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

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 period. 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, non-completion was associated with region other than Central Europe, lower systolic blood pressure, lower serum sodium, lower haemoglobin, lower estimated glomerular filtration rate, higher N-terminal pro-B-type natriuretic peptide, higher New York Heart Association functional class, prior heart failure (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 HF were at higher risk for non-completion of the run-in period in PARAGON-HF. Re-analysis of study outcomes accounting for the effect of run-in non-completion did not alter the estimated treatment effects of sacubitril/valsartan vs. valsartan.

• Authors: Kota Suzuki, Brian Claggett, Masatoshi Minamisawa, Milton Packer, Michael R Zile, Marc A Pfeffer, Lu-May Chiang, Martin Lefkowitz, John J V McMurray, Scott D Solomon, Akshay S Desai
• Journal: European journal of heart failure (Eur J Heart Fail) Vol. 23 Issue 12 Pg. 2085-2090 (12 2021) ISSN: 1879-0844 [Electronic] England
• PMID: 34114720 (Publication Type: Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 European Society of Cardiology.

Chemical References

• Aminobutyrates
• Angiotensin Receptor Antagonists
• Biphenyl Compounds
• Drug Combinations
• Tetrazoles
• sacubitril
• Valsartan

Topics

• Aminobutyrates (pharmacology, therapeutic use)
• Angiotensin Receptor Antagonists (adverse effects)
• Biphenyl Compounds
• Drug Combinations
• Heart Failure
• Humans
• Stroke Volume (physiology)
• Tetrazoles (pharmacology, therapeutic use)
• Valsartan