No net benefit from sildenafil in heart failure with ejection fraction

By Will Boggs MD

Sildenafil's combination of beneficial and deleterious effects results in no net benefit for patients with heart failure with preserved ejection fraction (HFpEF), according to results from the RELAX trial.

"Sildenafil improved vascular function and tended to improve endothelial function, two facets of the disease that are believed to be important therapeutic targets, but this did not translate to an improvement in exercise capacity," Dr. Barry A. Borlaug, from the Mayo Clinic and Foundation, Rochester, Minnesota, told Reuters Health by email.

"Two different measures of left ventricle contractility were decreased with sildenafil, even though the overall EF was unchanged. The clinical significance of this latter finding is unclear at this time," he said.

When the RELAX trial failed to show a benefit of sildenafil treatment on exercise capacity and clinical status in patients with HFpEF, Dr. Borlaug's team undertook a prospective ancillary study to examine ventricular, vascular, and endothelial function at rest and during exercise in 48 patients, including 25 randomized to placebo and 23 randomized to sildenafil.

Patients on sildenafil showed greater systemic afterload reduction and tended to show improved endothelium-dependent vasodilation, compared with patients on placebo, according to the March 17 Circulation: Heart Failure online report.

On the other hand, sildenafil treatment was associated with modest reductions in left ventricular contractility, despite the lack of effect on resting ejection fraction.

"It may be that improvements in vascular function are not sufficient to improve exercise capacity in people with HFpEF, or it may be that positive effects from the latter could be offset by negative effects on ventricular systolic function," Dr. Borlaug said.

"Right now, there is no evidence-based role for PDE5 (phosphodiesterase-5) inhibitors in HFpEF," Dr. Borlaug concluded. "The largest multicenter trial (RELAX) showed no benefit for exercise capacity, quality of life, and other markers of clinical status. There was one small single center study from Italy that showed many positive signals, but the patients enrolled in that study were not typical of 'garden variety' HFpEF patients that we see in the community, and this was of, course, only one small study."

"Further research would need to be done prior to recommending widespread use of PDE5 inhibitors in people with HFpEF," Dr. Borlaug concluded.

If it has any role now, it could be for the relief of symptoms, according to Dr. Andre M.S. Fernandes, from Federal University of Bahia, Brazil, who has used cardiac magnetic resonance imaging (MRI) to measure the effects of sildenafil on right ventricular function of patients with heart failure.

"I think that the most evidence that we have in literature for those with cardiac failure is an improvement in oxygen uptake and functional status, regardless the existence or not of an improvement on the EF," Dr. Fernandes said.

"I think that the journey of sildenafil in cardiac failure is not at the end," Dr. Fernandes concluded. "We need to select the patient that may have advantages with its use."

The National Heart Lung and Blood Institute and the American Heart Association funded this research. The authors declared no conflicts of interest.

SOURCE: http://bit.ly/1b0s54o

Circ Heart Fail 2015.

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