title: Effect of phosphodiesterase-5 inhibition on exercise capacity and clinical status in heart failure with preserved ejection fraction: a randomized clinical trial.
abstract: OBJECTIVE
  Studies in experimental and human heart failure suggest that phosphodiesterase-5 inhibitors may enhance cardiovascular function and thus exercise capacity in heart failure with preserved ejection fraction (HFPEF).
  
  
  OBJECTIVE
  To determine the effect of the phosphodiesterase-5 inhibitor sildenafil compared with placebo on exercise capacity and clinical status in HFPEF.
  
  
  METHODS
  Multicenter, double-blind, placebo-controlled, parallel-group, randomized clinical trial of 216 stable outpatients with HF, ejection fraction ≥50%, elevated N-terminal brain-type natriuretic peptide or elevated invasively measured filling pressures, and reduced exercise capacity. Participants were randomized from October 2008 through February 2012 at 26 centers in North America. Follow-up was through August 30, 2012.
  
  
  METHODS
  Sildenafil (n = 113) or placebo (n = 103) administered orally at 20 mg, 3 times daily for 12 weeks, followed by 60 mg, 3 times daily for 12 weeks.
  
  
  METHODS
  Primary end point was change in peak oxygen consumption after 24 weeks of therapy. Secondary end points included change in 6-minute walk distance and a hierarchical composite clinical status score (range, 1-n, a higher value indicates better status; expected value with no treatment effect, 95) based on time to death, time to cardiovascular or cardiorenal hospitalization, and change in quality of life for participants without cardiovascular or cardiorenal hospitalization at 24 weeks.
  
  
  RESULTS
  Median age was 69 years, and 48% of patients were women. At baseline, median peak oxygen consumption (11.7 mL/kg/min) and 6-minute walk distance (308 m) were reduced. The median E/e' (16), left atrial volume index (44 mL/m2), and pulmonary artery systolic pressure (41 mm Hg) were consistent with chronically elevated left ventricular filling pressures. At 24 weeks, median (IQR) changes in peak oxygen consumption (mL/kg/min) in patients who received placebo (-0.20 [IQR, -0.70 to 1.00]) or sildenafil (-0.20 [IQR, -1.70 to 1.11]) were not significantly different (P = .90) in analyses in which patients with missing week-24 data were excluded, and in sensitivity analysis based on intention to treat with multiple imputation for missing values (mean between-group difference, 0.01 mL/kg/min, [95% CI, -0.60 to 0.61]). The mean clinical status rank score was not significantly different at 24 weeks between placebo (95.8) and sildenafil (94.2) (P = .85). Changes in 6-minute walk distance at 24 weeks in patients who received placebo (15.0 m [IQR, -26.0 to 45.0]) or sildenafil (5.0 m [IQR, -37.0 to 55.0]; P = .92) were also not significantly different. Adverse events occurred in 78 placebo patients (76%) and 90 sildenafil patients (80%). Serious adverse events occurred in 16 placebo patients (16%) and 25 sildenafil patients (22%).
  
  
  CONCLUSIONS
  Among patients with HFPEF, phosphodiesterase-5 inhibition with administration of sildenafil for 24 weeks, compared with placebo, did not result in significant improvement in exercise capacity or clinical status.
  
  
  BACKGROUND
  clinicaltrials.gov Identifier: NCT00763867.
authors.affiliation: Department of Medicine, Mayo Clinic, Rochester, Minnesota 55905, USA. redfield.margaret@mayo.edu
authors.forename: Margaret M
authors.initials: MM
authors.lastname: Redfield
authors.forename: Horng H
authors.initials: HH
authors.lastname: Chen
authors.forename: Barry A
authors.initials: BA
authors.lastname: Borlaug
authors.forename: Marc J
authors.initials: MJ
authors.lastname: Semigran
authors.forename: Kerry L
authors.initials: KL
authors.lastname: Lee
authors.forename: Gregory
authors.initials: G
authors.lastname: Lewis
authors.forename: Martin M
authors.initials: MM
authors.lastname: LeWinter
authors.forename: Jean L
authors.initials: JL
authors.lastname: Rouleau
authors.forename: David A
authors.initials: DA
authors.lastname: Bull
authors.forename: Douglas L
authors.initials: DL
authors.lastname: Mann
authors.forename: Anita
authors.initials: A
authors.lastname: Deswal
authors.forename: Lynne W
authors.initials: LW
authors.lastname: Stevenson
authors.forename: Michael M
authors.initials: MM
authors.lastname: Givertz
authors.forename: Elizabeth O
authors.initials: EO
authors.lastname: Ofili
authors.forename: Christopher M
authors.initials: CM
authors.lastname: O'Connor
authors.forename: G Michael
authors.initials: GM
authors.lastname: Felker
authors.forename: Steven R
authors.initials: SR
authors.lastname: Goldsmith
authors.forename: Bradley A
authors.initials: BA
authors.lastname: Bart
authors.forename: Steven E
authors.initials: SE
authors.lastname: McNulty
authors.forename: Jenny C
authors.initials: JC
authors.lastname: Ibarra
authors.forename: Grace
authors.initials: G
authors.lastname: Lin
authors.forename: Jae K
authors.initials: JK
authors.lastname: Oh
authors.forename: Manesh R
authors.initials: MR
authors.lastname: Patel
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Kim
authors.forename: Russell P
authors.initials: RP
authors.lastname: Tracy
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Velazquez
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Anstrom
authors.forename: Adrian F
authors.initials: AF
authors.lastname: Hernandez
authors.forename: Alice M
authors.initials: AM
authors.lastname: Mascette
authors.forename: Eugene
authors.initials: E
authors.lastname: Braunwald
mesh_terms: D000368:Aged; D001794:Blood Pressure; D004311:Double-Blind Method; D017079:Exercise Tolerance; D005260:Female; D006304:Health Status; D006333:Heart Failure / Q000188:drug therapy* / Q000503:physiopathology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010045:Outpatients; D010101:Oxygen Consumption; D058986:Phosphodiesterase 5 Inhibitors / Q000627:therapeutic use*; D010879:Piperazines / Q000627:therapeutic use*; D011687:Purines / Q000627:therapeutic use; D000068677:Sildenafil Citrate; D013318:Stroke Volume; D013450:Sulfones / Q000627:therapeutic use*; D016896:Treatment Outcome; D016138:Walking
chemical_list: D058986:Phosphodiesterase 5 Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D000068677:Sildenafil Citrate