Duration of Heart Failure With Preserved Ejection Fraction and Outcomes With Sacubitril/Valsartan: Insights From the PARAGON-HF Trial
Graphical Abstract
Section snippets
Study Design and Patient Population
The design18 and primary results19 of PARAGON-HF have been reported previously. Briefly, PARAGON-HF was an international, prospective, randomized, double-blind, active comparator trial of sacubitril/valsartan vs valsartan in patients aged ≥ 50 years with chronic HF, left ventricular ejection fraction (LVEF) ≥ 45% within the 6 months prior to screening, New York Heart Association (NYHA) functional class II–IV, elevated natriuretic peptide levels, evidence of structural heart disease (left atrial
Results
From July 2014 to December 2016, 4,822 patients were randomized across 788 centers in 43 countries. Of those patients, 26 were excluded due to site violations of Good Clinical Practice during enrollment. Of the 4796 validly randomized patients, baseline HF duration was captured for 4784 (99.7%). Among them, the median HF duration was 1.5 years (interquartile range, 0.4–4.8 years).
Discussion
In this post hoc analysis of the global PARAGON-HF trial, we find that longer duration of chronic HF with LVEF ≥ 45% is independently predictive of clinical events. Sacubitril/valsartan was well tolerated and produced consistent relative treatment effects, irrespective of baseline HF duration; the greatest absolute effects occurred in those with the longest-duration HF. Improving outcomes remains a foundational clinical and research priority for all patients with HF, and these findings provide
Conclusions
In this exploratory analysis of the international PARAGON-HF trial, baseline duration of HF with LVEF ≥ 45% was independently associated with a higher risk of total HF hospitalization and cardiovascular death, and sacubitril/valsartan produced similar treatment effects, irrespective of the timing of initial HF diagnosis. These findings provide reassurance that longstanding HFpEF, even in the presence of apparent clinical stability, should not be a barrier to the implementation of
Lay Summary
Longer duration of chronic heart failure (HF) has been associated with worse outcomes, but data concerning the impact of HF duration on clinical outcomes and treatment responsiveness in chronic HF with preserved ejection fraction are limited. In this analysis of the PARAGON-HF trial, longstanding HF was associated with more comorbid conditions, worse health status and adverse clinical outcomes. Sacubitril/valsartan was well tolerated, and its treatment effects were consistent, regardless of
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Clinical Trial Registration: ClinicalTrials.gov number NCT01920711, https://clinicaltrials.gov/ct2/show/NCT01920711