Heart failure with preserved ejection fraction (HFPEF) is now felt to be the most common form of heart failure in the community, and is associated with significant morbidity and mortality. Currently, effective therapies are needed as trials of traditional renin-angiotensin antagonists have failed to show an improvement in outcomes or clinical status. Experimental work has suggested that phosphodiesterase-5 inhibitors may be able to enhance cardiovascular function and this exercise capacity in HFPEF.

The RELAX (Phoshphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Heart Failure with Preserved Ejection Fraction) trial compared the effects of the PDE-5 inhibitor sildenafil with placebo in patients with HFPEF. 216 stable outpatients with heart failure, an ejection fraction of >50%, elevated N-terminal brain-type natriuretic peptide or elevated invasively measured filling pressures, and reduced exercise capacity were recruited between 2008 and 2012. 113 patients were given Sildenafil, and 103 placebo, 20mg three times a day for 12 weeks, followed by 60mg, three times a day for 12 weeks. The primary endpoint was the change in peak oxygen consumption after 24 weeks of therapy.

At 24 weeks follow-up, the median changes in peak oxygen consumption were not significantly different (P=0.90) between the sildenafil and the placebo groups.  Similarly, the mean clinical status rank scores were not significantly different (P=.85), nor were changes in 6-minute walk distance (P=.92). Serious adverse events occurred in 16 placebo patients (16%), and 25 sildenafil (22%) patients.

Conclusions:

The use of the phosphodiesterase-5 inhibitor sildenafil in patients with HFPEF did not result in significant improvement in exercise capacity or clinical status when compared to placebo.

• Redfield MM, Chen HH, Borlaug BA et al. Phodiesterase-5 Inhibition on Exercise Capacity and Clinical Status in Heart Failure With Preserved Ejection Fraction. A Randomized Clinical Trial. JAMA 2013;309:1268-1277.