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J Okla State Med Assoc. Author manuscript; available in PMC 2017 February 07. Published in final edited form as: J Okla State Med Assoc. 2016 September ; 109(9): 437–438.
Clinical Question: In congestive heart failure patients with preserved ejection fraction, does spironolactone improve cardiac outcomes? Leslie Williams, DO and Cheyn Onarecker, MD St. Anthony Family Medicine Residency, Oklahoma City, OK
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Abstract Clinical Question—In congestive heart failure patients with preserved ejection fraction, does spironolactone improve cardiac outcomes? Answer—No. A randomized controlled trial of patients with heart failure and an ejection fraction > 45% showed that spironolactone did not significantly reduce the incidence of the primary composite outcome of death from cardiovascular causes, aborted cardiac arrest, or hospitalization for the management of heart failure. Level of Evidence for the Answer—A Search Terms—Congestive heart failure, Spironolactone, Ejection fraction, Preserved, Mineralocorticoids
Author Manuscript
Limits—English, Adults, Randomized Controlled Trials, Meta-analysis, and Systematic review Date Search Was Conducted—December 2015 Inclusion criteria—All randomized controlled trials, Meta-analyses, and systematic reviews in patients with congestive heart failure with preserved ejection fractions, who were taking spironolactone, and published in the past 5 years. Exclusion criteria—Age less than eighteen years, Eplerenone
Summary of the Issues
Author Manuscript
Heart failure is a disabling disease that affects more than 5 million Americans. It is also a major cause of morbidity and mortality worldwide.1 Up to 50% of patients with heart failure have a preserved ejection fraction (HFpEF), with an ejection fraction > 45%. Despite having a higher ejection fraction, however, patients with HFpEF have essentially the same morbidity and mortality rates as patients with heart failure that have reduced ejection fractions (HFrEF). HFpEF patients have a mortality rate up to 43% in 5 years.1 HFpEF disproportionally affects women and the elderly and is commonly associated with hypertension and diabetes mellitus. Many studies have been done on heart failure with decreased ejection fractions, but few studies have looked at therapies, and specifically pharmacotherapies, for HFpEF. Of the few studies performed, no significant benefits were seen during trials with angiotensin converting enzyme inhibitors, angiotensin receptor blockers, or beta blockers in patients with HFpEF.2
Williams and Onarecker
Page 2
Author Manuscript
Mineralocorticoid receptor antagonists, specifically spironolactone, have been investigated as a potential therapy for HFpEF patients, since they provide significant benefits to many patients with HFrEF. Aldosterone can stimulate myocyte hypertrophy and interstitial fibrosis, the dominant pathophysiological features of diastolic dysfunction in HFpEF, leading to increased left ventricular hypertrophy and worsening heart failure.2 Therefore, blocking this pathway with aldosterone receptor antagonists such as spironolactone has been of increasing interest as a potential treatment for patients with HFpEF.
Summary of the Evidence
Author Manuscript Author Manuscript
Two major randomized controlled trials (RCT) have looked at the use of spironolactone in patients with HFpEF. The first, the Aldo-DHF RCT, evaluated the efficacy and safety of long-term aldosterone receptor blockade in heart failure patients with preserved ejection fraction (HFpEF).3 This multicenter trial assigned 422 patients with NYHA Class II/III heart failure to receive 25 mg of spironolactone or placebo, with follow up at 12 months. Patients, 52% of whom were women, had a mean age of 67 and an ejection fractions >50% or evidence of diastolic dysfunction. The objective was to determine if spironolactone was superior to placebo in improving diastolic function and exercise capacity (VO2) in patients with HFpEF.3 Although the study showed a decreased diastolic dysfunction with spironolactone compared to the placebo (95% CI, p 45%, at least one sign and symptom of heart failure, and recent hospitalization for heart failure or an elevated BNP. The study showed a decrease in hospitalization rates in patients who were given spironolactone (95% CI, p=0.04) compared to placebo, but no reduction in the risk of deaths from cardiac causes or increase survival rate of cardiac arrest.4 Therefore, when
J Okla State Med Assoc. Author manuscript; available in PMC 2017 February 07.
Williams and Onarecker
Page 3
Author Manuscript
looking at the composite data – deaths from cardiac causes, aborted cardiac arrest, and hospitalization for management of heart failure – spironolactone was no better than placebo.4
Author Manuscript
One weakness of the study was that it only looked at one aspect of what was causing death or hospitalization in these patients, which was heart failure. Heart failure, however, is only one in a broad range of co-morbid conditions in this patient population. Also, patients were able to be enrolled in this study based on either BNP levels or previous hospitalization for heart failure. This category of patients were at a lower risk compared to those enrolled based on BNP levels. Patients in Russia and Georgia were primarily enrolled by hospitalization criteria alone, while those in the Americas were more evenly balanced in regards to the criteria used to enroll in the study. This difference had the potential to create a discrepancy in the results attributed to regional heterogeneity and coexisting conditions and/or practice patterns. Finally, results could have been significantly affected by the fact that a third of participants stopped taking the study drug, primarily due to side effectst.4
Conclusion Treatment protocols have been widely studied for patients with HFrEF, but there are limited studies regarding treatment of HFpEF. Only two major RCTs have looked at spironolactone in patients with HFpEF. The Aldo-DHF trial showed improvement of diastolic dysfunction and left ventricular remodeling compared to placebo, but no significant change in maximal exercise capacity. TOPCAT showed that, for patients with HFpEF, spironolactone did not reduce death from the composite primary outcome of death from cardiovascular events, aborted cardiac arrests, or hospitalizations from heart failure.
Author Manuscript
Acknowledgments “Clin-IQ is a shared resource made possible by Oklahoma Shared Clinical and Translational Resources, funded by grant NIGMS U54GM104938, National Institute of General Medical Sciences, National Institutes of Health.”
Reference list
Author Manuscript
1. Miller RJH, Howlett JG. Evolving role for mineralocorticoid receptor antagonists in heart failure with preserved ejection fraction. Current Opinion in Cardiology. 2015; 30(2):168–172. 2. Desai AS, Lewis EF, Li R, et al. Rationale and design of the Treatment of Preserved Cardiac Function on Heart Failure with an Aldosterone Antagonist Trial: A randomized, controlled study of spironolactone in patients with symptomatic heart failure and preserved ejection fraction. American Heart Journal. 2011; 162(6):966–972. [PubMed: 22137068] 3. Eldeman F, Wachter R, Schmidt AG, et al. Effect of spironolactone on diastolic function and exercise capacity in patients with heart failure with preserved ejection fraction: the Aldo-DHF randomized controlled trial. JAMA. 2013; 309:781–791. [PubMed: 23443441] 4. Pitt B, Pfeffer MA, Assmann SF, et al. Spironolactone for heart failure with preserved ejection fraction. NEJM. 2014; 370:1383–1392. [PubMed: 24716680]
J Okla State Med Assoc. Author manuscript; available in PMC 2017 February 07.
J Okla State Med Assoc. Author manuscript; available in PMC 2017 February 07. Published in final edited form as: J Okla State Med Assoc. 2016 September ; 109(9): 437–438.
Clinical Question: In congestive heart failure patients with preserved ejection fraction, does spironolactone improve cardiac outcomes? Leslie Williams, DO and Cheyn Onarecker, MD St. Anthony Family Medicine Residency, Oklahoma City, OK
Author Manuscript
Abstract Clinical Question—In congestive heart failure patients with preserved ejection fraction, does spironolactone improve cardiac outcomes? Answer—No. A randomized controlled trial of patients with heart failure and an ejection fraction > 45% showed that spironolactone did not significantly reduce the incidence of the primary composite outcome of death from cardiovascular causes, aborted cardiac arrest, or hospitalization for the management of heart failure. Level of Evidence for the Answer—A Search Terms—Congestive heart failure, Spironolactone, Ejection fraction, Preserved, Mineralocorticoids
Author Manuscript
Limits—English, Adults, Randomized Controlled Trials, Meta-analysis, and Systematic review Date Search Was Conducted—December 2015 Inclusion criteria—All randomized controlled trials, Meta-analyses, and systematic reviews in patients with congestive heart failure with preserved ejection fractions, who were taking spironolactone, and published in the past 5 years. Exclusion criteria—Age less than eighteen years, Eplerenone
Summary of the Issues
Author Manuscript
Heart failure is a disabling disease that affects more than 5 million Americans. It is also a major cause of morbidity and mortality worldwide.1 Up to 50% of patients with heart failure have a preserved ejection fraction (HFpEF), with an ejection fraction > 45%. Despite having a higher ejection fraction, however, patients with HFpEF have essentially the same morbidity and mortality rates as patients with heart failure that have reduced ejection fractions (HFrEF). HFpEF patients have a mortality rate up to 43% in 5 years.1 HFpEF disproportionally affects women and the elderly and is commonly associated with hypertension and diabetes mellitus. Many studies have been done on heart failure with decreased ejection fractions, but few studies have looked at therapies, and specifically pharmacotherapies, for HFpEF. Of the few studies performed, no significant benefits were seen during trials with angiotensin converting enzyme inhibitors, angiotensin receptor blockers, or beta blockers in patients with HFpEF.2
Williams and Onarecker
Page 2
Author Manuscript
Mineralocorticoid receptor antagonists, specifically spironolactone, have been investigated as a potential therapy for HFpEF patients, since they provide significant benefits to many patients with HFrEF. Aldosterone can stimulate myocyte hypertrophy and interstitial fibrosis, the dominant pathophysiological features of diastolic dysfunction in HFpEF, leading to increased left ventricular hypertrophy and worsening heart failure.2 Therefore, blocking this pathway with aldosterone receptor antagonists such as spironolactone has been of increasing interest as a potential treatment for patients with HFpEF.
Summary of the Evidence
Author Manuscript Author Manuscript
Two major randomized controlled trials (RCT) have looked at the use of spironolactone in patients with HFpEF. The first, the Aldo-DHF RCT, evaluated the efficacy and safety of long-term aldosterone receptor blockade in heart failure patients with preserved ejection fraction (HFpEF).3 This multicenter trial assigned 422 patients with NYHA Class II/III heart failure to receive 25 mg of spironolactone or placebo, with follow up at 12 months. Patients, 52% of whom were women, had a mean age of 67 and an ejection fractions >50% or evidence of diastolic dysfunction. The objective was to determine if spironolactone was superior to placebo in improving diastolic function and exercise capacity (VO2) in patients with HFpEF.3 Although the study showed a decreased diastolic dysfunction with spironolactone compared to the placebo (95% CI, p 45%, at least one sign and symptom of heart failure, and recent hospitalization for heart failure or an elevated BNP. The study showed a decrease in hospitalization rates in patients who were given spironolactone (95% CI, p=0.04) compared to placebo, but no reduction in the risk of deaths from cardiac causes or increase survival rate of cardiac arrest.4 Therefore, when
J Okla State Med Assoc. Author manuscript; available in PMC 2017 February 07.
Williams and Onarecker
Page 3
Author Manuscript
looking at the composite data – deaths from cardiac causes, aborted cardiac arrest, and hospitalization for management of heart failure – spironolactone was no better than placebo.4
Author Manuscript
One weakness of the study was that it only looked at one aspect of what was causing death or hospitalization in these patients, which was heart failure. Heart failure, however, is only one in a broad range of co-morbid conditions in this patient population. Also, patients were able to be enrolled in this study based on either BNP levels or previous hospitalization for heart failure. This category of patients were at a lower risk compared to those enrolled based on BNP levels. Patients in Russia and Georgia were primarily enrolled by hospitalization criteria alone, while those in the Americas were more evenly balanced in regards to the criteria used to enroll in the study. This difference had the potential to create a discrepancy in the results attributed to regional heterogeneity and coexisting conditions and/or practice patterns. Finally, results could have been significantly affected by the fact that a third of participants stopped taking the study drug, primarily due to side effectst.4
Conclusion Treatment protocols have been widely studied for patients with HFrEF, but there are limited studies regarding treatment of HFpEF. Only two major RCTs have looked at spironolactone in patients with HFpEF. The Aldo-DHF trial showed improvement of diastolic dysfunction and left ventricular remodeling compared to placebo, but no significant change in maximal exercise capacity. TOPCAT showed that, for patients with HFpEF, spironolactone did not reduce death from the composite primary outcome of death from cardiovascular events, aborted cardiac arrests, or hospitalizations from heart failure.
Author Manuscript
Acknowledgments “Clin-IQ is a shared resource made possible by Oklahoma Shared Clinical and Translational Resources, funded by grant NIGMS U54GM104938, National Institute of General Medical Sciences, National Institutes of Health.”
Reference list
Author Manuscript
1. Miller RJH, Howlett JG. Evolving role for mineralocorticoid receptor antagonists in heart failure with preserved ejection fraction. Current Opinion in Cardiology. 2015; 30(2):168–172. 2. Desai AS, Lewis EF, Li R, et al. Rationale and design of the Treatment of Preserved Cardiac Function on Heart Failure with an Aldosterone Antagonist Trial: A randomized, controlled study of spironolactone in patients with symptomatic heart failure and preserved ejection fraction. American Heart Journal. 2011; 162(6):966–972. [PubMed: 22137068] 3. Eldeman F, Wachter R, Schmidt AG, et al. Effect of spironolactone on diastolic function and exercise capacity in patients with heart failure with preserved ejection fraction: the Aldo-DHF randomized controlled trial. JAMA. 2013; 309:781–791. [PubMed: 23443441] 4. Pitt B, Pfeffer MA, Assmann SF, et al. Spironolactone for heart failure with preserved ejection fraction. NEJM. 2014; 370:1383–1392. [PubMed: 24716680]
J Okla State Med Assoc. Author manuscript; available in PMC 2017 February 07.
