AimsGuidelines recommend target doses (TD) of heart failure (HF) with reduced ejection fraction (HFrEF) medications regardless of sex. Differences in pharmacokinetics and pharmacodynamics may explain heterogeneity in treatment response, adverse reactions, and tolerability issues across sexes. The aim of this study was to explore sex‐based differences in the association between TD achievement and mortality/morbidity in HFrEF.Methods and resultsPatients with HFrEF and HF duration ≥6 months registered in the Swedish HF Registry between May 2000 and December 2020 (follow‐up until December 2021) were analysed. Treatments of interest were renin–angiotensin system inhibitors (RASI) or angiotensin receptor–neprilysin inhibitors (ARNI), and beta‐blockers. Multivariable Cox regression models were performed to explore the risk of cardiovascular mortality or hospitalization for HF across dose categories in females versus males. A total of 17 912 patients were analysed (median age 77.0 years, interquartile range [IQR] 70.0–83.0), 29% were female. Over a median follow‐up of 1.33 years (IQR 0.29–3.22), for RASI/ARNI there was no significant difference in outcome for females achieving 50–99% versus 100% of TD (hazard ratio 0.92, 95% confidence interval 0.83–1.03), whereas males showed a gradual lowering in risk together with the achievement of higher % of TD (p‐interaction = 0.030). For beta‐blockers the achievement of TD was associated with the lowest risk of outcome regardless of sex.ConclusionsOur findings suggest that females and males might differently benefit from the same dose of RASI/ARNI, and do represent a general call for randomized controlled trials to consider sex‐specific up‐titration schemes when testing HFrEF treatments in need of up‐titration.

中文翻译：

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实现心力衰竭药物目标剂量的预后作用中的性别差异：来自瑞典心力衰竭登记处的数据

目标指南推荐心力衰竭 (HF) 与降低射血分数 (HFrEF) 药物的目标剂量 (TD)，无论性别如何。药代动力学和药效学的差异可以解释不同性别治疗反应、不良反应和耐受性问题的异质性。本研究的目的是探讨 TD 成绩与 HFrEF 死亡率/发病率之间基于性别的差异。 方法和结果 2000 年 5 月至 2020 年 12 月期间在瑞典 HF 登记处登记的 HFrEF 和 HF 持续时间≥6 个月的患者（遵循‐截至 2021 年 12 月）进行了分析。感兴趣的治疗方法是肾素-血管紧张素系统抑制剂（RASI）或血管紧张素受体-脑啡肽酶抑制剂（ARNI）和β受体阻滞剂。采用多变量 Cox 回归模型来探讨女性与男性不同剂量类别的心血管死亡或心衰住院风险。总共分析了 17 912 名患者（中位年龄 77.0 岁，四分位数范围 [IQR] 70.0–83.0），其中 29% 为女性。在中位随访 1.33 年（IQR 0.29-3.22）中，对于 RASI/ARNI，达到 50-99% TD 的女性与 100% TD 的结果没有显着差异（风险比 0.92，95% 置信区间 0.83- 1.03），而男性则表现出风险逐渐降低，并且 TD 百分比更高（p‐相互作用= 0.030）。对于 β 受体阻滞剂，无论性别如何，TD 的实现都与最低的结果风险相关。结论我们的研究结果表明，女性和男性可能从相同剂量的 RASI/ARNI 中获得不同的益处，并且确实代表了对随机对照试验的普遍呼吁在测试需要上调剂量的 HFrEF 治疗时，请考虑针对性别的上调方案。