Duration of Heart Failure with Preserved Ejection Fraction and Outcomes with Sacubitril/Valsartan: Insights from the PARAGON-HF Trial.

AIMS: In this post hoc analysis of the PARAGON-HF trial, we evaluated clinical outcomes and response to sacubitril/valsartan by duration of heart failure (HF) with left ventricular ejection fraction ≥45% from initial diagnosis.

METHODS AND RESULTS: The primary outcome was a composite of total HF hospitalizations and cardiovascular death, analyzed using a semiparametric proportional rates method, stratified by geographic region. Among 4,784 (99.7%) randomized PARAGON-HF participants for whom baseline HF duration was captured, 1,359 (28%) had a HF duration of <6 months, 1,295 (27%) 6 months-2 years, and 2,130 (45%) >2 years. Longer HF duration was associated with higher comorbidity burden, worse health status, and a lower rate of prior HF hospitalization. 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 Score 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.