Key result
In a reanalysis accounting for run-in noncompletion, sacubitril/valsartan reduced the composite of total heart failure hospitalizations and cardiovascular death compared with valsartan (RR 0.86).
Why the study?
To identify patient factors associated with study discontinuation during the PARAGON-HF sequential run-in periods and estimate the implications of these discontinuations on the overall study results.
Does sacubitril/valsartan reduce the composite of total HF hospitalizations and cardiovascular death compared to valsartan in patients with HFpEF when accounting for run-in non-completion?
RCT (n=5,746)
Double-blind
Randomized
Yes
Does sacubitril/valsartan reduce the composite of total HF hospitalizations and cardiovascular death compared to valsartan in patients with HFpEF when accounting for run-in non-completion?
Re-analysis of the PARAGON-HF trial accounting for patients who failed the run-in period increased estimated event rates but did not alter the relative treatment benefit of sacubitril/valsartan over valsartan.
Supports sacubitril/valsartan benefit robustness in HFpEF after run-in adjustment; leaves open generalizability to broader populations.
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.
No takes yet. Share an insight, caveat, or question.
Suzuki et al. (2021) conducted an RCT in Heart Failure with Preserved Ejection Fraction (HFpEF) (n=5,746). Sacubitril/valsartan vs. Valsartan 160 mg twice daily was evaluated on Composite of total HF hospitalizations and death from cardiovascular causes (inverse probability-weighted analysis) (RR 0.86, 95% CI 0.74-1.00). In a reanalysis accounting for run-in noncompletion, sacubitril/valsartan reduced the composite of total heart failure hospitalizations and cardiovascular death compared with valsartan (RR 0.86).
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: