Influence of study discontinuation during the run‐in period on the estimated efficacy of sacubitril/valsartan in the PARAGON‐HF trial

Suzuki, K. et al. (2021) Influence of study discontinuation during the run‐in period on the estimated efficacy of sacubitril/valsartan in the PARAGON‐HF trial. European Journal of Heart Failure, (doi: 10.1002/ejhf.2262) (PMID:34114720) (Early Online Publication)

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Abstract

Aims: The 4822 patients randomized in the PARAGON-HF trial were a subset of 5746 initially eligible patients who entered sequential run-in periods. We identified patient factors associated with study discontinuation during the run-in period and estimated the implications of these discontinuations for the overall study result. Methods and Results: We utilized multivariable logistic regression models to identify patient factors associated with study discontinuation during the run-in. The efficacy of sacubitril/valsartan in a broader cohort approximating the full run-in population was estimated by weighting randomized patients according to the inverse probability of run-in completion. A total of 924 (16.1%) subjects failed to complete the run-in period. In multivariable models, noncompletion was associated with region other than Central Europe, lower systolic blood pressure, lower serum sodium, lower hemoglobin, lower estimated glomerular filtration rate, higher NT-proBNP, higher NYHA functional class, prior HF hospitalization, and lack of prior use of renin-angiotensin system inhibitors or beta-blocker. In repeat analysis of the effect of randomized treatment in PARAGON-HF giving greater weight to participants resembling those who failed to complete the run-in period, the incidence of HF hospitalizations and cardiovascular death was higher, and sacubitril/valsartan treatment reduced the composite of total HF hospitalizations and cardiovascular death compared with valsartan (rate ratio, 0.86; 95% confidence interval, 0.74–1.00). Conclusion: Patients with more advanced heart failure were at higher risk for noncompletion of the run-in period in PARAGON-HF. Reanalysis of study outcomes accounting for the effect of run-in noncompletion did not alter the estimated treatment effects of sacubitril/valsartan vs valsartan.

Item Type:Articles
Status:Early Online Publication
Refereed:Yes
Glasgow Author(s) Enlighten ID:McMurray, Professor John
Authors: Suzuki, K., Claggett, B., Minamisawa, M., Packer, M., Zile, M. R., Pfeffer, M. A., Chiang, L.‐M., Lefkowitz, M., McMurray, J. J.V., Solomon, S. D., and Desai, A. S.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:European Journal of Heart Failure
Publisher:Wiley
ISSN:1388-9842
ISSN (Online):1879-0844
Published Online:11 June 2021
Copyright Holders:Copyright © 2021 European Society of Cardiology
First Published:First published in European Journal of Heart Failure 2021
Publisher Policy:Reproduced in accordance with the publisher copyright policy

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