By Dr. Mustafa Toma (biography and disclosure) and Dr. Christopher Cheung, (biography and disclosures)
Disclosures: Dr. Mustafa Toma has previous received honoraria from Pfizer Canada.
A. Only published trial data is presented
B. Recommendations are consistent with published guidelines (Canadian Cardiovascular Society CCS 2014 HF Guidelines)
C. Treatments or recommendations in this article are unrelated to products/services/treatments involved in disclosure statements
What I did before
There are approximately 500,000 Canadians living with heart failure, although this climbs to more than 10% of patients older than 65 years. In the United States, heart failure is commonly encountered in the family physician’s office, and accounts for nearly 4 million outpatient visits per year, with up to one in 9 deaths listing heart failure as a contributing cause. Up to 50% of patients presenting with signs and symptoms of heart failure will have a preserved ejection fraction (HFpEF or diastolic dysfunction).(1) However, there is a lack of evidence for effective therapies in the management of HFpEF.
Beta-blockers, angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and mineralocorticoid receptor antagonists (MRAs) have all proven effective in the treatment of heart failure with reduced ejection fraction (HFrEF or systolic dysfunction).(2) However, clinical trials evaluating the treatment of HFpEF have not yielded significant improvements in clinical outcomes. The PEP-CHF, CHARM-Preserved, and I-PRESERVE trials evaluated ACE inhibitors and ARBs in the management of HFpEF and identified no mortality reduction but fewer hospital admissions.(3-5) In the OPTIMIZE-HF registry, beta-blockers were ineffective in reducing mortality or hospitalization in patients with HFpEF.(6) Therefore, current guidelines offer no specific recommendations for treating patients with HFpEF, apart from the managing their symptoms, medical comorbidities, and cardiovascular risk.(2)
What changed my practice
The recently published TOPCAT and ALDO-DHF trials provide new insight into the role of mineralocorticoid receptor antagonists (MRAs) in the management of HFpEF. Previously, in the RALES, EPHESUS, and EMPHASIS trials, MRAs (ie. Eplerenone and spironolactone) were demonstrated to reduce mortality and hospitalizations in patients with HFrEF.(7-9)
The TOPCAT trial was a large randomized, double-blinded trial enrolling 3445 patients with heart failure and a left ventricular ejection fraction (LVEF) of 45% or greater, comparing the use of spironolactone (15-45 mg daily) with placebo.(10) Patients had at least one sign and symptom of heart failure, and a serum potassium level <5.0 mmol/L. Those with systemic illnesses with a life expectancy less than 3 years, and severe renal dysfunction (eGFR <30 mL/min/1.73m2) were excluded.
The primary outcome of the TOPCAT trial was a composite of cardiovascular death, aborted cardiac arrest, and hospitalization for heart failure. The authors found no significant reduction in the primary outcome (HR 0.89, p=0.14), but a reduction in hospitalization for heart failure (HR 0.83, p=0.04). Secondary outcomes, including death from any cause, hospitalization for any reason, myocardial infarction, and stroke, were unchanged. Adverse events included a higher rate of hyperkalemia, less hypokalemia, and a higher rate of acute kidney injury but not requiring dialysis in the spironolactone group.
The most controversial finding in the TOPCAT trial was the heterogeneity of results across regions of enrollment. The primary outcome occurred less frequently in the spironolactone group compared to placebo in the Americas, including Canada, United States, Brazil, and Argentina (27.3% vs. 31.8%) compared to Russia and Georgia (9.3% vs. 8.4%). Patients who had a high BNP at baseline also achieved significant benefit with spironolactone vs. placebo (p=0.003), whereas spironolactone had no benefit in those without an elevated BNP.
The ALDO-DHF trial was published recently evaluating the role of spironolactone (25 mg daily) on diastolic function and exercise capacity in 422 patients with HFpEF.(11) Patients were 50 years and older with symptoms of heart failure (NYHA class II or III), LVEF >50%, echocardiographic evidence of diastolic dysfunction, and an exercise capacity of <25 mL/kg/min. Those with significant coronary artery disease, myocardial infarction or bypass surgery within 3 months, clinically significant pulmonary disease, and severe renal dysfunction were excluded.
Spironolactone significantly improved diastolic function compared to placebo (p<0.001), but had no effect on exercise capacity (p=0.81) at 12 months after randomization. Secondary endpoints, including systolic blood pressure and some measures of cardiac function and remodeling, were improved in the spironolactone group. However, symptoms of heart failure, quality of life measurements, and depressive symptoms, were unchanged, and there was a small reduction in 6-minute walk distance in the spironolactone group.
What I do now
The role of MRAs have been clearly established in the treatment of HFrEF. The recent TOPCAT and ALDO-DHF trials attempted to extend these clinical benefits to patients with HFpEF, a population in whom there are currently no effective therapies. The results of these two trials have provided more insight and perhaps raised more questions regarding the role of MRAs in this challenging population. There is a need for more prospective evidence to evaluate MRAs in the treatment of HFpEF.
Results from the TOPCAT trial suggest a potential role for MRAs in this challenging population, although this study was affected by heterogeneous recruitment between geographic regions. In the Americas, there was a significant reduction in the primary outcome of cardiovascular death, aborted cardiac arrest, and hospitalization for heart failure. Similarly, patients with an elevated BNP at baseline also achieved significant benefit with spironolactone, compared to those without an elevated BNP. In the ALDO-DHF trial, MRAs significantly improved diastolic dysfunction in patients with HFpEF, even after adjustment for the reduction in systolic blood pressure. Although this was not manifested in exercise capacity, these results suggest a possible role for spironolactone in improving cardiac function and remodeling.
Therefore, in certain patients with poor diastolic function, symptom burden, and frequent hospitalizations, one could consider using spironolactone to reduce hospitalizations, with possible benefits of cardiac remodeling, and reducing cardiovascular death and cardiac arrest. Adverse events were prevalent across both trials including hyperkalemia and worsening renal function, but not dialysis, highlighting the importance of routine follow-up and regular bloodwork after initiating spironolactone. Eplerenone may be considered in patients developing significant gynecomastia after the initiation of spironolactone.
Despite its prevalence and associated morbidity, there continues to be a lack of effective therapies for patients with HFpEF. Unlike patients with systolic dysfunction, patients with HFpEF are unlikely to benefit from beta-blockers, ACE inhibitors, or ARBs. The recent ALDO-DHF and TOPCAT trials demonstrated an improvement in diastolic function and reduced hospitalization in those treated with the spironolactone, with no effect on cardiovascular mortality in their primary analyses. Additional trials with rigorous enrollment criteria and follow-up will be needed to further evaluate if MRAs can reduce mortality in patients with heart failure with preserved ejection fraction.
Take home points
- There are a lack of effective therapies for suffering from heart failure with preserved ejection fraction (HFpEF).
- Patients with HFpEF are at increased risk for hospitalization and morbidity, and should have their symptoms managed as necessary (ie. with oral diuretics including furosemide).
- Patients with HFpEF should have their cardiovascular risk factors optimized, including blood pressure control and regular screening and treatment of diabetes and dyslipidemia.
- Recent studies have suggested a possible benefit of mineralocorticoid antagonists in patients with HFpEF. Select patients with HFpEF can be considered for this treatment and may also benefit from a referral to a cardiologist.
- Owan TE, Hodge DO, Herges RM, et al. Trends in prevalence and outcome of heart failure with preserved ejection fraction. N Engl J Med. 2006 Jul 20;355(3):251-9. (View with UBC or request from CPSBC)
- Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation. 2013 Oct 15;128(16):e240-327. (View with CPSBC or UBC)
- Cleland JG, Tendera M, Adamus J, et al. The perindopril in elderly people with chronic heart failure (PEP-CHF) study. Eur Heart J. 2006 Oct;27(19):2338-45. View Text
- 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 Sep 6;362:777-81. (View with CPSBC or UBC)
- Massie BM, Carson PE, McMurray JJ, et al. Irbesartan in patients with heart failure and preserved ejection fraction. N Engl J Med. 2008 Nov 11;359(23):2456-87. View Text
- Hernandez AF, Hammill BG, O’Connor CM, et al. Clinical effectiveness of beta-blockers in heart failure: findings from the OPTIMIZE-HF (Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure) Registry. J Am Coll Cardiol. 2009 Jan 13;53(2):184-92. (View with CPSBC or UBC)
- Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med. 1999 Sep 2;341(10):709-17. View Text
- Pitt, Remme W, Zannad, et al. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med. 2003 Apr 3;348(14):1309-1321. View Text
- Zannad F, McMurray JJV, Krum H, et al. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med. 2011 Jan 6;364(1):11-21. View Text
- Pitt B, Pfeffer MA, Assmann SF, et al. Spironolactone for heart failure with preserved ejection fraction. N Engl J Med. 2014 Apr 10;370(15):1383-92. View Text
- Edelmann 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 Feb 27;309(8):781-91. (View with UBC or request from CPSBC)