title: Oral sildenafil as long-term adjunct therapy to inhaled iloprost in severe pulmonary arterial hypertension.
abstract: OBJECTIVE
  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).m(2) 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.
authors.affiliation: Department of Internal Medicine, Pulmonary and Critical Care Medicine, University Hospital, Justus-Liebig-University Giessen, Klinikstrasse 36, 35392 Giessen, Germany. Ardeschir.ghofrani@innere.med.uni-giessen.de
authors.forename: Hossein A
authors.initials: HA
authors.lastname: Ghofrani
authors.forename: Frank
authors.initials: F
authors.lastname: Rose
authors.forename: Ralph T
authors.initials: RT
authors.lastname: Schermuly
authors.forename: Horst
authors.initials: H
authors.lastname: Olschewski
authors.forename: Ralph
authors.initials: R
authors.lastname: Wiedemann
authors.forename: André
authors.initials: A
authors.lastname: Kreckel
authors.forename: Norbert
authors.initials: N
authors.lastname: Weissmann
authors.forename: Stefanie
authors.initials: S
authors.lastname: Ghofrani
authors.forename: Beate
authors.initials: B
authors.lastname: Enke
authors.forename: Werner
authors.initials: W
authors.lastname: Seeger
authors.forename: Friedrich
authors.initials: F
authors.lastname: Grimminger
mesh_terms: D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D005260:Female; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000503:physiopathology; D016285:Iloprost / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use*; D011687:Purines; D000068677:Sildenafil Citrate; D013450:Sulfones; D014655:Vascular Resistance / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D010879:Piperazines; D011687:Purines; D013450:Sulfones; D014665:Vasodilator Agents; D000068677:Sildenafil Citrate; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D016285:Iloprost