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J Am Coll Cardiol, 2003; 42:158-164, doi:10.1016/S0735-1097(03)00555-2
© 2003 by the American College of Cardiology Foundation
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CLINICAL RESEARCH: PULMONARY HYPERTENSION

Oral sildenafil as long-term adjunct therapy to inhaled iloprost in severe pulmonary arterial hypertension

Hossein A. Ghofrani, MD*, Frank Rose, MD*, Ralph T. Schermuly, PhD*, Horst Olschewski, MD*, Ralph Wiedemann, MD*, André Kreckel, MD*, Norbert Weissmann, PhD*, Stefanie Ghofrani, MD*, Beate Enke, MD*, Werner Seeger, MD* and Friedrich Grimminger, MD, PhD*,*

* Department of Internal Medicine, Pulmonary and Critical Care Medicine, University Hospital, Justus-Liebig-University Giessen, Giessen, Germany.

Manuscript received February 10, 2003; accepted February 26, 2003.

* Reprint requests and correspondence: Dr. Friedrich Grimminger, Department of Internal Medicine, Klinikstrasse 36, 35392, Giessen, Germany.
Ardeschir.ghofrani{at}innere.med.uni-giessen.de

OBJECTIVES: We sought to investigate the impact of adjunct sildenafil on exercise capacity and hemodynamic parameters in patients with pulmonary arterial hypertension (PAH) who fulfilled predefined criteria of deterioration despite ongoing treatment with inhaled iloprost.

BACKGROUND: Inhaled iloprost is an effective therapy in PAH. The phosphodiesterase-5 inhibitor sildenafil exerts pulmonary vasodilation and may amplify prostanoid efficacy.

METHODS: Of 73 PAH patients receiving long-term inhaled iloprost treatment, 14 fulfilled criteria of deterioration unresponsive to conventional treatment. These patients received adjunct oral sildenafil over a period of nine to 12 months, leaving the inhalative iloprost regimen unchanged.

RESULTS: Before iloprost therapy, the baseline 6-min walking distance was 217 ± 31 m (mean ± SEM), with an improvement to 305 ± 28 m within the first three months of iloprost treatment and a subsequent decline to 256 ± 30 m after 18 ± 4 months. Adjunct therapy with sildenafil reversed the deterioration and increased the 6-min walk distance to 346 ± 26 m (p = 0.002, Wilcoxon test) at three months of combined therapy, with a sustained efficacy up to 12 months (349 ± 32 m, p = 0.002). The distribution of New York Heart Association functional classes (IV/III/II) improved from September 9, 2000, before sildenafil, to January 8, 2003, after nine to 12 months with sildenafil. All hemodynamic variables changed favorably: pulmonary vascular resistance decreased from 2,494 ± 256 before sildenafil to 1,950 ± 128 dynes·s·cm–5·m2 after three months of adjunct sildenafil (p = 0.036). Two patients died of severe pneumonia during the period of combined therapy. No further serious adverse events occurred.

CONCLUSIONS: In patients with severe PAH deteriorating despite ongoing prostanoid treatment, long-term adjunct oral sildenafil improves exercise capacity and pulmonary hemodynamics. A combination of prostanoids and sildenafil is an appealing concept for future treatment of pulmonary hypertension.

Abbreviations and Acronyms
  cGMP
  cyclic guanosine monophosphate
  NYHA
  New York Heart Association
  PAH
  pulmonary arterial hypertension
  PDE
  phosphodiesterase
  PPH
  primary pulmonary hypertension




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