Spironolactone dose in heart failure with preserved ejection fraction: findings from TOPCAT

• Published in: European journal of heart failure Vol. 22; no. 9; pp. 1615 - 1624
• Main Authors: Ferreira, João Pedro, Rossello, Xavier, Pocock, Stuart J., Rossignol, Patrick, Claggett, Brian L., Rouleau, Jean‐Lucien, Solomon, Scott D., Pitt, Bertram, Pfeffer, Marc A., Zannad, Faiez
• Format: Journal Article
• Language: English
• Published: Oxford, UK John Wiley & Sons, Ltd 01.09.2020; European Society of Cardiology (Wiley)
• Subjects: Aged; Cardiology and cardiovascular system; Discontinuation; Heart Failure - drug therapy; Heart failure with preserved ejection fraction; Human health and pathology; Humans; Life Sciences; Mean dose; Mineralocorticoid Receptor Antagonists; Spironolactone; Stroke Volume; Treatment effect; Treatment Outcome; Heart failure with preserved ejection fraction; Discontinuation; Spironolactone; Mean dose; Treatment effect; heart failure with preserved ejection fraction; treatment effect; mean dose; spironolactone; discontinuation
• ISSN: 1388-9842; 1879-0844
• DOI: 10.1002/ejhf.1909

Aims Spironolactone up‐titration may be limited by side effects that could be minimized at lower than target doses, but whether lower than target doses remain efficacious is unknown. In TOPCAT, spironolactone (or placebo) were started at 15 mg/day, and increased up to a maximum of 45 mg/day. The prognostic implications related to spironolactone dose are yet to be reported. We aimed to assess the average spironolactone/placebo doses provided during the trial, overall and within high‐risk subgroups (e.g. elderly, renal dysfunction, high potassium); discontinuation rates; and the efficacy of lower than target doses in heart failure with preserved ejection fraction. Methods and results Overall, 1767 patients from ‘TOPCAT‐Americas’ were included. Linear, logistic and Cox regressions were applied. Patients randomized to spironolactone received lower doses than placebo: 22.5 (15.0–27.5) mg/day vs. 27.5 (17.5–27.5) mg/day (P < 0.001). Patients aged ≥75 years, with an estimated glomerular filtration rate ≤60 mL/min/1.73 m2, and with potassium levels >4.5 mmol/L, received lower spironolactone doses (median ≈ 20 mg/day). This pattern of dose differences was not observed in patients taking placebo, where the between‐subgroup placebo doses were similar (spironolactone–placebo by subgroup Pinteraction < 0.05). Among patients taking spironolactone, 25.4% discontinued the drug during the first year, compared with 18.3% of the patients taking placebo (P < 0.001). Discontinuation rates in the aforementioned high‐risk subgroups reached 30% during the first year. Spironolactone reduced the primary outcome of heart failure hospitalization/cardiovascular death without significant heterogeneity between the study subgroups (Pinteraction > 0.1). Spironolactone discontinuation was associated with a two to fourfold higher risk of subsequent events. Conclusion Spironolactone (but not placebo) was used at lower doses among the elderly, those with renal dysfunction and with higher potassium levels. The effect of spironolactone was homogeneous across these subgroups. In patients unable to tolerate target doses, a low‐dose strategy should be preferred to stopping treatment. In patients not able to tolerate guideline‐recommended spironolactone doses, lower doses should be preferred and the treatment should not be stopped. CKD, chronic kidney disease; K+, serum potassium.