Don’t, don’t, don’t, don’t; Don’t you, forget about Aldosterone antagonists for HFrEF

By Kristin Watson posted 12 days ago


I am as big as a fan of anyone for use of angiotensin-receptor neprilysin inhibitor (ARNI) and sodium glucose co-transporter (SGLT) 2 inhibitor for those with heart failure with a reduced ejection fraction (HFrEF).1–4 It is amazing to witness, first-hand, the improvement in functional status and quality of life that these therapies have for those with HFrEF. This is in addition to the impact that these therapies have on mortality and hospitalization in this population. 1–3 We are fortunate to now have a “4 pillar regimen” for those with HFrEF: 1) evidence based beta-blocker 2) angiotensin converting enzyme inhibitor, angiotensin II receptor blocker, or ARNI 3) mineralocorticoid receptor antagonist (MRA) and 4) SGLT2 inhibitor.5 This blog hope to highlight the need not to forget MRA therapy with the advent of ARNI and SGLT2 inhibitors for those with HFrEF.

Data from the CHAMP-HF Registry shed light on suboptimal use of guideline directed medical therapy (GDMT) for those with HFrEF. 6 In this 2018 publication, 33.1% of those who qualified for MRA therapy, spironolactone or eplerenone, were treated with an agent from this class. Those not receiving therapy were older, had a milder New York Heart Association (NYHA) functional class, lower rate of prior hospitalization, and worse renal function compared to those prescribed a MRA. This highlights a major concern in this population – clinical inertia.7

Failure to start a MRA, or one of our other 4 pillars of treatment for HFrEF, without a contraindication to use, can lead to avoidable hospitalizations or death. HFrEF is progressive disease and starting treatment as soon as possible in those with NYHA II-IV is imperative.4,11,12 Too often a MRA is not initiated, when indicated, because a person with HFrEF is  deemed “stable” or “doing well” or there are misconceptions about contraindications/precautions to therapy. 6,7

Quick recap on MRA awesomeness.  Use in those with NYHA class II-IV HFrEF is associated with a lower the risk of death and the risk of heart failure (HF) hospitalization. Nine. Nine was number needed to treat (NNT) to prevent one death over a two year period in the landmark RALES trial which included those with moderate to severe HFrEF (NYHA class III-IV).8 The NNT to prevent cardiovascular death or HF hospitalization was 19 per year of follow-up in the EMPHASIS-HF trial which included those with HFrEF and NYHA II symptoms.

“Low blood pressure” may be cited as a reason by some providers for not initiating or titrating GDMT in those with HFrEF. 9 Fortunately, use of MRA therapy in those with HFrEF has little effect on systolic blood pressure (SBP).10 In the landmark RALES and EMPHASIS-HF trials, hypotension was similar between those with HFrEF receiving a MRA or placebo, this includes when baseline SBP was 105 mmHg or less. The clinical benefit of MRA therapy in the HFrEF is irrespective of baseline BP. This makes MRA therapy attractive even in those with advanced heart failure when blood pressure is often low. Baseline use of MRA therapy was high in the landmark SGLT2 inhibitor trials (~71%) and ARNI HFrEF trial (55.3%).1–3 This provides further evidence that a multitude of HFrEF therapies can be tolerated.

Hyperkalemia, a potentially life-threatening adverse effect, is not uncommon with use of MRA therapy.13,14 This should not discourage MRA use, when appropriate, but serves as reminder to select the correct starting dose based on a person’s renal function and ensure close laboratory monitoring.  Too often, monitoring of renal function and potassium does not occur in practice.15,16 Check out this piece more about management of hyperkalemia in those receiving renin-angiotensin aldosterone system inhibitors:

It is recognized that the costs of GDMT for HFrEF can be prohibitive, especially with the price of ARNI and SGLT2 inhibitor being steep for many. It is important to remember that even for those with insurance that multiple co-pays add up quickly and can force a person to choose between paying for medications vs. food, etc. Generic formulation of MRAs are available and may be a reasonable option for some from a cash price perspective when they do not have insurance. The cash price for a 30-day supply of 25 mg of spironolactone is $5.70 to $13.80.  The cost of a 30-day supply eplerenone is much higher ($125.10 to 130.20).17,18

It is imperative for all of us who care for those with HFrEF to optimize GDMT whenever possible. Too often there is an unjustifiable reason for why a person with NYHA class II-IV HFrEF is not on spironolactone or eplerenone. Clinicians are urged to identify when treatment can be initiated, and that close monitoring occurs. Doing so can work wonders – lowering the risk for death and hospitalization.

Title idea game from this 1985 hit by Simple Minds “Don’t You (Forget About Me)



  1. McMurray JJV, Packer M, Desai AS, et al. Angiotensin–Neprilysin Inhibition versus Enalapril in Heart Failure. N Engl J Med. 2014;371(11):993-1004. doi:10.1056/NEJMoa1409077
  2. McMurray JJV, Solomon SD, Inzucchi SE, et al. Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction. N Engl J Med. 2019;381(21):1995-2008. doi:10.1056/NEJMoa1911303
  3. Packer M, Anker SD, Butler J, et al. Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure. N Engl J Med. 2020;383(15):1413-1424. doi:10.1056/NEJMoa2022190
  4. Maddox TM, Januzzi JL, Allen LA, et al. 2021 Update to the 2017 ACC Expert Consensus Decision Pathway for Optimization of Heart Failure Treatment: Answers to 10 Pivotal Issues About Heart Failure With Reduced Ejection Fraction. J Am Coll Cardiol. 2021;77(6):772-810. doi:10.1016/j.jacc.2020.11.022
  5. Experts Tout Immediate Quadruple Therapy for HFrEF Patients. Medscape. Accessed October 3, 2021.
  6. Greene SJ, Butler J, Albert NM, et al. Medical Therapy for Heart Failure With Reduced Ejection Fraction: The CHAMP-HF Registry. J Am Coll Cardiol. 2018;72(4):351-366. doi:10.1016/j.jacc.2018.04.070
  7. Verhestraeten C, Heggermont WA, Maris M. Clinical inertia in the treatment of heart failure: a major issue to tackle. Heart Fail Rev. Published online May 30, 2020. doi:10.1007/s10741-020-09979-z
  8. Pitt D. ACE inhibitor co-therapy in patients with heart failure: rationale for the Randomized Aldactone Evaluation Study (RALES). Eur Heart J. 1995;16 Suppl N:107-110. doi:10.1093/eurheartj/16.suppl_n.107
  9. Peri-Okonny P, Mi X, Khariton Y, et al. Target Doses of Heart Failure Medical Therapy and Blood Pressure: Insights from the CHAMP-HF Registry. JACC Heart Fail. 2019;7(4):350-358. doi:10.1016/j.jchf.2018.11.011
  10. Serenelli M, Jackson A, Dewan P, et al. Mineralocorticoid Receptor Antagonists, Blood Pressure, and Outcomes in Heart Failure With Reduced Ejection Fraction. JACC Heart Fail. 2020;8(3):188-198. doi:10.1016/j.jchf.2019.09.011
  11. DeVore AD, Braunwald E, Morrow DA, et al. Initiation of Angiotensin-Neprilysin Inhibition After Acute Decompensated Heart Failure: Secondary Analysis of the Open-label Extension of the PIONEER-HF Trial. JAMA Cardiol. 2020;5(2):202-207. doi:10.1001/jamacardio.2019.4665
  12. Greene SJ, Butler J, Fonarow GC. Simultaneous or Rapid Sequence Initiation of Quadruple Medical Therapy for Heart Failure-Optimizing Therapy With the Need for Speed. JAMA Cardiol. 2021;6(7):743-744. doi:10.1001/jamacardio.2021.0496
  13. 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(6):543-551. doi:10.1056/NEJMoa040135
  14. Shah KB, Rao K, Sawyer R, Gottlieb SS. The adequacy of laboratory monitoring in patients treated with spironolactone for congestive heart failure. J Am Coll Cardiol. 2005;46(5):845-849. doi:10.1016/j.jacc.2005.06.010
  15. Rosano GM, Spoletini I, Vitale C, Agewall S. Hyperkalemia and Renin–Angiotensin–Aldosterone System Inhibitors Dose Therapy in Heart Failure With Reduced Ejection Fraction. Card Fail Rev. 2019;5(3):130-132. doi:10.15420/cfr.2019.8.2
  16. Rosano GMC, Tamargo J, Kjeldsen KP, et al. Expert consensus document on the management of hyperkalaemia in patients with cardiovascular disease treated with renin angiotensin aldosterone system inhibitors: coordinated by the Working Group on Cardiovascular Pharmacotherapy of the European Society of Cardiology. Eur Heart J - Cardiovasc Pharmacother. 2018;4(3):180-188. doi:10.1093/ehjcvp/pvy015
  17. Lexicomp. Spironolactone: Drug information - UpToDate. Accessed October 3, 2021.
  18. Lexicomp. Eplerenone: Drug information - UpToDate. Accessed October 3, 2021.