MRA Strongly Recommended in Treatment of Heart Failure with Reduced Ejection Fraction: 2021 ESC Guidelines

Pharmacotherapy is the cornerstone of treatment for Heart Failure with Reduced Ejection Fraction (HFrEF) and should be implemented before considering device therapy, and alongside non-pharmacological interventions.

The recently issued guidelines strongly recommend the use of mineralocorticoid Receptor Antagonist (MRA) in addition to an ACE-I and a beta-blocker, in all patients with HFrEF to reduce mortality and the risk of HF hospitalization (class 1A recommendation).

This marks a major change from the previous European Society of Cardiology (ESC) guidelines on the same topic issued in 2016, where only ACE-I and beta-blockers were class IA recommendations. In contrast, the recent guidelines mark the strong change in approach calling for the initiation of MRAs (Spironolactone or Eplenorone) along ACE-I and beta-blockers quickly and safely as possible.

Heart failure (HF) is a global pandemic affecting at least 26 million people worldwide1with an increasing prevalence of heart failure in India due to coronary heart disease, hypertension, obesity, diabetes, and rheumatic heart disease ranging from 1.3 to 4.6 million, with an annual incidence of 491 600–1.8 million.2

People with heart failure develop a poor quality of life due to various symptoms such as shortness of breath, dysphagiafatigue, sleeping difficulties, etc which takes their mental well being consequently affecting the quality of life. Poor QOL is related to high hospitalization and mortality rates.3-6

At regular intervals, the ESC releases guidelines to help health professionals manage people with heart failure (HF) according to the best available evidence. This year ESC has revised the format of the previous 2016 ESC HF Guidelines to make each phenotype of HF stand-alone in terms of its diagnosis and management.

On the issue of MRA, the guidelines strongly recommend the use of MRAs in all patients with heart failure with left ventricular reduced ejection fraction (LVEF<40%) to reduce mortality and the risk of HF hospitalization (class1A recommendation). In cases of Heart Failure with Mild Reduced Ejection Fraction (HFmrEF), the guidelines recommend that MRA may be used (a classII b level C) to reduce the risk of HF, hospitalization, and death.

Aldosterone receptor antagonists (also called anti mineralocorticoid, MCRA, or MRA) are a class of drugs that block the effects of aldosterone.

Therapy with MRA has a role in preventing these maladaptive effects in patients with CHF and left ventricular (LV) systolic dysfunction.7

MRAs block receptors that bind aldosterone and, with different degrees of affinity, other steroid hormones (e.g. corticosteroid and androgen) receptors. There are two types of MRAs namely Eplenorone and Spironolactone. Eplerenone is more specific for aldosterone blockade and, therefore, causes less gynecomastia.

What do Guidelines say?

Apart from the recommendations on indications, the guidelines also lay down various aspects for the use of MRA including dosage, how to use, what advice to give to patients as well as caution.

On the issue of Dosage the guidelines recommend starting with a low dose (Eplerenone/ Spironolactone: starting dose 25 mg once a day, target dose 50 mg once a day), and have continuous monitoring of blood chemistry at the given time intervals:

● 1 and 4 weeks after starting or increasing the dose

● 8 and 12 weeks

● 6, 9, and 12 months and 4-monthly thereafter

Also, dose up the titration after 48 weeks, states the guideline.

The guidelines call for doctors to ascertain a renal function and electrolyte level test before MRA therapy commencing. In case of potassium level rising above 5.5-6 mmol/L or creatinine rising to 221-310 lmol/L, immediately seek specialist advice.

Besides this, the guidelines also lay down what advice a doctor should give to the patient while prescribing them MRA. In particular, it states.

● Treatment is given to improve symptoms but may not be immediate and could be seen within a few months of starting the therapy

● Treatment is to prevent the worsening of HF leading to hospital admission and to increase survival.

● Avoid NSAIDs not prescribed by a physician/ over-the-counter and salt substitutes high in potassium.

The guidelines contraindicate the use of MRA in case of known allergic reactions. Also, guides the physician to seek cautions in certain conditions such as Significant hyperkalemia (K >5.0 mmol/L), significant renal dysfunction [creatinine > 221 lmol/L ( >2.5 mg/dL) or eGFR < 30 mL/min/1.73 m2 ].

Furthermore, the guideline states to look out for certain drug interactions, which includes (K supplements/K-sparing diuretics (e.g. amiloride and triamterene; beware combination preparations with furosemide), ACE-Is/ARBs/renin inhibitors, NSAIDs, Trimethoprim/trimethoprim-sulfamethoxazole, 'Low-salt' substitutes with a high K content, Strong CYP3A4 inhibitors, e.g. ketoconazole, itraconazole, nefazodone, telithromycin, clarithromycin, ritonavir, and nelfinavir (when eplerenone used).

References

1. Savarese, G., & Lund, L. H. (2017). Global Public Health Burden of Heart Failure. Cardiac failure review, 3(1), 7–11. https://doi.org/10.15420/cfr.2016:25:2

2. Huffman, Mark D, and DorairajPrabhakaran. "Heart failure: epidemiology and prevention in India." The National medical journal of India vol. 23,5 (2010): 283-8.

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7. Enrico Vizzardi,* Valentina Regazzoni, Giorgio Caretta, Mara Gavazzoni, EdoardoSciatti, IvanoBonadei, EleftheriaTrichaki, Riccardo Raddino, and Marco Metra