Ms. Kay Lotsa is a 48-year-old woman with a history of CKD stage 2 (baseline creatinine ~1.2 mg/dL) & type 2 diabetes mellitus. She has recently noticed progressively reduced exercise tolerance, leg swelling, and trouble lying flat. This prompted a hospital admission with a new diagnosis of decompensated heart failure. A transthoracic echocardiogram reveals LVEF of 35%. Ms. Lotsa is diuresed to euvolemia, and she is started on carvedilol 25mg BID, sacubitril/valsartan 49-51mg BID, and empagliflozin 10mg daily, which she tolerates well. Her eGFR is at her baseline of 55 mL/min/1.73 m² and serum potassium concentration is 3.9 mEq/L. Your team is anticipating she will be discharged home in the next one to two days and wants to start spironolactone. Which of the following is most important regarding her treatment with mineralocorticoid antagonists?

A

Spironolactone is contraindicated based on her level of renal impairment and should not be started

B

Serum potassium levels and kidney function should be assessed within 1-2 weeks of starting spironolactone

C

Eplerenone confers a higher risk of gynecomastia than does spironolactone

D

The patient will likely not benefit from initiation of spironolactone if her cardiomyopathy is ischemic in origin

Explanation

The correct answer is B – after starting a mineralocorticoid receptor antagonist (MRA), it is important to closely monitor renal function and serum potassium levels.

MRA (also known as aldosterone antagonists or anti-mineralocorticoids) show consistent improvements in all-cause mortality, HF hospitalizations, and SCD across a wide range of patients with HFrEF.

The RALES trial of spironolactone vs. placebo in highly symptomatic HFrEF (LVEF ≤ 35%, NYHA III-IV), trial of eplerenone vs placebo post-MI in patients with LVEF ≤ 40%, and EMPHASIS-HF trial of eplerenone vs placebo in less symptomatic HFrEF (LVEF ≤ 35%, NYHA II) altogether suggest MRAs confer improvements in all-cause mortality, HF hospitalizations, and sudden cardiac death in patients with HFrEF. Importantly, these benefits have been demonstrated across a wide range of HFrEF severity and etiologies, including ischemic cardiomyopathy (Option D).

Therefore, in patients with HFrEF and NYHA class II to IV symptoms, an MRA (spironolactone or eplerenone) is recommended to reduce morbidity and mortality, if eGFR is >30 mL/min/1.73 m2 and serum potassium is <5.0 mEq/L. Careful monitoring of potassium, renal function, and diuretic dosing should be performed at initiation and closely monitored thereafter to minimize risk of hyperkalemia and renal insufficiency (Class 1, LOE A). MRA therapy in this context provides high economic value.

Adverse Effects of MRAs

Both spironolactone and eplerenone are excreted by the kidney and due to their inhibition of aldosterone signaling, reduce potassium excretion in the urine. For these reasons, the initiation of MRAs is contraindicated in patients with eGFR of ≤30 mL/min/1.73m² or serum potassium levels of ≥5.0 mEq/L. After starting or intensifying MRA therapy, serum potassium levels and renal function should be rechecked at approximately 1 week, at 4 weeks, and every 6 months thereafter, provided clinical stability. Hyperkalemia can increase the risk of ventricular arrhythmias and death. Unfortunately, this often results in de-escalation or discontinuation of RAASi and a subsequent loss of long-term cardiorenal benefits of maximally tolerated GDMT.

The utility of prescribing potassium binders (e.g., patiromer, sodium zirconium cyclosilicate) to improve outcomes by facilitating continuation of  Patiromer and sodium zirconium cyclosilicate remove potassium by exchanging cations leading to increased fecal excretion and thereby lowering serum potassium levels. These have been FDA approved for treatment of hyperkalemia for patients receiving RAASi.

Therefore, the use of potassium binders (patiromer, sodium zirconium cyclosilicate) to improve outcomes by facilitating the continuation of RAASi therapy in patients with HF who experience hyperkalemia (serum potassium level ≥5.5 mEq/L) received a Class 2b recommendation (LOE B-R), but overall utility remains uncertain.

In the DIAMOND trial, patients with HFrEF and hyperkalemia were randomized to patiromer vs. control. In the run-in phase, all patients were started on patiromer, and subsequently, RAASi therapy was initiated/optimized. After this, patients were randomized to continue vs stop patiromer. Hard clinical primary endpoints of time to CV death or first CV hospitalization were changed to mean change in serum potassium due to challenges with recruitment related to the COVID-19 pandemic. There was a significant reduction in the mean change of potassium (0.03 mEq/L in the patiromer group vs. 0.13 mEq/L in the control). Additionally, 85% of the patiromer arm was able to be optimized on RAASi.

Aside from hyperkalemia, troublesome side effects of MRAs include gynecomastia and vaginal bleeding. Eplerenone results in lower rates of these side effects than spironolactone given greater specificity for the aldosterone receptor (Option C).

Main Takeaway

Mineralocorticoid receptor antagonists, like spironolactone and eplerenone, reduce all-cause mortality, HF hospitalizations, and sudden cardiac death in a wide range of patients with HFrEF. Monitoring renal function and potassium levels while on MRA therapy is imperative.

Guideline Loc.

Section 7.3.3
Section 7.3.6