Sildenafil Improves Exercise Capacity and Quality of Life in Patients with Systolic Heart Failure and Secondary Pulmonary Hypertension

Disclosure: None
Pub Date: Monday, August 25, 2008
Authors: Robyn Barst, MD, FAHA
Article:  Sildenafil Improves Exercise Capacity and Quality of Life in Patients with Systolic Heart Failure and Secondary Pulmonary Hypertension

Citation(s)

  1. Lewis GD, Shah R, Shahzad K, Camuso JM, Pappagianopoulos PP, Hung J, Tawakol A, Gerszten RE, Systrom DM, Bloch KD, Semigran MJ, ,  Sildenafil improves exercise capacity and quality of life in patients with systolic heart failure and secondary pulmonary hypertension.,  Circulation,  116 (14) 1555-62. View in PubMed

Clinical Question

Lewis et al. tested the hypothesis that sildenafil, the phosphodiesterase type-5 inhibitor, would lower pulmonary vascular resistance (PVR) and improve exercise capacity in patients with systolic heart failure and secondary pulmonary hypertension.

Summary

Lewis and colleagues studied 34 adult patients with symptomatic systolic heart failure and secondary pulmonary hypertension in a double-blind, placebo-controlled, 12-week, randomized trial evaluating the safety and efficacy of sildenafil (25-75 mg orally three times daily) compared with placebo. Patients underwent assessment at baseline and at week 12, which included resting and exercise hemodynamics and exercise capacity, assessed by both cardiopulmonary exercise testing with upright cycle ergometry and the 6-minute walk test. Quality of life was assessed with the Minnesota Living with Heart Failure questionnaire. Secondary pulmonary hypertension was defined as a mean pulmonary artery pressure at rest of at least 25 mm Hg. At the end of 12 weeks, there were significant improvements in hemodynamic parameters, both at rest and with exercise; exercise capacity assessed by both a 6-minute walk test and cardiopulmonary exercise testing; right ventricular ejection fraction at rest and with exercise; and quality of life using the Minnesota Living with Heart Failure score. Hemodynamic improvements were consistent with selective pulmonary vasodilatation, with a decrease in the PVR/systemic vascular resistance (SVR) ratio in addition to a decrease in absolute PVR. Furthermore, the patients in the sildenafil group had fewer hospitalizations for heart failure than the placebo-treated patients. The sildenafil appeared to be well tolerated with only a greater incidence of headache in the sildenafil group compared with placebo.

Clinical Implication/Application

The most significant prognostic parameters for patients with systolic heart failure are pulmonary artery pressure and right ventricular function.[1,2] Thus, novel therapeutic agents to improve secondary pulmonary hypertension in addition to effective therapy for systolic heart failure (e.g. angiotensin-converting enzyme inhibitors, beta blockers, and aldosterone-receptor blockers) are needed. To date, the only additional clinical trials evaluating secondary pulmonary hypertension in systolic heart-failure patients have combined isosorbide dinitrate and hydralazine. A theoretic advantage of sildenafil over isosorbide dinitrate is lack of tachyphylaxis, which is commonly seen with chronic nitrate therapy. Although these data are preliminary, with this study serving as a proof-of-concept pilot study, the therapeutic benefit of a phosphodiesterase inhibitor in heart-failure patients with secondary pulmonary hypertension is promising. Among the currently approved three classes of medications for the treatment of pulmonary arterial hypertension (defined as mean pulmonary artery pressure of at least 25 mm Hg at rest or >30 mm Hg with exercise, mean pulmonary capillary wedge pressure ≤15 mm Hg, and PVR >3 Wood units), prostacyclin analogues and endothelin receptor antagonists have also been evaluated in systolic heart failure.[3] However, in heart-failure patients with secondary pulmonary hypertension, the Endothelin Antagonist Bosentan for Lowering Cardiac Events in Heart Failure (ENABLE) study with bosentan was negative, resulting in fluid retention and increased morbidity assessed by increased hospitalizations for heart failure. The study evaluating continuous intravenous epoprostenol was also negative and associated with increased mortality, particularly in patients with coronary artery disease. However, the marked degree of heterogeneity, in at least the epoprostenol study, may have resulted in the inability to identify a subset of patients with systolic heart failure who could benefit from chronic intravenous epoprostenol or other prostacyclin analogues. Regardless, as we work toward improving medical therapy for patients with pulmonary hypertension of various causes, one must remain cognizant of the potential adverse effects with any of the vasodilators that have even mild degrees of systemic vasodilatation, in addition to pulmonary vasodilatation, in patients with coronary artery disease. Thus, although the use of angiotensin-converting enzyme inhibitors, beta blockers, and aldosterone-receptor blockers is safe and efficacious in most patients with systolic heart failure, vasodilator agents, such as those being developed for the treatment of pulmonary hypertension, must be used in a far more cautious manner due to concerns regarding myocardial ischemia in patients with varying degrees of coronary artery disease as well as myocardial hypertrophy and increased myocardial oxygen demands. Despite these limitations, it is exciting to see further investigation into treating patients with systolic heart failure now focusing on the right side of the heart, since it is now well appreciated that, in fact, it is the right ventricular ejection fraction that predicts outcome in these patients, as opposed to left ventricular ejection fraction.[4] In addition, with the right ventricular ejection fraction correlating with pulmonary artery pressure, the clinical significance of secondary pulmonary hypertension in patients with systolic heart failure cannot be underestimated.

One concern in treating patients with systolic heart failure and secondary pulmonary hypertension with increased pulmonary capillary wedge pressures, i.e. increased left heart filling pressures, is that, by increasing cardiac output, if there is any degree of left ventricular diastolic dysfunction, increasing right ventricular output could result in an increase in left ventricular filling pressure and pulmonary congestion. Although this is often seen with acute vasodilator drug testing with inhaled nitric oxide in these patients, for reasons that remain incompletely understood, this is rarely seen with phosphodiesterase type-5 inhibitors such as sildenafil in these same patients.[5] Further investigation is needed with this group of patients as more and more patients are now living longer, resulting in an increased prevalence of secondary pulmonary hypertension associated with systolic heart failure.

References

  1. Ghio S, Gavazzi A, Campana C, et al. Independent and additive prognostic value of right ventricular systolic function and pulmonary artery pressure in patients with chronic heart failure. J Am Coll Cardiol 2001;37(1):183-188.
  2. Juilliere Y, Barbier G, Feldmann L, et al. Additional predictive value of both left and right ventricular ejection fractions on long-term survival in idiopathic dilated cardiomyopathy Eur Heart J 1997;18(2):276-280.
  3. Barst RJ ed. Pulmonary arterial hypertension: diagnosis and evidence-based treatment. West Sussex, UK: John Wiley & Sons, Ltd., 2008.
  4. Voelkel NF, Quaife RA, Leinwand LA, et al. Right ventricular function and failure: report of a National Heart, Lung, and Blood Institute working group on cellular and molecular mechanisms of right heart failure. Circulation 2006;114(17):1883-1891.
  5. Wilkins MR, Wharton J, Grimminger F, Ghofrani HA. Phosphodiesterase inhibitors for the treatment of pulmonary hypertension. Eur Respir J 2008;32(1):198-209.
-- The opinions expressed in this commentary are not necessarily those of the editors or of the American Heart Association.