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Spironolactone dose in Heart Failure with Preserved Ejection Fraction: findings from TOPCAT

Abstract : Background: Spironolactone up-titration may be limited by side effects that could be minimized at lower than target doses, whether lower than target doses remain efficacious is unknown. In TOPCAT, spironolactone (or placebo) were started at 15mg/day, and increased up to a maximum of 45mg/day. The prognostic implications related to spironolactone dose are is yet to be reported. Aims: 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 HFpEF.Methods: 1767 patients from “TOPCAT-Americas” were included. Linear, logistic and Cox regressions were applied. Results: 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≥75years, with an eGFR≤60ml/min/1.73m2, and with a K+>4.5 mmol/L, received lower spironolactone doses (median≈20mg/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 interactionp<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. The discontinuation rates in the aforementioned “high-risk” subgroups reached 30% during the first year. Spironolactone reduced the primary outcome of HFH/CVD without significant heterogeneity between the studied subgroups (interactionp>0.1). Spironolactone discontinuation was associated with a 2 to 4-fold 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 homogenous across these subgroups. In patients unable to tolerate “target” doses, a low-dose strategy should be preferred to stopping treatment.
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Submitted on : Wednesday, June 10, 2020 - 11:50:53 AM
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Joao Pedro Ferreira, Xavier Rossello, Stuart Pocock, Patrick Rossignol, Brian Claggett, et al.. Spironolactone dose in Heart Failure with Preserved Ejection Fraction: findings from TOPCAT. European Journal of Heart Failure, Oxford University Press (OUP), 2020, 22 (9), pp.1615-1624. ⟨10.1002/ejhf.1909⟩. ⟨hal-02863467⟩

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