MRA use not associated with worse kidney outcomes in HFrEF

Safety of continuing mineralocorticoid receptor antagonist treatment in patients with heart failure with reduced ejection fraction and severe kidney disease: data from Swedish Heart Failure Registry

Literature - Guidetti F, Lund LH, Benson L, et al. - Eur J Heart Fail. 2023 Oct 5 [Online ahead of print]. doi: 10.1002/ejhf.3049

Introduction and methods

Background

MRAs are frequently underprescribed or discontinued in patients with HFrEF [1]—especially in those with CKD [2]—despite the strong level of evidence supporting their efficacy and safety, irrespective of baseline renal function [3-7].

Aim of the study

The authors evaluated the risk of renal outcomes, all-cause mortality, and all-cause hospitalization associated with MRA use across the eGFR spectrum in a large, real-world HFrEF cohort, including patients with severe CKD (i.e., eGFR <30 mL/min per 1.73 m²).

Methods

For this observational cohort study, data of 33,942 patients with HFrEF (EF <40%) who were enrolled in the Swedish Heart Failure Registry between 2012 and 2020 were collected. Dialysis at the index visit was an exclusion criterion. At the index date, MRA use and patients’ renal function were assessed.

Outcomes

The primary endpoint was a composite renal outcome of dialysis initiation, renal death, renal failure hospitalization, or hyperkalemia hospitalization after 1 year. Additional endpoints were all-cause mortality and all-cause hospitalization, both assessed at 1 year.

Main results

  • At the index date, 17,489 patients (51%) were prescribed an MRA. Use of MRA decreased with worsening renal function, ranging from 54% for patients with eGFR ≥60 mL/min per 1.73 m² (n=20,868) to 32% for those with eGFR <30 mL/min per 1.73 m² (n=1834). During follow-up , MRA discontinuation was observed in 11% of the patients, evenly distributed across the eGFR spectrum.
  • Of 38 patient characteristics, eGFR ≥60 mL/min per 1.73 m² was the strongest independent predictor of MRA use at baseline (OR for eGFR ≥60 vs.<30 mL/min per 1.73 m²: 2.85; 95%CI: 2.49–3.26). Other relevant predictors were potassium >5 mmol/L (compared with <3.5 mmol/L), more severe HF (i.e., higher NYHA class, use of HF devices or diuretics), beta-blocker use, history of hypertension, and liver disease.
  • In multivariable Cox regression analyses, the incidence rate of the composite renal outcome at 1 year was 14.6 per 1000 patient-years among MRA users compared with 17.5 per 1000 patient-years for nonusers (unadjusted HR: 0.83; 95%CI: 0.79–0.88). After adjustment for baseline patient characteristics such as age, sex, and NYHA class, the HR was 1.04 (95%CI: 0.98–1.10), which was consistent across the eGFR spectrum (P for interaction=0.29). In patients with eGFR <30  mL/min per 1.73 m², the adjusted HR was 1.01 (95%CI: 0.87–1.17).
  • The 1-year rate of all-cause mortality was 12.9 per 1000 patient-years for MRA users versus 15.9 per 1000 patient-years for nonusers (adjusted HR: 1.02; 95%CI: 0.97–1.08; P for interaction by eGFR class=0.39). The adjusted HR was 1.07 (95%CI: 0.92–1.25) for patients with eGFR <30  mL/min per 1.73 m².
  • The 1-year all-cause hospitalization rate was 55.6 per 1000 patient-years for MRA users versus 60.5 per 1000 patient-years for nonusers (adjusted HR: 0.99; 95%CI: 0.95–1.02; P for interaction by eGFR class=0.46). In patients with eGFR <30  mL/min per 1.73 m², the adjusted HR was 1.03 (95%CI: 0.91–1.17).

Conclusion

In a real-world Swedish cohort study, 51% of the HFrEF patients were prescribed an MRA and MRA use decreased with worsening renal function. However, MRA use was not associated with a higher risk of the composite renal outcome, all-cause mortality, and all-cause hospitalization at 1 year. The safety profile of MRAs was consistent across the eGFR spectrum and, notably, also in patients with severe CKD. The authors believe their “findings might suggest not to encourage MRA discontinuation in patients with severe CKD if strict laboratory surveillance is feasible.”

References

1. Zahir D, Bonde A, Madelaire C, Malmborg M, Butt JH, Fosbol E, et al. Temporal trends in initiation of mineralocorticoid receptor antagonists and risk of subsequent withdrawal in patients with heart failure: a nationwide study in Denmark from 2003-2017. Eur J Heart Fail 2022;24:539–547. https://doi.org/10.1002/ejhf.2418

2. Savarese G, Carrero JJ, Pitt B, Anker SD, Rosano GMC, Dahlström U, et al. Factors associated with underuse of mineralocorticoid receptor antagonists in heart failure with reduced ejection fraction: an analysis of 11 215 patients from the Swedish Heart Failure Registry. Eur J Heart Fail 2018;20:1326–1334. https://doi.org/10.1002/ejhf.1182

3. Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, 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;341:709–717. https://doi.org/10.1056/NEJM199909023411001

4. Zannad F, McMurray JJ, Krum H, van Veldhuisen DJ, Swedberg K, Shi H, et al.; EMPHASIS-HF Study Group. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med 2011;364:11–21. https://doi.org/10.1056/NEJMoa1009492

5. Pitt B, Remme W, Zannad F, Neaton J, Martinez F, Roniker B, et al.; Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study Investigators. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med 2003;348:1309–1321. https://doi.org/10.1056/NEJMoa030207

6. Eschalier R, McMurray JJ, Swedberg K, van Veldhuisen DJ, Krum H, Pocock SJ, et al. Safety and efficacy of eplerenone in patients at high risk for hyperkalemia and/or worsening renal function: analyses of the EMPHASIS-HF study subgroups (Eplerenone in Mild Patients Hospitalization And SurvIval Study in Heart Failure). J Am Coll Cardiol 2013;62:1585–1593. https://doi.org/10.1016/j.jacc.2013.04.086

7. Vardeny O, Wu DH, Desai A, Rossignol P, Zannad F, Pitt B, et al.; RALES Investigators. Influence of baseline and worsening renal function on efficacy of spironolactone in patients with severe heart failure: insights from RALES (Randomized Aldactone Evaluation Study). J Am Coll Cardiol 2012;60:2082–2089. https://doi.org/10.1016/j.jacc.2012.07.048

Find this article online at Eur J Heart Fail.

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