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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

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Abstract

Background

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.

Objective

We applied several methods to estimate the time to benefit of an HFrEF therapy, using sacubitril-valsartan as a case study.

Methods

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.

Results

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.

Conclusion

Using multiple approaches, the earliest benefit of sacubitril-valsartan compared to enalapril in stable HFrEF was found at about 1 month after initiation.

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Acknowledgements

We are grateful for all the statistical input of Annouschka Laenen (L-Biostat, KU Leuven, Leuven, Belgium).

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Authors and Affiliations

  1. Pharmacy Department, University Hospitals Leuven, UZ Leuven, Herestraat 49, 3000, Leuven, Belgium

    Lorenz Van der Linden, Julie Hias & Karolien Walgraeve

  2. Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium

    Lorenz Van der Linden & Julie Hias

  3. Department of Geriatric Medicine, University Hospitals Leuven, Leuven, Belgium

    Jos Tournoy

  4. Department of Public Health and Primary care, KU Leuven, Leuven, Belgium

    Jos Tournoy

  5. Department of Cardiovascular Sciences, KU Leuven, Leuven, Belgium

    Lucas Van Aelst & Christophe Vandenbriele

  6. Department of Cardiology, University Hospitals Leuven, Leuven, Belgium

    Lucas Van Aelst & Christophe Vandenbriele

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  1. Lorenz Van der Linden
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Correspondence to Lorenz Van der Linden.

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Funding

JH, LVDL, and CVDB are grant recipients of the Clinical Research Fund of UZ Leuven, Leuven, Belgium.

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LVA received lecture fees from Novartis. The other authors declare that they have nothing to disclose.

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LVDL provided the idea and wrote the first draft. Figures were rendered by JH. All authors reviewed the manuscript, provided substantial contributions, and approved its submission.

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Van der Linden, L., Hias, J., Walgraeve, K. et al. 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. Drugs Aging 39, 959–966 (2022). https://doi.org/10.1007/s40266-022-00987-2

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