Management Strategies with Aldosterone Antagonism: New Indications and New Trials

Educational Objectives

Consider the potential for hyperkalemia when using standard heart failure therapies and mineralocorticoid receptor antagonists on patients with heart failure.

Summary

Interviewer: Steven E. Nissen, MD, MACC

Take-home Messages:

• Mineralocorticoid receptor antagonists (MRAs) improve survival among patients with varying degrees of heart failure (HF).
• However, life-threatening hyperkalemia can occur when these drugs are used along with standard HF therapies, such as angiotensin-converting enzyme (ACE) inhibitors and ARBs.
• Two new drugs for treating hyperkalemia are in the final stage of FDA review, potentially providing new options to patient who might benefit from the cardiorenal protective effects of MRA therapy.

In recent years, there has been a resurgent interest in antagonizing aldosterone. We know that activation of mineralocorticoid receptors by aldosterone and cortisol has deleterious effects in patients with cardiovascular disease (CVD). Also, these receptors are not blocked by angiotensin-converting enzyme inhibitors, ARBs, or beta-blockers, so patients with even mild heart failure may have persistently elevated plasma aldosterone and cortisol levels.

Aldosterone antagonism, on the other hand:

• promotes conservation of potassium and magnesium, the depletion of which potentiates ventricular arrhythmias and sudden death
• inhibits fibroblast proliferation and perivascular fibrosis, which are promoted by chronic hyperaldosteronism
• promotes reversal of unfavorable coronary and renal vascular remodeling, which is modulated by endothelial-cell and baroreceptor dysfunction

Several trials have demonstrated the value of using mineralocorticoid receptor antagonists (MRAs) in the setting of heart failure (Table). In the placebo-controlled Randomized Aldactone Evaluation Study (RALES), adding the MRA spironolactone to standard therapy in patients with systolic HF and moderate-to-severe symptoms (i.e., New York Heart Association [NYHA] functional class III or IV symptoms) decreased the rate of death from any cause and the risk of hospitalization for CV reasons.¹ In EPHESUS (Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study), the selective MRA eplerenone, added to recommended therapy, reduced all-cause mortality and cardiac hospitalizations among patients with acute myocardial infarction (MI) complicated by HF with LV systolic dysfunction.²

The EMPHASIS-HF trial (Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure) evaluated the effects of adding eplerenone to evidence-based therapy on clinical outcomes in patients with systolic HF and mild symptoms (i.e., NYHA functional class II symptoms).³ Eplerenone reduced the rate of death from CV causes or hospitalization for HF by approximately 37% versus placebo in patients with functional class II HF.

That may seem like a powerful effect in mildly symptomatic patients, but a closer look at the study participants shows that the majority were veterans of heart disease: one-half had previously been hospitalized for HF and had a history of MI; also common were hypertension, atrial fibrillation, and diabetes.⁴ In an accompanying commentary to the trial results, Paul W. Armstrong, MD (Professor of Medicine at the University of Alberta, Edmonton), noted that the mean ejection fraction (EF) of 26% (nearly identical to that in the more severely symptomatic patients in RALES) is a cogent reminder of the discordance between functional class and LV function.

An additional feature marking the EMPHASIS-HF patients as high risk is that approximately one-quarter had left bundle branch block and the overall mean QRS duration was 122 msec (with one-quarter having a QRS duration >130 msec).

According to Barry H. Greenberg, MD, Professor of Medicine at the University of California, San Diego, and Director of the Advance Heart Failure Treatment Program there, the guidelines suggest considering aldosterone antagonist therapy for patients with class III or IV HF. For patients with milder HF (class II), he said, aldosterone antagonists should be limited to individuals at high risk of morbidity and mortality. This would include patients with a recent hospitalization or high levels of natriuretic peptide. For the post-MI population, he said, treatment may be considered for patients with evidence of HF and low EF (<40%) or low EF and evidence of diabetes. “That comes directly from the clinical trial data,” he stressed.

Reduction in All-Cause Mortality with Aldosterone Antagonists

Trial	Placebo	Aldosterone Antagonist	HR (95% CI)	Log-rank p Value
EPHESUS Post-MI	554/3,319	478/3,313	0.85 (0.75-0.96)	0.008
RALES Advanced HF	386/841	284/822	0.70 (0.60-0.82)	<0.001
EMPHASIS-HF Milder HF	356/1,373	249/1,364	0.76 (0.62-0.93)	0.008

CI = confidence interval; EMPHASIS-HF = Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure; EPHESUS = Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study; hr = hazard ratio; MI = myocardial infarction; RALES = Randomized Aldactone Evaluation Study.

Hyperkalemia — and Two New Drugs to Fight It

Of course, hyperkalemia is a concern when using these agents. In EMPHASIS-HF, it occurred in 8.0% of study participants, versus 3.7% in the placebo arm (p < 0.001). However, as an adverse event leading to study withdrawal, hyperkalemia was not a significant factor: 1.1% versus 0.9% with placebo therapy (p = 0.57).

Nevertheless, broader use of aldosterone antagonism has been limited, in part, because of concerns about hyperkalemia. Certainly it is a legitimate issue: publication of RALES sparked an increase in prescriptions for spironolactone and as a parallel increase in hospital admissions and death from hyperkalemia.⁵

More recently, Abbas et al. published worrisome data from a massive German nested case-control study of patients with HF receiving spironolactone plus continuous ACE/ARB therapy (n = 1,491,894).⁶ In this diverse real-world population, the risk of hyperkalemia associated with spironolactone use in those taking continuous ACE/ARB therapy was much higher (odds ratio: 13.59) than that observed in clinical trials.

The only agent currently available in the United States that lowers total body potassium levels is sodium polystyrene sulfonate, which was approved based on a trial from the early 1960s conducted in 32 hyperkalemic patients with azotemia at a time before dialysis was available. Its effects on serum potassium are unpredictable, and it has never undergone rigorous testing in clinical trials to prove its efficacy and safety for treatment of acute or chronic hyperkalemia.

Enter patiromer (Relypsa, Inc.) and sodium zirconium cyclosilicate (ZS Pharma), two drugs that bind potassium and clear it from the body, albeit with differing mechanisms of action. Patiromer is a potassium binder in oral suspension form. It has been submitted to the FDA for approval, with a decision expected in October 2015. ZS-9 is an insoluble zirconium silicate with a 3-dimensional crystalline lattice structure designed to preferentially trap potassium ions. A new drug application for ZS-9 was submitted to the FDA on May 26, 2015.

In phase III clinical trials, both drugs normalized levels of plasma potassium in hyperkalemic patients with chronic kidney disease (CKD), diabetes, or HF who were receiving RAAS inhibitors.^7,8 In the recently published AMETHYST-DN trial,⁹ Bakris and colleagues conducted a phase II dose-finding trial of patiromer in patients with stage 3 and 4 CKD who received RAAS inhibitors and had a baseline potassium level >5.0 mEq/l. Depending on their level of hyperkalemia, participants were given one of three starting doses, with adjustments made to achieve target potassium concentrations of ≤5 mEq/l.

Potassium concentrations were significantly reduced in each baseline hyperkalemia stratum at 4 weeks, with results persisting to 8 weeks. Perhaps more important, over an additional 44 weeks of maintenance therapy, most patients treated with patiromer remained normokalemic, and potassium levels increased quickly once the study drug was stopped.

According to Peter McCullough, MD, from the Baylor Heart and Vascular Institute in Dallas, Texas, “these drugs are going to help markedly keep patients on the drugs that are cardio- and reno-protective. For instance, the MRA drugs: we only use them in about 40% of the patients who need them because we’re limited by hyperkalemia, so this should be a dramatic change in our practice, and I think we’re very hopeful that we will see improved outcomes over time once these new drugs get on the market and get in use.”

Once approved based on the surrogate of potassium concentration, the hyperkalemia drugs need to be further tested to see if they will allow patients who are about to fail, or have failed, RAAS inhibitor treatment to stay on their drugs, according to nephrologist Wolfgang C. Winkelmayer, MD, ScD, Baylor College of Medicine, Houston, Texas, and an associate editor at JAMA.¹⁰

Readings

1. Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med 1999;341:709-17.

2. Pitt B, Remme W, Zannad F, et al. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med 2003;348:1309-21

3. Zannad F, McMurray JJV, Krum H, et al. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med 2011;364:11-21.

4. Armstrong PW. Aldosterone Antagonists — Last Man Standing? N Engl J Med 2011;364:79-80.

5. Juurlink DN, Mamdani MM, Lee DS, et al. Rates of hyperkalemia after publication of the Randomized Aldactone Evaluation Study. N Engl J Med 2004;351:543-51.

6. Abbas S, Ihle P, Harder S, Schubert I. Risk of hyperkalemia and combined use of spironolactone and long-term ACE inhibitor/angiotensin receptor blocker therapy in heart failure using real-life data: a population- and insurance-based cohort. Pharmacoepidemiol Drug Saf 2015;24:406-13.

7. Weir MR, Bakris GL, Bushinsky DA, et al. Patiromer in patients with kidney disease and hyperkalemia receiving RAAS inhibitors. N Engl J Med 2015;372:211-21.

8. Packham DK, Rasmussen HS, Lavin PT, et al. Sodium zirconium cyclosilicate in hyperkalemia. N Engl J Med 2015;372:222-31.

9. Bakris GL, Pitt B, Weir MR, et al. Effect of Patiromer on Serum Potassium Level in Patients With Hyperkalemia and Diabetic Kidney Disease: The AMETHYST-DN Randomized Clinical Trial. JAMA 2015;314:151-61.

10. Winkelmayer WC. Treatment of Hyperkalemia: From “Hyper K+” Strikeout to Home Run? JAMA 2015;314:129-30.

Disclosures

Barry H. Greenberg, MD, FACC
This author has nothing to disclose.

Interviewer: Steven E. Nissen, MD, MACC
Novo Nordisk A/S (G); Eli Lilly and Co (G); Amgen Inc (G); Orexigen Therapeutics Inc (G); Resverlogix Corp (G); Novartis AG (G); The Medicines Company (G); Pfizer Inc (G); AstraZeneca (G); VIVUS Inc (G);Takeda Pharmaceutical Co Ltd (G)

The planning committee reported nothing to disclose.

A = Advisory panel B = Speakers’ bureau C = Consultant fees/honoraria D = Data and Safety Monitoring Board E = Equity interests/stock options F = Fellowship support G = Grant support L = Licensing Agreement O = Other relationship R = Royalties S = Salary W = Expert witness

Acknowledgements

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