Van der Linden Lorenz, Hias Julie, Walgraeve Karolien, Tournoy Jos, Van Aelst Lucas, Vandenbriele Christophe
Pharmacy Department, University Hospitals Leuven, UZ Leuven, Herestraat 49, 3000, Leuven, Belgium.
Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium.
Drugs Aging. 2022 Dec;39(12):959-966. doi: 10.1007/s40266-022-00987-2. Epub 2022 Nov 21.
Foundational therapies in heart failure improve clinical outcomes in heart failure with a reduced ejection fraction (HFrEF). Underuse of these life-prolonging heart failure therapies, such as sacubitril-valsartan, is common in older adults and has been associated with worse clinical outcomes. Characterizing the early benefits seen with these therapies might help increase their uptake in older adults.
We applied several methods to estimate the time to benefit of an HFrEF therapy, using sacubitril-valsartan as a case study.
PARADIGM-HF was a randomized controlled study on sacubitril-valsartan versus enalapril in stable, ambulatory HFrEF patients (n = 8399). The primary endpoint, a composite of death from cardiovascular causes or a first hospitalization for heart failure, was significantly reduced (sacubitril-valsartan (21.8%) versus enalapril (26.5%), hazard ratio (HR) 0.80 (95% confidence interval [CI] 0.73-0.87). We extracted and tabulated the Kaplan-Meier (KM) curves of the primary endpoint. An individual patient dataset was then reconstructed. The following methods were applied to explore the time to benefit of sacubitril-valsartan versus enalapril: visual estimation of the point of divergence of the KM curves, statistical process control (SPC), unadjusted landmark analyses using Cox proportional hazards analysis with 30-day increments until significance was persistently achieved, and comparing the survival probabilities of the extracted life tables.
Six raters visually estimated the time to benefit at a median of 60 days (interquartile range 38-10 days). Using SPC we found an early benefit from 28 days on, using the longest predefined control period of 28 days. An absolute risk reduction of 1 and 2% was found after 59 and 250 days, respectively. The reconstructed dataset provided a similar HR of 0.8004 (95% CI 0.7331-0.8739). Landmark analyses persistently showed statistical significance from 390 days and later. Survival probabilities differed from 35 days onward.
Using multiple approaches, the earliest benefit of sacubitril-valsartan compared to enalapril in stable HFrEF was found at about 1 month after initiation.
射血分数降低的心力衰竭（HFrEF）的基础治疗可改善临床结局。这些延长生命的心力衰竭治疗方法，如沙库巴曲缬沙坦，在老年人中使用不足，且与较差的临床结局相关。了解这些治疗方法的早期益处可能有助于提高其在老年人中的使用率。
我们以沙库巴曲缬沙坦为例，应用多种方法评估HFrEF治疗的获益时间。
PARADIGM-HF是一项针对稳定的门诊HFrEF患者（n = 8399）比较沙库巴曲缬沙坦与依那普利的随机对照研究。主要终点为心血管原因死亡或首次因心力衰竭住院的复合终点，显著降低（沙库巴曲缬沙坦组为21.8%，依那普利组为26.5%，风险比（HR）为0.80（95%置信区间[CI] 0.73 - 0.87）。我们提取并列出了主要终点的Kaplan-Meier（KM）曲线。然后重建了个体患者数据集。应用以下方法探讨沙库巴曲缬沙坦与依那普利相比的获益时间：直观估计KM曲线的分歧点、统计过程控制（SPC）、使用Cox比例风险分析进行未经调整的标志性分析，以30天为增量直至持续达到显著性，以及比较提取的生命表的生存概率。
六位评估者直观估计的获益时间中位数为60天（四分位间距38 - 10天）。使用SPC，我们发现从28天开始有早期益处，使用最长的预定义对照期28天。在59天和250天后分别发现绝对风险降低1%和2%。重建数据集得出的HR相似，为0.8004（95% CI 0.7331 - 0.8739）。标志性分析从390天及以后持续显示出统计学显著性。生存概率从35天起不同。
采用多种方法，在稳定的HFrEF患者中，与依那普利相比，沙库巴曲缬沙坦的最早益处出现在开始治疗后约1个月。
