Elsevier

Journal of Cardiac Failure

Volume 29, Issue 11, November 2023, Pages 1494-1503
Journal of Cardiac Failure

Duration of Heart Failure With Preserved Ejection Fraction and Outcomes With Sacubitril/Valsartan: Insights From the PARAGON-HF Trial

https://doi.org/10.1016/j.cardfail.2023.05.003Get rights and content

Highlights

  • Longer duration of chronic heart failure (HF) with left ventricular ejection fraction (LVEF) ≥ 45% was associated with a higher comorbidity burden, lower baseline health status and adverse clinical outcomes in the PARAGON-HF trial.

  • Sacubitril/valsartan was well tolerated across the spectrum of HF duration, with consistent relative and higher absolute treatment effects in participants with the longest baseline HF durations.

  • Sustained focus on optimization of medical therapy at all stages of the HF disease course, in all clinical settings and across the HF spectrum, is needed to abrogate downstream disease progression.

ABSTRACT

Objective

In this post hoc analysis of the PARAGON-HF (Prospective Comparison of ARNI with ARB Global Outcomes in HFpEF) trial, we evaluated clinical outcomes and responses to sacubitril/valsartan by duration of heart failure (HF) with left ventricular ejection fraction ≥ 45% at initial diagnosis.

Methods and Results

The primary outcome was a composite of total hospitalizations due to HF and cardiovascular deaths, analyzed by using a semiparametric proportional rates method, stratified by geographic region. Among 4784 (99.7%) randomized participants in the PARAGON-HF trial for whom baseline HF duration was captured, 1359 (28%) had durations of HF of < 6 months, 1295 (27%) of 6 months–2 years, and 2130 (45%) of > 2 years. Longer HF duration was associated with higher comorbidity burdens, worse health status and lower rates of prior hospitalization due to HF. Over a median follow-up of 35 months, longer HF duration was associated with a higher risk of first and recurrent primary events (per 100 patient-years): < 6 months, 12.0 (95% CI, 10.4–14.0); 6 months–2 years, 12.2 (10.6–14.2); > 2 years, 15.8 (14.2–17.5). Relative treatment effects of sacubitril/valsartan vs valsartan were consistent, irrespective of baseline HF duration on the primary endpoint (Pinteraction = 0.112). Clinically meaningful (≥ 5 point) improvements in Kansas City Cardiomyopathy Questionnaire-Clinical Summary Scores were also similarly observed, irrespective of HF duration; (Pinteraction = 0.112). Adverse events were similar between treatment arms across HF duration categories.

Conclusions

In PARAGON-HF, longer HF duration was independently predictive of adverse HF outcomes. Treatment effects of sacubitril/valsartan were consistent, irrespective of baseline HF duration, suggesting that even ambulatory patients with longstanding HFpEF and predominantly mild symptoms stand to benefit from treatment optimization.

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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