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Sacubitril/Valsartan and NT-proBNP in PARAGON-HF Trial
Quick Takes
- Sacubitril/valsartan reduced NT-proBNP by ~19% compared with valsartan, 16 weeks post-randomization.
- Decreases in NT-proBNP predicted lower subsequent risk of the primary endpoint of total (first and recurrent) HF hospitalizations and CV death.
- HF patients with mid-range EF and elevated NT-proBNP may benefit from sacubitril/valsartan combination. Prospective studies are required to confirm these conclusions.
Study Questions:
What is the prognostic significance of baseline N-terminal pro–B-type natriuretic peptide (NT-proBNP), whether NT-proBNP modified the treatment response to sacubitril/valsartan, and the treatment effect of sacubitril/valsartan on NT-proBNP?
Methods:
The study cohort was comprised of 4,796 patients with heart failure with preserved ejection fraction (HFpEF) and elevated NT-proBNP randomized to sacubitril/valsartan or valsartan in the PARAGON-HF (Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction) trial. In this study, NT-proBNP was measured at screening in all patients and at five subsequent times in >2,700 patients: before, between, and after sequential valsartan and sacubitril/valsartan run-in periods, and 16 and 48 weeks post-randomization. The primary efficacy endpoint was a composite of total (first and recurrent) HF hospitalizations and cardiovascular (CV) death. Key secondary endpoints included components of the primary outcome and all-cause mortality. The study authors evaluated the association between screening NT-proBNP level and the primary endpoint using the semi-parametric proportional rates method, adjusted for 21 relevant covariates. They also performed a landmark analysis to assess the association between change in NT-proBNP from before the run-in period to week 16 and subsequent events occurring after the week 16 visit.
Results:
The study authors found that median NT-proBNP was 911 pg/ml (interquartile range, 464-1613 pg/ml) at screening. Screening NT-proBNP was strongly associated with the primary endpoint, total HF hospitalizations and CV death (rate ratio [RR], 1.68 per log increase in NT-proBNP; 95% confidence interval [CI], 1.53-1.85; p < 0.001). This relationship was stronger in patients with atrial fibrillation (adjusted RR, 2.33 [95% CI, 1.89-2.87] vs. 1.58 [95% CI, 1.42-1.75] in patients without atrial fibrillation; p interaction < 0.001) and weaker in obese patients (adjusted RR, 1.50 [95% CI, 1.31-1.71] vs. 1.92 [95% CI, 1.70-2.17] in nonobese patients; p interaction < 0.001). Screening NT-proBNP did not modify the treatment effect of sacubitril/valsartan compared with valsartan (p interaction = 0.96). Sacubitril/valsartan reduced NT-proBNP by 19% (95% CI, 14%-23%; p < 0.001) compared with valsartan 16 weeks post-randomization, with similar reductions in men (20%) and women (18%), and in patients with left ventricular EF ≤57% (20%) and >57% (18%). Decreases in NT-proBNP predicted lower subsequent risk of the primary endpoint.
Conclusions:
The authors concluded that baseline NT-proBNP predicted HF events but did not modify the sacubitril/valsartan treatment effect in patients with HFpEF. Sacubitril/valsartan reduced NT-proBNP consistently in men and women, and in patients with lower or higher EF.
Perspective:
Sacubitril/valsartan in the PARAGON-HF study did show significant benefit in HpEF possibly because of its heterogenous phenotype. But the findings of this study suggest that HF patients with mid-range EF (HFmrEF) and elevated NT-proBNP may benefit from sacubitril/valsartan combination. Prospective studies are required to confirm these conclusions.
Clinical Topics: Anticoagulation Management, Arrhythmias and Clinical EP, Geriatric Cardiology, Heart Failure and Cardiomyopathies, Prevention, Anticoagulation Management and Atrial Fibrillation, Implantable Devices, SCD/Ventricular Arrhythmias, Atrial Fibrillation/Supraventricular Arrhythmias, Acute Heart Failure, Heart Failure and Cardiac Biomarkers
Keywords: Anticoagulants, Arrhythmias, Cardiac, Atrial Fibrillation, Clinical Trials as Topic, Geriatrics, Heart Failure, Natriuretic Peptide, Brain, Obesity, Peptide Fragments, Secondary Prevention, Stroke Volume
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