João Pedro Ferreira1, Xavier Rossello2,3, Stuart J Pocock4, Patrick Rossignol1, Brian L Claggett5, Jean-Lucien Rouleau6, Scott D Solomon5, Bertram Pitt7, Marc A Pfeffer5, Faiez Zannad1. 1. Université de Lorraine, Centre d'Investigation Clinique-Plurithématique, CHRU Nancy, INSERM U1116, and FCRIN INI-CRCT (Cardiovascular and Renal Clinical Trialists), Nancy, France. 2. Department of Cardiology, Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain. 3. Department of Cardiology, Health Research Institute of the Balearic Islands (IdISBa), University Hospital Son Espases, Palma, Spain. 4. London School of Hygiene and Tropical Medicine, London, UK. 5. Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. 6. Montreal Heart Institute, Montreal, Canada. 7. Department of Medicine, University of Michigan School of Medicine, Ann Arbor, MI, USA.
Abstract
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 lowerspironolactone 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.
RCT Entities:
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.
Authors: Iain B Squire; Anders Gabrielsen; Peter J Greasley; Linda Wernevik; Judith Hartleib-Geschwindner; Julie Holden; Susanne Johansson; Anna Rudvik; José Sánchez; Krister Bamberg; Johanna Melin; Andrew Whittaker Journal: Clin Transl Sci Date: 2022-08-20 Impact factor: 4.438