Sildenafil in Heart Failure with Preserved Ejection Fraction: No RELAXing in Sight

Cardiology Review® Online, June 2013, Volume 29, Issue 3

Craig J. Beavers, PharmD, BCPS, CACP

Tracy E. Macaulay, PharmD, BCPS (AQ Cardiology), AA CC

Review

Study Design

It is believed that up to 50% of patients with heart failure (HF) syndrome have a normal, or preserved, ejection fraction (EF).1 These patients share similar symptoms and presentation as those with systolic failure but differ significantly in the pathophysiology, treatment, and disease progression. In HF with preserved ejection fraction (HFpEF), patients have elevated left ventricular diastolic filling pressures due to impaired relaxation and diastolic stiffness.2 Clinical trials to date utilizing established therapies for HF with reduced EF, such as angiotensin- converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and beta blockers, have failed to demonstrate substantial benefit.3-8 Without proven benefit from traditional HF therapies, mortality at 5 years is estimated to be 50%, with an associated high degree of morbidity.9

Researchers and practitioners hope to find promising results with novel therapies, including the recently evaluated use of sildenafil, a phosphodiesterase-5 (PDE-5) inhibitor. Inhibition of the phosphodiesterase- 5 enzyme leads to smooth muscle relaxation and a decrease in vascular resistance and improvement in endothelial dysfunction.10 The effects of PDE-5 inhibition have proven effective in the management of pulmonary arterial hypertension.11,12 Given the mechanism of action of PDE-5 inhibitors, it has been theorized that this class of medication could have the potential to improve hemodynamics, and potentially outcomes, in HFpEF.

With these concepts in mind, Redfield and colleagues devised the randomized, double-blind, parallel-group, placebo-controlled Phosphodiesterase- 5 Inhibition to Improve Clinical Status and Exercise Capacity in Heart Failure with Preserved Ejection Fraction (RELAX) trial.13 The primary end point studied was change in peak oxygen consumption at 24 weeks of therapy. Secondary outcomes included a composite hierarchical-rank clinical score in which patients were ranked on time to death, time to hospitalization (for cardiovascular or cardiorenal causes), change in Minnesota Living with Heart Failure Questionnaire (MLHFQ), and change in 6-minute walk distance at 24 weeks, and change in peak oxygen consumption and 6-minute walk distance at 12 weeks. In this National Heart, Lung, and Blood Institute-sponsored trial, patients were included with the following criteria:

• EF ≥50%

• Stable New York Heart Association (NYHA) Class II-IV symptoms on medical therapy

• Objective evidence of congestive HF

• Peak oxygen consumption ≤60% of age- and sex-adjusted normal value with respiratory exchange ratio of ≥1 on cardiopulmonary exercise testing

• Elevated (≥400 pg/mL) N-terminal fragment of the precursor to brain-type natriuretic peptide (NT-proBNP) level or elevated left ventricular filling pressure if NT-proBNP was <400 Patients were randomized to sildenafil or placebo starting at 20 mg 3 times daily for 12 weeks. After 12 weeks, the dose was increased to 60 mg 3 times daily for 12 weeks. If adverse events developed, such as headache, hypotension, or flushing, study personnel could recommend discontinuation or return to lower or previously tolerated doses of the study drug.

A total of 216 patients underwent randomization (113 vs 103 to sildenafil and placebo, respectively). The median age was 69 years and ~50% were male. The average EF was 60% and most patients were classified as NYHA Class II and III symptoms at the time of enrollment. Baseline pulmonary artery systolic pressure (PASP) by echocardiography was 41 mm Hg, median MLHFQ score was 43, peak oxygen consumption was 11.7 mL/kg/min, and median 6-minute walk distance was 308 m. Patients had multiple comorbidities including controlled hypertension, ischemic heart disease, diabetes, and atrial fibrillation. With the exception of history of hypertension (90% in placebo vs 80% in sildenafil), groups were well matched with regard to baseline characteristics and medications.

The investigators found that there was no difference in primary outcome of peak oxygen consumption after 24 weeks of therapy, with a change of -0.20 mL/kg/min [interquartile range (IQR), -1.70 to 1.11] in the sildenafil group versus -0.20 mL/kg/min [IQR, -0.70 to 1.00) in the placebo group (P = 0.90). With regard to secondary outcomes, there was no statistically significant difference in composite hierarchical- rank clinical score or in individual components with respect to death (3 in the sildenafil vs 0 in the placebo group, P = 0.25), hospitalization for CV or cardiorenal causes (15 in sildenafil vs 13 in the placebo group, P = 0.89), or change in MLHFQ (median sildenafil, -8 vs -8 placebo; P = 0.44), 6-minute walk distance at 24 weeks [sildenafil, 5.0 m (IQR, -37 to 55) vs placebo, 15.0 m [IQR, -26.0 to 45.0; P = 0.92], or any other secondary outcome. Furthermore, there were more serious adverse events in the sildenafil group, although significance was not reached [22% sildenafil vs 16% placebo (P = 0.22)].

Commentary Further Sildenafil Studies for HFpEF Unlikely

RELAX was designed as a proof of concept study, the results of which demonstrated a net neutral impact of sildenafil in patients with HFpEF. Interestingly, these findings conflict with both observational and animal studies that led to this evaluation.14 While the primary outcome was a surrogate marker and the trial was not powered to look at hard clinical end points, it is unlikely that further studies will be performed with PDE-5 inhibitors in this population.

The investigators highlight a limitation that the results might have been different if the population studied focused on patients with documented pulmonary arterial hypertension, profound right ventricular (RV) systolic dysfunction, and right ventricular failure.13 The evidence for this theory is based on a study by Guazzi and colleagues15 in which 44 patients treated with sildenafil 50 mg 3 times daily had significant improvements in central venous pressure, mean pulmonary arterial pressure, pulmonary vascular resistance, and RV systolic dysfunction. In contrast to the RELAX trial, the mean PASP was 53 mm Hg, indicating more severe disease. The Guazzi et al trial, unlike RELAX, evaluated strictly surrogate end points, and the authors did not include information about hospitalizations. Another difference between the 2 trials is the length of follow-up, with RELAX only looking at a 24-week time frame compared with a 1-year follow-up in the Guazzi et al trial.

As stated above, the lack of benefit with inhibition of PDE-5 in HFpEF adds to a growing list of failed pharmacotherapy efforts in the management of this syndrome. As such, it is becoming increasingly apparent that there may be a lot we do not know about the process and mediators of HFpEF. Further in-depth research is needed with respect to pathophysiology to help better comprehend management strategies, targeted drug therapy, and future drug development. Future research includes analyses of treatment of HFpEF with aldosterone receptor antagonists, ranolazine, and a novel agent that inhibits the enzyme angiotensin neprilysin.16-18 For now, care for HFpEF patients should continue to focus on strategies that reduce symptoms of this syndrome, including loop diuretics and stringent control of comorbidities, such as hypertension, diabetes, and atrial fibrillation.19

References

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7. Yusuf S, Pfeffer MA, Swedberg K, et al. Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-Preserved trial. Lancet. 2003;362:777-781.

8. Bergstrom A, Andersson B, Edner M, et al. Effect of carvedilol on diastolic functioning patients with diastolic heart failure and preserved systolic function. Results of the Swedish Doppler-Echocardiographic Study (SWEDIC). Eur J Heart Fail. 2004;6:453-461.

9. Vasan RS, Larson MG, Benjamin EJ, et al. Congestive heart failure in subjects with normal versus reduced left ventricular ejection fraction: prevealence and mortality in a population-based cohort. J Am Coll Cardiol. 1999; 33:1948-1955.

10. Schwartz BG, Jackson G, Stecher VJ, et al. Phosphodiesterase type 5 inhibitors improve endothelial function and may benefit cardiovascular conditions. Am J Med. 2013;126:192-199.

11. Galie N, Ghofrani HA, Torbicki A, et al. Sildenafil use in pulmonary arterial hypertension (SUPER) Study Group. N Engl J Med. 2005;353:2148- 2157.

12. Galie, N, Brundage BH, Ghofrani HA, et al. Tadalafil therapy for pulmonary arterial hypertension. Circulation. 2009;119:2894-2903.

13. Redfield MM, Chen HH, Borlaug BA, et al. Effect of phosphodiesterase- 5 inhibition on exercise capacity and clinical status in heart failure with preserved ejection fraction. JAMA. 2013;309:1268-1277.

14. Redfield MM, Borlaug BA, Lewis GD, et al. Phosphodiesterase-5 inhibition to improve clinical status and exercise capacity in diastolic heart failure (RELAX) trial: rationale and design. Circ Heart Fail. 2012;5:653- 659.

15. Guazzi M, Vicenzí M, Arena R. Pulmonary hypertension in heart failure with preserved ejection fraction: a target of phosphodiesterase-5 inhibition in a 1-year study. Circulation. 2011;124:164-174.

16. Desai AS, Lewis EF, Li R, et al. Rational and design of the treatment of preserved cardiac function heart failure with an aldosterone antagonist trial: a randomized, controlled study of spironolactone in patients with symptomatic heart failure and preserved ejection fraction. Am Heart J. 2011;162:966-972.

17. Jacobshagen C, Belardinelli L, Hasenfuss G, et al. Ranolazine for the treatment of heart failure with preserved ejection fraction: background aims, and design of the RALI-DHF study. Clin Cardiol. 2011;34:426-432.

18. Solomon SD, Zile M, Pieske B, et al. The angiotensin receptor neprilysin inhibitor LCZ696 in heart failure with preserved ejection fraction: a phase 2 double-blind randomized controlled trial. Lancet. 2012; 384(9851):1387-1395.

19. Jessup M, Abraham WT, Casey DE, et al. 2009 focused update: ACCF/AHA guidelines for the diagnosis and management of heart failure in adults: a report of the American College of Cardiology Foundation/ American Heart Association task force on practice guidelines: developed in collaboration with the International Society for Heart and Lung Transplantation. Circulation. 2009;119:1977-2016.

About the Author

Craig Beavers, PharmD, BCPS, CACP, is a Cardiovascular Clinical Pharmacy Specialist at the Centennial Medical Center in Nashville, TN. He received his PharmD from the University of Kentucky in Lexington, and is currently pursuing a master’s degree in public health. Dr. Beavers is on the American College of Cardiology Foundation National Cardiovascular Team Council and is a Cardiac Care Associate Member Representative in the Centennial Department of Cardiovascular Medicine. He was assisted in the writing of this article by Tracy E. Macaulay, PharmD, BCPS (AQ Cardiology), AACC, Adjunct Professor in the Department of Pharmacy Practice and Science College of Pharmacy at the University of Kentucky Health- Care Pharmacy Services and Gill Heart Institutes. She received her PharmD from the University of South Carolina and completed a Pharmacy Practice Residency at the Mayo Clinic in Rochester, MN, and a Cardiology Specialty Residency at The Ohio State University. Dr. Macaulay teaches pharmacy students and residents as well as medical students, residents, and fellows in a variety of areas related to cardiovascular pharmacotherapy and is also responsible for providing direct patient care for cardiology critical care patients.

Redfield MM, Chen HH, Borlaug BA, et al. Effect of phosphodiesterase-5 inhibition on exercise capacity and clinical status in heart failure with preserved ejection fraction: a randomized clinical trial. JAMA. 2013;309:1268-1277.