Initiation of eplerenone or spironolactone, treatment adherence, and associated outcomes in patients with new-onset heart failure with reduced ejection fraction: a nationwide cohort study

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Abstract

Background

The mineralocorticoid receptor antagonists (MRAs) eplerenone and spironolactone are beneficial in heart failure with reduced ejection fraction (HFrEF), but have not been prospectively compared. We compared clinical outcomes, daily dosages, and discontinuation rates for the two drugs in a nationwide cohort.

Methods

We identified all patients with HFrEF in the period 2016–2020, who were alive and had initiated MRA treatment at study start, 180 days after HF diagnosis. We estimated the 2-year risk of a composite of death and HF hospitalization, as well as each component separately, using Kaplan–Meier, cumulative incidence functions, and Cox proportional hazards models adjusted for age, sex, and comorbidities. Secondly, we assessed treatment withdrawal, cross-over, and daily drug dosage.

Results

We included 7479 patients; 653 (9%) on eplerenone and 6840 (91%) on spironolactone. Patients in the eplerenone group were younger (median age 65 vs. 69 years), and more often men (91% vs. 68%), both P < 0.001. In adjusted analyses, with spironolactone as reference, there were no differences in the risk of the composite of all-cause death and HF hospitalization (HR 1.02, 95% CI 0.82–1.27), all-cause death (HR 0.93, 95% CI 0.67–1.30), or HF hospitalization (HR 1.10, 95% CI 0.84–1.42). Treatment withdrawal occurred in 34% in the eplerenone group and 53% in the spironolactone group (P < 0.001), treatment cross-over in 3%, and 10%, respectively. Daily dose >25 mg at 12 months, was observed in 230 patients (37%) in the eplerenone group and 771 patients (12%) in the spironolactone (P < 0.001).

Conclusions

In a contemporary nationwide cohort of patients with new-onset HFrEF who initiated MRA, we found no differences in clinical outcomes associated with initiation of eplerenone vs. spironolactone. Treatment was more frequently withdrawn, and daily drug dosage was lower among patients treated with spironolactone.

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Most cited references 18

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2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure

Theresa A McDonagh, Marco Metra, Marianna Adamo … (2021)

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The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators.

B Pitt, F Zannad, W J Remme … (1999)

Aldosterone is important in the pathophysiology of heart failure. In a doubleblind study, we enrolled 1663 patients who had severe heart failure and a left ventricular ejection fraction of no more than 35 percent and who were being treated with an angiotensin-converting-enzyme inhibitor, a loop diuretic, and in most cases digoxin. A total of 822 patients were randomly assigned to receive 25 mg of spironolactone daily, and 841 to receive placebo. The primary end point was death from all causes. The trial was discontinued early, after a mean follow-up period of 24 months, because an interim analysis determined that spironolactone was efficacious. There were 386 deaths in the placebo group (46 percent) and 284 in the spironolactone group (35 percent; relative risk of death, 0.70; 95 percent confidence interval, 0.60 to 0.82; P<0.001). This 30 percent reduction in the risk of death among patients in the spironolactone group was attributed to a lower risk of both death from progressive heart failure and sudden death from cardiac causes. The frequency of hospitalization for worsening heart failure was 35 percent lower in the spironolactone group than in the placebo group (relative risk of hospitalization, 0.65; 95 percent confidence interval, 0.54 to 0.77; P<0.001). In addition, patients who received spironolactone had a significant improvement in the symptoms of heart failure, as assessed on the basis of the New York Heart Association functional class (P<0.001). Gynecomastia or breast pain was reported in 10 percent of men who were treated with spironolactone, as compared with 1 percent of men in the placebo group (P<0.001). The incidence of serious hyperkalemia was minimal in both groups of patients. Blockade of aldosterone receptors by spironolactone, in addition to standard therapy, substantially reduces the risk of both morbidity and death among patients with severe heart failure.