Estimating the Time to Benefit for Therapies in Heart Failure with Reduced Ejection Fraction: A Case Study of Sacubitril-Valsartan Using Reconstructed Data from a Randomized Controlled Trial

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.