March 26, 2013JAMA1,151 citations
Effect of Phosphodiesterase-5 Inhibition on Exercise Capacity and Clinical Status in Heart Failure With Preserved Ejection Fraction
Key Points
- To determine whether phosphodiesterase-5 inhibition using sildenafil improves exercise capacity and clinical status compared with placebo in patients with heart failure with preserved ejection fraction (HFPEF).
- Multicenter, double-blind, placebo-controlled randomized clinical trial involving 216 stable outpatients across 26 North American centers (NCT00763867).
Structured PICO
Does sildenafil improve exercise capacity and clinical status in stable outpatients with heart failure with preserved ejection fraction?
P
Population
216 stable outpatients with heart failure with preserved ejection fraction (LVEF ≥50%), elevated N-terminal brain-type natriuretic peptide or elevated invasively measured filling pressures, and reduced exercise capacity. Median age 69 years, 48% women. Conducted at 26 centers in North America.
I
Intervention
Sildenafil administered orally at 20 mg, 3 times daily for 12 weeks, followed by 60 mg, 3 times daily for 12 weeks (total 24 weeks of therapy).
C
Comparator
Matching placebo administered orally for 24 weeks.
O
Outcome
Change in peak oxygen consumption after 24 weeks of therapy.surrogate
In patients with heart failure with preserved ejection fraction, treatment with sildenafil for 24 weeks does not significantly improve exercise capacity or clinical status compared with placebo.
Abstract
IMPORTANCE: 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. DESIGN: 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. INTERVENTIONS: 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. MAIN OUTCOME MEASURES: 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%). CONCLUSION AND RELEVANCE: 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. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00763867.