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)?


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.


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.


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


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

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