Sildenafil and Exercise Capacity in Heart Failure
Abstract & Commentary
By Jonathan Abrams, MD, Professor of Medicine, Division of Cardiology, University of New Mexico, Albuquerque; Dr. Abrams serves on the speaker's bureau for Merck, Pfizer, and Parke-Davis
Source: Lewis GD, et al. Sildenafil improves exercise capacity and quality of life in patients with systolic heart failure and secondary pulmonary hypertension. Circulation. 2007;116:1555-1562.
An interesting therapeutic concept that has been put into clinical practice in the past several years is the use of nitric oxide donors for pulmonary hypertension. This report assesses subjects with significant pulmonary hypertension and with severe left ventricular failure and right ventricular dysfunction. Sildenafil (SIL), better known as Viagra, is a selective inhibitor of the PDE, which is "the predominate PDE isoform responsible for hydrolysis of intracellular cGMP in the pulmonary vasculature." This group previously reported a 6-month study of SIL in heart failure patients with pulmonary hypertension and normal LV function, with favorable results on exercise capacity in subjects given SIL in a double blind protocol. The present trial evaluates the effectiveness of SIL in patients with pulmonary hypertension related to impaired left ventricular systolic function (EF < 0.4) and class II-IV chronic heart failure on standard CHF therapy. Pulmonary hypertension was defined by a mean PA pressure of > 25. Thirty-four subjects were entered into the protocol and randomized to 50 mg of placebo or SIL 3 times daily for 12 weeks.
A wide variety of measurements were made, including right heart catheterization, blood gas, respiratory gas exchange during exercise, oxygen uptake, carbon dioxide output, respiratory gas exchange ratio, right-sided intra-cardiac pressures and cardiac output. Systemic and pulmonary vascular resistance was calculated. Exercise testing was measured by cardiopulmonary exercise testing with upright cycle ergometry and respiratory gas exchange. Rest and exercise first pass radionuclide ventriculography of the right and left ventricle was carried out both before and during exercise. The ejection fraction of each ventricle was calculated by standard nuclear techniques, as were LV end RV and diastolic volumes. A robust statistical analysis was utilized.
Results: Baseline cardiopulmonary testing was similar in the active SIL and placebo. Several patients required up titration of diuretics. All patients surpassed their anaerobic threshold and achieved reparatory exchange ratios over 1.0, consistent with maximum exercise effort. The primary outcome, Vo2 at peak exercise increased in SIL patients (12.2 ± 0.7 to 13.9 ± 1.0); placebo patients had no change in Vo2. Cardiac output increased, only in the SIL group, whose peak Vo2 correlated directly with the baseline resting PVR and RVEF. An improvement in RVEF in the SIL group was observed at rest and during exercise; placebo patients had no change. Neither group received any effect on LVEF or LV diastolic volume.
Hemodynamic Measurements: The SIL patient had a decrease in resting PVR and PVR/SVR that was statistically significant, but there was no change in systemic and pulmonary artery pressures, wedge pressure, or cardiac index. PVR at peak in exercise with SIL fell by 23 ± 6%, P = 0.008 vs baseline, with an increased peak exercise cardiac output vs baseline.
Quality of life (Minnesota Living with Heart Failure Score) improved with SIL patients but not placebo (53% vs 7%) and worsened in 13% of SIL group vs 27% of placebo patients. Three patients were not able to complete the 12-week trial. Adverse events were infrequent. There were fewer hospitalizations for heart failure in the SIL treatment patients (2 vs 7, P = 0.046).
Long-term follow-up of the 29 patients in this study is reported, with 15 subjects continuing to take SIL for up to 6 months while three completed the 12-week trial only. Long term benefit in a 6 minute walk was noted in those who took SIL for greater than 6 months. There were no deaths or adverse experiences, with sustained improvement in exercise capacity in the SIL group over 6 months. The drug was well tolerated and resulted in fewer hospital admissions than the placebo group. The improvement in peak Vo2 and 6-minute walk in this trial was a finding which suggested a prior trial using a single dose administration of SIL, which resulted in improvement in a variety of parameters. Right heart systolic function was improved, "likely attributable to afterload reduction because SIL reduced PVR." Of interest, the patients with the higher PVR had the greatest improvement in exercise capacity.
Lewis and colleagues conclude, "The present study is the first to suggest that prolonged administration of a selective PDE5 pulmonary vasodilator improves capacity in patients with heart failure. The improvement in quality of life in patients with SIL likely reflects enhanced exercise capacity." Lewis et al discuss the poor outcome of patients who have heart failure and RV dysfunction, and note that prior studies with pulmonary vasodilators (bosentan, epoprostenol) have had no positive effects. They cite the AAHFT study using isosorbide dinitrate and hydralazine, and emphasize that the drug is a nitric oxide donor and that it may be that the "common signaling pathway involving cGMP may provide additional benefits for currently approved pharmacotherapies for heart failure." It should be stressed that as opposed to nitrates, SIL is a selective pulmonary vasodilator and tolerance is yet to be described. Finally, Lewis et al stress that "this study should be considered a pilot trial because of the small sample size." At the same time, they suggest that there may be broad applicability to the use of PDE5 inhibitors, which deserve further investigation, and then suggest that PDE5 inhibition may be an important adjunctive therapy for patients with congestive heart failure and pulmonary hypertension if larger studies confirm these results.
This is a modest pilot study that potentially packs a wallop! While SIL was the first agent released for erectile dysfunction, it is of interest that originally Pfizer was testing this compound for angina in patients, presumably because of its vasodilator effects. The hemodynamic benefits of SIL and other nitric oxide inhibitors are well known. It would be ironic if these drugs turn out to have a much greater use, particularly in the very ill patient with depressed right and left ventricular function and pulmonary hypertension. This group of individuals are extremely frustrating, even though experienced practitioners use all of the resources available, including aldosterone blockade, ACE inhibition, beta blockade, etc. It will be of considerable interest to see the results of additional trials using larger cohorts for the assessments of efficacy and side effects following the promising outcomes in the first 2 (small) trials reported by this group.