RELAX: Sildenafil Falls Short in Preserved-EF Heart Failure

March 11, 2013

SAN FRANCISCO, California — It wasn't just the drug's mystique that led to the Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Diastolic Heart Failure (RELAX) trial [1]. Nor was it completely exasperation over a shortage of therapeutic agents for heart failure with preserved ejection fraction (HF-PEF). There was also a decade of observational data and small trials suggesting that sildenafil (Viagra/Revatio, Pfizer), a phosphodiesterase-5 (PDE-5) inhibitor, might improve exercise capacity and perhaps clinical outcomes in patients with HF-PEF [1].

The randomized RELAX trial that entered HF-PEF patients (LVEF >50%) in NYHA class 2-3, as it turned out, disappointed by showing no such improvements in patients (n=113) who received the drug at 20 mg three times daily for three months, followed by 60 mg three times daily for another three months, compared with a placebo control group (n=103). The trial's median patient age was 69 years.

Dr Margaret Redfield

There were no significant differences in the primary end point of change in peak oxygen consumption at 24 weeks, CV or renal hospitalization, echocardiographic cardiac magnetic resonance (CMR) indices of ventricular remodeling and diastolic function, pulmonary artery pressures, or quality of life on the Minnesota Living with Heart Failure Questionnaire. And there were even signs in the sildenafil group of deterioration in levels of some laboratory markers salient in HF, such as uric acid (p=0.02), endothelin 1 (p=0.046), cystatin C (p=0.01), creatinine (p=0.047), and natriuretic peptides (p=0.03); 24-week biomarkers were read at a core laboratory.

"Furthermore, there were more (but not significantly more) patients in the sildenafil group who withdrew consent, died, or were too ill to perform the cardiopulmonary exercise test, and patients treated with sildenafil had a higher incidence of vascular adverse events," write Dr Margaret Redfield (Mayo Clinic, Rochester, MN) and associates in the Journal of the American Medical Association. The study, conducted at 26 centers in Canada and the US, is published online today to coincide with Redfield's presentation of RELAX at the American College of Cardiology 2013 Scientific Sessions.

Safety End Points in RELAX

Safety end points* Placebo, n=103 (%) Sildenafil, n=113 (%)
Death 0 3
CV or cardiorenal hospitalization 13 13
Adverse events 76 80
"Serious adverse events" 16 22
Withdrawn or unwilling/unable to complete 24-wk cardiopulmonary exercise test 8 16

*All differences nonsignificant, p>0.05

"It may be that the primary therapeutic effects of PDE-5 inhibitors in heart failure involve the drugs' ability to dilate the pulmonary vascular bed, enhance right ventricular contractility, and reduce ventricular interdependence and that pulmonary arterial hypertension and right ventricular failure must be significant in order to observe clinical benefit in HF-PEF," write Redfield et al.

"Our subgroup analysis did not show any trends toward improvement in peak oxygen consumption in patients with higher pulmonary artery systolic pressure, but the presence of pulmonary arterial hypertension or right ventricular dysfunction was not assessed in this study."

The RELAX Study was funded by the National Heart, Lung, and Blood Institute of the National Institutes of Health, from which Redfield discloses receiving financial support; she also discloses receiving royalties from Annexon. Disclosures for the coauthors are listed in the paper. Pfizer provided the sildenafil and its matched placebo.

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