Effects of Sacubitril/Valsartan According to Natriuretic Peptide Levels in Patients Enrolled in PARADIGM-HF and PARAGON-HF

Background: Recent trials of new heart failure (HF) treatments suggest the effect of therapy may vary by N-terminal pro–B type natriuretic peptide (NT-proBNP) level. 

Objectives: The authors examined the efficacy of sacubitril/valsartan according to NT-proBNP levels in patients with reduced, mildly reduced, and preserved left ventricular ejection fraction (LVEF) enrolled in PARADIGM-HF (Prospective Comparison of Angiotensin Receptor–Neprilysin Inhibitor with Angiotensin-Converting–Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure Trial) and PARAGON-HF (Prospective Comparison of Angiotensin Receptor–Neprilysin Inhibitor with Angiotensin-Receptor Blockers Global Outcomes in HF with Preserved Ejection Fraction). 

Methods: Individual patient data from PARADIGM-HF and PARAGON-HF were pooled and participants were divided into categories defined by quintiles of NT-proBNP level. The primary outcome examined was the composite of HF hospitalization or cardiovascular death. 

Results: Among the 13,195 patients enrolled in both trials, 13,142 (99.6%) had a baseline NT-proBNP level measured. The rate of the primary outcome (per 100 person-years) increased with NT-proBNP levels: quintile 1, 5.9 (95% CI: 5.3-6.5); quintile 2, 7.5 (95% CI: 6.9-8.2); quintile 3, 9.0 (95% CI: 8.2-9.7); quintile 4, 12.0 (95% CI: 11.1-12.9); and quintile 5, 20.8 (95% CI: 19.6-22.2). The relative risk reduction in the primary outcome with sacubitril/valsartan was consistent across NT-proBNP levels: the HR in quintile 1 was 0.79 (95% CI: 0.65-0.96); quintile 2, 0.87 (95% CI: 0.72-1.04); quintile 3, 0.79 (95% CI: 0.66-0.93); quintile 4, 0.85 (95% CI: 0.73-0.99); and quintile 5, 0.86 (95% CI: 0.76-0.97; P for interaction = 0.86). The absolute risk reduction was greatest in NT-proBNP quintile 5; the number needed to treat for the primary outcome over the median follow-up of 31 months was 16 in quintile 5 vs 37 in quintile 1. 

Conclusions: The relative risk reductions with sacubitril/valsartan were consistent irrespective of NT-proBNP level in HF patients across the range of LVEF. Consequently, the absolute risk reductions were greatest in patients with higher NT-proBNP levels. (PARADIGM-HF [Prospective Comparison of Angiotensin Receptor–Neprilysin Inhibitor with Angiotensin-Converting–Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure Trial]; NCT01035255; and PARAGON-HF [Prospective Comparison of Angiotensin Receptor–Neprilysin Inhibitor with Angiotensin-Receptor Blockers Global Outcomes in HF with Preserved Ejection Fraction]; NCT01920711).