Seattle, WA - Researchers presenting new information on the use of sildenafil in the treatment of heart failure say the phosphodiesterase 5 (PDE5) inhibitor once known as the "Pfizer riser" is returning with force to its roots in the cardiac arena, with benefits that may go beyond pulmonary arterial hypertension (PAH).

Dr Marc Semigran

Sildenafil, first explored as an antianginal medication, actually gained initial marketing approval for the treatment of erectile dysfunction (as Viagra) and later for primary PAH (as Revatio). "Sildenafil took a detour below the belt before coming back to where it should be," Dr Marc Semigran (Massachusetts General Hospital, Boston, MA) quipped to heartwire. Semigran is senior author on a poster presented here at the Heart Failure Society of America 2006 Scientific Meeting suggesting that sildenafil may also improve exercise function and quality of life in systolic heart-failure patients with secondary PAH.

The rationale for evaluating sildenafil in the setting of heart failure—as in PAH—stems from observations that PDE5 is the principal enzyme responsible for cGMP catabolism in vascular smooth-muscle cells, while chronic LV systolic dysfunction is characterized by impaired nitric-oxide (NO)-cGMP-mediated vasodilation in pulmonary and skeletal-muscle circulatory systems.

First author on the study with Semigran, Dr Gregory D Lewis (Massachusetts General Hospital), presented results from an interim analysis of the randomized, double-blind, placebo-controlled study during an oral "poster highlight" session. As Lewis explained in an interview with heartwire, he and his colleagues set out to enroll patients with LV dysfunction, a group that had explicitly been excluded in the Sildenafil for Use in Pulmonary Arterial Hypertension (SUPER) study that led to sildenafil's approval for PAH. As such, Lewis et al's study enrolled 40 patients with NYHA class 3 or 4 systolic HF and secondary PAH, defined as a mean pulmonary arterial pressure >25 mm Hg, and randomized them either to placebo or oral sildenafil uptitrated to 50 mg three times daily for 12 weeks.

Interim results

Dr Gregory D Lewis

Lewis et al plan to enroll 40 patients in the study but today presented data for the first 28 patients. In these, said Lewis, patients randomized to sildenafil (n=14) experienced a 13% placebo-corrected improvement in six-minute-walk distance (p<0.05) as well as significant improvement in Minnesota Living with Heart Failure scores, which, he noted, have been shown to independently predict outcomes in HF patients. There were no significant differences in any adverse events between the two groups, with the exception of hospital admissions for heart failure, which were significantly lower in the patients taking sildenafil (7 vs 1, p=0.02).

While other systemic vasodilators have been tested in heart failure, Lewis believes sildenafil may be particularly potent in the pulmonary vasculature, thereby improving right ventricular performance.

He and his colleagues are also assessing other effects of the drug, and Lewis doesn't rule out a role for sildenafil in heart failure in the absence of PAH, although, he emphasizes, those analyses have not yet been done.

"We're going to look carefully at remodeling effects, as well as peripheral effects. Although we've been focused on the pulmonary vasculature, it is possible that this medication has peripheral effects that are also potentially of use in heart-failure patients—for example, improving endothelial function in the periphery. . . . Fortunately, we're talking about a drug with a long track record in humans, as opposed to a brand-new agent that's never been looked at, with unknown risks."

Beyond PAH?

Semigran, while emphasizing the preliminary nature of the research, also agreed that the limits of sildenafil therapy in the heart were not yet known. He also noted that the degree of PAH in the patients studied was not severe and further analysis is warranted to determine whether the benefits of sildenafil are confined to patients with a certain degree of PAH. "Many of these patients, if they have an LV filling pressure that's in the order of 20 mm Hg and a pulmonary artery pressure that's in the order of 25 mm Hg, their transpulmonary gradient is not that great, so we need to sort through our data and see whether those patients had a benefit as well," Semigran said. "It may be applicable to those patients who have pulmonary vasoconstriction, but it may also be more broadly available, particularly if some of the other mechanisms unrelated to the pulmonary circulation are operative."

Indeed, animal studies out of Johns Hopkins have pointed to a direct myocardial benefit of sildenafil in preventing hypertrophy in a rat model of hypertensive cardiomyopathy, Semigran pointed out.

"Nitric-oxide signaling and even natriuretic-peptide signaling are important throughout the body, and particularly in cardiovascular systems," Semigran said.