Dallas, TX - Two tiny randomized trials add to burgeoning observational and mechanistic evidence in favor of adding sildenafil, and perhaps other type-5 phosphodiesterase (PDE-5) inhibitors, to standard drug therapy in patients with heart failure [1,2].

Both placebo-controlled studies were consistent with each other in suggesting that patients with "garden-variety" heart failure from dilated cardiomyopathy who take a PDE-5 inhibitor in addition to their other HF medications can have less dyspnea and significantly improved exercise performance as measured in multiple ways, Dr David A Kass (Johns Hopkins University, Baltimore, MD), who was not part of either investigation, observed for heartwire.

Oxygen uptake at peak exercise (peak VO₂) increased over months of thrice-daily sildenafil in both studies, which enrolled patients with systolic heart failure, and there were the expected improvements in pulmonary-artery pressures and other hemodynamic measures.

In their 12-week follow-up of 34 patients with pulmonary hypertension secondary to the HF who were randomized to the active drug or placebo, Dr Gregory D Lewis (Massachusetts General Hospital, Boston) and colleagues saw those taking the PDE-5 inhibitor also perform significantly better on the six-minute-walk test and score higher on quality-of-life measures than they had at baseline [1].

"Long-term treatment with oral PDE-5 inhibition is a novel, well-tolerated approach to achieve selective pulmonary vasodilation in patients with heart failure and pulmonary hypertension," Lewis et al write in the in the October 2, 2007 issue of Circulation. "PDE-5 inhibition may represent an important adjunctive therapy for patients with heart failure complicated by secondary pulmonary hypertension if the beneficial effects observed in our study are confirmed in larger clinical trials."

Dr Marco Guazzi (San Paolo Hospital, Milan, Italy) and colleagues, in their six-month, 46-patient study, published in the November 27, 2007 issue of the Journal of the American College of Cardiology, observed evidence of sildenafil-related improvement in endothelial function not only in the pulmonary artery but in the systemic vasculature as well.

Its observed increase in peak VO₂, "which is not something that lots of heart-failure therapies have been terribly successful at budging," observed Kass, was particularly noteworthy. "With chronic heart-failure therapy, whether beta blockers or ACE inhibitors, you're lucky if you get it to go up by about 2 points [mL/kg per minute]. And in this study it went up by a whopping 4 points."

The "substantial improvement" in exercise performance suggests that peak VO₂ could potentially be "an important novel target" for treatment, Kass said. "[Sildenafil] isn't working quite the same way as ACE inhibitors, it's more pulmonary selective. Other drugs we have also improve endothelial function, and yet presumably on top of all that, because these patients were being treated with standard therapy, sildenafil would appear to do a bit more, and you'd think people would benefit from it."

In the study from Guazzi et al, the 23 patients who took sildenafil at 50 mg three times a day showed significant improvements in measures of pulmonary-artery pressure, endothelial function, exercise performance, and efficiency of ventilation, including peak VO₂, over three months (p<0.01 for all measures). There were similarly significant gains in subjectively measured emotional quality of life and "breathlessness."

No such changes were observed among the 23 patients assigned to placebo; randomized therapy was administered in a double-blind fashion and given on top of the standard heart-failure medications patients had been prescribed by their referring physicians.

The patients were all men younger than 65 and in stable NYHA class 2 or 3 heart failure with an LVEF <45% who experienced symptoms during exercise. Current smokers and patients on statins, antioxidant vitamins, or other drugs with effects on endothelial function had been excluded.

Although pulmonary-artery systolic pressure hadn't figured into Guazzi et al's eligibility requirements, at baseline it averaged nearly 34 mm Hg in the active-therapy group and nearly 32 mm Hg among controls. Kass, however, said he thinks the evidence suggests PDE-5 inhibitors may work in heart failure even if pulmonary-artery pressures aren't elevated.

Dr Marc J Semigran (Massachusetts General Hospital, Boston), senior coauthor on the Lewis et al report, told heartwire that a baseline pulmonary-artery pressure >25 mm Hg was an entry requirement and that such pulmonary-artery pressures probably account for an estimated 40% to 50% of patients with heart failure.

In the Lewis et al study, the patients in NYHA class 2-3 heart failure with such secondary pulmonary hypertension were evenly randomized in double-blind fashion to receive sildenafil or placebo for 12 weeks. The active drug was started at 25 mg thrice daily and increased every two weeks, as tolerated, to a maximum of 75 mg three times daily; patients were taking 49 mg three times a day, on average, by the end of the study.

Peak VO₂ at 12 weeks, the primary end point, had risen significantly in the sildenafil group compared with baseline and compared with the mean change in VO₂ among controls (p=0.02 for both comparisons). Sildenafil was also associated with significant improvements in pulmonary vascular resistance (p<0.05) and in cardiac output during exercise (p<0.05) and stroke volume at exercise (p=0.03) compared with placebo.

Patients taking sildenafil also increased their six-minute-walk distance by 62 m at 12 weeks compared with baseline (p=0.004) and walked a mean of 29 m more compared with the placebo group (p=0.047). Their scores on the Minnesota Living With Heart Failure questionnaire improved by averages of 13 points and 16 points over six and 12 weeks; scores in the control group didn't change.

All but one of the patients in the trial chose to initiate or continue with sildenafil on an open-label basis after the 12 weeks were completed, according to Lewis et al. Among the 13 who had previously been on active therapy and completed a six-month follow-up, the mean six-minute-walk distance advanced another 96 m (p=0.007), "indicating a sustained improvement in exercise capacity with sildenafil therapy," they write.

In an editorial accompanying the report from Guazzi et al, Dr Steven R Goldsmith (University of Minnesota, Minneapolis) argues, without impugning its quality, that the study did not convincingly indicate that a larger study of PDE-5 inhibition in heart failure is warranted—citing, among other concerns, a dearth of knowledge about sildenafil's mechanisms of action and the demonstrated hazards of other phosphodiesterase-suppressing agents in heart failure, notably the PDE-3 inhibitor milrinone.

"We have the ability not only to remember our past history with other agents that inhibit phosphodiesterase in chronic systolic heart failure but also to avoid repeating previous mistakes," Goldsmith writes. "I believe we should make every attempt to do so before embarking on larger trials in systolic heart failure with these interesting and potentially useful compounds."

But a larger trial of sildenafil, although not in "systolic" heart failure and short of a full-fledged outcomes study, appears imminent. Funded by the National Institutes of Health, the placebo-controlled, randomized Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Diastolic Heart Failure (RELAX) trial is scheduled to start in early 2008 with a projected enrollment of 190 patients with heart failure and preserved LV function, according to Dr Margaret Redfield (Mayo Clinic, Rochester, MN), one of the lead investigators. The primary end point, she informed heartwire, is change in peak VO₂ over 24 weeks, but a plethora of secondary and tertiary end points will explore other functional measures; clinical, renal, and neuroendocrine effects; and changes in cardiac structure.