Effect of Phosphodiesterase-5 Inhibition on Exercise Capacity and Clinical Status in Heart Failure With Preserved Ejection Fraction: A Randomized Clinical Trial

Study Questions:

Does the phosphodiesterase-5 (PDE-5) inhibitor sildenafil lead to improved exercise capacity and clinical status in patients with heart failure with preserved ejection fraction (HFPEF)?

Methods:

RELAX (Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Heart Failure With Preserved Ejection Fraction) was a multicenter, double-blind, placebo-controlled trial of sildenafil (60 mg daily titrated to 180 mg daily) in patients with New York Heart Association class II-IV heart failure and left ventricular EF (LVEF) ≥50%. Patients had to have a baseline peak oxygen consumption (pVO2) <60% predicted and elevated N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels. The primary outcome of interest was the change in pVO2 after 24 weeks of therapy. Changes in 6-minute walk distance, NT-proBNP, and cardiac magnetic resonance imaging measures were also assessed.

Results:

There were 113 patients randomized to sildenafil and 103 to placebo with 91 and 94, respectively, included in the final analysis. Mean patient age was 69 years, 48% were women, and the median [IQR] baseline pVO2 was 11.7 [35-49] (median 41% of predicted). After 24 weeks of therapy, the median change in pVO2 in the intervention group (-0.20 [-1.70-1.11] was not significantly different from that of placebo (-0.20 [-0.70-1.00], p = 0.90). Likewise, the change in 6-minute walk distances were similar in sildenafil (5 [-0.37-55] m) and placebo (15 [-26-45]) groups, and there was no difference in LV mass or end-diastolic volume after 24 weeks of therapy. The change in creatinine (increase by 0.05 mg/dl in sildenafil compared with 0.01 mg/dl in placebo) and NT-proBNP levels (increase by 15 pg/ml in sildenafil compared with decrease of 23 pg/ml in controls) were significantly higher in patients taking sildenafil.

Conclusions:

The investigators concluded that PDE-5 inhibition with sildenafil did not lead to improvements in exercise capacity in patients with HFPEF.

Perspective:

Unfortunately, improvements in pVO2 can be limited by chronotropic incompetence, which may have been a confounder in this study. Nonetheless, there was no difference or trend toward improvement in 6-minute walk distance, and measures to suggest improvement in ventricular diastolic also did not show trends toward benefit. One could question if a longer study duration may be needed to achieve improvements in the chosen endpoints. Back to the drawing board....

Clinical Topics: Diabetes and Cardiometabolic Disease, Heart Failure and Cardiomyopathies, Noninvasive Imaging, Prevention, Acute Heart Failure, Heart Failure and Cardiac Biomarkers, Magnetic Resonance Imaging, Exercise

Keywords: Phosphodiesterase Inhibitors, Phosphodiesterase 5 Inhibitors, Purines, Exercise, Piperazines, Creatinine, Sulfones, New York, Magnetic Resonance Imaging, Heart Diseases, Oxygen Consumption, Heart Failure, Cyclic Nucleotide Phosphodiesterases, Type 5, Diastole, Heart Ventricles, Natriuretic Peptide, Brain


< Back to Listings