Background: While disease modifying therapies exist for heart failure (HF) with reduced
left ventricular ejection fraction (LVEF), few options are available for patients
in the higher range of LVEF (>40%). Sacubitril/valsartan has been compared with a
renin-angiotensin- system (RAS) inhibitor alone in two similarly designed clinical
trials of patients with reduced and preserved LVEF, permitting examination of its
effects across the full spectrum of LVEF. Methods: We combined data from PARADIGM-HF
(LVEF eligibility≤40%; n=8,399) and PARAGON-HF (LVEF eligibility≥45%; n=4,796) in
a prespecified pooled analysis. We divided randomized patients into LVEF categories:≤22.5%
(n=1269), >22.5% to 32.5% (n=3987), >32.5% to 42.5% (n=3143), > 42.5% to 52.5% (n=1427),
> 52.5% to 62.5% (n=2166), >62.5% (n=1202). We assessed time to first cardiovascular
death and HF hospitalization, its components, and total heart failure hospitlizations,
all-cause mortality and non-cardiovascular mortality. Incidence rates and treatment
effects were examined across categories of LVEF. Results: Among 13,195 randomized
patients, we observed lower rates of cardiovascular death and HF hospitalization,
but similar rates of non-cardiovascular death, among patients in the highest vs. lowest
groups. Overall sacubitril/valsartan was superior to RAS inhibition for first cardiovascular
death or heart failure hospitalization (HR 0.84, 95% CI 0.78, 0.90), cardiovascular
death (HR 0.84, 95% CI 0.76, 0.92), heart failure hospitalization (HR 0.84, 95% CI
0.77, 0.91), and all-cause mortality (HR 0.88, 95% CI 0.81, 0.96). The effect of sacubitril/valsartan
was modified by LVEF (treatment-by-continuous LVEF interaction p=0.02), and benefit
appeared to be present for individuals with EF primarily below the normal range, although
the treatment benefit for cardiovascular death diminished at a lower ejection fraction.
We observed effect modification by LVEF on the efficacy of sacubitril/valsartan in
both men and women with respect to composite total HF hospitalizations and cardiovascular
death, although women derived benefit to higher ejection fractions. Conclusions:The
therapeutic effects of sacubitril/valsartan, compared with a RAS inhibitor alone,
vary by LVEF, with treatment benefits, particularly for heart failure hospitalization,
that appear to extend to patients with heart failure and mildly reduced ejection fraction.
These therapeutic benefits appeared to extend to a higher LVEF range in women compared
with men. Clinical Trial Registration: URL: https://clinicaltrials.gov PARAGON-HF
Unique Identifier: NCT01920711. PARADIGM-HF Unique Identifier: NCT01035255.
