Université de Lorraine, Centre d'Investigation Clinique-Plurithématique, CHRU Nancy, INSERM U1116, and FCRIN INI-CRCT (Cardiovascular and Renal Clinical Trialists), Nancy, France.
Department of Cardiology, Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain.
Eur J Heart Fail. 2020 Sep;22(9):1615-1624. doi: 10.1002/ejhf.1909. Epub 2020 Jun 19.
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.
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 m , 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 P < 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 (P > 0.1). Spironolactone discontinuation was associated with a two to fourfold higher risk of subsequent events.
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.
螺内酯剂量的增加可能会受到副作用的限制，而这些副作用在低于目标剂量时可能会减轻，但低于目标剂量是否仍然有效尚不清楚。在 TOPCAT 研究中，螺内酯（或安慰剂）起始剂量为 15mg/天，最大剂量增至 45mg/天。与螺内酯剂量相关的预后意义尚未报道。我们旨在评估试验中提供的螺内酯/安慰剂的平均剂量，包括总体和高危亚组（如老年人、肾功能不全、高钾血症）；停药率；以及在射血分数保留的心力衰竭中低于目标剂量的疗效。
总共纳入了来自“TOPCAT-美国”的 1767 名患者。应用线性、逻辑和 Cox 回归。接受螺内酯治疗的患者比安慰剂组接受的剂量低：22.5（15.0-27.5）mg/天比 27.5（17.5-27.5）mg/天（P<0.001）。年龄≥75 岁、估算肾小球滤过率≤60mL/min/1.73m2 和血钾水平>4.5mmol/L 的患者接受较低剂量的螺内酯（中位数≈20mg/天）。这种剂量差异模式在服用安慰剂的患者中并未观察到，其中亚组间安慰剂剂量相似（螺内酯-安慰剂按亚组 P<0.05）。在服用螺内酯的患者中，有 25.4%的患者在第一年中停止服用该药，而服用安慰剂的患者中这一比例为 18.3%（P<0.001）。在上述高危亚组中，第一年的停药率达到 30%。螺内酯降低心力衰竭住院/心血管死亡的主要终点，各研究亚组之间无显著异质性（P>0.1）。螺内酯停药与随后事件的风险增加两到四倍相关。
在老年人、肾功能不全和血钾水平较高的患者中，螺内酯（而非安慰剂）的剂量较低。螺内酯在这些亚组中的作用是同质的。在不能耐受目标剂量的患者中，应首选低剂量策略，而不是停止治疗。
