patients

A Combination Treatment for Pulmonary Hypertension

The summary below is from the full report titled “Addition of Sildenafil to Long-Term Intravenous Epoprostenol Therapy in Patients with Pulmonary Arterial Hypertension. A Randomized Trial.” It is in the 21 October 2008 issue of Annals of Internal Medicine (volume 149, pages 521-530). The authors are G. Simonneau, L.J. Rubin, N. Galiè, R.J. Barst, T.R. Fleming, A.E. Frost, P.J. Engel, M.R. Kramer, G. Burgess, L. Collings, N. Cossons, O. Sitbon, and D.B. Badesch, for the PACES Study Group.

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